Cardiovascular Medicine

Third Edition
James T. Willerson, Jay N. Cohn, Hein J.J. Wellens,
and David R. Holmes, Jr. (Eds)

Cardiovascular Medicine
Third Edition
James T. Willerson, MD Jay N. Cohn, MD
President Professor of Medicine
The University of Texas Health Science Director
Center in Houston Rasmussen Center for Cardiovascular
President-Elect and Medical Director Disease Prevention
Texas Heart Institute Cardiovascular Division
Houston, TX, USA University of Minnesota
Minneapolis, MN, USA

Hein J.J. Wellens, MD David R. Holmes, Jr., MD

Emeritus Professor Consultant
Department of Cardiology Cardiovascular Medicine
University of Maastricht Professor of Medicine
Masstricht, The Netherlands Scripps Professor in Cardiovascular
Medicine
Mayo Clinic College of Medicine
Rochester, MN, USA

Credits for figures and tables appear after the index.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Control Number: 2006935533

ISBN-10: 1-84628-188-1 3rd edition eISBN-10: 1-84628-725-1

ISBN-13: 978-1-84628-188-4 3rd edition eISBN-13: 978-1-84628-725-1
ISBN 0-443-07000-8 2nd edition, published in 2000 by Churchill Livingstone

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 Preface
T
he third edition of Cardiovascular Medicine is the product of our continuing
effort to provide an authoritative and comprehensive review of important,
clinically relevant cardiovascular disease topics. As compared to the second
edition, this third edition contains 27 new chapters and a 30% expansion and update
of mechanistic, diagnostic, and therapeutic approaches to cardiovascular medicine.
Each chapter is written by one or more experts on the topic. We have also added
two additional editors, Dr. Hein J.J. Wellens, a leading worldwide authority on
cardiac arrhythmias, their recognition and treatment, and Dr. David Holmes, Jr.,
a worldwide leader in interventional cardiovascular medicine.
The continued rapid growth of new knowledge and new techniques has chal-
lenged the physician with a wide array of management options. We believe the third
edition of Cardiovascular Medicine will guide the dedicated physician to more
knowledgeable and effective preventive and therapeutic efforts in patients with car-
diovascular disease.
The specialty of cardiovascular medicine has become increasingly international.
Advances in basic science and clinical research are not restricted to national bound-
aries. Global interaction among scientists and physicians has rapidly expanded, as
a result of major improvements in rapid communication, and the growing recogni-
tion of our interdependence in advancing clinical science. We have therefore main-
tained our commitment to include contributions from American, European, and
Asian-Pacific experts to provide a balanced discussion of opinions from gifted physi-
cians active worldwide in the care and treatment of patients with cardiovascular
diseases.
We hope that the organization of the third edition will enhance its value. Diag-
nostic approaches are considered from a methodological perspective in separate
chapters in the beginning of the book, but are readdressed later in separate chapters
dealing with specific disease categories. Chapters on clinical syndromes are designed
to incorporate anatomic, mechanistic, diagnostic, and treatment considerations.
Whether using the book as a quick reference guide or as a source for comprehensive
coverage of a topic, the reader should have access to up-to-date information in an
accessible format.
We are committed to a long-term effort to update this book so that it keeps
abreast of new and important advances. We shall therefore provide our readers access
to a Web site that will update as necessary all clinically related chapters every three
months by adding new diagnostic and therapeutic information of importance.
The third edition of Cardiovascular Medicine is accompanied by a CD-rom that
presents the entire book on-line, but that also includes an introductory section on
heart sounds of virtually every conceivable cardiovascular abnormality and associ-
ated echocardiographic images. These images serve as an outstanding educational
opportunity for physicians in training, cardiovascular nurses, and cardiovascular
technical associates who are involved in cardiovascular imaging procedures and for
physicians updating their auscultatory and echocardiographic skills in cardiovascu-
lar diagnosis.
We wish to express our appreciation to our editors at Springer for the oppor-
tunity to present the third edition of Cardiovascular Medicine and for their assis-
tance and patience in bringing it to fruition. Our heartfelt thanks go to our families
and our collaborators at the Texas Heart Institute and The University of Texas
Health Science Center in Houston, Texas; the University of Minnesota Medical
School in Minneapolis, Minnesota; the Mayo Clinic College of Medicine in Roch-
ester, Minnesota; and Maastricht University in Maastricht, The Netherlands. We
deeply appreciate the expertise and dedicated assistance of Suzy Lanier at the Texas
Heart Institute and The University of Texas Health Science Center in Houston;
Amy Brown and Cheryl Tincher at the University of Minnesota Medical School

v
vi pr eface

in Minneapolis; and Karyn Hughes and Ann Turner at the Mayo Clinic in
Rochester.
We are very grateful to our colleagues throughout the United States and around
the world who have contributed important chapters. Finally, we express our great
appreciation to our teachers, students, and patients from whom we have learned
so much. It is to them and our families that we dedicate the third edition of
Cardiovascular Medicine.

James T. Willerson, MD
Jay N. Cohn, MD
Hein J.J. Wellens, MD
David R. Holmes, Jr., MD
 Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
ACC/AHA Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix

SECTION I Introduction: Cardiac Signs and

Symptoms, and Selected Noninvasive
Diagnostic Methods
1 Anatomy of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
L. Maximilian Buja

2 The History and Physical Examination . . . . . . . . . . . . . . . . . . . . 19

Thomas C. Smitherman and James T. Willerson

3 Electrocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Anton P.M. Gorgels

4 Chest X-Ray. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Mary Ella Round

5 Introduction to Echocardiography. . . . . . . . . . . . . . . . . . . . . . . . . 93
Raymond F. Stainback

6 Nuclear Cardiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Arthur Iain McGhie, K. Lance Gould, and
James T. Willerson

7 Cardiovascular Magnetic Resonance Imaging. . . . . . . . . . . . . . . 161

Warren J. Manning

8 Computed Tomographic Cardiovascular Imaging . . . . . . . . . . . . 181

Matthew J. Budoff

SECTION II Congenital Heart Disease in the Adult

9 Normal and Abnormal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . 205

Robert H. Anderson and Anton E. Becker

10 Pathophysiology, Clinical Recognition, and Treatment of

Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Steven R. Neish and Jeffrey A. Towbin

11 Echocardiography in the Adult with Congenital

Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Julie A. Kovach

12 Congenital Heart Disease in the Adult:

Interventional Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Charles E. Mullins

vii
viii contents

13 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Magdi Habib Yacoub, Anselm Uebing,
Rosemary Radley-Smith, and Michael A. Gatzoulis

SECTION III Valvular Heart Disease

14 Valvular Heart Disease: Anatomic Abnormalities . . . . . . . . . . . 369

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

15 Aortic Valve Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

Blase A. Carabello

16 Pulmonary and Tricuspid Valve Disease . . . . . . . . . . . . . . . . . . . 393

Otto M. Hess, Urs Scherrer, Pascal Nicod, and
Blase A. Carabello

17 Mitral Valve Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Maurice L. Enriquez-Sarano and Robert L. Frye

18 Rheumatic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

Y.S. Chandrashekhar and Jagat Narula

19 Infective Endocarditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Walter R. Wilson and Eddy Barasch (Second Edition),
revised for The Third Edition by Layne O. Gentry and
Temple W. Williams, Jr.

20 The Assessment and Therapy of Valvular Heart

Disease in the Cardiac Catheterization Laboratory . . . . . . . . . . 463
Paul Sorajja and Rick A. Nishimura

21 Echocardiographic Assessment of Valvular Heart Disease . . . . 487

Raymond F. Stainback

22 Magnetic Resonance Imaging of Valvular Disease . . . . . . . . . . . 537

Scott D. Flamm and Raja Muthupillai

23 Balloon Dilatation of the Cardiac Valves . . . . . . . . . . . . . . . . . . . 557

Igor F. Palacios and Pedro L. Sánchez

24 Valvular Heart Disease: Surgical Treatment . . . . . . . . . . . . . . . . 581

William E. Cohn, O.H. Frazier, and Denton A. Cooley

SECTION IV Coronary Artery Disease

25 Coronary Artery Disease: Pathologic Anatomy

and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
L. Maximilian Buja and Hugh A. McAllister, Jr.

26 Inflammation, C-Reactive Protein, and

Vulnerable Plaques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Paolo Calabró, James T. Willerson, and
Edward T.H. Yeh
†
Deceased.
 contents ix

27A Atherosclerotic Vulnerable Plaques: Pathophysiology,

Detection, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

27B Biomarkers of Inflammation as Surrogate Markers in

Detection of Vulnerable Plaques and Vulnerable Patients . . . . . 641
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

28 Global Differences in Atherosclerosis . . . . . . . . . . . . . . . . . . . . . 653

Philip A. Poole-Wilson

29 Coronary Artery Disease: Regulation of Coronary

Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Robert J. Bache

30 Coronary Heart Disease Syndromes: Pathophysiology and

Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
James T. Willerson, Attilio Maseri, and Paul W. Armstrong

31 Silent Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699

Matthew B. O’Steen and Neal S. Kleiman

32 Coronary Disease in Women. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713

Allen P. Burke, Frank D. Kolodgie, and Renu Virmani

33 Exercise Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729

Bernard R. Chaitman, Masarrath J. Moinuddin, and
Junko Sano

34 Coronary Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745

Robert F. Wilson and Carl W. White

35 Echocardiographic Evaluation of Coronary Artery Disease . . . . 811

Stephanie A. Coulter

36A Myocardial Perfusion Imaging Utilizing Single Photon

Emission Computed Tomography Techniques. . . . . . . . . . . . . . . 841
George A. Beller

36B Cardiac Positron Emission Tomography. . . . . . . . . . . . . . . . . . . . 855

K. Lance Gould

37A Magnetic Resonance Imaging of the Myocardium . . . . . . . . . . . 871

Raymond J. Kim, Igor Klem, and Robert M. Judd

37B Magnetic Resonance Angiography and Evaluation of

Vulnerable Plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
Javier Sanz, Marc Sirol, Zahi A. Fayad, and
Valentin Fuster

38 Medical Treatment of Stable Angina . . . . . . . . . . . . . . . . . . . . . . 911

James J. Ferguson III, Dipsu D. Patel, and
James T. Willerson
x contents

39 Medical Treatment of Unstable Angina, Acute

Non–ST-Elevation Myocardial Infarction, and
Coronary Artery Spasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
James T. Willerson and Paul W. Armstrong

40 Treatment of Acute ST-Elevation Myocardial Infarction . . . . . . 963

Paul W. Armstrong and James T. Willerson

41 Kawasaki Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

Hirohisa Kato

42 Percutaneous Coronary Intervention and Stable Angina . . . . . . 995

David R. Holmes, Jr.

43 Percutaneous Coronary Intervention for Unstable

Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Pim J. de Feyter and Peter P.T. de Jaegere

44 Percutaneous Coronary Intervention for Acute

Myocardial Infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
David R. Holmes, Jr.

45 Drug-Eluting Coronary Stents. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031

Carey D. Moyer, Peter B. Berger, and Christopher J. White

46 Surgical Treatment of Coronary Artery Disease. . . . . . . . . . . . . 1051

William E. Cohn, O.H. Frazier, and Denton A. Cooley

47 Coronary Artery Bypass Surgery and Percutaneous

Coronary Revascularization: Impact on Morbidity and
Mortality in Patients with Coronary Artery Disease . . . . . . . . . 1073
James M. Wilson, James J. Ferguson III, and Robert J. Hall

48 Cardiac Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113

Michael X. Pham, Jonathan N. Myers, and Victor F. Froelicher

SECTION V Basic Aspects of Myocardial Function,

Growth, and Development
49 Cardiac Development: Toward a Molecular Basis for
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
Michael D. Schneider and Eric N. Olson

50 Fueling the Heart: Multiple Roles for Cardiac Metabolism. . . . 1157

Heinrich Taegtmeyer

51 Cardiac Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177

Ali J. Marian and James T. Willerson

52 Regulation of Cardiac Contraction and Relaxation . . . . . . . . . . 1189

Arnold M. Katz

53 Pathophysiology and Clinical Impact of Diastolic

Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
Gilles W. de Keulenaer and Dirk L. Brutsaert
 contents xi

SECTION VI Myocardial Disease

54 Myocardial Disease: Anatomic Abnormalities . . . . . . . . . . . . . . 1219

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

55 Dilated Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233

Biykem Bozkurt and Douglas L. Mann

56 Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261

Diane Fatkin, J.G. Seidman, and Christine E. Seidman

57 Restrictive Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1285

James T. Willerson, L. Maximilian Buja, and
†
John Goodwin

58 Other Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301

James T. Willerson and L. Maximilian Buja

59 Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
Jay W. Mason, Sanjeev Trehan, and Dale G. Renlund

60 Evaluation of Myocardial Disease in the Cardiac

Catheterization Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1349
James J. Ferguson III and Tomas Klima

61 Echocardiography in the Evaluation of

the Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359
Stephanie A. Coulter

62 Pathophysiology and Clinical Recognition of Heart Failure . . . 1379

Jay N. Cohn

63 The Medical Management of Heart Failure. . . . . . . . . . . . . . . . . 1397

Jay N. Cohn

64 Heart Transplantation: Indications, Outcome, and

Long-Term Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
Leslie W. Miller

65 Heart Transplantation: Pathogenesis, Immunosuppression,

Diagnosis, and Treatment of Rejection. . . . . . . . . . . . . . . . . . . . . 1443
Leslie W. Miller

66 Surgical Treatment of Advanced Heart Failure . . . . . . . . . . . . . . 1461

O.H. Frazier, Igor D. Gregoric, and William E. Cohn

SECTION VII Pericardial Disease

67 Pericardial Disease: Anatomic Abnormalities. . . . . . . . . . . . . . . 1479

Hugh A. McAllister, Jr., L. Maximilian Buja, and
†
Victor J. Ferrans

68 Pericardial Disease: Etiology, Pathophysiology, Clinical

Recognition, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
Ralph Shabetai

†
Deceased.
xii contents

SECTION VIII Vascular Disease

69 Molecular and Cellular Physiology of Differentiated

Vascular Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511
Michael Sturek, Eric A. Mokelke, Jürgen R. Sindermann,
Leonard P. Adam, and Keith L. March

70 Cardiovascular Regulation: Basic Considerations . . . . . . . . . . . . 1525

Giuseppe Mancia, Thomas F. Lüscher, John T. Shepherd,
George Noll, and Guido M. Grassi

71 Vascular Remodeling in Health and Disease. . . . . . . . . . . . . . . . 1541

Luis G. Melo, Massimiliano Gnecchi, Christopher A. Ward,
and Victor J. Dzau

72 Vascular Endothelial Cell Function and Thrombosis . . . . . . . . . 1567

H. Roger Lijnen, Jef M. Arnout, and Désiré Collen

73 Atherosclerosis: Pathologic Anatomy and Pathogenesis . . . . . . . 1581

L. Maximilian Buja and Hugh A. McAllister, Jr.

74 Atherosclerosis: Pathogenesis, Morphology, and

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593
Antonio M. Gotto, Jr., and John A. Farmer

75 Detection of Early Cardiovascular Disease . . . . . . . . . . . . . . . . . 1615

Daniel A. Duprez and Jay N. Cohn

76 Diseases of the Aorta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1623

James T. Willerson, Joseph S. Coselli, Scott A. LeMaire,
Ross M. Reul, Igor D. Gregoric, George J. Reul, and
Denton A. Cooley

77 Aneurysms of the Peripheral Arteries . . . . . . . . . . . . . . . . . . . . . 1663

Paul W. Wennberg and Henna Kalsi

78 Peripheral Arterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681

Alan T. Hirsch, Henna Kalsi, and Thom W. Rooke

79 Venous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1705

Samuel Z. Goldhaber

80 Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1717
Pinak B. Shah and Douglas W. Losordo

81 Carotid Artery Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1741

Christopher J. White

82 Endovascular Procedures for the Treatment of Peripheral

Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1755
Kathryn G. Dougherty and Zvonimir Krajcer

83 B-Mode Ultrasound: A Noninvasive Method for

Assessing Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1783
John R. Crouse, Curt D. Furberg, Mark A. Espeland, and
Ward A. Riley
 contents xiii

84 Intravascular Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1797

Seung-Ho Hur, Yasuhiro Honda, Peter J. Fitzgerald, and
Paul G. Yock

85 Arterial Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811

Gary E. McVeigh, Alan J. Bank, and Jay N. Cohn

86 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833
Bernard Waeber, Hans-Rudolph Brunner, Michel Burnier, and
Jay N. Cohn

87 Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871
Henry S. Loeb and Jay N. Cohn

88 Autonomic Dysfunction and Hypotension . . . . . . . . . . . . . . . . . 1883

Christopher J. Mathias

89 Cerebrovascular Disease/Transient Ischemic Attack . . . . . . . . . 1911

Hashem M. Shaltoni and Frank M. Yatsu

SECTION IX Electrical Disturbances of the Heart

90 Sinus Node Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925

David G. Benditt, Scott Sakaguchi, Keith G. Lurie,
and Fei Lu

91 Supraventricular Tachycardias . . . . . . . . . . . . . . . . . . . . . . . . . . . 1943

Hein J.J. Wellens

92 Atrial Fibrillation and Flutter . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955

Peter A. Brady and Bernard J. Gersh

93 Preexcitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979
Hein J.J. Wellens

94 Atrioventricular Nodal and Subnodal

Conduction Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1991
Hein J.J. Wellens

95 Transesophageal Echocardiography for Patients with

Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999
Warren J. Manning

96 Broad QRS Tachycardias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2007

Hein J.J. Wellens

97 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2019
David G. Benditt and Scott Sakaguchi

98 Sudden Cardiac Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2039

Abdi Rasekh, Mehdi Razavi, and Ali Massumi

99 Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085

Dan M. Roden, Dawood Darbar, and Prince J. Kannankeril
xiv contents

100 Cardiac Pacemakers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103

Sanjay Dixit and Francis E. Marchlinski

101 The Implantable Cardioverter-Defibrillator . . . . . . . . . . . . . . . . . 2119

William H. Sauer and David J. Callans

102 Catheter Ablation of Supraventricular and

Ventricular Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2139
Luz-Maria Rodriguez, Carl Timmermans, and
Hein J.J. Wellens

103 Surgical Treatment of Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 2163

Spencer J. Melby, James L. Cox, and
Ralph J. Damiano, Jr.

SECTION X Cardiac Effects of Systemic Disorders,

Pregnancy, Aging, and Environmental
Changes
104 Pulmonary Thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177
Herbert L. Fred, Shahzad Hashim, and Fady A. Joudah

105 Pulmonary Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . 2203

Evangelos D. Michelakis and Stephen L. Archer

106 Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . 2247

Rosa Maria Estrada-Y-Martin and Steven D. Brown

107 Tumors of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2267

Raymond F. Stainback, Yasmin S. Hamirani,
Denton A. Cooley, and L. Maximilian Buja

108 Endocrine Disorders and the Heart. . . . . . . . . . . . . . . . . . . . . . . . 2295

Victor R. Lavis, Michalis K. Picolos, and
James T. Willerson

109 Connective Tissue Diseases and the Heart . . . . . . . . . . . . . . . . . 2331

Frank C. Arnett and James T. Willerson

110 Substance Abuse and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . 2357

Paul A. Grayburn and Eric J. Eichhorn

111 Cardiovascular Involvement in Acquired Immune

Deficiency Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2371
Melvin D. Cheitlin, Priscilla Hsue, and Merle A. Sande

112 Cardiac Involvement in Skeletal Myopathies and

Neuromuscular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2385
Ali J. Marian and James T. Willerson

113 Hematologic Disease and Heart Disease . . . . . . . . . . . . . . . . . . . 2409

Martin D. Phillips and James T. Willerson

114 Hypercoagulable State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423

Andrew I. Schafer
 contents xv

115 Aging and the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . 2439

Samer S. Najjar, Gary Gerstenblith, and
Edward G. Lakatta

116 Pregnancy and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453

Susan Wilansky, Christina S. Reuss, and
James T. Willerson

SECTION XI Surgery and the Heart

117 Evaluation of Patients for Noncardiac Surgery . . . . . . . . . . . . . . 2487

James B. Froehlich and Kim A. Eagle

118 Anesthesia for Cardiovascular Operations. . . . . . . . . . . . . . . . . . 2501

N. Martin Giesecke and John R. Cooper, Jr.

119 Intraoperative Hemodynamic Monitoring . . . . . . . . . . . . . . . . . . 2515

Rebecca A. Schroeder, Shahar Bar-Yosef, and
Jonathan B. Mark

SECTION XII The Genetic Basis for

Cardiovascular Disease
120 Classification of Genetic Disorders . . . . . . . . . . . . . . . . . . . . . . . 2551
Dianna M. Milewicz

121 Inherited Disorders of Connective Tissue . . . . . . . . . . . . . . . . . . 2557

Dianna M. Milewicz

122 Muscular Dystrophies Affecting the Heart . . . . . . . . . . . . . . . . . 2567

C. Thomas Caskey

123 Genetic Basis for Cardiac Arrhythmias . . . . . . . . . . . . . . . . . . . . 2577

Connie R. Bezzina and Arthur A.M. Wilde

124 Genetic Aspects of Congenital Heart Disease. . . . . . . . . . . . . . . 2599

Dianna M. Milewicz

SECTION XIII Preventive Cardiology

125 Coronary Risk Factors: An Overview . . . . . . . . . . . . . . . . . . . . . 2609

Donald M. Lloyd-Jones and William B. Kannel

126 Preventive Cardiology: The Effects of Exercise . . . . . . . . . . . . . . 2631

Amit Khera, Jere H. Mitchell, and Benjamin D. Levine

127 Smoking, Secondhand Smoke, and

Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2649
Joaquin Barnoya and Stanton A. Glantz

128 Management of Cholesterol Disorders . . . . . . . . . . . . . . . . . . . . . 2667

Scott M. Grundy
xvi contents

129 Cardiovascular Complications of Obesity and the

Metabolic Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693
Paul Poirier and Robert H. Eckel

130 Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721

Robert D. Simari and Elizabeth G. Nabel

131 Molecular Biology for the Clinician . . . . . . . . . . . . . . . . . . . . . . . 2731

Sara Arab, Liyong Zhang, Yuichiro Maekawa,
Urszula Zurawska, and Peter P. Liu

132 Stem Cell Therapy for Cardiac Diseases . . . . . . . . . . . . . . . . . . . 2745

Emerson C. Perin, Guilherme V. Silva, and
James T. Willerson

133 Cost-Effectiveness Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2771

William S. Weintraub

134 Erectile Dysfunction and Cardiovascular Disease . . . . . . . . . . . 2791

Sanjay Kaul and James S. Forrester

135 Cardiovascular Disease and Insulin Resistance . . . . . . . . . . . . . 2803

Ramzi A. Ajjan and Peter J. Grant

136 The Heart and the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2819

Martin R. Cowie

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2839
Credits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2907
 Contributors

Leonard P. Adam, PhD Robert J. Bache, MD

Cardiovascular Drug Discovery Department of Medicine
Bristol-Myers Squibb University of Minnesota
Pennington, NJ, USA Minneapolis, MN, USA

Ramzi A. Ajjan, MRCP, MMed.Sci, Alan J. Bank, MD

PhD Department of Cardiology
Molecular Vascular Medicine St. Paul Heart Clinic
Faculty of Medicine and Health St. Paul, MN, USA
University of Leeds
Leeds, UK
Eddy Barasch, MD
Robert H. Anderson, BSc, MD, St. Francis Hospital
FRCPath The Heart Center
Cardiac Unit Roslyn, New York, USA
Institute of Child Health
University College Joaquin Barnoya, MD, MPH
London, UK Department of Epidemiology
University of California,
Sara Arab, MD San Francisco
Toronto General Hospital San Francisco, CA, USA
Research Institute and
University Health Network Departamento de Investigacion y
Toronto General Hospital Docencia
Toronto, Ontario, Canada Unidad de Cirugía Cardiovascular
de Guatemala
Stephen L. Archer, MD Guatemala
Department of Medicine
University of Alberta,
Shahar Bar-Yosef, MD
Edmonton, Alberta, Canada
Department of Anesthesiology
Duke University Medical Center
Paul W. Armstrong, MD and
Department of Medicine Anesthesiology Service
University of Alberta Veterans Affairs Medical Center
Edmonton, Alberta, Canada Durham, NC, USA

Frank C. Arnett, MD
Internal Medicine, Pathology Anton E. Becker, MD, PhD
The University of Texas Academic Medical Center
Houston Medical School University of Amsterdam
Houston, TX, USA Amsterdam, The Netherlands

Jef M. Arnout, PhD George A. Beller, MD

Faculty of Medicine Department of Internal Medicine
Center for Molecular and Vascular Cardiovascular Division
Biology University of Virginia
University of Leuven Health System
Leuven, Belgium Charlottesville, VA, USA

xvii
xviii con tr ibu tors

David G. Benditt, MD, FACC, FRCPC, Michel Burnier, MD

FHRS Nephrology
Department of Medicine Department of Medicine
Cardiovascular Division University Hospital
University of Minnesota Medical CHUV
School Lausanne, Switzerland
Minneapolis, MN, USA
Paolo Calabró, MD
Peter B. Berger, MD Department of Cardiothoracic
Interventional Cardiology Science
Geisinger Clinic Second University of Naples
Danville, PA, USA Naples, Italy
Connie R. Bezzina, PhD David J. Callans, MD
Experimental and Molecular Cardiology, Medicine
Cardiology Group Hospital of the University of
Department of Clinical and Pennsylvania
Experimental Cardiology Philadelphia, PA, USA
Academic Medical Center
Amsterdam, The Netherlands Blase A. Carabello, MD
Biykem Bozkurt, MD, FACC Department of Medicine
MEDVAMC Cardiology Houston Veterans Affairs Medical
Michael E. DeBakey Veterans Affairs Center
Medical Center and Baylor College Houston, TX, USA
of Medicine
Houston, TX, USA C. Thomas Caskey, MD
The University of Texas Health
Peter A. Brady, MD, FRCP Science Center
Division of Cardiovascular Diseases Houston, TX, USA
Mayo Clinic and Mayo Foundation
Rochester, MN, USA Samuel Ward Casscells, MD
The University of Texas Health
Steven D. Brown, MD Science Center at Houston
Department of Medicine Texas Heart Institute
The University of Texas Health Center Houston, TX, USA
at Tyler
Tyler, TX, USA Bernard R. Chaitman, MD
Cardiovascular Research
Hans-Rudolph Brunner, MD (Retired) Division of Cardiology
Riehen, Switzerland Saint Louis University School of
Medicine
Dirk L. Brutsaert, MD, PhD St. Louis, MO, USA
Cardiology Department
AZ Middelheim Hospital Y.S. Chandrashekhar, MD, DM
University of Antwerp Department of Medicine/Division
Antwerp, The Netherlands of Cardiology
Matthew J. Budoff, MD, FACC, FAHA Vetrans Affairs Medical Center
Division of Cardiology Minneapolis, MN, USA
Harbor-UCLA Medical Center
Torrance, CA, USA Melvin D. Cheitlin, MD
Department of Medicine
L. Maximilian Buja, MD San Francisco General Hospital
The University of Texas Health Science San Francisco, CA, USA
Center at Houston
Houston, TX, USA Jay N. Cohn, MD
Rasmussen Center for
Allen P. Burke, MD Cardiovascular Disease
Medical School Prevention
University of Maryland School of Cardiovascular Division
Medicine University of Minnesota
Baltimore, MD, USA Minneapolis, MN, USA
 con tr ibu tors xix
William E. Cohn, MD Dawood Darbar, MBChB, MD
Minimally Invasive Surgical Medicine
Technology Vanderbilt University School of
Texas Heart Institute Medicine
Houston, TX, USA Nashville, TN, USA

Désiré Collen, MD, PhD Sanjay Dixit, MB BS

Center for Molecular and Vascular Department of Medicine
Biology University of Pennsylvania Health
University of Leuven System
Leuven, Belgium Philadelphia, PA, USA

Denton A. Cooley, MD Kathryn G. Dougherty, CRTT, CVT

Texas Heart Institute Clinical Research
Houston, TX, USA St. Luke’s Episcopal Hospital
Texas Heart Institute
John R. Cooper, Jr., MD Houston, TX, USA
Cardiovascular Anesthiology
Texas Heart Institute Daniel A. Duprez, MD, PhD
Houston, TX, USA Cardiovascular Division
University of Minnesota
Joseph S. Coselli, MD Minneapolis, MN, USA
Division of Cardiothoracic Surgery
Michael E. DeBakey Department of Victor J. Dzau, MD
Surgery Department of Medicine
Baylor College of Medicine Duke University Medical Center
and Durham, NC, USA
Adult Cardiac Surgery;
Cardiothoracic Surgery Kim A. Eagle, MD
Texas Heart Institute at St. Luke's Department of Internal Medicine
Episcopal Hospital University of Michigan Medical
Houston, TX, USA School
Ann Arbor, MI, USA
Stephanie A. Coulter, MD
Department of Adult Cardiology Robert H. Eckel, MD
Texas Heart Institute Division of Endocrinology, Metabolism
Houston, TX, USA and Diabetes
University of Colorado at Denver and
Martin R. Cowie, MD, MSc, FRCP Health Sciences Center
National Heart and Lung Institute Aurora, CO, USA
Imperial College
London, UK Eric J. Eichhorn, MD
Medical City/Baylor Plano Hospital
James L. Cox, MD Dallas, TX, USA
Surgery and
Washington University School of University of Colorado Health Science
Medicine/Barnes Jewish Hospital Center
St. Louis, MO, USA Denver, CO, USA

John R. Crouse, MD Maurice L. Enriquez-Sarano, MD

Internal Medicine Department of Cardiovascular
Wake Forest University School of Diseases and Internal Medicine
Medicine Mayo Clinic
Medical Center Boulevard Rochester, MN, USA
Winston Salem, NC, USA
Mark A. Espeland, PhD
Ralph J. Damiano, Jr., MD Department of Biostatistical Sciences
Surgery Wake Forest University Health
Washington University School of Sciences
Medicine/Barnes Jewish Hospital Medical Center Boulevard
St. Louis, MO, USA Winstom-Salem, NC, USA
xx con tr ibu tors

Rosa Maria Estrada-Y-Martin, MD Herbert L. Fred, MD, MACP

Division of Pulmonary, Critical Care Internal Medicine
and Sleep Medicine The University of Texas Health
The University of Texas Health Science Science Center at Houston
Center at Houston Houston, TX, USA
Houston, TX, USA
James B. Froehlich, MD, MPH
John A. Farmer, MD Department of Internal Medicine
Medicine University of Michigan
Baylor College of Medicine Ann Arbor, MI, USA
Houston, TX, USA
Victor F. Froelicher, MD
Diane Fatkin, MD, BSc (Med), FRACP Cardiology
Molecular Cardiology Department of Veterans Affairs
Victor Chang Cardiac Research Palo Alto Health Care System
Institute Palo Alto, CA, USA
Darlinghurst, NSW, Australia
Robert L. Frye, MD
Zahi A. Fayad, PhD Cardiovascular Diseases
Cardiovascular Institute Mayo Clinic
Mount Sinai School of Medicine Rochester, MN, USA
New York, NY, USA
Curt D. Furberg, MD, PhD
James J. Ferguson III, MD Public Health Sciences
Cardiology Research Wake Forest University School of
Texas Heart Institute Medicine
Houston, TX, USA Winston-Salem, NC, USA
†
Victor J. Ferrans, MD, PhD
Valentin Fuster, MD, PhD
Cardiovascular Institute
Pim J. de Feyter, MD, PhD
Mount Sinai Hospital
Department of Cardiology
New York, NY, USA
Erasmus MC-Thorax Center
Rotterdam, The Netherlands
Michael A. Gatzoulis, MD, PhD,
Peter J. Fitzgerald, MD, PhD, FACC FACC, FESC
Division of Cardiovascular Medicine National Heart and Lung Institute
Stanford University Medical Center Royal Brompton Hospital
Stanford, CA, USA Sydney Street
London, UK
Scott D. Flamm, MD
Departments of Radiology and Layne O. Gentry, MD
Cardiology St. Luke’s Episcopal Hospital
Texas Heart Institute Houston, Texas, USA
Houston, TX, USA
Bernard J. Gersh, MB, ChB,
James S. Forrester, MD DPhil
Department of Cardiology Division of Cardiovascular Diseases
Cedars-Sinai Medical Center and Internal Medicine
Los Angeles, CA, USA Mayo Clinic
Rochester, MN, USA
O.H. Frazier, MD
Cardiopulmonary Transplantation Gary Gerstenblith, MD
Texas Heart Institute Medicine
and The Johns Hopkins University
Division of Thoracic and School of Medicine
Cardiovascular Surgery Baltimore, MD, USA
The University of Texas Medical School
Houston, TX, USA N. Martin Giesecke, MD
Texas Heart Institute
†
Deceased. Houston, TX, USA
 con tr ibu tors xxi
Stanton A. Glantz, PhD Scott M. Grundy, MD, PhD
Medicine (Cardiology) Center for Human Nutrition
University of California, The University of Texas Southwestern
San Francisco Medical Center at Dallas
San Francisco, CA, USA Dallas, TX, USA

Massimiliano Gnecchi, MD Robert J. Hall, MD (Retired)

Cardiology Houston, TX, USA
University of Pavia and
IRCCS Policlinico San Matteo Yasmin S. Hamirani, MD
Pavia, Italy St. Agnes Hospital
Baltimore, MD, USA
Samuel Z. Goldhaber, MD
Cardiovascular Division
Department of Medicine Shahzad Hashim, MD
Brigham and Women’s Hospital Internal Medicine
Harvard Medical School The University of Texas Health Science
Boston, MA, USA Center at Houston
Houston, TX, USA
†
John Goodwin, SPK, MD, FRCP,
FACC, FESC Otto M. Hess, MD
Department of Cardiology
Anton P.M. Gorgels, MD, PhD Swiss Cardiovascular Center
Department of Cardiology Bern, Switzerland
Cardiovascular Research Institute
Maastricht, The Netherlands Alan T. Hirsch, MD
Epidemiology, Medicine, and Radiology
Antonio M. Gotto, Jr., MD, DPhil Abbott Northwestern’s Vascular Center
Weill Medical College of Cornell and
University Division of Epidemiology and
New York, NY, USA Community Health
Minneapolis Heart Institute
K. Lance Gould, MD University of Minnesota School of
Department of Medicine Public Health
The University of Texas Medical Minneapolis, MN, USA
School
Houston, TX, USA David R. Holmes, Jr., MD
Cardiovascular Medicine
Peter J. Grant, MD, FRCP Mayo Clinic College of Medicine
Molecular Vascular Medicine Rochester, MN, USA
Faculty of Medicine and Health
University of Leeds Yasuhiro Honda, MD, FACC
Leeds, UK Division of Cardiovascular Medicine
Stanford University Medical Center
Guido M. Grassi, MD Stanford, CA, USA
Clinica Medica
University of Milano-Bicocca
Monza, Milan, Italy Priscilla Hsue, MD
Department of Medicine
Paul A. Grayburn, MD San Francisco General Hospital
Internal Medicine San Francisco, CA, USA
Baylor University Medical Center
Dallas, TX, USA Seung-Ho Hur, MD, PhD
Division of Cardiovascular Medicine
Igor D. Gregoric, MD Stanford University Medical Center
Mechanical Circulatory Support Stanford, CA, USA
Texas Heart Institute
Houston, TX, USA Peter P.T. de Jaegere, MD, PhD
Intervention Cardiology
Erasmus MC
†
Deceased. Rotterdam, The Netherlands
xxii con tr ibu tors

Fady A. Joudah, MD Igor Klem, MD

Internal Medicine DCMRC
Houston Veterans Affairs Medical Duke University Medical Center
Center Durham, NC, USA
Houston, TX, USA
Tomas Klima, MD
Robert M. Judd, PhD Department of Pathology
Duke Cardiovascular Magnetic Texas Heart Institute
Resonance Center Houston, TX, USA
Duke University
Durham, NC, USA
Frank D. Kolodgie, PhD
Cardiovascular Pathology Institute
Henna Kalsi, MD
Gaithersburg, MD, USA
Cardiovascular Medicine
Mayo Clinic
Rochester, MN, USA Julie A. Kovach, MD
Division of Cardiology
Prince J. Kannankeril, MD, MSCI University of Michigan Health
Department of Pediatrics System
Vanderbilt University Ann Arbor, MI, USA
Nashville, TN, USA
Zvonimir Krajcer, MD
William B. Kannel, MD, MPH, FACC Peripheral Vascular Program
Preventive Medicine Texas Heart Institute
Boston University School of Medicine Houston, TX, USA
Boston, MA, USA
Edward G. Lakatta, MD
Hirohisa Kato, MD, PhD, FACC Laboratory of Cardiovascular
Cardiovascular Research Institute Science
Kurume University National Institute on Aging,
Kurume, Japan National Institute of Health
Baltimore, MD, USA
Arnold M. Katz, MD (Retired)
Norwich, VT, USA Victor R. Lavis, MD
Internal Medicine (Endocrinology)
Sanjay Kaul, MD The University of Texas-Houston
Division of Cardiology Medical School
Cedars-Sinai Medical Center Houston, TX, USA
Los Angeles, CA, USA
Scott A. LeMaire, MD
Gilles W. de Keulenaer, MD, PhD
Division of Cardiothoracic Surgery
Department of Cardiology
Michael E. DeBakey Department of
AZ Middelheim Hospital
Surgery
University of Antwerp
Baylor College of Medicine
Antwerp, Belgium
and
Cardiovascular Surgery
Amit Khera, MD
Texas Heart Institute
Division of Cardiology
St. Luke's Episcopal Hospital
The University of Texas Southwestern
Houston, TX, USA
Medical Center
Dallas, TX, USA
Benjamin D. Levine, MD
Raymond J. Kim, MD Institute for Exercise and
Departments of Medicine and Environmental Medicine
Radiology Presbyterian Hospital of Dallas
Duke University Dallas, TX, USA
Durham, NC, USA
H. Roger Lijnen, PhD
Neal S. Kleiman, MD Center for Molecular and Vascular
Cardiac Catheterization Laboratory Biology
Methodist DeBakey Heart Center KU Leuven
Houston, TX, USA Leuven, Belgium
 con tr ibu tors xxiii
Peter P. Liu, MD Keith L. March, MD, PhD
Toronto General Hospital Medicine, Cellular and Integrative
University of Toronto Physiology, and Biomedical
Toronto, Ontario, Canada Engineering
Indiana University School
Donald M. Lloyd-Jones, MD, ScM of Medicine
Department of Preventative Medicine Indianapolis, IN, USA
Northwestern University Feinberg
School of Medicine Francis E. Marchlinski, MD
Chicago, IL, USA Department of Medicine
University of Pennsylvania Health
Henry S. Loeb, MD
System
Department of Cardiology
Philadelphia, PA, USA
Edward Hines JR VA Hospital
Hines, IL, USA
Ali J. Marian, MD
Douglas W. Losordo, MD The University of Texas Health
Cardiovascular Medicine Science Center at Houston
Caritas St. Elizabeth’s Medical Center Texas Heart Institute
Boston, MA, USA Houston, TX, USA

Fei Lu, MD, PhD Jonathan B. Mark, MD

Department of Medicine Department of Anesthesiology
University of Minnesota Medical Duke University Medical Center
School and
Minneapolis, MN, USA Anesthesiology Service
Veterans Affairs Medical Center
Keith G. Lurie, MD Durham, NC, USA
Medicine and Emergency Medicine
University of Minnesota Medical
School Attilio Maseri, MD
Minneapolis, MN, USA Cardiothoracic and Vascular
Department
Thomas F. Lüscher, MD, PhD University Vita-Salute San Raffaele
Internal Medicine Milan, Italy
Department of Cardiology
University of Zurich Jay W. Mason, MD
Zurich, Switzerland Department of Cardiology
Covance Cardiac Safety Services
Mohammad Madjid, MD Reno, NV, USA
Internal Medicine
The University of Texas Health Science Ali Massumi, MD
Center at Houston Baylor College of Medicine
Houston, TX, USA St. Luke’s Episcopal Hospital
and
Yuichiro Maekawa
Texas Heart Institute
University of Toronto
Houston, TX, USA
Toronto, Canada

Giuseppe Mancia, MD, PhD Christopher J. Mathias, DPhil, DSc,

Clinica Medica FRCP, FMedSci
University of Milano-Bicocca Autonomic Unit and University
Monza, Milan, Italy Department of Clinical
Neurology
Douglas L. Mann, MD National Hospital for Neurology and
Baylor College of Medicine Neurosurgery and Institute of
Texas Heart Institute Neurology
Houston, TX, USA London, UK
and
Warren J. Manning, MD Neurovascular Medical Unit
Cardiovascular Division Imperial College Faculty of Medicine
Beth Israel Deaconess Medical Center at St. Mary’s Hospital
Boston, MA, USA London, UK
xxiv con tr ibu tors

Hugh A. McAllister, Jr., MD (Retired) Eric A. Mokelke, PhD

Previously at Baylor College of Cellular and Integrative Physiology
Medicine and The University of Indiana University School of Medicine
Texas-Houston Medical School and Indianapolis, IN, USA
Texas Heart Institute
Houston, Texas, USA Carey D. Moyer, MD
Cardiology Associates of West Reading
Arthur Iain McGhie, MD The Reading Hospital and Medical
Department of Internal Medicine Center
Division of Cardiology West Reading, PA, USA
University of Missouri—Kansas City/
Mid America Heart Institute Charles E. Mullins, MD
Kansas City, MO, USA Department of Pediatrics
Baylor College of Medicine/Texas
Gary E. McVeigh, MD, PhD Children’s Hospital
Department of Therapeutics and Houston, TX, USA
Pharmacology
Queen’s University Belfast Raja Muthupillai, PhD
Belfast, Northern Ireland Clinical Science—MR and Department
of Radiology
Spencer J. Melby, MD Philips Medical Systems and Baylor
Department of Surgery College of Medicine
Washington University School of Houston, TX, USA
Medicine/Barnes Jewish Hospital
St. Louis, MO, USA Jonathan N. Myers, PhD
Department of Cardiology
Department of Veterans Affairs Palo
Luis G. Melo, PhD
Alto Health Care System
Department of Physiology
Palo Alto, CA, USA
Queen’s University
Kingston, Ontario, Canada
Elizabeth G. Nabel, MD
National Heart, Lung, and Blood
Evangelos D. Michelakis, MD
Institute
Division of Cardiology
National Institutes of Health
University of Alberta
Bethesda, MD, USA
Edmonton, Alberta, Canada
Samer S. Najjar, MD
Dianna M. Milewicz, MD, PhD Laboratory of Cardiovascular Science
Internal Medicine National Institute on Aging
The University of Texas Medical Baltimore, MD, USA
School at Houston
Houston, TX, USA Jagat Narula, MD, PhD
Department of Medicine
Leslie W. Miller, MD University of California Irvine School
Department of Medicine of Medicine
George Town University Orange, CA, USA
George Town, WA, USA
Steven R. Neish, MD
Jere H. Mitchell, MD Department of Pediatrics
Internal Medicine and Physiology Texas Children’s Hospital
Moss Heart Center Houston, TX, USA
Department of Internal Medicine
Division of Cardiology Pascal Nicod, MD
The University of Texas Southwestern Department of Internal Medicine
Medical Center University of Lausanne
Dallas, TX, USA Lausanne, Switzerland

Masarrath J. Moinuddin, MD, MPH Rick A. Nishimura, MD

Department of Cardiology Division of Cardiovascular Diseases
Wright State University Mayo Clinic
Dayton, OH, USA Rochester, MN, USA
 con tr ibu tors xxv
George Noll, MD Philip A. Poole-Wilson, MD, FRCP,
Internal Medicine FMedSci
Department of Cardiology National Heart and Lung Institute
University of Zurich Faculty of Medicine
Zurich, Switzerland Imperial College London
London, UK
Eric N. Olson, PhD
Molecular Biology Rosemary Radley-Smith, FRCP
The University of Texas Southwestern Department of Pediatrics
Medical Center Harefield Hospital
Dallas, TX, USA Middlesex, UK

Abdi Rasekh, MD
Matthew B. O’Steen, MD
Texas Heart Institute
Department of Cardiology
Houston, Texas, USA
Baylor College of Medicine
Houston, TX, USA
Mehdi Razavi, MD
Department of Cardiology
Igor F. Palacios, MD Cleveland Clinic
Interventional Cardiology Cleveland, OH, USA
Harvard Medical School
and
Dale G. Renlund, MD
Massachusetts General Hospital
Division of Cardiology
Boston, MA, USA
University of Utah School
of Medicine
Dipsu D. Patel, MD, MPH Salt Lake City, UT, USA
Department of Cardiology
St. Luke’s Episcopal Hospital George J. Reul, MD
Houston, TX, USA Department of Surgery
Texas Heart Institute
Emerson C. Perin, MD, PhD Houston, TX, USA
Stem Cell Center
Texas Heart Institute Ross M. Reul, MD
Houston, TX, USA Department of Surgical Innovation
Texas Heart Institute
Houston, TX, USA
Michael X. Pham, MD, MPH
Department of Cardiology
Department of Veterans Affairs Palo Christina S. Reuss, MD
Alto Health Care System Division of Cardiology
Palo Alto, CA, USA Mayo Clinic Scottsdale
Scottsdale, AZ, USA

Martin D. Phillips, MD
Ward A. Riley, BA, MS, PhD
Senior Medical Director
Wake Forest University Health
Aventis Behring, LLC
Sciences
King of Prussia, PA, USA
Winston-Salem, NC, USA

Michalis K. Picolos, MD Dan M. Roden, MD

Medicine Division of Endocrinology Clinical Pharmacology
The University of Texas-Houston Vanderbilt University School of
Medical School Medicine
Houston, TX, USA Nashville, TN, USA

Paul Poirier, MD, PhD, FRCPC Luz-Maria Rodriguez, MD, PhD

Department of Cardiology Department of Cardiology
Quebec Heart Institute/Laval Univer- Faculty of Medicine
sity Faculty of Pharmacy University of Maastricht
Ste-Foy, Québec, Canada Maastricht, The Netherlands
xxvi con tr ibu tors

Thom W. Rooke, MD Rebecca A. Schroeder, MD

Vascular Center Department of Anesthesiology
Mayo Clinic Duke University Medical Center
Rochester, MN, USA and
Anesthesiology Service
Mary Ella Round, MD Veterans Affairs Medical Center
Department of Radiology Durham, NC, USA
St Luke’s Episcopal Hospital
Houston, TX, USA Christine E. Seidman, MD
Department of Genetics
Scott Sakaguchi, MD, FACC and Medicine
Department of Medicine Howard Hughes Medical Institute
Cardiovascular Division Harvard Medical School
University of Minnesota Boston, MA, USA
Minneapolis, Minnesota, USA
J.G. Seidman, PhD
Pedro L. Sánchez, MD, PhD Department of Genetics
Instituto de Ciencias del Corazón and Medicine
(ICICOR) Howard Hughes Medical Institute
Hospital Clínico Universitario de Harvard Medical School
Valladolid Boston, MA, USA
Valladolid, Spain
Ralph Shabetai, MD, FACC
Merle A. Sande, MD Department of Cardiology
Infectious Diseases/Internal Medicine VA Health Care System
Harborview Medical Center/University La Jolla, CA, USA
of Washington
Seattle, WA, USA Pinak B. Shah, MD
Cardiovascular Medicine
Junko Sano, MD Caritas St. Elizabeth’s Medical Center
Division of Cardiology Boston, MA, USA
St. Louis University School
of Medicine Hashem M. Shaltoni, MD
St. Louis, MO, USA Neurology—Stroke Program
The University of Texas Health
Javier Sanz, MD Science Center at Houston
Cardiovascular Institute Houston, TX, USA
Mount Sinai School of Medicine
New York, NY, USA John T. Shepherd, MD, PhD
Department of Physiology
William H. Sauer, MD Mayo Clinic Foundation
Department of Medicine Rochester, MN, USA
University of Colorado
Denver, CO, USA Guilherme V. Silva, MD
Stem Cell Center
Andrew I. Schafer, MD Texas Heart Institute
Department of Medicine Houston, TX, USA
University of Pennsylvania
Philadelphia, PA, USA Robert D. Simari, MD
Division of Cardiovascular Diseases
Urs Scherrer, MD Mayo Clinic College of Medicine
Department of Cardiology Rochester, MN, USA
University of Lausanne
Lausanne, Switzerland Jürgen R. Sindermann, MD
Krannert Institute of Cardiology
Michael D. Schneider, MD Indianapolis, IN, USA
Medicine, Molecular and Cellular
Biology, and Molecular Physiology Marc Sirol, MD
and Biophysics Cardiovascular Institute
Baylor College of Medicine Mount Sinai School of Medicine
Houston, TX, USA New York, NY, USA
 con tr ibu tors xxvii
Thomas C. Smitherman, MD Bernard Waeber, MD
Department of Internal Medicine Division of Clinical
Division of Cardiology Pathophysiology
and the Cardiovascular Institute Department of Medicine
University of Pittsburgh School of University Hospital
Medicine and University of CHUV
Pittsburgh Medical Lausanne, Switzerland
Center-Presbyterian
Pittsburgh, PA, USA Christopher A. Ward, PhD
Department of Physiology
Paul Sorajja, MD Queen’s University
Division of Cardiovascular Diseases Kingston, Ontario, Canada
and Internal Medicine
Mayo Clinic College of Medicine William S. Weintraub
Rochester, MN, USA Department of Medicine
Christian Care Health System
Raymond F. Stainback, MD, FACC, Newark, DE, USA
FASE
St. Luke’s Episcopal Hospital Hein J.J. Wellens, MD
Texas Heart Institute Department of Cardiology
Houston, TX, USA University of Maastricht
Maastricht, The Netherlands
Michael Sturek, PhD
Cellular and Integrative Physiology Paul W. Wennberg, MD
Indiana University School Section of Vascular Medicine
of Medicine Mayo Clinic
Indianapolis, IN, USA Rochester, MS, USA

Carl W. White, MD
Heinrich Taegtmeyer, MD, DPhil
Department of Medicine
Internal Medicine
University of Minnesota
Division of Cardiology
Minneapolis, MN, USA
The University of Texas-Houston
Medical School
Christopher J. White, MD
Houston, TX, USA
Department of Cardiology
Ochsner Clinic Foundation,
Carl Timmermans, MD, PhD
New Orleans, LA, USA
Department of Cardiology
Faculty of Medicine
Susan Wilansky, MD, FACC, FASE
University of Maastricht
Department of Cardiology
Maastricht, The Netherlands
Mayo Clinic
Scottsdale, AZ, USA
Sanjeev Trehan, MD
Cardiology of Tulsa Arthur A.M. Wilde, MD, PhD
Tulsa, OK, USA Experimental and Molecular
Cardiology Group
Jeffrey A. Towbin, MD Department of Clinical and
Department of Pediatric Cardiology Experimental Cardiology
Baylor College of Medicine Academic Medical Center
Houston, TX, USA Amsterdam, The Netherlands

Anselm Uebing, MD James T. Willerson, MD

Adult Congenital Heart Disease Unit The University of Texas Health
Royal Brompton Hospital and Harefield Science Center at Houston
NHS Trust Texas Heart Institute
London, UK Houston, TX, USA

Renu Virmani, MD Temple W. Williams, Jr., MD

CVPath Institute, Inc. The Methodist Hospital
International Registry of Pathology Corporation
Gaithersburg, MD, USA Houston, Texas
xxviii con tr ibu tors

James M. Wilson, MD Edward T.H. Yeh, MD

Department of Cardiology Department of Cardiology
St. Luke's Episcopal Hospital The University of Texas, MD Anderson
Texas Heart Institute Cancer Center
Houston, TX, USA Houston, TX, USA

Robert F. Wilson, MD, PhD Paul G. Yock, MD

Department of Medicine Department of Bioengineering
University of Minnesota Stanford University
Minneapolis, MN, USA Stanford, CA, USA

Walter R. Wilson, MD Liyong Zhang, MD

Mayo Clinic and Foundation The Heart and Stroke and Richard
Rochester, NY, USA Lewar Center of Excellence
University of Toronto
Magdi Habib Yacoub, FRS Toronto, Canada
Heart Science Centre
Imperial College London Urszula Zurawska
Harefield, Middlesex, UK University of Toronto
Toronto, Canada
Frank M. Yatsu, MD
Neurology—Stroke Program
The University of Texas Health Science
Center at Houston
Houston, TX, USA
 ACC/AHA
Guidelines
Many of the topics covered by chapters in Cardiovascular Medicine, Third
Edition, are researched by writing groups of the American College of Car-
diology and the American Heart Association, and the research results in
guidelines that are prepared jointly by these groups. Members of the writing
groups are experts in their cardiovascular specialties, and the guidelines
undergo a rigid review process before being approved and published in the
ACC/AHA Joint Guidelines collection.

A direct link to the Guidelines collection is provided below:

http://www.americanheart.org/presenter.jhtml?identifier=3004542

References to the guidelines and applicable chapters are listed below.

ACC/AHA/ESC 2006 Guidelines for Management of Patients with Ventric-

ular Arrhythmias and the Prevention of Sudden Cardiac Death. Executive
Summary (Circulation. 2006;114:1088–1132)
Chapters 94, 96, 97, 98, 99, 101, 102.

ACC/AHA/ESC 2006 Guidelines for the Management of Patients with

Atrial Fibrillation. Executive Summary (Circulation. 2006;114:700–752)
Chapters 92, 93, 95, 99, 103.

AC/AHA 2006 Guidelines for the Management of Patients with Valvular

Heart Disease. Executive Summary (Circulation. 2006;114:450–527) and
Full Text.
Chapters 15, 16, 17, 23, 24.

AHA/ACC 2006 Guidelines for Secondary Prevention for Patients with

Coronary and Other Atherosclerotic Vascular Disease (Circulation. 2006;
113:2363–2372)
Chapters 26, 27a, 27b, 28, 30, 74, 128.

AHA/ACC 2006 Guideline Update on Perioperative Cardiovascular Evalua-

tion for Noncardiac Surgery: Focused Update on Perioperative Beta-Blocker
Therapy (Circulation. 2006;113:2662–2674)
Chapter 117

ACC/AHA 2006 Clinical Performance Measures for Adults with ST-Eleva-

tion and Non ST-Elevation Myocardial Infarction. A Report of the ACC/
AHA Task Force on Performance Measures (Circulation. 2006;113:607–
608)
Chapters 39, 40

xxix
xxx acc /a h a gu i de l i n e s

ACC/AHA 2005 Guidelines for the Management of Patients with Peripheral Arte-
rial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic). Executive
Summary (Circulation. 2006;113:1474–1547) and Full Text (Circulation. 2006;113:
463–654)
Chapters 77, 78, 80, 81, 82.

ACCF/AHA 2005 Clinical Competence Statement on Cardiac Imaging with

Computed Tomography and Magnetic Resonance (Circulation. 2005;112:
598–617)
Chapters 7, 8, 22.

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of

Chronic Heart Failure in the Adult (Circulation. 2005;112:e154–e235)
Chapters 62, 63, 64.

ACC/AHA 2005 Key Data Elements and Definitions for Measuring the
Clinical Management and Outcomes of Patients with Chronic Heart Failure
(Circulation. 2005;112:1888–1916)
Chapters 62, 63, 64.

ACC/AHA 2005 Guideline Update for Percutaneous Coronary Intervention.

Summary Article (Circulation. 2006;113:156–175)
Chapters 42, 43, 44, 45.

ACCF/AHA 2005 Clinical Competence Statement on Cardiac Imaging with

Computed Tomography and Magnetic Resonance (Circulation. 2005;112:
598–617)
Chapters 7, 8, 22.

ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery.
Full Text (Circulation. 2004;110:340–437) and Summary Article (Circula-
tion. 2004;110:1168–1176)
Chapter 46, 47.

ACC/AHA 2004 Guidelines for the Management of Patients with ST-Eleva-

tion Myocardial Infarction. Full Text (Circulation. 2004;110:82–293). Execu-
tive Summary (Circulation. 2004;110:588–636)
Chapter 40.

ACC/AHA/ASNC 2003 Guidelines for the Clinical Use of Cardiac Radio-

nuclide Imaging. Full Text and Executive Summary. (Circulation. 2003;108:
1404–1418).
Chapters 6, 36a, 36b.

ACC/AHA/ESC 2003 Guidelines for the Management of Patients with

Supraventricular Arrhythmias. Full Text and Executive Summary (Circula-
tion. 2003;108:1871–1909).
Chapters 90, 91, 92, 93.

ACC/AHA/ASE 2003 Guidelines for the Update for the Clinical Application
of Echocardiography. Summary Article (Circulation. 2003;108:1146) and Full
Text.
Chapters 5, 11,12, 21, 35, 61, 95.

ACC/AHA 2002 Guideline Update for the Management of Patients with

Chronic Stable Angina. Summary Article (Circulation. 2003;107:149) and
Full Text.
Chapter 38.
 acc /a h a gu i de l i n e s xxxi

ACC/AHA 2002 Guideline Update for the Management of Patients with

Unstable Angina and Non-ST Segment Elevation Myocardial Infarction.
Full Text and Summary Article (Circulation. 2002;106:1893)
Chapter 39

ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac

Pacemakers and Antiarrhythmia Devices. Full Text and Summary Article
(Circulation. 2002;106:2145)
Chapters 100, 101.

ACC/AHA 2002 Guideline Update for Exercise Testing. Summary Article

(Circulation. 2002;106:1883)
Chapter 33
SEC TION I

Introduction:
Cardiac Signs
and Symptoms,
and Selected
Noninvasive
Diagnostic
Methods
 1 Anatomy of the Heart
L. Maximilian Buja

Embryologic Development . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

External Anatomy of the Heart and Great Vessels . . . . . . 7 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Pericardium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Key Points recently formed cardiac tube is a single chambered structure

and is composed of the following components, extending
• External looping and internal septation to form four-
from inferior (caudal) to superior (cephalad): the sinus
chambered heart.
venosus, which connects to the major veins; the atrium; the
• Relationship of embryologic defects to congenital heart
ventricle; the bulbus cordis or conus; and the truncus arterio-
disease.
sus, which connects through six pairs of aortic arches to two
• Structure-function relationships of the pericardium.
dorsal aortae1–7 (Fig. 1.1).
• Distribution of the coronary arteries and anatomic
Initially, the single chambered heart is a straight tube
variations.
residing in the pericardial cavity. The bulboventricular por-
• Definition of anatomic right and left atria and right and
tion grows much more rapidly than the pericardial cavity. As
left ventricles.
a result, further extension in a longitudinal direction cannot
• Structure of the four cardiac valves and concept of func-
occur, and the heart tube is forced to bend. The cephalic
tional valve apparatus.
ventricular portion of the tube bends in a ventral and caudal
• Anatomy of the cardiac conduction system and cardiac
direction and to the right, whereas the caudal atrial portion
innervation.
progresses in a dorsal and cranial direction and to the left.
This chapter presents basic features of the anatomy of the This process, known as d(dextro)-bulboventricular looping,
heart and great vessels, including the embryologic devel- results in the atrial region establishing a position superior to
opment of these structures and their configuration in the the ventricular region and the cardiac apex being pointed to
mature state. Basic knowledge of cardiovascular anatomy is the left (Fig. 1.1).
essential for effective diagnosis and treatment of cardiovas- The external shape changes are accompanied by a
cular diseases. complex process of internal septation that leads to the for-
mation of a four-chambered heart (Fig. 1.2). In the atrium,
a septum primum forms and then develops two openings:
Embryologic Development ostium primum and ostium secundum. A septum secun-
dum then develops on the right of the septum primum.
The foramen ovale is formed in the midportion of the devel-
Basic Embryology
oping interatrial septum as a result of the growth and
Development of the cardiovascular system occurs in the positioning of the septum secundum adjacent to the
early first trimester fetus. Beginning at about 3 weeks’ gesta- septum primum. The sinus venosus is incorporated into the
tion, elements of splanchnic mesoderm differentiate into a superior portion of the developing atria. Ventricular septa-
primitive cardiac tube and pericardial cavity, and vascular tion is partially accomplished by the upward growth of
channels form and fuse to form blood vessels.1–7 The primi- muscular tissue to form the muscular interventricular
tive cardiac tube results from the moving together and fusion septum. Endocardial cushion tissue develops and provides
of two lateral endothelial heart tubes. Subsequently, the the essential tissue for formation of the atrioventricular
epimyocardial mantle and cardiac jelly develop. These com- valves, the closure of the ostium primum in the atrial
ponents differentiate into the endocardium, producing the septum, and the formation of the membranous interven-
internal endothelial lining of the heart, the myocardium tricular septum.
forming the muscular wall, and the epicardium or visceral The primitive bulbus cordis contributes several key
pericardium producing the outside covering of the heart. The components of the forming heart. The proximal third of the

3
4 chapter 1

I to functional closure of the foramen ovale and ductus arte-

I II
I II III riosus and, subsequently, fibrous closure of these structures.
Truncus IV These closures establish complete separation of the right-
Conoventricular
arteriosus At.r Tr. sided and left-sided circulations in the mature cardiovascular

s
sulcus Art. At.l.
s

nu
nu

system.

Co

s
Co

nu
Ventricle

Co
Atrium Ventricle

A 2.08 mm B 3.0 mm C 5.2 mm

Relationship to Congenital Heart Disease
III Knowledge of normal and abnormal embryologic develop-
IV
III VI ment of the heart and blood vessels provides an essential
IV
VI basis for and understanding of the morphogenesis of congeni-
Tr.
Art. tal heart disease.8,9 The position of the atria is determined
Tr. by general body habitus. The anatomic right atrium is defined
At.r Art. At.l. At.r At.l.
s as the atrium receiving the systemic venous drainage. The
nu
us

anatomic left atrium is defined as the atrium receiving the

Co
Con

pulmonary venous drainage. In situs solitus, the right atrium

Vent.r. Vent.l. Vent.r. Vent.l. is on the right and the left atrium on the left side of the body.
In situs inversus, the anatomic right atrium is on the left side
and the anatomic left atrium is on the right side of the body.
D 6.0 mm E 8.8 mm The right and left ventricles are normally connected to the
FIGURE 1.1. Ventral views of human embryonic hearts that show corresponding atria, but the ventricles may be inverted.
bending of cardiac tube and establishment of major anatomic com- Inversion of the ventricles is a major feature of a condition
ponents. At., atrium; l., left; r., right; Tr. Art., truncus arteriosus.
known as congenitally corrected transposition of the great
vessels. This condition arises when the primitive heart
undergoes levo(l)-bulboventricular looping rather than the
usual dextro(d)-bulboventricular looping; hence, the alterna-
tive designation of corrected transposition as l-transposition.
Other positional anomalies of the heart include dextrocardia
and right-sided aortic arch.
bulbus cordis forms the trabeculated part of the right ven- Abnormalities in atrial septation give rise to three types
tricle; the midportion, or conus cordis, forms the outflow of atrial septal defects; in order of frequency they are the
tracts of both ventricles; and the distal part, the truncus ostium secundum defect, ostium primum defect, and sinus
arteriosus, forms the proximal parts of the aorta and pulmo- venosus defect. Ostium secundum defects are located in
nary artery. The junction between the primitive ventricle the midportion of the interatrial septum and result from
and the bulbus cordis is designated the primary interven- inadequate formation of septum secundum and/or septum
tricular foramen. While the ventricular septation process primum to cover the foramen ovale. Ostium primum defects
proceeds, the primitive ventricle develops into the major are located in the inferior portion of the interatrial septum
component of the definitive left ventricle, and the proximal and result from a defect in formation of endocardial cushion
one third of the bulbus cordis gives rise to the major compo- tissue. Severe endocardial cushion deficiency can lead to
nent of the definitive right ventricle. a common atrioventricular canal anomaly with ostium
Separate aortic and pulmonary channels are formed by primum atrial septal defect, membranous ventricular septal
separation of the truncus arteriosus by a spiral aorticopul- defect, and abnormal atrioventricular valve. The sinus
monary septum (Fig. 1.3). As a result of extensive remodeling venosus atrial septal defect is located in the superior portion
of the double aortic arch system, the definitive major vessel of the interatrial septum and results from defective incor-
system develops into a single aorta with left-sided aortic poration of the primitive sinus venosus into the forming
arch, a pulmonary trunk with right and left main pulmonary heart; this defect is often associated with partial anomalous
arteries, and the ductus arteriosus, which connects the aortic pulmonary venosus drainage into the right atrium. Abnor-
arch and the left pulmonary artery. malities in ventricular septation give rise to ventricular
The heart develops in the fetus as myocardial contractile septal defects, usually in the region of the membranous
activity commences, and a functional circulation is estab- septum. Formation of the membranous interventricular
lished. The foramen ovale in the interatrial septum and the septum involves contributions from the conal ridges of the
ductus arteriosus remain open. In the fetus, pulmonary vas- bulbus cordis and the endocardial cushions. Deficiencies in
cular resistance is high in the unexpanded lungs and sys- contributions from these embryonic structures leads to the
temic vascular resistance is low. As a result of these anatomic formation of membranous ventricular septal defects. Abnor-
and physiologic features, the fetal circulation involves right malities in septation of the great vessels give rise to con-
to left shunting of blood across the open foramen ovale and genital complete transposition of the great vessels, or
the patent ductus arteriosus to provide oxygenated blood d-transposition, since the abnormal septation of the great
from the placenta to the general circulation (Fig. 1.4). After vessels occurs with normal dextro-bulboventricular looping
birth, the lungs expand, pulmonary vascular resistance and the atria and ventricles are in normal position. Con-
drops, and systemic vascular resistance increases. This leads genital complete transposition is often accompanied by
 a natom y of t h e h e a rt 5

Septum spurium

Interatrial
septum primum
Ostium I

Atrio-vent. canal

Intervent. septum

A 4–5 mm B 6–7 mm

Septum II
S. sp.
Septum Septum I
Ostium II spurium Ostium II
(opening)
Septum I Ostium I
Right Ostium I
atrium Septum II (closed)
(closing)
(caudal limb)
A_V. canal cushion
Intervent. foramen
(closes at 15–17 mm.)
Left
ventricle

C 8–9 mm D 12–15 mm

Septum II Crista
S. sp. Ostium II terminalis
in septum I
S II Functional
outlet F.O.
Foramen
ovale Septum I
(valvula F.O.)
S II

Atriovent.
valves

Bundle
of his

E 25–30 mm F 100 mm. to birth

FIGURE 1.2. Longitudinal sections of embryonic heart in frontal hatching, and epicardium in solid black. The lightly stippled areas
plane that show extent of growth of various cardiac septa at progres- in the atrioventricular canal in B and C indicate location of dorsal
sive stages of development. These diagrams depict the stages of and ventral endocardial cushions of the atrioventricular canal before
partitioning of the human embryo. Stippled areas indicate the dis- they have grown sufficiently to fuse with each other in the plane of
tribution of endocardial cushion tissue; muscle is shown in diagonal the diagram.

atrial or ventricular septal defects or other congenital tions occur 10 times more often in stillborn than in liveborn
lesions. Severe maldevelopment of the heart can give rise to infants. Children with congenital heart disease are predomi-
a hypoplastic left heart or hypoplastic right heart and asso- nantly male. However, specific defects have a definite sex
ciated valvular atresia. Other anomalies include vascular preponderance: females have a higher incidence of patent
rings, persistent patent ductus arteriosus, and coarctation of ductus; arteriosus and atrial septal defect are more common
the aorta. in females; and males have a higher incidence of valvular
Cardiovascular malformations occur in about 0.8% of aortic stenosis, congenital aneurysm of the sinus of Valsalva,
live births.10 However, the incidence of congenital heart coarctation of the aorta, tetralogy of Fallot, and congenital
disease is significantly higher because cardiac malforma- complete transposition of the great arteries.10
6 chapter 1

Pulmonary
Dextrodorsal channel S.-v. truncus
Truncus ridge
arteriosus truncus ridge
communis Aortic
channel
Dextrodorsal
conus ridge
Right S.-v.
atrium conus
Conovent. flange ridge
Left Arrow
Conus atrium in aortic
art. channel Ventral
atriovent.
Atrioventricular canal
canal cushion

Dorsal atriovent.
canal cushion
Right
ventricle Left
Interventricular ventricle
septum
A B
FIGURE 1.3. Frontal plane dissections of developing heart show upward, in order to show the absence of truncus ridges in the early
important relations in establishing aortic and pulmonary outlets. stages and their relationships in later stages.
The truncus arteriosus has been drawn with its cut end turned

Septum I
Superior vena cava (remnant)
Crista Margin of interatrial
terminalis foramen II

Septum II Septum I = valvula

foraminis ovalis

Limbus of
foramen Orifices of
ovale pulmonary veins

Valve of Left atrium

inferior
vena cava
Mitral valve
Valve of
coronary
sinus Tendinous
Tricuspid valve cords
Septum
membranaceum Papillary
muscle
Interventricular septum
(muscular portion)
Trabeculae
carneae of
Right ventricle left ventricle

FIGURE 1.4. Schematic drawing to show interrelations of septum from the inferior vena cava passes through the foramen ovale to the
primum and septum secundum during the latter part of fetal life. left atrium while the remainder eddies back into the right atrium
Note especially that the lower part of septum primum is positioned to mix with the blood being returned by way of the superior vena
so as to act as a one-way valve at the oval foramen in septum secun- cava.
dum. The split arrow indicates that a considerable part of the blood
 a natom y of t h e h e a rt 7

External Anatomy of the Heart and Pericardium

Great Vessels
The pericardial cavity is a fluid-filled space that surrounds
The anatomy of the heart and great vessels has been well the heart and proximal great vessels. The pericardial space
documented in previous publications.11–17 The normal loca- is enclosed by a thin layer of connective tissue that is lined
tion of the heart is in the mediastinum to the left of the by a single layer of mesothelial cells. There are two compo-
midline with the cardiac apex pointed to the left (Fig. 1.5). nents: the visceral and parietal pericardium. The visceral
The heart is rotated and tilted in the chest, and as a result pericardium covers the epicardium of the heart, and the
about two thirds of the anterior surface of the heart is com- parietal pericardium forms the outer layer. The superior
posed of the right ventricle, and the left third of the anterior extent of the pericardial cavity representing the transition
surface is composed of the left ventricle. The right inferior of visceral to parietal pericardium occurs approximately 2 to
border (obtuse border) of the heart is formed by the right 3 cm superior to the heart at the level of the great vessels,
ventricle and the left lateral border is formed by the left thereby enclosing the proximal aorta and pulmonary trunk
ventricle. Located superior to the right and left ventricles in the pericardial cavity (Fig. 1.5). The pericardial cavity
are the right and left auricles of the right and left atria, normally contains about 20 cc of serous fluid, which serves
respectively. The anterior superior surface of the heart is to lubricate the heart and facilitate cardiac motion.
constituted by the outflow portion (conus) of the right The pericardium can be affected by a variety of inflam-
ventricle and the pulmonary trunk, which extends from matory and neoplastic conditions. Hemorrhage into the peri-
right to left as it exits the pericardium. The pulmonary cardium may occur as a result of cardiac rupture, usually
trunk then gives rise to the left and right main pulmonary secondary to acute myocardial infarction, or rupture of the
arteries. The aorta is located posterior to the pulmonary proximal aorta following aortic dissection. The severity of
trunk. The aorta takes origin from the left ventricle and is cardiac dysfunction secondary to pericardial disease is influ-
oriented from left to right as it exits the pericardium. The enced acutely by the amount and rapidity of fluid accumula-
aorta then curves to the left and inferiorly, creating a left- tion in the pericardial cavity and chronically by the severity
sided aortic arch. The aortic arch gives origin to the right of inflammation and fibrosis. Rapid accumulation of 100 to
innominate, left common carotid, and left subclavian arter- 200 mL of fluid or blood in the pericardial cavity can induce
ies. The aorta then continues inferiorly as the descending cardiac tamponade, whereas the slow accumulation of
thoracic aorta. several hundred milliliters can be accommodated in the

Innominate Left subclavian artery

artery
Right innomi-
nate vein Left innominate vein
R. int. mam. vein
Pleura
Thymus gland
Reflection of
pericardium
Vena cava
sup. Pulmonary
Asc. aorta artery
Pleura
Probe in Fibrous
transv. pericardium
sinus Serous
Right pericardium
auricle Conus
arteriosus

Right Left
atrium auricle

Coronary
sulcus
Margo
Right obtusus
ventricle

Left
ventricle
Anterior
Margo longi-
acutus tudinal
Incisura sulcus
apicis Apex
cordis
Pleura
FIGURE 1.5. Ventral view of heart in situ
with the pericardial sac opened.
8 chapter 1

cavity with stretching of the pericardial lining before well as biventricular enlargement.15 The thickness of the
impaired cardiac function develops. walls of the cardiac chambers is as follows: right and left
atria, 0.1 to 0.2 cm; right ventricle, 0.4 to 0.5 cm; left ventri-
cle, 1.2 to 1.5 cm (free wall, excluding papillary muscles and
Heart large trabeculae). The average circumferences of the cardiac
valves are as follows: aortic, 7.5 cm; pulmonic, 8.5 cm; mitral,
10.0 cm; and tricuspid, 12.0 cm.
Basic Structure
The anatomy of the heart has been documented in detail.11–17
Coronary Vasculature
The heart is composed of three layers: the epicardium, the
myocardium, and the endocardium. The epicardium consists The anatomy and physiology of the coronary circulation have
of fatty connective tissue and is lined by the visceral peri- been described in detail.18–25 In the normal heart, oxygenated
cardium. The major coronary arteries and veins traverse the blood is supplied by two coronary arteries that are the first
epicardium. The myocardium constitutes most of the mass branches of the aorta. The origin of the left and right coro-
of the heart and is composed of cardiac myocytes, vessels, nary arteries from the aorta is through their ostia positioned
and connective tissue. The cardiac myocytes represent in the left and right aortic sinuses of Valsalva, which are
approximately 80% of the mass but only 20% of the number located just distal to the left and right cusps, respectively, of
of cells in the myocardium. The endocardium is divided into the aortic valve (Figs. 1.5, 1.6, and 1.7). The left main coro-
the nonvalvular (visceral) and valvular endocardium. The nary artery is a short vessel with a length of 0.5 to 1.5 cm.
endocardium consists of thin fibrocellular connective tissue, The left main coronary artery divides into left anterior
which is lined by a single layer of endothelial cells. descending and left circumflex branches and, occasionally, a
left marginal branch. The left anterior descending coronary
artery and its left diagonal and septal branches supply the
Cardiac Dimensions
anterior portion of the left ventricles and interventricular
Several sources have provided information regarding dimen- septum. The left circumflex coronary artery and its circum-
sions and measurements of the heart.11–17 The weight of the flex marginal branches supply the lateral left ventricle. The
heart varies in relationship to body dimensions, including right coronary artery supplies the right ventricle and, in
length and weight. Hudson11 has published a useful guide about 90% of hearts, it extends posteriorly to give rise to the
regarding fresh heart weight in males and females. The adult posterior descending coronary artery.
male heart weight has the following parameters: 0.45% of There is considerable variation in the anatomic distribu-
body weight, average 300 g, range 250 to 350 g. The adult tion of the coronary arterial branches. However, in most
female heart weight has the following parameters: 0.40% of hearts, branches from both the left circumflex and right
body weight, average 250 g, range 200 to 300 g. Selective mea- coronary arteries contribute to the blood supply of the pos-
surements of right ventricular and left ventricular weights terior left ventricle, resulting in a so-called balanced circula-
can be made, and ranges have been established for determina- tion. In about 10% of hearts, the right coronary artery is
tion of selective enlargement of right and left ventricles as small, and the left circumflex coronary artery gives origin

Right pulmonary veins Left pulmonary veins

Left auricle
Vena cava superior Left atrium

Aorta Circumflex branch

Posterior and Left coronary
left aortic semi- artery
lunar valves Left aortic sinus
Right aortic Great cardiac vein
semilunar valve Left pulmonary
Right coronary semilunar valve
artery Right and anterior
Small cardiac pulmonary semilunar
vein valves
Anterior cardiac Pulmonary artery
veins Conus arteriosus
Preventricular.
arteries Anterior descending
Right marginal branch of left
artery coronary artery
Left ventricle
Right ventricle
Anterior longitudinal
sulcus
FIGURE 1.6. Cephalic view of the heart with
Incisura apicis cordis the epicardium removed to expose the injected
coronary vessels.
 a natom y of t h e h e a rt 9

Vena cava superior

Superior Superior right
left pulmonary pulmonary vein
vein
Inferior right
pulmonary vein
Inferior left
pulmonary vein Terminal
Left atrium sulcus
Oblique vein of
left atrium Right atrium
Interatrial sulcus Vena cava
inferior
Great cardiac vein Valvula venae
cavae
Small
Coronary sinus cardiac vein
Right
coronary
Posterior vein of artery
left ventricle Right
ventricle
Middle cardiac
vein
Diaphragmatic Posterior descend-
surface of left ing branch of right
ventricle coronary artery

FIGURE 1.7. Dorsocaudal view of the heart Posterior longitudinal sulcus

with the epicardium removed to expose the
injected coronary vessels.

to the posterior descending coronary artery and provides the cardiac collaterals); and intramural branches, which com-
sole blood supply for the posterior left ventricle, creating a municate with the cardiac cavities (arterioluminal vessels).
left dominant circulation. Rarely, the converse right domi- In the normal adult heart, the collateral vessels are thin
nant circulation exists when the left circumflex is small and walled, small channels, usually less than 50 μm in diameter,
the posterior left ventricle is supplied primarily by left ven- and they contribute little to total coronary blood flow. In
tricular branches of the right coronary artery. response to coronary arterial narrowing and myocardial
The major blood supply to the sinoatrial node via the ischemia, the capacity of the coronary collateral system can
sinus node artery is derived from the proximal right coro- greatly increase. The myocardial collateral vessels can
nary artery in about 60% of hearts and from the left circum- increase in diameter into the range of 200 to 600 μm or
flex coronary artery in about 40% of hearts.18 The major
atrioventricular nodal artery is derived from the coronary
artery that gives rise to the posterior descending branch,
which is the right coronary artery in about 90% and the left
circumflex coronary artery in about 10% of hearts. Endocardium Myocardium Epicardium
The epicardial coronary arteries deliver oxygenated blood Arterioluminal
to the intramyocardial arteries, arterioles, and capillaries vessel
leading to oxygen and substrate extraction in the myocar- Myocardial sinusoid
dium (Fig. 1.8). A small amount of unoxygenated blood flows Intertrabecular space Coronary artery
directly into the ventricular cavities via the thebesian veins. Anastomoses
Anastomosis between
However, most desaturated blood traverses the myocardial myocardial sinusoids between
coronary arteries
venules and veins into the epicardial veins, which drain into Arteriosinusoidal
vessel
the coronary sinus located in the inferoposterior region of
Trabeculae carneae Arteriovenous
the right atrium. anastomosis
Collateral blood vessels form during embryologic devel- Capillary bed
opment of the heart, and they connect different components Myocardial sinusoid Venovenous
of the coronary arterial circulation.18–25 The coronary collat- Capillaries emptying into anastomosis
eral system is composed of four types of vessels: intramural myocardial sinusoids
Thebesian vein Coronary vein
branches of the same coronary artery (homocoronary collat-
erals); intramural branches of two or more coronary arteries Anastomosis between
thebesian veins
(intercoronary collaterals); atrial branches, which connect FIGURE 1.8. Diagram of the ventricular wall, showing the relation-
with the vasa vasorum of the aorta and other vessels (extra- ship between the various intramural vascular channels.
10 chapter 1

greater, develop muscular media, and transport significant

amounts of blood flow (Fig. 1.9). In addition to the types of
collateral vessels described above, collateral channels also
can develop proximal and distal to a stenosis in a given coro-
nary artery.

Right and Left Atria and Ventricles

The right and left atria and right and left ventricles have
distinctive anatomic features (Figs. 1.10 to 1.17). The ana-
tomic right ventricle is characterized as follows: distinct
muscular infundibulum (conus) arteriosus, which separates
the right semilunar (pulmonary) valve and the right atrioven-
tricular (tricuspid valve); single large anterior papillary
muscle; and coarse trabecular muscles (trabeculae carneae
cordis) at the apical and inflow portion of the chamber.11–17
Key landmarks of the right ventricular infundibular (conus)
region from inferior to superior are the membranous inter-
ventricular septum; the crista supraventricularis, an inverted
V-shaped structure with parietal and septal limbs; and the
pulmonic valve. The anatomic left ventricle has the follow-
ing features: fibrous continuity of annulus of left semilunar
(aortic) valve and anterior leaflet of left atrioventricular
(mitral) valve, two well-developed papillary muscles (antero-
lateral and posteromedial), and fine trabecular muscles at the
apical and inflow portion of the chamber.11–17 These features
allow determination of the anatomic right ventricle and ana-
FIGURE 1.9. Radiograph of postmortem coronary arteriogram dem-
onstrating an extensive coronary collateral system in a case of coro- tomic left ventricle in complex congenital anomalies involv-
nary heart disease. The proximal part of the left anterior descending ing displacement of the various components of the heart.
artery is obliterated by old disease (O). The more distal part of the
anterior descending artery (A) has filled through a rich anastomotic
network (X) that has formed in the substance of the interventricular Cardiac Valves
septum between branches of the anterior (A) and posterior (P)
descending arteries. The four-chambered heart has four valves: the right semilu-
minar or pulmonic valve; the right atrioventricular or tricus-
pid valve; the left semilunar or aortic valve; and the left

Ligamentum arteriosum

Left pulmonary artery Aorta

Probe in transverse sinus

Right pulmonary
artery
Right auricle
Left pulmonary Vena cava superior
veins
Left atrium Right ventricle
Foramina Crista terminalis
venarum
minimarum
Right pulmonary Left ventricle
veins
Interatrial
sulcus Right atrium
Limbus fossae Tricuspid
ovalis valve:
Fossa ovalis Anterior cusp
Orifice of coronary sinus Medial cusp
Valvula sinus coronarii
Posterior cusp
Valvula venae cavae
Vena cava inferior Musculus pectinatus
FIGURE 1.10. Right anterior oblique
Right coronary artery view of the excised heart, with the right
Small cardiac vein atrium opened to show its internal
configuration.
 a natom y of t h e h e a rt 11

Ascending aorta Right coronary artery

Superior
vena cava Pulmonary cone
Right auricular
appendage Crista supraventricularis
Crista
terminalis Papillary muscle
of conus
Pulmonary
vein
Interventricular septum
membranaceum
Limbus
fossae ovalis Septal cusp of
tricuspid valve
FIGURE 1.11. Right side of the heart Valve of inferior (cut)
opened in a plane approximately parallel vena cava
to the septa, to show the interior of the (eustachian v.) Anterior
right atrium and the right ventricle. A papillary
segment of the septal leaflet of the tri- Inferior vena cava muscle (cut)
cuspid valve has been removed to expose
more fully the region of the membra- Valve of coronary Posterior
nous portion of the interventricular sinus (thebesian v.) papillary
septum. muscle (cut)

Aorta Papillary muscle of conus

Crista supraventricularis Conus arteriosus
Pulmonary artery
Anterior pulmonary semilunar valve
Vena cava superior

Crista terminalis
Limbus fossae
ovalis
Fossa
ovalis

Right
atrium
Right
coronary artery
Vena cava inferior Anterior
FIGURE 1.12. Ventral view of the heart Tricuspid valve: Anterior cusp papillary
muscle
with the walls of the right atrium and of left
ventricle opened to show their internal Posterior cusp ventricle
configuration. This heart has an unusu- Medial cusp
ally well-developed moderator band, and Trabecula carnea Moderator band Left ventricle
Posterior papillary muscle Muscular interventricular septum
the position of the foramen ovale is Chorda tendineae Anterior papillary muscle
somewhat more cephalic than usual.
12 chapter 1

FIGURE 1.13. Photograph of opened right heart demonstrating conus arteriosus, i.e., infundibulum; CS, coronary sinus; PV, pul-
actual structures depicted in the illustrations. Note the muscular monic valve; RA, right atrium; RV, right ventricle.
infundibulum separating the tricuspid and pulmonic valves. CA,

Aorta
Pulmonary trunk
Superior
vena cava
Great cardiac vein
Orifice of right
coronary artery
Left coronary artery
Right superior
Right semilunar pulmonary vein
valve of aorta
Adherent
Interventricular margin of
septum valv. foram ov.
membranaceum
Interventricular Mitral valve (cut)
septum
musculare
Coronary sinus
Papillary
muscle Inferior
(cut) vena cava

FIGURE 1.14. Left side of the heart opened in a plane approximately been removed to expose more fully the region of the membranous
parallel to the septa, to show the interior of the left atrium and left portion of the interventricular septum and the aortic orifice.
ventricle. A portion of the anterior leaflet of the mitral valve has
 a natom y of t h e h e a rt 13

Left atrium
Valve of inferior
vena cava
Septum membra-
naceum
(atriovent. part.)
Septum membra-
naceum (interven-
tricular part.) Mitral
Atrioven- valve
tricular
bundle
Tricuspid
valve

Papillary
muscle Papillary
muscles

Interventricular
septum

FIGURE 1.15. Frontal section through a heart fixed in

diastole, showing a ventral view of the dorsal portion.
The plane of section passes through the septum mem-
branaceum and both atrioventricular ostia.

FIGURE 1.16. Photograph showing the relationship of the membra-

nous interventricular septum (lighted) to the tricuspid annulus and FIGURE 1.17. Photograph of opened left ventricle showing continu-
septal leaflet of the tricuspid valve. While the membranous interven- ity of the anterior mitral leaflet and the annulus of the aortic valve.
tricular septum is entirely contained in the left ventricle, the supe- AML, anterior mitral leaflet; LC, left cusp of aortic valve; NCC,
rior portion of the interventricular septum extends superior to the noncoronary cusp of aortic valve; PPM, posterior papillary muscle;
tricuspid annulus. This anatomic relationship allows for left ven- RC, right coronary cusp of aortic valve.
tricular to right atrial shunts in certain pathologic states, such as
infective endocarditis of the aortic valve. MIS, membranous inter-
ventricular septum; SLTV, septal leaflet of the tricuspid valve.
14 chapter 1

Pulmonary annulus fibrosus Conus ligament

Ant. descending br.

Right coronary art.

Left coronary art.

Aortic
Circumflex br. annulus fibrosus

Left fibrous
triangle Atrioventricular
bundle
Right fibrous
friangle
Annulus fibrosus
Annulus fibrosus of tricuspid valve
of mitral orifice

Anastomosing branch Post. descending br. of right coronary a.

FIGURE 1.18. Ventricular portion of the heart viewed from above tricular musculature to them. Epicardial fat has been removed from
with the atria removed, to show the four cardiac valves and the the atrioventricular sulcus in order to show the coronary arteries.
fibrous triangles, the annuli fibrosi, and the attachment of the ven-

atrioventricular or mitral valve (Figs. 1.18 to 1.21). The pul- cially prominent and are known as the noduli of Arantius.
monic and aortic semilunar valves each have three cusps The most common congenital valve lesion is a malformed
separated by three commissures, and the cusps insert into a aortic valve, either a unicuspid or bicuspid valve.
fibrous connective tissue annulus. The aortic valve cusps are The tricuspid or right atrioventricular valve has three
designated as the left and right cusps in relationship to the leaflets (cusps) that are separated by three commissures and
coronary ostia and a third, noncoronary cusp. With valve insert into a fibrous annulus. The leaflets are designated as
closure during diastole, the cusps of the aortic and pulmonic the lateral, medial, and anterior leaflets. The leaflets are
valves make contact along a line about 1 to 2 mm below the attached to the ventricular muscle by multiple chordae ten-
free margin. The central points of maximal contact are espe- dineae, which extend from the ventricular surfaces of the

Ant. desc. branch of

Pulmonary
left coronary art.
semilunar valve

Pulmonary
Noncoronary cusp of
conus
aortic semilunar v.

Septum
Septal cusp of
membranaceum
tricuspid valve

Bundle of his
Muscular part of
interventricular
septum Mitral valve

FIGURE 1.19. Interior of the ventricular base of the heart, exposed interventricular septum membranaceum, and the mitral, the tricus-
by removal of the apical half of the ventricles. The interventricular pid and the aortic valves.
septum has been partially removed to show the relations of the
 a natom y of t h e h e a rt 15
leaflets to the mural ventricular wall as well as a well-
developed anterior papillary muscle and a diminutive struc-
ture, the papillary muscle of the conus.
The mitral or left atrioventricular valve has a highly
developed and coordinated group of structures that are
referred to as the mitral valve apparatus (Figs. 1.18 to 1.21).
The mitral valve apparatus consists of fibrous annulus, ante-
rior and posterior leaflets, anterior and posterior commis-
sures, multiple chordae tendineae, and anterolateral and
posteromedial papillary muscles. Chordae tendineae extend
from the ventricular surfaces of both leaflets and attach to
both papillary muscles. Chordae tendineae exhibit a branch-
ing pattern with primary chordae arising from the papillary
muscles and branching into secondary and then tertiary
chordae, which insert into the valvular leaflets. Mitral valve
dysfunction can result from a wide variety of pathologic
processes affecting any component of the mitral apparatus,
including the myocardium.
The anterior mitral leaflet is usually a single structure, FIGURE 1.21. Photograph of mitral valve showing a portion of the
whereas the posterior leaflet may be divided into two or three anterior mitral leaflet and the posterior leaflet consisting of multiple
scallops (Fig. 1.21). The anterior mitral leaflet normally has scallops. AML, anterior mitral leaflet; PML, posterior mitral leaflet.
a significantly larger area and longer length from annulus to
free margin that the posterior mitral leaflet. As a result, the
anterior leaflet contributes about two thirds of the area of of the anterior leaflet from annulus to free margin is an
leaflet tissue involved in closure of the mitral orifice during important anatomic feature of myxomatous degeneration of
systole. Expansion of the posterior leaflet to equal the length the mitral valve. Other features include general redundancy,
thickening, and a glistening white appearance of leaflet
tissue and chordae tendineae.

Cardiac Conduction System and

Cardiac Innervation
The anatomy of the cardiac conduction system has been
defined by meticulous study (Fig. 1.22).26,27 The sinoatrial
node is located in the superficial subepicardium of the
superior right atrium at the junction of the superior
vena cava and the right auricular appendage. The sinoatrial
node contains myocytes that are specialized for the genera-
tion of electrical impulses and constitute the cardiac
pacemaker. The electrical impulse propagates selectively
along certain paths in the atria; however, the existence of
anatomically distinct conduction pathways in the atria is
difficult to demonstrate. Atrioventricular conduction is
accomplished by specialized structures, the more proximal
atrioventricular node (node of Tawara) and the more
distal atrioventricular bundle (bundle of His). The atrioven-
tricular node is positioned in the inferior interatricular
septum just anterior and medial to the ostium of the coro-
nary sinus. The specialized conduction tissue then extends
through the fibrous skeleton separating the atria and ven-
tricles to connect to the bundle of His, which is located at
the apex of the muscular interventricular septum. The His
bundle gives origin to the right and left bundle branches,
which extend through the subendocardium of the interven-
tricular septum into the right and left ventricular free
walls.
The heart has a dual innervation from the sympathetic
FIGURE 1.20. Photograph of left ventricle showing aortic valve and (thoracolumbar) and parasympathetic (craniosacral) divisions
a portion of the mitral apparatus, including the anterior mitral
leaflet, chordae tendineae, and papillary muscles. AML, anterior
of the autonomic nervous system (Fig. 1.23). These nerves
mitral leaflet; APM, anterior papillary muscle; CT, chordae tendin- interact with the conduction tissue to provide neural modu-
eae; LC, left cusp of aortic valve; PPM posterior papillary muscle. lation of cardiac function.
16 chapter 1

Superior Right pulmonary

vena cava vein Left pulmonary
vein
Sino-atrial
node
Left
atrial wall
Fossa
ovalis

Coronary Mitral
orifice valve

Inferior
vena cava Septum
membranaceum
Atrio-ventricular
node Bifurcation
of bundle

Main atrio-
ventricular bundle
(bundle of his) Left
branch of
bundle
Right branch
of bundle
Purkinje
fibers under
Branch of bundle in endocardium
moderator band of papillary musc. FIGURE 1.22. Schematic diagram of heart
opened frontally, demonstrating the location
Branch under septal endocard. and relations of the several parts of the sino-
atrial and atrioventricular conduction system.

Superior cardiac
Superior cervical nerve
ganglion

Superior cardiac
nerve Middle cardiac nerve
Inferior cervical Superior cardiac branch
ganglion
Vagus nerve Inferior cervical ganglion
First thoracic ganglion
Ansa of vieussens

Inferior
cardiac
branch Superficial
cardiac
plexus
Ganglion of
Deep cardiac wrisberg
plexus

Pulmonary
plexus

Right
coronary
plexus Left
coronary
plexus

FIGURE 1.23. Ventral view of thorax to show

the nerve supply to the heart.
 a natom y of t h e h e a rt 17

Summary 11. Hudson REB. Structure and function of the heart. In: Cardio-
vascular Pathology, vol 1. Baltimore: Williams & Wilkins,
1965:1–52.
This chapter presented a description and illustration of the
12. Barry A, Patten BM. The structure of the adult heart. In: Gould
embryologic and anatomic features of the heart and great SE, ed. Pathology of the Heart and Blood Vessels, 3rd ed. Spring-
vessels. The embryologic development of the cardiac struc- field, IL: Charles C Thomas, 1968:91–130.
tures was presented, and the relationship of cardiac develop- 13. Patten BM. The cardiovascular system. In: Morris’s Human
ment to congenital heart diseases was discussed. Key Anatomy, 10th ed. Philadelphia: Blakiston, 1942:582–785.
components of the mature heart were described and illus- 14. Reiner L. Gross examination of the heart. In: Gould SE, ed.
trated, including the pericardium, the coronary arteries, the Pathology of the Heart and Blood Vessels, 3rd ed. Springfield,
four cardiac valves, the right and left atria and ventricles, and IL: Charles C Thomas, 1968:1111–1149.
the cardiac conduction system and cardiac innervation. The 15. Davies MJ, Pomerance A, Lamb D. Techniques in examination
and anatomy of the heart. In: Pomerance A, Davies MJ, eds.
relationship of structure to function was considered. Under-
The Pathology of the Heart. Oxford: Blackwell Scientific,
standing cardiovascular anatomy is important for the diag-
1975:1–48.
nosis and treatment of cardiovascular diseases. 16. Ludwig J, Lie JT. Heart and vascular system. In: Ludwig J, ed.
Current Methods of Autopsy Practice, 2nd ed. Philadelphia:
References WB Saunders, 1979:21–50, 668–673.
17. Silver MM, Freedom RM. Gross examination and structure of
1. Patten BM. The development of the heart. In: Gould SE, ed. the heart. In: Silver MD, ed. Cardiovascular Pathology, 2nd ed.
Pathology of the Heart and Blood Vessels, 3rd ed. Springfield, New York: Churchill Livingstone, 1991:1–42.
IL: Charles C Thomas, 1968:20–90. 18. James TN. The coronary circulation and conduction system
2. Patten BM. Section on heart. In: Human Embryology, 2nd ed. in acute myocardial infarction. Prog Cardiovasc Dis 1968;
New York: McGraw-Hill, 1953:656–705. 10:410–446.
3. Patten BM. The development of the circulatory system. In: 19. Shaper W. The Collateral Circulation of the Heart. New York:
Foundations of Embryology. New York: McGraw-Hill, 1958: American Elsevier, 1971.
484–539. 20. Crawford T. The anatomy of the coronary arteries. In: Pathology
4. Sadler TW. Cardiovascular system. In: Langman’s Medical of Ischaemic Heart Disease. London: Butterworths, 1977:4–17.
Embryology, 5th ed. Baltimore: Williams & Wilkins, 1985: 21. Gregg DE, Patterson RE. Functional importance of coronary
168–214. collaterals. N Engl J Med 1980;303:1404–1406.
5. Olson EN, Srivastava D. Molecular pathways controlling heart 22. Willerson JT, Hillis LD, Buja LM. Pathogenesis and pathology
development. Science 1996;272:671–676. of ischemic heart disease. In: Ischemic Heart Disease: Clinical
6. Patten BM. Developmental defects at the foramen ovale. Am J and Pathophysiological Aspects. New York: Raven Press, 1982:
Pathol 1938:14:135–161. 7–83.
7. Kramer TC. The partitioning of the truncus and conus and 23. Marcus ML. The Coronary Circulation in Health and Disease.
the formation of the membranous portion of the interventric- New York: McGraw-Hill, 1983.
ular septum in the human heart. Am J Anat 1942;71: 24. Baroldi G. Diseases of extramural coronary arteries. In: Silver
343–370. MD, ed. Cardiovascular Pathology, 2nd ed. New York: Churchill
8. Edwards JE. Congenital malformations of the heart and great Livingstone, 1991:487–563.
vessels. In: Gould SE, ed. Pathology of the Heart and Blood 25. Boudoulas H, Gravanis MB. Ischemic heart disease. In:
Vessels, 3rd ed. Springfield, IL: Charles C Thomas, 1968: Gravanis MD, ed. Cardiovascular Disorders: Pathogenesis
262–478. and Pathophysiology. St. Louis, MO: Mosby, 1993:14–16.
9. Berry CL. Congenital heart disease. In: Pomerance A, Davies 26. Lev M. The conduction system. In: Gould SE, ed. Pathology of
MJ, eds. The Pathology of the Heart. Oxford: Blackwell Scien- the Heart and Blood Vessels, 3rd ed. Springfield, IL: Charles C
tific Publications, 1975:533–578. Thomas, 1968:180–220.
10. Friedman WF. Congenital heart disease in infancy and child- 27. Hudson REB. The conducting system: anatomy, histology and
hood. In: Braunwald E, ed. Heart Disease. A Textbook of pathology in acquired disease. In: Silver MD, ed. Cardiovas-
Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders, cular Pathology, 2nd ed. New York: Churchill-Livingstone,
1992:887–965. 1991:1367–1428.
 2 The History and Physical
Examination
Thomas C. Smitherman and James T. Willerson

Importance of the Patient History . . . . . . . . . . . . . . . . . . . 19 Physical Examination of the Patient with

Differential Diagnosis of the Signs and Symptoms Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Commonly Seen in Heart Disease. . . . . . . . . . . . . . . . 19

Importance of the Patient History severe left ventricle (LV) outflow obstruction or severe LV
hypertrophy. Dyspnea may be caused by pulmonary or
The importance of a carefully obtained and accurate history cardiac problems but sometimes is simply a manifestation
from the patient with cardiovascular disease cannot be over- of anxiety. Easy fatigability can be caused by heart or lung
emphasized. In many instances, such a history enables the disease or by extracardiac factors, such as anemia, thyrotoxi-
examiner to recognize the etiology of the problem relatively cosis, obesity, renal disease, or a systemic malignancy.
rapidly. Without it, evaluation of the patient’s problem is A careful history should elucidate the patient’s family
much less effective and definitive. history, any substance abuse, any evidence of syncope,
The patient’s general appearance often helps the physi- dyspnea, orthopnea, chest pain, abdominal pain, discomfort
cian to focus questions so as to obtain a meaningful history. in the legs while walking, headaches, muscle weakness,
The patient’s family history may also assist the physician in hemoptysis, tiring unduly rapidly with physical effort, palpi-
the history-taking process, given that the genetic risks for tations, fever, diaphoresis, loss of appetite, weight loss or
cardiovascular disease are very important, especially when gain, and history related to the presence or absence of risk
cardiovascular disease has occurred at a relatively young age factors for cardiovascular diseases.
in a patient’s father, mother, siblings, or grandparents. Risk A carefully obtained history from a patient with cardio-
factors for specific cardiovascular diseases enable the physi- vascular disease almost always leads the knowledgeable
cian to elicit specific complaints related to the patient’s car- physician toward a more rapid and correct diagnosis of the
diovascular problem. A history of substance abuse should patient’s cardiovascular problem and the development of an
lead to specific questions. Cardiovascular abnormalities effective treatment plan. When an accurate and careful
detected on physical examination should also help the exam- history is not or cannot be obtained, it is often difficult to
iner to elucidate a meaningful history. identify the correct etiology of a cardiovascular problem, and
We have found it useful to focus on a set of questions can lead to the use of less than optimal diagnostic and thera-
immediately directed at an apparent or a suspected cardio- peutic interventions.
vascular abnormality during the first few minutes of the Heart disease is manifested by various signs and symp-
patient interview. General questions may be asked later. toms. Cardiac dysfunction influences many organ systems,
The examiner must try to obtain both subjective and and many noncardiac illnesses are expressed in findings
objective, even quantitative, answers to specific questions. similar to those produced by cardiovascular disease.
Although it is necessary to know about the presence of chest
pain, dyspnea, and easy fatigability, it is also necessary to
determine the specific type of pain present and what pro- Differential Diagnosis of the Signs and
vokes and relieves it. Similarly, learning the amount of effort Symptoms Commonly Seen in Heart Disease
required before dyspnea occurs or the amount of effort
required before the patient tires is useful in determining
Dyspnea
specific etiologies for a particular cardiovascular problem
and in determining the severity of the patient’s limitation. Dyspnea, the labored breathing usually referred to as short-
In evaluating the patient with chest pain, one must deter- ness of breath, is a distressful sensation of air hunger. It is
mine whether the pain is anginal or pleuritic in quality. abnormal only when the sensation of breathlessness is inap-
Pleuritic pain raises questions concerning pulmonary or propriate to the level of physical activity that provoked it. The
pericardial pain, whereas anginal pain suggests the presence major causes of dyspnea are listed in Table 2.1. Although sub-
of one of the coronary artery disease (CAD) syndromes or stantial information is available on the normal control of

19
20 chapter 2

TABLE 2.1. Causes of dyspnea and the lungs are abnormal, differentiation of the etiology
Heart disease of the dyspnea is difficult but imperative. To differentiate
Left ventricular failure cardiac from pulmonary dyspnea, associated signs and symp-
Restrictive cardiomyopathy toms of heart disease should be sought. Progressive dyspnea
Constrictive pericarditis over a relatively short time is usually an important clue to
Pulmonary venous obstruction
Mitral stenosis
cardiac dyspnea, as opposed to the generally long-standing
Cor triatriatum symptoms of pulmonary disease. The presence of pulmonary
Left atrial myxoma disease is usually obvious from the history and physical
Left atrial thrombus examination. Chronic progressive shortness of breath with a
Tamponade productive cough, chronic rhonchi and wheezes, diminished
Pulmonary disease breath sounds, and respiratory capacity, with abnormal pul-
Obstructive airways disease
Chronic obstructive pulmonary disease
monary function test values and the absence of evidence of
Asthma heart disease, help to confirm pulmonary disease as the chief
Restrictive lung disease cause of dyspnea. Radiologic evidence of specific cardiac or
Interstitial or diffuse alveolar lung disease pulmonary disease may provide cogent evidence for the
Disorders of chest wall and bellows function cause of dyspnea.
Kyphoscoliosis Evidence of acute infection should be sought because it
Arthritis
Neuromuscular disease
is frequently the cause of worsening symptoms in chronic
Obesity lung diseases. Redistribution of pulmonary blood flow to the
Vascular disease upper lung fields, usually a sign of increased pulmonary
Pulmonary embolism venous pressure and, hence, evidence of cardiac dyspnea,
Primary pulmonary hypertension must be interpreted cautiously in the face of chronic obstruc-
High altitude exposure tive lung disease, which may cause this radiologic change
Anemia without raised pulmonary venous pressure.
Anxiety (hyperventilation syndrome) Pulmonary emboli frequently cause dyspnea. The pres-
ence of conditions favoring venous thromboembolism or
hemoptysis, pleuritic chest pain, fever, tachycardia, and jaun-
dice from the history and physical examination, coupled
ventilation, the mechanism of the uncomfortable breathless- with evidence of acute right heart strain on examination and
ness of dyspnea is unclear. It is notable that some causes of electrocardiogram (ECG), and atelectasis or a pleural-based
marked hyperpnea, such as metabolic acidosis, do not cause parenchymal radiodensity with a rounded profile toward the
dyspnea. The same can be said of the hyperpneic phase of hilus (Hampton’s lump) on chest radiography, may provide
Cheyne-Stokes respiration. However, the examination can clues to pulmonary emboli, especially large ones. If emboli
point to some abnormalities that eventually lead to dyspnea. are small, however, there may be insufficient clinical clues
When left-sided congestive heart failure (CHF) and to establish the diagnosis, and helical (spiral) computed
obstruction to filling of the left side of the heart develop, as tomographic scanning of the pulmonary arteries and lungs
occurs with mitral stenosis and left atrial myxoma, pulmo- or perfusion and ventilation lung scintigraphy of the lungs
nary venous and pulmonary capillary pressures are chroni- may be necessary. Pulmonary arteriography may be required
cally elevated, causing interstitial and intraalveolar edema. rarely.
This interferes with normal pulmonary compliance and The characteristic features of disorders with an intracar-
reduces airway size and oxygen diffusion. Disorders associ- diac right-to-left shunt (e.g., pulmonary stenosis, pulmonary
ated with intracardiac right-to-left shunts are accompanied hypertension, and severe anemia) usually facilitate the estab-
by chronic systemic hypoxia. With uncomplicated right ven- lishment of the cause of dyspnea in patients with these
tricle (RV) outflow obstruction, there is hypoperfusion of the disturbances. Patients with psychogenic dyspnea tend to
pulmonary vasculature. In pulmonary disease, ventilatory demonstrate prominent sighing respiration with large and
impairment is present; this can be attributed to either an erratic title volumes. Other symptoms of hyperventilation
obstructive or a restrictive phenomenon. Pulmonary embo- and neurotic behavior may also be present.
lization is followed by a reduction in pulmonary flow in the Orthopnea is dyspnea in the recumbent posture. It is
affected segments, with consequent ventilation-perfusion usually due to LV failure or inflow obstruction. More of the
abnormalities. Bronchospasm may occur in the wake of a lung is below the level of the heart during recumbency, and
pulmonary embolus, probably mediated by the release of consequently pulmonary capillary pressure is further raised.
substances that lead to contraction of smooth muscle. The Patients can often approximately quantify its severity on the
dyspnea that may occur with pulmonary hypertension with basis of the number of pillows necessary to achieve relief.
a normal cardiac output is not well understood but may be Resumption of upright posture provides quick relief. Similar
related in part to reflex-stimulated hyperventilation. There symptoms may be encountered in patients with pulmonary
may be hypoxemia with severe anemia and at high altitudes, disease. The mechanisms involved are probably less efficient
especially during exertion. movement of the ventilatory apparatus and pooling of secre-
Cardiac and pulmonary disorders account for the vast tions in the recumbent position.
majority of cases of dyspnea. When either system is involved Paroxysmal nocturnal dyspnea occurs several hours after
in the absence of disease of the other, differentiation of the assumption of a recumbent position. It, too, is usually due
cause of dyspnea is usually not difficult. When both the heart to LV failure or inflow obstruction. Pulmonary venous pres-
 t h e h istory a n d ph ysica l e x a m i nat ion 21
sure is raised by the lowered position of the lungs relative to Angina Pectoris
the heart and by return of extravascular fluid to the intravas-
cular space. Typically, the patient wakes, sits upright, and Angina pectoris results from an imbalance between myo-
seeks fresh air. Pulmonary disease may cause a similar syn- cardial oxygen demand and oxygen delivery by coronary
drome, probably for the same reason that it may cause artery flow. It is most commonly due to a significant reduc-
orthopnea. tion in coronary blood flow. Coronary atherosclerosis is the
most common cause of this reduction. However, angina
may also be caused by disorders that increase myocardial
Chest Pain oxygen demand, such as aortic stenosis and hypertrophic
Pain from different sources may be expressed as chest dis- obstructive cardiomyopathy, or by disorders that both
comfort. Visceral pain is noted in the somatic area with increase myocardial oxygen demand and decrease coronary
which it shares a final common pathway. The demarcation artery flow, such as aortic regurgitation. The characteristic
of visceral pain, however, is less precise than that of somatic findings on physical examination and the ECG in patients
pain because of the distribution of visceral pain to several with aortic valvular and subvalvular disease usually make
adjacent spinal cord segments. Chest pain due to cardiac it easy to differentiate angina complicating these disorders
disease consequently must be differentiated from that due from angina caused by CAD. Angina is typically described
to disorders of other thoracic viscera and the upper as substernal squeezing, pressure, heaviness, burning,
abdomen. Some of the important causes of chest pain are aching, or a bursting sensation. The patient may describe it
listed in Table 2.2. graphically with a clenched fist over the midchest (Levine’s
sign). (Interestingly, patients often insist that the sensation
is a discomfort, not pain.) Radiation of the pain occurs
often, usually to the left shoulder, neck, jaw, and ulnar dis-
TABLE 2.2. Causes of chest pain
tribution of the left arm. Radiation to the same areas on the
Heart disease right side and to the epigastrium also occurs. Pain referral
Angina pectoris to the interscapular or left scapular regions occurs less
Atheromatous coronary artery disease
Nonatheromatous coronary artery disease commonly.
Aortic stenosis Typical stable angina is precipitated by exertion, emo-
Aortic insufficiency tional upsets, cold exposure, or eating and is usually relieved
Idiopathic hypertrophic subaortic stenosis (hypertrophic by rest or nitroglycerin within 5 minutes. It may be accom-
obstructive cardiomyopathy)
panied by dyspnea when myocardial ischemia is associated
Myocardial infarction
Congestive cardiomyopathy with LV dysfunction (diastolic, systolic, or both) or mitral
Pulmonary hypertension regurgitation. Stable angina is predictable in both its fre-
Mitral valve prolapse (click-murmur) syndrome quency and case of provocation. We find it useful to use the
Pericarditis Cedars-Sinai grading system to classify possible anginal dis-
Dissection of the aorta comfort into three categories—typical angina, atypical
Pulmonary disease angina, and nonanginal chest discomfort—based on a simple
Pulmonary embolism three-point system. The location and nature of the discom-
Pleuritis
Pneumothorax fort, its provocation by stressors, and its prompt relief with
Pneumonia rest and nitrates are each given one point. Typical angina
Tumor requires 3 points, atypical angina 2 points, and nonanginal
Collagen disease discomfort 0 or 1 point.
Atelectasis
Musculoskeletal disease
Arthritis
Costochondritis (Tietze’s syndrome)
Bursitis Unstable Angina Pectoris and Acute
Intravertebral disk disease Myocardial Infarction
Thoracic outlet syndrome
Muscle spasm Unstable angina refers to pain that occurs at night (nocturnal
Fracture angina), at rest (angina decubitus), with increasing frequency
Metastatic tumor or hematologic (leukemia) or plasma cell or duration, or with less predictable provocation and relief.
(myeloma) malignancy It may be accompanied by either a normal ECG or one with
Neural disease manifestations of ischemia. With acute myocardial infarc-
Intercostal neuritis
tion (MI), the discomfort is similar to that of angina but
Herpes zoster
occurs or continues at rest and is more intense and more
Gastrointestinal disorders (“referred” chest pain)
Hiatal hernia prolonged, often requiring opiate analgesics for relief. It is
Cholecystitis frequently associated with diaphoresis and nausea and vom-
Pancreatitis iting. It can be accompanied by dyspnea or by palpitations or
Ulcer disease syncope when LV failure or cardiac rate or rhythm dis-
Bowel disease
turbances complicate the MI. The ECG and biomarkers for
Neoplasm myocardial necrosis, along with the history, facilitate
Emotional duress or anxiety (e.g., neurocirculatory asthenia, differentiation of stable angina from unstable angina pecto-
DaCosta’s syndrome)
ris and MI.
22 chapter 2

The Chest Discomfort of Microvascular Angina Chest Pain of Noncardiac Origin

(Syndrome X)
Patients with pulmonary problems may present with chest
The discomfort of microvascular angina must be distin- pain. When pain is a manifestation of pneumonia, pleurisy,
guished from angina associated with flow-limiting epicardial pneumothorax, or pulmonary embolus, it is usually pleuritic.
coronary artery disease. This entity is more common in Gastrointestinal disorders, especially those of the esophagus,
women than men, especially premenopausal women, and is may be associated with referred pain to the chest. Although
often seen in patients who are younger than most patients the pain of inflammation, diffuse spasm, rupture of the
with flow-limiting epicardial coronary artery disease. This esophagus, peptic ulcer disease, pancreatitis, or cholecystitis
disorder is diagnosed when the patient has angina-like dis- may mimic angina, there are usually sufficiently specific
comfort, ST-segment depression with exercise testing, or complaints and atypical features for angina in a well-taken
other evidence of exercise-induced ischemia, but with normal history to point to a gastrointestinal origin. Proper labora-
coronary arteriograms and no documented propensity to epi- tory and radiologic examinations reveal the source of the
cardial coronary arterial spasm. In up to half of patients, the pain. It must be remembered that noncardiac disorders can
discomfort is similar to typical angina, but in the other half act as a trigger for angina in the patient with CAD, and the
there are distinctly atypical features, especially prolonged confirmation of noncardiac disease does not always elimi-
discomfort and limited relief by nitrates. The causes of this nate the possibility that the patient’s discomfort is angina.
disorder remain uncertain. Coronary arteriography is often A frequent cause of chest pain of noncardiac origin is
required to unambiguously distinguish this disorder from anxiety (DaCosta’s syndrome, neurocirculatory asthenia,
atheromatous coronary artery disease. soldier’s heart, cardiac neurosis). Although the pain may
mimic angina, it is typically fleeting and lancinating or a
prolonged aching pain; it usually occurs after rather than
Pericarditis during effort. It is commonly associated with evidence of the
hyperventilation syndrome. Unfortunately, the many prob-
Chest pain resulting from pericarditis is usually pleuroperi-
lems and fears that accompany chronic heart disease often
cardial and increases in severity with coughing; deep breath-
leave anxiety and a cardiac neurosis in their wake, so the
ing; sometimes with swallowing; and movement, especially
symptoms of cardiac disease and neurosis coexist and must
assumption of the supine position. A friction rub on exami-
be carefully ferreted out by the physician.
nation and the typical electrocardiographic, echocardio-
Occasionally, costochondritis (Tietze’s syndrome), the
graphic, and computed tomographic features usually serve to
thoracic outlet syndrome, intercostal nerve herpes zoster,
differentiate it from angina.
chest wall pain, and disorders of the thoracic and cervical
spine may cause chest discomfort that must be differentiated
Dissecting Aneurysm of the Thoracic Aorta from pain of cardiac origin; with herpes zoster infection and
chest wall pain, the severe pain may precede the develop-
Pain caused by a dissecting aneurysm of the thoracic aorta ment of the characteristic skin rash by several days.
may also mimic angina, but it is characteristically of a
tearing or ripping quality and is typically most severe in the
suprasternal notch, the neck, the back, or the lumbar region. Cough and Hemoptysis
It is often excruciatingly severe and requires narcotic anal-
Coughing is a voluntary or reflex act to clear the tracheo-
gesics for relief. Associated findings, such as pulse deficits,
bronchial tree of secretions or particulate matter. The stimu-
acute aortic regurgitation, a widened or disfigured aortic
lus for coughing is usually produced by mucosal irritation
profile on chest radiography, or new neurologic deficits,
from the larynx to second-order bronchi, which are respon-
should raise the index of suspicion for this disorder, espe-
sive to inflammatory, mechanical, chemical, and thermal
cially in the patient with systemic arterial hypertension.
stimuli. The nature of the cough is an important factor in
Computed tomography, with special protocols for this order,
identifying its cause and the cough should be defined as
transesophageal echocardiography (TEE), or magnetic reso-
productive or nonproductive, with characterization and
nance imaging (MRI) are usually necessary to establish the
quantification of the sputum.
diagnosis with certainty.
Cough may be an early manifestation of pulmonary
venous hypertension due to LV failure or pulmonary venous
obstruction, as in mitral stenosis. It may be overlooked as a
Other Cardiac Disorders
symptom of heart disease if respiratory infection precipitates
The chest pain that accompanies prolapse of the mitral valve cardiac decompensation. The cough of early heart failure is
(click-murmur syndrome), congestive cardiomyopathy, and nonproductive or productive of only small amounts of whitish
pulmonary hypertension may mimic angina closely, but a sputum. It most frequently is nocturnal, occurring soon after
carefully taken history usually reveals atypical features for the patient assumes the supine position, and may continue
angina. Physical, radiographic, echocardiographic, perfusion as a prominent symptom interfering with sleep. It is related
scintigraphic, and electrocardiographic examinations usually to bronchiolar edema and may be present without rales.
clarify the probable cause of the chest discomfort in these Patients with mitral stenosis may also experience bouts of
cases. Occasionally, however, only coronary arteriography coughing, which may be confused with chronic bronchitis.
will exclude the presence of significant coronary artery Blood streaking of the sputum may occur after a paroxysm
narrowing. of coughing related to pulmonary venous congestion. Cough
 t h e h istory a n d ph ysica l e x a m i nat ion 23
TABLE 2.3. Causes of hemoptysis hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
Cardiac syndrome), and several vasculitides (especially Wegener’s
Pulmonary venous hypertension granulomatosis, periarteritis nodosa, and systemic lupus ery-
Left ventricular failure thematosus). Fortunately, these problems are usually easily
Mitral stenosis differentiated from cardiac disease because of their charac-
Eisenmenger’s syndrome
teristic features.
Pulmonary
Infection
Pneumonitis Palpitations
Bronchitis
Bronchiectasis Palpitations are a subjective consciousness of the beating of
Abscess the heart (Table 2.4). Alterations in heart rate, rhythm, or
Tumor
Trauma or foreign body
force of contraction may be experienced as palpitation. This
sensation may be appreciated by the patient as a stopping,
Vascular
Rupture of atrioventricular fistula skipping, fluttering, jumping, pounding, or racing of the
Thoracic aortic aneurysm heart or as nervousness or uneasiness in the chest. With
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu tachyarrhythmia, the patient may be able to describe the
syndrome) manner of onset and the rate and regularity of heartbeat. It
Primary pulmonary hypertension is important to note associated symptoms related to the
Pulmonary embolism beating of the heart, particularly any change in the level of
Goodpasture’s syndrome consciousness. Palpitations may be related to the occurrence
Vasculitides of a cardiac arrhythmia but also can be experienced with no
Polyarteritis nodosa disturbance at all in rhythm or rate. Enhanced contractility
Systemic lupus erythematosus or a heightened awareness of autonomic function with
Wegener’s granulomatosis
anxiety may sensitize the individual to the heartbeat.
Bleeding diathesis Premature contractions of supraventricular or ventricu-
lar etiology may be experienced as an early beat, a pause or
skipped beat, or “flopping” or “thudding” related to the
intensely contractile beat after the premature beat.
may also be a manifestation of CHF in children with large Paroxysmal bouts of supraventricular tachyarrhythmias
left-to-right shunts. A chronic nonproductive cough similar are often appreciated as being abrupt in onset. They may be
to that noted in early LV failure is common in patients with irregular, as with atrial fibrillation, atrial flutter, or paroxys-
pulmonary fibrosis or infiltration and lesions that compress
the trachea and bronchi, such as lung tumors and aortic
aneurysms. Pulmonary infection produces a purulent, exu-
dative cough. In chronic obstructive pulmonary disease TABLE 2.4. Causes of palpitations
(COPD), the cough is productive, with purulence dependent Extrasystoles
on the presence and severity of acute and chronic bronchitis. Atrial premature beats
The sputum of patients with bronchiectasis is characteristi- Atrioventricular junctional (nodal) premature beats
cally mucopurulent, malodorous, and copious. Ventricular premature beats
Hemoptysis is a relatively rare manifestation of cardiac Tachyarrhythmias
disease. The important causes of hemoptysis are itemized in Supraventricular
Regular
Table 2.3. Occasionally, high pulmonary venous pressure Sinus tachycardia
resulting from chronic CHF or mitral stenosis may lead to Paroxysmal supraventricular tachycardia
the rupture of pulmonary capillaries and the production of Atrioventricular junctional tachycardia
blood-streaked sputum. Hemoptysis in mitral stenosis may Atrial flutter
Irregular
be small in amount and recurrent or quite brisk when related
Atrial fibrillation
to rupture of endobronchial bronchopulmonary venous vari- Paroxysmal supraventricular tachycardia or atrial flutter with
cosities. This is particularly likely when an abrupt increase varying atrioventricular block
in pulmonary venous pressure occurs with increased heart Multifocal atrial tachycardia
rate. Eisenmenger’s syndrome also is sometimes associated Ventricular tachycardia
with prominent hemoptysis; in these patients, hemoptysis Bradycardia
presumably results from rupture of pulmonary arterioles as Sinus bradycardia
a consequence of increased pulmonary artery pressure and Sinus arrest
Second- or third-degree atrioventricular block
resistance. Encroachment on the tracheobronchial tree by an
Conditions associated with increased force of cardiac
aortic aneurysm may lead to either a small amount of hemop-
contraction
tysis or fatal exsanguination. Thyrotoxicosis
Hemoptysis is usually due to disease in the lungs or Anemia
the pulmonary vasculature. It is a relatively common mani- Fever
festation of pulmonary infection, tumors, trauma, pulmo- Certain drugs, including catecholamines and cardiac
glycosides
nary embolism and infarction, and disorders affecting the
Anxiety states
pulmonary vasculature, such as Goodpasture’s syndrome,
24 chapter 2

mal supraventricular tachycardia with variable atrioventric- TABLE 2.5. Causes of syncope
ular (AV) block and multifocal atrial tachycardia, or regular, Cardiac
as with paroxysmal supraventricular tachycardia, or atrial Decreased cerebral perfusion due to cardiac dysrhythmia or
flutter with a consistent pattern of AV conduction. Cessation conduction defect
of these arrhythmias is likewise often abrupt. Ventricular Left ventricular outflow obstruction
Valvular aortic stenosis
tachycardia is as frequently manifested by its symptoms Supravalvular aortic stenosis
than as appreciation of palpitation. Other causes of palpita- Discrete subvalvular aortic stenosis
tions include hyperkinetic states (e.g., intense exertion, fever, Hypertrophic obstructive cardiomyopathy
thyrotoxicosis, hypoglycemia, anemia, AV fistula, and Tetralogy of Fallot
pheochromocytoma). Orthostatic hypotension
Drugs that may be associated with the production of Vasovagal (vasodepressor, psychogenic)
palpitations include amphetamines, ephedrine, aminophyl- Micturition syncope
line and other sympathomimetic agents, xanthine-contain- Cough syncope
ing beverages (coffee, tea, and cola), alcohol, tobacco, and Carotid sinus syncope
excessive digitalis glycosides or thyroid hormone. Hypokale- Glossopharyngeal neuralgia
mia, hypercalcemia, and hypoxia may produce palpitations
Metabolic
by inducing atrial or ventricular rhythm disturbances. Hypoglycemia
Anxiety states may be associated with palpitations because Hypoxia
of a heightened appreciation of cardiac function, emotional Hyperventilation
duress, hyperventilation, or tachycardia, usually sinus Central cerebral mechanisms
tachycardia. Cerebrovascular accident
In cases where determination of the cause of palpitations Transient ischemic attacks
Subclavian steal syndrome
is difficult, the history and physical examination and appro- Migraine
priate laboratory data can be greatly aided by dynamic ECG Vasculitis
(Holter) monitoring or event ECG monitoring with a careful Tumor
diary of the time and nature of symptoms. We find Holter Seizure disorder
monitoring to be helpful mostly in those cases where palpita- Somatization of symptoms
tions occur at least every day or two, and event monitoring
to be more helpful when palpitations are less frequent. Exer-
cise testing also may demonstrate the occurrence of arrhyth-
mia during an increased workload or immediately after its systemic arterial blood pressure and diminished cerebral
cessation. perfusion. Postexertional syncope occurs in hypertrophic
obstructive cardiomyopathy due to an abrupt worsening of
the muscular outflow obstruction that probably results from
Syncope
a rapid drop in LV filling and blood pressure in the face of a
Complete AV block is the most common cause of Stokes- sustained increased inotropic state that occurs with cessa-
Adams attacks, but markedly fast or slow heart rates of any tion of exercise. Sudden and severe valvular obstruction
cause may be responsible. Unduly rapid or slow supraven- occurring with left atrial myxoma or ball-valve thrombus or
tricular or ventricular dysrhythmias or second-degree AV with thrombosis or malfunction of a prosthetic valve may
block produces fainting as a consequence of the inability of also produce syncope. Tetralogy of Fallot is the most common
the heart to maintain normal cardiac output at these form of congenital heart disease associated with syncope.
extremes of heart rate. The patient’s ability to cope with Systemic vasodilatation with increased right-to-left shunting
cardiac dysrhythmia is influenced by the overall status of (probably associated with infundibular spasm) is likely the
the heart and the presence of other forms of disease (e.g., mechanism for fainting during “spells” in children with
cerebral vascular disease, anemia). Syncope may occur either tetralogy of Fallot. Primary pulmonary hypertension may be
at the onset of, during, or after the termination of the dys- associated with syncope.
rhythmia. Bradyarrhythmias and, occasionally, advanced AV The most common cause of fainting is neurocardiac
block are sometimes encountered with vasovagal episodes, syncope, which can be either cardioinhibitory (bradycardia,
but also may occur with fainting associated with carotid enhanced parasympathetic tone) or vasodepressor (hypoten-
sinus disease, traction on an esophageal diverticulum, medi- sion, decreased sympathetic tone) or both in cause. Fre-
astinal tumors, gallbladder disease, glossopharyngeal neural- quently, there is a history of triggers for syncope, such as
gia, pleural and pulmonary irritation, and rapid decompression noxious stimuli, venipuncture, heat exposure, emotional
of pericardium, pleural, and peritoneal spaces by needle or duress, or prolonged standing. Autonomic manifestations are
catheter aspiration of fluid (Table 2.5). often present, with pallor, perspiration, epigastric distress or
Other forms of heart disease also may be associated with nausea, pupillary dilatation, yawning and hyperventilation,
syncope. Effort syncope is one of the cardinal manifestations visual blurring, auditory diminution, weakness, or confu-
of hemodynamically significant aortic stenosis. Arteriolar sion preceding actual loss of consciousness.
vasodilatation during muscular work or as the result of acti- In some patients, stimulation of the carotid sinus (carotid
vation of high-pressure baroreceptors in the left heart, with sinus hypersensitivity) leads to a profound decrease in sys-
failure to increase cardiac output to balance this fall in temic arterial pressure or a marked slowing of heart rate or
peripheral vascular resistance, results in a reduction in both. Symptoms may be precipitated by relatively minor
 t h e h istory a n d ph ysica l e x a m i nat ion 25
stimuli, such as head motion or a tight collar. Fainting is Seizure disorders are not usually difficult to distinguish
often precipitous, without presyncopal manifestations. from syncope, with the exception of complex partial sei-
Orthostatic or postural hypotension with a significant zures. Assistance in differentiating this form of syncope
fall in systemic arterial blood pressure is a result of a failure from other varieties is provided by the presence of aura,
of adaptive reflexes or mechanical mechanisms to compen- seizure activity, the lack of blood pressure, heart rhythm or
sate in the upright posture. It may occur as a result of neuro- rate disturbance, and the postictal state. Dysrhythmias that
pathic disorders, such as diabetes mellitus, amyloidosis, tabes produce fainting may also produce convulsion. An electro-
dorsalis, and alcoholic neuropathy and in neurodegenerative encephalogram (EEG) can be helpful in establishing the
disorders, such as pure autonomic insufficiency (Bradbury- cause of syncope in some patients.
Eggleston syndrome), multiple system atrophy (Shy-Drager Conversion disorder may express itself as fainting spells;
syndrome), dementia with Lewy bodies, and Parkinson’s these episodes often occur under dramatic circumstances.
disease. In younger patients with otherwise unexplained There usually is no change in pulse rate, systemic arterial
orthostatic intolerance and hypotension and exaggerated blood pressure, or skin tone. The fainting can occur with
sinus tachycardia, the postural tachycardia syndrome (POTS) grace and without injury, most frequently in young women,
should be considered. Tilt-table testing is often required to often with a degree of detachment in the description of the
confirm the diagnosis. Other common causes of postural event (la belle indifférence).
hypotension include dehydration, physical deconditioning or Differential assistance with the problem of syncope is
debilitation, sympathectomy, or the administration of anti- provided by noting heart rate and rhythm, systemic arterial
hypertensive or antidepressant medications. blood pressure, and respiration, as well as skin color and neck
Cough syncope occurs usually in obese men with COPD veins, during syncopal attacks. The type of onset, precipitat-
and is rare in women or children. It is caused by interaction ing and alleviating factors, body position, and duration of
of a number of mechanisms that lead to decreased cardiac symptoms are also helpful in establishing etiology. Fainting
output and central effects; among these are a rise in intra- of cardiac etiology tends to produce pallor and cyanosis,
thoracic pressure with a fall in venous return, a marked jugular venous distention, and shortness of breath. Some
increase in cerebrospinal fluid pressure and compression of abnormality of heart rate or rhythm is common. When periph-
intracranial vascular beds, a concussive effect produced by eral mechanisms reduce cerebral flow, pallor is prominent
the sudden rise in intracranial cerebrospinal fluid pressure, but not usually accompanied by cyanosis or dyspnea, and
an increase in cerebral vascular resistance induced by the jugular venous pressure is not elevated. Disturbance of
hypocapnia of coughing, and increased vagal tone. primary cerebral flow often produces florid features and slow,
Micturition syncope is a sudden loss of consciousness stridorous respiration. Syncope related to Stokes-Adams
after nocturnal voiding. It is probably caused by Valsalva attacks is abrupt and is not posturally related. Fainting with
maneuver–mediated reflex vagal tone and a fall in peripheral dysrhythmias most frequently occurs in a sitting or standing
vascular resistance enhanced by the abrupt drop in intraab- position. Although these characteristics of history and physi-
dominal volume. It most commonly occurs after substantial cal examination are helpful, dysrhythmias and transient
alcohol consumption. heart block can at times be elusive to document. Dynamic
Glossopharyngeal neuralgia may cause reflex stimula- electrocardiographic (Holter) monitoring, event electrocar-
tion of the vagus and result in fainting. Profound bradycardia diographic monitoring and exercise stress testing may uncover
is often associated with the disorder. In addition, there is these abnormalities when they are not present at rest.
often pain localized to the base of the tongue, pharynx, or
larynx; tonsillar area; and ear; followed by syncope. Pressure
Cardiac Enlargement
in sensitive areas may also produce fainting.
Metabolic derangements that lead to hypoxia or hypogly- The most common cause of cardiac enlargement is CHF
cemia may cause fainting. Disturbances of the vascular (Table 2.6). The heart enlarges as a compensatory mechanism
supply within or leading to the cranial vault may produce in the face of volume or pressure overload. Cardiac muscle
syncope and certainly enhance the ability of other causes may hypertrophy and undergo dilatation as contractile
to produce a fainting spell. Vertebrobasilar transient isch-
emic attacks are a common cause of this form of syncope.
Movement of the head into certain positions may cause TABLE 2.6. Causes of Cardiac Enlargement
obstruction of vertebral flow, particularly in certain spinal
disorders. The subclavian steal syndrome is caused by major Congestive heart failure
Valvular heart disease
occlusion of the proximal subclavian artery with shunting Volume or pressure overload (e.g., left-to-right shunts, systemic
of blood via the vertebral artery to the distal subclavian arterial hypertension)
vessel during exercise as a result of vasodilatation and Heart muscle disease (ischemia or cardiomyopathy)
reduced resistance in the arterial vascular bed with exercise High-output failure
Ventricular aneurysm
of the affected arm. A vascular bruit may be heard in the
supraclavicular area, and there is reduced blood pressure on Large stroke volume
Athlete’s heart
the affected side. Aortic arch syndrome (Takayasu’s arteritis, Complete heart block
Oriental pulseless disease) with involvement of the carotid
Pericardial effusion
vertebral system is frequently associated with blackout
Cardiac cysts and tumors
spells. Occasionally, cerebral vasospasm with migraine
Absence of the pericardium
causes fainting.
26 chapter 2

efficiency and ability to do work decline. Valvular heart TABLE 2.7. Causes of murmurs
disease, pressure overload of the systemic or pulmonary Valvular heart disease
circuit, and significant shunting of cardiac output are poten- Stenosis
tial causes of cardiomegaly. Disease of the heart muscle itself Insufficiency of congenital or acquired etiology
due to ischemia or cardiomyopathy may also cause cardiac Nonvalvular outflow obstruction
enlargement—either specific chamber enlargement or the Supravalvular and subvalvular outflow obstruction
Hypertrophic obstructive cardiomyopathy
heart may be generally enlarged. Congestive cardiomyopathy
often produces four-chamber enlargement. High-output Shunts (extracardiac and intracardiac)
states with heart failure due to beriberi heart disease, AV Complex congenital heart disease producing turbulence
fistula, anemia, and thyrotoxicosis may produce cardiac dila- Physiologic murmurs
tation. Long-standing complete heart block with relatively Hyperdynamic states
Anemia
large stroke volume is occasionally associated with enlarge- Fever
ment of the heart without other evidence of heart disease. Thyrotoxicosis
The heart of the normal, well-conditioned athlete may also Pregnancy
enlarge. This normal compensatory dilatation and hypertro- Atrioventricular fistula
Excitement
phy is associated with a large stroke volume and a relatively
Flow across normal valves in high-volume states
slow heart rate. The pericardium may be partly or completely Diastolic rumble in mitral and tricuspid regurgitation, atrial
absent on a congenital basis, which allows some expansion and ventricular septal defect, patent ductus arteriosus
of the heart and may be mistaken for heart disease. Complete heart block
Pericardial effusion with apparent enlargement of the Austin Flint murmur of aortic regurgitation
Innocent murmurs of childhood
heart must be distinguished from cardiomegaly resulting
Anatomic distortion producing turbulence
from CHF. Evidence of significant valvular disease, hyper-
Straight back syndrome
tension, congenital heart disease, or cardiomyopathy is Pectus excavatum
usually absent. A history of pericarditis or of factors predis- Chest deformity
posing to pericarditis may be present. There is no definite High- to low-pressure communication
specific chamber enlargement on chest radiography with Ruptured sinus of Valsalva aneurysm
pericardial effusions; globular cardiac enlargement (“water- Coronary fistula
Anomalous origin of left coronary artery from
bottle heart”) occurs instead. The enlarged globular appear-
pulmonary artery
ance of pericardial effusion most frequently must be Atrioventricular fistula
differentiated radiographically from the cardiac enlargement Arteriopulmonary connection
associated with primary myocardial disease. With pericar- Dilatation or stenosis of large or small vessels
dial effusion, heart sounds are often distant, and a pericardial Aneurysm or dilatation of aorta or pulmonary artery
friction rub may be present. The echocardiogram, radionu- Coarctation
Peripheral pulmonary stenosis
clide ventriculogram, or computed tomography of the chest
Atherosclerotic vascular narrowing
are diagnostic of pericardial effusion when the effusion is Pulmonary embolism
large enough to allow its detection. In patients with primary Alteration of arterial or venous flow in nonconstricted vessels
myocardial disease, the heart sounds are usually of normal Venous hum
intensity, and prominent third and fourth heart sounds (S3 Mammary souffle
and S4 gallops) and murmurs of tricuspid or mitral regurgita- High brachiocephalic flow in children
High flow in collateral vessels
tion, or both, are often present.
Intercostal or bronchial collaterals in coarctation of aorta,
Pericardial cysts most frequently produce a rounded or pulmonic stenosis, or atresia
lobulated radiographic appearance and usually occur at the Aortic regurgitation
right cardiophrenic angle. Sometimes they are confused with Sounds resembling murmurs
cardiomegaly or ventricular aneurysm. They are not usually Fusion of S3 and S4 gallops
associated with symptoms. Tumors invading the pericar- Prolonged gallop sounds
Pericardial and pleural friction rubs
dium are usually metastatic, but primary tumors occur
rarely and may produce pericardial effusion.
Ventricular aneurysm may produce an abnormal bulge
in the cardiac contour, especially along the anterolateral LV
wall. Persistent ST-segment elevation on the ECG occurs in be physiologic, occurring without anatomic abnormalities,
about 25% of these patients. Ventricular aneurysms may be or may be observed in hyperdynamic circulatory states, as
associated with intractable CHF, recurrent ventricular dys- in anemia, fever, and thyrotoxicosis. Murmurs may be inno-
rhythmias, and systemic embolic disease. cent (i.e., occurring without any significant anatomic or
functional abnormality); these are most common in children
and young adults. Murmurs must be distinguished from tur-
Murmurs
bulent flow in veins (venous hum), increased flow during
The generation of a murmur is caused by turbulence of blood pregnancy (mammary souffle), bruits with AV fistulas or
flow within the heart or blood vessels. Murmurs occur due dilated intercostal arterial vessels, or friction rubs. Murmurs
to the disruption of smooth laminar flow and production of should be characterized in terms of their timing, quality,
eddies that generate vibrations. The presence of a murmur pitch and intensity, and point of maximal intensity and radi-
may reflect organic heart disease (Table 2.7). Murmurs may ation and of the effect of various physiologic or pharmaco-
 t h e h istory a n d ph ysica l e x a m i nat ion 27
logic maneuvers on their intensity. Grade 1 murmurs are Edema
faint and can be appreciated only with careful auscultation;
grade 2 murmurs are relatively soft but readily audible; grade Peripheral edema is a relatively late finding in the natural
3 murmurs are prominent and loud; grade 4 murmurs may history of CHF. Right ventricle failure causes edema forma-
be associated with a thrill and are very loud; grade 5 are tion by elevation of systemic venous pressure. Left ventricle
extremely loud murmurs; and grade 6 murmurs can be heard decompensation results in fluid and salt retention, producing
with the stethoscope held above the chest wall or even edema as a result of reduced effective renal perfusion and the
without a stethoscope. consequently increased renin production and subsequent
Murmurs are classified on the basis of their duration or aldosterone secretion. Congestive heart failure is also associ-
timing as being systolic, diastolic, or continuous. Specific ated with excessive secretion of antidiuretic hormone, which
murmurs resulting from heart disease are discussed in other leads to water retention. Furthermore, chronic LV failure
chapters in this book. may lead to RV failure in the wake of chronic pulmonary
venous and arterial hypertension. The resulting increased
ventricular volumes that follow salt and water retention help
Gallops to maintain cardiac output through the Frank-Starling
Cardiac gallops are low-frequency vibrations that are best mechanism but at the cost of an increase in the ventricular
heard with light pressure with the bell of the stethoscope. end-diastolic pressures and myocardial oxygen demand.
Third heart sounds generally occur between 0.12 and 0.24 Peripheral edema formation should lead the physician to
second after the aortic component of the second heart sound. search for other evidence of LV or RV disease, or both. When
Clinically, the third heart sound (S3 gallop) may be a physio- these are not present, other etiologic factors must be sought.
logic sound in children and young adults. It may be produced Constrictive pericarditis may be manifested by edema, and
by factors that generate increased rate or volume of flow with many patients have been followed mistakenly with the diag-
high cardiac output or by conditions associated with cardiac nosis of right-sided heart failure of uncertain cause or cryp-
dilatation and altered ventricular compliance, as in CHF. togenic hepatic cirrhosis. Kussmaul’s sign, pulsus paradoxus,
Fourth heart sounds (S4 gallop) follow the P wave and precede a pericardial friction rub or knock, pericardial calcification,
the QRS complex. They occur with atrial contraction. and a relatively small heart for the degree of edema point to
Increased amplitude and audibility of these low-frequency the correct etiology.
vibrations are usually associated with increased ventricular In adults, edema formation occurs in dependent areas
stiffness (decreased compliance) from pressure or volume of the body. Some noncardiac diseases may lead to edema
overload or with acute mitral regurgitation, systemic arterial formation with a similar distribution; notable among these
hypertension, cardiomyopathy, or CAD. Audible fourth heart are chronic renal disease, profound hypoalbuminemia,
sounds may also be present during increased ventricular Cushing’s disease, and premenstrual edema.
filling with normal compliance, as in high-output states and Local obstruction of venous or lymphatic drainage usually
with first-degree heart block. Right-sided gallops are aug- causes asymmetric edema collection. In hepatic cirrhosis,
mented by inspiration. During periods of rapid heart rate, ascites is usually large in volume relative to peripheral edema,
third and fourth heart sounds may be superimposed to form except in the case of “cardiac” cirrhosis, in which peripheral
a louder single “summation” gallop. Other diastolic sounds edema may have been prominent before the onset of ascites.
to be differentiated from S3 and S4 gallops are the opening Facial edema may occur with CHF, but it is more com-
snap of the mitral valve, the pericardial knock of constrictive monly caused by trichinosis, renal disease, and superior vena
pericarditis, and the “tumor plop” of atrial myxoma. The caval syndrome. It may also follow severe respiratory effort
opening snap of the mitral (or tricuspid) valve occurs earlier provoked by asthma or an upper respiratory obstruction.
than the S3 gallop (0.02 to 0.12 second after the onset of the
aortic component of the second heart sound). The sound is
Rales
usually a high-pitched, brief, sharp event heard well with the
diaphragm of the stethoscope, and the sound radiates widely Elevation of pulmonary capillary pressure to a level above
over the left precordium. The tumor plop of atrial myxoma the plasma oncotic pressure may be accompanied by transu-
is an early diastolic sound of relatively low frequency that dation of fluid into the alveolar spaces, producing moist rales.
may be confused with an opening snap or third heart sound. Left ventricle failure and mitral stenosis are the most
Usually, it is of lower frequency and occurs later than most common cardiac causes. Pulmonary edema is characterized
mitral valve opening snaps and slightly earlier than a S3 by excessive transudation of fluid and moist, bubbling inspi-
gallop. The pericardial knock of constrictive pericarditis is ratory rales throughout the lung fields, whereas lesser degrees
ordinarily higher pitched, occurs earlier, and is louder than of decompensation are characterized by more localized phys-
the S3 gallop. Artificial pacemakers may also produce dia- ical findings with greater involvement of the lung bases.
stolic sounds that are extracardiac in origin. A sharp, high- Noncardiac causes of pulmonary edema include especially
frequency clicking or snapping sound may occur 0.08 to 0.12 the adult respiratory distress syndrome, but also pulmonary
second before the first heart sound and may be related to embolism, exposure to high altitudes, salicylate intoxica-
pacemaker-induced intercostal muscle contraction. In some tion, overdose of narcotic analgesics, neurogenic pulmonary
instances, this sound signifies penetration of the electrode edema, and reexpansion of a lung after pneumothorax.
tip into or through the myocardium, but it also may be Many other disorders produce similar sounds. Atelectasis
audible in normally positioned and normally functioning is characterized by fine, dry, crackling rales at the lung bases,
pacemakers. which clear with deep breathing or coughing. Pulmonary
28 chapter 2

infection with an inflammatory infiltrate produces evidence drainage from the abdomen passes through the diaphragm;
of consolidation in addition to rales. In COPD, somewhat therefore, direct communication may be present from
coarser rales are typical and are usually accompanied by abdominal to pleural spaces. Pancreatitis is occasionally
rhonchi, decreased breath sounds, wheezes, and prolongation associated with a left pleural effusion that has an increased
of expiration. Pulmonary fibrosis is accompanied by distinc- amylase concentration. Hypoalbuminemia resulting from
tive dry, fine-to-medium inspiratory rales. cirrhosis, the nephrotic syndrome, or other etiology may be
associated with right-sided or bilateral pleural effusions.
Tumors (primary or metastatic) to the lung or pleura are fre-
Pleural Effusion
quently associated with pleural effusions, often bloody and
The surfaces of the visceral and parietal pleurae are normally high in protein content and lactate dehydrogenase concentra-
separated by a thin layer of fluid generated by the visceral tion. Hypothyroidism may produce large pleural (and peri-
pleura. A number of factors may alter the balance between cardial) effusions that have low protein content.
production and normal absorption of this fluid (Table 2.8). Pulmonary infarction often produces a bloody pleural
The visceral pleura is drained by the pulmonary veins and effusion, although a nonsanguineous effusion is also compat-
lymphatics, and the parietal pleura is drained by systemic ible with the diagnosis. Collagen vascular or connective
veins and lymphatics. Transudation of fluid into the pleural tissue disease, especially systemic lupus erythematosus,
space may occur with marked elevation in pressure in either may be accompanied by pleural effusion; the pleural effusion
the systemic or the pulmonary venous beds because pleural that occurs in some patients with rheumatoid arthritis typi-
drainage depends on both, but it occurs more frequently cally has low glucose content. The postpericardiotomy and
with elevation of both pressures. Therefore, although pleural post-MI (Dressler) syndromes are often associated with
effusion may occur with LV or RV failure alone, it is more pleural effusions. Disruption of the thoracic duct by trauma
frequent with combined LV and RV decompensation. Failure- or tumor produces a chylous effusion; bleeding from thoracic
induced effusions are commonly bilateral. Unilateral pleural vascular structures may produce hemothorax or bloody
effusions caused by CHF are usually right-sided. pleural effusion.
Pleural effusion related to CHF is usually accompanied Acute effusions and CHF-associated pleural effusions are
by other signs and symptoms of cardiac decompensation. generally transudates. Long-standing pleural effusions often
Factors that compromise lymphatic clearance may also result have increased amounts of protein, regardless of the cause.
in pleural effusion. Inflammatory involvement of the pleura Effusions with high specific gravity and increased protein
or adjacent pleural structures is a common cause of pleural content are characteristic of tumor and inflammation. The
effusion. In addition to an outpouring of fluid due to the number and type of cells present in a pleural effusion can
inflammatory process, the lymphatic drainage may be com- provide helpful information, as can measurements of lactate
promised or obstructed by inflammation. dehydrogenase and glucose.
Bacterial, mycobacterial, and, occasionally, fungal and
viral pulmonary and pleural infections produce pleural effu-
Cyanosis
sions, as may abdominal inflammatory processes. Lymphatic
Desaturation of hemoglobin imparts a bluish coloration to
the skin that is best appreciated in the mucous membranes,
TABLE 2.8. Causes of pleural effusions nail beds, conjunctiva, and earlobes. Cyanosis is recognized
Congestive heart failure when 5 g/dL of unoxygenated hemoglobin is present, and
Left and right heart failure (if unilateral, usually right-sided arterial saturation has fallen to 75% to 85%. Because recog-
effusion) nition of cyanosis depends on the absolute quantity of reduced
Pulmonary venous hypertension with right heart failure hemoglobin present per 100 mL of blood, recognition of cya-
Inflammation of pleura and/or lung nosis in severely anemic patients can be difficult. Occasion-
Infection ally, particularly with polycythemia, it can be recognized at
Collagen disease with pulmonary involvement somewhat higher levels of arterial saturation.
Systemic lupus erythematosus Cyanosis is divided into central and peripheral types
Rheumatoid arthritis (Table 2.9). Central cyanosis occurs with arterial desatura-
Autoimmune phenomena after heart injury tion because of inadequate oxygenation of hemoglobin due
Postpericardiotomy syndrome
to pulmonary dysfunction with ventilation-perfusion, oxygen
Postmyocardial infarction syndrome (Dressler’s syndrome)
diffusion, or ventilatory abnormalities; right-to-left shunting
Tumor
Primary of desaturated venous blood into the systemic arterial circuit;
Metastatic ambient atmospheric hypoxia; or an abnormality of hemo-
Pulmonary embolus with pulmonary infarction globin itself and its ability to transport oxygen. Central cya-
Abdominal ascites nosis is seen primarily in the nail beds, face, lips, and tongue.
Patients with cyanotic congenital heart disease usually have
Subdiaphragmatic inflammatory processes
Pancreatitis a right-to-left shunt as a consequence of markedly increased
Hypothyroidism pulmonary vascular resistance, RV outflow obstruction, or
transposition of the great vessels. The most common form
Trauma
of congenital cyanotic heart disease is tetralogy of Fallot.
Disruption of or damage to the thoracic duct
Central cyanosis may occur in association with venoarterial
Hypoalbuminemia
shunting of poorly oxygenated venous blood in patients with
 t h e h istory a n d ph ysica l e x a m i nat ion 29
TABLE 2.9. Causes of cyanosis the fingers or toes (widening of the normal angle of entrance
Peripheral cyanosis of the nail into the digit to 180 degrees or more) through
Decreased blood flow or vasoconstricted states edema, increased vascularization, and fibrous tissue over-
Reduced cardiac output growth in the subungual area. There is bulbous enlargement
Shock of the tips of the digits and sponginess of the proximal nail
Congestive heart failure
Cold exposure
bed. Clubbing can be familial or acquired, associated with
Peripheral arterial and/or venous disease an underlying disorder, especially of the heart, lungs, liver,
Central cyanosis or alimentary tract. Familial clubbing can occur in other-
Arterial unsaturation due to impaired gas exchange in lungs wise healthy individuals. Clubbing has been reported to
Hypoxia due to general hypoventilation with increased PCO2 occur in association with certain occupations, such as jack-
and decreased PaO2 hammer operation. The pathogenesis of clubbing is not clear.
Regional hypoventilation with respect to perfusion
Perfusion of unventilated regions of lung
Characteristically, it is associated with systemic arterial
Impaired diffusion oxygen and desaturation and therefore is most commonly
Low inspired oxygen tension seen in patients with cyanotic congenital heart disease or
Right-to-left shunts advanced pulmonary disease. It rarely occurs with central
Intracardiac cyanosis due to abnormal hemoglobin and does not occur
Extracardiac with peripheral cyanosis. Asymmetric clubbing may be
Hemoglobinopathy found in patients with shunts with unequal distribution of
False cyanosis unsaturated blood, as in reversed shunting from patent
Argyria ductus arteriosus. Clubbing without cyanosis is found in
bacterial endocarditis, in chronic suppurative pulmonary
diseases, and with intrathoracic disorders, especially lung
cancer. Clubbing has also been associated with arteriovenous
atrial and ventricular septal defects and patent ductus arte- shunts, cirrhosis of the liver, and ulcerative colitis.
riosus when severe pulmonary hypertension causes reversal
of the shunting of blood, formerly from left to right, to right
to left. Differential cyanosis of hands and feet can be expected Physical Examination of the Patient with
when venous and arterial mixing occurs after blood leaves Heart Disease
the heart and pulmonary circuit. Toes, for example, are more
cyanotic than fingers in a patent ductus arteriosus with The examination of the patient with heart disease is
right-to-left shunt; fingers may be more cyanotic than toes approached in much the same way as a detective approaches
with transposition of the great vessels and a reversed shunt a criminal problem. Rather than a single sign or symptom
from a patent ductus arteriosus. Cyanosis caused by intra- that provides the exact diagnosis, it is usually a combination
cardiac shunt lesions persists with oxygen administration, of symptoms and physical signs or the absence of such that
whereas that due to pulmonary etiology is often corrected. enables the examiner to suspect or recognize the presence of
Abnormal hemoglobins may produce cyanosis. Clubbing a particular abnormality. The examination is most efficient
often is found in association with long-standing central, but if the physician approaches the patient in a logical pattern,
not peripheral, cyanosis. Central cyanosis due to hemoglobin directing full attention to the solution of the problem at
abnormalities is not usually associated with clubbing. hand. One systematic pattern in which a patient may be
Peripheral cyanosis unrelated to desaturation of central examined is as follows:
arterial blood may be observed in peripheral vascular beds in
states of low flow or vasoconstriction, for example, cardio- 1. Inspection of the patient
genic shock or severe CHF or with exposure to cold or in the 2. Measurement of systemic blood pressure, pulse rate, and
presence of peripheral venous or arterial disease. It may pulse regularity
occur in vasomotor abnormalities, such as Raynaud’s disease. 3. Examination of the carotid and peripheral arteries
It is seen in areas where venous stasis is common, such as 4. Examination of the jugular venous pulse
the ear lobes and lower extremities. It is due to extensive 5. Palpation and inspection of the precordium
local desaturation of hemoglobin in peripheral extremities. 6. Auscultation of the heart and lungs
The bluish skin color in argyria is sometimes mistaken
for cyanosis. It is caused by silver deposition in skin and can
Inspection
be distinguished from cyanosis by the lack of involvement
of mucosal membranes and failure of the skin to blanch with Inspection of the patient should include a careful, yet rela-
pressure. Patients with polycythemia may also exhibit true tively rapid, appraisal of the patient from head to foot. The
cyanosis with lesser degrees of arterial desaturation because examiner is specifically interested in the general appearance
of stagnation and sludging of blood flow in peripheral areas of the patient. Does he or she look ill? Is the patient dyspneic?
due to increased blood viscosity. Although general impressions can be erroneous, they are
often helpful in corroborating the patient’s previously elic-
ited symptoms. In selected instances, one may be interested
Clubbing
in continuing the inspection by asking the patient to perform
Clubbing of the fingers and toes has been defined as loss of such tasks as walking a certain distance or climbing a flight
the normal angle between the cuticle and the distal end of or two of stairs in the company of the examiner.
30 chapter 2

The initial inspection of the patient should assess the In summary, a general inspection of the patient at rest,
general body configuration. Is the patient abnormally tall or and, where applicable, with stress is of immense importance.
short? Is he or she obese? Does the appearance suggest the Accuracy in diagnosing the etiology of the abnormality in
possibility of Marfan’s syndrome? Are the color, pigmenta- a patient with cardiac disease depends largely on having
tion, and texture of the skin normal? Hemochromatosis can thought of the appropriate possibilities on the basis of valu-
be recognized by the characteristic pigmentation, and sclero- able clues obtained by a careful and thorough general inspec-
derma can be recognized by the thickening of the skin over tion of the patient.
the hands and fingers and around the mouth and eyes. The
eyelids may be violaceous in dermatomyositis, and there
Blood Pressure Measurement
may be a scaly erythematous eruption over the joints of the
fingers. Episodic flushing of the skin is a hallmark of the The current method of measuring blood pressure depends on
carcinoid syndrome, which can cause tricuspid regurgitation auscultatory detection of the Korotkoff sounds over a periph-
and pulmonic stenosis. Systolic pulsation in the eyeballs or eral artery (usually the brachial artery or the popliteal artery)
ear lobes is sometimes seen in severe tricuspid insufficiency. at a point distal to the cuff compression of the vessel. The
Xanthelasma, xanthomata, or both may be manifestations of apparatus for measuring blood pressure consists of a com-
hyperlipidemia and are seen in some patients with athero- pression bladder within a cloth cuff, a valve that allows
sclerotic vascular disease. reduction of pressure in the cuff, and a manometer that mea-
The presence or absence of a straight back, as well as the sures pressure in the cuff. The bladder and the cuff should
sternal deformities, such as pectus excavatum, should be be wide enough to encompass at least half of the forearm (or
noted because sternal or spine deformities may distort or thigh) and the length of the bladder should be at least three
displace the heart and lead to erroneous signs of cardiac quarters of the circumference of the forearm (or thigh) to
enlargement. Telangiectases of the lips, tongue, buccal which it is applied. Many cuffs are marked to indicate if the
mucosa, and fingertips are seen in patients with hereditary length of the bladder is correct relative to the circumference
hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). of the extremity. If the cuff is too small for the extremity
Fine linear hemorrhages (splinter hemorrhages) under the being examined, false elevations in the blood pressure record-
fingernails may be the result of trauma in normal individu- ing will result. The cuff must be at mid-chest level during
als but may also be a manifestation of bacterial endocarditis. the determination of blood pressure. For each 1.2 cm devia-
Conjunctival petechiae also are present in some patients tion from mid-chest level, the arterial pressure will be arti-
with bacterial endocarditis, but they may be seen in a high factually raised or lowered 1 mm of Hg. Measurement of
percentage of patients immediately after open-heart surgery. blood pressure should be made with the patient in a basal
In the latter situation, such petechiae usually are not a mani- state and as relaxed and comfortable as possible. The cuff is
festation of endocarditis. fully deflated and then applied snugly. Before auscultation
In female patients, a broad chest with widely spaced the cuff pressure that is necessary to obliterate the distal
nipples and hypoplastic breast tissue in association with a arterial pulse is determined. The stethoscope is then posi-
webbed neck suggests Turner’s syndrome; defects of the tioned gently but firmly directly over the artery (either the
atrial and ventricular septa and coarctation are the usual brachial or popliteal) and the cuff is inflated to a level in
cardiovascular abnormalities seen in these patients. Down excess of that required to obliterate the distal pulse. While
syndrome is recognized by the simian crease in the palms listening carefully as the cuff is deflated, the examiner deter-
and by other typical physical features. Atrial septal defects, mines the systolic blood pressure, the point at which the first
ventricular septal defects, AV canal defects, and patent tapping sound occurs for several consecutive beats. The dia-
ductus arteriosus are cardiac abnormalities commonly asso- stolic pressure is that point at which definite muffling of the
ciated with this syndrome. sounds occurs. One should also note and record the point at
Cyanosis, as discussed above, when central, may be a clue which the sounds totally disappear if it is different from the
to the presence of congenital heart disease or pulmonary pressure level at which they become muffled. Blood pressure
dysfunction. Peripheral cyanosis may be indicative of a low- is usually measured with the patient in the seated position
flow state, CHF, vasoconstriction, or peripheral arterial or with the arm supported at mid-chest level. Blood pressure
venous disease. measurements should also be made in both arms. Differ-
Clubbing, as discussed above, may be a clue to the pres- ences in systolic blood pressures between the two arms can
ence of cyanosis related to congenital heart disease or infec- be a valuable clue in diagnosing disorders, such as athero-
tious endocarditis, as well as to the presence of advanced sclerotic vascular disease involving the arterial supply of one
lung disease or lung cancer. of the upper extremities; dissecting aortic aneurysm involv-
Abnormalities of the extremities may be a clue to the ing the blood supply to one of the arms, coarctation of the
presence of heart disease in some patients. The Holt-Oram aorta involving the origin of the left subclavian artery, or
syndrome is characterized by a thumb resembling a finger supravalvular aortic stenosis. Blood pressure measurements
(being hypoplastic and in the same plane as the remainder of should also be made in the supine and upright positions in
the fingers), short forearms, and a forward thrust of the selected patients, especially the elderly or in those patients
shoulders. Atrial septal defects are seen in some patients in whom orthostatic hypotension is suspected. Normally
with this disorder. Flushing of the nail beds with each heart- systolic blood pressure in the supine position is a few mm
beat (Quincke pulse) is a sign of a hyperkinetic circulation Hg higher than in the seated position and diastolic blood
and is commonly seen in patients with severe aortic regur- pressure is a few mm Hg lower than in the seated position.
gitation. Anemia may be recognized by noting the pale color Blood pressure measurements should be made routinely
of the nail beds, the conjunctivae, or both. in the legs of patients with hypertension, suspected coarcta-
 t h e h istory a n d ph ysica l e x a m i nat ion 31
tion of the aorta, aortic dissection, or peripheral vascular TABLE 2.11. Causes of orthostatic hypotension
disease. In the adult, systolic blood pressure is usually 10 to Idiopathic
15 mm Hg higher in the legs compared with that in the arms. Hyponatremia
When there are marked pressure differences between the
Hypovolemia
arms and legs, artifactual differences should also be excluded
Drugs (e.g., tranquilizers, antihypertensive agents)
(e.g., those produced by improper cuff size). A significantly
higher systolic blood pressure in the legs than in the arms is Central nervous system disease (e.g., syringomyelia, tabes
dorsalis)
often found in patients with severe aortic regurgitation (Hill’s
Addison’s disease
sign). Lower systolic blood pressures are found in the legs of
patients with coarctation of the aorta and severe aortoiliac Pheochromocytoma
disease. Wernicke’s syndrome
Normal blood pressure for adults younger than 50 years Amyloidosis
old is considered to be below 120 mm Hg systolic and below Diabetes mellitus
80 mm Hg diastolic. In any individual patient, however, tran- Primary autonomic insufficiency
sient fluctuations above or below these normal values, espe- After sympathectomy
cially in the systolic blood pressure, are a common occurrence Physical deconditioning
and probably reflect changes in physiologic state. For example,
systolic blood pressure rises with fever, anxiety, sudden
fright, and exercise. However, with sedation and during sleep,
both systolic and diastolic blood pressures tend to fall. Alter- and 100 beats/min, although this is subject to the same physi-
ations in pulse pressure (the difference between systolic and ologic influences as for systemic blood pressure. Sinus tachy-
diastolic pressures) may or may not be associated with cardia is diagnosed with a regular sinus rate of more than 100
cardiac disease (Table 2.10). beats/min, whereas sinus bradycardia refers to a regular sinus
In some patients, systolic blood pressure may fall dra- rate of less than 60 beats/min. It may be the result of a slow
matically in the erect position, resulting in syncope. Such sinus, an AV junction, or a ventricular pacemaker. Atrial
postural hypotension not uncommonly occurs even in a fibrillation is a chaotic atrial rhythm recognized on physical
normal person initially arising from bed after a prolonged examination by finding an abnormally irregular radial pulse.
illness. In this instance, postural hypotension and syncope Occasional transient irregularity of the radial pulse may
result from pooling of blood in the vessels in the lower result from either atrial or ventricular premature beats. In
extremities. At present, the most common cause of postural this situation, the pause that follows the premature or early
hypotension is in the use of antihypertensive agents. Addi- beat is short in the case of atrial extrasystoles and relatively
tional causes of postural hypotension are listed in Table long after ventricular extrasystoles. A bigeminal pulse is
2.11. made up of coupled beats with regular alteration of the height
of the pressure pulses. This occurs as the result of premature
atrial or, more commonly, premature ventricular contrac-
Regularity and Configuration of Pulses
tions. The height of the radial pulse varies because of the
Pulse rate and regularity are determined by palpating the increased diastolic filling period after the premature ven-
radial artery. The normal adult heart rate varies between 60 tricular beat, so the subsequent stroke output is greater than
that associated with the ventricular extrasystole.
Pulsus paradoxus (Fig. 2.1) is diagnosed when the systolic
blood pressure falls more than the normal 10 mm Hg during
TABLE 2.10. Causes of pulse pressure abnormalities normal inspiration. The mechanism of pulsus paradoxus is
Increased Narrow thought to be predominantly the result of pulmonary vascu-
Pulse Pressure Pulse Pressure lar pooling during inspiration and accentuated by conditions
Sinus bradycardia Severe heart failure that
Complete heart block Shock 1. limit the normal inspiratory increase in blood flow from
Emotion Aortic stenosis (usually the right ventricle to the pulmonary artery,
Exercise occurs but is not always 2. cause a greater-than-normal inspiratory pooling in the
present)
Aortic regurgitation lungs,
Atrioventricular fistulas Hypovolemia 3. cause wide extremes of intrathoracic pressure during
Fever Vasoconstrictive agents inspiration and expiration, or
Anemia
4. interfere with venous return to the atrium relatively
more during inspiration.
Hyperthyroidism
Beri-beri Pulsus paradoxus is seen in patients with pericardial effu-
Inelastic aorta (elderly patients) sion of sufficient size to impede venous return to the heart
Abnormal connections between during inspiration, that is, pericardial tamponade, less com-
aorta and pulmonary artery monly with constrictive pericarditis, and in association with
(patent ductus arteriosus, severe asthma or chronic obstructive pulmonary disease and
aorticopulmonary window) hypovolemic shock.
Rupture of sinus of Valsalva Pulsus alternans refers to a pulse pattern in which there
aneurysm
is regular alternation between the heights of the pressure
32 chapter 2

Normal carotid
Start insp. Start exp. DN
140
BA
Pressure–mm Hg

120
LV
100
80
60 Bisferiens carotid
40
20 DN DN
0
1 sec.
FIGURE 2.1. This paradoxical pulse was present in a patient with
pericardial tamponade. Note the marked fall in brachial artery (BA)
and left ventricular (LV) systolic pressure, with inspiration (Insp.)
followed by a rise during expiration (Exp.). Anacrotic carotid

Shudder
pulses (Fig. 2.2). Such a finding may signify LV dysfunction,
usually severe, and therefore may be associated with any
disease leading to ventricular failure or with events, such as
extreme tachycardia, that might impair ventricular func-
tion, if only temporarily. Pulsus alternans is occasionally Anacrotic DN
induced by a ventricular ectopic beat. AN DN
notch
The equality of pulses should be checked over the carot- FIGURE 2.3. Examples of normal, bisferiens, and anacrotic carotid
ids and in both the upper and lower extremities. Unilateral pulses. The anacrotic carotid pulse with the shudder was obtained
reduction or absence of the pulse over one of these vessels from a patient with severe valvular aortic stenosis. AN, anacrotic
notch; DN, dicrotic notch.
suggests localized obstruction of that artery.
Pulse configuration may provide an important clue to
cardiac disease. It is best determined by palpitation of the
carotid artery, providing, of course, that the patient does not nificant valvular aortic stenosis. In these patients, the carotid
have intrinsic carotid arterial disease. The carotid pulse is pulse is of small volume and the anacrotic notch is palpable
best examined with the patient reclining with the trunk of the relatively low on the carotid upstroke. At the summit or peak
body elevated at 15 to 45 degrees to the horizontal plane. The of the carotid, a shudder may be felt. The entire carotid
sternocleidomastoid muscles should be relaxed and the head upstroke in these patients is markedly delayed. In the adult
either not rotated or rotated very slightly away from the exam- patient, assessment of the carotid upstroke is the single most
iner. The forefinger is generally used with light and then, if valuable clue to the presence of hemodynamically significant
necessary, slightly heavier pressure in an attempt to assess the valvular aortic stenosis in the absence of intrinsic carotid
upstroke, the peak, and the downstroke of the carotid impulse. arterial disease. In contrast, in aortic regurgitation, the carotid
For precise separation of the various components of the carotid upstroke is extremely rapid and the pulse is sometimes
contour, listening simultaneously to the heart sounds may be described as a water-hammer pulse. The bisferiens pulse is
helpful. The normal configuration of the carotid pulse con- found in some patients with severe aortic regurgitation, some
sists of a smooth and rapid upstroke (Fig. 2.3). The summit of with combined aortic stenosis and regurgitation, and some
the carotid pulse is smooth and dome shaped. The descending patients who have hypertrophic obstructive cardiomyopathy
limb from the systolic peak is less steep. The carotid incisura (HOCM). In patients with HOCM, the carotid upstroke is typi-
or dicrotic notch is not usually identifiable by palpation. Char- cally rapid (Fig. 2.4).
acteristic abnormalities of the carotid pulse are listed in Table
2.12. Examples of some of these abnormal carotid pulses are
shown in Figure 2.3. An anacrotic carotid pulse is usually
TABLE 2.12. Arterial pulse abnormalities
seen in patients who have isolated and hemodynamically sig-
Abnormality Description

Anacrotic pulse A small, slowly rising pulse with a

200 notch on the ascending limb, such
that there are two deflections on the
upstroke of the carotid
mm Hg

BA Bisferiens pulse Two palpable systolic peaks of almost

100 equal height
Dicrotic pulse A second peak during diastole
LV Water-hammer pulse Characterized by rapid and sudden
0 systolic expansion
FIGURE 2.2. An example of pulse alternans. The brachial arterial
Idiopathic hypertrophic A carotid pulse with a very rapid
(BA) and left ventricular (LV) systolic pressures vary in a regular
Subaortic stenosis pulse upstroke, sometimes having a
manner, such that every other pressure is reduced. Pressure is indi-
bisferiens quality
cated on the vertical axis.
 t h e h istory a n d ph ysica l e x a m i nat ion 33

Carotid 1 A P
DN
2 2

Carotid

A H
V
Jug.
Carotid C
pulse
FIGURE 2.4. Three different examples of carotid pulses in patients
with idiopathic hypertrophic subaortic stenosis. Note the character-
istic rapid upstroke in all three and the “double hump” in the carotid
downstroke in the top two examples. The systolic ejection period is
prolonged in all three. DN, dicrotic notch. Y
X
A systolic thrill may be palpable over the carotid vessels. FIGURE 2.5. A normal jugular venous pulse configuration. Note
the prominence of the A wave and that the X trough is deeper than
This vibration is produced by turbulent blood flow and rep- the Y trough. A 2, aortic valve closing; P2, pulmonary valve closing.
resents the physical counterpart of a loud murmur heard on
auscultation. In general, a thrill over the carotid is transmit-
ted from the aortic root in patients with valvular heart patient sit upright for adequate examination (Fig. 2.6). Light-
disease, especially valvular aortic stenosis. Alternatively, a ing is also of extreme importance; either oblique or tangen-
carotid thrill may represent local arterial disease, in which tial lighting with respect to the vein is helpful. The right
the thrill is usually unilateral and associated heart disease external jugular vein is usually the easier to assess.
is absent. The examiner should also listen with a stethoscope
for bruits over the carotid vessels. A bruit over a carotid
V V
artery may represent a transmitted murmur from the precor-
dium, as occurs in patients with valvular heart disease (espe-
cially aortic valve disease), or it may be a manifestation of
intrinsic occlusive disease of the carotid vessel itself.
Severe
A A
Examination of the Jugular Venous Pulse
V V
The information obtained from examination of the jugular
venous pulse includes an estimation of the level of venous Moderate
A A
pressure and an evaluation of the individual components
(Fig. 2.5). The external jugular vein is generally used to assess Y
both the level and the waveform of venous pressure, although Y
the internal jugular vein can also be used. The jugular veins
reflect right atrial (RA) events with only minimal delay, and Y Y
the venous pulsations can be differentiated from arterial
pulsations in several ways. The pulsation seen at the anterior A Normal
C V C V
border of the sternocleidomastoid muscle is usually arterial,
whereas pulsations at its posterior border are usually venous.
Venous pulsations are influenced by respiration, tending gen-
X Y X Y
erally to fall with inspiration and rise with expiration. Three
separate pulsations can usually be identified in the venous
pulse, in contrast to the single systolic pulsation noted in the
arterial wave configuration (Fig. 2.5). The venous pulsation
can usually be obliterated by light pressure over the external LR LR
jugular vein, whereas the arterial pulsations usually cannot
1 2 3 1 2 3
be so easily obliterated. In examining venous configuration, FIGURE 2.6. The jugular venous pulse configuration in a patient
the position of the patient is important. The higher the with severe tricuspid regurgitation, a patient with moderate tricus-
central venous pressure, the more vertical the subject should pid regurgitation, and a control patient. Bottom, Murmur of tricus-
be so that the venous waveform can be adequately examined. pid regurgitation. Note the prominent V waves in the jugular venous
pulse with severe and moderate tricuspid regurgitation. L and R,
The patient is usually positioned with the trunk at an angle timing of left and right ventricular third heart sounds (S3), respec-
of 15 to 45 degrees to the horizontal plane, although if venous tively, in relation to the jugular venous pulse. Note: A, C, X, V, and
pressure is extremely high, it may be necessary to have the Y waves are all explained on p. 34.
34 chapter 2

The sternal angle of Louis is used as a reference point for

measurement of venous pressure because it is approximately
5 cm above the level of the right atrium from supine to
upright posture. After positioning the patient appropriately, VPB
so the top of the level of the external jugular venous column Second lSB
can be identified, the vertical distance between the angle of (400 cps)
Louis and the top of the venous column is measured. Addi-
tion of 5 cm to the value obtained provides an approximation
of venous pressure in centimeters of water. The normal Fourth ISB
venous pressure should be no more than 6 to 7 cm when it is (400 cps)
measured in this way. In some patients, the venous pressure
will be so high that, even in the upright position, no definite A
upper level of the venous column is apparent. In the normal
patient, venous pressure falls during inspiration, in contrast Jugular “cannon”
venous pulse A
to the situation in some patients with cardiac tamponade or
RV failure. Other causes of elevated jugular venous pressure FIGURE 2.7. A “cannon” A wave is demonstrated. It occurs when
are listed in Table 2.13. the right atrium contracts on a closed tricuspid valve and is typically
seen after a ventricular premature beat (VPB), as shown here, and in
The normal waveform of the external jugular vein is the patient with complete heart block. LSB, left sternal border.
demonstrated (see Fig. 2.5). The A wave is the most prominent
positive deflection in the external jugular pulse in the normal
subject. It originates as a result of atrial contraction with a ventricular ectopic beats), as a result of the reduction in pres-
subsequent rise in RA pressure, which is reflected in the neck sure in the jugular veins as blood flows into the right atrium.
veins. It can be distinguished by its upstroke preceding that Its trough is usually deeper than that of the Y descent. In the
of the carotid arterial pulse palpated simultaneously on the normal jugular venous configuration, it is the most conspicu-
opposite side of the neck. It is often easier, however, to ous wave. The generation of the X descent depends on three
compare jugular venous waveforms in conjunction with factors: atrial relaxation, the size of the RA cavity, and a
timing of the heart sounds. The A wave in the jugular venous decrease in intrathoracic pressure as a result of LV contractil-
pulse occurs almost simultaneously with the first heart ity. The X descent is usually exaggerated when RV stroke
sound (S1). The size of the A wave depends on several factors, output is high, as occurs with a left-to-right shunt such as in
including the force of RA contraction, the resistance to RA atrial septal defect or with exercise, fever, or anxiety. The X
emptying and RV filling, and the cardiac rhythm. Prominent descent may also be very sharp in constrictive pericarditis. In
A waves occur with tricuspid valve obstruction. Pulmonic atrial fibrillation and with tricuspid regurgitation, the X
stenosis and pulmonary hypertension in the presence of an descent either is not present or is partially abolished so that
intact septum also result in prominent A waves due to the Y trough is the deepest negative deflection.
decreased ventricular compliance. In assessment of the A The origin of the jugular C wave is still disputed.
wave, the size and contractile strength of the right atrium Although it may be a transmitted impulse from the underly-
must be considered (i.e., if it is large and dilated, it may have ing carotid artery, it most likely represents the rising up of
reduced contractile strength). In this situation, the A waves the tricuspid valve cusps at the onset of RV systole.
generated in the jugular venous pulse may not be impressive The V wave begins during the period of ventricular con-
despite the presence of conditions, such as significant tricus- traction, and it is caused by passive filling of the right atrium
pid valve obstruction or pulmonary hypertension. When via venous return in the presence of a closed tricuspid valve.
the right atrium contracts during ventricular systole with The sudden termination of RA filling associated with opening
a closed tricuspid valve, “cannon A waves” are produced of the tricuspid valve represents the descending limb of the
(Fig. 2.7). This is seen in complete AV block and occurs in V wave, or Y descent. The amplitude of the V wave depends
other situations where AV dissociation exists (e.g., ventricu- on the amount of blood in the right atrium during ventricu-
lar tachycardia or ventricular ectopic beats). lar systole. With tricuspid regurgitation (see Fig. 2.6), the
The X descent may be noticeable in other situations where systolic venous wave is due to regurgitation of blood from
AV dissociation exists, including ventricular tachycardia (and the right ventricle into the jugular venous system, so that
the V waves with significant tricuspid regurgitation are very
large and in some instances larger than the A wave. Promi-
nent V waves, equaling the A waves in amplitude, have also
TABLE 2.13. Causes of elevated jugular venous pressure
been noted in patients with atrial septal defects. The Y
Right ventricular failure descent follows the pulmonary component of the second
Vascular pulmonic stenosis heart sound (P2) and begins with the opening of the tricuspid
Infundibular pulmonary stenosis valve (see Fig. 2.5). Because the Y descent is a manifestation
Pulmonary hypertension of ventricular filling, abnormalities in RV filling caused by
Tricuspid stenosis or insufficiency changes in RV compliance will be reflected in the Y descent.
Hypervolemia Friedreich’s sign refers to a prominent Y descent in the
venous pulse seen in constrictive pericarditis, in which
Pericardial tamponade
the initial portion of RV filling is rapid after opening of the
Constrictive pericarditis
tricuspid valve, followed by subsequent sudden resistance to
Superior vena caval obstruction
further filling as the expansion of the right ventricle is
 t h e h istory a n d ph ysica l e x a m i nat ion 35
abruptly checked. This sign is not specific for constrictive When palpable, the RV impulse is present in the fourth and
pericarditis, however, but also may be seen in restrictive fifth intercostal spaces immediately adjacent to the left
cardiomyopathies. The Y descent in tricuspid stenosis is sternal border. It is usually best appreciated with the heel of
markedly prolonged and damped due to the delayed RA emp- the palm. In most adults without RV enlargement, this
tying resulting from the tricuspid valve obstruction. The end impulse is not palpable, although in thin subjects it may be.
of the steep Y descent corresponds to the point at which a The RV impulse is usually palpable in situations where RV
third heart sound originating from the right ventricle would hypertrophy or dilatation is present (e.g., in patients with
be heard. A LV third heart sound frequently occurs earlier mitral stenosis, myocardial disease, severe tricuspid regurgi-
than the end of the steep Y descent. tation, RV outflow obstruction, or pulmonary hypertension).
After the Y descent, there may be another rise in the Abnormal precordial pulsations should also be sought,
venous pressure just before the A wave; this late positive such as those that occur after MI or during myocardial isch-
wave is known as the H wave (see Fig. 2.5). This rise has been emia. They may be noted in any area between the pulmonary
attributed to the inrush of blood into the right ventricle, artery and the cardiac apex and are not uncommonly found
resulting in an upward movement of the tricuspid valve in the left parasternal region, in the fourth and fifth inter-
cusps. It is most likely to be noted with slow heart rates. costal spaces, sometimes making their differentiation from
One further point must be made about examination of a RV impulse difficult.
the cervical veins to warn the reader about venous hums, The second and third left intercostal spaces should be
continuous murmurs heard over the cervical veins. They are carefully examined for the presence of a pulsation indicative
commonly present in children and in some young adults, of pulmonary artery enlargement. The pulmonary artery is
presumably reflecting a hyperkinetic cardiovascular system. usually not palpable in the absence of pulmonary artery
The important point to make is that a venous hum may be enlargement except in very thin patients, pregnant patients,
mistaken for a heart murmur. This hum tends to be of low and some patients with the straight back syndrome. In the
or medium pitch. It may be heard over the anteroinferior absence of these situations, however, a palpable pulmonary
cervical region and sometimes over the anterior chest. It artery pulsation in adults without a hyperkinetic circulation
tends to become slightly louder during diastole. The inten- usually means either a dilated pulmonary artery (secondary
sity of the hum is increased by placing the patient in the to an increase in pulmonary artery pressure and resistance)
upright position, by inspiration, and by positioning the head or increased pulmonary artery blood flow.
in such a way that the cervical veins become attenuated. It Heart sounds may have a palpable counterpart. A loud
is reduced in intensity or disappears entirely on the patient’s second heart sound in association with pulmonary or sys-
assuming the supine position, during expiration, with the temic arterial hypertension may be palpable in the second and
Valsalva maneuver, with direct compression of the veins, and third left intercostal spaces just adjacent to the sternum. First
with positioning the head so that the cervical veins become heart sounds may be palpable at the cardiac apex in patients
kinked or compressed. with mitral stenosis. As already noted, the fourth heart sound,
or presystolic gallop, may be palpable in patients with reduced
LV compliance. A third heart sound, or protodiastolic gallop,
Inspection, Palpitation, and Percussion
may also be palpable in some patients with conditions, such
of the Precordium
as myocardial disease or significant mitral regurgitation.
Inspection and palpitation of the precordium in the patient Systolic and diastolic thrills associated with heart
with cardiac disease are important and valuable, but often murmurs are detected by palpation. The finding of a systolic
overlooked, parts of the physical examination. Percussion thrill indicates significant valvular heart disease and is
plays a less important role, but can be used in an attempt to usually associated with a loud systolic murmur. Systolic
outline the borders of the heart in dextrocardia and thrills palpable in the second and third intercostal spaces to
dextroversion. the right of the sternum usually indicate hemodynamically
Inspection and palpation of the precordium can provide significant valvular aortic stenosis. Those palpable in the
clues to the underlying abnormality in the patient with heart same locations to the left of the sternum may indicate either
disease. With the patient supine, the examiner should care- hemodynamically significant valvular pulmonic or aortic
fully inspect and palpate the precordium, attempting to stenosis. Systolic thrills along the lower left sternal border
determine the presence and location of a LV and a RV impulse. may occur as the result of severe tricuspid regurgitation,
The normal LV impulse is felt at the cardiac apex near the with ventricular septal defects, and occasionally in associa-
area of the left midclavicular line. It usually covers an area no tion with hypertrophic obstructive cardiomyopathy. Systolic
greater than 3 cm in diameter, and the outward thrust is not thrills at the apex usually indicate hemodynamically signifi-
sustained. It is usually best appreciated with the tips of the cant mitral regurgitation or LV outflow obstruction. Dia-
fingers. With LV enlargement, the apex impulse may also stolic thrills along the lower left sternal border may occur
become sustained, as in patients with significant aortic ste- with either tricuspid or mitral valve obstruction. A diastolic
nosis, or it may become more rapid, diffuse, and forceful, as apical thrill, best appreciated directly over the point of
in patients with significant aortic regurgitation. It may also maximal impulse with the patient in the left lateral decubi-
consist of a double impulse, representing both a visible coun- tus position, usually identifies the presence of hemodynami-
terpart to the fourth heart sound and an apical systolic thrust, cally significant mitral valve stenosis.
or representing regions of LV dyskinesis. A palpable tactile To accurately time a thrill, it is helpful to listen to the
counterpart to the fourth heart sound is present in some heart sounds or palpate a carotid artery as well as the pre-
patients with LV outflow obstruction, CHD, systemic arterial cordium, to determine whether the thrill occurs in systole
hypertension, and myocardial disease of various causes. or diastole.
36 chapter 2

Auscultation
Auscultation should never be done in isolation from the other
features of the cardiac examination; rather, it is an integral
part of the total examination, and when the information
obtained from auscultation is combined with that obtained
Fifth lSB
from general inspection, examination of the arteries and
jugular veins, and inspection, palpitation, and percussion of (25 cps)
the precordium, a satisfactory hypothesis regarding the abnor-
mality of the patient in question can usually be formulated. S4 S1 S.M. S3
The examiner should choose a stethoscope that is com- S2
fortable. The earpieces should fit the ear canal snugly without
penetrating to an uncomfortable depth. The tubing of the Apex
stethoscope should allow maximal sound transmission, (25 cps)
which occurs when the internal diameter of the tubing is
approximately 3 mm. Double-tube stethoscopes are associ-
ated with less distortion of heart sounds than are single tube
models. The basic components of a stethoscope, whether
separate or tunable parts of a single component, are a bell
and a diaphragm, which are used, respectively, for low- and Carotid
high-pitched sounds and murmurs.
During auscultation, the examiner should concentrate
solely on listening to and analyzing heart sounds. Ausculta- FIGURE 2.8. The low-frequency fourth (S4) and third (S3) heart
sounds. The S4 precedes the first heart sound (S1), and the S1 occurs
tion is most likely to be successful when both physician and in mid-diastole. S2, second heart sound; LSB, left sternal border; SM,
patient are comfortable and auscultation is performed under systolic murmur.
very quiet circumstances. Strict attention should be paid to
each of the various heart sound components audible during follow whatever pattern one finds easiest, but one approach
systole and diastole. The examiner should listen for the first is to listen with the diaphragm in the second and third inter-
heart sound, for systolic murmurs and clicks, for the second costal spaces to the right of the sternum initially, followed
heart sound and its splitting with respiration, for the pres- by listening to the same areas to the left of the sternum. The
ence of a third and fourth heart sound, and for diastolic diaphragm can then be moved down the sternal border to the
murmurs and diastolic clicks, each in turn excluding the fourth and fifth intercostal spaces and then to the apex and
other events of the cardiac cycle, paying strict attention to from there into the axilla to listen to heart sounds. One can
that portion of the cycle in which the sound in question is then switch to the bell of the stethoscope and listen in the
located. It is easy, unfortunately, to overlook the presence of fourth and fifth intercostal spaces to the left of the sternum,
gallops, clicks, and even murmurs unless they are listened followed by auscultation at the apex. We have found it easier
for specifically. Several different areas of the precordium to have the patient lie in the left lateral decubitus position
should be examined with both the diaphragm and the bell at the end of the routine portion of the auscultatory examina-
and the patient must be in the ideal position to bring out tion so one can listen with the bell directly over the cardiac
heart sounds as each circumstance dictates. apex and along the left sternal border.
The diaphragm of the stethoscope is most effective in In appropriate situations, a few additional areas require
identifying high-pitched sounds, such as systolic clicks, examination. Specifically, the first and second intercostal
opening snaps of valves, splitting of the second heart sound, spaces below the left midclavicular area should be auscul-
the first heart sound, certain systolic murmurs, and pulmo- tated when patent ductus arteriosus is suspected; a continu-
nary and aortic regurgitation. The diaphragm should be ous murmur audible in this area may represent a patent
firmly applied to the chest, and one should listen both to the ductus arteriosus. The systolic murmur of coarctation of the
right and left of the sternum in the second, third, and fourth aorta may be heard well in the left infraclavicular region, in
intercostal spaces and at the cardiac apex. the suprasternal notch, or in the back on the midthoracic
The bell is used to hear low-frequency diastolic murmurs region at the level of the fourth or fifth spinous process. The
(i.e., tricuspid and mitral stenosis) and the diastolic gallop systolic murmur of mitral regurgitation may radiate to the
sounds, the third (S3) and fourth (S4) heart sounds (Fig. 2.8). axilla and up the vertebral column so as to be audible even
Diastolic gallop sounds are often best heard with the patient on the top of the head, or it may radiate toward the sternum
in the left lateral decubitus position and by listening with and up along the left sternal border. Murmurs resulting from
the bell in the third and fourth left parasternal intercostal pulmonary arterial stenosis and pulmonary AV fistulas may
spaces and over the apical impulse. Gallop sounds are usually be heard over the lungs. Scars should be examined for the
best heard with application of only very light pressure with presence of a continuous murmur suggestive of AV fistulas
the bell to the skin; firm pressure may result in inability to (Table 2.18).
hear an S3 or S4 even when it is present. After completion of the routine auscultation, in selected
It is best to establish a routine for the sequence of areas patients it can be helpful to determine how heart sounds
in which one listens to the heart sounds; this ensures that change after mild exercise. This can be done by asking the
each of the important areas will be auscultated. One can patient to perform a few sit-ups and then listening to the
 t h e h istory a n d ph ysica l e x a m i nat ion 37
heart sounds again. Not uncommonly, this will either bring Expiration Inspiration
out or make louder an S3 or S4. It may also help to accentuate 1 22 1 22
the murmur of mitral stenosis when the obstruction across
the mitral valve is not severe. Normal

First Heart Sound A2 P2 A2 P2

Events in the left ventricle and aorta might be, at least in part,
responsible for the genesis of the first heart sound (S1); however,
LBBB
convincing evidence that mitral and tricuspid valve closure
plays a major role in the production of S1 has also been pre-
P2 A2 P2 A2
sented. S1 is often initiated by a low-frequency component
occurring immediately after the onset of rise in LV pressure. FIGURE 2.9. (Top) Normal splitting of the second heart sound.
Bottom: Paradoxical splitting. In normal splitting, pulmonary valve
The first high-frequency component of S1 occurs during the
closure (P2) follows aortic valve closure (A 2), and the splitting
early phase of pressure rise in the left ventricle. The second increases with inspiration. In paradoxical splitting, aortic valve
high-frequency component occurs at the time of opening of the closure follows pulmonic closure, and the splitting is widest during
aortic valve. The next component occurs at the first peak of the expiration. The paradoxical splitting of the second heart sound
aortic pulse, and the final component, when present, appears (bottom) occurred as the result of a left bundle branch block (LBBB).
to coincide with maximal expansion of the aortic wall. S1 may
sound split to the examiner’s ear or may sound as if it is single.
Three general abnormalities can occur with respect to
It decreases in loudness with the following conditions: LV
splitting of S2. First, S2 may be a single sound, with neither
hypertrophy, a dilated left ventricle, a prolonged PR interval,
audible nor detectable splitting. Second, the splitting may be
and reduced strength of contraction of the left ventricle. The
wide during inspiration and may remain wide during expira-
first heart sound increases in amplitude when the LV cavity is
tion, so that the splitting sounds “fixed” to the ear. Third, para-
small, when it is less compliant, when it is hypertrophied but
doxical splitting (i.e., wider splitting of S2 during expiration
the hypertrophy is predominantly the result of increased
and narrowing during inspiration) may occur (Fig. 2.9). A
muscle mass rather than connective tissue, and when LV con-
single S2 (in some instances narrowly split sounds beneath the
tractility occurs rapidly. The first heart sound is usually soft
capability of the human ear to detect splitting) is heard in
in the presence of aortic regurgitation and loud with mitral
elderly people, in patients with truncus arteriosus (although a
stenosis of hemodynamic significance. The first heart sound
split S2 may be occasionally heard in this abnormality), with
varies in intensity with atrial fibrillation, being somewhat
ventricular septal defects complicated by severe pulmonary
softer after a long pause. Short PR intervals (the interval
hypertension, and with severe pulmonary hypertension of any
between atrial systole and ventricular systole) also result in
etiology. Fixed splitting of S2 often but not invariably occurs
increased intensity of the first heart sound. Where complete
with atrial septal defects. Apparent fixed splitting of S2 is
heart block or advanced AV block exists, the first heart sound
sometimes found in patients with right bundle branch block,
varies in intensity on a beat-to-beat basis.
partial anomalous venous return, ventricular septal defect,
and mild pulmonary hypertension. The important causes of
Second Heart Sound
paradoxical splitting of S2 are listed in Table 2.14, and an
The second heart sound (S2) usually has two separate audible example of paradoxical splitting of S2 is shown in Figure 2.9.
components; aortic valve closure provides one component
(A 2) and pulmonic valve closure contributes the second (P2) Clicks
(Fig. 2.9). Splitting of the S2 is best heard in the second and
Systolic and diastolic clicks are high-frequency sounds
third intercostal spaces to the left of the sternum. P2 is not
usually associated with some form of cardiovascular abnor-
usually heard low along the left sternal border or at the
mality. The different types of systolic and diastolic clicks
cardiac apex, except in situations where pulmonary artery
and their distinguishing features and associated cardiovas-
pressure is significantly increased. In the normal situation,
cular abnormalities are listed in Table 2.15. Examples of
the widest splitting of S2 occurs during inspiration (Fig. 2.9).
some of these are shown in Figures 2.10 and 2.11.
During expiration, S2 becomes single, or the splitting between
A 2 and P2 becomes narrower. The amplitude of the A 2 is
proportional to the peak value of the first derivative (dP/dt) TABLE 2.14. Causes of paradoxical splitting of the second heart
of the pressure difference between the aorta and the left sound
ventricle. Correspondingly, the amplitude of the P2 is propor-
Left bundle branch block
tional to the dP/dt between the pulmonary artery and the
Right ventricular ectopic beats
right ventricle. Increased pressure in the aorta or pulmonary
artery is usually accompanied by a louder A 2 or P2, respec- Right ventricular pacing
tively. Systemic hypertension and coarctation cause loud Angina Pectoris
aortic components, whereas pulmonary hypertension results Left ventricular failure
in a loud pulmonary component of the second heart sound. Left ventricular outflow obstruction
Left and right ventricle outflow obstruction, whether valvu- Severe systemic hypertension
lar, subvalvular, or supravalvular, usually results in fainter Paradoxical splitting occurs in some patients with these abnormalities but
components of the S2, and sometimes A 2 or P2 is absent. not in all of them.
38 chapter 2

TABLE 2.15. Systolic and diastolic clicks

Systolic clicks Diastolic clicks

Early systolic clicks Mid- and late systolic clicks Opening snaps

Valvular aortic stenosis Mitral valve prolapse Mitral valve

High-frequency sounds usually occurring The most common cause of a high- A high-frequency sound audible along
0.02–0.06 s from the initial high- frequency click or clicks occurring in the left sternal border and at the
frequency component of the first heart middle to late systole. Usually these cardiac apex in patients with mitral
sound. These clicks do not change their clicks move closer to the first heart stenosis and in a rare patient without
timing with respect to the first heart sound with inspiration, with mitral valve disease. The presence of
sound, respiration, or change in position, assumption of the upright position, large amounts of calcium in the mitral
nor does the intensity of the click with amyl nitrate inhalation, and with valve apparatus may result in the
fluctuate with respiration. The aortic the Valsalva maneuver. The click may absence of an opening snap even when
valve ejection click either slightly be preceded by, enveloped by, or significant mitral stenosis is present.
precedes or occurs simultaneously with followed by a systolic murmur, or there The opening snap of the mitral valve
the carotid upstroke. This type of may be no audible systolic murmur. usually occurs 0.03 to 0.14 s after the
ejection click is commonly heard in the Aortic regurgitation high-frequency component of aortic
patient with a bicuspid aortic valve that Middle to late systolic clicks occur valve closure. In mitral stenosis, one
is not heavily calcified. rarely in patients with significant can use the aortic closure and the
aortic regurgitation. mitral valve opening click as an
Valvular pulmonary stenosis indication of the severity of the mitral
An early systolic click with approximately valve obstruction. With increasing
the same timing as for the aortic click. severity of the mitral valve obstruction,
These clicks become significantly softer this interval becomes progressively
or disappear during inspiration and shorter.
become louder with expiration. One
may also estimate the severity of the Mitral disk prosthesis
valvular pulmonary stenosis by the Also a high-frequency sound, usually
closeness of the pulmonary systolic best heard along the left sternal border
click to the initial high-frequency or at the cardiac apex. With
deflection of S1 with increasing severity. malfunction of the prosthesis resulting
The click is closer to S1. from either tissue ingrowth,
paravalvular regurgitation, or thrombus
Dilated pulmonary artery or dilated aorta interference, the opening click may
High-frequency clicks occurring with become markedly reduced in intensity.
ejection timing are also heard in some With severe mitral paravalvular
patients with these abnormalities. The regurgitation, the interval from aortic
click occurring with a dilated closure to mitral valve opening may
pulmonary artery that either is due to become markedly reduced, whereas
pulmonary hypertension or is idiopathic with tissue ingrowth or thrombus
usually is not significantly diminished interference, this interval may be
in intensity during inspiration. significantly prolonged.

Mitral valve prolapse Tricuspid valve

Early systolic click or clicks occur in Some patients with tricuspid stenosis
some patients with this entity. and patients with tricuspid prostheses
Typically, these clicks move closer to have opening snaps of their tricuspid
the first heart sound with inspiration, valve. This is also a high-frequency
with assumption of the upright sound audible along the left sternal
position, with the Valsalva maneuver, border and at the apex.
and with amyl nitrate administration.
Their relationship to the carotid Mitral valve prolapse
upstroke is variable in that they may Diastolic clicks have been recorded in
precede, occur simultaneously with, or some patients with this abnormality,
follow the carotid upstroke but these clicks are extremely unusual.

Ebstein’s anomaly
Early systolic click is audible in some
patients with this abnormality.
Aneurysm of the membranous
ventricular septum
Some patients with this abnormality also
have an early systolic click.

Aortic valve prosthesis

The intensity of the opening click of
disk-and-ball aortic prostheses should
be approximately 50% or more of that of
the closing click in the second right
intercostal space. Abnormal function of
the aortic prosthesis is suggested by
gross reduction in the intensity of the
opening click of the prosthesis.
 t h e h istory a n d ph ysica l e x a m i nat ion 39

FIGURE 2.10. (A) Midsystolic clicks in the recordings of

the heart sounds at the base and apex of the left precor- Second lSB
dium in a patient with mitral valve prolapse. Typically, (400 cps)
Base S1 S1 EC S
S2 2
such a patient has a midsystolic click (MSC) that moves (400 cps) S1 A2 P2 Carotid
closer to the first heart sound (S1) with inspiration and Multiple systolic clicks
with sitting and standing. However, as shown here, some Apex
patients with mitral valve prolapse have early systolic (400 cps) Inspiration Expiration

ejection clicks and early midsystolic ejection clicks. (B)

A middle to late systolic click in another patient with Carotid
mitral valve prolapse. (C) Ejection click in a patient with A C Inspiration Expiration
valvular pulmonic stenosis in the left second intercostal
space. It becomes softer and often disappears with inspi-
ration and is easily audible during expiration. (D) An Second lSB
early systolic ejection click in a patient with a bicuspid (400 cps)
A2 P2
aortic valve. The intensity of this click does not change 2nd LICS
with respiration. The typical systolic ejection murmur in MSC MSC
Apex CL 2 CL 2 CL 2
a patient with an obstructed bicuspid aortic valve is also (40 cps) SM SM SM SM
shown. ECG, electrocardiogram; LICS, left intercostal Carotid ECG
space; LSB, left eternal border; SM, systolic murmur. B D

Murmurs tricuspid regurgitation typically (but not always) increases in

intensity with inspiration (see Fig. 2.6).
Innocent or functional murmurs do not represent pathologic Table 2.16 lists distinguishing features of the common
abnormalities. Innocent murmurs may occur as a result of systolic murmurs. The examiner should remember that more
increased velocity of blood flow across normal valves due to than one murmur indicative of valvular heart disease can
extracardiac factors. They are heard in patients with anemia exist in a given patient. For example, it is not uncommon to
or thyrotoxicosis and after exercise. Innocent murmurs are find systolic and diastolic murmurs indicative of both valvu-
usually short, soft systolic murmurs that often change in lar obstruction and regurgitation. The common types and
intensity or disappear with changes in position, with rest, locations of diastolic murmurs are listed in Table 2.17, and
and/or with correction of an underlying abnormality, such as two examples are shown in Figure 2.11. The common types
anemia. Diastolic murmurs are rarely, if ever, innocent of continuous murmurs are listed in Table 2.18.
murmurs. Innocent murmurs are common in children. Occa-
sionally, the differentiation of an innocent or benign systolic
murmur from one indicative of serious underlying cardiac
pathology is difficult from the physical examination alone. 2 2
ES P ES
Systolic murmurs are classified as either systolic ejection A AP
murmurs, holosystolic murmurs, or continuous murmurs.
Systolic ejection murmurs terminate before the second heart PCG-PA
sound and peak in intensity in early to midsystole, becoming X X
1
softer thereafter. Valvular aortic and pulmonary stenosis SM
MDM MDM
(Fig. 2.10) are characterized by systolic ejection murmurs.
Holosystolic murmurs extend throughout systole, beginning PCG-MA
immediately after the first heart sound and extending up to
the second sound. Continuous murmurs are both systolic
and diastolic with the murmur peaking in late systole, envel-
oping the second sound, and continuing into diastole. The
murmur of mitral regurgitation is an example of a holo-
systolic murmur (Fig. 2.12). The holosystolic murmur of
X
X

ECG
SM
DM
Second
lSB Apex
(HF) S2 (LF)
S1 FIGURE 2.12. The holosystolic murmur typical of mitral insuffi-
A B S1 S2 OSMV
DM ciency is demonstrated at the apex (second panel with heart sounds).
FIGURE 2.11. Two diastolic heart murmurs are demonstrated. (A) The jugular venous pulse is shown in the third panel, and the
A high-frequency (HF) diastolic decrescendo murmur (DM) in a patient’s electrocardiogram (ECG) is shown in the bottom panel. A,
patient with aortic regurgitation. (B) A low-frequency (LF) diastolic aortic closure sound; ES, ejection sound; MA, mitral area; MDM,
rumble typical of mitral stenosis occurring immediately after an mid-diastolic murmur; P, pulmonic closure sound; PA, pulmonary
opening snap of the mitral valve (OSMV). LSB, left sternal border; artery position; PCG, phonocardiogram; SM, systolic murmur; X,
SM, systolic murmur. descent of jugular venous pulse.
40 chapter 2

TABLE 2.16. Systolic ejection murmurs

Location Differential diagnosis

Second and third right and/or A “flow” murmur indicative of either increased stroke volume or turbulence around the aortic valve
left intercostal spaces but not hemodynamically significant aortic valve obstruction
Valvular aortic stenosis. This murmur is audible anywhere over the left precordium and radiates up
and toward the right shoulder and into both carotid arteries. If the obstruction is due to a bicuspid
aortic valve that is not heavily calcified, there is usually an associated systolic ejection click
Supravalvular aortic stenosis. Usually occurs in children or young adults and can be associated
with a characteristic physical appearance, namely elfin facies, and mental retardation. There is
often a systolic blood pressure difference of greater than 15 mm Hg between the two arms, with
blood pressure being higher in the right arm
Subvalvular aortic stenosis (bar or diaphragm immediately beneath the aortic valve). In addition to
the systolic murmur, there is often an associated diastolic murmur of aortic regurgitation. A
systolic ejection click is usually not present
Valvular pulmonary stenosis. This murmur is usually loudest to the left of the sternum. There is
an associated systolic ejection click that decreases or disappears with inspiration and becomes
prominent during expiration
Coarctation of the aorta. This murmur may also be heard medial to the left scapula posteriorly
and/or under the left clavicle anteriorly. The murmur is usually associated with systemic arterial
hypertension and diminished or absent femoral pulses
Atrial septal defect. Typically, a soft murmur caused by increased blood flow across the pulmonary
valve and often associated with “fixed splitting” of the second heart sound
Infundibular pulmonary stenosis. This murmur is best heard to the left of the sternum. There is
usually no associated ejection click
Peripheral pulmonary stenosis. This murmur may also be heard over the back
Second to fifth left intercostal Hypertrophic obstructive cardiomyopathy (HOCM)
spaces This murmur usually does not radiate well into the carotid arteries. The murmur typically
increases with Valsalva maneuver and upright position and in the beat following a ventricular
premature beat. It characteristically decreases with squatting. On occasion, however, the
Valsalva maneuver and squatting do not result in the expected changes in intensity of this
murmur
Cardiac apex Valvular aortic stenosis. On occasion this murmur may be loudest at the apex rather than at the
base, making its differentiation from mitral regurgitation more difficult
Mitral regurgitation resulting from papillary muscle dysfunction. This murmur often is of ejection
type, beginning after the first heart sound, peaking in midsystole, and ending before the second
sound. On occasion, however, this murmur is holosystolic rather than ejection
Holosystolic murmurs Tricuspid regurgitation. This murmur typically increases with inspiration and is associated with
Fourth and fifth left intercostal prominent V waves in the jugular venous pulse. Occasionally the inspiratory increase in the
spaces murmur does not occur
Ventricular septal defects. This murmur has no phasic respiratory change and is often associated
with a systolic thrill along the left sternal border
Rheumatic mitral regurgitation and/or mitral regurgitation due to endocarditis
Mitral regurgitation due to ruptured chordae tendineae
Mitral regurgitation secondary to papillary muscle dysfunction. This murmur may have an ejection
quality in some patients
“Relative” mitral regurgitation. This is the mitral regurgitation due to left ventricular failure and
an abnormal spatial relationship of the mitral leaflets and papillary muscles
Mitral regurgitation with HOCM or left atrial myoxma

Friction Rubs Gallop Sounds

Pericardial friction rubs may be mistaken for cardiac The third heart sound, or protodiastolic gallop (S3) may be
murmurs, but they can be differentiated by their rough, physiologic in children and young adults, but is an abnormal
rubbing, harsh quality, and by the fact that they have at least sound in adults older than 30 years. Its origin is most likely
two components (systolic and diastolic) and sometimes three from either the mitral or tricuspid valve leaflets, supporting
audible components (systolic, diastolic, and presystolic). structures, the ventricular myocardium, or a combination. It
They may be audible anywhere over the left precordium. is found in patients with severe myocardial disease and in
They are often evanescent. They can occur in the presence those with hemodynamically significant valvular insuffi-
of any disorder that causes pericarditis, for example, with ciency, including aortic, mitral, tricuspid, and pulmonary
viral pericarditis, after MI or cardiac surgery, in uremia, after valvular insufficiency. A third heart sound is demonstrated
chest injury, with malignant implants into the pericardium, in Figure 2.8. The presence of a third heart sound is incom-
and in association with systemic collagen diseases, espe- patible with a diagnosis of hemodynamically severe mitral
cially systemic lupus erythematosus. obstruction in the absence of substantial coexistent mitral
 t h e h istory a n d ph ysica l e x a m i nat ion 41
TABLE 2.17. Diastolic murmurs
Location Differential Diagnosis

High-pitched diastolic decrescendo Aortic regurgitation. This is a blowing murmur that immediately follows the second heart
murmurs sound. In general, valvular aortic regurgitation murmurs are best heard along the left
sternal border in the second and third intercostal spaces, and aortic regurgitation due to
aortic root disease (e.g., syphilis, spondylitis, dissection) are best heard to the right of the
sternum. Its timing and quality are similar to the murmur of valvular aortic regurgitation
Low-pitched diastolic rumbles Atrial septal defect. This murmur results from increased flow across the tricuspid valve
Third to fourth left intercostal spaces Tricuspid stenosis. This murmur may become louder during inspiration and with maneuvers
Fourth to fifth left intercostal spaces that increase venous return to the right atrium. Rheumatic fever or right atrial myxoma
may be etiologies
Cardiac apex Mitral stenosis. This low-pitched diastolic murmur follows immediately after the opening
snap of the mitral valve when the latter is present. It is often best heard by having the
patient lie on the left side and listening directly over the point of maximal impulse. The
length of the diastolic murmur correlates directly with the severity of mitral obstruction
Flow rumbles due to a large left-to-right shunt, such as with large ventricular septal defects.
These occur just after the second heart sound and are usually short in duration
Austin Flint murmur. Apical diastolic rumble ordinarily of short length occurring in some
patients with severe aortic regurgitation. This murmur usually results from vibration of the
septal leaflet of the mitral valve due to the regurgitation aortic jet. The murmur may rarely
result from late diastolic mitral regurgitation
Carey-Coombs murmur. Short mid-diastolic rumble noted rarely in patients with acute
rheumatic fever; murmur results from inflammation involving mitral valve leaflets
“S3 rumble complex.” Some patients with hemodynamically significant mitral regurgitation
have a short diastolic rumble that follows the third heart sound. The rumble reflects a flow-
related and relative mitral obstruction
Left atrial myxoma may also produce a murmur that mimics mitral stenosis, except that it
ordinarily is not associated with an opening snap of the mitral valve

insufficiency. However, an S3 can be produced by significant presystolic and protodiastolic gallop sound. It is recognized
aortic regurgitation or severe tricuspid regurgitation, even in with certainty by demonstrating a single loud gallop sound
the patient with severe mitral valve obstruction. An S3 that at relatively rapid heart rates, which at slower heart rates
is audible or becomes significantly more prominent during resolves into its individual components (i.e., S3 and S4).
inspiration is likely of RV origin. The tumor plop sound of
atrial myxoma is a high-frequency mid-diastolic sound that
Heart Sounds from Prosthetic Valves
may be mistaken for an S3.
The fourth heart sound, or presystolic gallop (S4), is an Mechanical prosthetic cardiac valves normally produce
abnormal sound (see Fig. 2.8). It is thought to originate within clicks that identify their opening and closing. Figure 2.13
the left or right ventricle as a result of the left or right atrium identifies the timing of these sounds for both aortic and
being forced to contract more vigorously than normally due mitral prosthetic valves. The opening and closing clicks of
to reduced ventricular compliance in the ventricle from these valves are high-frequency sounds best heard with the
which the sound originates. It is almost always found in diaphragm of the stethoscope. The opening click of the aortic
patients with severe CAD, LV outflow obstruction, or sys- prosthesis is best heard along the left sternal border and over
temic arterial hypertension and in patients in sinus rhythm the left precordium. The closing click of the aortic valve is
with substantial mitral regurgitation of recent onset. It is not best heard in the second and third left intercostal spaces.
present in patients with atrial fibrillation because of the The opening and closing clicks of the mitral prosthesis are
absence of a discrete forceful atrial contraction. best heard at the lower left sternal border and the cardiac
A summation gallop is a prominent sound that occurs at apex. In recent decades, tilting disk valves have accounted
rapid heart rates and represents the summation of both a for almost all of mechanical valve replacements. The most

TABLE 2.18. Continuous murmurs*

Location Differential Diagnosis

First to second left intercostal spaces (and under left clavicle) Patent ductus arteriosus
Second to fourth left intercostal spaces Aorticopulmonary septal defect
Usually best heard in the second to third left intercostal spaces; occasionally Surgical shunts, such as aortopulmonary anastomoses
may be best heard at the right of the sternum in the same area
Usually best heard along the lower left sternal border, although it may be Rupture of sinus of Valsalva aneurysm
audible over the entire precordium
Audible over the left precordium Coronary arteriovenous fistulas
May be audible anywhere that they occur Atrioventricular fistulas
*Continuous murmurs depend on a continuous pressure gradient in systole and diastole, such as occur in arterial and venous communications.
42 chapter 2

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4. Otto CM. Clinical evaluation and management of chronic septal rupture after acute myocardial infarction. N Engl J Med
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 3 Electrocardiography
Anton P.M. Gorgels

Electrical Activation of the Heart . . . . . . . . . . . . . . . . . . . 43 The Normal Electrocardiogram . . . . . . . . . . . . . . . . . . . . . 47

The P-QRS-T-U Complex. . . . . . . . . . . . . . . . . . . . . . . . . . . 44 The Abnormal Electrocardiogram . . . . . . . . . . . . . . . . . . . 49
Recording the Electric Activity . . . . . . . . . . . . . . . . . . . . . 44 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Lead Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

T
his chapter covers basic information about the differ- (automaticity), (2) conducting the electrical impulse, and (3)
ent aspects of the standard electrocardiogram (ECG) initiating contraction.
in adult clinical cardiology. Arrhythmias, including
monogenetic forms, conduction disturbances, and ECG find- Depolarization and Repolarization
ings in congenital cardiology are discussed elsewhere in this
The basic electrophysiologic action is depolarization of cells
book.
that are in a state of polarization. The amount of polarization
Electrocardiography, more than 100 years after its inven-
differs between automatic cells and conducting and contract-
tion by Einthoven, remains one of the most frequently used
ing cells. This process is driven by different ion currents,
bedside tools for the evaluation of the cardiac patient. Its old
with sodium, calcium, and potassium being the most impor-
age does not imply that electrocardiography has become a
tant ones. Sodium is the ion used for depolarization, calcium
rusty static science. On the contrary, along with the develop-
follows thereafter to initiate and maintain contraction, and
ment of new pathophysiologic concepts, electrocardiography
potassium is needed to repolarize the cell. During the state
was reevaluated, resulting in new insights as to the use of
of polarization sodium concentration is high outside and
the ECG in current daily practice. Examples of such develop-
potassium concentration is high inside the cell. This is phase
ments are new insights into cellular electrophysiology and
4 of the action potential. During depolarization, sodium
cardiogenetics, leading to the definition of new ECG syn-
enters the cell quickly (phase 0); after a slight repolarization
dromes, such as the Brugada syndrome and better under-
(phase 1), the plateau phase is reached, during which calcium
standing of existing syndromes such as the long QT
influx occurs (phase 2). Finally repolarization occurs through
syndrome. Availability of new imaging techniques has facili-
potassium currents (phase 3). The equilibrium of ion concen-
tated revisiting electrocardiographic–anatomic correlations.
trations is restored by energy-dependent ion pumps, such as
The advent of possibilities to reopen a coronary artery, either
the sodium/calcium exchanger and the sodium/potassium
by thrombolytic therapy or by percutaneous coronary inter-
pump.
vention, has led to new information in the ECG regarding
ischemia and infarction, as to the site of occlusion within
Automaticity
the coronary system and the area at risk, and to noninva-
sively diagnose reperfusion of the ischemic tissue. Other Automatic cells are less polarized than the other cardiac cells
features of electrocardiography are its easy and repeated and have the ability of spontaneous depolarization during the
applicability. This enables, better than any other technique, resting phase 4. This leads to spontaneous de- and repolariza-
the study of the dynamic behavior and natural history of tion, allowing automatic activity. These cells are located
cardiac diseases. within the sinus node, the atrioventricular (AV) node, and the
This chapter discusses new findings in standard electro- specific distal conduction system. Differences in speed of
cardiography and the use of the ECG to describe the dyna- phase 4 depolarization lead to a hierarchical organization,
micity of cardiac disease. allowing the sinus node to dominate the heart rhythm. The
other potential pacemakers are depressed by the faster activa-
Electrical Activation of the Heart tion rate, a phenomenon, known as overdrive suppression. In
cases of failure of the dominant pacemaker or conduction
The pump function of the heart is accomplished by electrical block, the secondary pacemakers become active, frequently
activation of the myocardium. This process occurs through after a pause, and prevent in this way the heart from asystole.
depolarization of cells, aimed at (1) driving the heart action The ensuing rhythm is called an escape rhythm.

43
44 chapter 3

Conduction Recording the Electric Activity

Depolarization of a cardiac cell is propagated to a neighbor-
ing cell. In this way propagation of the electrical impulse Electrode Leads
occurs, resulting in activation of the whole heart.
Excitation of the cells spreads along myocardial cells The electric activity of the heart is recorded from the body
or specifically conducting fibers, such as the Bachmann surface using electrode leads. These consist of a positive pole,
bundle in the atria and the His–bundle–branch–Purkinje connected to either a negative pole (bipolar leads) or a refer-
system in the ventricles. After atrial activation the impulse ence (zero) pole (unipolar leads). An electrical activation front
passes through the AV node. Here the impulse is slowed with the main direction toward the positive pole, records an
down, allowing time for the blood to pass to the ventricles. upward deflection (Fig. 3.2A). An activation front going in a
Also the AV node has the property of decremental con- direction opposite to the positive pole, is recorded as a down-
duction and block at higher rates, preventing impulses ward deflection (Fig. 3.2B), and activation perpendicular to
from passing to the ventricles in cases of atrial tachycardias, this pole is electrically silent (Fig. 3.2C).
such as atrial fibrillation. In this way the ventricles
are protected in cases of high-imposed rates. Once the Factors Influencing the Amplitude
impulse has passed the AV node, conduction through of Electrocardiogram Deflections
the distal conduction system, that is, the His bundle, the
right (RBB) and left bundle branch (LBB), and the Purkinje An activation front directly toward the electrode results in a
network, is fast and in an all-or-none fashion. These proper- larger amplitude than an activation front with an angle to
ties secure prompt and synchronous activation of both the + pole (Fig. 3.3). Larger amplitudes will also be recorded
ventricles. in cases of increased wall thickness, such as in myocardial
hypertrophy, because of the larger activation front (Fig.
3.4A,B) or with the electrode located closer to the myocar-
dium (Fig. 3.4C).
The P-QRS-T-U Complex Similarly, smaller voltages than usual can be observed
and may include the total P-QRS-T complex (Table 3.1). This
Electrocardiography is the graphic representation of cardiac is seen (1) in cases of an electrode more distant to the myo-
electrical activity, registered at the body surface. Cardiac cardium (Fig. 3.5B)); (2) in conditions affecting both atrial and
activation starts with discharge of the sinus node; the
electrical activity spreads over the atria, and passes to the
ventricles through the AV node, the His bundle, and A
the bundle branches. Sinus node activity and conduction
through the specific conduction system are electrically
silent. Therefore, the basic electrocardiogram consists of
a P wave as the result of atrial activation, followed by an +
isoelectric PQ interval during conduction through the spe-
cific conduction system, the QRS complex because of ven-
tricular myocardial depolarization, the isoelectric ST
segment during homogeneous and simultaneous myocardial
activation, and the T wave as the consequence of repolariza- B
tion of ventricles (Fig. 3.1). The T wave has the same polarity
as the QRS complex because the sequence of myocardial
repolarization is reversed. The T wave is followed by a small
final deflection with a similar polarity known as the U +
wave.

R
+
P T
FIGURE 3.2. (A) Any electrical activity in the hemi-segment
directed toward the positive pole is recorded as an upward deflec-
AV conduction Q tion. (B) Any electrical activity in the hemi-segment directed away
S from the positive pole is recorded as a downward deflection. (C)
FIGURE 3.1. The basic electrocardiogram (see text). Wave fronts perpendicular to the + pole are electrically silent.
 elect roca r diogr a ph y 45

+ +

FIGURE 3.3. The electrode depicts a larger amplitude when the

activation front is directed right toward the + pole, than in case of
an angle with this electrode. B

C
TABLE 3.1. Low-voltage ECG
Low voltage Extremity leads Precordial leads

Global cardiac muscle loss + +

Insulation myofibrils +
Pericardial fluid
Pleural fluid
Emphysema
Obesity FIGURE 3.4. The voltage (A) will be higher when the electrode is
closer to the myocardium (B) or when the myocardial wall thickness
RV dilatation + − is increased (C).

A B

+ +

C D

+ +

FIGURE 3.5. Mechanisms to induce low

voltage ECG. (A) Normal situation. (B) Elec-
trode more distant to myocardium. (C) Decrease +
in myocardial wall thickness. (D) Interposed
tissue or substance between myocardium and
electrode. (E) Storaged substance within the
myocardium causing electrical insulation.
46 chapter 3

A rotation of the dominant vector perpendicular to Einthoven’s

triangle.
R Changes in Electrocardiogram Deflections
2 1 Due to the Activation Sequence
+ Electrical activity recorded from global structures such as
S cardiac compartments are the result of the direction, force,
and timing of activation of the myocardial walls (Fig. 3.6).
Consecutive activation of the proximal vs. the distal wall
will lead to a positive/negative deflection, in cases of ven-
B tricular activation in an RS complex (Fig. 3.6A). In contrast,
activation of the distal wall first and subsequently the proxi-
R mal wall will lead to a QR complex (Fig. 3.6B). Activation of
1 2 both walls simultaneously results in cancellation of both
forces, resulting in no deflection (Fig. 3.6C).
+
Q Lead Systems

The Standard 12 Electrocardiogram

C
To enable the heart to be viewed in a standardized way and
from different sites, lead systems were developed. The first
three were the three bipolar leads I, II, and III, based on
1 1 Einthoven’s triangle. Lead I measures the potential differ-
+ ences between the left arm and the right arm, lead II between
the right arm and the left foot, and lead III between the left
arm and the left foot. A simple mathematic relation exists
among these three leads: At every instant during the cardiac
FIGURE 3.6. Activation sequence and resulting ECG configura- cycle the potential in lead II equals the sum of the voltages
tion. See text. in leads I and III: I + III = II. This basic relation is Einthoven’s
law. These bipolar limb leads were followed by the aug-
mented unipolar limb leads, aVR, aVL, and aVF, aimed at
deriving more local information from different parts of the
heart. These leads were constructed by using one of the limb
ventricular myocardium, such as in myocarditis, and dilated electrodes as the positive pole and the combined other two
cardiomyopathy, where loss of myocardial wall thickness as the reference electrode. Lead aVR equals the potential dif-
plays a role (Fig. 3.5C); (3) in the presence of extracardiac ference between the right arm and the reference potential,
interposing tissue, such as in obesity, pleural or pericardial which is the mean of the potentials of the left arm and the
effusion, increased air content, for instance, in emphysema, left leg. Lead aVF equals the potential of the left foot minus
or pneumothorax (Fig. 3.5D); and (4) in cardiac amyloidosis the mean of the potentials of the left arm and right arm, and
or storage diseases, where myocardial cells are insulated by lead aVL records the potential difference between the left
nonconductive material (Fig. 3.5E). Low voltage restricted to arm and the mean potential of the left leg and the right arm.
the QRS complex in the extremity leads, and thus with These three bipolar and three unipolar limb leads form the
normal voltage in the precordial leads, is seen in cardiac hexaxial lead system in the frontal plane (Fig. 3.7A,B).
dilatation, especially of the right ventricle (RV). This is the Subsequently, precordial leads V1, V2, V3, V4, V5, and V6
result of increased intracardiac volumes (Brody effect1) and/or were developed to obtain information in the transversal

A B C aVR aVL
- I + aVR aVL
- - I
I
II III
FIGURE 3.7. Electrode lead system
in the frontal plane. (A) Einthoven’s
+ + triangle. (B) Hexaxial lead system
III II positioned within the ventricles
aVF III II with the electrical center at the
aVF base of the left ventricle (C).
 elect roca r diogr a ph y 47
V9 V8
V7

V6 0˚ V6
V1 V2
V5
V4
V3
V5
30˚
V1 V4 V6r
V2 V3 60˚
120˚ 75˚
90˚
FIGURE 3.8. Precordial leads. Placement on the chest and position V5r
to the ventricles in the transverse plane.
V4r
V3r V1
plane. These leads have their positive pole at a specific pre- V2
cordial site and the combined limb electrodes as a reference FIGURE 3.9. Additional leads. Right precordial and left posterior
electrode. The most common system is the Wilson central leads.
terminal, which consists of inputs from three limbs (right
arm, left arm, and left leg) connected through 5000-Ohm
resistors. In this way six precordial leads are constructed
positioned from the right (lead V1) to the left lateral side (Fig. The Normal Electrocardiogram
3.8). Leads V1 and V2 are located more superiorly on the chest
in the four intercostal space, lead V3 is midway between
The P Wave
leads V2 and V4, and leads V4 to V6 are in the same transversal
plane with V4 being in the fifth intercostal space. It should Atrial activation starts from the sinus node, which is located
be realized that the plane formed by the six precordial leads at the right superior side in the right atrium. Therefore, the
is not in an exactly transverse direction. right atrium is activated first and from right superior to
The frontal leads are more at a distance from the heart, inferior. Thereafter the left atrium is activated, which is a
whereas the precordial leads are located closer to the myo- left posteriorly located structure. The normal P wave is
cardium. This allows the potential in the frontal plane to be therefore in the frontal plane, and is usually positive in I and
analyzed preferably according to a vectorial approach (single II and negative in lead aVR, with an axis in the frontal plane
dipole model). The potentials recorded in the precordial leads between 0 and 90 degrees (Fig. 3.10). In the transversal plane
are determined not only by the global cardiac activation but lead V1 records initial positivity during right atrial activation
also by local events close to their exploring electrode. There- and thereafter negativity during left atrial activation. Lead
fore, the analysis fits also with the multiple dipole array V6 records positive deflections throughout right and left atrial
model.2 activation.
The height of the P wave normally does not exceed
2.5 mm and its duration of 110 ms. Above that latter value
Additional Leads
conditions are present such as left atrial enlargement,
Apart from the standard 12 leads, additional leads are fre- intraatrial fibrosis, or the use of medication, slowing
quently used. Right precordial leads V3R to V6R are placed intraatrial conduction.
opposite to the regular precordial leads (Fig. 3.9). The most
frequently used lead is V4R, which is particularly useful to
The PQ Interval
record right-sided processes such as right ventricular infarc-
tion. Less frequently, leads V7 at the left posterior axillary The PQ or PR interval consists of the time of atrial activa-
line, V8 at the left midscapular line, and V9 left paraverte- tion, for conduction through the AV node, and the distal
brally, all at the V6 level, are used, usually to diagnose pos-
terior wall infarction.

The Format of the 12-Lead Electrocardiogram

The 12-lead ECG is mostly recorded in an order according to
2
their historical sequence of development, that is, first leads 1
2 1
I, II, and III, thereafter the augmented limb leads aVR, aVL,
and aVF, and finally the precordial leads. Especially regard-
ing the frontal plane, a more logical order would be to use
the sequence aVL, I, −aVR, II, aVF, and III. Because this way II
of representing the leads also has disadvantages, in the fol- V1
lowing discussion the traditional representation is used. All
recordings are taken at a paper speed of 25 mm/s and at a FIGURE 3.10. Left and right atrial activation and resulting P wave
calibration of 10 mV/cm. configuration in the frontal and transverse plane.
48 chapter 3

conduction system, the latter comprising the His bundle, -90˚

-120˚ -60˚
bundle branches, and Purkinje network, until the ventricular aVL
myocardium becomes activated. The AV node starts to be -150˚ -30˚
activated about midway through the P wave. Atrioventricu- 0˚ EA LAD
lar nodal conduction is characterized by its slowness (allow-
180˚ 0˚
ing time for the blood to pass from the atria to the ventricles)
and long refractory period. The latter is useful to prevent fast
RAD NA
atrial activity (such as atrial fibrillation or flutter) to reach 150˚ 30˚
60˚
the ventricles. Conduction slowing is decremental, implying 90˚ II
that the higher the imposing rate the more the conduction 120˚ 60˚
90˚
will be impaired. Conduction time through the AV node is FIGURE 3.12. Assessment of the QRS axis in the frontal plane.
at normal rates between 100 and 130 ms. Left: In this example in lead aVL R height is equal to S depth. The
In contrast, conduction through the distal conduction overall direction is therefore 0 and thus the axis is perpendicular to
system is fast and because of the absence of decremental aVL. The axis could either be +60 or –120 degrees. Lead II shows a
positive QRS complex, therefore the axis is +60 degrees. Right:
conduction properties, the impulse traverses in an all-or- Definition of normal and abnormal QRS axes in the frontal plane.
none fashion, securing prompt and synchronous activation NA, normal axis; LAD, left axis deviation; RAD, right axis devia-
of both ventricles. Conduction time through the distal con- tion; EA, extreme axis deviation.
duction system is between 35 and 55 ms.
The total PR interval is usually between 120 and 200 ms. duction delay, as seen in ischemia or fibrosis; or prolonged
A PR interval above this value is called prolonged conduction conduction times due to increased muscle mass, as seen in
and is due to a number of conditions such as ischemia, fibro- hypertrophy or ventricular dilatation.
sis, myocarditis, the use of medication, etc. A prolonged PR The height of the QRS complex is dependent on many
interval should not be called first-degree block because the factors such as age, thickness of the thoracic wall, and indi-
impulse is not blocked but only delayed in conduction. vidual differences in stature.

The QRS Complex The Electrical Axis

The QRS configuration is determined by the activation In clinical practice the electrical axis is frequently used to
sequence and contribution of both ventricles. Under normal indicate the main electrical activation front. The axis can be
circumstances the thin-walled right ventricle contributes assessed for any part of the P-QRS-T complex. The axis is
little to the dominant activation fronts and therefore to the defined as the global direction of electrical activation. A
QRS configuration. Activation mapping of the human heart convenient way to determine the axis is to go from a lead
has revealed that the first structure to be activated is the where the global direction is (most) perpendicular to, for
interventricular septum, immediately followed by the domi- example, an isoelectric segment or a lead with an equal
nant activation front, directed laterally, and finally the left upward and downward deflection. The next step is to assess
and right posterobasal areas are depolarized.3 Initial septal in another lead whether this direction is toward or opposite
activation leads to a negative deflection in leads I and aVL from its positive pole (Fig. 3.12).
(septal q), after which the activation spreads to the lateral The QRS axis is normally between −30 and 90 degrees.
and posterior wall. The dominant force in the direction of Between −30 and −90 degrees left axis deviation is present,
these leads results therefore in an R wave (Fig. 3.11). In the and between 90 and 180 degrees right axis deviation. The
transverse plane this activation sequence leads to an rS, term extreme axis is used in case of an axis between −90 and
an RS, and a qR complex in V1, V3 or V4, and V6, respectively 180 degrees.
(Fig. 3.11).
The normal QRS width does not exceed 90 ms. The height Clinical Significance of the QRS Axis
of the R wave is less than 25 mm in V5 and V6, and 20 mm in Axis deviation may occur due to factors such as (1) the ana-
leads I and aVL. The Q wave is not wider than 40 ms. Widen- tomic position of the heart; (2) gain of forces in a specific
ing of the QRS may be due to sequential activation of both direction, for instance, right axis deviation in right ventricu-
ventricles in the bundle branch block; intramyocardial con- lar hypertrophy; (3) loss of forces in a localized area, such as
in myocardial infarction; and (4) changes in the activation
2
sequence such as in conduction delay or block in the bundle
branches or in the left anterior or posterior fascicle.
lead I
2
1 2 V5 The ST Segment
1
1
The ST segment occurs during calcium influx into the myo-
cardium allowing contraction to occur. This process is
V3 simultaneous and homogeneous throughout the ventricles
V1
and therefore the ST segment is usually isoelectric. In the
normal ECG lead V2 may show some ST elevation, especially
in men.
FIGURE 3.11. Normal activation of the ventricles and resulting ST segment deviation may occur as the consequence of
QRS configuration in the frontal and transverse plane. a disease process, such as hypertrophy, ischemia, pericardi-
 elect roca r diogr a ph y 49
tis, or infarction, and is then called a primary ST segment aVL
change. When ST-T changes occur as the result of a concomi-
tant ECG abnormality, such as in bundle branch block, pre-
excitation, or a paced rhythm, secondary ST-T segment
changes are present.
2 2
1 1
The T Wave and the QT Interval
The T wave reflects the repolarization of the ventricles and II
although it has a similar polarity as the QRS complex, slight V1
differences in axis may be present, but usually not more than
45 degrees. Changes in polarity and T wave configuration
FIGURE 3.13. Left atrial hypertrophy. Electrical forces in left atrial
may be due to many different causes and are outlined in hypertrophy in the frontal and transverse plane and the resulting P
more detail below. wave configuration.
The duration of the QT interval is generally used to indi-
cate the duration of the repolarization time. This interval is
rate dependent and normalization is done using different
methods, Bazett’s formula [corrected QT interval (QTc) = QT
(ms)/√R − R(s)] being the most frequently used. Normal values muscle, enlargement of the atrial compartment, slowing of
are below 440 ms for men and below 450 ms for women. The conduction, and prolonged conduction time due to the larger
QT interval is prolonged in the setting of the long QT syn- muscular mass.5 This change leads to an increase in voltage
drome, comprising different congenital and acquired forms. and, in cases of left atrial pathology, to an increase in dura-
tion of the latter part of the P wave. Leads II, aVL, and V1
usually depict these abnormalities best (Figs. 3.13 and 3.14A).
The U Wave Lead II shows a wide P wave with a prominent second part,
The normal U waves are likely to be produced by the repo- frequently after a notch due to a transition from right to left
larization of the His-Purkinje system, but there is some atrial activation. In lead aVL typically a late positive deflec-
doubt about whether large or inverted U waves are produced tion is observed. In lead V1 small initial positivity, due to
in this manner. It is suggested that abnormal U waves are right atrial activation, is followed by deep and broad late
actually due to split T waves created by two voltage gradients negativity. Criteria for left atrial enlargement are P wave
across the ventricular myocardium. The first voltage gradi- duration in lead II ≥ 110 ms,6 and late negativity in lead V1 ≥
ent is responsible for the first part of the T wave (the usual 1 mm2 (Table 3.2).7
T), and the second voltage gradient is responsible for the Another important P wave abnormality in this setting is
second wave that is currently called an abnormal U wave.4 interatrial conduction block and retrograde activation of the
left atrium (Fig. 3.14B).8
Diagnosing left atrial enlargement and intraatrial con-
duction block has important clinical implications as it fre-
The Abnormal Electrocardiogram
quently indicates left ventricle (LV) disease, for instance
mitral valve disease, LV hypertrophy, or end diastolic pres-
ECG abnormalities can be divided grossly into (1) configura-
sure elevation, but it also indicates a substrate for atrial
tional changes and (2) time and sequence related changes of
arrhythmias, such as atrial fibrillation.
the P-QRS-T complex. The latter changes are disturbances
of the heart rhythm and are discussed elsewhere.
Right Atrial Enlargement
Configurational changes, considered here, are P wave
abnormalities (such as atrial enlargement and hypertrophy, In right atrial enlargement mostly the initial part of the P
and atrial infarction), changes in QRS configuration (increase wave is distorted, because the right atrium is activated before
in QRS voltage, for instance, in hypertrophy, widening of the left atrium. The increase in voltage and duration will lead
QRS duration as in bundle branch block, decrease in QRS to superposition on left atrial activation in lead II and thus
voltage, localized changes such as in healed infarction), ST to a tall P wave (Figs. 3.15 and 3.16). In lead V1 prominent
segment changes (acute coronary syndromes, acute pericar- initial positivity is seen. Criteria for right atrial enlargement
ditis), and primary T-wave abnormalities (acute ischemic or are a P wave in lead II ≥ 0.25 mV (2.5 mm) and lead V1 ≥
postischemic T-wave changes, electrolyte abnormalities). 0.15 mV (1.5 mm) (Table 3.2). Also criteria in the QRS complex,
In the examples given below one can observe that many and related to RV hypertrophy, have been defined to diagnose
disease states will simultaneously change different parts of right atrial enlargement. A qR pattern in V1, a QRS voltage
the P-QRS-T complex. of 4 mm or more, has been found to be very specific.9 Right
atrium (RA) enlargement is present in congenital and valvu-
lar heart disease and in pulmonary hypertension.
Changes in the P-Wave Configuration
Increased sympathetic tone also sometimes results in a
more cranial origin of the sinus, and faster atrial activation
Left Atrial Enlargement
with superposition of right and left atrial activation results
Changes in the P wave, indicating overload of the left atrium, in taller P waves in the inferior leads, mimicking right atrial
are due to several factors, such as hypertrophy of the atrial enlargement.
50 chapter 3

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4 FIGURE 3.14. ECG with left atrial hypertro-

phy (A) and interatrial conduction block (B). (A)
Sinus rhythm, 70 beats/min, wide P wave,
120 ms in lead II, with prominent terminal
aVL V5 aVL V5 part, >1 mm2, in V1, indicating left atrial hyper-
trophy, in this case in anterior wall infarction.
(B) Sinus rhythm, P waves with markedly pro-
longed terminal part, negative in leads II, III,
aVF V6 aVF V6 and aVF, due to interatrial conduction block
with retrograde left atrial activation.

TABLE 3.2. Criteria for left and right atrial enlargement

P wave QRS Sens Spec PV

Left atrial enlargement II, III, aVF ≥120 ms 65% 70%

V1 ≥1 mm2 51% 87%
Right atrial enlargement II >2.5 mm Low Low 20%
V1 ≥1.5 mm
qR Low Low
QRS ≤ 4 mm 100%
QRSV2/V1 ≥ 5 46% 90% 80%
Biatrial enlargement V1 pos 1.5 mm
peak neg
peak ≥1 mm2
PV, predictive value; Sens, sensitivity; Spec, specificity.

2 2 I V1
1
1
II II V2

V1

III V3
FIGURE 3.15. Right atrial hypertrophy. Electrical forces in right
atrial hypertrophy in the frontal and transverse plane and the result-
ing P wave configuration.

aVR V4

aVL V5
FIGURE 3.16. Right atrial and ventricular hypertrophy. Sinus
rhythm, rate 75 beats/min electrical axis shifted to the right, +120
degrees, prominent positive P waves in V1 and V2, indicating right
atrial hypertrophy, tall R waves in III and V1, persistent s in V6, sec-
ondary T wave abnormalities indicating severe right ventricular aVF V6
hypertrophy. Case of severe primary pulmonary hypertension.
 elect roca r diogr a ph y 51

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.17. Biatrial hypertrophy. (A) Sinus

rhythm, rate 75 beats/min, wide and tall P
wave in lead II, prominent biphasic P wave in aVL V5 aVL V5
lead V1, indicating biatrial enlargement, right
axis deviation, s in V1, abnormal ST-T seg-
ments, indicating right ventricular overload.
(B) Same patient in atrial fibrillation. Note
huge fibrillation waves in V1. Case of restric- aVF V6 aVF V6
tive cardiomyopathy.

Biatrial Enlargement fibrosis, and impaired cell-to-cell coupling that may cause
impaired intramyocardial conduction and also impaired
In biatrial hypertrophy features of both right and left atrial
bundle branch conduction. This leads to widening of the
hypertrophy are present (Table 3.2 and Fig. 3.17): (1) P wave
QRS complex and altered initial activation. The result will
in lead II is taller and wider than normal, 2.5 mm and 0.12 s,
be disappearance of the septal q and a delayed intrinsicoid
respectively; and (2) left atrial enlargement is combined with
deflection. The latter is assessed as an increase of the qR time
QRS criteria for right atrial enlargement.
in V5 beyond 50 ms. Increase of dominant forces of the basal
left ventricle due to the larger muscle mass causes the electri-
cal axis to shift leftward. Increased atrial contribution to fill
Changes in QRS Configuration the less compliant left ventricle leads to left atrial hypertro-
phy, and the presence of subendocardial demand ischemia
Conditions with Voltage Increase
leads to secondary ST T abnormalities, apparent as down-
L EFT VENTRICULAR HYPERTROPHY sloping ST depression in the anterolateral leads I, aVL, V5,
Left ventricular hypertrophy is an important ECG diagnosis. and V6. The latter is more frequently present in pressure than
The ECG features are based on the pathophysiologic and in volume overloaded left ventricles.
structural changes in the left heart. Increased load to the left Voltage criteria were developed to diagnose left ventricu-
ventricle such as in hypertension or aortic valve disease lead lar hypertrophy (LVH); all have a similar drawback of a high
to increased wall thickness and therefore an increase of the specificity at the expense of a low sensitivity (Table 3.3).7 The
QRS voltage. The hypertrophic process is accompanied by Cornell voltage criteria for LVH include sex specificity.10

TABLE 3.3. Voltage criteria for left ventricular hypertrophy

Sensitivity (%) Specificity (%) Accuracy (%)

RI+SIII > 25 mm 10.6 100 55

RaVL > 7.5 mm 22.5 96.5 59.5
RaVL > 11 mm 10.6 100 55
RaVF > 20 mm 1.3 99.5 50
SV1 + RV5–6 ≥ 35 mm 42.5 95 74
SV1 + RV5–6 > 33 mm 55.6 89.5 73
In V1 − V5 any S + R > 45 mm 45 93 69
RV5–6 > 26 mm 25 98 62
RaVL + SV3 > 2.8 mV in men 42 96 68
RaVL + SV3 > 2.0 mV in women
Romhilt-Estes score 60 97 78
52 chapter 3

TABLE 3.4. Romhilt-Estes score to diagnose left ventricular hypertrophy (LVH)

QRS changes Points Total

Voltage criteria 3
R or S in frontal plane
≥20 mm
SV1 − V2 ≥ 20 mm
RV5 − V6 ≥ 30 mm
Frontal axis ≥−30 2
ID in V5 − V6 ≥ 0.05 s 1
QRS duration ≥0.09 s 1
ST-T changes ST depression without dig 3
ST depression with dig 1
P wave Terminal part V1 ≥1 mm2 3
LVH probable 4
LVH present 5
Dig, digitalis.

Apart from gender, other factors influence the accuracy of tricle, this compartment has less opportunity to be exposed
the ECG, such as obesity decreasing sensitivity and black in the ECG, even when pathologic changes are present. This
race decreasing specificity.11 Combined QRS voltage and holds especially during the regular synchronous activation
duration criteria, expressed as their product, have been found of both ventricles. When sequential activation is present,
to increase sensitivity to 51%.12 To improve the accuracy of such as in left- or right-sided aberrant conduction, abnormali-
the ECG diagnosis of LVH, scoring systems were developed ties will be apparent more easily. In RVH rightward forces
(Table 3.4),7 including not only changes in the QRS complex counteract the left ventricular forces and could even become
but also in the P wave and the ST segment. More recently, the dominant direction of electrical activation (Table 3.5).7 In
continuous rather than dichotomous scoring systems were the frontal plane this leads to rightward shift of the electrical
developed, increasing the sensitivity without sacrificing spe- QRS axis. In the precordial leads, the QRS configuration in
cificity.13 Although echocardiography is more sensitive than the V1 lead shows the most pronounced consequence of the
the ECG to diagnose LVH, both techniques contain inde- rightward force; this may vary from a diminished depth of
pendent prognostic information and, at least in hypertensive the S wave to the occurrence of a tall R wave and a qR
patients, both should be performed to fully assess the complex. The latter indicates severe RVH, frequently in the
increased risk.14 setting of high pulmonary artery pressures (Fig. 3.19). Another
Unloading the left ventricle can lead to regression of hyper- feature of hypertrophy is conduction delay in the right bundle
trophy and to normalization of the ST segment, and decrease or the RV myocardium. This will lead to a secondary R and/
in the voltage and width of the QRS complex (Fig. 3.18).15 or delayed intrinsicoid deflection of RV, best seen in V1 (Fig.
3.20).
R IGHT VENTRICULAR HYPERTROPHY
Right ventricular pressure and/or volume overload leads to Dilatation of the RV. Dilatation of the RV frequently
right ventricular hypertrophy (RVH) and dilatation of the accompanies hypertrophy, due to the thin-walled RV not
right ventricle.16 Owing to the thinner wall of the right ven- prepared to generate high pressures. RV dilatation is seen in

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4 FIGURE 3.18. Left ventricular hypertrophy

(LVH) (A) and regression of LVH (B). Sinus
rhythm, 75/min, electrical axis +30 degrees,
absence of septal q waves, increased QRS
aVL V5 aVL V5 voltage in the precordial leads, ST-T segment
changes in V6, indicating severe LVH. Clini-
cally severe aortic valve stenosis. (B) General-
ized decrease in voltage indicating regression
aVF V6 aVF of LVH 2 months after aortic valve
V6
replacement.
 elect roca r diogr a ph y 53
TABLE 3.5. Criteria for RVH atrial and ventricular premature beats, or atrial fibrillation/
Criterion Sens Spec flutter. Bradycardia is rare and an agonal sign. The P wave is
usually normal and only rarely tall P waves are present. The
V1 R/S V1 ≥ 1 6 98
R ≥ 7 mm 2 99 QRS complex shows a rightward shift and signs of right ven-
QR 5 99 tricular conduction delay, apparent as an S in lead I, a Q in
S < 2 mm 6 98 lead III (McGinn and White’s sign), and a late R in leads aVR
IDT ≥ 0.35 s 8 98 and V1. The amount of right ventricular conduction delay cor-
V5 − V6 R/S ≤ 1 16 93 relates with the extent of obstruction within the pulmonary
R < 5 mm 13 87 circulation. Right ventricle dilatation may cause a general-
S ≥ 7 mm 26 90
ized voltage decrease in the extremity leads and slow R pro-
V1 + V6 RV1 + SV6 > 10.5 18 94
gression in the precordial leads. ST elevation in leads aVR and
QRS axis ≥110 degrees 15 96 V1 is part of the picture, and is probably due to demand isch-
SISIISIII 24 87
emia. In the subacute phase these signs gradually normalize
IDT, intrinsicoid deflection (time from onset to R wave peak). within a few days, but negative T waves develop especially in
leads V1 to V4, which remain for days to weeks.
RV Hypertrophy in Chronic Obstructive Pulmo-
nary Disease. In chronic obstructive pulmonary disease
the extremity leads as a generalized decrease in QRS voltage, (COPD) the ECG is determined by the amount of RVH and
and an undetermined electrical axis. In the precordial leads RV dilatation due to pulmonary hypertension, the increased
RV dilatation is observed as slow R progression and a persist- pulmonary volume due to conditions such as emphysema and
ent S until V6. This is due to extension of the RV anterolater- backward tilt of the apex of the heart as the low diaphragm
ally. ECG signs of RV dilatation may normalize when pulls down on the pericardium. The latter leads to general-
pressure or volume overload in the pulmonary circulation ized decrease in voltage and an upward shift of the QRS axis
improves (Fig. 3.21). in the frontal plane. Sinus tachycardia and not infrequently
atrial fibrillation is present, a QRS axis in the frontal plane
Acute RV Pressure Overload (Pulmonary
pointing in an extreme direction leading to the typical SISIISIII
Embolism). Acute RV pressure overload may occur in several pattern, and in the precordial leads a shallow s wave in V1 as
clinical circumstances, the most important being acute pul-
the consequence of RVH, slow R progression, and a persistent
monary embolism. The ECG is important to support the
s wave in V6 due to RV dilatation (Fig. 3.23).
correct diagnostic workup in a suspicious clinical condition.
The sudden increase of the resistance in the pulmonary cir-
BIVENTRICULAR HYPERTROPHY
culation leads to abrupt changes in the right ventricle, such
as a sudden decrease in stroke volume, dilatation, conduction RV Involvement in LV Disease. Left ventricle disease,
delay, and ischemia. The typical ECG features in the acute such as hypertensive heart disease, myocardial infarction,
phase (Fig. 3.22 and Table 3.6)17 are sinus tachycardia, right and mitral and aortic valve abnormalities, are usually

A B C
I V1 I V1 I V1

II V2 II V2 II V2

III V3 III V3 III V3

aVR V4 aVR V4 aVR V4

aVL V5 aVL V5 aVL V5

aVF V6 aVF V6 aVF V6

FIGURE 3.19. Development of right ventricular hypertrophy (RVH). forces counteracting left ventricle (LV) activation (cancellation), the
Three panels illustrating the development of RVH. All panels show shallow s sign, which is consistent with RVH. (B) Recorded 6 years
sinus rhythm. (A) QRS axis is 35 degrees. A s is present in lead I. later, it shows right axis deviation (+110 degrees), a qR pattern, an s
Also a small s is present in V1, as the result of right ventricle (RV) in V6. Changes are even more pronounced in panel C.
54 chapter 3

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

aVF V6 aVF V6

FIGURE 3.20. Right ventricular hypertrophy in right bundle branch synchronous activation of both ventricles. (B) During RBBB, signs
block (RBBB). (A,B) RBBB in the same patient with ischemic heart of RVH are more evident because of the sequential activation of both
disease and mitral regurgitation. Sinus rhythm, left atrial hypertro- ventricles. RBBB has a qR pattern, delayed intrinsicoid deflection
phy, left axis deviation, q wave in V2. (A) Note the shallow S during and tall R.

reflected in the ECG. With increasing severity of these condi- heart disease (Fig. 3.24); in valvular heart disease, such as
tions the pulmonary circulation may become pressure or mitral regurgitation; and in hypertrophic cardiomyopathy
volume overloaded and in this way the right ventricle (HCM) (Fig. 3.25; Table 3.7). Next to signs of LVH, frequently
becomes involved. Diagnosing RV involvement in LV disease left atrial hypertrophy is present, and signs of RV involve-
is therefore a marker of the severity of the disease process. ment are present, such as increased voltage signs of hyper-
The ECG can give clues as to the presence of this situation. trophy, the typical feature being a tall R and a deep S in V3
Biventricular hypertrophy (BVH) may occur in hypertensive (Katz-Wachtel complex), rightward shift in the frontal plane,

A B
I V1 I V1

II V2 II V2

V3
III V3 III
FIGURE 3.21. RV dilatation and regression
after heart failure treatment. (A) Recorded
V4 during severe congestive heart failure. Sinus
aVR aVR V4 tachycardia, 95 beats/min. Left atrial enlarge-
ment, low voltage in the extremity in contrast
to the precordial leads, slow R progression in
the precordial leads due to RV dilatation. (B)
V5 V5 Recorded after treatment. Slowing of the sinus
aVL aVL
rate, 75 beats/min, no left atrial hypertrophy,
normalization of voltage in the extremity
leads, R progression in the precordial leads.
The dynamic QRS behavior is explained by RV
aVF V6 aVF V6
dilatation and subsequent normalization.
 elect roca r diogr a ph y 55

A B C D

I I

II II

III III

aVR aVR

aVL aVL

aVF aVF

V1 V1

V2 V2

V3 V3

FIGURE 3.22. Acute RV pressure overload. V4 V4

Four panels with ECGs recorded during the
acute, subacute, and later stages of acute pul-
monary embolism. Left ECG shows sinus
tachycardia rightward shift of QRS axis, S1, V5 V5
Q3, T3 pattern, right bundle conduction delay,
S in V6 and ST elevation in aVR and V1. These
changes normalize over time, but T wave nega-
tivity in V1 to V4 remains for weeks to V6 V6
months. 400 ms

increase of the intrinsicoid deflection of the RV (as measured

in lead V1), and dilatation such as decrease of QRS voltage in
the extremity leads and slow R progression in the precordial
leads.
TABLE 3.6. Pulmonary embolism
P wave P pulmonale 8% Hypertrophic Cardiomyopathy. The 12-lead ECG is
Atrial arrhythmias 22% abnormal in 75% to 95% of HCM patients. The abnormali-
QRS complex Frontal axis > 90 degrees 33% ties are related to (1) the involvement of the respective com-
Axis undetermined 31% partments, (2) the hemodynamic consequences, and (3) the
Voltage <5 mm in extremity leads 20% stage and severity of the disease. Involvement of the ventri-
S lead I and/or aVL 73%
Q in lead III and/or aVF 49% cles and/or atria leads to LV and/or RV and LA and/or RA
RBBB incomplete 53% hypertrophy (Fig. 3.25). Abnormal initial activation (pseudo–
RBBB complete 14% ␦-wave), Q waves (pseudo-infarction), and QRS widening
Slow R progression precordial leads 51% (pseudo–bundle branch block) may also be present. ST-T
RBBB, right bundle branch block. abnormalities and prolonged QT interval are not unusual.
56 chapter 3

I
V1 I V1

II V2 II V2

III V3
III V3

V4
aVR aVR V4

aVL V5
aVL V5

aVF V6
aVF V6

FIGURE 3.23. RV hypertrophy and dilatation in emphysema. Sinus

rhythm, generalized decrease in voltage, extreme axis deviation,
small s in V1, slow R progression in the precordial leads, persistent FIGURE 3.24. Biventricular hypertrophy. Atrial fibrillation, left
S in V6. axis deviation due to left anterior hemiblock, positive criteria for
LVH, qR in V1 and delayed intrinsicoid deflection, persistent S in V6.
Hypertensive heart disease.

I V1

II V2

III V3

aVR V4

aVL V5

aVF V6

FIGURE 3.25. Sinus rhythm, 75 beats/min, wide P waves, 120 ms in precordial leads, consistent with right ventricular dilatation, tall
in lead II, >1 mm2 in V1, indicating left atrial hypertrophy, electrical R in V1 to V3, suggesting RVH, R in V6 > V5 indicating LVH. Widened
axis in frontal plane perpendicular to all leads (indeterminate axis), QRS complexes. Case of hypertrophic cardiomyopathy.
discrepancy of low voltage in the extremity leads with high voltage
 elect roca r diogr a ph y 57
TABLE 3.7. Right ventricle (RV) involvement in left ventricle
(LV) disease
I V1
LV disease RV involvement

LVH Rightward shift electrical axis

Old infarction Slow R progression precordial leads
II V2
LBBB Low voltage extremity leads
In RBBB tall R´
In RBBB persistent R´ over precordial leads
III V3
In LBBB increased R V1−V2

aVR V4
Marked T-wave inversion in the precordial leads should alert
the clinician to the diagnosis of the apical form of HCM.
Arrhythmias such as atrial fibrillation and ventricular
ectopic activity, and also conduction disturbances such as
AV junctional delay or block and bundle branch block, are aVL V5
seen.

Widening of the QRS Complex aVF V6

L EFT BUNDLE BRANCH BLOCK FIGURE 3.27. Intermittent left bundle branch block. Sinus rhythm,
In left bundle branch block (LBBB) both ventricles are acti- the first and last two beats show wide QRS, left axis deviation,
vated through the right bundle branch. Slowing of conduc- absence of the septal q, widened QRS, 140 ms, notch in mid-QRS,
tion or complete block may be structural or functional. secondary ST-T segment changes, indicating left bundle branch
block. The middle five beats show normal conduction due to slight
Therefore, LBBB may be intermittent, through mechanisms slowing in rate. The T wave abnormalities during normal conduc-
such as fast (phase 3 block) or slow rate (phase 4 block), ret- tion are caused by the preexisting LBBB, a phenomenon known as
rograde invasion into one of the bundles by premature ven- the cardiac memory sign.
tricular beats, or a mechanism called acceleration dependent
block.
The configuration of LBBB in the ECG is explained by myocardium, such as hypertrophy, dilatation, ischemia, or
the activation sequence of the ventricles through the right use of medication, and is termed overcomplete LBBB. A
bundle branch solely. This structure inserts into the right typical QRS configuration but without widening of the QRS
ventricle anteriorly in the apex. Therefore, the first part to is named incomplete LBBB.
be activated is the right ventricular anterior wall, which may
result in a tiny r wave in lead V1 (Figs. 3.26 and 3.27). There- Additional Heart Disease and LBBB. Additional fea-
after the interventricular septum is activated from right to tures in the LBBB may unmask concomitant heart disease
left, resulting in initial positivity in the lateral leads I, aVL, (Table 3.9). In LVH the Sokolow index (SV1or2 + RV5or6 ≥ 35 mm)
and V6. The LV apex is the structure next to be activated, is valid in LBBB. In old myocardial infarction (MI) and LBBB
frequently leading to slightly less voltage due to the smaller the QRS is frequently distorted; slurring in the initial
amount of tissue. This is typically seen as a notch at the upstroke in leads I, aVL, and V6 (Chapman’s sign), slurring in
nadir of the QRS complex. Finally the lateral wall is acti- the terminal upstroke in V4 and V5 (Cabrera’s sign), Q waves
vated, producing positivity in the lateral leads. The serial in the leads I and aVL, and notches in the leads II, III, and
activation of the LV and the conduction through the myocar- aVF all indicate scar due to previous MI.
dium results in a widened QRS complex, but not exceeding Right ventricular hypertrophy (RVH) is apparent in the
140 ms (Table 3.8). Exceeding this duration suggests addi- ECG as a rightward shift of the QRS axis and gain of initial
tional reasons for slow or prolonged conduction within the voltage (R wave) in the leads V1 to V3, and RV dilatation as
low voltage in the extremity leads (Fig. 3.28). Acute ischemia
is diagnosed by recording additional ST segment changes

1 3
2
lead I
TABLE 3.8. Criteria for LBBB and RBBB
3 2 3 V6
1 LBBB RBBB

1 Axis −30° to +60° 0°–120°

2 QRS width 120–140 ms 120–130 ms
V1
Septal q wave Absent Present
Late R lateral leads Present Absent
FIGURE 3.26. Left bundle branch block. Directional changes in left V1 rS complex RsR´ complex
bundle branch block in the frontal and transverse plane and the
V6 RR´ complex Rs complex
resulting QRS configuration.
58 chapter 3

TABLE 3.9. LBBB and additional heart disease

LVH Sokolow index positive
Acute MI Additional ST segment changes
Old MI Initial slurring I, aVL, V6 (Chapman’s sign)
Slurring S wave V4 − V5 (Cabrera’s sign)
Septal MI Q wave I, aVL
Inferior MI Notches II, III, aVF
RVH/dilatation Vertical/right axis
Low voltage extremity leads
Tall R V1–3
MI, myocardial infarction.

next to the secondary repolarization abnormalities due to the the use of medication impairing conduction, such as class IA
LBBB. Serial comparison of subsequent ECG's is very helpful and IC drugs and tricyclic antidepressant drugs.
for this purpose. Very specific is ST positivity in leads with Also concomitant heart disease can influence the typical
a positive QRS complex. RBBB configuration. Examples are the initial r wave in V1
increasing in height and width in old posterior wall infarc-
R IGHT BUNDLE BRANCH BLOCK tion, but disappearing in septal infarction (Fig. 3.30B,C); in
In right bundle branch block (RBBB), sequential activation of concomitant RVH the secondary R’ wave increases in height
the left ventricle and right ventricle occurs due to conduction (Fig. 3.20). The RBBB masks left ventricular hypertrophy by
delay or block in the right bundle (Fig. 3.29). First the left decreasing the Sokolow index (Fig. 3.31).
ventricle is activated in the usual way, that is, firstly septal
activation from to left to right, leading to a septal q wave in
Distortion of the QRS Complex
leads I and aVL, followed by activation of the other parts of
the LV. The dominant direction in the lateral direction The QRS complex will be distorted due to local changes
results in a large R wave in these same leads. After this, due within the myocardium, such as scar formation, fibrosis,
to the right bundle branch block (RBBB) the right ventricle infiltration by proteins, granulomas, tumor metastases, etc.
is activated, leading to a late S, in the leads I and aVL, and a This distortion leads to changes of the QRS complex due to
tall secondary R in lead V1. The s wave in the lateral leads absent, diminished, or delayed local activation. Pseudoin-
typically has a rounded shape due to slow activation of the farction is diagnosed when one or more of the above-
RV through the myocardium rather than through the mentioned QRS distortions are present in the absence of
Purkinje network (Table 3.8; Fig. 3.30A). ischemic heart disease. Examples are infiltrative heart
The RBBB is caused by similar pathologic mechanisms disease such as cardiac sarcoidosis, hypertrophic cardiomy-
as in LBBB, such as hypertrophy, dilatation, ischemia, and opathy, and preexcitation syndromes.

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

aVF V6 aVF V6
FIGURE 3.28. Changes in LBBB due to additional heart disease. (A) in V2 to V3, consistent with RVH. (B) LBBB in healed myocardial
LBBB and right ventricular overload. Sinus rhythm, low voltage in infarction. Sinus rhythm, notches in V4 and V5 (Cabrera’s sign) and
the extremity leads, indicating right ventricular dilatation, tall R Q in V6.
 elect roca r diogr a ph y 59

lead I V1
1 2 I
V6
2
1 3 V2
II
3
V1
III V3

FIGURE 3.29. Right bundle branch block. Directional changes in

the frontal and the transverse plane and the resulting changes in aVR V4
QRS configuration.

aVL V5

aVF V6
HEALED INFARCTION
After acute myocardial infarction the ischemic myocardium FIGURE 3.31. Right bundle branch block masks left ventricular
becomes necrotic and heals within weeks with scar forma- hypertrophy. Atrial arrhythmia leading to changing RR intervals,
tion. This leads in the QRS to the following possible changes: leading to intermittent RBBB. Note the decrease in voltage in lead
I and aVL during RBBB and the positive Sokolow index in the syn-
(1) decrease of R voltage due to less myocardium to be acti- chronous QRS, which is masked during RBBB.
vated, (2) a Qr complex due to incomplete loss of myocardium
and slow local conduction, (3) a QS complex in case of loss
of local myocardium (Figs. 3.30B and 3.32). Dependent on the
mentioned QRS distortions are present in the absence of
leads showing these changes, the infarction can be classified
ischemic heart disease. Examples are infiltrative heart
as anterior, inferior, or lateral. The loss of myocardium in
disease such as cardiac sarcoidosis (Fig. 3.33), hypertrophic
cases of posterior wall infarction leads to a gain of R voltage
cardiomyopathy, and preexcitation syndromes.
in the precordial leads.
Based on the changes in the QRS, complex scoring
Decrease in QRS Voltage
systems were developed to estimate the infarct size.18
A number of mechanisms and causes of a decrease in voltage
PSEUDOINFARCTION have been mentioned above. Another not infrequent cause is
The QRS complex will also be distorted due to other local starvation, a typical example being anorexia nervosa. Proba-
changes within the myocardium, such as fibrosis, infiltra- bly due to protein loss of the myocardium, a generalized
tion by foreign materials, granulomas, and tumor metasta- decrease of voltage occurs (Fig. 3.34).19 In addition, the ECG
ses. This will lead to changes of the QRS complex due to is characterized by sinus bradycardia and long QT time. The
absent, diminished, or delayed local activation. Pseudoin- latter may lead to torsades de pointes and sudden cardiac
farction is diagnosed when one or more of the above- death. After refeeding the ECG picture is reversible.

A B C

I V1 I V1 I V1

II V2 II V2 II V2

III V3 III V3 III V3

aVR V4 aVR V4 aVR V4

aVL V5 aVL V5 aVL V5

aVF V6 aVF V6 aVF V6

FIGURE 3.30. Right bundle branch block and changes in configura- ing in Q waves in leads II, III, and aVF. Complete RBBB with a high
tion due to location of myocardial infarction. (A) Sinus rhythm, QRS initial R in V1 as the result of posterior wall infarction. (C) Right
axis +60 degrees, normal initial QRS activation but late right ven- bundle branch block in anteroseptal myocardial infarction. Sinus
tricular activation best seen as a late wide S in lead I and aVL (and tachycardia, slightly prolonged PR interval, likely due to distal con-
typically also in V6) and a late R’ in V1 (rSR’ complex). (B) RBBB in duction delay. Due to muscle loss in the septum, the initial r in lead
healed inferoposterior wall myocardial infarction. Sinus rhythm, V1 is absent, leading to the typical qR pattern in this situation.
left axis deviation due to myocardial loss in the inferior wall, result-
60 chapter 3

The ECG has proven to be a very useful tool for that purpose.
STEMI usually leads to more immediate damage than non-
1 STEMI and therefore treatment strategies are more aggres-
sive, including thrombolytic therapy and primary and rescue
2 PCI (percutaneous coronary intervention). Non-STEMI,
however, also comprises high-risk situations, such as proxi-
mal left anterior descending branch (LAD) disease and left
3 main and proximal three-vessel disease, and ECG character-
istics have been described for their identification.22 The ECG
also diagnoses anterior versus non-anterior (inferior, poste-
4 rior, lateral, and combinations) and basal versus apical STEMI
locations. In both instances the former conditions involve
larger areas at risk.23 Right ventricular and atrial infarction
and involvement of the specific conduction system can also
1 be identified, all being situations indicating higher risk. The
FIGURE 3.32. Different QRS configurations in healed myocardial ECG of STEMI has been correlated with the culprit coronary
infarction. (1) Normal tissue, qR complex. (2) Subendocardial infarc- artery and a proximal or distal site of occlusion in that
tion, Qr complex as the result of slow conduction and muscle loss. vessel. These findings are helpful not only for assessment of
(3) Transmural infarction, QS complex due to total loss of local
activation. (4) Subepicardial infarction, qr or r complex, as the result the area at risk but also to guide the interventional cardiolo-
of normal subendocardial activation and epicardial muscle loss. gist to the culprit lesion in cases of multivessel disease. The
ECG also gives information about the acuteness24 and the
severity of STEMI, facilitating in both situations the choice
of the most appropriate treatment strategy.
The ST Segment
T HE ISCHEMIA VECTOR
The most important cause of ST segment changes, either ST
The term ischemia vector implies the direction and magni-
elevation or depression, is ischemia of the myocardium. This
tude of the ST segment deviation during acute ischemia.
can either be demand ischemia, occurring during situations
Similarly to the QRS vector, the most convenient way to
such as exercise, anemia, or tachycardia, but also supply
determine its direction is to go from a lead with an isoelec-
ischemia in the setting of a critical stenosis frequently due
tric ST segment. The ST vector is perpendicular to this lead
to plaque instability. This situation is covered by the term
and points to the direction of leads with ST elevation. Assess-
acute coronary syndrome, being further classified as ST ele-
ment of the direction of the ischemia vector facilitates
vation acute myocardial infarction (STEMI)20 and non-ST
assessing the site of (most) ischemia, and the amount of ST
elevation acute myocardial infarction (non-STEMI).21
elevation provides information about its severity. Especially
in the frontal plane, this vector has been shown to be helpful
Acute Coronary Syndromes for this purpose.
Management of STEMI and non-STEMI strongly depends on
the assessment of the risk of extensive damage to the myo- STEMI
cardium and its possible complications such as heart failure, Occlusion of an epicardial coronary artery or of a side branch
ventricular arrhythmias, and sudden or nonsudden death. leads to acute transmural myocardial ischemia (also termed

A B
I V1
I V1

II V2
II V2

III V3
III V3

aVR V4
aVR V4

FIGURE 3.33. Distortion of the QRS complex.

aVL V5 Cardiac sarcoidosis. (A) Sinus rhythm, left
aVL V5
atrial hypertrophy, atypical widening of the
QRS complex with pseudoinfarction pattern in
aVF leads II and III. (B) Same patient with RBBB.
V6
aVF V6 Involvement of the conduction system is fre-
quent in cardiac sarcoidosis.
 elect roca r diogr a ph y 61

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

aVF V6 aVF V6
FIGURE 3.34. Decrease in P-QRS-T voltage. Anorexia nervosa. Before (A) and during (B) an episode of anorexia nervosa. Note sinus brady-
cardia, axis deviation to vertical, generalized loss of voltage, deflections in lead I almost being absent.

acute myocardial infarction). The site and extent of the features, such as bradycardia because of sinus node and AV
ischemic area depends on (1) the artery being occluded, (2) node dysfunction (both also frequently aggravated by strong
the perfusion area of the occluded coronary, and (3) the site vagal discharges occurring in this setting), atrial infarction,
of occlusion within the vessel. The system coronary artery right ventricular infarction, inferoposterior wall infarction
is shown in Figure 3.35. of the left ventricle, and mitral regurgitation. Recognizing
proximal RCA occlusion is therefore important so as to be
Anatomy of the Coronary Artery System. The LAD prepared for these possible complications.
runs along the anterior part of the interventricular septum
and perfuses the interventricular septum and the anterior ST Elevation in Acute Myocardial Infarction. Elec-
and anterolateral part of the left ventricle. In 40% to 50% of trodes facing the ischemic area record ST elevation in acute
cases this vessel wraps around the apex and also perfuses the transmural myocardial ischemia. This is considered to be the
inferoapical area. The LAD is usually the most dominant consequence of differences in shape and height of the plateau
coronary branch, and occlusion leads to the largest infarc- phase of endocardial and epicardial action potentials. In
tions with possible complications such as heart failure, ven- anterior wall infarction ST elevation is observed in the pre-
tricular arrhythmias, and death. By way of the first septal cordial electrodes, at least in V2 and V3. In inferior wall in-
perforator, it also perfuses the His bundle and the right and farction ST elevation occurs in at least leads II, III, and aVF.
left bundle branch, the latter also being supplied by the right Lateral infarction is apparent in leads I, aVL, V5, and V6. The
coronary artery (RCA). As a consequence, RBBB and intra- situation is more complex in posterior wall infarction because
Hissian block can occur in LAD occlusion and indicate a no standard leads face this part of the LV. The precordial
proximal obstruction and therefore a large area at risk. leads record the reverse of ST elevation of the posterior wall,
The circumflex branch (CX) runs along the mitral annulus that is, ST segment depression. In clinical trials and in clini-
to the lateral and posterior parts of the LV. Side branches cal practice, posterior wall infarction, mostly in the setting
perfuse the posterolateral, posterobasal, and not infrequently, of CX disease, is underdiagnosed and therefore undertreated,
also the inferolateral part of the left ventricle. Also atrial resulting in increased morbidity and mortality.
branches can branch off. This may lead to atrial infarction
in case of occlusion or to sinus node dysfunction, because
in 40% of cases, this structure is perfused by this branch.
Only in a minority (10%), does the CX perfuse the interven-
CX
tricular and interatrial septum, including the AV node. The
rare occasion of AV conduction delay or block in the setting LAD
of CX occlusion therefore identifies dominance of this RCA
vessel. D1 OM
The RCA runs opposite to the CX in the groove between S1
the right ventricle and atrium and perfuses the conus pul-
monalis; the right atrium, including the sinus node (in 60% PL
RV RDP
of cases); the right ventricle; the interventricular septum,
including the posteromedial papillary muscle; the interatrial IA
septum, including the AV node; the posterior wall; and some-
times also the posterolateral wall of the left ventricle. Occlu-
sion of the RCA, therefore, may lead to distinct clinical FIGURE 3.35. Scheme of the coronary artery system. See text.
62 chapter 3

aVR aVL

V6
V5
V4
V1 V2 V3

III aVF II FIGURE 3.36. Proximal LAD occlusion in anterior wall

myocardial infarction. Directional changes in the frontal
and the transverse plane and the resulting changes in
the ST segment.

In the following subsection the ischemia vector is used In the frontal plane the result will be an ST vector in the
to explain the ECG changes in different forms of acute superior direction (Fig. 3.36). The ECG will show ST eleva-
STEMI and the resulting assessment of the area at risk. tion in leads aVL and aVR and ST depression in the inferior
leads. It should be noted that ST negativity in leads II, III,
Acute Anterior Wall Myocardial Infarction. The and aVF does not indicate absence of ischemia or subendo-
LAD perfuses anterior, basal, apical, lateral, and frequently cardial ischemia, but is the result of more dominant forces
inferior parts of the LV (Fig. 3.35). The resulting ECG during at the opposite site. In the transverse plane the vector will
obstruction depends on the involvement and size of these point anteriorly and sometimes even anteromedially leading
respective segments. The more proximal the occlusion, the to marked ST elevation in V1 and ST depression in V6 (Figs.
more segments will be ischemic. By definition the anterior
3.36 and 3.37A).
wall will always take part, resulting in an anterior direction
of the ST vector in the transversal plane and thus in ST Distal Occlusion. In cases of a distal occlusion, below
segment elevation in leads V2 and V3. The ST segment behav- the dominant diagonal and septal side branches, the apical
ior in the other leads depends on the competing forces in the segments can be exposed leading to an inferior direction of
basal versus the apical area and the medial versus the lateral the ST vector in the frontal plane (Figs. 3.37B and 3.38). The
area. The apical part is smaller than the more basally located ECG now shows ST elevation or isoelectric ST segments in
segments. Involvement of the septum and the lateral areas the leads II, III, and aVF, and ST depression in lead aVR and
depends on the location of the obstructing lesion before a sometimes in aVL. The ST vector in the transversal plane is
dominant septal or diagonal branch, most frequently being oriented in a lateral direction, which leads to ST elevation
the proximal branches, perfusing the basal areas (Fig. 3.35). in lead V6 and sometimes to ST depression in lead V1
(Fig. 3.38).
Proximal Occlusion. An occlusion before the first
septal and diagonal branch will lead to dominance of the Occlusion Behind the First Septal Branch. In cases
basal part balanced between the septal and lateral segments. in which the septal tree is spared, ischemia in the lateral

A B
I V1 I V1

II V2 II V2

III V3 III V3
FIGURE 3.37. (A) Anterior wall myocardial
infarction due to proximal LAD occlusion.
Sinus rhythm, the ST segment vector is per-
aVR V4 aVR pendicular to lead I, resulting in the frontal
V4
plane in ST elevation in aVL and aVR, and ST
depression in the inferior leads. In the trans-
verse plane typically there is ST depression in
V5 V6. (B) Anterior wall myocardial infarction due
aVL aVL V5 to distal LAD occlusion. ST elevation is present
in the precordial leads indicating anterior wall
infarction. In the frontal plane the ST seg-
V6 ments in the inferior leads are isoelectric, indi-
aVF aVF V6 cating distal occlusion behind the major septal
and diagonal branches.
 elect roca r diogr a ph y 63

aVR aVL

V6
V5
V4
V1 V2 V3

FIGURE 3.38. Distal LAD occlusion in anterior wall

III aVF II
myocardial infarction. Directional changes in the frontal
and the transverse plane and the resulting changes in the
ST segment.

wall will dominate and the frontal ST vector will point later- marginal branch from the CX. In that case V2 and V3 will
ally (Figs. 3.39 and 3.40A), frequently perpendicular to lead depict ST depression. When this same picture is present but
II. This leads to ST depression in leads III and aVR, ST eleva- also V1 and aVR are elevated, left main or three-vessel disease
tion in lead aVL, and an isoelectric ST segment in lead II. In have to be considered (see below).
the transversal plane the ST behavior is similar to that in
distal occlusion. Acute Non-Anterior Wall Myocardial Infarction.
Non-anterior wall infarction comprises involvement of the
Occlusion Behind the First Diagonal Branch. Oc- posterior, inferior, and lateral parts and combinations. The
casionally the first diagonal branch originates before the first culprit vessel could be either the RCA or the CX or one of
septal branch or there is an anterolateral (intermediate) its side branches.
branch taking off between the LAD and CX. In these circum- The ECG gives information about which of both vessels
stances the occlusion can be located behind the first diagonal is occluded and whether the right ventricle is involved. The
and before the first septal perforator (Figs. 3.40B and 3.41). latter points to a proximal RCA obstruction and identifies a
The ST vector points medially in the frontal plane, leading high-risk situation with early and late hemodynamic and
to ST elevation in leads III and aVR, and sometimes to ST arrhythmic complications such as cardiogenic shock, sinus
segment negativity in lead aVL. In the transverse plane and AV node conduction impairment (sinus arrest or brady-
similar behavior will be observed as in a proximal occlusion cardia, AV block of different degrees), and ventricular
(see above). arrhythmias.
The ECG findings as described have a high specificity,
RCA Occlusion. In cases of RCA occlusion, the isch-
but a limited sensitivity to predict the correlation with the
emia vector in the frontal plane will point in an inferomedial
coronary anatomy. Most sensitive are ST depression in the
direction, because the RCA perfuses the right ventricle and
inferior leads and ST elevation in aVR to predict a proximal
the inferior part of the septum and of the left ventricle (Figs.
occlusion, and absence of ST depression in the inferior leads
3.42 to 3.44). This leads to ST segment elevation in leads II,
to predict a distal occlusion (Table 3.10).25
III, and aVF, ST being higher in lead III than in lead II. Con-
Occlusion of a Diagonal Branch. Occlusion of a sequently lead I will show ST depression. Usually also aVR
dominant mostly first diagonal branch or of an anterolateral and aVL show ST segment depression. Rarely ST elevation in
branch results in ST elevation restricted to the leads V2, V3, aVR is observed. This identifies also more basally located
I, and aVL. This picture should be differentiated from other ischemia, due to either a dominant posterior descending
STEMIs with ST elevation in I and aVL, such as a dominant branch or to multivessel disease.

aVR aVL

V6
V5
V4
FIGURE 3.39. Anterior wall myocardial infarction with V1 V2 V3
involvement of the first diagonal, but not the first septal III II
branch. Directional changes in the frontal and the trans- aVF
verse plane and the resulting changes in the ST
segment.
64 chapter 3

A B

I V1 I V1

FIGURE 3.40. (A) Anterior wall myocardial

II V2 II V2
infarction with involvement of the first diago-
nal, but not the first septal branch. Because of
dominance ischemia of the lateral wall, the ST
III V3 III V3 segment vector points perpendicular to aVF in
lateral direction. Therefore, III, aVR, and aVF
show ST depression and in the transverse plane
also, VI has ST depression. (B) Anterior wall
aVR V4 aVR V4 myocardial infarction with involvement of the
first septal, but not the first diagonal branch.
Because of dominance ischemia of the septum,
aVL V5 aVL V5 the ST segment vector points perpendicular to
aVF in medial direction. Therefore, III, aVR,
and aVF show ST elevation and the ST segment
in aVL may be depressed. In the transverse
aVF V6 aVF V6 plane, V1 has ST elevation and V6 ST
depression.

aVR aVL

V6
V5
V4
V1 V2 V3
FIGURE 3.41. Anterior wall myocardial infarction with
III aVF II involvement of the first septal, but not the first diagonal
branch. Directional changes in the frontal and the trans-
verse plane and the resulting changes in the ST
segment.

TABLE 3.10. Criteria to identify the occlusion site in the LAD

Criterion Occlusion site Sens Spec PPA NPA

CRBBB Proximal to S1 14 100 100 62

ST↑V1 ≥2.5 mm Proximal to S1 12 100 100 61
ST↑aVR Proximal to S1 43 95 86 70
ST↓V5 Proximal to S1 17 98 88 62
Q aVL Proximal to D1 44 85 67 69
ST↓ II ≥1.0 mm Proximal to S1/D1 34 98 93 68
Q V5 Distal to S1 24 93 71 53
ST↓ aVL Distal to D1 22 95 87 46
No ST↓ III Distal to S1/D1 41 95 92 53

NPA, negative predictive accuracy; PPA, positive predictive accuracy; RBBB, right bundle branch block.

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.42. Inferior wall infarction due to proximal
III aVF II
RCA occlusion. Directional changes in the frontal and
the transverse plane and the resulting changes in the ST
segment.
 elect roca r diogr a ph y 65

I V1 V2

II V2 V1

III V3 V3r
FIGURE 3.43. Inferior wall infarction due to
proximal RCA occlusion. Atrial fibrillation,
complete atrioventricular (AV) block, junc- aVR V4 V4r
tional escape rhythm with QRS configuration
similar to conducted beats, ST elevation in
leads II, III, and aVF, ST in III higher than in aVL V5 V5r
II, ST depression in lead I. In V2 to V3 ST
depression due to posterior wall infarction and
in the right precordial leads ST elevation as a V6
aVF V6r
sign of right ventricular involvement.

CX Occlusion. In CX occlusion the ischemia vector in tion, apparent in the precordial leads V1 to V4, but also in lead
the frontal plane points in an inferolateral direction, leading V4R as ST depression. When the distal RCA is the culprit,
also to ST elevation in leads II, III, and aVF, but now lead II the posterior wall of the left ventricle and the posterior
is equal to or higher than III. Consequently, in lead I the ST septum, but not the right ventricle, is involved. This leads to
segment will be isoelectric or elevated (Figs. 3.45 and 3.46). a slight rightward shift of the ST vector now coming more
CX Side Branch. Circumflex branch occlusion or one of perpendicular to V4R, resulting in an isoelectric ST segment.
its side branches may also lead to posterolateral and even When the RCA is occluded in the proximal part, the isch-
pure posterior wall infarctions (Figs. 3.47 and 3.48). The ECG emic right ventricle will shift the ST vector more to the
will predominantly show ST depressions and may fail to right, and now the right precordial leads become positive.
have two contiguous leads with ST elevation. The latter is a Conduction Disturbances in STEMI. The conduc-
guideline requirement to diagnose STEMI. This has led to tion system is perfused by different coronary arteries (Fig.
underrecruitment of CX infarctions in clinical trials and, as 3.49). All parts of the conduction system can be involved in
stated previously, to underdiagnosis and undertreatment of STEMI. Sinus node and AV node dysfunction is frequently a
patients with CX infarctions. feature of RCA or CX disease. Sinus bradycardia, sinoauricu-
The Value of V4R. The described ECG findings in the lar block of different degrees, and sinus arrest may occur in
frontal plane correlate well with the culprit vessel but depend this setting. First-degree AV nodal conduction delay, or
on the dominance of the vessel within the coronary system. Mobitz I (or Wenckebach block) or complete AV block may
More specific, therefore, is the assessment of involvement of occur. Reperfusion usually leads to fast recovery. The LAD
the right ventricle, because this compartment is always per- perfuses the His bundle and ischemia may induce prolonged
fused by the RCA. For this purpose, assessment of a right- PR interval, Mobitz II block, and complete AV block. The
ward shift of the ischemia vector in the transverse plane is proximal part of the right bundle is perfused by the first
very useful. To be able to record this feature the use of right septal perforator of the LAD, and the RBBB in this setting
precordial leads V3R to V6R is needed. Lead V4R has been identifies a proximal LAD occlusion and a large area at risk.
found to be the most sensitive and specific lead. The direc- The RBBB has the typical QR configuration in lead V1, due
tion of the ST vector in the transverse plane is determined to loss of the initial septal r wave. Additional fascicular
by the involvement of the posterior wall, the posterior blocks may occur, anterior fascicular block more frequently
septum, and the right ventricular posterior and anterior wall. than posterior hemiblock (Fig. 3.50). Both situations indicate
In cases of CX occlusion, only the posterior wall is involved, increased risk of large infarctions, posterior more than ante-
leading to an ischemia vector pointing in a posterior direc- rior block. This is likely due to the double blood supply of

CX aVR aVL

V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.44. Inferior wall infarction due to distal RCA
occlusion. Directional changes in the frontal and the III aVF II
transverse plane and the resulting changes in the ST
segment.
66 chapter 3

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.45. Inferior wall infarction due to CX
III aVF II occlusion. Directional changes in the frontal and the
transverse plane and the resulting changes in the ST
segment.

I V1 V2

II V2 V1

III V3 V3r

aVR V4 V4r

aVL V5 V5r
FIGURE 3.46. Inferior wall infarction due to CX occlusion. Sinus
rhythm, ST elevation in the inferior leads, lead II equal to III, isoelec-
tric ST segment in I, ST depression in aVR and aVL; ST depression V2
aVF V6 V6r and V3 due to posterior wall infarction and ST elevation in V5 to V6
due to lateral infarction. The right precordial leads show ST depres-
sion indicative of CX occlusion.

CX aVR aVL

I
V6
RCA
V5
V4r
V4
V1 V2 V3
FIGURE 3.47. Occlusion of an obtuse postero-
III aVF II lateral branch of the CX. Directional changes
in the frontal and the transverse plane and the
resulting changes in the ST segment.

I V1 V2
AV node His RBB
LAD
II V2 V1

AF
III V3 V3R

aVR V4 V4R PF
RCA
aVL V5 V5R

RDP
aVF V6 V6R FIGURE 3.49. The AV conduction system and its blood supply. See
text. AF, anterior fascicle; LAD, left anterior descending branch;
FIGURE 3.48. Posterolateral infarction with predominantly ST His, bundle of His; PF, posterior fascicle; RBB, right bundle branch;
depression. RCA, right coronary artery; RDP, right descending posterior.
 elect roca r diogr a ph y 67
these situations. Serial comparison of ECGs recorded within
and without the ischemic episodes is helpful in identifying
I V1 additional ischemic changes (Figs. 3.51 and 3.52). Criteria
were developed in LBBB to help in diagnosing acute infarc-
tion.27 These criteria are highly specific but their sensitivity
II V2 is low (Table 3.11).
Isolated Right Ventricular Infarction. When only the
right ventricle is ischemic, no counteraction of the posterior
III V3 forces is present and this will lead to ST elevation in the
standard precordial leads. Because the right ventricle is an
inferior structure, some ST elevation in the inferior leads II,
III, and aVF also may be present (Fig. 3.53). Recognizing RV
aVR V4
infarction is important, because this condition may be con-
fused with an LAD infarction. Usually, however, no grade 3,
but rather grade 2 ischemia is present. Isolated right ventricu-
aVL V5 lar infarction is seen in three possible situations: (1) a non-
dominant RCA, (2) a collaterally perfused RCA, or (3) an
isolated occlusion of a right ventricular branch.
aVF V6 Atrial Infarction. A frequently unrecognized condition
is an atrial infarction. The ECG signs of atrial infarction are
elevation of the Ta segment, the repolarization phase of the
FIGURE 3.50. RBBB and posterior fascicular block in anteroseptal
atria, in leads I, II, III, V5, or V6, or a depression in the pre-
wall infarction. Sinus rhythm, right axis deviation, q wave in lead
III, absence of septal q in RBBB. cordial leads that may exceed 0.15 mV and 0.12 mV in leads
I, II, and III (Fig. 3.54). Recognizing infarction of the atria is
important because of its clinical implications. It can occur
both in RCA or CX occlusion and indicates a proximal loca-
the left bundle, that is, both from the LAD and from the
tion of the lesion. Atrial infarction is often complicated by
RCA. Complete LBBB is a rare complication in the setting of
atrial fibrillation and also by more serious conditions, such
STEMI, likely because of this double blood supply. This rare
as atrial thrombosis and even rupture of the atrial wall.
occasion, therefore, implies multivessel disease and an
extensive area at risk (Fig. 3.51).
ST R ECOVERY FOLLOWING R EPERFUSION
Acute Ischemia in Cases of a Widened QRS Persistent ST deviation is the hallmark of transmural isch-
Complex. Widened QRS complexes occur in conditions emia. In the preintervention era the ST segment gradually
such as BBB, ventricularly paced rhythms,26 and preexcita- returned to baseline within the first 24 hours, frequently
tion syndromes. Diagnosing acute infarction is complicated being accompanied by T-wave inversion and Q-wave forma-
by the primary repolarization abnormalities occurring in tion. Resolution of ST segment elevation and T-wave

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.51. A. Ischemia-induced LBBB.

During chest pain LBBB is present with addi-
tional ischemic ST segment changes. (B) On aVL V5 aVL V5
relief of chest pain, QRS widening diminishes
indicating the ischemic nature of the conduc-
tion impairment. Rate-related LBBB as a mech-
anism is excluded because of the equal heart aVF aVF
V6 V6
rates in both situations. Case of left main ste-
nosis and multivessel disease.
68 chapter 3

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5

FIGURE 3.52. ST segment changes in ven-

aVF
aVF tricular paced rhythm. (A) Baseline. (B) During
V6 V6
ischemia. Note the marked ST segment depres-
sion in the precordial leads during ischemia.

TABLE 3.11. Criteria to diagnose acute MI in LBBB

Odds ratio (95% conficence
Criterion interval) Score

ST segment elevation ≥1 mm concordant with QRS complex 25.2 (11.6–54.7) 5

ST segment depression ≥1 mm in lead V1, V2, or V3 6.0 (1.9–19.3) 3
ST segment elevation ≥5 mm discordant with QRS complex 4.3 (1.8–10.6) 2
To obtain a sensitivity of 78% and a specificity of 90%, the minimal total score should be 3 (modified from Sgarbossa
et al.26)

I V1 V2

II V2 V1

I V1

III V3 V3r
II V2

aVR V4 V4r III V3

aVR V4
aVL V5 V5r

aVL V5

aVF V6 V6r
aVF V6
FIGURE 3.53. Isolated right ventricular infarction. ST elevation is
present in leads II, III, and aVF, the ST vector is directed to the right FIGURE 3.54. Atrial infarction. Inferoposterior wall infarction due
+120 degrees (perpendicular to aVR). ST elevation is most pro- to RCA occlusion. Ta segment elevation and prolonged atrial con-
nounced in leads V1 to V4 and in the right precordial leads, due to duction or repolarization time, leading to merging of the P wave
the lack of counter forces from the posterior wall. into the QRS complex.
 elect roca r diogr a ph y 69
inversion is accelerated when the occluded vessel is reopened,
either by thrombolytic therapy or percutaneous coronary I
intervention. T-wave inversion is frequently one of the
earliest signs of reperfusion, but is seen in only 60% of reper- II
fused cases. The speed and completeness of ST segment nor-
III
malization is a marker not only of reopening of the culprit
vessel, but also of the quality of reperfusion at the tissue
aVR
level. ST segment normalization of 30% or less is associated
with poor reperfusion, 31% to 70% with moderate reperfu-
aVL
sion, and 71% or more with good reperfusion. The amount
of ST segment resolution correlates with clinical outcomes,
aVF
such as heart failure and death, in the subacute and late
phase after MI. V1
In about half of the patients receiving thrombolytic
therapy and 10% of those with a PCI, the initial change is V2
an increase of ST segment elevation at the time of onset of
reperfusion, followed by ST segment normalization. Absence V3
of ST segment resolution following thrombolytic therapy,
especially in large infarctions, is an indication for PCI. V4
Continuous ST segment monitoring is the best way to
document reflow in the infarct related coronary artery. It V5
allows recognition of reopening, the quality of the reperfu-
sion, and eventual reocclusion. V6
The onset of reperfusion is frequently accompanied by
ventricular arrhythmias, the accelerated idioventricular FIGURE 3.55. Accelerated idioventricular rhythm in reperfused
rhythm (AIVR) being the most typical one (Fig. 3.55). These acute anterior wall myocardial infarction.
arrhythmias relate with worse quality of reperfusion at the
tissue level.28
formation, and (3) persistent or recurrent ST elevation
(Fig. 3.56).29
INTRAVENTRICULAR SEPTAL RUPTURE A FTER STEMI
Acute infarctions are not infrequently complicated by rupture L EFT VENTRICULAR A NEURYSM
of the free wall, the interventricular septum, or a papillary No or suboptimal reperfusion leads to persistent ischemia,
muscle. Free wall rupture leads in most cases to electrome- hibernation, and finally necrosis or apoptosis of the myocar-
chanical dissociation and sudden death. Rupture of a papil- dium with scar formation and not infrequently aneurysm
lary muscle leads to severe acute pulmonary edema, and formation. Electrocardiographically this leads to loss of QRS
interventricular septal rupture leads to cardiogenic shock. In voltage or Q formation and persistence of ST segment eleva-
surviving patients the ECG is characterized by (1) sinus tion. Serious ventricular arrhythmias often develop in these
tachycardia, (2) subacute infarction evident as Q wave situations.

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.56. Interventricular septum rupture in aVL V5 aVL V5

inferior wall infarction. (A) Reperfused small inferior
wall infarction with Q-wave formation and normal-
ization of the ST segment, T-wave negativity in lead
III. (B) Recurrent complaints with sinus tachycardia aVF V6 aVF V6
and new ST elevation.
70 chapter 3

Acute Pericarditis ment strategy, most likely surgical coronary revasculariza-

tion. The ECG in left main disease is similar to that of
Acute pericarditis leads to epicardial injury and in this way proximal three-vessel disease, and therefore they are dis-
to generalized ST elevation, except for lead aVR (Fig. 3.57). cussed together.
Also part of the picture is Ta depression, best seen in lead II The ischemia vector in left main disease in the frontal
and V1. Pain, fever, or hemodynamic compromise leads to plane typically points in the superior direction, not infre-
sinus tachycardia, and atrial fibrillation may occur. When quently even the right superior (extreme axis) direction, indi-
pericardial effusion is present, it may lead to generalized loss cating involvement of the basal parts of the left ventricle.
of voltage of the P-QRS-T complex. Alternation of the QRS This leads to ST segment elevation in leads aVR and some-
voltage is seen in hemodynamic compromising effusions, times in lead III, whereas the other frontal leads show ST
frequently in the setting of malignancies. In the subacute depression. In the precordial leads V1 usually is elevated,
phase of pericarditis the ST segment normalizes and abnor- whereas the other precordial leads show ST depression. Some
mal T waves are seen, such as flat or inverted T waves, which specific features of the ECG pattern include (1) ST depression
can remain for a prolonged period of time. in eight leads or more in the 12-lead ECG30; (2) elevation in
aVR and V1; (3) being higher in aVR than in lead V131; (4) severe
Non-STEMI down-sloping ST configuration in the precordial leads, typi-
cally in lead V4; and (5) ST elevation in lead III, not being
Non-STEMI comprises coronary syndromes with a seem-
present in lead II (Fig. 3.58).
ingly less severe acute course, such as shorter lasting or
spontaneously relieving chest pain, normalization of the
ST vector in the Frontal Plane to Identify
ECG, and less increase of cardiac plasma enzymes. There-
the High-Risk Patient
fore, the diagnostic and therapeutic strategies are frequently
less aggressive and invasive than in STEMI patients. However, In the above discussion the usefulness of assessing the isch-
non-STEMI contains high-risk categories such as (1) left emia vector has been clarified. The ST vector can be used to
main stenosis, proximal three-vessel disease, and graft occlu- identify patients with a large area at risk (Fig. 3.59). Vectors
sion; (2) proximal LAD occlusion; and (3) as mentioned before, pointing inferiorly or laterally indicate lower risk than
acute pure posterior wall infarctions. Left main and three- vectors in a superior or extreme direction. In cases of a pos-
vessel disease frequently do not express as STEMI because terior vector in the transversal plane inferomedial, the infe-
the ECG changes are the consequence of a complex interplay rior and inferolateral or lateral direction indicates RCA or
due to subcritical stenoses at multiple sites, collateral circu- CX disease. When the vector is directed anteriorly, distal
lation, and frequently already-old infarction(s). This leads to LAD disease is diagnosed. In case of a superior or extreme
ST changes caused by endo- and epicardial ischemia in dif- direction, the possibilities are high-risk situations such as
ferent sites in the heart. proximal LAD disease and left main or three-vessel
disease.
Left Main and Three-Vessel Disease
The T Wave
One of the most critical conditions in clinical cardiology is
ischemia due to left main stem stenosis. Frequently no com-
Ischemic T-Wave Behavior and Its
plete obstruction is present, unless collateral circulation
Clinical Significance
from the RCA has developed. In most instances in left main
disease, multiple stenoses also are found in the other coro- DURING ISCHEMIA
nary arteries. Also not rarely an old MI is seen in the stan- ST-segment elevation is a characteristic feature of acute
dard ECG. Recognizing left main disease is important in transmural ischemia of ventricular myocardium. Also more
directing the patient without delay to the most optimal treat- discrete abnormalities due to ischemia may be observed

A B
I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

V5 V5
aVL aVL

aVF V6 aVF V6
FIGURE 3.57. Acute pericarditis.
 elect roca r diogr a ph y 71

–60∞
I V1

aVR aVL

II V2
high-risk
ischemia
vector
I
III V3

aVR V4

+120∞ II
aVL V5
aVF
FIGURE 3.59. High-risk ST vector. ST segment vectors between
−60 and 120 degrees, leading to ST elevation in aVR suggesting
V6 high-risk situations such as proximal LAD occlusion, left main
aVF
and/or three-vessel disease.

FIGURE 3.58. Left main and/or three-vessel disease. ST depression

is present in most leads and is typically down sloping. Lead aVR
shows more ST elevation than V1.

during the repolarization phase of the ventricles: (1) Early, both in unstable angina and in acute MI. Starting with nega-
probably subendocardial, ischemia may present predomi- tivity of only the terminal portion of the T wave, this is fol-
nantly as shortening of the QT interval. It is observed in lowed within hours or days by total negativity. In patients
subtotal stenosis of the culprit artery or in complete obstruc- admitted with a normal ECG after an episode of chest pain,
tion in the presence of collateral circulation. (2) Peaked T it is therefore helpful to repeat ECG recordings, because the
waves are another early feature of acute ischemia and are possible rapid onset of T-wave negativity unmasks the isch-
classified as grade 1 ischemia32 (Fig. 3.60). Pronounced ST- emic nature of the chest complaints.
segment elevation leads to incorporation of the T wave in the
ST segment. Severe ischemia with marked ST-segment eleva-
SITE OF T-WAVE A BNORMALITY IN R ELATION TO
tion is sometimes accompanied by alternation of the ST
CORONARY A NATOMY
segment and the T wave.41–43
Generally, negative T waves are observed in the leads showing
ST-segment elevation during chest pain. These changes may
A FTER ISCHEMIA also be seen in other leads, suggesting a larger area of isch-
After an episode of chest pain, relieving spontaneously or by emia than suggested during the chest pain episode. Negative
an intervention, negative T waves are commonly observed, T waves in leads II, III, and AVF are related to inferior wall

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

FIGURE 3.60. Peaked T waves during the aVL

acute phase of ischemia. The T-wave abnor- V5 aVL V5
malities are localized in the precordial leads,
indicating a critical stenosis in the LAD. After
relief of ischemia, terminal T-wave negativity aVF V6 aVF V6
is seen.
72 chapter 3

ischemia with either right coronary artery or circumflex giant T-wave negativity (Fig. 3.61B). This latter phenomenon
branch occlusion and in the precordial leads to the anterior has been described to predict a good prognosis, as evidenced
wall, being perfused by the left anterior descending branch. by recovery of R waves and preservation of left ventricular
A diagnostic problem is presented by an ischemic event in function.35
the posterior wall. Here the postischemic changes are present
as increased positivity of the T waves in the precordial T HE TAKO -TSUBO SYNDROME
leads. This novel syndrome (transient left ventricular apical bal-
looning syndrome and stress-induced cardiomyopathy) is
T HE HIGH LAD SYNDROME another cause of temporary (giant) T-wave inversions, QT
The development of negative T waves in the precordial leads prolongation, and Q waves, most of these features resolving
from at least V2 to V4 after an episode of ischemia has been within days to weeks.36,37 This syndrome of chest pain or
found to be useful to identify a subgroup of patients with heart failure is caused by severe sudden stress, occurs most
increased risk of subsequent anterior wall STEMI or sudden frequently in women, and induces severe temporary apical
cardiac death33,34 (Fig. 3.60). Coronary angiographic correla- dyskinesia in the setting of a normal coronary
tions revealed invariably severe stenosis in the left anterior angiogram.38
descending branch or total occlusion in the presence of col-
lateral circulation. As the dominant vessel of the coronary R ECOVERY OF T-WAVE A BNORMALITIES
artery system, recurrence of the obstruction will lead to FOLLOWING ISCHEMIA
extensive MI of the anterior wall. In patients with non-STEMI because of proximal LAD ste-
nosis who have survived at least 6 months after the ischemic
T-WAVE CHANGES FOLLOWING R EPERFUSION IN STEMI event, normalization occurs within 6 weeks in half of this
As pointed out above, the occurrence of terminal T-wave population and in 80% within 6 months. Similar findings
negativity is also very helpful in assessing reperfusion during are seen after balloon angioplasty, revealing normalization
thrombolytic therapy in acute MI. It has been shown to be of the T wave in 90% of patients after 28 weeks.39,40 Persis-
one of the earliest noninvasive signs that the infarct vessel tence of T-wave inversion is reportedly related to worse
is reopening 28,35 (Figs. 3.60B and 3.61A). Sensitivity, specific- outcome in comparison with those with recovery of their T
ity, and the likelihood ratio in this study of terminal T-wave wave.
negativity to predict reperfusion were 63%, 94%, and 10.6%,
respectively. Close ECG monitoring of this finding and other Other Causes of ST-T Wave Changes
noninvasive signs of reperfusion, such as disappearance of CARDIAC M EMORY
chest pain, decrease of ST-segment elevation, the occurrence Cardiac memory refers to persistent T-wave changes that
of ventricular premature beats with long coupling interval, follow resumption of sinus rhythm after a period of altered
and accelerated idioventricular rhythms during this phase, activation sequence.39 Prolonged alteration of activation
are useful to diagnose reperfusion. sequence has a variety of causes including ventricular pacing,
intermittent LBBB, ventricular tachycardia, ventricular
GIANT T WAVES AND QT PROLONGATION extrasystoles, and ventricular preexcitation. T-wave changes
After an ischemic event the QT interval may increase con- are more prominent and have slower regression dependent on
siderably. QT prolongation is sometimes combined with the duration and extent of abnormal activation.40

A B

I V1 I V1

II V2
II V2

V3
III V3 III

V4
aVR V4
aVR

V5 aVL V5
aVL
FIGURE 3.61. Postischemic T-wave changes
and giant T waves. (A) ECG taken after relief
of ischemic chest pain. Note terminal T-wave
aVF V6 inversion. (B) One day later, giant negative T
aVF V6 waves have developed.
 elect roca r diogr a ph y 73
The T-wave polarity during normalization of the QRS
width is dependent on the QRS polarity during QRS widen-
ing: Negative QRS complexes during abnormal depolariza- I V1
tion lead to negative T waves during normal activation and
vice versa (Fig. 3.27).
II V2
E ARLY R EPOLARIZATION
Early repolarization has elevated, upward, concave ST seg-
ments, located commonly in precordial leads, with recipro- III V3
cal depression in aVR; tall, peaked, and slightly asymmetrical
T waves with notch; and slur on the R wave.44 The other
V4
accompanying features in the ECG are vertical axis, shorter aVR
and depressed P-R interval, abrupt transition, counterclock-
wise rotation, presence of U waves, and sinus bradycardia.
V5
Males dominate and patients are often younger than 50 years aVL
of age. The incidence of 1% to 2% is found equally common
in all races. Degree and incidence of ST elevation decrease
V6
as age advances. Exercise or isoproterenol administration aVF
may normalize the ST segment. Early repolarization is a FIGURE 3.62. Hypothermia. Sinus bradycardia, late positive deflec-
benign condition. If the ECG conforms to a classic pattern tions in the QRS complex, known as Osborn waves, mild ST-segment
of this syndrome on serial ECGs, it would exclude the unnec- elevation, most prominent in the anterolateral leads.
essary hazards of present-day revascularization therapy for
MI such as primary angioplasty or thrombolytic therapy, or
aggressive management of acute pericarditis.
such as hypercalcemia, brain damage, cardiac arrest, Chagas’
HYPOTHERMIA
disease, ischemic heart disease, and the Brugada syndrome.
Hypothermia slows both conduction and repolarization, in
this way prolonging all measured ECG intervals.45–49 Also AV
nodal block may be part of the picture. The presence of T HE LONG QT SYNDROME
Osborn waves in hypothermic patients appears to be a func- The long QT syndrome is characterized by a prolonged QT
tion of temperature rather than the electrolyte or acid–base interval and torsades de pointes ventricular arrhythmias,
status (Fig. 3.62).43 Below a temperature of 30°C, the J waves leading to collapse and sudden death. Hereditary and acquired
are detectable in 80% of patients. Ventricular fibrillation is forms exist, and recently the genetic aspects of the former
a major risk at core body temperatures below 27°C. and the pharmacologic aspects of the latter conditions have
The electrophysiologic mechanism of Osborn waves is gained much attention. Characteristics of the ST-T interval
suggested to be related to an epicardial–endocardial voltage have been described in relation to the genetic form of
gradient associated with the localized spike and dome morphol- LQTS.50,51 The ECG during sinus rhythm shows, besides the
ogy of Ito-mediated action potential in ventricular epicar- prolonged QT interval, a dynamic behavior of the T wave,
dium but not endocardium.40 such as T-wave alternation and bifid T waves, depending on
Osborn waves are most commonly observed in hypother- the rate and regularity of the preceding rhythm and the state
mia. Also other conditions reportedly may cause J waves, of the autonomic nervous system (Fig. 3.63).

I V1

II V2

III V3

aVR V4

aVL V5

aVF V6
FIGURE 3.63. The long QT syndrome. Alter-
nation of the T waves.
74 chapter 3

A B C D E F
I I

II II

III III

aVR aVR

aVL aVL

aVF aVF

V1 V1

V2 V2

V3 V3

V4 V4

V5
V5

V6 V6
KALIUM KALIUM
(mmol/L) (mmol/L) NaHCO3
FIGURE 3.64. Hyperkalemia. Six panels showing increasing levels pearance of P wave, widening of the QRS complex, and occurrence
of serum potassium (A–D) and abrupt normalization on sodium of peaked and negative T wave. On treatment rapid normalization
bicarbonate infusion (E,F). Note the gradual flattening and disap- is seen.

Recently also a short QT syndrome was described as a

familial cause of sudden cardiac death.52

ELECTROLYTE A BNORMALITIES 53
Changes in Serum Potassium Concentration. The
changes in the surface ECG are frequently correlated with
endo
the serum potassium level. However, no constant relation-
ships between the potassium level and the ECG abnormali-
ties exist. The more acute and severe the abnormalities, epi
the better the correlation. Probably the ECG changes are the
result of the extra-intracellular myocardial potassium gradi-
70 mV
ent. This gradient is decreased in hyperkalemia and increased
90 mV
in hypokalemia.
R
Hyperkalemia. Hyperkalemia, frequently occurring in
renal failure, extensive tissue damage, or adrenal dysfunc- J
T
tion, may lead to profound changes in the ECG. Depending
on the level of serum potassium, the cardiac action potential
shows diminished diastolic polarization, slowing of phase 0, Q
S
slowed conduction, and shortening of the action potential
duration (Figs. 3.64 and 3.65). Above serum levels of 5.8 mmol/
L the T wave become peaked and small, and with increasing FIGURE 3.65. Hyperkalemia. Scheme of underlying mechanism.
levels ST segment depression and disappearance of the U See text.
 elect roca r diogr a ph y 75

A B

I V1 I V1

II V2 II V2

III V3 III V3

aVR V4 aVR V4

aVL V5 aVL V5
FIGURE 3.66. Hypokalemia. (A) Hypokale-
mia, as shown by the bifid T waves merging
with U waves. (B) Normalization of repolariza-
tion waves after restoration of potassium aVF V6 aVF V6
concentration. 400 msec

waves is seen. Above 6.k mmol/L atrial, atrioventricular and nature of the ECG, the deflections in the respective leads
ventricular conduction impairment is seen. This leads to a being the consequence of timing, direction, and strength of
decrease in and broadening of the P waves, a prolonged PR the electrical instantaneous forces. Standard recordings are
interval, and widening of the QRS complex and T-wave nega- derived from six leads in the frontal plane and six leads in
tivity. At higher levels no P waves are visible anymore and the transversal plane. Additional (mostly right precordial)
the widened QRS fuses with the T wave. This ECG picture leads are used mainly for the purpose of diagnosing RV
may be confused with slow ventricular tachycardia. Indeed, infarction. The ECG is especially helpful not only in diag-
lethal ventricular arrhythmias may occur in this setting. nosing structural and functional aspects of cardiac disease
The ECG changes in hyperkalemia are more prominent but also in monitoring its natural history, in assessing its
in cases of concomitant hyponatremia, acidosis, or severity, in identifying the patient at risk, and in evaluating
hypocalcemia. the effect of treatment. Structural changes of the four cardiac
compartments are recognized, such as left and right atrial
Hypokalemia. Hypokalemia, a frequent complication
and ventricular hypertrophy, infarction, and cardiomyopa-
of the use of diuretics, leads to decreasing potassium levels
thy. Also conduction disturbances in atria and ventricles can
and to flattening of the T waves, ST depression, and increase
be diagnosed, leading to specific widening of the P wave and
of the U wave (Fig. 3.66). This further leads to increasing
QRS complex. In the left and right bundle branch block,
fusion of the T and U waves until both waves are not to be
sequential activation of the ventricles is present, allowing
distinguished anymore. In this setting torsades de pointes
more accurate assessment of each ventricle separately.
arrhythmias may occur. Also digitalis-induced arrhythmias
Changes from the typical configuration of the right and left
occur more frequently in hypokalemic states. The picture is
bundle branch block give information about additional
enforced by concomitant hypercalcemia.
disease affecting the heart.
Changes in Serum Calcium Concentration. Cal- The ECG has proven to be especially useful in diagnosing
cium influences the duration of the plateau phase of the acute ischemia. ST elevation and non-ST elevation acute
monophasic action potential. The ECG picture is dependent coronary syndromes are recognized, enabling the stratifica-
on the ionized calcium concentration rather than on the tion of patients to different diagnostic and treatment strate-
amount of protein bound calcium. The correlation between gies. Assessment of the acuteness and severity of the
serum calcium levels and the ECG is better than in distur- ischemia, the area at risk, and the coronary vessel involved
bances of the potassium metabolism. In hypocalcemia the can be derived from the surface ECG. For the latter purpose,
repolarization phase is prolonged, especially at the expense the directional change of the ST segment, as depicted by the
of lengthening of the ST segment, whereas the QRS and T ST vector, was found to be very useful. ST vectors pointing
wave duration remain the same. In hypercalcemia QT short- in a rightward direction, leading to ST elevation in aVR,
ening is seen, due to shortening of the ST segment, and in identify high-risk patients both in STEMI, such as in proxi-
severe cases the T wave follows the QRS complex directly. mal LAD occlusion, and in non-STEMI, such as in main
stem or three-vessel disease. In inferoposterior infarction,
high-risk situations are recognized by diagnosing right ven-
Summary tricular involvement and atrial infarction. Recognizing con-
duction abnormalities in ischemic syndromes is also of help
Electrocardiography is the graphic one-dimensional repre- in identifying the high-risk patient.
sentation of the electrical activity of the heart as recorded The analysis of T-wave changes has been found to be
from the body surface. The basic principle is the vectorial important in acute, subacute, and chronic coronary syn-
76 chapter 3

dromes, and in a number of other important disorders, such the prediction of major cardiovascular events. JAMA 2004;
as early repolarization, hypothermia, the long and short QT 292:2343–2349.
syndrome, and electrolyte abnormalities. 16. Bommer K, Weinert L, Neumann A, Neef J, Mason DT, De
Marias A. Determination of right atrial and ventricular size by
two-dimensional echocardiography. Circulation 1979;60:
Acknowledgments 91–100.
The artwork of Adri van den Dool and Geert-Jan van 17. Sreeram N, Cheriex EC, Smeets JL, Gorgels AP, Wellens HJ.
Value of the 12–lead electrocardiogram at hospital admission
Zonneveld is greatly acknowledged.
in the diagnosis of pulmonary embolism. Am J Cardiol
1994;73(4):298–303.
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 4 Chest X-Ray
Mary Ella Round

Principles of Chest Radiography. . . . . . . . . . . . . . . . . . . . . 80 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

Pathophysiologic Principles Pertaining to the
Radiographic Signs of Cardiovascular Disease . . . . . . 86

Key Points pass through the aortic valve, while the mitral valve and
its annulus lie posterior and inferior to that diagonal.
• Chest x-ray is perhaps the simplest radiologic test, and • Aortic dissection is not a plain chest film diagnosis.
yet it is highly valuable, as it can be used to diagnose and • Pulmonary venous pressure greater than 10 to 12 mm Hg
assess the severity of cardiovascular diseases and the results in redistribution or “cephalization” of blood from
response to therapy. the lung bases into the upper lobe vessels, while peribron-
• Optimal image acquisition is essential for the proper chial “cuffing” and fluid accumulation in the interlobu-
interpretation of the findings on a chest x-ray. lar septa, referred to as Kerley B lines, suggest a
• To reduce oversights, a consistent approach to film inter- pulmonary venous pressure between 20 and 30 mm Hg.
pretation should be followed for each observation. Elevated pulmonary venous pressure greater than
• A “good” inspiratory effort is indicated by the right hemi- 30 mm Hg demonstrates symmetric small parenchymal
diaphragm being inferior to the eighth posterior right rib. densities in addition to the above findings.
If an image is obtained during expiration, the cardiac • Pulmonary arterial hypertension is manifested by
silhouette appears larger and the pulmonary markings decreased caliber of the lower lobe segmental arteries
are more prominent. (pruning) and dilatation of the central or main pulmo-
• The interpretation of the cardiac size, silhouette, and nary arteries.
pulmonary parenchymal markings depends on the posi- • Radiographic signs do not correlate well with pulmonary
tioning and projection of the patient. embolic disease, and further testing is required, if clini-
• An increased or “splayed” angle of carina suggests eleva- cally suspicious.
tion of the left mainstem bronchus secondary to left • Fewer than 10% of the patients with pulmonary embo-
atrial enlargement as seen in cardiomyopathy or mitral lism show the classic signs referred to as the Hampton’s
stenosis. hump, the Westermark sign, and the Fleischner sign.
• Visualizing the edge of the lung is necessary for diagnos- • Radiographic findings on a chest x-ray are similar in car-
ing a pneumothorax. diomegaly and pericardial effusion.
• Pulmonary vascular markings are normally distinct.
Indistinct markings, fissural thickening, and septal lines Conventional chest radiography remains one of the most
suggest vascular congestion and radiographic diagnosis of frequently ordered radiologic examinations in clinical cardi-
congestive heart failure. ology. Chest radiographs are universally available, relatively
• The cardiac diameter divided by the widest chest diame- inexpensive, and cost-effective. The exam can be used to
ter should be less than 60%. The average value is 45% in assess patient response to therapy or to monitor the status of
a 70-kg man. cardiovascular disease.
• The volume of the left ventricle must increase by approx- This chapter is limited in its scope. A brief summary of
imately 66% in order to produce an abnormal cardiotho- radiographic technique is provided. Radiographic findings in
racic ratio. the normal patient population and the critically ill are
• A dilated right ventricle will not affect the cardiothoracic addressed. A sample algorithm for evaluating the chest radio-
ratio. graph is presented. Finally, radiographic interpretation
• In the lateral view on a chest x-ray, a line drawn from the specifically as it pertains to cardiovascular disease is
junction of the sternum and diaphragm to the carina will reviewed.

79
80 chapter 4

Principles of Chest Radiography tial absorption and the image documents a contrast between
the lung parenchyma and the vertebral body.
The purpose of the conventional chest radiograph is to
Principles of Radiologic Technique
visualize clearly the thoracic anatomy on the posterior ante-
An x-ray is a bundle of electromagnetic energy called a rior (PA) and lateral radiographs. Optimal chest x-ray images
photon. The average energy of an x-ray photon is 30 kiloelec- are the product of appropriate utilization of peak kilovoltage,
tron volts (keV). Radiographic image production entails the amperage, and time expressed as milliampere-seconds2 (Fig.
x-ray photons passing through tissue and interacting with an 4.1). The kilovoltage peak (kVp) determines the maximum
image receptor. The image receptor can be a radiographic energy of the emitted photons from the x-ray tube. The mil-
film. In computed radiology or digital imaging, the image liampere-seconds (mAs) measures the tube current and expo-
receptor is a computer chip that can store and display the sure time in seconds. This parameter determines the number
radiographic image on a digital screen. The quantity and of photons emitted. Typically chest radiographs are per-
quality of the x-ray beam affects the interaction within formed at 120 kVp and 5 mAs. Equally important factors
various tissues in the body. Conversely, the composition of include characteristics of the x-ray generator, the target film
the anatomic tissues affects the x-ray beam interaction. The distance (72 inches), compatible film–screen combinations,
radiation that exits the patient will have varying energies, and the appropriate use of a grid. Depending on the clinical
which can translate to different shades of gray on the image question, these factors can be altered to best visualize the
receptor.1 anatomy in question. For example, the technical exposure
To create an image the x-rays must be absorbed at differ- factors can be altered to visualize the ribs or lungs. Overex-
ent levels. The interaction of the x-ray with matter may be posure of the chest x-ray is appropriate in patients sustaining
one of three interactions—the x-ray may be absorbed, scat- blunt trauma in which it is critical to visualize the medias-
tered, or transmitted. X-rays can pass through the lung paren- tinal soft tissue structures and the pulmonary parenchyma
chyma unimpeded, but they cannot pass through the behind the heart (Fig. 4.2). A higher mA, however, also could
vertebral body. The image receptor then detects the differen- lead to secondary or scattered Compton radiation, which is

FIGURE 4.1. The cardiac silhouette, pulmonary vasculature, pul- The technical factors used to obtain this PA radiograph (A)
monary parenchyma, diaphragmatic surfaces, and costophrenic were 110 kVp and 1.6 mAs and, for the lateral (B), 110 kVp and
angles should all be clearly visible without the use of a “bright” light 6.5 mAs.
in both the posteroanterior (PA) (A) and the lateral (B) projections.
 c h e s t x- r a y 81

FIGURE 4.2. “Overpenetrated” PA (A) and lateral (B) chest x-rays at the expense of “burning out” the lungs, including the pulmonary
of the patient as in Figure 4.1 obtained with 120 kVp and 3.0 mAs. vasculature.
This technique demonstrates the thoracic spine through the heart

often referred to as “fog” as it can obscure the pulmonary cessed, the image is permanent and further adjustments
interstitium, bronchi, and pulmonary vessels (Fig. 4.3). cannot be made. This can sometimes result in repeating the
Conventional film–screen radiography is limited by these image to answer clinical questions. Digital imaging
technical parameters. Once a conventional image is pro- can record a wider range of tissues with one exposure. This

FIGURE 4.3. Effect of secondary (Compton) radiation “fog” on the pulmonary parenchyma and vasculature are clearly demon-
“image clarity” in the same patient as in Figure 4.1: 110 kVp and strated. (B) Radiation “fog” diminishes image clarity, particularly
1.6 mAs (A); 110 kVp and 6.9 mAs (B). (A) The image is “sharp” and as it relates to the lungs and the pulmonary vasculature.
82 chapter 4

information provides quantitative data on the attenuation projection is anterior to posterior or anteroposterior (AP).
characteristics of the tissues to visualize the thorax with or Obtaining radiographs at maximum inspiration is limited in
without overlying structures. Radiographic images can now this setting. Since the patient is supine or semierect, the
be obtained, interpreted, processed, stored and retrieved blood flow is redistributed to the upper lobe pulmonary veins
more quickly.3 Computed radiography (CR) or digital radiog- and the heart is magnified.4
raphy has largely replaced conventional screen–film combi- Inspiratory effort is evaluated by the diaphragmatic
nation techniques. A common technique in CR uses a excursion. A “good” inspiratory effort is indicated by the
photostimulable phosphor plate within a cassette to store right hemidiaphragm being inferior to the eighth posterior
transmitted x-rays. An exposed cassette is scanned with a right rib (Fig. 4.4). When evaluating patients with more com-
low-energy laser beam to encode the digital image. Newer pliant lungs, the 11th rib may be visualized. Frequently
technologies include using a photoconductor such as amor- patients with chronic obstructive pulmonary disease will
phous selenium to convert x-rays directly into electrical also demonstrate an increased inspiratory lung volume. The
charges. This technique is used in digital radiography right hemidiaphragm is usually higher than the left. If an
(DR).3 image is obtained during expiration, the cardiac silhouette
appears larger and the pulmonary markings are more
prominent.
Principles Regarding the Chest X-Ray
The routine chest radiograph includes the posteroanterior
Normal Chest X-Ray
(PA) and lateral projections. Each is obtained with the patient
erect and in deep inspiration if the patient is able. Ideally, The normal anatomic landmarks of the mediastinum visual-
patients are imaged without overlying radiopaque foreign ized on the PA radiograph include the aorta, the lateral
bodies or artifacts. Chest radiographs are obtained usually margin of the left subclavian artery, the aorticopulmonary
with a high kilovoltage and milliamperage to decrease expo- clear space or “window,” the main pulmonary artery, the
sure time and cardiac motion. lateral margin of the left auricular appendage, the lateral
Posteroanterior (PA) refers to the direction of the x-ray margin of the left ventricle, and, on the right, the brachioce-
beam through the chest. The patient is positioned with the phalic artery, the superior vena cava, and the lateral margin
anterior chest wall closest to the film. The lateral chest x-ray of the right atrium (Figs. 4.5 to 4.7).
is obtained with the patient’s left side closest to the film. The right hilum is typically higher than the left. The
This positioning coupled with the x-ray source 72 inches hilar densities are composed mainly of right and left main
from the detector results in the most radiographically accu- pulmonary arteries and their primary divisions. The azygous
rate representation of the cardiac size. vein is seen at the junction of the trachea and the right main-
Patients who are unable to be imaged in the radiology stem bronchus.
department may require portable chest radiography exami- The carina and the bronchi are best visualized on the PA
nations. The cassette is placed behind the patient and the radiograph. Usually the carina angle is acute. If the angle is

FIGURE 4.4. Effect of inspiration (A) and expiration (B) of the same patient as in Figure 4.1 obtained within minutes of each other. (B) In
expiration, both the superior mediastinum and the cardiac silhouette increased in transverse diameter.
 c h e s t x- r a y 83

FIGURE 4.5. Normal PA chest x-ray shows, along the left side of
the cardiac silhouette, from superior to inferior, the lateral margin
of the left subclavian artery (straight black arrow), the aortic arch
(asterisk) the aorticopulmonary window (arrowhead), the main pul-
monary artery (p), the left auricular appendage (open black arrow),
and the lateral wall of the left ventricle (large white arrow). On the
right, the superior vena cava (curved black arrow), the azygos vein
(small white arrow), and the wall of the right atrium (curved open
arrow) are visible.

increased or “splayed,” then the elevation of the left main-

stem bronchus may be secondary to left atrial enlargement
as seen in cardiomyopathy or mitral stenosis.
On the lateral chest x-ray, normal anatomic landmarks
include the anterior wall of the right atrium, the posterior
segment of the aortic arch and the proximal descending
aorta, the posterior left atrium, the posterior left ventricle,
and the inferior vena cava. The retrosternal clear space is a
radiolucent area posterior to the sternum and anterior to the
ascending aorta. Right ventricular enlargement may encroach
upon the retrosternal clear space. Left ventricular enlarge-
ment is noted on the lateral exam when the left ventricle
border projects greater than 2 cm behind the inferior vena
cava (Fig. 4.7B).
The lobar pulmonary arteries arise from the main pul-
monary arteries.5–7 The lobar arteries accompany the lobar
and segmental bronchi branching out from each hilum. In
the upper lobes, the pulmonary arteries extend superolater- FIGURE 4.6. Normal chest x-ray. (A) PA. (B) Lateral. Major land-
ally from the superior portion of the hilum. The arterial marks on cardiac silhouette are marked. RA, right atrium; LV, left
margins are normally sharply defined. The arteries branch ventricle.
and gradually diminish in caliber. The upper lobe veins are
less numerous than the pulmonary arteries. Normally, the
84 chapter 4

FIGURE 4.7. Relationship of the posterior wall of the left ventricle

to the inferior vena cava on a lateral chest x-ray as an estimate of
cardiac size. (A) On the erect PA chest x-ray, the heart appears
enlarged with left ventricular preponderance. (B) However, on the
lateral chest x-ray, the distance between the inferior vena cava
(arrowheads) and the posterior wall of the left ventricle (arrows) is
less than 2 cm (double-ended arrow), indicating that the heart is not
enlarged.

pulmonary arteries, bronchi, veins, and accompanying inter- Principles for Assessing the
stitial tissue are visible up to 2 cm from the visceral pleural Radiographic Examination
surface over the convexity of the lung (Fig. 4.8).
The lower lobe arteries and veins extend inferiorly and A consistent approach to film interpretation should be fol-
laterally from the inferior aspect of the hila.6 There is a dif- lowed for each observation. Some clinicians interpret images
ference in the size of the pulmonary vessels in the upper lung from the center radiating outward or vice versa. The
zones compared with the lower, as a result of pressure varia- approach is not as important as a consistent algorithm. This
tion in the blood flow from the apex to base. A similar provides the observer with a system to evaluate areas of
volume of lung at the base of the lung has a four to eight secondary interest that might otherwise be forgotten. This
times increased blood flow as a similar volume at the apex.8 suggested approach or checklist may help in evaluating car-
These findings are not so apparent on the supine diovascular disorders while starting with areas of secondary
radiograph. interest.
 c h e s t x- r a y 85

FIGURE 4.8. Normal left upper lobe pulmonary vasculature as

seen on an erect PA chest x-ray. The pulmonary arteries (a) extend
upward from the superior aspect of the hilum in an arborizing
pattern as they leave the hilum, the arteries are 3 to 4 mm in width
with sharply defined margins. The arteries branch, taper, and gradu-
ally disappear as they approach the periphery of the lung. A left
upper lobe vein (v) is visible in the second anterior interspace lateral
to the arteries. It extends obliquely downward toward the left atrium
in a course that is inconsistent with its arising from the pulmonary
artery.

Assessing the chest radiograph should begin with assess-

ing the patient identification parameters and date, including
the year. Appropriate comparison x-rays or complementary
studies should be available for possible correlation. Briefly
the positioning of the patient and the projection of the radio-
graph should be noted. Posterior and lateral imaging is not
always possible in the acutely ill patient. The interpretation
of the cardiac size, silhouette, and pulmonary parenchymal
markings depends on the positioning and projection of the
patient (Fig. 4.9). In the critically ill patient evaluation may
start with overlying or indwelling lines and tubes.9 A list of
possible lines and tubes that one may find in a critically ill
patient is shown in Table 4.1.
Considering chest x-ray findings outside the thorax first
may be helpful to identify secondary findings. The soft
FIGURE 4.9. Effect of erect (A) and supine (B) posture on the PA
tissues may give clues of trauma or prior surgeries. Cardiac chest x-ray of the same patient obtained within minutes of each
surgery, thyroid procedures, and breast surgeries are other. (A) The erect PA chest x-ray was obtained with a target film
frequently noted by surgical clips or wires. Next, evaluation distance (TFD) of 72 inches and in deep inspiration. (B) The supine
of the abdomen can exclude intraperitoneal gas or spleno- chest x-ray was obtained at a TFD of 46 inches and in deep inspira-
tion. Recumbency produces positional redistribution of blood
megaly. Visualizing the bowel gas pattern is also important. throughout the cardiovascular system, resulting in increased trans-
Evaluating the bony thorax for subtle cough fractures may verse diameter of the superior mediastinum and the cardiac silhou-
also explain chest pain in the cardiology patient. Back pain ette as well as increased width of the upper lobe vessels.
86 chapter 4

from a thoracic aortic aneurysm may be suggested clinically; TABLE 4.2. Chest x-ray evaluation
however, careful evaluation of the thoracic vertebral bodies Check identifying parameters and date of exam
may document a compression wedge fracture. The pleura Recognize the positioning of the patient, inspiratory effort, and
should be evaluated for a pneumothorax or pleural effusion. projection
Visualizing the edge of the lung is necessary for diagnosing Lines, tubes, and cardiac devices
a pneumothorax. In the supine patient the air migrates Soft tissues
anteromedially and can outline the heart. The upright exam Thyroid, breast, and cardiac procedures
may show a pneumothorax at the apex of the lung. A pleural Upper abdomen
effusion can be diagnosed as a crescent or meniscus in the Bowel gas pattern, free intraperitoneal air, splenomegaly
lateral or posterior costophrenic sulcus. Evaluating the lungs Bones
for an infectious or neoplastic abnormality may be the most Cough fractures, surgeries, compression fractures, metastasis
natural evaluation of the chest x-ray. Evaluating the lungs in Pleura
the middle of the algorithm ensures that secondary findings Pleural effusion, pneumothorax
will not be missed. The pulmonary vascular markings should Lungs
be evaluated for three separate findings. Pulmonary vascular Neoplasm, inflammatory process
markings are normally distinct. If the markings appear Pulmonary vascular markings
indistinct, vascular congestion should be considered. Fis- Indistinctness, septal lines, fissural thickening
sural thickening and septal lines are two other radiographic Mediastinum (may best be evaluated by CT)
Tumor, lymphadenopathy, aortic pathology
signs to include in the imaging diagnosis of congestive heart
failure. Classically, the redistribution of pulmonary blood Cardiac pericardial silhouettes (may best be evaluated by
echocardiography)
flow is used to make the diagnosis of heart failure. Patients
Cardiomegaly, pericardial effusion
in congestive heart failure may not be able to stand or gener-
ate a deep inspiratory effort to demonstrate these findings on Pathophysiologic principles pertaining to the radiographic signs of
cardiovascular disease
the supine or semierect anterior posterior portable chest
radiograph.
Finally, the evaluation of the cardiac and mediastinal
silhouettes can proceed. Checking the width of the medias-
tinum and the contour can help the diagnosis of tumors,
aneurysms, or lymphadenopathy. Many factors contribute to
the mediastinal contour including patient positioning as
well as the projection of the radiograph (Fig. 4.9). With aging, cardiomegaly can look the same on a chest x-ray. It is impor-
the mediastinum may widen from vascular tortuosity. Even tant to evaluate the cardiothoracic ratio. A false-positive
the depth of inspiration affects the contour (Fig. 4.4). Subtle diagnosis of cardiomegaly is possible in the supine AP exam
abnormalities may be missed on chest radiographs and at poor inspiratory effort. When there is a question of cardiac
further evaluation with other cross-sectional modalities size or a pericardial effusion, echocardiography would best
such as computed tomography (CT) may be necessary. evaluate the heart. A useful list for assessing a chest x-ray is
The size and shape of the heart are determined by both shown in Table 4.2.
the pericardium and the heart. A pericardial effusion and

Pathophysiologic Principles Pertaining

to the Radiographic Signs of
TABLE 4.1. Lines, tubes, and devices in a critically ill patient Cardiovascular Disease
Percutaneous indwelling central catheter
Central venous catheter Heart
Pulmonary artery catheter
The cardiac silhouette should be evaluated for size and con-
Intraaortic balloon pump
figuration, signs of chamber preponderance (the chest x-ray
Pacemaker
does not distinguish between chamber dilatation and hyper-
Cardiac defibrillator
trophy), cardiovascular disease, coronary calcification, and
Left ventricular assist device left ventricular aneurysm.
Endotracheal tube A normal cardiac silhouette size may be determined by
Tracheostomy tube the cardiothoracic ratio. The PA view should be used. The
Intratracheal oxygen catheter cardiac diameter divided by the widest chest diameter should
Stents be less than 60%.10 The average value is 45% in a 70-kg
Feeding tube man.10 The volume of the left ventricle must increase approx-
Nasogastric tube imately 66% in order to produce an abnormal cardiothoracic
Intraesophageal monitor ratio.11 Since the right ventricle does not contribute to the
cardiac silhouette, a dilated right ventricle will not affect the
Temperature probe
cardiothoracic ratio. An accurate chest x-ray assessment of
pH probe
cardiac size is obtained from the inferior vena cava to the
Chest tube
left ventricular wall distance.
 c h e s t x- r a y 87

Valves the diagnosis of aortic dissection include aortography, trans-

esophageal echocardiography, and magnetic resonance
Cardiac valves are not visualized on a chest x-ray unless they imaging (MRI).
are calcified, typically at the annulus. Annular calcification Aortic aneurysms can present as a mass immediately
usually involves the aortic and mitral valves and is relatively adjacent to or indistinguishable from the aortic contour.
common in the elderly. Aortic valve calcification, on a chest Leaking aneurysms may widen the mediastinum and are
x-ray, is best located by following the ascending aorta down- associated with a hemothorax.
ward to its origin at the valve in the PA view. In the lateral
view on a chest x-ray, a line drawn from the junction of the
sternum and diaphragm to the carina will pass through the Pulmonary Vasculature
aortic valve, while the mitral valve and its annulus lie pos-
terior and inferior to that diagonal (Fig. 4.10). Pulmonary vasculature alterations do reflect altered pulmo-
Calcification of the mitral annulus is typically broad, nary hemodynamics.15–17
irregular and most commonly appears in a reversed C or J
configuration to the left of the spine and caudal to the atrial Pulmonary Venous Hypertension
appendage on the PA view of a chest x-ray.
Elevated pulmonary venous pressure is associated with car-
diomegaly. Occasionally pleural fluid collections develop.
Aorta Pulmonary venous pressure greater than 10 to 12 mm Hg
The diagnosis of acute aortic dissection must be considered results in redistribution or “cephalization” of blood from the
in any patient with the appropriate clinical symptoms and lung bases into the upper lobe vessels. Redistribution is man-
aortic ectasia or laminar aortic calcification.12–14 However, ifested on the erect PA chest x-ray by an increase in the
aortic dissection is not a plain chest film diagnosis. The number and caliber of upper lobe vessels. The upper lobe
diagnosis can be established or excluded with an intravenous vessels extend further toward the pleura. The upper lobe
contrast–enhanced helical CT. Other methods used to make vessels remain sharply demarcated (Fig. 4.11).

FIGURE 4.10. Cardiac valve sites. (A) On the lateral chest x-ray, the by its prosthesis (arrow), and the location of the tricuspid is shown
aortic valve (arrow) lies on or above a diagonal line connecting the by the upward arc (arrowhead) in the cable of the right ventricular
junction of the sternum and the diaphragm with the carina. (B) On electrode.
the frontal chest x-ray, the location of the mitral valve is indicated
88 chapter 4

FIGURE 4.11. Elevated pulmonary venous pressure without pulmo-

nary edema. This 18-year-old patient has a ventricular septal defect,
as reflected by the cardiac configuration. The intrinsic pulmonary
hypervolemia results in increased caliber of the upper lobe vessels,
whose margins remain distinct. There is no peribronchial cuffing.

Pulmonary venous pressure between 20 to 30 mm Hg

results in peribronchial “cuffing” (Fig. 4.12). The pulmonary
vessels are indistinct. Fluid accumulation in the interlobular
septa is evidenced by Kerley B lines. These are 1.0-cm, linear,
pleura-based densities visible on the lateral chest wall on the
PA chest x-ray and retrosternally on the lateral radiograph.
Elevated pulmonary venous pressure greater than
30 mm Hg demonstrates symmetric small parenchymal den-
sities in addition to the findings described at lesser pressures.
Kerley A lines are 2 to 3 cm long irregular linear densities
1 mm in width. These course obliquely from the lung to the
hilum and represent lymphatic channels (Fig. 4.13). These
findings may be manifest in other conditions. For example,
thickening of the interlobular septa or fissures may be seen
in anthracosis, hemosiderosis, occupational exposure, viral
pneumonia, or lymphangitic spread of carcinoma.

FIGURE 4.12. Interstitial pulmonary edema. (A) The normal radio- in the number and caliber of right upper lobe vessels whose margins
graphic appearance of this patient’s right lung. Note, particularly, are now indistinct (arrows, compare with A) and peribronchial
the medial right upper lobe artery (arrows) and the wall of the bron- “cuffing” (arrowheads), all representative of elevated pulmonary
chus (arrowhead). (B) Signs of interstitial edema include an increase venous pressure with interstitial pulmonary edema.
 c h e s t x- r a y 89
Abrupt or severe cardiac decompensation secondary to a
massive myocardial infarction or ruptured valvular leaflets
may result in a central symmetric consolidation.7

Pulmonary Arterial Hypertension

On the PA chest x-ray pulmonary arterial hypertension is
manifested by decreased caliber of the lower lobe segmental
arteries and dilatation of the central or main pulmonary
arteries (Fig. 4.14). In chronic obstructive pulmonary disease,
precapillary hypertension results in spasm of precapillary
arterioles. Persistent arterial hypertension causes the spasm
to move progressively proximally to involve the small arter-
ies. Persistent spasm results in hypertrophy and hyperplasia
of the muscular layer or media of the arteries that further
elevates pulmonary artery pressure. Classically, the radio-
graphic appearance of pulmonary artery hypertension is
referred to as “pruning” of the pulmonary arteries. The
pathophysiology demonstrates the distal vessels to appear
normal with hypertrophy of the central pulmonary arteries
and early divisions.

Pulmonary Embolism
The chest x-ray is usually the first imaging study performed
when pulmonary embolic disease is suspected and it is
usually nonspecific. One large study concluded the chest
radiograph to be normal in 12% of patients with pulmonary
emboli.18,19 Radiographic signs do not correlate well with
pulmonary embolic disease, and further testing is required
if clinically suspicious.18 Nonetheless, it is important to use
chest radiographs to exclude other causes of disease, such as

FIGURE 4.13. Alveolar pulmonary edema. (A) On the PA chest x-

ray, pulmonary vasculature is almost completely obscured by the
bilateral symmetric alveolar pattern parenchymal densities. Peri- FIGURE 4.14. Pulmonary arterial hypertension, seen in a PA chest
bronchial “cuffing” (arrowhead) is marked. (B) The lateral chest x- x-ray of this patient with chronic obstructive pulmonary disease, is
ray shows the “rosette” character of the alveolar fluid, unsharpness manifest by dilation of the main pulmonary arteries (arrowheads).
of the interlobar fissures (arrows) representative of subpleural edema, It is important to be aware that the basilar segmental arteries are
and a small pleural effusion (arrowhead). not “pruned,” but rather have a string-like appearance.
90 chapter 4

A B
FIGURE 4.15. PA (A) and lateral (B) chest x-ray in a patient with pericardial effusion.

pneumonia, pneumothorax, rib fractures, aortic dissection, in cardiac size on serial chest x-ray, a flask-shaped heart, and
pleural effusions, pericardial effusion, tumor, and hiatal relatively clear lung fields would favor the diagnosis of peri-
hernia. cardial effusion (Fig. 4.15). The presence of calcification, par-
Nonspecific radiograph findings in pulmonary embolic ticularly ring-shaped calcification, best visualized on the
disease include an elevated hemidiaphragm, pleural effusion, lateral view of a chest x-ray, would suggest the diagnosis of
and atelectasis. constrictive pericarditis. Epicardial fat and pericardial cysts
Although most pulmonary emboli occur without chest could alter the cardiac silhouette by obscuring the diaphrag-
x-ray findings, three classic radiographic signs have been matic angles.
described for pulmonary embolic disease. These signs occur
in fewer than 10% of patients with pulmonary emboli.18,19
The Hampton’s hump is a wedge-shaped pleural-based density Summary
representing a lung infarction secondary to an embolus. The
Westermark sign is proximal pulmonary arterial dilatation Chest x-ray remains one of the oldest and most commonly
and peripheral oligemia. The Fleischner sign is a large central used radiographic techniques. It can be used to diagnose
pulmonary artery due to central thrombus with abrupt taper- cardiovascular conditions and assess the response to treat-
ing. Helical CT is most accurate in detecting pulmonary ment. Appropriate image acquisition in conjunction with a
emboli. systematic approach is essential for proper interpretation of
Septic pulmonary emboli manifest as multiple ill-defined a chest x-ray. A good inspiratory effort and an erect position
wedge-shaped or round peripheral nodules on chest radio- are important determinants of a good-quality chest x-ray.
graphs. These can be associated with infected central venous Typically, the cardiac silhouette occupies about 45% of the
catheters, tricuspid valve endocarditis, or peripheral septic widest chest diameter. An increase beyond 60% indicates
thrombophlebitis. left ventricular enlargement, at least by 66%. Enlargement
of the right ventricle does not significantly affect the cardio-
thoracic ratio. Left atrial enlargement may be evident as
widening or splaying the angle of carina as well as fullness
Pericardial Diseases
and straightening of the left heart border. Chest x-ray find-
It is difficult to distinguish between cardiomegaly resulting ings of cardiomegaly due to chamber enlargement and peri-
from chamber dilatation and pericardial effusion on a chest cardial effusion are largely similar and not sufficiently
x-ray, as the findings are practically similar. An acute increase helpful in differentiating these two conditions.
 c h e s t x- r a y 91
A chest x-ray is not sufficiently sensitive or specific for 8. Glazier JB, DeNardo GL. Pulmonary function studied with the
the diagnosis of aortic dissection, which could be easily Xenon 133 scanning technique: normal values and a postural
diagnosed by spiral CT. Chest x-ray is quite useful in the study. Am Rev Respir Dis 1966;94:188.
diagnosis of pulmonary congestion and could provide some 9. Kazerooni EA, Goss BH. Cardiopulmonary Imaging. Philadel-
phia: Lippincott Williams & Wilkins, 2004:26.
evidence of left atrial pressure. An increased pulmonary
10. Danzer CS. The cardio-thoracic ratio: an index of cardiac
artery pressure is diagnosed by pruning of the middle and enlargement. Am J Med Sci 1919;157:513–521.
distal pulmonary arteries and dilatation of the main 11. Miller SW. Cardiac Radiography. The Requisites. St. Louis:
pulmonary artery. A chest x-ray has a poor sensitivity Mosby, 1996:6.
and specificity for the diagnosis of pulmonary embolism, 12. Razavi M. Acute dissection of the aorta: options for diagnostic
a condition readily diagnosed by spiral CT pulmonary imaging. Cleve Clin J Med 1995;62:360–365.
angiography. 13. Dowd SB, Wilson BG, Hall JD, et al. Review of techniques used
to image aortic dissection. Radiol Technol 1996;67:223–230.
14. Petasnick JP. Radiologic evaluation of aortic dissection. Radiol-
ogy 1991;180:297–305.
References 15. Simon M, Potchen EJ, Le May M. The radiographic assessment
of pulmonary hemodynamics. In: Simon M, Potchen EF, Le Nay
1. Fauber TL. Radiographic Imaging and Exposure. St. Louis: M, eds. Frontiers of Pulmonary Radiology. New York: Grune &
Mosby, 2004:46. Stratton, 1969:205–221.
2. Curry TS III, Dowdy JE, Murry RC Jr. Christensen’s Physics of 16. Healy RF, Dow JW, Sosman MC, Dexter L. The relationships
Diagnostic Radiology, 4th ed. Philadelphia: Lea & Febiger, of the roentgenographic appearance of the pulmonary artery to
1990:196–218. pulmonary hemodynamics. AJR 1949;62:777–787.
3. Fauber TL. Radiographic Imaging and Exposure. St. Louis: 17. Palla A, Petruzzelli S, Donnemaria V, et al. Radiographic assess-
Mosby 2004:291. ment of perfusion impairment in pulmonary embolism. Eur J
4. Chen MYM, Pope TL, Ott DJ. Basic Radiology. New York: Radiol 1985;5:252–255.
McGraw-Hill 2004:22. 18. The Prospective Investigation of Pulmonary Embolism Diag-
5. Muller NL, Fraser RS, Colman NC, Pare PD. Radiologic Diag- nosis (PIOPED) Investigators. Value of the ventilation/perfu-
nosis of Diseases of the Chest. Philadelphia: WB Saunders, sion scan in acute pulmonary embolism. Results of the
2001:18. prospective investigation of pulmonary embolism diagnosis
6. Harris JH. The pulmonary arteries and veins: their radio- (PIOPED). JAMA 1990;263:2753–2759.
graphic identification. Med Radiograph Photogr 1963;39: 19. Torassi GD, Floyd CE, Coleman RE. Improved noninvasive
52–53. diagnosis of acute pulmonary embolism with optimally
7. Milne ENC, Pistolesi M. Reading the Chest Radiograph. St. selected clinical and chest radiographic findings. Acad Radiol
Louis: Mosby-Year Book, 1993:9–79. 1996;3:1012–1018.
 5 Introduction to
Echocardiography
Raymond F. Stainback

Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Parametric Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Indications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Methods for Improving Two-Dimensional Imaging. . . . 125
Two-Dimensional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 97 Three-Dimensional Echocardiography. . . . . . . . . . . . . . . 128
Doppler Examination and Hemodynamics . . . . . . . . . . . 114 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Key Points raphy, harmonic imaging modalities, parametric imaging

modes, and selected three-dimensional techniques.
• Echocardiography is a safe, noninvasive, and widely
• Echocardiography examinations using standardized and
available method that often provides a definitive ana-
novel imaging modes are frequently applied to a wide
tomic and hemodynamic diagnosis and guides medical
range of new clinical treatments, including assessment
management.
of left ventricular assist devices.
• Although long viewed as clinically “mature,” echo-
• In this growing field, important quality assurance mea-
cardiography has undergone further “revolutionary”
sures have evolved along with imaging techniques to
advances during the past 10 years, including not only
improve the quality of delivered care.
technologic breakthroughs but also new clinical applica-
tions for older techniques. Echocardiography is a safe, noninvasive, and widely available
• The recent explosion of potential “add-on” techniques method that often provides a definitive anatomic and hemo-
presents echocardiographers with challenging questions dynamic diagnosis and guides medical management. The
about what constitutes real clinical progress and what modern echocardiography machine is a highly sophisticated,
techniques should be incorporated into the standard multimodal device that is an integral part of any cardiovas-
examination protocol. By becoming familiar with their cular care center. Ultimately, however, echocardiography
clinical indications, echocardiographers can use these remains operator-dependent and subject to the physical prin-
techniques selectively, on an “as-needed” basis, and thus ciples of ultrasound. Efficient usage of this technology
streamline patient care. depends on basic training1–4 in imaging techniques, machine
• Because of increased availability and clinical utility, settings, new technology, continuing education, quality
echocardiography’s usage has greatly expanded in recent assurance, data storage and retrieval,5 and reporting stan-
years. However, echocardiography demands a major com- dards.6–9 Accordingly, this chapter discusses the fundamen-
mitment in terms of time, personnel, ongoing training, tal physical principles of cardiovascular ultrasonography,
and technology. with an emphasis on classic two-dimensional (2D) and
• An understanding of the physics of ultrasound is essen- Doppler methods for transthoracic (TTE) and transesopha-
tial for performing echocardiography examinations and geal (TEE) echocardiography. This discussion will help echo-
interpreting their results. cardiographers design protocols for performing TTE or TEE
• A comprehensive transthoracic echocardiography exami- 2D and Doppler examinations and will provide a basis for
nation includes systematic acquisition of a set of two- understanding the more advanced imaging techniques. For
dimensional and M-mode views, along with spectral certain echocardiography-derived measurements of cardiac
Doppler and color Doppler evaluation of the intrathoracic mass, volume, area, and dimensions, interested readers
cardiovascular structures (e.g., the myocardium, cardiac should refer to other echocardiography chapters in this book
valves, pericardium, and great vessels). or to a comprehensive echocardiography textbook.
• Transthoracic and transesophageal echocardiography are
frequently used as complementary imaging techniques. Historical Perspective
Accordingly, the advantages and disadvantages of these
two methods should be understood. The first clinical cardiac ultrasound examination was per-
• Newer imaging modalities that are being introduced into formed in 1953 by two Swedish researchers, Inge Edler, a
the standard examination include contrast echocardiog- physician, and Hellmuth Hertz, an engineer, who used an

93
94 chapter 5

“ultrasonic reflectoscope” obtained from a shipyard and TABLE 5.1. Echocardiography indications: general categories
designed to detect structural defects in boats.10,11 The first Patients with signs or symptoms of cardiovascular disease
images consisted of A-mode signals that were hard to inter- Valvular heart disease (potentially pathologic murmurs)
pret and often misleading. However, the clinical impact of
Endocarditis
these images and their subsequent refinements was so sig-
Ischemic heart disease
nificant that, in 1970, Elder and Hertz received the Lasker
Chest pain syndromes (suspected to be cardiopulmonary in origin)
Prize in Medicine. By that time, the clinical aspects of their
technique were based primarily on M-mode examination.12 Congestive heart failure (systolic or diastolic)
During the 1970s, cardiology was revolutionized by further Cardiomyopathies
advances in surface planar imaging techniques (oscillating Pericardial disease
mechanical sector scanners,13 linear array transducers,14 and Hypertension/hypertensive heart disease
phased array transducers15,16) which provided recognizable, Atrial fibrillation/flutter
moving, cross-sectional images of the cardiac anatomy for Cardioembolic disease
the first time. M-mode17 and then “real-time” moving-image Disease of the aorta
capability18 was quickly adapted to TEE probes17,18 providing Suspected cardiac neoplasm
new higher-resolution esophageal imaging windows on the
Congenital heart disease
heart and aorta. Clinical spectral Doppler echocardiography
Hemodynamic instability/critically ill patients
techniques were introduced in the early 1980s.19,20 By 1986,
Suspected device malfunction (prosthetic valve, pacemaker lead,
the concept of an integrated M-mode, 2D, and spectral
ventricular assist device)
Doppler examination for use in clinical practice had fully
Invasive procedures (procedure monitoring, postprocedure
taken shape.21 This breakthrough was soon followed by the assessment)
addition of color-flow Doppler,22–26 biplane TEE,27–29 and then Cardiovascular surgery (intraoperative)
multiplane TEE imaging techniques.30,31 Pericardiocentesis
Cardiac biopsy
Percutaneous ASD closure (TEE/ICE)
Clinical Applications Electrophysiology, selected (TEE/ICE, lead extraction, RFA)
Percutaneous valve procedures
Throughout the 1980s and 1990s, the important role of 2D Screening echocardiography
and Doppler echocardiography in the diagnosis and manage-
Marfan syndrome (asymptomatic family members)
ment of many cardiovascular conditions became clearly
Hypertrophic cardiomyopathy (asymptomatic family members)
established, to the point of essentially replacing interven-
Familial dilated cardiomyopathy (asymptomatic family members)
tional hemodynamic testing in many cases. (The echocar-
diography indications are listed in Table 5.1.) From the late Cardiotoxic chemotherapy exposure (pre- and posttreatment)
1980s32 through the 1990s, a large number of clinical studies ASD, atrial septal defect; ICE, intracardiac echocardiography; RFA, radio-
frequency ablation; TEE, transesophageal echocardiography.
established echocardiography as a viable noninvasive means
of identifying “diastolic dysfunction” by analyzing several
routinely acquired blood-flow spectral Doppler,33–36 color M-
mode,37 and tissue Doppler imaging (TDI) parameters. This
led to a widespread realization that echocardiography can clinical focus that uses echocardiography for research and
readily identify a large, previously unrecognized subset of patient management.60–64
patients with congestive heart failure resulting from dia- In the 1990s, exercise and pharmacologic stress echocar-
stolic dysfunction despite a normal or near-normal left ven- diography came into widespread clinical use for the assess-
tricular ejection fraction.38 The comprehensive Doppler ment of myocardial ischemia, myocardial viability,65–72 and
examination can frequently help distinguish between certain valvular heart disease.73–77 The accuracy of stress echocar-
forms of diastolic dysfunction (e.g., constrictive,35 restric- diography continues to undergo refinement with the incor-
tive,39–41 hypertrophic,42 and ischemic43 cardiomyopathies) poration of newer imaging and Doppler techniques (see the
and can estimate the left atrial pressure,44–46 assess disease sections on Tissue-Doppler Imaging, Contrast Harmonics,
prognosis,40,47–53 and follow up the response to therapy.54–56 and Three-Dimensional Echocardiography, below).
Ongoing refinements include the use of increasingly sensi- With the development of intravascular and intracardiac
tive and specific anatomic and physiologic parameters to ultrasonography, the boundary between noninvasive and
assess not only diastolic heart failure but also ventricular invasive imaging techniques became blurred. Intravascular
mass,57 systolic function,58 and valvular heart disease. ultrasonography (IVUS),78 uses a shallow, high-resolution
radial image display (Fig. 5.1) that is ideal for assessing vas-
cular structures.78–82 Ongoing technologic refinements
Technologic Breakthroughs and Evolving include commercially available real-time, three-dimensional
Clinical Applications (3D) echocardiography83–87 (Figs. 5.10C, 5.45, 5.48, and 5.49),*
Although long viewed as clinically “mature,” echocardiog- miniature handheld ultrasonic devices (Fig. 5.2),88–92 and
raphy has undergone further “revolutionary” advances during intracardiac echocardiography (ICE).93–102 The latter
the past 10 years, including not only technologic break-
throughs but also new clinical applications for older tech- * To preserve the sequence of a typical TTE or TEE examination,
niques.59 The hemodynamic assessment of left ventricular the figures in this chapter are not always numbered sequentially,
assist devices (LVADs) is just one example of an emerging according to their order of appearance in the text.
 i n t roduct ion to echoc a r diogr a ph y 95
Echocardiography contrast agents (intravenously deliv-
ered, highly echoic microbubbles) and harmonic imaging
modalities (see below) have greatly improved the diagnostic
accuracy of left ventricular functional assessment during
routine and stress echocardiography. Microbubbles improve
endomyocardial detection by “opacifying” the blood pool.
Currently, two different echocardiography contrast agents
(microbubbles) are approved by the United States Food and
Drug Administration (FDA) for this indication. Left ventric-
ular opacification is possible only when microbubbles persist
within the imaging field during imaging. Conversely, another
application of microbubbles, myocardial contrast echocar-
diography (MCE) uses ultrasound energy to burst microbub-
bles within an area of interest. Intermittent observations
regarding the rate of myocardial microbubble replenishment
allow myocardial perfusion characteristics to be determined.
Although FDA approval is still pending, recent clinical
research suggests that MCE is a potentially important emerg-
ing clinical modality.123–126 Experimental studies have also
shown that acoustically active intravenous microbubbles
with surface ligands may permit “targeted” pathology-
specific ultrasound imaging.127,128 Additionally, microbubbles
may eventually also become vehicles for the localized deliv-
FIGURE 5.1. Intravascular ultrasound image from within a right ery of pharmacologic or gene therapy.129
coronary artery after deployment of a stent. Luminal dimensions The recent explosion of potential “add-on” techniques
are in millimeters. Submillimeter structures include a bright plaque presents echocardiographers with challenging questions
calcification (arrowhead) and a coronary stent wire in cross section about what constitutes real clinical progress and what
(arrow).
techniques should be incorporated into the standard exami-
nation protocol. By becoming familiar with their clinical
indications, echocardiographers can use these techniques
selectively, on an “as-needed” basis, and thus streamline
technology uses a phased array transducer and a planar patient care.
imaging-sector display analogous to a small intravascular
TEE probe that is inserted into the circulation percutane-
ously. This small ultrasound catheter has, in fact, been
employed as a TEE probe experimentally in tiny subjects.103
New clinical indications for ICE include guidance of electro-
physiologic radiofrequency ablation procedures,104 deploy-
ment of percutaneous atrial septal occluders101 (Fig. 5.3), and
monitoring of other interventional procedures.102 Because
IVUS and ICE are invasive techniques, they will not be dis-
cussed further in this chapter.
Novel parametric imaging modes enable rapid depiction
and quantitation of intramyocardial functional heterogene-
ity. Real-time, color-coded TDI105 (Figs. 5.41–5.45) and derived
strain (Fig. 5.46) and strain-rate image data (Fig. 5.47)106–109 are
now commercially available because of increased processing
speeds. These new Doppler methods for analyzing myocar-
dial motion produce familiar anatomic images with super-
imposed physiologic data (a color-encoded “parametric”
display). The combined anatomic and physiologic data are
stored digitally for either real-time or retrospective off-line
analysis. The clinical utility of parametric imaging tech-
niques (myocardial Doppler imaging) will increase as more
reference values110–112 and validation studies become available
for the assessment of cardiomyopathies, coronary artery
disease,113,114 ventricular dyssynchrony115,116 and other pathol-
ogies. Tissue-Doppler-imaging–derived “outcome indices”
are being developed117 to improve candidate selection for
cardiac resynchronization therapy (CRT)115,118–121 (Fig. 5.44) or FIGURE 5.2. Small handheld echocardiography device (arrow)
CRT refinement.117,122 being used at the bedside.
96 chapter 5

A
FIGURE 5.3. (A) Fluoroscopic image of an intracardiac echocardiog- (B) ICE ultrasound image obtained in the same patient. LA, left
raphy (ICE) device in the right atrium (arrow) just before release of atrium; RA, right atrium; RAA, right atrial appendage.
an atrial septal occluder (arrowhead) from its deployment catheter.

Indications cal examination, chest roentgenography, electrocardiography,

or other imaging procedures) or symptoms of cardiovascular
The indications for echocardiography are increasingly promi- disease. Important exceptions include screening of patients
nent in evidenced-based clinical practice guidelines.130–139 with a family history of genetically transmitted cardiovas-
Although these indications are too extensive to review here, cular disease. Examples include asymptomatic first-degree
Table 5.1 summarizes their general categories. Indeed, echo- relatives of patients with Marfan syndrome, other familial
cardiography indications are so numerous that one might aortic aneurysms, hypertrophic cardiomyopathy, or sus-
more appropriately ask when this method should not be used. pected familial dilated cardiomyopathy. In addition, echocar-
Because of increased availability and clinical utility, echo- diography may be used for baseline and follow-up evaluation
cardiography’s usage has greatly expanded in recent years. of left ventricular function in asymptomatic patients who
However, echocardiography demands a major commitment are to receive potentially cardiotoxic chemotherapeutic
in terms of time, personnel, ongoing training, and technol- agents.132,136–139
ogy. It is a valuable resource that must be deployed appropri-
ately. Echocardiography is not indicated for situations in
Transthoracic Versus Transesophageal
which it would not influence patient care; nor is it indicated
Echocardiography
for asymptomatic patients in whom detection of mild sub-
clinical lesions or misleading imaging artifacts could cause Because almost all the imaging modalities available for TTE
harm or increase cost because of a need for subsequent con- are also applicable to TEE, some confusion may exist regarding
firmatory procedures. No randomized clinical trials assess- the relative merits of these two methods. In fact, they are
ing the outcome of diagnostic imaging tests are available,132 complementary approaches, whose advantages and disadvan-
so expert opinion is based on summaries of clinical obser- tages vary depending on the diagnosis and imaging conditions.
vational studies.132,136–139 Consensus opinion regarding the Because TEE is semi-invasive and typically requires conscious
inclusion of additional new imaging modalities (e.g., con- sedation, it is usually preceded and “guided” by TTE. Because
trast, 3D, tissue harmonics, TDI) is not addressed in recent of numerous possible imaging windows, TTE often provides a
echocardiography guideline statements. However, clinical superior and more comprehensive Doppler examination. It can
guidelines do address the frequency with which indicated also provide a superior analysis of ventricular wall motion,
examinations should be repeated. Clinical research fre- particularly when echocardiography contrast agents are used.
quently relies on quantitative echocardiography methods140 Occasionally, a comprehensive surface echocardiogram will
that may go beyond the scope of routine clinical protocols. obviate the need for TEE. However, even in the best of hands,
a surface examination may be technically inadequate or it may
raise clinical suspicion concerning an underlying pathologic
condition that requires further evaluation by TEE. The trans-
Echocardiography as a Screening Tool
esophageal approach permits superior anatomic evaluation of
Echocardiography is not generally recommended as a screen- the posterior cardiac structures in most cases and optimal
ing tool for asymptomatic patients who lack signs (on physi- Doppler evaluation under special circumstances (e.g., assess-
 i n t roduct ion to echoc a r diogr a ph y 97
ment of periprosthetic mitral regurgitation, left atrial append- The propagation time (in seconds) required for sound
age assessment, congenital heart disease; or for aortic valve energy to complete 1 cycle of compression and rarefaction
planimetry). is called a period. In diagnostic ultrasonography, a typical
In the intensive care unit (ICU), TEE may be useful when period ranges from 0.1 to 0.5 μs, depending on the sound fre-
surface echocardiography is not logistically possible (e.g., in quency. Period and frequency are inversely related (period =
an intubated patient whose condition is unstable). Because 1/frequency). The wavelength is the propagation length,
TEE does not invade the operative field, it has largely sup- within a medium, of one complete cycle. Frequency and
planted intraoperative epicardial imaging and is widely used wavelength are also inversely related.
for hemodynamic monitoring during cardiovascular surgery. An “echograph machine” works by electrically stimulat-
At the end of cardiopulmonary bypass, TEE may be used to ing a piezoelectric element, called a “crystal” or ceramic,
assess congenital cardiac repairs, complex heart valve proce- that is housed within a transducer (Fig. 5.4). Mechanical
dures, left ventricular myomectomies, tumor removals, deformation of the crystal produces ultrasound waves that
LVAD implants, and aortic dissections involving the aortic are transmitted into the patient’s body, where they are scat-
root. Accordingly, a separate field of perioperative (intraop- tered, are reflected, or eventually fade (attenuate). The energy
erative) TEE has emerged, as practiced by dedicated cardiolo- from reflected ultrasound (echoes) deforms the transducer’s
gists, specially trained cardiovascular anesthesiologists,141,142 piezoelectric crystal, creating a faint electrical impulse that
and some cardiovascular surgeons. is amplified, processed, recorded, and displayed in the famil-
iar formats seen throughout this chapter.
Echocardiographic image resolution (clarity, or the degree
Two-Dimensional Imaging to which adjacent points in an image may be distinguished
as separate) is linked to ultrasound frequency. To clearly
show thin structures such as the endocardium, the valve
The Physics of Ultrasound
apparatus, and small mass lesions, basic surface echocardio-
An understanding of the physics of ultrasound is essential grams require an axial and lateral spatial resolution of 1 to
for performing echocardiography examinations and inter- 2 mm. An ultrasound wavelength of <1 mm is necessary to
preting their results. Sound comprises the directional (lon- achieve that resolution.
gitudinal) propagation of compressions and rarefactions of At all frequencies, the speed of ultrasound (propagation
an acoustic medium (air, tissues, fluids). The frequency velocity) in soft tissue is approximately 1,540 ms (1.54 mm/
(number per unit time) of these compressions and rarefac- μs). At a frequency of 1 MHz (1 million cycles per second),
tions is reported in cycles per second or hertz (Hz) (1 Hz = sound has a wavelength of 1.54 mm in soft tissue. Because
1 cycle/s). The spectrum of sounds audible by the human ear wavelength and frequency are inversely related, the wave-
ranges from 20 to 20,000 Hz. The term ultrasound denotes length of a 2-MHz signal is half that of a 1-MHz signal
sounds that are higher (>20 kHz) than the human audible (1.54 mm/2 = 0.77 mm). This wavelength is less than the
range. necessary spatial resolution, which is why a minimum

A B
FIGURE 5.4. (A) Broadband combined imaging and Doppler transducer with imaging gel and index mark (arrow). (B) Nonimaging “Pedoff”
transducer for dedicated continuous-wave Doppler examination.
98 chapter 5

frequency of 2 MHz is required for surface echocardiography. graphic imaging based on subtle reflections at tissue inter-
Higher ultrasound frequencies (20–40 MHz) produce even faces. However, the heart is surrounded by two strong
finer degrees of spatial resolution, allowing even ultrastruc- ultrasound attenuators—lung and bone—both of which tend
tural vascular layers to be measured with IVUS (Fig. 5.1). to variably reflect, scatter (lung), or absorb (bone) ultrasound
Reflected soundwaves may produce a wide variety of energy. This set of circumstances poses a major (and in some
imaging artifacts that can either be recognized as such or patients insurmountable) problem for cardiac ultrasound
can lead to erroneous interpretation. One reason for these imaging. The key to optimal imaging is the sonographer’s
artifacts is that the sound energy gradually attenuates as it degree of experience and the machine’s technologic ability
becomes more distant from its source. This attenuation to extract maximal usable information even from highly
eventually makes it impossible for the operator to distin- attenuated signals (see Contrast Harmonics, below). As dis-
guish reflected ultrasound signals from random background cussed above, TEE can be used adjunctively when surface
“noise” at a limiting depth of interrogation. However, signal echocardiography attenuation artifacts prevent adequate
attenuation is directly related to soundwave frequency, so it examination.
is more common at higher frequencies. High-frequency For further details about ultrasound physics, a number of
(high-resolution) imaging is possible only at shallower excellent references are available.143–147
imaging depths (low tissue penetration). This interplay
between ultrasound wavelengths, image resolution, and
signal attenuation explains why medically useful ultraso- Transthoracic Echocardiography
nography is constrained to a frequency range of 2 to 40 MHz
and to certain imaging depths. Transthoracic echocardiogra- Ordering an Echocardiogram
phy operates at one end of an imaging depth range of approxi- A comprehensive TTE examination includes systematic
mately 2 to 24 cm, and IVUS (Fig. 5.1) operates at the other acquisition of a set of 2D and M-mode views, along with
end (<1 cm). Transesophageal echocardiography (Fig. 5.26) spectral Doppler and color Doppler evaluation of the intra-
and ICE (Fig. 5.3) operate in the middle range (Table 5.2). thoracic cardiovascular structures (e.g., the myocardium,
Two-dimensional images are created from pulses of ultra- cardiac valves, pericardium, and great vessels). For ease of
sound. The pulse repetition frequency (in kHz) is inversely communication, ordering a comprehensive examination is
related to imaging depth. Along with the wavelength, the sometimes casually called “getting an echo.” The word
pulse duration and pulse length also affect image resolution. “echo” is potentially confusing for order-entry personnel and
Axial resolution (in which resolving points are aligned or in sonographers, however, because the necessary extent of the
parallel with the ultrasound beam) is superior to lateral reso- examination may be unclear. An initial comprehensive
lution (in which resolving points are perpendicular to the examination, including 2D imaging and Doppler evaluation,
ultrasound beam). is required for most patients. A limited 2D (anatomic-only)
Echocardiography machines produced in the 1980s oper- exam is reserved for following up certain previously diag-
ated with single-frequency transducers (2.5, 4, and 7 MHz) nosed pathologic conditions. To ensure that the clinical ques-
that had to be manually changed, depending on imaging- tion is addressed, all orders for an echocardiogram should
depth requirements (deep vs. shallow, in an adult vs. a pedi- include the exact indication for the study, pertinent details
atric patient). Modern transducers are “broadband,” or of the patient’s cardiovascular medical and surgical history,
“multifrequency,” and can better balance near- and far-field and pertinent physical findings when available. The patient’s
imaging by sending and receiving multiple frequencies age, sex, height, weight, and blood pressure at the time of the
simultaneously. examination should also be recorded. If possible, previous
Differences in acoustic impedances related to density echocardiography exams should be reviewed.5
and stiffness between adjacent media (e.g., tissue planes)
determine the extent to which soundwaves are either
Scanning Techniques
reflected or transmitted. Blood, myocytes, collagen, and
adipose tissue differ only slightly with respect to acoustic Without proper scanning procedures and machine settings,
impedance, and this fact forms the basis for echocardio- even the most advanced imaging devices may prove inade-
quate. Appropriate patient positioning is an important
element of good sonography. In the echocardiography labora-
TABLE 5.2. Cardiovascular ultrasound modalities tory, optimal results are generally obtained with the subject
lying comfortably in the left lateral decubitus position, but
Practical image Axial resolution
Modality f (MHz) depth (cm) (mm) this position is not always attainable by intubated, wounded,
or otherwise ill patients. As in cardiac auscultation, the left
TTE 2.5–5 25 1–2
lateral decubitus position allows gravity to decrease the dis-
TEE 4–7 20 0.5 tance from the myocardium to the listening device (trans-
ICE 5–10 10–15 0.2 ducer) by reducing the amount of interposed lung. To enable
IVUS 20–40 0.5–1.0 0.05 full access to apical windows and avoid apical foreshortening
Depth, maximum imaging depth; ICE, intracardiac ultrasound; IVUS, intra- of views, one should use a special echocardiography bed with
vascular ultrasound; TEE, transesophageal echocardiography; TTE, transtho- a pull-away section (Fig. 5.5). Extension of the patient’s left
racic echocardiography; f = ultrasound frequency.
arm, combined with gentle gravity-induced left lateral tho-
Note: axial resolution is also affected by emitted pulse length and pulse
duration. Indicated depth and resolution values are estimates; lateral resolu- racic extension, causes the ribs to spread slightly, minimiz-
tion (not shown) is poorer than axial resolution. ing acoustic shadowing. Depending on the body habitus,
 i n t roduct ion to echoc a r diogr a ph y 99
displayed on the right. In predominantly short-axis or cross-
sectional views, left-sided structures appear to the right of
the screen, and right-sided structures appear to the left, as if
the viewer were standing at the foot of a supine patient,
looking toward the head. Because the heart lies obliquely in
the chest, this is only a rough comparison, but it is consistent
with display standards for other types of axial imaging (i.e.,
computed tomography and magnetic resonance imaging). A
small icon (index mark), which varies depending on the man-
ufacturer, should appear to the right of the image sector (Fig.
5.6). This icon corresponds to a ridge or groove (Fig. 5.4A)
placed on one side of the otherwise symmetric imaging
transducer. In TTE, anterior structures appear at the top of
the screen, and more posterior structures appear toward the
bottom (Fig. 5.6).

FIGURE 5.5. Sonographer obtaining apical views, using a special Transthoracic (Surface) Echocardiography Views
echocardiography bed with a pull-away section (bracket), which
facilitates proper positioning of the transducer. PARASTERNAL LONG -A XIS (PSLAX) VIEW
Left Ventricular Inflow and Outflow Tracts. The
however, other positions (e.g., supine, semiupright, and right surface examination begins with a parasternal long-axis
lateral decubitus) may be used to optimize certain views. view of the left ventricular inflow and outflow tracts and
Because the typical examination lasts for 30 to 45 minutes the aortic root. The transducer is usually placed adjacent to
(not including the setup time), the sonographer should be the sternum in the left third or fourth intercostal space,
seated comfortably and ergonometrically, typically on the although optimal patient-imaging “window” positions may
patient’s left side (Fig. 5.5). Alternatively, scanning from the vary greatly from one patient to another. An initial high-
patient’s right side has some advantages, but it requires depth setting is selected to include anatomic features pos-
the sonographer to reach around the patient’s thorax, and this terior to the left ventricular chamber (Fig. 5.6). Subsequent
may be problematic. A coupling medium (ultrasonographic shallower, “optimized” views are focused on the left
gel) (Fig. 5.4A) is used to maximize ultrasound transmission ventricular myocardium and the valves (Figs. 5.7 to 5.9).
between the transducer and the patient’s body, in part by Important measurements (e.g., left ventricular end-diastolic
eliminating air interfaces. Breathing instructions are often septal- and posterior-wall thickness; left ventricular end-
crucial. For example, “breathe out and hold” can transiently diastolic and end-systolic internal chamber diameters) are
eliminate lung attenuation, bringing the heart into full view. obtained from a carefully selected midline imaging plane
“Small breath in and hold” can elevate the diaphragm and that bisects both the aortic and the mitral valve annuli
perhaps raise a rib-shadowed inferior left ventricular wall during diastole (Fig. 5.7A) and systole (Fig. 5.7B). A common
into view (apical two-chamber view). During normal breath- pitfall is acquisition and measurement of “off-axis” para-
ing, the heart moves phasically across the otherwise station- sternal views that yield erroneously small ventricular
ary imaging plane. This translational motion causes
endocardial segments (and other structures) recorded during
systole to be from a different anatomic location than those
recorded during diastole, leading to erroneous analyses of
segmental wall motion and anatomic volume measurements.
The sonographer can often “coach” a patient to stop breath-
ing at an ideal point in the respiratory cycle. When data are
then acquired during a brief breath-hold, the respiratory com-
ponent of cardiac translation, a common pitfall of real-time
planar imaging, can be eliminated.

The Planar Image Display

The planar image is sector-shaped. Ultrasound emanates
from the smallest portion of the displayed sector, which
appears at the top of the screen in echocardiograms of adults.
The broader, more distant portion of the image, derived from
diverging echoes, appears at the bottom of the screen. Because
the transducer position varies greatly throughout an exami- FIGURE 5.6. Parasternal long-axis view at increased depth. An
nation, spatial orientation entails a distinct learning curve index mark (arrowhead) always appears to the right of the image
sector. *, posterior pericardial effusion; **, pleural effusion; aAo,
related to poorly visualized adjacent thoracic anatomic land- ascending aorta; dAo, descending thoracic aorta; LA, left atrium; LV,
marks. In predominantly long-axis views, caudal structures left ventricle; RVOT, right ventricular outflow tract; Vb, vertebral
appear to the left of the screen, and cephalad structures are body.
10 0 chapter 5

A B
FIGURE 5.7. Parasternal long-axis view at a shallower, “optimized” tract; single arrow, mitral valve chordae tendineae; double-headed
depth. (A) Diastolic image with the mitral valve (double arrows) arrow, left ventricular outflow-tract dimension/diameter for calcu-
open and the aortic valve (single arrow) closed. Ao, aortic root; dAo, lating left ventricular outflow-tract flow. Line a indicates the orthog-
descending thoracic aorta; LA, left atrium; LV, left ventricle; RVOT, onal image plane shown in Figure 5.10A. Line b indicates the
right ventricular outflow tract. (B) Systolic image with the mitral orthogonal image plane shown in Figure 5.10B. Line c indicates the
valve closed and the aortic valve open. *, left ventricular outflow orthogonal image plane shown in Figure 5.11A.

diameters and erroneously large myocardial thicknesses. be imaged and measured if possible. This may require a
In addition to obtaining a “midline” image, the sonographer separate parasternal long-axis view at a more cephalad
should also scan incrementally toward both the medial and transducer position (Fig. 5.8). Note that aortic measure-
lateral aspects of the aortic and mitral valves to exclude ments distal to the aortic valve leaflets are obtained during
pathology along the extent of each valve’s leaflet coaptation diastole.
zone. Generally, measurements of parasternal diameters
should be obtained from 2D views (as opposed to M-mode). Right Ventricular Inflow Tract (Fig. 5.9). With the
Although M-mode measurements have certain advantages transducer in an optimized left-sided, parasternal long-axis
(fast sample rates and improved temporal resolution), their position, a subtle leftward and anterior tilting motion often
use can be limited by oblique cut planes imposed by patient easily produces the right ventricular inflow tract view, which
imaging-window constraints. The ascending aorta should includes the tricuspid valve and right atrium.

FIGURE 5.8. Parasternal long-axis view at the level of the aortic FIGURE 5.9. Parasternal long-axis view of the right ventricular
root and ascending aorta. The double arrows indicate the mitral inflow tract and tricuspid valve. Arrow, coronary sinus. A, tricuspid
valve anterior leaflet. Measurements of the proximal aorta are valve anterior leaflet; I, inferior vena caval ostium; P, tricuspid valve
obtained during diastole (with the aortic valve closed). a, Aortic root posterior leaflet; RA, right atrium; RV, right ventricle. (Note: With
diameter, sinus of Valsalva level; b, sinotubular junction diameter; more “septal” angulation, the tricuspid valve anterior and septal
c, ascending aortic diameter. leaflets may be seen in this view.)
 i n t roduct ion to echoc a r diogr a ph y 101
PARASTERNAL SHORT -A XIS VIEW Aortic, Tricuspid, and Pulmonary Valve Level (Fig.
5.11). Further cephalad positioning of the imaging plane
Left Ventricle (Fig. 5.10). With the transducer in above the left ventricular level reveals the aortic valve in the
an optimized left-sided parasternal long-axis position, a short-axis view. With that valve centered in the imaging
90-degree clockwise transducer rotation will produce left sector, subtle transducer adjustments will show the three
ventricular short-axis views. These “breadloaf” slices aortic cusps in perfect symmetry during diastolic closure.
should be obtained in the region of the apex (not shown), Color Doppler examination at this level (not shown) will
at the midpapillary muscle level (Fig. 5.10A), and through detect aortic regurgitation. Slightly cephalad, when imaging
the basal segments at the chordal and mitral valve leaflet conditions are ideal (in pediatric cases and frequently in
level (Fig. 5.10B). This approach will show the basal, middle, adults), the left and right coronary ostial locations within
and apical coronary artery distributions that correspond the aortic root can be recorded. The adjacent tricuspid valve,
to the standard 17-segment model.6 The left ventricular atria, interatrial septum, and right ventricular outflow tract
short-axis view should be perpendicular to the left ventri- are also visualized in this view. The pulmonary valve’s long
cular long axis. Ideal parasternal left ventricular axis (perpendicular to the aortic valve) is often not optimized
short-axis views are not obtainable when the left ventricle’s at the aortic leaflet level and is best seen in a separate,
major axis within the chest is located in an extreme slightly more cephalad imaging plane just above the aortic
anterior-to-posterior position (“horizontal” heart); in valve cusps. Branching of the left and right pulmonary arter-
such patients, only limited “oblique” or oval-shaped short- ies should be documented if possible (Fig. 5.11B). This view
axis views are possible, and these may be difficult to is important for Doppler evaulation of the right ventricular
interpret. out flow tract (Fig. 5.12).

A B

C
FIGURE 5.10. (A) Parasternal short-axis view of the left ventricle of the mitral anterior leaflet; AL, anterolateral commissure; P1,
at the papillary muscle level. AL, anterolateral papillary muscle; anterior scallop of mitral valve posterior leaflet; P2, middle scallop
PM, posterolateral papillary muscle. Line a indicates the orthogonal of the mitral valve posterior leaflet; P3, posterior scallop of the mitral
image plane shown in Figure 5.13A (apical four-chamber view). Line valve posterior leaflet; PM, posteromedial commissure; RVOT, right
b indicates the orthogonal image plane shown in Figures 5.7 and ventricular outflow tract. (C) Three-dimensional surface-rendering
5.13E (parasternal long-axis views and apical three-chamber). Line mode from the cut plane shown in Figure 5.10A, looking toward the
c indicates the orthogonal image plane shown in Figure 5.13D mitral valve. The arrow labels are the same as in B. AL, anterolateral
(apical two-chamber view). (B) Parasternal short-axis view, mitral commissure; PM, posteromedial commissure; RVOT, right ventric-
valve level. A1, anterior segment of the mitral anterior leaflet; A 2, ular outflow tract; *, left ventricular outflow tract.
middle segment of the mitral anterior leaflet; A 3, posterior segment
 10 2 chapter 5

A PICAL FOUR-CHAMBER VIEW (Fig. 5.13A)

This view is a good starting point from which one can easily
attain the other apical views by simply rotating the trans-
ducer. The cardiac apex and left ventricular major axis should
be centered within the imaging sector. The interventricular
septum appears on the left side of the sector, with the oppos-
ing lateral wall on the right side. The other apical views are
obtained by rotating the transducer counter clockwise around
the central axis. This view is used for Doppler evaluation of
the mitral valve (Fig. 5.14), the pulmonary veins (Fig. 5.15),
myocardial tissue Doppler (Fig. 5.16), and trisuspid valve (Fig.
5.17).

A PICAL FIVE-CHAMBER VIEW (Fig. 5.13B)

Angling the transducer slightly anteriorly from the four-
chamber view position produces the apical five-chamber
view, which shows the anterior interventricular septum, the
left ventricular outflow tract, and an oblique cut across the
A aortic valve.

A PICAL FOUR-CHAMBER VIEW: CORONARY SINUS L EVEL

(Fig. 5. 13C)
A slight inferior angulation of the imaging plane from the
apical four-chamber view will show the coronary sinus and
the inferior interventricular septum.

A PICAL T WO -CHAMBER VIEW (Fig. 5.13D)

By rotating the transducer 90 degrees counterclockwise from
the apical four-chamber view, one can see the left ventricular
anterior and inferior walls in opposition, as well as the mitral
valve and left atrium (two chambers).

A PICAL T HREE-CHAMBER (LONG -A XIS) VIEW (Fig. 5.13E)

An additional transducer rotation, approximately 30 degrees
counterclockwise past the apical two-chamber view, will
bring the right ventricular outflow tract, left ventricular
outflow tract, and aortic valve (long axis) into view. Analo-
B gous to the parasternal long-axis view, the apical three-
FIGURE 5.11. (A) Parasternal short-axis view, aortic valve level. chamber view shows similar anatomic features but focuses
Arrowhead, interatrial septum; single arrow, pulmonary valve; on the left ventricular endocardium. This view (along with
double arrows, tricuspid valve. L, left coronary cusp of the aortic
valve; LA, left atrium; N, noncoronary cusp of the aortic valve; R, the apical five-chamber view) is important for spectral
right coronary cusp of the aortic valve; PA, pulmonary artery; RA, Doppler evaluation of the left ventricular outflow tract (Fig.
right atrium. (B) Parasternal short-axis view, pulmonary artery (PA) 5.18).
level. Double-headed arrow, pulmonary annulus dimension for right Contrast echocardiography for improved endocardial
ventricular outflow-tract flow assessment. Ao, ascending aorta; L,
left PA at the pulmonary bifurcation; R, right PA at the pulmonary
definition (Fig. 5.19) is performed in apical views.
bifurcation; RVOT, right ventricular outflow tract. Note: The right
PA is directly posterior to the ascending aorta. Subcostal Views (Figs. 5.20 and 5.21)
While the patient lies supine with relaxed abdominal muscles
(the knees may be slightly flexed), the flat side of the trans-
ducer is placed on the abdomen. The transducer surface is
Apical Views (Fig. 5.13)
placed in the immediate right subcostal or mid-subxiphoid
With the patient carefully positioned, placing the transducer region, pointing toward the right shoulder. Gentle downward
over the palpated point of the left ventricular apical impulse pressure produces the subcostal four-chamber view (Fig.
is often a good way to start looking for apical windows. If 5.20A). Clockwise transducer rotation produces the subcos-
the transducer is not placed exactly over the cardiac apex and tal short-axis views (Fig. 5.20B). The subcostal view is impor-
properly aligned with the left ventricular major axis, apical tant for evaluating right ventricular function, left ventricular
“foreshortening” will occur. Because this condition impairs segmental wall motion (of the septum and lateral wall), the
ventricular segmental wall-motion analysis and volume interatrial septum, and pericardial effusion. This view may
assessment, avoidance of apical foreshortening is a crucial be excellent in patients with obstructive lung disease (hyper-
aspect of accurate scanning. expanded lungs) and can salvage an otherwise technically
 i n t roduct ion to echoc a r diogr a ph y 10 3

A B

C D
FIGURE 5.12. (A) Color-flow Doppler image of the right ventricular pulmonary valve annulus. Note the valve-closure artifact (arrow)
outflow tract and pulmonary valve: yellow (aliased) color is seen at and absence of an opening artifact, indicating a good sample-volume
the pulmonary valve (arrow). (B) Color-flow Doppler image of the position. Note the automated time-velocity integral (TVI = 0.141 m
pulmonary trunk, showing a normal pulmonary artery bifurcation. or 14.1 cm, arrowhead) from electronic outlining of the spectral
This is an important view for excluding a patent ductus arteriosus Doppler envelope (dotted curve). (D) Continuous-wave Doppler
or proximal pulmonary artery stenosis (not present in this normal image, right ventricular outflow tract (pulmonary valve). Note the
example). L, left pulmonary artery; R, right pulmonary artery. (C) typical small pulmonary valve opening (left arrow) and closing
Pulsed Doppler view of right ventricular outflow at the level of the (right arrow) artifacts.

difficult exam because multiple subcostal views can fre- Although a patient’s body habitus may cause considerable
quently be attained. The inferior vena cava should be imaged variation in image quality, this view should be attempted. It
along its long axis as it crosses the diaphragm and enters the can be used to detect an aortic arch aneurysm or dissection.
right atrium (Fig. 5.21A). Dynamic motion of the inferior Pulsed Doppler interrogation in the region of the proximal
vena cava during normal respiration and while the patient descending aorta is used to assess the severity of aortic insuf-
gently sniffs is used to assess the right atrial pressure (Fig. ficiency. Color Doppler and continuous-wave (CW) Doppler
5.21B; Table 5.3). The hepatic vein is also imaged along its in the same region (ligamentum arteriosum) can detect
long axis for coaxial pulsed Doppler interrogation (Fig. 5.21C). coarctation of the aorta and patent ductus arteriosus, which
The upper abdominal aorta, lying alongside the inferior vena are important potential incidental diagnoses.
cava, can be imaged in the short- and long-axis orientations
(Fig. 5.22). From this position, pulsed Doppler examination Modified Views
of the descending thoracic aorta is used to assess the severity
Sonographers should be familiar with certain “modified”
of aortic regurgitation. The subcostal four-chamber view is
views (not shown) that are obtained with the patient supine
used for analyzing feasibility and the needle angle and depth
or in the right lateral decubitus position. Such views include
required for percutaneous pericardiocentesis procedures.
the superior right parasternal window (for visualizing the
(Note: Real-time echocardiography guidance of percutaneous
superior vena cava and for CW Doppler evaluation of aortic
pericardiocentesis is from the apical four-chamber view,
valve stenosis) and a modified right apical four-chamber view
remote from the sterile needle site.)
(for accurate assessment of tricuspid regurgitation and for
ventricular visualization when apical windows are poor). A
Suprasternal Notch
posterior thoracic window may be useful for visualizing the
In most (but not all) patients, the aortic arch may be visual- descending thoracic aorta when a pleural effusion is present
ized along its short (not shown) and long axes (Fig. 5.23). as an acoustic medium.
10 4 chapter 5

A B

C D

E
FIGURE 5.13. Apical views. (A) Apical four-chamber view. Arrow- a indicates the orthogonal image plane shown in Figure 5.13A (apical
head, apical segment; single arrow, mid-septum; double arrows, four-chamber view). Line b indicates the orthogonal image plane
lateral wall. (B) Apical five-chamber view. Arrowhead, left ventricu- shown in Figure 5.13B (apical five-chamber view). Line c indicates
lar outflow tract; double arrows, anterior septum. (C) Apical four- the orthogonal image plane shown in Figure 5.13C (apical four-
chamber view, coronary sinus level. Single arrow, coronary sinus chamber, coronary sinus level). (E) Apical three-chamber (apical
entering the right atrium; double arrow, inferior portion of the long-axis) view. Arrowhead, left ventricular outflow tract; single
septum. (D) Apical two-chamber view. *, coronary sinus in short arrow, anterior septum; double arrows, inferolateral wall. RVOT,
axis; single arrow, anterior wall; double arrows, inferior wall. Line right ventricular outflow tract.
 i n t roduct ion to echoc a r diogr a ph y 10 5

A B

C D
FIGURE 5.14. Mitral valve Doppler interrogation, apical four- mitral deceleration time. E, E-wave; A, A-wave. (C) Pulsed Doppler
chamber view. (A) Mid-diastole. Small double lines at the open image, at the mitral annulus level, showing an automated mitral
mitral-leaflet tips indicate the proper pulsed Doppler sample-volume inflow–time-velocity integral (TVI = 0.144 m) used for determining
position for obtaining mitral E and A velocities (B) and the mitral mitral valve flow. Although the same patient is shown in views B
deceleration time (double-headed arrow, view B). The double-headed and C, the aliased, high-velocity, systolic mitral regurgitation signal
arrow (A) indicates the proper position for measuring the mitral (MR, black arrows) appears in view C but not view B because the
annulus diameter and the appropriate level for pulsed Doppler pulsed-Doppler sample volume is appropriately placed on the atrial
sample-volume placement when obtaining mitral annulus velocities side of the mitral-leaflet closure line in view C. (D) Continuous-wave
(C) used for calculating mitral valve forward flow. (B) Pulsed Doppler Doppler examination across the mitral valve detects, in this case, a
image obtained at the mitral valve-leaflet tips. Double-headed arrow, trivial/mild high-velocity mitral regurgitation lesion (arrow).

Standard M-Mode Views septal motion, and the independent motion of tiny vegeta-
tions. If M mode is to be used for parasternal measurements,
M-mode recordings from the parasternal long-axis view (at the operator and interpreter must ensure that the M-mode
the aortic valve, mitral valve, and left ventricular levels) and beam is exactly tangential to the long axis of the measured
from the short-axis view (at the pulmonary valve level) are a structure. Because this goal is not always technically possi-
feature of the standard examination (Fig. 5.24). The M-mode ble, assessment of ventricular and aortic dimensions fre-
display shows data reflected from a single, linear interrogat- quently relies on the 2D image (Fig. 5.7). Classic M-mode
ing beam, displayed over time. M mode provides a rapid patterns can indicate obstructive lesions of the left ventricu-
sample rate [1800 frames per second (fps) versus <100 fps for lar outflow tract and a variety of pathologic valve conditions
2D imaging] and superior axial resolution. This enables (see Chapter 21). The mitral anterior leaflet’s E-point septal
detection of small, thin, fast-moving structures (e.g., heart separation distance (Fig. 5.24B) can be an important clue to
valves, small masses, and endocardial surfaces) and accurate left ventricular dilatation and systolic dysfunction. Because
timing of their motion, particularly in the setting of tachy- of its superior sample rate, M mode, combined with color
cardia. M mode is useful for detecting partial right ventricu- Doppler (color M mode), can assist in the timing of color-flow
lar free-wall diastolic collapse in pericardial tamponade, as Doppler phenomena, especially during tachycardia (see
well as ventricular contractile dyssynchrony,148 paradoxical Chapter 21).
10 6 chapter 5

A B
FIGURE 5.15. Color Doppler (A) and pulsed Doppler (B) examina- stolic (D) pulmonary vein forward flow and late diastolic reverse
tion of the right superior pulmonary vein from the apical window. flow during atrial contraction (A). The orange area indicates flow
The pulsed sample volume is placed approximately 1 cm into the toward the transducer. LV, left ventricle; RA, right atrium; RV, right
pulmonary vein (arrow, image A). (B) Normal systolic (S) and dia- ventricle.

Transesophageal Echocardiography Training and experience with safe probe passage and with
conscious sedation are important elements of the examina-
Technical Aspects tion. Because imaging windows are available only from the
esophagus or stomach, TEE offers less freedom to obtain
In size and design, the semiflexible TEE probe is similar to coaxial Doppler flow signals than does TTE, potentially lim-
a gastroscope. Because the TEE probe does not incorporate a iting the amount of hemodynamic data available in certain
fiberoptic visualization system, however, it must be “blindly” cases. The desired TEE views are produced by combinations
passed into the esophagus. An uncommon but potentially of the following maneuvers: (1) probe-tip deflection in the
life-threatening complication is esophageal perforation. medial, lateral, antegrade, and retrograde directions by means
of hand-operated controls; (2) electronic rotation of the
imaging crystal (which is stationary within the probe tip)
throughout 180 degrees; (3) advancement and withdrawal of
the probe within the esophagus; and (4) clockwise and coun-
terclockwise rotation of the probe within the esophagus (Fig.
5.25). In different patients, available TEE images may vary
considerably, depending on the orientation of the heart
within the chest and the heart’s relationship to the esopha-
gus. Usually, the left atrium lies directly anterior to the
esophagus, and that structure’s blood pool provides an
extremely good acoustic window on the posterior cardiac
structures. The left atrium and the mitral valve are generally
seen with exceptional resolution, as are the pulmonary veins,
interatrial septum, descending thoracic aorta, proximal
superior vena cava, and proximal pulmonary veins. Struc-
tures positioned more anteriorly (the tricuspid or pulmonary
valve) or apically (the left ventricular apex) in the “far field”
may variably suffer from image attenuation or shadowing
related to calcifications or prosthetic valves.

Image Display
The TEE image display can differ from one laboratory
to another. Most operators display the small “sound-
emanating” portion of the TEE image sector at the top of the
FIGURE 5.16. Apical four-chamber myocardial tissue Doppler screen (Fig. 5.26). Because the transducer is positioned within
image, with the sample volume placed in the basal lateral wall near
the mitral valve annulus. The myocardial velocity is normal, going
a posterior structure (the esophagus), this situation creates a
toward the transducer during systole (S) and away from the trans- unique display in which the posterior anatomy appears at the
ducer in early (E′) and late (A′) diastole. top of the screen with the anterior structures toward the
 i n t roduct ion to echoc a r diogr a ph y 10 7

A B
FIGURE 5.17. Tricuspid valve interrogation by continuous-wave tricuspid-valve regurgitation velocity (VEL) and derived peak-
Doppler in the four-chamber view, using a combined imaging and systolic right ventricular pressure gradient (PG) were obtained by
Doppler transducer for color Doppler guidance (A) and a dedicated placing an electronic caliper on the spectral Doppler peak-velocity
nonimaging transducer (B) in the same patient. Note the improved position (+).
clarity of the spectral Doppler envelope in image B. The automated

A B

C D
FIGURE 5.18. Selected left ventricular outflow-tract Doppler inter- leaflet closure artifact (arrow) and the lack of an opening artifact
rogations from the apical window. (A) Color-flow Doppler image, indicate a good sample-volume position. Note the automated time-
apical five-chamber view. Note that the color in the left ventricular velocity integral measurement (TVI, arrowhead) from outlining of
outflow tract changes from blue to orange (arrow) when the velocity the spectral Doppler envelope (dotted curve). (D) Continuous-wave
exceeds the Nyquist limit of 53 cm/s, as indicated on the color scale Doppler image across the LVOT and aortic valve. Note the normal,
(arrowhead). (B) Color-flow Doppler image of the left ventricular automatically derived low peak-flow velocity (Vmax), peak gradient
outflow tract (LVOT) (arrow) in the apical three-chamber view. (C) (Pk Grad), and mean gradient (Mn Grad), as well as the aortic valve
Pulsed Doppler image of the LVOT, obtained with the sample (AoV) TVI obtained by outlining the continuous-wave spectral
volume immediately proximal to the aortic annulus. The aortic- Doppler envelope (dotted curve).
10 8 chapter 5

A B

C
FIGURE 5.19. Apical four-chamber view in fundamental frequency (A), tissue harmonic (B), and contrast harmonic (C) imaging modes, in
the same technically difficult case, with increasingly apparent left ventricular endocardial border delineation. LV, left ventricle.

A B
FIGURE 5.20. Subcostal four-chamber view (A) and subcostal left ventricular short-axis view (B). *, liver; double arrows, inferior wall or
diaphragmatic wall; single arrow, anterior wall; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
 i n t roduct ion to echoc a r diogr a ph y 10 9

A B

FIGURE 5.21. Subcostal view of the inferior vena cava (arrow) entering
the right atrium during normal respiration (A) and with normal “collapse”
during an inspiratory “sniff” (B) indicating normal (low) right atrial pres-
sure. (C) Normal pulsed Doppler image of the hepatic vein, via the sub-
costal window, with predominant antegrade inflow (below baseline)
during systole (S) and diastole (D). A normal small flow reversal occurs
after atrial contraction (A). Arrowhead, normal augmentation of antegrade
inflow velocities during inspiration. x = x-descent; y = y-descent. V, sys-
tolic V wave; *, liver. C

bottom of the screen [see Fig. 5.11A (TTE) vs. 5.28A (TEE) and
Fig. 5.13A (TTE) vs. 5.26B (TEE)]. The caudal anatomy remains
displayed on the left and cephalad structures on the right.
Accordingly, by convention, there is a potentially confusing
“up-down” inversion of the anatomy in the TEE image rela-
tive to the surface image. All commercial echocardiography
machines have an up-down image-inversion mode. Some
practitioners intentionally invert the TEE image in up-down
fashion (placing the small part of the sector at the bottom) to
make the anterior-posterior image display consistent on both
surface and TEE images. This inversion is not incorrect, and
the choice of TEE display is up to the individual laboratory

TABLE 5.3. Estimated right atrial pressure

IVC, response to Estimated RAP
IVC, baseline inspiration (mm Hg)

Small or slit-like Complete collapse 0–4

Normal (1.5–2.0 cm) ≥50% decrease 5–10
Normal <50% decrease 10–15
Dilated <50% 15–20
Dilated No change >20
IVC, inferior vena cava; RAP, right atrial pressure. Inferior vena cava observed FIGURE 5.22. Color-flow Doppler image of the suprarenal abdomi-
in the subcostal view during normal respiration or while the patient “sniffs” nal aorta in the long-axis view, from the subcostal window, in an
gently to decrease intrathoracic pressure. imaging plane adjacent to that seen in Figure 5.21.
110 chapter 5

A B

C
FIGURE 5.23. The aortic arch in a long-axis, small suprasternal- the blood-flow vector is tangential to the interrogating ultrasound
notch view (A). 䉱, right pulmonary artery, short axis; arrowhead, vector (black stripe, arrowhead). Solid orange indicates laminar flow
left brachiocephalic (innominate) vein; single arrow, left common toward the transducer; solid blue indicates laminar flow away from
carotid artery; double arrow, left subclavian artery; aAo, ascending the transducer. (C) Pulsed Doppler image of the distal aortic arch,
aorta; dAo, descending aorta. (B) Color-flow Doppler image showing showing normal systolic antegrade flow below the baseline (single
an aliasing phenomenon (aliasing velocity >81 cm/s, white arrows) arrow) and normal lesser retrograde early diastolic flow (above the
in the ascending (left black arrow) and descending (right black baseline, double arrows) related to coronary artery and aortic-arch
arrow) thoracic aorta, with complete absence of a color signal when vessel runoff.

or clinician. In all cases, the index mark remains to the right hood that TEE will detect unexpected findings that could
of the sector apex (Fig. 5.26B), as in TTE. alter patient care.

Sequence of Standard Views Transesophageal Views

Laboratory protocols for TTE (surface) examination should PERICARDIUM AND VENTRICLES (Fig. 5.26)
establish a consistent sequence of required views. Although The examination should include a sequence of images
TEE examination protocols should also define all of the obtained at an adequate depth to visualize all ventricular
required views or images, the order of image acquisition may epicardial (pericardial) and endocardial segments, including
vary. For instance, TEE examinations may follow a “pathol- the cardiac apex. Frequently, a stable imaging window can be
ogy-directed” sequence of views designed to answer the found (usually on gentle probe-tip retroflection followed by
clinical question in a timely fashion in case the patient slight probe withdrawal and rotation) so that the left ventri-
cannot tolerate the probe or becomes hemodynamically cle’s major axis lies in the center of the imaging sector in all
unstable before the exam is completed. After the chief indi- of the orthogonal planes. In this case, the transesophageal
cation for the examination has been addressed, further views four-chamber view (near 0 to 30 degrees of transducer rota-
are obtained to complete the study. Obtaining a comprehen- tion), bicommissural view (near 60 degrees), two-chamber
sive/complete TEE exam (in which all views and appropriate view (near 90 degrees), and apical three-chamber view (long-
Doppler evaluations are present) is particularly important axis view, usually near 120 degrees but up to 160 degrees in
when evaluating diseases that potentially involve multiple older patients) (Fig. 5.26) can all be obtained by electronically
cardiac sites (e.g., rheumatic heart disease, endocarditis, an adjusting the imaging angle of the transducer. In some patients
atypical myxoma with multiple foci, and the cardiovascular with relatively “vertical” hearts (in which the ventricular
source of an embolus). In fact, completeness of examination long axis is relatively parallel to the esophagus), views of the
is important whenever possible because of the high likeli- cardiac apex can be difficult or impossible to achieve.
 i n t roduct ion to echoc a r diogr a ph y 111

A B

C
FIGURE 5.24. (A) Aortic valve M-mode tracing with normal, wide closure line; EPSS, E-point septal separation; LV, left ventricle; RV,
systolic cusp separation (double arrows) and a central diastolic right ventricle. (C) M-mode tracing of the left ventricle at the papil-
closure line (single arrow). LA, left atrium; RVOT, right ventricular lary muscle level. EDD, left ventricular end-diastolic dimension;
outflow tract. (B) Mitral valve, M mode. Single arrow, posterior ESD, left ventricular end-systolic dimension; LV, left ventricle; RV,
mitral leaflet; double arrows, anterior mitral leaflet. E, mitral leaflet right ventricle.
early diastolic position; A, mitral “A-wave” position; C, mitral

T RANSESOPHAGEAL VIEWS AT A DECREASED “OPTIMIZED”

DEPTH (Figs. 5.27 to 5.33)
After viewing the “big picture,” as described above, the
examiner may decrease or “optimize” the depth to view
near-field structures in greater detail and at improved
(increased) frame rates. The cardiac structures should be
viewed in the long-axis, short-axis, and (in many cases) inter-
mediate, oblique imaging planes. Because of patient varia-
tion, standard anatomic views do not always occur at specific
transducer angles. Figures 5.26 through 5.33 show the basic
TEE views. Additional or modified views may be obtained
as appropriate. Doppler interrogations should mirror those
performed during TTE examinations. Transverse or horizon-
tal views lie close to a transducer angle of 0 to 30 degrees.
Intermediate views (30 to 60 degrees) allow assessment of
the aortic valve along its short axis (Fig. 5.28), the left atrial
appendage [which is imaged in multiple views (Figs. 5.32B
and 5.33)], the mitral bicommissural region (Fig. 5.27), and
proper alignment of the pulmonary veins (Fig. 5.32) and pul-
monary valve. Vertical or “long-axis” views of the left ven-
tricle, aortic root, mitral valve, superior vena cava (bicaval
view, Fig. 5.31), and descending thoracic aorta are generally
obtained from 90- to 120-degree angles. A patent foramen
ovale may be documented in the TEE bicaval view by using FIGURE 5.25. Schematic diagram of a transesophageal probe,
intravenous agitated normal saline (Fig. 5.31). Various showing left and right lateral flexion, anteflexion, retroflexion, and
strategies may be needed to systematically obtain all the rotation of the imaging plane through 180 degrees.
112 chapter 5

A B

C D

E
 i n t roduct ion to echoc a r diogr a ph y 113
FIGURE 5.26. Transesophageal views of the left ventricle (at the terior leaflet scallops of the mitral valve—the anterior (P1), middle
mid-esophagus level) showing the entire ventricular myocardium (P2), and posterior (P3) scallops—in the systolic (closed) position.
and pericardium (at increased depth). Note: The indicated trans- This view is important for localizing posterior-leaflet prolapse or
ducer angles may vary considerably among patients. (A) Five- chordal-rupture lesions. Left arrowhead, posteromedial papillary
chamber view (transducer angle approximately 0 degrees in the muscle tip; right arrowhead, anteromedial papillary muscle tip. (D)
horizontal plane). Compare with transthoracic echocardiography Two-chamber view (transducer angle approximately 90 degrees in
(TTE) image, Figure 5.13B. Arrowhead, left ventricular outflow the vertical plane). Compare with TTE image, Figure 5.13D. Arrow-
tract; LA, left atrium; LV, left ventricle; RA, right atrium; RV, left head, apex; single arrow, anterior wall; double arrows, inferior wall.
ventricle. (B) Four-chamber view (transducer angle approximately 30 (E) Three-chamber view (transducer angle approximately 120 to 160
degrees). Compare with TTE image, Figure 5.13A. Arrow, index degrees). Compare with TTE image, Figure 5.13E. Single arrow,
mark; arrowhead, left ventricular apex. (C) Bicommissural view anterior septum; double arrows, inferolateral wall; Ao, aortic root;
(transducer angle approximately 60 degrees) showing the three pos- LA, left atrium; RVOT, right ventricular outflow tract.

necessary views. It is important to maintain both a station- Ninety-degree transducer advancement from the left ven-
ary probe and a stationary transducer angle position while tricular short-axis position will produce the gastric left ven-
recording complete individual cardiac cycles, so that the tricular long-axis view (Fig. 5.37A). Clockwise probe rotation
same anatomic features can be visualized throughout systole from the left ventricular long-axis view will produce the
and diastole. The probe can then be manipulated systemati- right ventricular and tricuspid valve long-axis view (Fig.
cally in a logical, incremental fashion to acquire subsequent 5.37B). Even if the tricuspid valve was obscured in trans-
images according to the examination protocol or in a pathol- esophageal windows, it can often be seen clearly in this view.
ogy-directed sequence that reflects the indication for the In most but not all cases, the left ventricular outflow tract
exam. can be visualized and evaluated for obstruction or insuffi-
ciency with Doppler methods from a horizontal-plane, “deep-
Transgastric Views gastric” view, obtained by further advancing the probe to the
cardiac apex (Fig. 5.38A,B), or from a more proximal modified
This additional imaging window is obtained by advancing
left ventricular long-axis view (Fig. 5.38C). Gradual probe
the TEE probe into the stomach. During this advancement,
withdrawal from the gastric LV short axis view produces the
one can usually obtain a low transesophageal (gastroesopha-
mitral valve short-axis view (Fig. 5.39) just below the gastro-
geal-junction) view (Fig. 5.34), which shows the posteriorly
esophageal junction. As in surface imaging (compare with
located coronary sinus along its long axis and the lower
Fig. 5.10B), this view can be important for determining indi-
portion of the tricuspid valve. Though sometimes ignored,
vidual scallop involvement in mitral valve dysfunction.
this view can be important for detailed tricuspid valve assess-
ment, for guiding coronary sinus catheter placement in the
operating room, or for visualizing other pathologic condi-
Transesophageal Views: Descending Thoracic
tions of the coronary sinus. Further probe advancement into
Aorta (Fig. 5.40)
the stomach yields a short-axis view of the left ventricle, at
the papillary muscle level (Figs. 5.35 and 5.36), which appears Because of its generally excellent imaging windows, TEE is
inverted relative to the analogous TTE view (Fig. 5.10A). an important modality for detecting pathologic conditions of

A B
FIGURE 5.27. Transesophageal bicommissural view at decreased missure (right arrowhead). Three posterior mitral valve scallop
depth during systole (A) and diastole (B), showing the mitral valve’s regions (P1 to P3) are present.
posteromedial commissure (left arrowhead) and anterolateral com-
114 chapter 5

A B
FIGURE 5.28. Transesophageal short-axis view of the aortic valve atrium; RVOT, right ventricular outflow tract. For analogous trans-
in diastole (A) and systole (B). *, left atrial appendage; arrowhead, thoracic echocardiography view (inverted), see Figure 5.11A. Note:
interatrial septum; single arrow, pulmonary valve; double arrows, The appropriate transducer angle varies from 30 to 90 degrees
tricuspid valve; L, left coronary cusp; LA, left atrium; N, noncoro- depending on the patient’s age and the left ventricle-aortic root
nary cusp; PA, pulmonary artery; R, right coronary cusp; RA, right angle.

the aorta, for example, dissection (Fig. 5.30), atheroma (Fig.

40B,D), and intramural hematoma. The aortic root and
ascending aorta should be visualized in the other transesoph-
ageal views noted above (Figs. 5.26A,E and 5.28 to 5.30). The
rest of the thoracic aorta, from the midtransverse arch to the
level of the diaphragm, is visualized by rotating the probe
leftward, away from the heart, toward the left paravertebral
region (transducer position = 0 degrees). The aorta should be
centered within the imaging sector. Representative short- and
long-axis aortic views are sequentially acquired at 5-cm
intervals or whenever important pathology is encountered.
The descending thoracic aorta (diaphragm level) is usually
seen in the short-axis view when the teeth (incisors) are even
with the probe’s 35- to 40-cm depth mark, depending on
patient size. The curvilinear distal arch is visualized in the
short-axis view by using intermediate (30 to 60 degrees) trans-
ducer angles as the probe is gradually withdrawn so that the
incisors are at approximately the probe’s 25-cm depth mark
(Fig. 5.40C). The mid-arch is visualized in the short-axis view
at a transducer angle of approximately 90 degrees. The distal FIGURE 5.29. Transesophageal echocardiogram of the great vessels,
ascending aorta and proximal aortic arch frequently lie in a in the short-axis view (horizontal plane), at the level of the ascend-
ing aorta and right pulmonary artery (RPA), showing typical side-
TEE “blind spot” because of interposed airways.
by-side short-axis “circles” of the ascending aorta (aAo), superior
vena cava (SVC), and right superior pulmonary vein (arrowhead).
This view is important for excluding anomalous right superior pul-
Doppler Examination and Hemodynamics monary venous drainage into the superior vena cava and for viewing
the proximal great vessels. Line a indicates the orthogonal image
planes shown in Figures 5.26E and 5.30A. Line b indicates the
When sound is reflected from a stationary target, the return- orthogonal image plane shown in Figure 5.31A. Line c indicates the
ing reflected frequency is the same as the original transmit- orthogonal image plane shown in Figure 5.32A. PA, pulmonary
ted frequency. When sound returns from a moving target, artery.
however, the reflected frequency is higher than the transmit-
ted frequency if the target is moving toward the receiver. In
medical ultrasound, the transducer is both the sound emitter
and sound receiver. The reflected sound has a lower fre-
quency if the target is moving away from the receiver. Known
as the Doppler shift,
 i n t roduct ion to echoc a r diogr a ph y 115

A B
FIGURE 5.30. (A) Long-axis view of the aortic root and ascending right ventricular outflow-tract collapse indicating associated peri-
aorta in a patient with Type A aortic dissection (arrow). The intimal cardial tamponade; black arrowhead, left coronary artery ostium;
flap extends proximally to the right coronary artery ostium (black single arrow, dissection flap within the right coronary sinus of Val-
arrowhead). Double arrows, pericardial effusion; LA, left atrium; salva; double arrows, right atrial compression; FL, false lumen; LA,
RA, right atrium. (B) Short-axis view of the aortic root. *, partial left atrium; TL, true lumen.

A B

FIGURE 5.31. Transesophageal “bicaval” views. (A,B) Similar anatomy,

but view A optimizes tricuspid-valve visualization (downward arrowhead)
and is useful for Doppler interrogation. IVC, inferior vena cava; LA, left
atrium; RAA, “broad-based” right atrial appendage; SVC, superior vena
cava. View B shows the thin fossa ovalis (single arrow) which, in this case,
is patent. Arrowhead, eustachian valve of the IVC; bracket, patent fossa
ovalis (PFO) tunnel. (C) Intravenous agitated saline contrast bubbles
transit from the right atrium (RA) to the left atrium (double arrows) via
the PFO on relaxation of a Valsalva maneuver. The RA and superior vena
cava (SVC) are completely “opacified” by intravenous injection of saline
contrast. C
116 chapter 5

A B
FIGURE 5.32. Transesophageal view of the superior pulmonary right atrium. (B) The left superior pulmonary vein (arrow) lies
veins. (A) The right superior pulmonary vein (arrow) with the pulsed immediately posterior to the left atrial appendage (LAA). LA, left
Doppler sample volume approximately 1 cm inside the os; adjacent atrium; LV, left ventricle.
is the right-sided superior vena cava (SVC). LA, left atrium; RA,

Doppler shift (Hz) = Reflected frequency − Transmitted accurate velocity reported (since cos 0 degrees = 1). When the
frequency, path of a moving insonated target is not parallel to the inter-
rogating sound beam, the reported velocity will be lower
this physical principle explains why a stationary listener
than the true velocity, proportional to cos ∅ of the intercept
notices an abrupt fall in the pitch of an approaching train’s
angle between the ultrasound beam and the true direction
whistle just after the train passes and begins to move away.
of blood movement:
The velocity of a moving insonated target (e.g., blood cells or
the myocardium in motion) can be calculated by using the Measured velocity = True velocity × cos ∅
Doppler equation to analyze the returning sound frequency
initially emitted from the transducer: Because cos 20 degrees = 0.94, Doppler alignment errors of
<20 degrees will result in a velocity measurement error of
Sound propagation speed × Doppler shift <6%, which is acceptable without correction in most clinical
Velocity =
2 × Transmitted frequency × cos ∅ situations. Note that because cos 60 degrees = 0.5, an inter-
cept angle of 60 degrees will yield only half of the true veloc-
If blood is moving parallel (coaxial) to the interrogating ity, and an intercept angle of 90 degrees (cos 90 degrees = 0)
sound beam, the complete Doppler shift is measured and an will produce no measurable blood-flow velocity (Fig. 5.23B).

A B
FIGURE 5.33. Transesophageal view of the left atrial appendage left atrial tissue (*) is seen between the LAA and the left upper pul-
(LAA). The “narrow-based” LAA is imaged in both the horizontal monary vein (LUPV). Ao, aortic root; LA, left atrium; LV, left
(A) and the vertical (B) plane. A normal prominent “reflection” of ventricle.
 i n t roduct ion to echoc a r diogr a ph y 117

FIGURE 5.34. Transesophageal view at the gastroesophageal junc- FIGURE 5.35. Transgastric image of the left ventricle in the short-
tion. Arrowhead, coronary sinus in long axis, showing entry into axis view at the papillary muscle level. AL, anterolateral papillary
the right atrium (RA). Compare with TTE image, Figure 5.13C. LV, muscle; LV, left ventricle; PM, posteromedial papillary muscle; RV,
left ventricle; RV, right ventricle. right ventricle.

A B
FIGURE 5.36. Transgastric image of the left ventricle in the short- endocardial definition improved. Upper arrowhead, inferior wall;
axis view at the papillary muscle level. (A) Fundamental frequency lower arrowhead, anterior wall. Line a indicates the orthogonal
imaging mode: the result is technically poor, with an attenuated image plane shown in Figure 5.37A. Line b indicates the orthogonal
image and a low signal-to-noise ratio. (B) Tissue harmonic imaging image plane shown in Figure 5.37B. LV, left ventricle; RV, right
mode in the same patient. Intracavitary “noise” is decreased and ventricle.

A B
FIGURE 5.37. Transgastric long-axis views of the left and right Right ventricle: normal tricuspid valve chordae tendineae arise from
ventricles. (A) Left ventricle (LV): normal mitral valve chordae ten- the right ventricle (RV) anterior papillary muscle (*). RA, right
dineae arise from the posteromedial (*) and anterolateral (arrow) atrium.
papillary muscles. LA, left atrium; LAA, left atrial appendage. (B)
 118 chapter 5

A B

FIGURE 5.38. (A) Deep gastric view of the left ventricle (transducer angle
approximately 0 degrees). This view enables coaxial Doppler evaluation
of the left ventricular outflow tract by means of transesophageal echocar-
diography. See Figure 5.13B for the analogous surface echocardiography
view. Ao, aorta; LV, left ventricle; RVOT, right ventricular outflow tract.
(B) Color Doppler image of the left ventricular outflow tract with an
appropriately placed pulsed-Doppler sample volume (arrow). (C) A modi-
fied transgastric long-axis view of the left ventricle (LV), often at a trans-
ducer angle of >90 degrees, frequently enables Doppler evaluation of the
left ventricular outflow tract (arrow) when the deep gastric view is not
C possible. Ao, aortic root; LV, left ventricle.

A B
FIGURE 5.39. Transgastric image of the left ventricle, in the short- the orthogonal TEE imaging plane shown in Figures 5.26C and
axis view, at the mitral valve level. (A) Mitral valve posterior leaflet: 5.27A (bicommissural view). AL, anterolateral commissure; PM,
anterior (P1), middle (P2), and posterior (P3) scallops; mitral valve posteromedial commissure; RV, right ventricle. (B) Obtaining a
anterior leaflet: anterior (A1), middle (A 2), and posterior (A 3) seg- color-Doppler image at this level is important. In this same patient,
ments. This view is important for localizing mitral regurgitation it shows significant functional regurgitation along the entire zone
lesions. Compare with TTE image, Figure 5.10B. Line a indicates of mitral leaflet coaptation.
 i n t roduct ion to echoc a r diogr a ph y 119

A B

C D
FIGURE 5.40. Transesophageal views of the descending thoracic pleural effusion. (C) Normal left subclavian artery (arrow) at the level
aorta. (A) Normal aorta. (B) Grade II calcified atheroma (arrowhead) of the aortic isthmus. (D) Descending thoracic aorta in long axis, with
in the mid-descending thoracic aorta. *, atelectatic lung; **, large left complex atheroma and mobile atherosclerotic “debris” (arrow).

Because the exact path of the blood flow cannot be precisely high-frequency shifts and corresponding high-velocities
determined, even with anatomic guidance, velocity mea- (>7 m/s) created by obstructive or regurgitant orifices. Con-
surements are determined from several different imaging tinuous-wave Doppler examination has the disadvantage of
locations so that the highest values can be used. range ambiguity, because velocities anywhere along the
interrogating beam are displayed. Range ambiguity can be
problematic when serial obstructive lesions occur along the
Spectral Doppler line of interrogation [e.g., in combined dynamic left ventricu-
Spectral Doppler imaging comprises two modalities: con- lar outflow-tract (LVOT) obstruction and aortic valve steno-
tinuous wave (CW) and pulsed wave (PW). On the spectral sis]. Barring the presence of serial stenoses, the highest
Doppler display, Doppler shift–derived velocities moving recorded velocities may be assumed to arise from the obstruc-
toward the transducer appear as positive deflections above tive orifice in question. The CW Doppler modality is inte-
the baseline (see Fig. 5.14B). Flow velocities moving away grated along with pulsed-wave Doppler in an imaging
from the transducer are displayed below the baseline (see Fig. transducer. This may be useful for positioning the interrogat-
5.18C). ing beam with anatomic and color Doppler guidance.
However, the true direction of a jet lesion within the ana-
tomic orifice may be difficult to judge with either anatomic
Continuous-Wave Doppler
or color Doppler guidance. Superior CW spectral Doppler
Basic Concepts. Continuous-wave Doppler uses a dedi- envelopes are recorded with a dedicated nonimaging trans-
cated crystal to continuously transmit signals while an adja- ducer (Fig. 5.4B), which has a smaller footprint that is more
cent crystal continuously receives the reflected signals. This easily brought into coaxial alignment with jet lesions, using
modality has the advantage of being able to measure the a variety of surface windows.
12 0 chapter 5

Continuous-Wave Doppler and the Pressure- TABLE 5.4. Routine sites for continuous-wave Doppler
examination
Velocity Relationship. When blood crosses a small,
restricted orifice (e.g., stenotic valve, incompetent valve, or Parasternal long axis, RV inflow tract TV
ventricular septal defect), its velocity increases relative to Parasternal short axis (at AoV and RVOT TV, PV
the pressure difference between the two chambers. The peak level)
instantaneous pressure drop across a narrow orifice is calcu- Apical four-chamber TV, MV
lated with the simplified Bernoulli equation: Apical five-chamber LVOT
Apical three-chamber LVOT, MV
ΔP = 4V 2 Subcostal* AoV (if AS*)
Sternal notch Descending Aorta,
where the peak velocity (V) is derived from the CW spectral
AoV* (if AS)
Doppler display (Fig. 5.17B). Mean pressure gradients are
Right parasternal* AoV* (if AS)
determined by calculating the instantaneous pressure gradi-
Modified apical* TV if difficult TR
ent (4V 2) at multiple time intervals during the flow period
velocity*
and by averaging the results. Echocardiography machines
* Add if a pathologic condition is detected. It is desirable to repeat the evalu-
and off-line analysis programs automatically calculate peak ation with a nonimaging probe for accurate V TR and for left-sided valve
instantaneous and mean pressure gradients in millimeters obstructive lesions (i.e. AS, MS).
of mercury (mm Hg) when the CW Doppler spectral envelope AoV, aortic valve; AS, aortic stenosis; LVOT, left ventricular outflow tract;
is manually outlined with a tracker ball (Fig. 5.18D). With MV, mitral valve; PV, pulmonary valve; RV, right ventricular; RVOT, right
ventricular outflow tract; TR, tricuspid regurgitation; TV, tricuspid valve.
CW Doppler, the spectral display has a characteristically
“filled-in” appearance because of turbulent blood flow; a
large number of velocities occur at all points below the peak
instantaneous velocities represented by the envelope’s outer Pulsed Doppler
edge (Figs. 5.12D and 5.18D). Table 5.4 lists the sites routinely
used for CW Doppler interrogation. The CW Doppler pres- Basic Concepts. In pulsed Doppler mode, the piezoelec-
sure-velocity relationship is used to measure pressure gradi- tric crystal alternates between sending and receiving at a
ents across obstructed valve orifices, ventricular septal defined pulse repetition frequency. After sending out an
defects, and dynamic left and right ventricular outflow ultrasonic pulse, the machine “knows” when to listen for
obstructive lesions, as well as to identify and qualitatively the returning signal by calculating the send and receive time
assess severity of valve regurgitation lesions. of flight to the desired depth at which the Doppler frequency
shift is to be measured. The sonographer chooses the Doppler
Pulmonary Artery Pressure Calculation. The peak depth by placing a sample volume in a desired location, using
right ventricular systolic pressure (RVSP) is routinely calcu- the image sector for anatomic guidance (Figs. 5.12C, 5.14B,C,
lated with the simplified Bernoulli equation, as this approach 5.15A,B,C, and 5.18A). Range discrimination is an inherent
yields highly useful information, and up to 80% of individu- property of pulsed Doppler mode because the blood velocity
als have at least trivial tricuspid regurgitation (TR), the is measured at a known distance from the transducer. The
velocity of which (VTR) may be measured by CW Doppler. In maximum blood speed that can be measured with pulsed
the absence of right ventricular outflow obstruction, the Doppler at a given depth is called the Nyquist limit, which
peak systolic pulmonary artery pressure (SPAP) is the sum is half the pulse repetition frequency. When blood velocities
of the RVSP and the estimated right atrial pressure exceed the Nyquist limit, the spectral Doppler display erro-
(RAP)149: neously indicates that blood is moving in the wrong direc-
tion. This phenomenon is called aliasing (see Fig. 5.14C for
RVSP = 4VTR2 pulsed Doppler aliasing and Figs. 5.12A and 5.18A,B for color
Doppler aliasing). For practical purposes, pulsed Doppler
SPAP = 4VTR2 + RAP mode can unambiguously measure blood flow velocities of
up to about 2 m/s at normal imaging depths. With normal
The RAP can be determined by measuring the degree of laminar flow, the typical pulsed Doppler spectral envelope
inferior vena cava (IVC) collapse approximately 2 cm from has bright edges and a dark center (Fig. 5.18C). This is because
the IVC–right atrium (RA) junction (subcostal view) during all the blood cells within the sample volume are moving in
normal inspiration or a “sniff” (Fig. 5.21; Table 5.3).150 During the same direction and at roughly the same velocity, as rep-
positive-pressure mechanical ventilation, a small, collapsing resented by bright spectral envelope edges. The principal
IVC indicates a low RAP, although an enlarged and noncol- applications for pulsed Doppler mode are assessing cardiac
lapsing IVC does not necessarily indicate an elevated RAP output, regurgitant volumes, shunts, and diastolic function.
under this circumstance.151 When the TR velocity is faint, its Table 5.5 indicates standard sites for pulsed Doppler
spectral Doppler envelope can be enhanced by intravenous evaluation.
injection of agitated saline solution during interrogation.152
The peak CW Doppler-derived gradient of the pulmonary Stroke Volume and Cardiac Output. Where laminar
valve insufficiency (PI) jet (4V PI2), also measurable in most flow is present, the instantaneous flow rate is the product of
patients, has been shown to approximate the mean pulmo- the cross-sectional area (CSA) and the instantaneous flow
nary artery pressure153: velocity (cm/s) at the same site. Integrating the area under a
pulsed Doppler flow-velocity curve yields the time-velocity
Mean PAP = 4(VPI)2 integral (TVI) distance, reported in centimeters. The TVI
 i n t roduct ion to echoc a r diogr a ph y 121
TABLE 5.5. Routine sites for pulsed Doppler examination Technical Notes. In sinus rhythm, stroke volumes are
Parasternal short axis, RVOT RVOT/PV annulus ideally calculated from 3 to 5 averaged TVIs. In irregular
level rhythms (atrial fibrillation), stroke-volume calculations
Apical four-chamber MV leaflet tips and MV should be derived from 5 to 10 averaged TVI measurements.
annulus, right superior Premature ventricular contraction (PVC) and post-PVC cycles
pulmonary vein should be excluded. Precise diameter measurements are
Apical five-chamber LVOT essential because this linear variable is squared during flow
Apical three-chamber LVOT calculations, so any error is compounded. Ideally, three
Subcostal Hepatic vein, aorta* (if AI) diameter values are obtained from different cycles to ensure
Sternal notch Descending aorta at isthmus reproducibility. With satisfactory data, comparison of the
* Add if a pathologic condition is detected.
LVOT and RVOT stroke volumes can be used to calculate
AI, aortic insufficiency; LVOT, left ventricular outflow tract; MV, mitral
right-to-left shunts (QP = pulmonary flow, QS = systemic
valve; PV, pulmonary valve; RVOT, right ventricular outflow tract. flow). The CO can be measured at rest or during exercise or
pharmacologic interventions. The outflow tract CSA and
TVI measurements are essential components of valve-area
calculations using the continuity equation. In addition, the
indicates the distance a volume of blood would travel during LVOT or RVOT stroke volume (in the absence of reference
the flow period within a conduit that has a certain CSA. The valve-insufficiency lesions) may be subtracted from the
flow during a cardiac cycle (stroke volume) can be calculated mitral annular stroke volume to calculate the mitral regur-
by multiplying the CSA of a conduit by the integrated flow- gitant volume. An aortic valve regurgitation volume may be
velocity curve (TVI) distance. calculated in analogous fashion using the RVOT or mitral
annulus forward stroke volume as a reference value (in the
Left Ventricular Outflow Tract. Integrating the
absence of significant reference-valve regurgitation).
area under the LVOT pulsed-Doppler velocity curve yields
the LVOT TVI in centimeters (Fig. 5.18C). It is valid to assume
that the normal LVOT is circular (CSA = π r 2 = D 2 × π/4 = D 2 Color-Flow Doppler
× 0.785) (r = radius). The LVOT diameter (D) is measured in
Color-flow Doppler is a multigated pulsed Doppler technique
the parasternal long-axis view (Fig. 5.7B). The LVOT area,
that is valuable for visualizing overall flow patterns within
stroke volume (SV), and cardiac output (CO) can be calcu-
the heart and great vessels. Instead of measuring the direc-
lated as follows:
tion and velocity of flow at a specific location (as with spec-
tral Doppler), this method assigns colors to the pixels
CSA = D 2 × 0.785
throughout an anatomic region of interest, depending on the
SV (cm3) = CSA (cm2) × TVI (cm) measured flow direction and velocity. Color-flow informa-
tion is superimposed on the anatomic gray-scale image so
CO = SV × HR
that flow patterns can be correlated with the anatomy. Cal-
culating the velocity shift at numerous sites in “real time”
Right Ventricular Outflow Tract. The right ven-
requires considerable computing speed. With older machines,
tricular outflow tract (RVOT) stroke volume and cardiac
the color-flow sample rate can be unacceptably slow (i.e.,
output are obtained in analogous fashion, using the equa-
<12 fps) when color sectors are too large. With parallel pro-
tions shown above (see Fig. 5.11B for the RVOT diameter and
cessing, newer machines largely eliminate this concern. A
Fig. 5.12C for the RVOT TVI). The RVOT diameter measure-
color map (Figs. 5.12B and 5.23B, upper right of images) is
ment, obtained in the parasternal short-axis view (Fig. 5.11B)
shown alongside the anatomic image, indicating the direc-
may be less reliable than the LVOT diameter measurement
tion of flow. Typically, blue (at the bottom of the map) indi-
because of a somewhat retrosternal RVOT location that can
cates flow away from the transducer, and orange/red (at the
cause lateral RVOT image “dropout” from sternal or rib
top of the map) indicates flow toward the transducer (“BART”
shadowing.
= blue away, red toward). The number at either end of the
Mitral Annulus. The mitral annulus stroke volume color map indicates the color-Doppler Nyquist limit, which
and cardiac output are obtained in analogous fashion (see Fig. is typically below 1 m/s and generally set in the range of 50
5.14A for mitral annulus diameter and Fig. 5.14C for mitral to 60 cm/s for detecting and analyzing regurgitant lesions.
annulus TVI). The mitral annulus diameter (Fig. 5.14A) may Color-Doppler aliasing is extremely common, because
be difficult to measure if annular calcification or some other normal intracardiac blood velocities often exceed 60 cm/s.
leaflet deformity impairs leaflet motion. Although the mitral When this happens, the color abruptly changes to the hue
annulus is elliptical and not circular, the four-chamber view assigned to flow moving in the opposite direction. This color
places the annulus dimension between the major and minor “wraparound” effect clearly delineates flow-velocity bound-
mitral axes of the valve’s ellipse. This may explain why aries, thereby identifying zones of mild acceleration (e.g., at
assuming a circular mitral annulus has proved valid when a valve annulus) (Figs. 5.12A and 5.18A,B) and proximal flow-
using the four-chamber annulus diameter. Note that pulsed convergence zones associated with regurgitant lesions (see
Doppler readings obtained at the mitral leaflet tips cannot Chapter 21). When blood flow is exactly tangential to the
be used for calculating mitral valve flow because the leaflet- direction of the interrogating beam, no color (black) is dis-
tip orifice area (which is smaller than the annular orifice played (Fig. 5.23B). Color-Doppler mode is highly sensitive in
area) cannot be reliably measured. detecting (if not quantitating) regurgitant jet lesions, because
12 2 chapter 5

turbulent high-velocity flow is labeled with an easily recog- (e.g., strain, strain rate) can be displayed in anatomic M-mode
nizable speckled or mosaic color pattern (Fig. 5.39B). Color- format so that physiologic conditions within different myo-
Doppler gain and Nyquist-limit settings are easily adjustable; cardial segments can be displayed simultaneously (Figs. 5.45,
they can markedly affect color-Doppler results and their 5.46, and 5.47).
interpretation. Color-Doppler mode is beset by numerous
potential artifacts, which cannot be reviewed here. Addition-
ally, its appearance varies, depending on the equipment Tissue Synchronization Imaging
manufacturer. Tissue synchronization imaging (TSI) is a relatively new
term for images produced by color coding myocardial pixels
Tissue Doppler with time-to-peak velocity values derived from TDI data.
Color values for delayed time-to-peak velocity values are
Tissue-Doppler is analogous to pulsed Doppler assessment
somewhat arbitrarily determined, but this method calls
of blood flow velocity. Instead of being placed in the blood
attention to myocardial segments that contract late because
pool, however, the tissue Doppler sample volume is placed
of conduction abnormalities or “dyssynchrony” (Figs. 5.44D
in a myocardial segment (Figs. 5.16 and 5.41C). Appropriate
and 5.45).
filters are applied so that only the high-amplitude but rela-
Myocardial segments that do not contract or thicken
tively low velocities inherent in myocardial motion are
(i.e., scarred or hibernating myocardium) may exhibit con-
included. Tissue-Doppler studies are usually performed in
siderable translational motion because of tethering by adja-
the apical views because longitudinal myocardial motion is
cent contracting segments. Thus, one possible pitfall is that
coaxial to the interrogating beam in this situation. Longi-
TDI will encode tethered nonviable (scarred) segments or non-
tudinal descent of the cardiac base is an important indica-
contracting but viable segments (hibernating myocardium)
tor of systolic function. A growing body of literature has
with velocity information. In this case, TDI erroneously
shown that even localized myocardial tissue Doppler can
gives nonviable segments the appearance of contractility
provide important information about diastolic function.
where there is none. Another TDI-based modality that may
Moreover, this information is less affected by loading condi-
address this contractility problem is strain-rate imaging.
tions than are blood flow pulsed Doppler filling patterns.
Tissue Doppler can be used to assess left ventricular fill-
ing pressures, to detect overt and subclinical cardiomy- Strain, Strain Rate, and Strain-Rate Imaging
opathy, and to distinguish constrictive from restrictive Derived from Doppler106–111
cardiomyopathy.39,45,46,56
These additional imaging modes are derived from the myo-
cardial TDI velocity information discussed above. The con-
Parametric Imaging cepts of strain and strain rate are not new. However, the
recent commercial availability of their ultrafast derivation
Tissue Doppler Imaging and myocardial parametric display could produce a number
of clinically useful applications.
New ultrasound technology allows extremely high-frequency
Strain is another word for deformation. Strain can be
imaging and measurement of myocardial tissue velocities of
calculated as the change in length (L) between two points
>100 fps within the imaging sector. The pixels that represent
within a myocardial segment (L − L o) divided by the original
the anatomic myocardium are color coded to depict the myo-
length (L o).
cardial direction and velocity throughout the cardiac cycle
(Figs. 5.41 to 5.44). This type of moving anatomic and func- Strain = (L − Lo)/Lo
tional display (TDI) is a parametric imaging modality.105 In normal myocardium, L (systolic length) is shorter than the
Changing color patterns within the anatomic image can “original” diastolic length (L o). Therefore, normal myocar-
indicate regions of myocardial dysfunction with a sensitivity dium has negative systolic strain (because of segmental
potentially surpassing that of traditional gray-scale myocar- shortening) and positive diastolic strain (because of segmen-
dial wall-motion analysis. When one or more sample volumes tal lengthening) (Fig. 5.46). When regional myocardial defor-
(Figs. 5.42 and 5.44C) are placed within the myocardium, mation does not occur (L = L o), strain is zero, indicating an
relatively high-fidelity curvilinear graphs of the average lon- absence of contractility regardless of whether the segment
gitudinal myocardial velocity can be generated. Comparison is moving through space because of tethering. Strain is
of the time-to-peak longitudinal velocities measured in expressed as a percentage of L o.
opposing myocardial segments may be an adequate proxy for The strain rate is the speed at which regional myocardial
identifying dyssynchronous mechanical systole that may be shortening or lengthening occurs. The strain rate is calcu-
improved by cardiac resynchronization therapy (CRT) in lated from the myocardial tissue Doppler velocities (V)
heart failure patients (Fig. 5.44).117–122 obtained from two nearby points (V1 and V2) separated by a
distance L.
Curved Anatomic M-Mode Display Strain rate = (V2 − V1)/L
Curved anatomic M mode is a newer myocardial Doppler The strain rate is also called the instantaneous spatial
imaging format that can show the timing of myocardial velocity gradient, which is the rate at which two points are
motion (velocity) throughout a selected “length” of myocar- approaching each other because of myocardial thickening
dium (Fig. 5.43). Other forms of myocardial physiologic data (during contraction) or moving further apart because of myo-
 i n t roduct ion to echoc a r diogr a ph y 12 3

A B

C
FIGURE 5.41. Normal tissue Doppler image in the apical four- (Upper right) The downward arrowhead next to the color scale indi-
chamber view. (A) Normal, synchronous systolic longitudinal myo- cates myocardial motion away from the transducer. (Lower left) The
cardial motion toward the transducer produces a uniform orange-red downward arrowhead shows early diastolic timing of the acquired
appearance. Upper right: the upward arrow next to the color scale image. (C) Tissue Doppler sample volume located in the basal lateral
indicates myocardial motion toward the transducer. Lower left: The wall (arrowhead), with corresponding tissue spectral Doppler
upward arrow shows late systolic timing of the acquired image. (B) tracing. The arrow and arrowhead depict the direction and timing
Normal, synchronous diastolic longitudinal myocardial motion of the images shown in views A and B.
away from the transducer produces a uniform blue appearance.

cardial lengthening. Strain is the time integral of the strain respectively, so Doppler-derived longitudinal strain imaging
rate (much as TVI is the time-velocity integral of the Doppler can show only part of the picture.
flow-velocity curve over time). Because strain is produced by
shortening of the myocardial fibers, strain and strain rate
Strain and Strain-Rate Imaging by Means of
may be better indicators of myocardial contractility than is
Speckle Tracking
the tissue-velocity information from which these parameters
are derived. Speckle tracking is a new modality that is still undergoing
One pitfall of Doppler-derived strain measurements of clinical experimental validation. Discrete, brightly echoic
myocardial tissue is that this method can effectively describe intramyocardial pixels can be “recognized” by the echocar-
only longitudinal strain of the basal and midventricular seg- diography device and tracked during the cardiac cycle. The
ments from the apical views. This is because (as explained distance through which nearby speckles approach each
above) pulsed Doppler imaging is accurate only in a direction other (strain) and the rate at which this is accomplished
coaxial to the interrogating ultrasound signal. Ventricular during the cardiac cycle (strain rate) may be derived from
longitudinal shortening is only one of the three vectors that the longitudinal, circumferential (torsional motion), or
describe myocardial motion. Inward myocardial motion radial inward motion of myocardial speckles (Fig. 5.48).
(radial thickening) and left ventricular torsional motion (cir- Though still in the early stages of clinical development, this
cumferential shortening, which is prominent in the apex) new modality may become an important tool for evaluating
may also be described by radial and circumferential strain, myocardial health.
12 4 chapter 5

FIGURE 5.42. Tissue Doppler image of “opposing” segments of the spectral Doppler velocity pixel intensity displayed over time. Simul-
septal wall (yellow circle) and the lateral wall (green circle) in a taneous display of the septal wall (yellow line) and lateral wall
normal patient. Systolic myocardial motion inward, toward the (green line) average velocity curves, which show near-synchronous
transducer, appears orange (upward arrow), and diastolic motion achievement of peak velocity values (upward arrow) by the opposing
outward, away from the transducer, appears blue (downward arrow- segments, as well as a synchronous negative directional peak veloc-
head), as in Figure 5.41. The graph at right indicates the average ity (downward arrowhead).

FIGURE 5.43. Tissue Doppler image in curved anatomic M-mode the basal to the middle and apical septum. Three cardiac cycles are
format in the same (normal) patient shown in Figures 5.41 and 5.42. shown. Uniform timing of the red-to-blue color change from systole
This format shows simultaneous myocardial velocity readings, as (S) to diastole (D) indicates a synchronous myocardial velocity
defined by the color scale along a defined line of myocardium from change along the entire septum.
 i n t roduct ion to echoc a r diogr a ph y 12 5

A B

C D
FIGURE 5.44. Myocardial dyssynchrony, as shown by tissue a markedly delayed lateral-wall time-to-peak velocity (right arrow,
Doppler imaging (apical four-chamber view) in a patient with left green curve). Ventricular longitudinal motion between the opposing
bundle-branch block. (A) Early systolic septal motion toward the segments is discordant or “dyssynchronous.” (D) In the same patient,
transducer (red), with simultaneous lateral wall motion away from a novel myocardial Doppler imaging format uses an automated
the transducer (blue). (B) Late systole in the same cardiac cycle, time-to-peak delay color scale to effectively show the heterogeneous
showing septal motion away from the transducer and simultaneous left ventricular contractile pattern. Segments with delayed time-to-
delayed lateral wall motion toward the transducer (red). (C) Simul- peak velocities (>400 ms) are shown in orange (see color scale). Auto-
taneous time plots of the mean tissue velocities within septal mated time-to-peak velocity calculations of four myocardial
(yellow circle) and lateral-wall (green circle) sample volumes confirm segments (+’s) are shown in the table [basal septum (1 BS); middle
an early septal time-to-peak velocity (left arrow, yellow curve) and septum (2 MS); midlateral (3 ML); basal lateral (4 BL)].

Methods for Improving Two-Dimensional monic mode has greatly enhanced endocardial detection and
Imaging improved both routine and stress echocardiographic surface
imaging in patients with previous “technically” difficult
exams (Figs. 5.19A,B and 5.36A,B). However, this mode may
Tissue Harmonics make valve leaflets and other easily imaged thin structures
Fundamental frequency imaging involves creating an image appear unusually thickened even when they are normal in
by processing reflections that have the same frequency as the reality; this illusion is due to the fact that, compared with
originally transmitted frequency. Until the late 1990s, this fundamental frequency imaging, harmonic imaging has an
modality was the only 2D option that was commercially increased pulse length requirement. With experience, echo-
available. Sound frequencies that are multiples of the funda- cardiographers have learned to “read through” this phenom-
mental frequency are known as harmonic frequencies. If the enon and to refrain from calling normal leaflets thickened
fundamental transmitted frequency is 2.5 MHz, the second because of their appearance in this mode.
harmonic frequency is 5 MHz (2 × 2.5 MHz). Because sound-
waves behave nonlinearly as they pass through tissues, the
waves produce harmonic frequencies that, until recently,
Contrast Echocardiography
were not “listened for” by ultrasound machines. Although
this sound energy is minute, it undergoes less distortion than To clarify the left ventricular endocardial border and improve
the fundamental frequencies, so it is used to great effect for spectral Doppler signals, the examiner can intravenously
distinguishing tissue signals from noise. The tissue-har- administer microbubbles, sometimes called microspheres or
12 6 chapter 5

A B

C
FIGURE 5.45. Three-dimensional tissue Doppler imaging: acquisi- three-chamber (C) views. In this case, delayed time-to-peak longi-
tion of a three-dimensional volumetric data set allows the simulta- tudinal velocities are clearly localized to the mid-distal anterior
neous display of apical four-chamber (A), two-chamber (B), and septum and inferior walls (arrows, orange).

A B
FIGURE 5.46. Doppler-derived longitudinal strain rate imaging in ation. Positive strain rate periods: SRE; early diastolic “E” strain
the septum (apical four-chamber view) of a healthy 30-year-old man. rate; SRA, late diastolic “A” strain rate. (B) Anatomic M-mode dis-
A narrow imaging sector was used to maximize the sample rate plays the strain rate throughout the entire septum during a single
(185 fps in this case). (A) Localized strain-rate analysis within an cardiac cycle. Yellow indicates negative strain (myocardial longitu-
oval sample volume, middle septum. Negative strain-rate period dinal shortening/compression rate), while blue indicates a positive
(myocardial shortening): SR IVCT, strain rate of isovolumic contrac- strain rate (myocardial longitudinal lengthening rate).
tion; SRS, systolic strain rate; SR IVRT, strain rate of isovolumic relax-
 i n t roduct ion to echoc a r diogr a ph y 12 7

FIGURE 5.47. Strain rate imaging (SRI) using the speckle tracking dots on the anatomic M-mode display (lower left) correspond to dots
method [two-dimensional (2D) strain] in the left ventricular para- placed on discrete myocardial segments of the 2D image (upper left)
sternal short-axis view. The circumferential (A, arrows), radial (B, and the colored lines of the mean strain-rate plot (on right), allowing
arrows), and longitudinal (not shown) components of myocardial regional SRI comparison.
strain and strain rate can be analyzed with this method. Color-coded

ultrasound contrast agents as an adjunct to the routine

examination. Microspheres (diameter = 2.5 to 4.0 μm) are
smaller than red blood cells (diameter, 6 to 8 μm), transit the
pulmonary circuit, and variably persist in the circulation,
depending on their shells and the physical properties of the
contained gas. Microspheres strongly reflect fundamental
imaging frequencies and also resonate within ultrasonic
fields, producing relatively strong harmonic frequencies. As
a result, microspheres are hyperechoic in the bloodstream
and “light up” the cardiac chambers, improving detection of
the left ventricular endocardial border. Because more than
half of all echocardiograms are obtained to assess left ven-
tricular function and because 5% to 25% of examinations
(depending on a number of factors) are “suboptimal” for accu-
rately assessing all endocardial segments, the clinical use of
contrast agents, particularly for stress echocardiography, has
increased dramatically. The first FDA-approved agent con-
sisted of an albumen shell containing air. Air is highly
soluble in blood, however, so it rapidly leaks out of the micro-
sphere, causing rapid bubble shrinkage and relatively poor FIGURE 5.48. Apical-window three-dimensional volume data set
representation. “Anyplane” two-dimensional images (apical four-
microsphere persistence in the circulation. Newer FDA- chamber, two-chamber, and short-axis views) have been selected
approved contrast agents have less permeable shells that are retrospectively for simultaneous moving-image display and subse-
filled with high-molecular-weight inert gases with low solu- quent volume and segmental wall-motion analysis.
12 8 chapter 5

bility; these agents persist longer154 and have greater clinical appear almost white, the weakest processed signals are
utility for left ventricular opacification. darkest gray. The familiar gray-scale display allows interpret-
ers to roughly distinguish certain tissue types (e.g., scarred
Technical Notes or calcified tissue is usually much brighter than normal
myocardial or leaflet tissue). Manufacturers routinely provide
CONTRAST A RTIFACTS
a “colorized” gray-scale option, also referred to as pseudo-
An ultrasound field with sufficient energy (power) will
color or B color (not to be confused with B-mode imaging).
destroy exposed circulating microspheres. The ultrasound
Although resultant recruitment of the high-resolution retinal
system’s power-output setting must be adjusted downward
cone receptors is theoretically beneficial for recognizing
during contrast imaging to avoid apical swirling, which may
faint structures (endocardial borders, thrombus, etc.), this
be particularly prominent with low-flow states such as
modality is probably only equivalent to gray-scale imaging,155
dilated cardiomyopathy or an apical aneurysm. With local
and its use is based mainly on the examiner’s choice and the
bubble destruction, absence of near-field left ventricular con-
ambient lighting conditions. In our laboratory, selective B
trast can be mistaken for an apical mural thrombus. On the
color is used according to sonographer preference (Figs. 5.14C,
display screen, the ultrasound system’s power output is
5.16, and 5.19C), although it is not used in combination with
shown as the mechanical index (MI), which is a unitless
color Doppler imaging, since color-flow Doppler information
indicator of the negative acoustic pressure within an ultra-
can be obscured.
sound field. To achieve relatively uniform blood-pool con-
trast, the MI should be reduced to ≤0.5.
Three-Dimensional Echocardiography
CONTRAST ATTENUATION
This is another common artifact that occurs when overly The cardiac anatomy is complex, curvilinear, and constantly
concentrated bubbles “overreflect” the ultrasound signal at moving. Throughout the cardiac cycle, its component
shallow depths, obscuring the blood pool at greater depths. features change their configuration and position within
Because of limited contrast persistence and eventual dilu- 3D space. While observing the systematically acquired
tion, attenuation is a transient phenomenon. It can be mini- 2D images described previously in this chapter, experienced
mized by gradual contrast injection. Alternatively, image echocardiographers, in effect, assemble a 3D construct of
acquisition can be delayed until the attenuation resolves. the heart within their brain. Recording, measuring,
Left ventricular attenuation in the parasternal views can and conveying this construct to others is problematic,
occur because of overlying contrast material within the however. In the right hands, 2D echocardiography is “good
intervening right ventricular chamber, so apical windows are enough” for many clinical purposes. Nevertheless, real-
generally superior for left ventricular contrast echocardiog- time 3D echocardiography (sometimes referred to as four-
raphy. Other important contrast echocardiography artifacts dimensional, given the additional time element) became
exist, and they warrant further detailed study. somewhat of a “holy grail” for echocardiographers. During
the 1990s, static 3D “birdcage” images utilized “spark-gap”
techniques. This approach was time-consuming and not
Contrast Harmonics
in real time, although it showed a parity between 3D echo-
When used with fundamental frequency imaging alone, con- cardiography with magnetic resonance imaging (MRI) for
trast echocardiography improves left ventricular endocar- determining left ventricular volume, ejection fraction,
dial-border detection. Modern ultrasonographic systems are and important anatomic relationships.156–158 The first recog-
also configured to image contrast agents in “harmonic mode” nizable moving 3D anatomic reconstructions became
by transmitting at one frequency (e.g., 2 MHz) and construct- possible during the early 1990s, using painstaking methods
ing images based only on the returning first harmonic fre- of sequential electrocardiographic and respiratory phase-
quency (e.g., 4 MHz for a transmitted frequency of 2 MHz). gated linear or rotational, incremental, sequential scanning
Because high-amplitude fundamental frequencies that return of planar digital images.159,160 These images, derived from
from the soft tissue are “ignored,” the myocardium appears ordinary 2D imaging transducers, assembled the planar
very dark owing to its relative lack of contrast. Conversely, data (pixels) into a 3D volumetric data set (voxels) for
the adjacent blood pool is very bright, as it is populated by off-line reconstructions. Because the data sets were acquired
high concentrations of microspheres emitting harmonic fre- from numerous different cardiac cycles (as in cardiac
quencies. Contrast harmonic mode improves the diagnostic MRI or ultrafast computed tomography) the potential for
accuracy of endocardial border detection (Fig. 5.19C), includ- motion artifacts was great. However, this phase of develop-
ing identification of segmental wall-motion abnormalities ment led to important imaging concepts, such as surface
and assessment of left ventricular volume. This mode can renderings (Fig. 5.10C), and validation of 3D quantitative
also be used to detect luminal filling defects caused by methods.
thrombi. Recently, after undergoing substantial evolution, real-
time 3D pyramidal volume data sets became obtainable at
acceptable resolutions and frame rates during single cardiac
Color-Scale (B-Color) Imaging
cycles, without the need for sequential scanning methods.
The echocardiograph machine produces a gray-scale image Now available commercially, this technology is a descen-
based on the intensity of the returning signal within a dant of matrix-array transducer technology, as initially
defined dynamic range. Whereas the most intense echoes described by Sheikh and associates.161 Currently, large-
 i n t roduct ion to echoc a r diogr a ph y 12 9

A B

FIGURE 5.49. Parasternal long-axis

three-dimensional volume data set rep-
resentation with simultaneous display
of orthogonal two-dimensional image
planes: left ventricular long- (A) and
short-axis (B) views from the same
cardiac cycles.

volume 3D data sets can be assembled from four cardiac assessment is feasible. M-mode evaluation of the native
cycles recorded during a single breath-hold. Data from aortic valve (Fig. 5.50) during routine device “speed-change”
each cycle are assembled, reducing the potential for a evaluations can be used to determine the cycle rate (pulsatile
motion artifact. Smaller-volume data sets can be acquired pusher-plate devices) or impeller rotational speed (axial-flow
from a single cardiac cycle, permitting high-resolution pumps) at which aortic valve opening ceases, indicating
morphologic analysis. Current 3D technology permits the complete device support. Pulsed and CW Doppler studies of
simultaneous display of orthogonal imaging planes selected the device at both its inlet (Fig. 5.51A,B) and outlet (Fig.
from within the volumetric data set. The instantaneous 5.51C,D) cannulas are done to assess pump performance. By
display of “any-plane” 2D images enhances the viewer’s subtracting the pulsed Doppler-derived LVOT stroke volume
appreciation of anatomic relationships and allows “optimal” or cardiac output (see Doppler discussion, above) from the
2D planar images (Figs. 5.45, 5.48, and 5.49) to be constructed RVOT cardiac output (total cardiac output), flow in the ven-
from a “volumetric” data set off-line, potentially streamlin- tricular assist device can be determined. Although few clini-
ing image acquisition and avoiding apical foreshortening. cal data exist, appropriate pump speed settings may be
Color Doppler data may also be rendered in 3D, thereby selected accordingly.
potentially improving the quantitation of regurgitant lesions.
However, both 3D and 2D imaging remains subject to the
The Digital Echocardiography Laboratory
same physical principles of ultrasonography, which can
result in artifacts. Application of various echocardiography Because an echocardiogram consists of a large volume of
contrast and harmonic-imaging techniques, including 3D moving-image data, super-VHS videotape has traditionally
Doppler and 3D parametric imaging, is under clinical been the most cost-effective review and archival medium.
investigation. However, thanks to recent advances in computer software
and hardware, echocardiography laboratories are rapidly
moving from the videotape era to the digital age. With digital
Left Ventricular Assist Device Assessment
technology, the examination is broken up into a series of
Several varieties of ventricular assist devices are either discrete moving-image loops, each of which can be rapidly
under investigation or have been approved for clinical use. retrieved and viewed as often as necessary for interpretation.
The standard echocardiography examination, with certain Digital loops from the current and previous exams may be
easy-to-perform modifications, is a viable means of follow- displayed side by side for comparison. Sharing digital exams
ing up both device and native cardiac function.60,63,64,162,163 with colleagues is easy, causes no degradation in quality,
Routine anatomic and hemodynamic echocardiography and can be done throughout a hospital or clinic via Picture,
13 0 chapter 5

A B

C D
FIGURE 5.50. Left ventricular assist device (LVAD) assessment. which decreases incrementally as the pump speed is increased, with
M-mode imaging of the aortic valve cusps in a patient with a con- shared left ventricular output between the device and the native left
tinuous axial flow left ventricular assist device during different ventricular outflow tract. In D, the aortic valve does not open, indi-
pump speed settings: (A) 8000 rpm; (B) 9000 rpm; (C) 10,000 rpm; (D) cating complete LVAD support. Note: Device inlet location = LV
11,000 rpm. Arrows (A–C) indicate the period of leaflet opening, apex; device outlet location = ascending aorta (not shown).

Archiving, and Collection System (PACS). In contrast, video- anatomic and hemodynamic evaluation of simple and
tapes are difficult to retrieve from storage and can be lost or complex cardiac pathology. Although generally safe, this
broken. Videotape examinations can be reviewed only by powerful technique is potentially subject to image acquisi-
using time-consuming rewind and fast-forward procedures, tion and interpretation errors. Accordingly, a field of profes-
and video copying degrades the image quality. In addition to sional echocardiography has emerged to address matters of
its above-mentioned advantages, digital echocardiography continuing medical education, to establish training, prac-
permits efficient off-line data analysis, reduces overall physi- tice, and quality-assurance guidelines, and to research emerg-
cian interpretation times, incorporates standardized report- ing technologies and clinical applications. This chapter has
ing tools, and reduces storage needs. A digital echocardiography covered basic concepts regarding the physical principles of
laboratory facilitates quality-assurance measures. For all ultrasound and has presented a spectrum of common clinical
these reasons, conversion to digital echocardiography is applications. It has presented the basic transthoracic and
desirable and cost-effective.5 transesophageal echocardiography views as a basis for under-
standing subsequent echocardiography chapters within this
book. This chapter presents the modern echocardiography
Summary machine as a potentially complex multimodal device. Many
of the newer imaging modes are not yet routinely performed.
Since its initial introduction more than 50 years ago, echo- However, their selected application, when appropriate, may
cardiography has emerged as the most frequently used cardiac facilitate pathophysiologic diagnosis and thus improve
imaging technique. In many cases, it provides a definitive patient care.
 i n t roduct ion to echoc a r diogr a ph y 131

A B

C D
FIGURE 5.51. (A,B) Left ventricular assist device (LVAD) inlet conduit in a modified parasternal or modified apical view. (C)
cannula assessment, apical four-chamber view. Color Doppler Outlet-conduit flow in a patient with a pulsatile, pusher-plate device.
(arrow, A) indicates exit of blood from the left ventricular apex into Note: Outlet flow is not timed with the cardiac cycle. Forward flow
a pulsatile, pusher-plate–type LVAD. Apical inlet-cannula flow (arrow) can occur during ventricular systole (S) or diastole (D) as
ceases (arrow, B) during the pulsatile LVAD ejection phase (no device timed by the electrocardiographic tracing. (D) In a patient with an
filling occurs). (C,D) LVAD outlet cannula flow assessment using axial flow LVAD, outlet-cannula flow is phasic with the intrinsic
pulsed Doppler with the sample volume placed within the outlet cardiac cycle and “unloads” the heart continuously.

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 6 Nuclear Cardiology
Arthur Iain McGhie, K. Lance Gould, and
James T. Willerson

Myocardial Perfusion Imaging . . . . . . . . . . . . . . . . . . . . . 137 Positron Emission Tomography: Assessment of

Single Photon Emission Myocardial Perfusion. . . . . . . . . . . . . . . . . . . . . . . . . . 147
Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Radionuclide Ventriculography. . . . . . . . . . . . . . . . . . . . . 149

Myocardial Perfusion Imaging pharmacologic coronary arteriolar vasodilators, that is, coro-
nary flow reserve, becomes impaired in the presence of coro-
nary artery stenosis of moderate severity. Coronary flow
Physiologic Principles reserve, illustrated in Figure 6.2, is defined as the ratio of
Briefly, the underlying physiological principles of stress-rest maximum flow or perfusion during stress or pharmacologic
perfusion imaging are as follows: at rest, coronary flow is vasodilation to resting flow or perfusion. Figure 6.3 relates
normal even in the presence of a narrowing of up to 85% stenosis severity (horizontal axis) to coronary flow reserve
diameter stenosis (Fig. 6.1).1 Stress, usually in the form of expressed as the relative increase of flow in multiples times
dynamic exercise or vasodilatation, results in an increase in the initial baseline resting flow (vertical axis). The dashed
coronary flow. In a normal coronary artery, flow increases line indicates resting flow and the solid line is flow reserve.
2- to 2.5-fold with dynamic exercise or by three- to four- The gray zone indicates the range for multiple observations.
fold with maximal coronary vasodilation.2–6 However, the With progressive narrowing, baseline flow remains normal
increase in flow in a stenosed coronary is attenuated. Despite until the coronary artery is narrowed by 80% to 85% diam-
an increase in flow proximally, there is an increase in the eter stenosis. However, coronary flow reserve begins to
pressure gradient across the stenosis, resulting in a drop in decrease at 40% to 50% diameter stenosis for a vasodilatory
pressure and flow distal to the stenosis. This causes a het- stimulus increasing flow normally to four times baseline.
erogeneous distribution of blood flow during stress, with a For a stimulus increasing flow to five or six times baseline
greater increase in myocardial perfusion in the area sub- levels, coronary flow reserve would be reduced by an even
tended by the normal coronary artery relative to the myocar- milder 30% diameter stenosis. For the experimental stenoses
dium supplied by the stenotic artery. In certain circumstances, upon which Figure 6.3 was based, normal arterial diameter
coronary flow may actually decrease distal to the stenosis, and stenosis length were constant and relatively uniform for
resulting in subendocardial ischemia. This phenomenon of each stenosis in a progressive series of experimental coro-
myocardial steal may occur in two circumstances. In the nary artery constrictions. Consequently, percent narrowing
presence of a severe coronary stenosis, the coronary pressure related well to flow reserve with some data scatter (gray area
distal to the stenosis may decrease enough during stress that of Fig. 6.3) due to variable physiologic conditions of heart rate
it is insufficient to perfuse the endocardium, resulting in and aortic pressure, which may alter flow reserve somewhat.7
subendocardial ischemia despite an increase in total flow in In humans, absolute dimensions and length stenoses are
the proximal epicardial artery. This is sometimes referred to highly variable, with the consequence that percent diameter
as vertical steal. Alternatively, in the presence of one or more stenosis is poorly related to coronary flow reserve.7–13
diseased vessels with collaterals between their distal beds, However, both experimentally and in humans, it has been
there may be an unequal fall in the pressure between the two shown that directly measured coronary flow reserve is equiv-
distal perfusion beds. This can result in blood being shunted alent to, interchangeable with, and predicted by the arterio-
away from the distal bed with the higher perfusion pressure graphic geometry of coronary artery stenoses if all stenosis
to the one with the lower perfusion pressure. This is referred dimensions are accounted for including percent stenosis,
to as horizontal steal, and also can result in the production absolute cross-sectional lumen area, length, and shape.7,14–16
of subendocardial ischemia in the affected area.
Therefore, resting coronary flow or myocardial perfusion
Mechanisms Underlying Coronary Flow Reserve
imaging at rest does not sensitively reflect the presence or
severity of coronary artery disease. However, the capacity to To explain maintenance of normal resting coronary flow but
increase flow to high levels in response to exercise stress or reduced coronary flow reserve during progressive coronary

137
13 8 chapter 6

Rest no image defect 5

maximum flow
80% diameter stenosis
4
80 cc/min/100 g
80 cc/min/100 g

Coronary flow reserve

3

Image defect 50% of max flow

80% diameter stenosis
2

160 cc/min/100 g 320 cc/min/100 g

×2 increase ×4 increase resting flow
1

Image defect 85% of max flow

40% diameter stenosis 0 20 40 60 80 100

272 cc/min/100 g 320 cc/min/100 g Percent diameter narrowing
×3.4 increase ×4 increase FIGURE 6.3. Coronary flow reserve expressed as a ratio of maximal
flow to resting flow is given on the vertical axis, with percent diam-
eter narrowing given on the horizontal axis. With progressive nar-
rowing, resting flow does not change (dashed lines), whereas the
FIGURE 6.1. Principles for the detection of coronary artery disease maximal potential increase in flow or coronary flow reserve begins
with perfusion imaging under conditions of maximal coronary to fall at approximately 50% diameter narrowing. Shaded areas
vasodilation. With an 80% diameter narrowing, coronary flow represent the limits of variability of data about the mean plotted by
reserve is limited to an approximately twofold increase over resting the solid and dashed lines.
levels compared with a fourfold increase in nonstenotic arteries.
The abnormal area therefore has 50% less activity, reflecting 50%
decrease in regional maximal flow compared with the normal
maximum. A milder stenosis of approximately 40% diameter nar-
rowing will produce a mild relative defect of approximately 15%
below maximal flow, indicating a mild lesion.

constriction, consider the stenotic coronary artery as two

resistances in series, that is, a narrowed tube and a distal
coronary vascular bed, represented schematically in Figure
6.4. Normally, the distal coronary bed resistance at rest is
high. In this schema, the driving pressure for flow is the total

Rest no image defect

80 cc/min/100 g
80 cc/min/100 g

MAX =2 and 4
ABS CFR=
REST

160 cc/min/100 g 320 cc/min/100 g FIGURE 6.4. Diseased coronary circulation as two resistances in
×2 increase ×4 increase series. Rs indicates the resistance of the stenotic artery, and Rb
indicates the resistance of the distal vascular bed. The effects of
reducing Rb with the use of vasodilators are shown by the dashed
line. The equation shows the relation between resistance and flow
MAXs
REL CFR= = 0.5 (F) for various segments of the curves. For a given total pressure
MAXn gradient across the narrowed tube and distal vascular bed, flow is
Image defect 50% of max determined primarily by Rb if Rb is large. Changes in the stenotic
FIGURE 6.2. Concept of absolute coronary flow reserve (ABS CFR) resistance Rs have little effect until the value of Rs approaches that
and (REL CFR) relative coronary flow reserve. of Rb.
 n ucle a r ca r diology 13 9
pressure gradient across the stenosis and distal vascular bed, bed resistance equally for both normal and stenotic arteries.
which is approximately central aortic pressure since venous When the maximum flow in the stenotic artery is normal-
pressure is relatively small. Therefore, flow is determined ized by normal maximum flow, the effects of pressure, heart
approximately by aortic pressure divided by the sum of the rate, or vasomotor tone on flow in the numerator and denom-
resistances of the stenosis (Rs) and of the distal vascular bed inator of this ratio cancel out. Therefore, relative differences
(Rb) in series. If the distal bed resistance is large compared in regional maximum flow, or relative flow reserve, are deter-
with the stenosis resistance, as normally found at rest, large mined primarily by geometric stenosis severity. Relative
changes in the stenosis resistance will have little effect on flow reserve, therefore, is a measure of stenosis severity rela-
flow, which is determined primarily by distal vascular bed tively independent of physiologic variables.
resistance. Therefore, a progressive stenosis up to a point will Rather than considering absolute coronary flow reserve
have no hemodynamic effect on resting coronary blood flow. to be competitive or antithetical to relative flow reserve,
However, as the stenosis becomes sufficiently severe to these measurements are independent variables providing
create a resistance comparable to that of the distal vascular complementary information. Absolute flow reserve is the
bed, the distal bed vasodilates, loses its ability to autoregu- flow capacity of the stenotic coronary artery and vascular
late, and further narrowing causes a fall in resting coronary bed under whatever conditions of pressure, workload, hyper-
blood flow. When the stenosis becomes sufficiently severe trophy, vasomotor tone, or stenoses are present. It reflects the
that its resistance is much greater than that of the distal cumulative summed effects of these various factors without
vascular bed, autoregulation will be lost and flow will be being specific for the mechanism or cause of altered flow
determined predominantly by the stenosis resistance alone. reserve. Relative coronary flow reserve reflects more speci-
Further arterial narrowing then causes resting flow to fall as fically the effects of the stenosis independent of and
shown in Figure 6.4. Thus, the coronary vascular system is not affected by the other physiologic variables if normal
normally a low-flow, high-resistance circulation at rest. Cor- maximum flow is high enough. Thus, absolute and relative
onary vasodilators or stress convert this normally low-flow, coronary flow reserve are complementary.
high-resistance system into a high-flow, low-resistance
system in which coronary stenoses, even mild ones, limit
maximum flow. Such logic explains why imaging regional
myocardial perfusion at maximum coronary vasodilation Single Photon Emission Tomography
can be used to detect coronary narrowing.
Physics and Instrumentation
Use of radionuclides to image the heart depends on the
Absolute and Relative Coronary Flow Reserve ability to detect emitted electromagnetic radiation from
The concept of coronary flow reserve, defined as maximum injected radionuclides. The radionuclide is usually either
flow divided (normalized) by resting control flow, has evolved taken up by the myocardium or remains in the intravascular
into an accepted functional measure of stenosis severity compartment. The emitted gamma rays are detected by a
since first proposed (Fig. 6.2).7–13,17,18 Its validity has been con- scintillation counter where the emitted electromagnetic
firmed and applied clinically by noninvasive imaging and by radiation is converted into electrical energy and transformed
invasive methods. These clinical methods measure pharma- into a digital format to produce images either of myocardial
cologically induced increases in coronary blood flow, most activity or the cardiac blood pool.
commonly with intravenous dipyridamole for noninvasive
studies and intracoronary papaverine for invasive studies.
Scintillation Counter
More recently intravenous adenosine has been used.
However, changes in aortic pressure and heart rate are These counters are usually made of sodium iodide thallium
known to alter cardiac workload and therefore baseline coro- [NaI(Tl)] activated crystal. The purpose of the scintillation
nary blood flow as well as altering maximum coronary flow crystal is to convert the energy of γ-radiation into visible
under conditions of maximal vasodilation.18 Consequently, light. When a γ-ray interacts with the atom in the crystal, a
absolute coronary flow reserve, as measured by flow meter, high-speed electron is produced. This electron in turn dis-
also varies with aortic pressure and heart rate independent turbs other atoms in its path, creating more high-speed elec-
of stenosis geometry due to differential effects of these vari- trons. The number of high-speed electrons generated is in
ables on resting and maximal coronary flow. Under markedly proportion to the γ-ray’s total kinetic energy. These electrons
varying physiologic conditions, or from patient to patient, move through the crystal until trapped by an atom of thal-
absolute coronary flow reserve may not reliably or specifi- lium, when their kinetic energy is converted into a photon
cally reflect severity of coronary artery narrowing since it of light, that is, a scintillation. This whole process occurs
may be altered by physiologic factors unrelated to stenosis within a microsecond of the initial interaction between the
geometry. high-energy photon and the crystal. Every γ-ray absorbed by
In contrast, relative maximum coronary flow or relative the crystal results in the production of a large number of
flow reserve is defined as maximum flow in a stenotic artery photons, which is in direct proportion to the energy of the
divided (normalized) by the normal maximum flow in the γ-rays.
absence of stenosis. During maximal coronary vasodilation Subsequently, a photomultiplier converts these photons
physiologic variables, such as aortic pressure, heart rate, of light into an electrical signal, which then amplifies the
metabolic demand, and vasomotor tone alter distal coronary electrical signal. Photons of light are detected by the photo-
14 0 chapter 6

multiplier using a thin plate, called a photocathode, which

releases electrons in proportion to the photons striking it.
The electrons are then accelerated through a series of usually
10 plates, known as dynodes, which multiply the electrons
striking them in proportion to voltage difference between
the plates. This results in an amplification factor of approxi-
mately 1 million. Following this, the electrons are collected
by an anode, and an electrical impulse is generated by a pre-
amplifier. The energy of the γ-ray absorbed by the crystal and
the subsequent light released by the crystal are directly pro-
portional to the height of this electrical pulse, that is,
voltage.
A device called a pulse height analyzer is used to prese-
lect the range of energies to be counted (energy window) from
the distribution of available energies (energy spectrum). Any
energies corresponding to γ-rays with this predetermined
energy window are rejected. Discriminating the energy of
the γ-ray is important as it facilitates (1) selection of different
radionuclides with different energies and (2) the elimination
of less energetic γ-rays scattered by the patient’s tissue prior
to detection by the scintillation device. However, pulses gen-
erated by the unscattered γ-rays are not all of exactly the
same amplitude, and they are distributed around the exact
characteristic energy of the radionuclide (photopeak). The
less spread of the radionuclide around the photopeak, the FIGURE 6.5. Schematic diagram of a gamma camera.
better the energy resolution of the system, and therefore
the better the inherent counting and imaging characteristics
of the device.

Single-Crystal Gamma Camera

This camera uses a large (300–500 mm), thin (75–125 mm) the predetermined range, it is referred to as either a trigger
NaI(Tl) crystal with an array of photomultiplier tubes cover- impulse or a signal (s) pulse. This signals that the scintil-
ing one side of the crystal. On the other side of the crystal lation event should be counted. Each time a trigger impulse
is a lead plate with multiple holes in it called a collimator is received by the cathode ray tube, it allows the emission
(Fig. 6.5). This causes selective interference by blocking those of electrons from the electron gun. The x and y positional
rays not traveling in the selected direction. In some ways, impulses are transmitted to the horizontal and vertical
the collimator is analogous to the lens of a photographic plates, creating a deflection in the path of the electrons cor-
camera resulting in a preselection of γ-rays before they strike responding to the scintillation coordinates. Electrons hit
the crystal. The most commonly used collimator in nuclear the phosphor screen of the cathode ray tube, creating a
cardiology is a parallel-hole collimator. The lead septa small scintillation that can be recorded on photographic
between the holes absorb most of the γ-rays not traveling film. However, today computers are used for image display,
parallel to the holes. The larger the diameter or shorter the processing, analysis, and archiving purposes. Therefore, the
length of the holes, the higher is the sensitivity of the colli- x, y, and z pulses are also relayed to the computer interface
mator, and the smaller the diameter or longer the length unit. These impulses first must be converted from analog
of the holes, the higher the spatial resolution of the to digital format using an analog-to-digital converter (ADC).
collimator. The ADC converts the pulse height into discrete numbers.
The γ-rays passing through the holes of the collimator The x and y impulses both have an ADC, whereas the z
strike the crystal and produce a scintillation. Photons pro- impulse signals the ADCs to convert the analog pulses to
duced by the scintillation are detected by all the photomul- digital numbers.
tiplier tubes; photomultiplier tubes closer to the event The current generation of gamma cameras performs real-
gather more light than those farther away. All output from time corrections for (1) tube drift, (2) energy variations, and
the photomultipliers is relayed into electronic computer cir- (3) spatial nonlinearity. Tube drift correction automatically
cuitry where it is processed. A positional analyzer deter- adjusts the photomultipliers so that each one generates the
mines and assigns x and y Cartesian coordinates to the same pulse voltage when it gathers photons from the same
point in the crystal where the scintillation occurs. In addi- light source. This correction is required because the earth’s
tion, output of all the photomultipliers is summed, repre- magnetic field affects the photomultiplier’s output as a func-
senting the total energy of the γ-ray that interacted with the tion of its angle and is particularly important in rotational
crystal, to form an energy or z pulse. The z pulse is sent to tomography. The energy correction factor compensates for
the pulse height analyzer, and it is set to accept a prese- differences in response of individual photomultiplier tubes,
lected range of energies (see above). If the z pulse is within differences in the crystal, or differences in regional light-
 n ucle a r ca r diology 141
gathering properties. Energy-specific field floods need to be
acquired periodically to generate the time-dependent energy
maps. This predetermined map is then applied by a correc-
tion circuit in real time. This normalizes the relationship of
the energy window to the shape of the spectrum, practically
abolishing the variations in energy response. Linearity cor-
rection is required because the gamma camera positioning
scheme does not perfectly image straight radioactive line
sources. A phantom of straight lines in horizontal and verti-
cal positions is imaged. The displacement is measured and
stored, allowing the linearity circuit to correct lines so that
they appear perfectly straight in the image.

Acquisition Modes
Planar acquisition is the simplest means of acquisition,
where the γ-camera acquires data in one dimension in mul-
tiple projections, usually in three, that is, anterior, left ante-
rior oblique, and left lateral projection. Right anterior and left
posterior oblique projections may be obtained depending on
the circumstances. Despite obtaining multiple projections,
the spatial resolution is limited. This occurs because of over-
lapping activity from either noncardiac structures or overlap
between normal and abnormal segments within the heart.
For example, the presence of adjacent pulmonary activity
may overlap the posterolateral wall in the left anterior FIGURE 6.6. Schematic representation of the process of backprojec-
oblique, making the anteroseptum appear hypoperfused; tion. Multiple planar views are taken around 360 degrees or 180
alternatively, a small perfusion defect may not be detected degrees, with data being back-projected in space to define the origin
of the data in space (see text for further details).
because of activity in normal myocardium in an adjacent but
different plane.
Tomographic acquisition, also known as single photon
emission computed tomography (SPECT), is now the most
common acquisition mode for myocardial perfusion imaging.
A series of planar images are obtained usually in a 180- high-frequency statistical noise, hence the term filtered
degree rotation from 45 degrees right anterior oblique (RAO) backprojection.
to 45 degrees right posterior oblique (RPO). Using a tech-
nique called filtered backprojection, a computer creates a set
Radiopharmaceuticals
of transaxial images from these planar images, allowing the
radioisotope distribution to be displayed in three dimen- 201
Thallium
sions. From these transaxial images horizontal and vertical
long axis sections and short axis sections are constructed. This cation is a potassium analog and was the first widely
This results in improved contrast and enhanced spatial reso- used radioisotope in the assessment of myocardial perfusion.
lution, when compared to planar imaging. However, this Myocardium uptake occurs by both active and passive
technique is more exacting, in terms both of equipment and mechanisms involving Na,K–adenosine triphosphatase
acquisition technique, and of requiring more rigorous quality (ATPase).19,20 Uptake of 201thallium (201Tl) by the myocyte is
control. not affected by either ischemia or hypoxia unless these pro-
Filtered backprojection uses an algorithm that is depen- cesses result in cell death.21–24 There is a linear relationship
dent on the fact that each photon that interacts with the between 201Tl uptake and coronary blood flow, with a ten-
crystal must pass through the collimator, which defines the dency to underestimate and to overestimate at the upper and
path of the photon because the holes in the collimator are lower limits of the physiologic range, respectively.25–28 Thal-
parallel. The reconstruction algorithm back-projects or sends lium washes out of the myocardium by diffusion with a
back the counts from their recorded position on the crystal, half-life in the myocardium of 4 to 8 hours. The rate is pri-
along a line perpendicular to the face of the crystal (Fig. 6.6). marily dependent on the 201Tl concentration gradient between
The back-projected lines cross at the origin of the radiation, the myocardium and blood.29,30
and these points are recorded in computer memory from In comparison to a normal coronary artery, lower coro-
which tomograms are generated. However, the reconstruc- nary flow rates are achieved in a stenosed artery during
tion algorithm deposits counts in each pixel along the back- stress. As a consequence, there is less 201Tl uptake by the
projected line, producing a star-shaped artifact and in-plane myocardium in this artery’s distribution. Following stress,
blurring of the image. To reduce these artifacts, the images coronary flow returns to baseline levels and is the same in
are modified by a filter that eliminates unwanted low- and both the normal and stenosed artery. However, because of
14 2 chapter 6

the unequal distribution of 201Tl in the myocardium during and resting myocardial perfusion with one injection at
stress, clearance of 201Tl is heterogeneous. The greater maximal stress. However, the short residence time in the
concentration gradient between the normal myocardium myocardium mandates rapid data acquisition, and failure to
and blood results in a higher washout rate of 201Tl than do so may potentially lead to image artifacts because of the
in the hypoperfused myocardium where the 201Tl concen- changing myocardial distribution of 99mTc-teboroxime during
tration gradient is less. As a consequence, there is a trend acquisition. Despite the initially encouraging clinical results
for the myocardial concentration of 201Tl to equalize with of 99mTc-teboroxime,45 its rapid clearance made it very diffi-
time in the normal and abnormally perfused myocardium. cult to use in the clinical arena, resulting in preference for
Therefore, there is apparent “redistribution” of 201Tl, with the other 99mTc-labeled radiopharmaceuticals and the subse-
the stress-induced perfusion defect apparently reversing quent withdrawal of the product from the marketplace by the
during rest imaging 3 to 4 hours later. A perfusion defect manufacturer.
following stress that has resolved by time of distribution In contrast, the kinetics of sestamibi are in many ways at
imaging is considered to represent ischemic and viable the opposite end of the spectrum to teboroxime. It is a lipo-
myocardium. philic cation that accumulates in the myocardium in propor-
Conversely, a defect still present at the time of redistri- tion to blood flow, although at higher coronary flow rates the
bution imaging was classically interpreted as representing relationship becomes nonlinear, resulting in an underestima-
nonviable scar tissue. However, several studies, using either tion of coronary flow. It has a first-pass extraction fraction of
improvement in regional ventricular function following 65%, which is lower than either 201Tl or teboroxime. However,
revascularization or myocardial uptake of 18fluorine- its net extraction is higher because it is avidly retained by
fluorodeoxyglucose (FDG), have identified viable myocar- myocytes with little bidirectional exchange of sestamibi
dium in 40% to 60% of fixed 201Tl perfusion defects.31–33 with minimal redistribution and slow clearance.46 The
Several studies from Bonow and associates34–36 have shown volume of distribution for sestamibi is so large that saturation
that either performing late–24-hour redistribution imaging of myocardial uptake does not occur. Uptake occurs primar-
or reinjecting an additional dose of 201Tl after 4-hour redis- ily by diffusion, resulting primarily from negative electrical
tribution in the presence of an apparent “fixed” perfusion gradients across sarcolemmal and inner mitochondrial mem-
defect results in reversibility of a significant proportion of branes, and to a lesser extent concentration gradients.47
these defects, and that this correlates with myocardial Carvalho and associates48 demonstrated that 90% of 99mTc-
uptake of FDG. The same workers were able to show that sestamibi in vivo activity is associated with mitochondria as
areas of hypoperfused myocardium, where the reduction the original free cationic complex.
in 201Tl uptake is only mild or moderate, that did not Clinical studies to date indicate that imaging with 99mTc-
redistribute are still viable.37 However, Kitsiou and asso- sestamibi has demonstrated a similar degree of accuracy for
ciates38 have shown that although mild-to-moderate the overall detection of coronary artery disease, but usually
perfusion fixed defects contain viable myocardium, these results in higher quality images and is more accurate for the
areas are less likely to show functional improvement after detection of individual coronary artery stenoses.34,49 Use can
revascularization than mild-to-moderate defects that are be made of 99mTc-sestamibi’s long myocardial retention time,
reversible. which allows for a patient to be imaged up to 4 to 6 hours
after administration of 99mTc-sestamibi. This has been useful
in triaging patients presenting to the emergency room with
99m chest pain and also in evaluating therapeutic interventions
Technetium-Labeled Perfusion Agents
in the setting of acute myocardial infarction where 99mTc-
99m
Technetium (99mTc)-labeled radiopharmaceuticals were labeled radiopharmaceutical can be given acutely, with
developed in the early 1980s. Three agents, sestamibi, tebo- imaging to be performed later when the patient is in a more
roxime, and tetrofosmin, are approved for clinical use by the stable condition and environment.50–55 The higher count
United States Food and Drug Administration. In comparison rates and the lack of redistribution also allow gated tomo-
to 201Tl, 99mTc-labeled radiopharmaceuticals offer significant graphic acquisitions to be performed. This increases the
advantages, including (1) a shorter 6-hour half-life, which accuracy of the technique and allows the evaluation of endo-
allows a larger patient dose to be administered, typically 25 cardial wall motion and myocardial thickening, providing
to 35 mCi compared to 3 to 4 mCi of 201Tl; and (2) higher important information on regional and global ventricular
energy, 140 for 99mTc photons versus 74 keV for 201Tl, reducing function.56–58
the scatter fraction and resulting in superior energy discrimi- Tetrofosmin is the most recent 99mTc-labeled radiophar-
nation. These advantages typically translate into higher maceutical approved for clinical use. Like its predecessor,
quality images.39,40 99m
Tc-sestamibi, tetrofosmin is a lipophilic cation, which
Teboroxime has kinetic properties that are different from diffuses across the sarcolemmal and mitochondrial mem-
the other currently available 99mTc-labeled radiopharmaceu- branes.59–61 Similar to sestamibi, tetrofosmin tends to under-
ticals. It is extremely lipophilic, and myocardial uptake cor- estimate flows greater than 2 mL/min/g and to overestimate
relates closely with coronary blood flow over a wide range of flows less than 0.2 mL/min/g.62 Munch and colleagues63
flow rates and has very rapid myocardial washout.41 Unlike reported that 99mTc-tetrofosmin had a shorter myocardial
201
Tl, teboroxime washout is largely flow dependent, and it half-life and higher heart-liver ratios than 99mTc-sestamibi.
appears that the rate of washout from the myocardium may In a canine model using adenosine, Glover and associates64
allow differentiation between viable and nonviable tis- observed that 99mTc-tetrofosmin uptake underestimated the
sue.42–44 Theoretically, it may be possible to evaluate stress flow heterogeneity more than 201Tl. A clinical study65 com-
 n ucle a r ca r diology 14 3
paring 99mTc-tetrofosmin with 201Tl SPECT imaging using decreased calcium uptake, (2) activation of adenylate cyclase
dipyridamole stress had findings that tended to support those through A 2-receptors in smooth muscle cells, and (3) possible
reported by Glover and associates. In this clinical study, 201Tl modulation of sympathetic neurotransmission.78,79 Dipyri-
imaging identified more reversible defects than 99mTc- damole may alter systemic hemodynamics with a slight
tetrofosmin SPECT imaging, and in addition, the authors fall in blood pressure and slight increases in the heart
noted that the magnitude of reversible perfusion defects also rate and pressure-rate product. Once adenosine leaves the
was more severe in the 201Tl images. Similar findings have interstitium, it undergoes rapid intracellular metabolism
also been reported by others.66,67 However, in general terms, via adenosine kinase by phosphorylation to adenosine
clinical experience has shown that tetrofosmin is compara- monophosphate or deamination by adenosine deaminase.80
ble to the other currently available myocardial perfusion Dipyridamole undergoes hepatic biotransformation to a
agents.68–70 monoglucuronide and is excreted in the bile.81 Patients
should be in a fasting state and should not have taken
any xanthine medications (theophylline) in the previous 36
hours and caffeine beverages (including decaffeinated coffee
Choice of Stress
or tea and cola) in the preceding 24 hours. It is contraindi-
cated in patients with a history of significant reversible
Exercise
airways obstruction. An infusion of 0.142 mg/kg/min of
The cardiovascular response to dynamic exercise results dipyridamole is given over 4 minutes and with the radiophar-
in an increase in cardiac output. The peripheral resistance maceutical being administered 3 to 4 minutes later. Con-
decreases in active muscles and increases in resting tissues; tinuous clinical, electrocardiographic, and blood pressure
overall there is a fall in systemic vascular resistance.71 There monitoring is performed during the procedure, with imaging
is an increase in heart rate in response to exercise, mediated being performed in the usual manner. Serious adverse
by alterations in the autonomic nervous system. The increase reactions have been reported following intravenous dipyri-
is linearly related to workload and oxygen uptake. The heart damole, including fatal and nonfatal myocardial infarction,
rate response to maximal dynamic exercise is dependent on ventricular fibrillation, symptomatic ventricular tachycar-
many factors, especially the individual’s age and health. The dia, transient cerebral ischemia, and bronchospasm.69 The
increases in cardiac output during dynamic exercise increases effects of dipyridamole are usually rapidly reversed by
systolic arterial blood pressure, with little alteration in the the administration of aminophylline, which antagonizes the
diastolic pressure. Dynamic exercise is the most commonly effects of adenosine at the A 2-receptor.82 Side effects are
used means of stress when using nuclear techniques. The reported in approximately 50% of patients following intrave-
procedure is carried out in a manner almost identical to nous dipyridamole at the dose of 0.568 mg/kg. Chest pain
conventional exercise electrocardiography. In addition, the occurs in approximately 15% to 40% and ST segment depres-
patient should have an intravenous cannula placed in a large sion in 5% to 20% of patients. The presence of either or both
vein in the antecubital fossa prior to stress. At peak exercise, does not reliably predict the presence of angiographically
the patient is injected with the radiopharmaceutical and con- significant disease, although it is more common in their
tinues exercising for a further 60 to 90 seconds. The timing presence. Noncardiac symptoms are relatively common and
of imaging following exercise is dependent on the particular include flushing, nausea, light-headedness, and mild
radiopharmaceutical being used. headaches.
Adenosine, the mediator of dipyridamole’s vasodilating
action, is a powerful coronary arterial vasodilator.83,84
Vasodilator Pharmacologic Stress
Maximal coronary vasodilatation is obtained with an intra-
Pharmacologic stress is being increasingly used. The main venous infusion rate of 100 to 140 μ/kg/min. This increases
indication for its use is when the patient is unable to exercise coronary blood flow velocity by 4.4-fold. The effects are
adequately. Reasons for this are varied and include concomi- maximal 2 minutes after the onset of the infusion and return
tant medical conditions, such as peripheral vascular disease, to baseline within 2 to 3 minutes of its discontinuation. It
morbid obesity, and neurologic disease; poor motivation; is widely used as a pharmacologic stress and has a compara-
and antianginal medication (in particular β-adrenergic and ble diagnostic accuracy when compared with dipyridamole
calcium channel antagonists). It is also indicated for stress- myocardial perfusion imaging.85–87 The short half-life of ade-
ing patients with left bundle branch block (LBBB) or a paced nosine results in it being better tolerated by patients. Verani’s
rhythm because of the problem of artifactual reversible septal group88 reported their experiences with this technique in 607
perfusion defects when exercise stress is used. patients. Small but significant mean increases in heart rate
Dipyridamole is widely used in conjunction with myo- and falls in the systolic and diastolic blood pressures were
cardial perfusion imaging and has a similar diagnostic accu- observed. First- and second-degree atrioventricular (AV) block
racy to exercise imaging.72–74 Dipyridamole is a highly basic occurred in 10% and 4% of patients, respectively; ischemic
and hydrophobic pyrimidine derivative that induces an ST segment depression was identified in 13% of cases. Side
increase in endogenous adenosine levels by blocking uptake effects were frequent but well tolerated; flushing occurred in
of adenosine by red cells and endothelium.75–77 The increased 35%, chest pain in 34%, headache in 21%, and dyspnea in
concentrations of adenosine in the interstitial fluid results 19% of patients. In the majority of patients, the side effects
in relaxation of vascular smooth muscle. This may be medi- ceased rapidly after terminating the adenosine infusion. The
ated by a number of possible mechanisms, including (1) an side effects were severe in only 2% of patients, and in only
inhibition of slow inward calcium current resulting in six of 607 patients was it necessary to discontinue the
14 4 chapter 6

infusion. No serious adverse reactions were reported. Recent cise adequately to attain these goals for whatever reason, for
studies of selective adenosine A 2A-receptor agonists have example, arthritis, deconditioning, neurologic disease, or
shown that the vasodilator effects of adenosine can be peripheral vascular disease. The presence of LBBB or a paced
obtained without many of the side effects.89–91 ventricular rhythm is an indication for vasodilator stress
Vasodilator stress imaging can be supplemented with because of the reversible septal perfusion defects that can be
exercise, using either isometric handgrip or low-level tread- produced by abnormal ventricular activation. In addition,
mill exercise.92,93 The former has been used quite exten- pharmacologic stress is generally utilized when stress myo-
sively following evidence of increased coronary flow when cardial perfusion imaging is performed in the setting of a
used in combination with dipyridamole.94 But later data, recent unstable angina or myocardial infarction, because of
using Doppler-derived indices of flow, have produced con- the relative lack of effect on hemodynamics. The main role
flicting evidence.6 Therefore, it probably confers benefit by of dobutamine in nuclear cardiology is when the use of dipyr-
different mechanisms, including an increase in afterload idamole or adenosine is contraindicated, usually in a patient
or vasoconstriction of small to moderate-sized arteries. with reversible obstructive airways disease.
Exercise also improves image quality by improving target-
201
to-background ratios,95,96 probably by causing splanchnic Thallium
vasoconstriction.
Typically 3 mCi of 201Tl is injected at peak stress and imaging
is commenced early, within 10 to 15 minutes, because of the
Sympathomimetic Pharmacologic Stress kinetics of 201Tl. A second set of images is acquired approxi-
mately 4 hours later after redistribution has occurred. If
Dobutamine is a potent sympathomimetic agent with stimu- incomplete redistribution has occurred and myocardial via-
latory effects on β1-, β2-, and α1-adrenoreceptors with pre- bility is a clinical concern, then either a second injection of
dominantly inotropic and a lesser chronotropic effects.97,98 1.5 mCi can be given and the patient reimaged 10 to 30
Therefore, dobutamine produces an increase in myocardial minutes later (reinjection imaging) or alternatively the
oxygen requirement by causing an increase in myocardial patient can be reimaged 24 hours later. Thallium images are
contractility and systolic blood pressure and at higher doses increasingly being acquired as electrocardiogram (ECG)-
an increase in heart rate. The dose for dobutamine is usually gated images to provide functional data in addition to perfu-
10 μg/kg/min increased by increments every 3 to 5 minutes sion. If 201Tl imaging is being performed primarily to assess
to a maximal infusion rate of 30 to 40 μg/kg/min. Side effects viability rather than stress-induced ischemia, then a rest-
that can occur with this agent include palpitation, headache, redistribution protocol is used. In this protocol, 3 mCi of 201Tl
paresthesia, nausea, tremor, ventricular arrhythmia, and is injected at rest with imaging being performed 15 to 30
marked ST segment depression. Side effects usually resolve minutes later and again at 4 hours, with the option of obtain-
rapidly following discontinuation of the infusion. The effects ing a 3rd set of images after 24 hours.
of dobutamine are similar to those of dynamic exercise, and
in the presence of coronary artery disease myocardial isch- 99m
Tc-Labeled Radiopharmaceuticals
emia may be provoked.99,100 It produces an increase in coro-
nary flow of between two- and threefold, which is less than The most widely used protocol for this group of pharmaceu-
is typically seen with either dipyridamole or adenosine.101 ticals is the same-day rest-stress protocol. Typically 8 to
Studies indicate that dobutamine stress myocardial per- 9 mCi are injected at rest with imaging being performed
fusion has clinical utility; however, it is usually reserved approximately 1 hour later. The patient is stressed around
for patients with a contraindication to adenosine or 1 to 4 hours following the rest injection and receives around
dipyridamole.102–105 25 to 30 mCi at peak stress. The stress images are acquired
15 to 60 minutes later; if the patient has been exercised,
then imaging can be acquired 15 minutes after stress;
Imaging Protocols however, if pharmacologic stress has been utilized, then
imaging is delayed 45 to 60 minutes to allow for hepatic
Over the years different imaging protocols have been devel- and visceral clearance of the radiopharmaceutical. The
oped with the advent of new radiopharmaceuticals with dif- same-day stress-rest protocol involves performing stress
ferent kinetics and the use of different pharmacologic stress imaging first using the smaller 8 to 9 mCi dose, with rest
agents. The American Society of Nuclear Cardiology (ASNC) imaging being performed 1 to 4 hours later using the 25 to
has published guidelines in an effort to standardize imaging 30 mCi dose. This has the advantage that if the stress images
protocols.106 are normal, then rest imaging does not need to be per-
formed. However, it has the disadvantage that the stress
images are acquired using the lower dose of the 99mTc labeled
Choice of Stressor
radiopharmaceutical and therefore may be of lower quality,
If the patient can exercise adequately, exercise is preferred which may adversely affect the diagnostic accuracy of the
over pharmacologic stress in most circumstances. Adequate images. The third protocol that is used is a 2-day protocol
exercise is achieved when the patient achieves more than with the rest and stress images being acquired on separate
85% of his maximum predicted heart rate for age and exer- days. This protocol is particularly useful in two particular
cises of an adequate period of time, that is, longer than 6 situations. The first is when imaging is being performed for
minutes on a Bruce protocol. Circumstances where pharma- diagnostic purposes, usually in patients with a low pretest
cologic stress is preferred is when the patient will not exer- likelihood, in which the stress portion is performed first
 n ucle a r ca r diology 14 5
and if these images are normal, rest imaging is not required. Vertical
The second application is in obese patients to maximize Short axis long axis
image quality by using the higher dose of the 99mTc radio-
pharmaceutical (0.31 mCi/kg) for both the rest and the stress Apical Mid Basal Mid
1
images. 7
13 8 12 2 6
Hybrid Protocols 14 16 17
The other protocol that is widely used is the dual-isotope 9 11
15 3 5
protocol. In this protocol, 2.5 mCi of 201Tl is injected at rest 10
with rest images being acquired 10 minutes later. Then the 4
patient is stressed and 25 mCi of 99mTc-labeled radiopharma-
ceutical is injected at peak stress, with the stress images LAD RCA LCX
acquired 15 to 90 minutes later depending on the stressor FIGURE 6.7. Schematic diagram showing the standardized segmen-
used. If a fixed perfusion defect is seen, then 24-hour 201Tl tation and assignment of the coronary artery territories. LAD, left
anterior descending; RCA, right coronary artery; LCX, left circum-
imaging can be performed. The main disadvantage of the
flex coronary arteries.
technique is the greater interpretive skill required to read
the images because of the differences between the rest and
stress images resulting from differences in the physical prop-
erties of 201Tl and 99mTc.
circumflex coronary artery supplies the middle and posterior
portions of the left ventricular wall, and the right coronary
Analysis of Images
artery supplies the apical, inferior, and inferoseptal aspects
For the most part, tomographic imaging has replaced planar of the left ventricle (Fig. 6.7). Figure 6.8 demonstrates 201Tl
techniques because of enhanced contrast and spatial resolu- tomograms following exercise and redistribution from a
tion and consequently improved sensitivity for the identifi- patient with disease of the left anterior descending and right
cation and localization of coronary artery disease.107 The coronary arteries. There are moderate-severe perfusion
myocardial territories subtended by the left anterior descend- abnormalities involving both the anterior and septal as well
ing coronary artery consist of the apical, anterolateral, ante- as the inferior, inferoseptal, and inferolateral aspects of the
rior and anteroseptal portions of the left ventricle; the left left ventricle. In addition, there is evidence of left ventricular

FIGURE 6.8. Exercise-redistribution of

201
Tl from a patient with disease of the
left anterior and right coronary arteries.
Representative short, vertical long, and
horizontal tomograms are shown fol-
lowing exercise and redistribution. Per-
fusion defects are present in the anterior
and septal walls indicative of left ante-
rior descending coronary (LAD) isch-
emia as well as the inferior, inferoseptal,
and inferolateral walls indicative of
right coronary ischemia (RCA). In
addition, there is transient dilatation
of the left ventricle and a fall in the
ejection fraction with exercise indica-
tive of stress-induced left ventricular
dysfunction.
14 6 chapter 6

decompensation with stress as manifested by transient dila-

Anterior
tation of the left ventricle and a fall in the left ventricular
ejection fraction with stress.
Interpretation of the images begins with analyzing the
raw projection sets looking for potential factors that may
result in image artifacts, for example, diaphragmatic or Septal Lateral
breast attenuation, and patient motion. Then, the recon-
structed tomograms are evaluated for the presence of perfu-
sion defects, including the severity (extent and intensity) of
defects, and their location with respect to specific coronary
distributions. The gated tomograms are also reviewed for Posterior
global and regional function both at rest and following stress. PATIENT NORMAL
Other markers of increased risk such as transient dilatation > 2.5 SD
of the left ventricle poststress and, in the case of 201Tl imaging,
increased lung uptake are noted. Semiquantitative scoring is 1.0–2.0 SD
widely used in the analysis of images, where one representa-
tive apical, middle, and basal short axis section and one verti- 0–1.0 SD
cal short axis section at rest and following stress are scored
according to the severity of the perfusion defect. From this
1.0–2.0 SD
analysis, a sum stress score, sum rest score, and a sum dif-
ference score are generated.108 Semiquantitative analysis of
2.0–2.5 SD
images using this technique provides important prognostic
information.109 There are important gender-related differ- COMPARISON > 2.5 SD
ences in tissue attenuation that need to be taken into account
when interpreting images. In males, the anterior and lateral FIGURE 6.10. The patient’s polar map (top left) is compared with
normal polar map (top right) obtained from patients with less than
segments normally demonstrate the highest relative activity, a 5% likelihood of coronary artery disease. Areas that are outside
with the posterior and septal segments demonstrating lower of 2.5 standard deviations (SDs) of normal are blacked out (bottom
activity. In contrast, females normally demonstrate some- left).
what higher activity in the inferoposterior segments as com-
pared to the anterior and lateral segments.110 Subjective
analysis of images is usually also supplemented with com-
puter analysis. Quantitative computer techniques for the
analysis of tomograms evaluate the extent and severity of the section, with subsequent short axis sections being obtained
defects and the amount of reversibility present. Improvement from progressively more basal portions of the left ventricle,
sensitivity with only marginal effects on specificity are with the most basal short axis section forming the outer
found when computer-generated analysis is combined with border of the polar map. Polar maps are divided into approxi-
the qualitative visual evaluation of the images.111–113 The mately 100 segments. The profiles from the patient’s seg-
results of these computer-generated analyses are usually dis- ments are compared to a data bank of gender-matched normal
played as polar maps or “bull’s eye” displays (Fig. 6.9). The profiles previously acquired from a group of normal individu-
center of the polar map is obtained from an apical short axis als (usually patients with <5% probability of coronary
disease). Any of the patient’s segments falling 2.5 standard
deviations below the normal mean value are plotted
(Fig. 6.10).
Recognition of image artifacts is very important when
interpreting SPECT myocardial perfusion images. Many
Ant Ant factors have been identified as potentially causing artifacts,
including patient motion, soft tissue attenuation (breast
tissue, lateral chest wall fat, diaphragm), overlying visceral
activity, LBBB, left ventricular hypertrophy, reconstruction
Septal Lat Septal Lat
artifacts, flood field nonuniformity, and center of rotation
errors.114 Breast tissue attenuation is a common occurrence,
Post and results in a lower count density in the anterior wall of
Post the left ventricle of women (anterior/inferior count density
ratio = 1.0 in women and 1.2 in men). Diaphragmatic attenu-
ation results in perfusion abnormalities involving the infe-
rior wall of the left ventricle and can be minimized by
Stress Redistribution
imaging the patient in the prone position.115 Motion during
FIGURE 6.9. Polar maps from a patient with right coronary artery acquisition is a common cause of image artifacts. This can
disease (see Color Plates 5 to 6). There is hypoperfused area involv-
ing the inferior and posterolateral aspects of the left ventricle in the
occur following exercise resulting from the phenomenon
stress map. The redistribution map shows that this is almost com- sometimes referred to as “upward-creep.” This results from
pletely reversible. Ant, anterior; Lat, lateral; Post, posterior. changes in depth of respiration from deep to shallower
 n ucle a r ca r diology 147
breathing resulting in the heart “creeping” up in the thorax TABLE 6.1. Comparative diagnostic accuracy of attenuation-
during the acquisition. Delaying the start of imaging for 10 corrected and nonattenuation-corrected single-photon emission
computed tomography
minutes after cessation of exercise usually eliminates this
phenomenon. Patient motion during acquisition may result Sensitivity Specificity Normalcy
in the production of factious perfusion abnormalities, and First author NC AC NC AC NC AC
can usually be easily identified by examining a cine display 121
Ficaro 78% 84% 46% 82% 88% 98%
of the planar projection images.116 One of the advantages of
Hendel125 76% 78% 44% 50% 86% 96%
using Tc-labeled radiopharmaceuticals is that it allows for
repeat imaging, as there is no change in the myocardial dis- Links*126 84% 88% 69% 92% 69% 92%
tribution with time, unlike 201Tl. Therefore, if a patient Gallowitsch124 89% 94% 69% 84% NA NA
moves, then the acquisition can be repeated, or if diaphrag- Ficaro†122 93% 93% 84% 88% 78% 85%
matic attenuation is identified, the imaging can be repeated * Includes motion correction and depth dependent blur correction.
using the prone position. Most gamma-camera manufactur- † Includes scatter correction.
ers provide software packages that will help correct for AC, attenuation-corrected single photon emission computed tomography
patient motion. The presence of LBBB can result in septal (SPECT); NA, not available; NC non–attenuation-corrected SPECT.
perfusion abnormalities, which may be reversible when exer-
cise is used for stress and can usually be avoided by using
vasodilator pharmacologic stress.117
The use of ECG-gated acquisitions (see Radionuclide
Ventriculography, below, for details on electrocardio-
graphically gated acquisitions) during myocardial perfusion Positron Emission Tomography:
imaging provides important incremental data over static Assessment of Myocardial Perfusion
imaging. There has been an exponential increase in its use
over the last 10 years, with currently approximately 80% of
Basic Principles
studies being performed using ECG-gated acquisition com-
pared to only 3% in 1993.118 Initially, it was thought that this A positron is a positively charged particle with the same
type of acquisition could only be performed using 99mTc- mass as an electron but with a positive charge. They are
labeled radiopharmaceuticals because of the higher count emitted along with a neutrino by certain unstable atoms,
rates. However, it has been shown that it is also possible to usually elements with a low atomic number, in the process
acquire ECG-gated SPECT images using 201Tl.119 The addi- of radioactive decay. The positron travels 1 to 3 mm in tissue
tional ECG-gated data provide important information regard- before colliding with an electron. When this occurs both the
ing regional and global ventricular function, including wall positron and the electron are annihilated, with conversion
thickening, ventricular volumes, and ejection fraction both of their combined mass into electromagnetic γ-radiation.
at rest and following stress. In addition, the use of gated Two photons are given off, each with an energy of 511 keV,
images appears to improve the specificity of the technique that travel in opposite directions at approximately 180
by better differentiating between attenuation and scar in degrees to each other. When a photon pair is detected by a
“fixed” perfusion defects. pair of radiation detectors, connected through an electrical
Another important development in SPECT imaging that coincidence counting circuit, an annihilation event is
is under continuing evaluation and refinement is the use of recorded. This circuit is set so that one decay is recorded only
attenuation correction techniques to minimize the effects if both detectors are activated simultaneously (within 4 to
of breast and diaphragmatic attenuation artifacts. Several 10 nanoseconds) by the photon pair. All other events are
studies have evaluated the effect of attenuation correction on rejected. Therefore, radioactive decays occurring outside the
the accuracy of stress myocardial perfusion imaging.120–126 sample volume between the detectors are excluded from the
The findings from these studies are summarized in Table count data since an unpaired photon striking only one of
6.1.127 These studies have shown that attenuation correction the detectors is not counted. Therefore, collimation is accom-
does result in an improvement in diagnostic accuracy, mainly plished electronically with coincidence counting, rather
from improvement in specificity, and also an increase in than with lead collimators, as in single-photon imaging. The
interpretative confidence. The combination of attenuation electronic collimation of coincidence counting provides
corrected and ECG-gated images does appear to result in an higher efficiency and better count statistics resulting in posi-
increase in diagnostic accuracy, with improvements in both tron emission tomography’s (PET) superior spatial and con-
sensitivity and specificity. Most gamma-camera manufactur- trast resolution to that of SPECT systems.
ers now offer attenuation correction options on their imaging Generically, PET cameras contain 1000 to 1500 detectors
equipment and both the ASNC and the Society of Nuclear in three to eight banks of rings, attached to photomultiplier
Medicine have concluded that attenuation correction is a tubes (PMTs) in ratios ranging from one to eight detectors for
useful adjunct to myocardial perfusion imaging.128 Despite each PMT. Scintillations from the coincidence detectors are
this, the technology to date has not been widely applied in converted to electronic signals from the PMTs that are sub-
clinical practice. The reasons for this are likely multifacto- sequently converted to digital information; then the data are
rial, but include the added cost of the equipment, increased stored and processed on a computer to reconstruct a tomo-
technical knowledge and quality assurance required to suc- graphic image using filtered backprojection. A transmission
cessfully implement the technology, and lack of reimburse- image for attenuation correction is obtained by placing a ring
ment for attenuation correction. of activity around the patient for imaging the target organ
14 8 chapter 6

before injection of radiotracer. The positron radiotracer is Evaluation of Myocardial Perfusion

then injected intravenously and an emission image obtained
Myocardial perfusion can be evaluated using either a diffus-
by backprojection techniques. The emission image is cor-
ible tracer, such as O-15–labeled water, or by using an extract-
rected for attenuation loss, random coincidences, scattered
able tracer, such as Rb-82– or N-13–labeled ammonia.
radiation, dead-time losses, and variation in detector sensi-
Experimentally it has been shown that there is a very close
tivity. The burgeoning role of PET imaging in oncology has
correlation between the myocardial distribution of micro-
resulted in increased availability of PET/computed tomogra-
spheres and O-15–labeled water over a wide range of coronary
phy (CT) scanners, which have presented interesting options
flows.130,131 As O-15–labeled water labels both the cardiac
for their use in the field of cardiovascular medicine.129 These
pool and the myocardium, the blood pool activity is sub-
scanners have the potential to facilitate evaluation of both
tracted using O-15–labeled carbon monoxide which labels
the coronary anatomy from CT coronary angiography and
the red blood cells. Although this technique has been used
myocardial perfusion, with PET providing both anatomic
successfully in clinical studies, it is technically demanding
and physiologic data.
and is not used in routine clinical practice.
The extractable tracers, Rb-82– and N-13–labeled ammo-
Positron-Emitting Radiopharmaceuticals
nia, have been widely used in clinical practice.7,14,16,17,132–134 For
Several positron-emitting radioisotopes are used in cardiac imaging purposes, it is assumed that these tracers are distrib-
PET imaging. Typically, these have a short physical half-life uted to and retained by the myocardium in relation to coro-
(rubidium-82, t1/2 = 76 seconds; oxygen-15, t1/2 = 2.1 minutes; nary blood flow; however, this is not the case. Myocardial
carbon-11, t1/2 = 20.4 minutes; nitrogen-13, t1/2 = 10 minutes; uptake of N-13–labeled ammonia is nonlinear, starting to
fluorine-18, t1/2 = 110 minutes) when compared to conven- plateau at coronary flow rates greater than 2.5 to 3.0 mL/g/
tional single-photon–emitting isotopes (Fig. 6.11). The short min.135 However, the relative high first-pass extraction (60–
half-life minimizes radiation to the patient and enables 70%), rapid blood clearance, and comparatively long myocar-
sequential studies to be performed over a short period of dial retention time results in very good quality images.
time. In addition, O-15, C-11, F-18, and N-13 can be incorpo- Typically, 10 to 5 mCi of N-13 ammonia is injected at rest;
rated into metabolic substrates used by the heart, facilitating after a 4-minute delay to allow for blood pool clearance, rest
evaluation of the metabolic processes of the myocardium in images are acquired with stress images being acquired 40
vivo. However, synthesis of these radiolabeled substrates is minutes after the first injection of N-13–labeled ammonia.
technically complex and demands both a radiochemist and The myocardial uptake of Rb-82 is also nonlinear with coro-
an on-site cyclotron. Rubidium-82 is an exception; it is gen- nary blood flow, with an underestimation of flows greater
erator produced from the parent compound strontium-82, than 2.5 to 3.0 mL/g/min, and it has a first-pass extraction of
which has a half-life of 25 days and is available 50% to 60%. However, it does have the advantage of being
commercially. generator produced and readily available commercially, and

FIGURE 6.11. Rubidium-82 images from a patient

showing multivessel ischemia. A severe reversible perfu-
sion defect involving the inferior, inferolateral, and
inferoseptal walls of the left ventricle consistent with
ischemia in the left circumflex and right coronary arter-
ies. In addition, there is a reversible defect involving the
anterior and anterolateral walls indicative of ischemia in
the left anterior descending coronary distribution.
 n ucle a r ca r diology 14 9
its short high-life means that rest and stress imaging can be flow and the clearance is reduced in proportion to the reduc-
performed back to back in rapid succession resulting in a tion in oxidative metabolism.150,151
complete study being acquired in 30 to 60 minutes. However,
the short half-life does mandate that pharmacologic stress be
Comparison of SPECT and PET Perfusion Imaging
used. Generally, 30 to 50 mCi of Rb-82 are injected in a
volume of 10 mL over 20 to 30 seconds with a fresh generator; There are several theoretical reasons to believe that PET is
later, toward the end of the generator life (4 weeks), 30 to more accurate than its single photon counterpart. First, the
40 mL are required to deliver a similar dose of Rb-82. Emis- intrinsic resolution of this technology affords higher resolu-
sion data are acquired over 5 to 8 minutes with the second, tion images. Second, the ability to correct for attenuation
stress dose being administered 10 minutes later during the using a transmission scan should also improve the diagnostic
dipyridamole or adenosine infusion (Fig. 6.11). accuracy of the technique. It should be remembered, however,
that there is the potential for the production of image arti-
facts.152 The main disadvantages of the PET technology are
its limited availability and the significantly higher capital
Evaluation of Myocardial Metabolism
expenditure and running and maintenance costs.
The most widely evaluated and used labeled compounds are Early studies from the 1980s evaluating PET in the diag-
F-18–labeled fluorodeoxyglucose (FDG), carbon-11–labeled nosis of coronary artery disease indicated that this technique
palmitate, and carbon-11–labeled acetate. F-18–labeled FDG was accurate for diagnosing coronary artery disease.153–155
is the most clinically utilized radiolabeled substrate and is Three comparative trials in the 1990s suggested that PET
used for assessment of myocardial viability. The relatively had a superior diagnostic accuracy to SPECT imaging.141,156,157
long half-life of F-18 means that although it is cyclotron- However, the evidence was not conclusive; one study did not
produced, it can be shipped to PET facilities without access demonstrate any statistically significant difference; another,
to an on-site cyclotron. Under fasting conditions, fatty acids which showed significantly higher sensitivity and specific-
are the main energy source for normal myocardium; however, ity, has been criticized for its methodology and analysis.158
in the presence of ischemia, the myocardium increases its The recent resurgence of interest in cardiac PET imaging,
utilization of glucose as its source for high-energy phos- resulting from the increased availability of PET scanners
phates. This enhanced utilization of glucose in ischemic from increased oncologic use, has brought the issue of the
myocardium can be detected by F-18 FDG-PET imaging. The utility of cardiac PET imaging in clinical practice to the fore
radiolabeled intermediary undergoes phosphorylation by the again. In a recent study, comparing contemporary PET and
hexokinase reaction, but cannot be metabolized any further SPECT imaging techniques, PET was found to outperform
in the glycolytic pathway. Hence, the phosphorylated FDG is SPECT imaging, with sensitivities of 81% and 75%, p =. 34;
trapped within the cytosol of the myocardium and accumu- specificities of 93% and 58%, p =. 0001; and diagnostic accu-
lates in proportion to exogenous metabolism of glucose.136,137 racies of 86% and 68%, p =. 002, for PET and SPECT,
As discussed above, fatty acids are the preferred substrate respectively.159
under fasting conditions and account for 90% of oxygen
consumed under aerobic conditions, and for this reason
carbon-11–labeled palmitate has been used extensively to Radionuclide Ventriculography
evaluate myocardial metabolism.138–142 The uptake of the pal-
mitate is primarily dependent on blood flow. Thereafter, Radionuclide ventriculography is one of the most widely
clearance C-11 palmitate is biexponential, with an early fast used techniques for evaluating ventricular function. This
component that reflects fatty acid β-oxidation and a second essentially noninvasive method of assessing ventricular
slower component that results from incorporation of the function can be easily performed and provides a reproducible,
fatty acids into the endogenous lipid pool. In the presence of accurate evaluation of both right and left ventricular func-
myocardial ischemia, β-oxidation is reduced and therefore tion. There are basically two methods of performing radio-
clearance of C-11 palmitate is reduced, with a corresponding nuclide ventriculography.
increase in the proportion of fatty acids being incorporated
into the lipid pool.143,144
First-Pass Radionuclide Angiocardiography
C-11–labeled acetate has been used to evaluate oxidative
phosphorylation.145–149 The myocardial avidly extracts acetate This technique involves following the passage of a radioac-
and is activated to acetyl–coenzyme A (CoA) in the cytosol tive tracer through the central circulation. It requires the use
and then is oxidized in the mitochondria via the tricar- of a gamma camera with a high count rate capability, usually
boxylic acid cycle, which is the final common pathway for 1 × 105 to 5 × 105 counts per second. This high count rate
oxidative metabolism. The clearance of this radiolabeled capability is optimally provided by a multicrystal gamma
intermediary of myocardial metabolism is also biexponen- camera, for example the Baird-Atomic, which is both expen-
tial. The rapid early phase reflects oxidative phosphorylation, sive and can be used solely for first-pass imaging studies.
while the slower, later phase reflects incorporation of the However, some of the current digital single crystal Anger
acetate into the amino acid and lipid pool. Rate constants gamma cameras have improved count rate capabilities and
calculated from the rapid, early clearance phase correlate are reputed to provide satisfactory count statistics.
closely with the rate of myocardial oxygen consumption over The radioisotope is administered as a compact bolus,
a wide range of physiologic values. In the presence of myo- 1 mL plus 20 mL saline flush, through a large vein, usually
cardial ischemia, uptake is reduced in proportion to blood antecubital or jugular.160 An anterior or 30-degree right
15 0 chapter 6

anterior oblique projection is used to optimize separation of A

the atria from the ventricles. The former is preferred because ED3 ED4 ED5
900 ED2
the position is more reproducible, it enhances resolution ED6
EDEND
by minimizing the distance between the detector and the 700
ED1
chest wall, and during exercise studies motion artifact is Counts
500
minimized by pressing the chest wall firmly against the 0.025 sec
ES2 ES3 ES4 ES5 ES6
detector. The right and left ventricles overlap in these pro- 300 ES1
1 second
jections; however, this does not pose a problem during the
first pass of the radionuclide bolus. Data are usually acquired 0
Time (sec)
in a series of images with high temporal resolution. The
optimal framing interval is determined by the sensitivity of
the camera and the patient’s heart rate. For example, when B C
using a multicrystal gamma camera during an exercise 5000 2920 1.00 128
study, the framing interval will be 25 msec. In a patient 2190 .75 96
4000
with normal hemodynamics, the whole first-pass transit is Counts Counts Volume
1460 %EDV .50 (mL) 64
encompassed by 600 frames. The most commonly used 0.025 sec
3000
0.025 sec
radiopharmaceutical is 99mTc, complexed either to diethyl- 730 .25 32
enetriamine pentaacetic acid (DTPA) or sulfur colloid. 0 0 0 0 0 .25.50.75
0 .25 0 .25 .50
This enables optimal excretion of the isotope via the kidneys Time (sec) Time (sec)
to decrease background accumulation, which is an impor- FIGURE 6.12. Calculation of left ventricular ejection fraction and
tant consideration if more than one study is being per- volumes from first-pass radionuclide angiocardiography. (A) Uncor-
formed.161 Clinical studies using 195gold (Au) have found it to rected counts measured within the left ventricular region of interest
be a suitable alternative to 99mTc.162,163 The half-life of 195Au during the levophase. (B) Summed systolic and diastolic segments.
is only 30.5 seconds, allowing multiple studies to be per- (C) Final volume curve after normalization and background correc-
tion. ED, end-diastole; ES, end-systole; EDV, end-diastolic volume.
formed without imposing a prohibitive radiation burden on
the patient or increasing background activity that occurs
with 99mTc.
Following acquisition of the data, right and left ventricu-
lograms are constructed from which ejection fractions and
ventricular volumes can be calculated.164 A number of time- the use of a multicrystal gamma camera or a digital Anger
activity curves are obtained; the number depends on the camera with high count rate capabilities. Additionally, eval-
time taken for the bolus to traverse the chamber of interest, uation of regional wall motion function is poorer in compari-
usually five to ten individual beats in a normal patient. The son to the gated equilibrium technique.
count rate reaches a maximum at end-diastole when ven-
tricular volume is largest and falls in proportion to the ven-
Gated Equilibrium Radionuclide Ventriculography
tricular volume to reach a minimum at end-systole. Data
from individual beats are summed to provide a single curve, In this technique, the patient’s red blood cells are labeled
which is then corrected for background. The ejection fraction with 25 to 35 mCi of 99mTc-pertechnetate, using either an in
and ventricular volumes are then calculated from the vivo or in vitro method. The in vitro or modified in vitro
normalized, background corrected time-activity curve methods result in a consistently higher labeling efficiency.
(Fig. 6.12). Scintigraphic data are acquired using a conventional single
The first-pass technique has the advantage of excellent crystal Anger gamma camera in multiple planar projections.
image contrast and chamber separation because of the Usually an anterior, left anterior oblique and left lateral or
absence of background activity from adjacent great vessels posterior oblique are acquired (Fig. 6.13). The left anterior
and organs, in particular the lung. In addition, acquisition oblique (LAO) that best separates the right and left ventricles
time is short, usually between 20 and 30 seconds, which is is chosen, that is, the best septal projection. The detector is
an advantage for an exercise study’s acquisition of data only also angled to separate the left atrium from the left ventricle.
during peak exercise. The first-pass technique also provides The anterior projection is usually at 45 degrees less than the
a means for the detection and quantitation of intracardiac best septal projection, and the left lateral projection is usually
shunts.165–168 For both right-left and left-right shunts, the at 45 degrees more oblique than the best septal projection.
time-activity curves that are generated resemble dye-dilution In addition, the scintigraphic data are acquired gated to the
curves and are analyzed using a similar methodology. Despite electrocardiogram, with each R-R interval being divided
these advantages, it does have significant limitations. First, equally into a predetermined number of time bins, usually
one is limited to two to three acquisitions per patient study 16 to 32 time bins (Fig. 6.14). During acquisition, scinti-
because of the increasing radiation exposure to the patient graphic data are stored in memory in one of these time bins,
and the increasing background activity. Second, the tech- such that at the end of the acquisition each time bin will
nique is more demanding both on personnel and equipment: contain scintigraphic data from numerous, typically 300, R-
(a) it requires a compact bolus injection; (b) any patient R intervals (Fig. 6.15).
motion or ventricular arrhythmia, for example, coughing or Gated equilibrium radionuclide ventriculography is one
one ventricular ectopic beat occurring during acquisition, of the most accurate means of assessing ventricular func-
can seriously degrade the radionuclide data; and (c) it requires tion and can be easily performed using readily available
 n ucle a r ca r diology 151
ANT LAO LAT technique does have some limitations: (1) overlap between
cardiac chambers, which can usually be resolved using mul-
tiple views; (2) limited spatial resolution, when compared to
contrast ventriculography or echocardiography; and (3) longer
acquisition times when compared to first-pass techniques,
a minimum of 2 minutes, which can pose a problem during
exercise studies in patients with limited or unpredictable
exercise capabilities.
Many of these problems can be resolved by tomographic
gated radionuclide ventriculography by providing an
accurate three-dimensional representation of the entire
cardiac blood pool.169–171 Using this technique, all chambers
AL ANT are separated in space, which enables assessment of very
limited ventricular segments without concern about adja-
cent and potentially superimposed segments. This tech-
SEP LAT
AP
nique provides an accurate means for assessing both
AP
P P global and regional ventricular function with a higher diag-
I I
AP nostic accuracy than either contrast or planar radionuclide
FIGURE 6.13. Assessment of regional left ventricular function ventriculography.
from a gated radionuclide ventriculogram. Anterior (ANT), left ante-
rior oblique (LAO), and left lateral (LAT) projections in end-diastole
are shown. Corresponding segmentation is given below. AL, antero- Exercise Radionuclide Ventriculography
lateral: AP, apical; I, inferior; P, posterior; SEP, septal; LAT, lateral.
Exercise radionuclide ventriculography is performed using
either the first-pass or gated equilibrium techniques. The
commonly used gated-equilibrium technique is described
here. A resting study is performed in the usual manner, but
performing the left anterior oblique projection last, with the
nuclear imaging systems. It facilitates acquisition of multi- patient lying supine on a specially designed bicycle table-
ple projections or multiple studies up to 6 hours after ergometer that has adjustable shoulder restraints and handle
administration of the isotope. The high count densities bars to minimize movement of the patient’s torso during
achieved, typically 300 counts/cm2 in the left ventricle, exercise. After obtaining the resting left anterior oblique
enable an evaluation of region wall motion that is superior projection, exercise is commenced. The exercise test is per-
to the evaluation possible with the first-pass technique. The formed in exactly the same manner as with other exercise

FIGURE 6.14. Sixteen frames from a gated

radionuclide ventriculogram in the “best
septal” left anterior oblique projection. The
end-diastolic frame is the first image, located
in the upper left of the figure; the end-systolic
frame is the eighth image of the series.
15 2 chapter 6

R Wave R Wave intravascular compartment, and the activity within the ven-
1 2 3 4 5 6 7 8 9 10 111213141516 tricle is proportional to ventricle volume.177
Left ventricular ejection fraction (LVEF) is calculated
using the left anterior oblique projection by drawing a region
of interest (ROI) around the left ventricle in end-diastole and
end-systole. After correcting the counts in the ROIs for back-
ground activity, the ejection fraction is calculated from the
formula
LVEF = EDc − ESc/EDc
A
where EDc and ESc are end-diastolic and end-systolic counts
corrected for background, respectively.
Ventricular volumes can be calculated using a nongeo-
Frame 1 Frame 2 Frame 3 Frame 4 metric count-based technique.178,179 This methodology uses
B measured ventricular activity normalized for the acquisition
time per frame and the activity in a known volume from a
peripheral venous blood sample. Estimation of left ventricu-
lar volume is calculated using the formula
Frame 1 Frame 2 Frame 3 Frame 4 Volume = K (Corrected LV counts)/(No. of cardiac cycles)
C
(Time/frame)(Blood activity)
where K is a correction constant to adjust for attenuation,
which is usually determined from a regression equation
Frame 1 Frame 2 Frame 3 Frame 4 using contrast angiography as a reference. This usually suf-
fices for most individuals who are of normal size and shape,
heart size, etc. However, in some patients, it is necessary to
FIGURE 6.15. Schema explaining the principle of electrocardio-
graphic-gated acquisition in radionuclide ventriculography. The correct for individual variations, which can be successfully
cardiac cycle is divided into equal intervals (16 in this example). done using a simple geometric technique.180,181 Using these
Counts recorded during each interval are stored in different com- data, stroke volume and cardiac output can be calculated
puter frames. After a single cardiac cycle (row A), there are no rec- using radionuclide ventriculography.182,183 When the tomo-
ognizable images. After 20 cardiac cycles (row B), the images begin
to be recognizable. After 400 cardiac cycles (300,000 counts per
graphic technique is used, ventricular volume is usually cal-
frame), image quality has improved considerably (row C). culated using a geometric technique. Knowing the pixel
volume, the ventricular volume can be calculated by
summing the number of pixels in each tomographic section
in the left ventricular ROI. Values obtained using this tech-
nique correlate well with other techniques, and have the
advantage of not requiring any correction for attenuation.184
tests, with continual monitoring of the electrocardiogram, Valvular regurgitation can be evaluated by calculating
heart rate, and blood pressure. Typically, the first stage of the ratio of left to right ventricular stroke counts.185,186 Nor-
exercise is performed at 200 kilo/pound/meters (kpm) for 3 mally, the right and left ventricular stroke volumes are equal.
or 4 minutes and increased by 200-kpm increments (less if However, in the presence of valvular regurgitation the stroke
patient has a limited exercise capacity) to a symptom-limited volume is greater in the ventricle with the affected valve.
maximum. Scintigraphic data are acquired during the last 2 Ventricular stroke counts are obtained by subtracting the
minutes of each stage of exercise, when the hemodynamics end-systolic from the end-diastolic frame, resulting in a
have equilibrated. The hemodynamic response is different stroke volume image. In this image, the activity in the left
from that with erect exercise.172,173 During supine exercise, and right ventricular regions is proportional to their respec-
there is less increase in end-diastolic volume and heart rate, tive stroke volumes. These data can be expressed in terms of
but a greater increase in systolic blood pressure when com- either the stroke volume ratio (LV stroke counts/RV stroke
pared to erect exercise. This does not appear to adversely counts, normal value <1.2) or as the regurgitant fraction
affect the sensitivity of the technique.174 There are signifi- (LV-RV stroke counts/LV stroke counts ×100, normal value
cant gender-related differences in the left ventricular response <20%). The systematic overestimation of this technique
to exercise. Women have a greater increase in end-diastolic results from right atrial/right ventricular overlap. Assess-
volume and less increase in left ventricular ejection fraction ment of valvular regurgitation using this technique is some-
in comparison to men.175,176 what crude. It is not possible to detect mild regurgitation or
clearly quantitate the severity of the regurgitation. In addi-
tion, the accuracy is increasingly compromised when the
Analysis of Radionuclide Ventriculograms
LVEF is ≤35%. Valvular regurgitation can also be estimated
Data from radionuclide ventriculograms can be used to using Fourier amplitude images.187
provide many parameters of ventricular function. The method Diastolic function can also be assessed by radionuclide
is relatively independent of geometric assumptions because ventriculography.188 The variables used are the peak filling
there is complete mixing of the 99mTc-labeled red cells in the rate (PFR), measured as the slope of a third-order polynomial
 n ucle a r ca r diology 15 3
radionuclide ventriculograms.193 Each pixel has its own time-
activity curve, which is maximal in end-diastole and at
minimum in end-systole, whose fundamental frequency is
determined by the heart rate. The time-activity curve is
sinusoidal in shape and can be approximated using a single
cosine function of the frequency of the time-activity curve.
This allows each pixel within the region of the heart to be
expressed as a single mathematical value, which can be
color-coded. The amplitude of this cosine wave, equivalent
to the change in counts during the cardiac cycle, is propor-
tional to the stroke volume of the pixel. Therefore, the ampli-
tude image gives a regional representation of stroke volume.
FIGURE 6.16. High temporal resolution time-activity curve For example, in a region of akinesis the pixels will show
obtained from radionuclide ventriculography. Each point represents time-activity curves of reduced amplitude, resulting in the
20 ms. Variables used to assess left ventricular rapid filling include amplitude image showing absent activity in that region. The
peak filling rate (PFR), measured as the slope of a third-order poly- phase of the cosine wave can also be expressed in a similar
nomial fit to the rapid filling phase; time to peak filling rate (TPFR),
fashion. The R-R interval is considered to represent 360
measured from end-systole; and contributions of rapid diastolic
filling (RDF) and atrial systole (AS), expressed as % of stroke volume. degrees, with the R wave occurring at 0 degrees, which coin-
EDV, end-diastolic volume. cides with the peak of the cosine wave. For pixels in areas of
the ventricle where the onset of contraction is delayed, the
peak of the cosine wave will also be delayed. This may be
the result of either abnormal electrical activation or delayed
onset of contraction, for example, myocardial ischemia or
scarring. This delay can be expressed in terms of phase delay
or increased phase angle. For example, an area of dyskinesis
fit to the rapid filling phase, time to peak filling rate (TPFR), will result in a phase delay of around 180 degrees. Similarly,
measured from end-systole, and the contribution of rapid pixels in the atria have time-activity curves that are com-
diastolic filling (RDF) and atrial systole (AS) expressed as a pletely out of phase with the ventricles, equivalent to a phase
percent of stroke volume (Fig. 6.16). However, noninvasive delay of 180 degrees. These data can be expressed in a phase
assessment of diastolic function, whether obtained using image, in which each pixel is color-coded according to its
radionuclide or Doppler-echocardiographic techniques, has phase angle. Fourier images are useful in evaluating regional
several limitations. These result from the dependence of wall motion in patients with coronary artery disease at
these variables of diastolic function on other variables, such rest and exercise.194–196 These images can also identify con-
as heart rate, preload and afterload, and ejection fraction, duction abnormalities and have been used to localize the
making their interpretation difficult. Therefore, their clini- site of arrhythmias and also atrioventricular accessory
cal utility is limited. However, they may be helpful in pathways.197–199
patients with clinical features of cardiac failure but with a
normal ejection fraction.
Assessment of Right Ventricular Function
Regional ventricular function can be assessed either
qualitatively or quantitatively using radionuclide ventricu- The complex geometry of the right ventricular poses major
lography. The former method, using visual analysis of an problems for all imaging modalities. However, radionuclide
endless-loop cine display, is the most widely used. There is techniques are less geometrically dependent than other con-
good correlation between visual assessments of radionuclide ventional imaging techniques, for example, contrast ven-
and contrast ventriculograms, and reproducibility of the two triculography or echocardiography, for the reasons discussed
techniques is comparable.189,190 Quantitative techniques have earlier. Three radionuclide techniques are used to assess
been developed and can be broadly classified into geometric right ventricular function. The first-pass technique, as
techniques (usually modifications of methods developed for described for the left ventricle, can be applied to the right
contrast ventriculography) and nongeometric techniques ventricle.200 This is probably the optimal technique for
specifically designed for radionuclide ventriculography. assessing right ventricular function, but suffers from the
The most commonly used nongeometric techniques use disadvantages as discussed previously. The gated equilibrium
the regional ejection fraction and Fourier transform–derived technique can also be used, but overlap of cardiac chambers
phase and amplitude images. The regional ejection fraction is a significant limiting factor.201–203 The right ventricular
image is obtained by subtracting the background-corrected ejection fraction is calculated from the left anterior oblique
end-systolic from the background-corrected end-diastolic projection, because this affords the best separation of the two
frame.191 The resulting image is normally crescent-shaped, ventricles. However, the right atrial and right ventricular
delineating the left ventricular borders. If there is an area of overlap in this projection, resulting in a systematic underes-
regional hypokinesis or akinesis, there is thinning or absence timation of the right ventricular ejection fraction. Despite
of the crescent in this area. The data can also be presented this, there is a good correlation with other methods of assess-
in actual regional ejection fraction values with the left ven- ing right ventricular function using this technique.204 A good
tricle typically being divided into three or five segments.192 compromise is the gated first-pass technique that involves
Fourier phase analysis has been applied to the evaluation of injecting a bolus of 99mTc pertechnetate and acquiring
15 4 chapter 6

ECG-gated scintigraphic data from the time the bolus is seen reserve as a single integrated functional measure of stenosis
entering the superior vena cava until it leaves the main pul- severity reflecting all its geometric dimensions. J Am Coll
monary artery.205 This gives excellent spatial resolution of Cardiol 1986;7:103.
the right atrium and right ventricle with no background 17. Gould KL. Coronary Artery Stenosis. New York. Elsevier Sci-
entific, 1990.
contamination from lungs or the left heart chambers. Radio-
18. Gould KL, Kirkeeide R, Buchi M. Coronary flow reserve as a
isotopes of inert noble gases, 81Kr and 133Xe, have also been physiologic measure of stenosis severity, part I: relative and
used to assess right ventricular function.206–209 These radio- absolute coronary flow reserve during changing aortic pressure,
isotopes are rapidly excreted during their first passage part II: determination from the arteriographic stenosis dimen-
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 7 Cardiovascular Magnetic
Resonance Imaging
Warren J. Manning

Technical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . 162 Native Coronary Artery Disease Integrity . . . . . . . . . . . 169

Specific Considerations of Cardiovascular Magnetic Coronary Artery Bypass Graft Patency . . . . . . . . . . . . . . 171
Resonance in the Cardiac Patient . . . . . . . . . . . . . . . 163 Myocardial Viability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Thoracic Aorta and Great Vessels . . . . . . . . . . . . . . . . . . 164 Nonischemic Cardiomyopathies . . . . . . . . . . . . . . . . . . . 172
Pulmonary Embolism, Pulmonary Artery, and Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Pulmonary Vein Assessment . . . . . . . . . . . . . . . . . . . 165 Cardiac Tumors and Masses . . . . . . . . . . . . . . . . . . . . . . 174
Quantitative Assessment of Ventricular Volumes Pericardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
and Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 175
Detection of Coronary Artery Disease . . . . . . . . . . . . . . 168 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Key Points • Cardiovascular magnetic resonance provides the non-

invasive means to assess myocardial viability and fibro-
• Spin-echo imaging is commonly used for assessment of
sis accurately.
cardiac and great vessel anatomy. With classic spin-echo
• Cardiovascular magnetic resonance has great value for
imaging, rapidly moving blood appears dark.
characterizing paracardiac and extracardiac tumors and
• At current field strengths (1.5 and 3.0 tesla), cardiovascu-
their extension into the myocardium, cardiac chambers,
lar magnetic resonance (CMR) imaging is considered safe
or neighboring mediastinal structures.
for bioprosthetic and mechanical heart valves.
• Both spin-echo CMR and CT are capable of measuring
• Older (pre-2000) cardiac pacemakers and implantable
pericardial thickness accurately.
defibrillators are an absolute contraindication to higher
• Cardiovascular magnetic resonance has great utility
field (≥0.5 T) CMR. Patients with newer pacemaker
for both simple and complex congenital heart disease.
systems may be safely scanned using specific protocols.
Coronary MRI for identification and characterization of
• Cardiovascular magnetic resonance is an important
anomalous coronary arteries is widely accepted.
noninvasive technique for evaluating thoracic aortic
aneurysms.
• The clinical “gold standard” for the diagnosis of pulmo- More than any other noninvasive imaging technique, the
nary embolism is contrast CT angiography (CTA). For flexibility of cardiovascular magnetic resonance (CMR)
patients who are not candidates for CTA due to renal imaging offers the promise to dramatically expand our ability
dysfunction or contrast allergic history, pulmonary to evaluate patients with known or suspected cardiovascular
artery magnetic resonance angiography (MRA) is an disease. The combined attributes of superior image quality
excellent noninvasive alternative with high sensitivity and flexibility for assessment of cardiac anatomy, ventricular
and specificity. function, viability, perfusion, valvular function, great vessel
• Cine CMR provides an excellent means for quantitative anatomy, blood flow, and native coronary artery and coronary
assessment of left and right ventricular volumes, global artery bypass graft integrity give CMR unmatched potential
ejection fraction, regional systolic function, and biven- for the comprehensive evaluation of the cardiovascular
tricular mass. system. Currently accepted clinical applications of CMR
• Available data suggest dobutamine stress CMR is a sensi- continue to expand rapidly1 (Table 7.1). Hardware (gradients
tive technique for the noninvasive recognition of coro- and high field systems) advances now allow for sub-second
nary artery disease (CAD). data acquisitions with “real-time” imaging, and software
• Coronary artery bypass graft patency is well evaluated advances and novel contrast agents promise to further exploit
by spin echo, gradient echo, and gadolinium–diethylene- CMR’s advantages over competing noninvasive imaging
triamine pentaacetic acid (DTPA)-enhanced three- methods. The introduction of a comprehensive CMR exami-
dimensional (3D) enhanced coronary magnetic resonance nation,2,3 in which cardiac anatomy, function, viability, per-
imaging (MRI). fusion, valvular, and coronary artery assessment is performed

161
16 2 chapter 7

TABLE 7.1. Current clinical applications for cardiovascular magnetic resonance (CMR)
1. Indications for CMR in acquired diseases of the vessels
a. Diagnosis and monitoring of thoracic aortic aneurysm, dissection, aortic wall hematoma, and penetrating ulcer
b. Assessment of pulmonary artery dilation and dissection
c. Characterization of pulmonary vein stenosis
2. Indications for CMR in coronary artery disease
a. Assessment of global and regional left and right ventricular systolic function at rest and with pharmacologic stress
b. Assessment of regional myocardial perfusion at rest and stress
c. Determination of viability
3. Indications for CMR in valvular heart disease
a. Assessment of the severity of aortic stenosis and mitral stenosis
b. Quantitative assessment of mitral and aortic regurgitation
4. Indications for CMR in cardiomyopathies and pericardial disease
a. Differentiation of ischemic versus nonischemic cardiomyopathy and underlying etiology (including hypertrophic cardiomyopathy,
noncompaction, arrhythmic right ventricular cardiomyopathy (ARVC), and iron deposition)
b. Characterization of mass, biventricular volumes, and ejection fraction
c. Identification of pericardial thickening, circumferential, and local pericardial effusions
5. Indications for CMR in congenital heart disease
a. Anomalous coronary artery disease
b. Quantification of intracardiac shunt
c. Characterization of simple and complex coronary anatomy
d. Identification of aortic and pulmonary pathology (e.g., coarctation, patent ductus arteriosus)
e. Characterization of anomalies of the ventricles
f. Anomalous pulmonary venous drainage
Adapted from Pennell et al.1

during a single 1-hour session, will lead to decreased utiliza- where there may be rapid flow in the ascending aorta with
tion of other imaging tests (e.g., echocardiography, radionu- relatively stationary flow in the descending thoracic aorta).
clide ventriculography and radionuclide perfusion, diagnostic The flow void can be emphasized using thin sections or
x-ray coronary angiography), especially for follow-up care/ longer echo times.
monitoring. Cardiovascular magnetic resonance training With gradient-echo sequences, commonly used for func-
guidelines for both those in fellowship4,5 and practitioners tion/cine CMR, a single RF pulse is applied with a much
who have completed fellowship have now been developed.5–7 shorter echo time. Little signal is then lost due to washout
The relative cost advantage/disadvantage of CMR as com- effects, but stationary tissue (often surrounding blood vessels;
pared with these other imaging technologies will need to be e.g., muscle) will be saturated because of repeated RF stimu-
defined by future cost-effectiveness studies. lation. Thus, signal from stationary tissues is suppressed
(“dark”) due to repeated RF stimulation, while areas of rapid
Technical Considerations blood flow (arterial flow) will have continuous inflow of
unsaturated blood with a resultant “bright” signal. There-
A review of magnetic resonance (MR) physics is beyond the fore, on gradient-echo images, rapidly moving laminar blood
scope of this chapter, and readers are referred elsewhere.8,9 flow appears bright, while stagnant blood will appear rela-
Unlike other imaging techniques, CMR images may depict tively “dark.” In addition, areas of turbulent/chaotic blood
blood and other tissues as bright, dark, or of an intermediate flow (corresponding to valvular stenoses, aortic insufficiency,
intensity depending on the specific CMR sequence that is mitral regurgitation) will appear dark due to local turbu-
employed, the use of exogenous contrast, and whether the lence/phase dispersion. The relative “size” of these signal
tissue of interest (e.g., blood) is rapidly or slowly moving, voids is dependent on the echo time. Steady-state free preces-
and whether blood flow is laminar or turbulent. The most sion imaging is relatively insensitive to inflow effects and
common CMR approaches are the spin echo (“black blood”), also depicts blood as bright.
the k-space segmented gradient echo, and the steady-state Both gradient-echo and SSFP imaging are commonly used
free precession (SSFP; trueFISP, balanced FFE, FIESTA; for cine CMR imaging of ventricular and valvular function.
“bright blood”) sequences. For all CMR imaging sequences, specific prepulses may
Spin-echo imaging is commonly used for assessment of highlight or suppress specific tissues (e.g., fat saturation pre-
cardiac and great vessel anatomy. With classic spin-echo pulse will suppress signal from fat; inversion recovery (180-
imaging, rapidly moving blood appears dark because a pair degree) prepulses will emphasize T1-weighting). Exogenous
(90 and 180 degrees) of sequential radiofrequency (RF) pulses intravenous contrast [e.g., gadolinium–diethylenetriamine
is applied. Rapidly moving blood will move out of the imaging pentaacetic acid (Gd-DTPA)] may be used in combination
plane during the time interval between these two RF pulses, with both spin-echo and gradient-echo approaches and has
leading to an absence of signal, or flow void (i.e., “black been particularly valuable for viability assessment of myo-
blood”). Stagnant blood, which would be exposed to both RF cardial fibrosis/scar, for assessment of regional myocardial
pulses, will appear relatively bright. Variations may be high- perfusion, and for characterization of tumors/masses.10 These
lighted when viewing an image containing blood experienc- extracellular CMR contrast agents are minimally nephro-
ing different phases of the cardiac cycle (e.g., early systole, toxic with a highly favorable anaphylaxis profile.11,11a
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 16 3
Another very useful CMR sequence is phase velocity
mapping, in which the velocity of blood perpendicular to
the imaging plane is encoded, providing localized flow data
somewhat analogous to pulsed Doppler echocardiography.
This approach is particularly valuable for quantifying regur-
gitant volumes and flows through the great vessels, conduits,
and valves.
In contrast to general magnetic resonance applications
outside of the heart, the vast majority of CMR applications
depend on accurate R wave detection for electrocardiographic
(ECG) triggering. In the presence of a rate-controlled irregu-
larly irregular rhythm such as atrial fibrillation, image
quality will be acceptable,12 but high-grade ventricular
ectopy or a regularly irregular rhythm (e.g., trigeminy)
often leads to significant image degradation. In these situa-
tions, real-time CMR is often used, with reduction in spatial
and temporal resolution.13 In limited situations, peripheral
pulse (PPU) triggering may be adequate, but we have gener-
ally found image quality to be inferior to ECG triggering.

Specific Considerations of Cardiovascular

Magnetic Resonance in the Cardiac Patient
In addition to general restrictions regarding CMR [ferro-
magnetic intracranial clips, transcutaneous electrical nerve A
stimulation (TENS) units, intraauricular implants, shrapnel,
etc.], there are also special considerations for CMR (and
general magnetic resonance scanning) in the cardiac patient.
A comprehensive discussion of CMR safety with regard to
implanted devices is beyond the scope of this chapter. Readers
are referred to comprehensive sources (www.mrisafety.
com).14 At current field strengths [1.5 and 3.0 tesla (T)], CMR
imaging is considered safe for both bioprosthetic and mechan-
ical heart valves.14 However, a local image artifact (loss of
signal/image distortion) will occur in the region immedi-
ately surrounding the valve prosthesis (Fig. 7.1). Similarly,
sternotomy wires, thoracic vascular clips, and ostial coro-
nary artery bypass graft markers are not a contraindication

B
FIGURE 7.2. (A) Posteroanterior (PA) chest x-ray in a patient with
LV a prior coronary artery bypass graft surgery with sternal wires (solid
arrow) and bypass graft markers (broken arrow). (B) Gradient-echo
CMR in the transverse plane at the level of the origin of the saphe-
nous vein bypass grafts. Note the artifacts from the saphenous vein
markers (solid arrow) as well as sternal wires (broken arrow).

to imaging, but localized artifacts will be present (Fig. 7.2),

thereby limiting assessment of adjacent structures. The rela-
FIGURE 7.1. A single image from a cine cardiovascular magnetic
resonance (CMR) in the two-chamber view. Note the artifact (black
tive size of the image artifact is increased with gradient-echo
arrow) resulting from a bileaflet mechanical mitral valve prosthesis. and SSFP sequences (versus spin-echo sequences). While the
LV, left ventricle. composition metal of intracoronary stents will cause a local
16 4 chapter 7

Thoracic Aorta and Great Vessels

For many years, CMR had its greatest clinical impact on the
assessment of the thoracic aorta in the patient with known
or suspected thoracic aortic aneurysm (Fig. 7.4) or aortic
dissection (Fig. 7.5). Cardiovascular magnetic resonance
compares favorably to spiral or multidetector computed
tomography (CT) because CMR employ no ionizing radiation
or requirement for potentially nephrotoxic iodinated con-
trast. Comprehensive data regarding the presence of a dissec-
tion, entry and exit points, the presence of intraluminal
thrombus, involvement of the great vessels, and coexistent
aortic insufficiency and pericardial effusion are also readily
obtained. Transverse, coronal, and sagittal images using
ECG gating T1-weighted spin-echo techniques are initially
acquired for anatomic imaging.19,20 The sine qua non of aortic
dissection for spin-echo imaging is the identification of an
intimal “flap” separating the true and false lumen. Breath-
hold 3D contrast-enhanced (CE) magnetic resonance angio-
gram (MRA) is then obtained to define the aortic lumen
either with21 or without22,23 ECG gating. Cine SSFP or gradi-
ent-echo acquisitions can then be obtained if a dissection
flap is identified. In addition to the classic finding of an
intimal flap, eccentric aortic wall thickening may also be
seen, possibly representing an early dissection or intramural
hematoma.24 In experienced hands, CMR, CT with iodinated
contrast, and multiplane transesophageal echocardiography

FIGURE 7.3. Gradient-echo coronary CMR in a patient with a

widely patent mid-left anterior descending (LAD) stent. Note the
signal void in the area corresponding to the stent (white arrows)
with visualization of the LAD lumen proximal and distal to the
stent.

susceptibility effect (dark area) (Fig. 7.3), no adverse events

have been reported at 1.5 T,15 yet for many years, patients
receiving intracoronary stents were instructed to avoid all
MR scanning for at least 2 months. This error has now been
corrected with the April 2005 decision by the United States
Food and Drug Administration (FDA) to approve immediate
MR scanning for both the Boston Scientific (Boston, MA) and
Johnson & Johnson drug-eluding stents.
The area of safety with regard to CMR scanning among
patients with cardiac pacemakers and implantable cardiode-
fibrillators (ICDs) is currently in a state of flux. When CMR
is the only imaging modality available, uncomplicated CMR
has been performed at low field strengths (0.2 T) using spe-
cific protocols16 and with proper safeguards in place. Such
devices (and the presence of permanent pacemaker leads
alone) had been considered an “absolute” contraindication to
higher field (≥0.5 T) CMR scanning due to the potential for
unpredictable device reprogramming, myocardial stimula-
tion, or heating of the device leads.14 Protocols have now been
described for safe scanning at 1.5 T for patients with modern
(post-2000) pacemaker systems.17,18 This area is likely to
receive considerable attention and will evolve in the coming FIGURE 7.4. Aortic aneurysm: three-dimensional (3D) coronary
years. magnetic resonance angiogram (MRA).
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 16 5
(TEE) have similarly high sensitivity, specificity, and accu-
racy for identification of thoracic aortic dissection.19,20,25–27
Cardiovascular magnetic resonance and spiral or multidetec-
tor CT have specific advantages (as compared with multi-
plane TEE) for providing information regarding the extent of
the dissection into the great vessels and abdominal aorta.
Both TEE and CMR also permit determination of aortic valve
involvement and aortic insufficiency (Fig. 7.5), though valve
morphology is better defined by TEE. Both TEE and CMR
can often provide information regarding the involvement of
the proximal coronary arteries. Study time and access are
important factors in the choice of imaging test. For CMR
aortic dissection assessment, a comprehensive assessment
can usually be completed within 30 minutes, with close
patient monitoring. We generally recommend CMR (or CT)
for patients who are hemodynamically stable and for follow-
up studies in younger patients with chronic aneurysms or
dissection, refer stable older patients with good renal func-
tion to CT, and utilize TEE for those with clinical instability,
claustrophobia, or renal dysfunction.
In addition to aortic aneurysm and dissection, CMR is
also useful for the assessment of congential aortic lesions
such as aortic coarctation (Fig. 7.6) and patent ductus arterio-
sus, as well as more complex abnormalities involving the FIGURE 7.6. A 3D contrast-enhanced (CE) magnetic resonance
great vessels (discussed later). Phase velocity methods may angiogram (MRA) in a 17-year-old boy with an aortic coarctation
be used to quantify velocity gradients28 as well as flow (arrow). Note the extensive collateral vessels.
through shunts and to quantify pulmonic–systemic flows.
From a practical perspective, patients with congenital car-
diovascular lesions are often referred for CMR imaging for fied or suspected on a prior imaging (echocardiography, x-ray
confirmation or better definition of an abnormality identi- angiography) study.

Pulmonary Embolism, Pulmonary Artery, and

Pulmonary Vein Assessment
Compared to imaging of the aorta, CMR of the pulmonary
artery is more technically demanding of patient cooperation,
with breath-holding due to artifacts related to motion as
the lungs expand and collapse. Additionally, the pulmonary
F arteries branch in a complex fashion, with their diameter
progressively decreasing at each bifurcation. Finally, suscep-
tibility between the blood–tissue interface and air leads to
signal loss at the vessel–lung interface. Although spin-echo
approaches can be used to define the anatomy of the pulmo-
T nary trunk and the proximal portions of the right and left
main pulmonary arteries, 3D CE-MRA is the mainstay of
pulmonary artery assessment.29,30 This is especially applica-
ble to patients who are suspected of having acute (or chronic)
pulmonary thromboembolism. The clinical “gold standard”
for the diagnosis of pulmonary embolism is contrast x-ray
pulmonary angiography and CT angiography (CTA). The
latter has become extremely popular with the widespread
availability of multidetector CT scanners in the emergency
department. For patients who are not candidates for pulmo-
nary CTA due to renal dysfunction or contrast allergic
FIGURE 7.5. Coronal diastolic frame cine gradient-echo CMR in a history, pulmonary artery MRA is an excellent noninvasive
patients with an ascending aortic dissection (black arrows). Note alternative with high sensitivity and specificity. Similar to
the dissection flap (black arrows) begins immediately superior to the conventional angiography, pulmonary emboli present as an
aortic valve leaflet. Flow is seen in both the true (T) and false (F)
lumen. Signal void (white arrow) from local turbulence is seen in
abrupt discontinuation (signal void) of the arterial lumen
the left ventricular cavity immediately below the aortic valve and (Fig. 7.7). Pulmonary artery dissection is a rare condition
is due to associated aortic insufficiency. that may mimic aortic dissection in symptoms, for which
16 6 chapter 7

FIGURE 7.8. Pulmonary vein CE-MRA in a 65-year-old man with

atrial fibrillation who underwent pulmonary vein ablation 1 month
previously. Note the focal stenosis (arrow) of the left lower pulmo-
nary vein.

FIGURE 7.7. Pulmonary artery 3D CE-MRA in a patient with a right ventricular volumes, global ejection fraction, regional
pulmonary embolism (arrow) with abrupt loss of vasculature. systolic function, and biventricular mass (Fig. 7.9) in patients
with known disease. Cardiovascular magnetic resonance is
used for validation of ventricular volumes assessed by
pulmonary artery CE-MRA as well as gradient-echo and new technologies such as 3D echocardiography and cardiac
spin-echo methods have been shown to be quite accurate.31 CT.36–38 Advantages of CMR include the ability to obtain
With increasing interest in pulmonary vein ablation as high temporal and spatial resolution tomographic data in
a mainstream therapy for patients with atrial fibrillation, true short- and long-axis orientations, the outstanding endo-
monitoring of patients for asymptomatic pulmonary vein cardial border definition provided by current SSFP sequences,
stenosis has become important. Pulmonary vein CE-MRA and the relative ease of data analysis. Semiautomated
has been shown to be a very accurate method for monitoring methods allow for the delineation of the endocardial and
the size of the pulmonary arteries32–34 and for identifying epicardial borders with very high accuracy and reproduc-
stenoses32,34,35 (Fig. 7.8). Preliminary data suggest identifica- ibility for determination of ventricular volumes, stroke
tion of the ablation site is also possible using delayed enhance- volume, and ejection fraction both in normal and focally
ment CMR methods.35a deformed ventricles.39–42 As compared with M-mode or 2D
echocardiography, which is limited to acoustic windows
Quantitative Assessment of Ventricular with suboptimal results in many obese and elderly patients,
Volumes and Mass comprehensive, high temporal and spatial resolution true
short-axis volumetric data sets are easily acquired in nearly
Although rarely used for first-line assessment, volumetric all subjects in less than 8 minutes. Though in theory 3D
cine CMR is becoming increasingly recognized as the clini- echocardiography and cardiac CT offer similar volumetric
cal gold standard for the quantitative assessment of left and data, the superior spatial (versus 3D echocardiography) and

FIGURE 7.9. End-

diastolic (ED) and end-
systolic (ES) images
from cine short-axis
data sets demonstrating
the use of endocardial
border definition and
calculation of end-dia-
stolic and end-systolic
volumes.
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 167

A A

B
FIGURE 7.10. Cine steady-state free precession (SSFP) images in the
(A) two-chamber and (B) short-axis orientations demonstrating
prominent trabeculations (arrows) consistent with noncompaction.

temporal (versus CT) resolutions of CMR make it the strong

preference when accurate and reproducible assessments are
needed. Volumetric CMR is especially valuable for quantita- B
tive information regarding left ventricular volume and mass
in patients with asymmetric deformations/hypertrophy, and
defining cardiomyopathies (such as hypertrophic cardiomy-
opathy and noncompaction (Fig. 7.10),43 or monitoring ven-
tricular volumes in patients with regurgitant valvular lesions.
Left ventricular aneurysms may be recognized as severe wall
thinning (less than 4 mm) and diastolic bulging of the left
ventricular free wall (Fig. 7.11). Left ventricular pseudo-
aneurysm or false aneurysms may also be readily identified
on CMR due to their lack of myocardium in the wall of the
aneurysm44 with relatively narrow neck. The superior repro-
ducibility of CMR for both left and right ventricular mea-
sures thereby provides more clinical utility in the monitoring

FIGURE 7.11. (A) Cine SSFP two-chamber and delayed enhance-

ment CMR in the (B) two-chamber and (C) short axis orientation of
a 54-year-old patient with an inferior infarction and aneurysm. Note
the transmural hyperenhancement (B,C) that is visible in the infe-
rior and inferolateral walls with a small thrombus (B, arrow) visible
along the subendocardial border.

C
16 8 chapter 7

of patients.42,45,46 Volumetric CMR methods are also ideal for terpretable for ischemia within the CMR environment. Thus
regional left ventricular assessment with the 17-segment real-time monitoring of wall motion and close patient super-
model (six basal, six middle, four apical, with a true apex)47 vision is imperative. Physiologic stress is possible within the
that is generally utilized. Left ventricular mural thrombi CMR environment, and supine bicycle ergometry units have
may be identified on spin-echo images as a density/mass been developed for such an application,54 but pharmacologic
filling the left ventricular apex, especially in an area corre- stress is more commonly used in combination with graded
sponding to a left ventricular aneurysm44,48 or as filling doses of dobutamine (similar protocols to that used for dobu-
defects on cine gradient-echo or SSFP imaging. Delayed tamine stress echocardiography), with cine images typically
enhancement (DE) CMR methods may also depict transmu- acquired in the four- and two-chamber orientations along
ral hyperenhancement in the wall of a true aneurysm with with three short-axis levels (base, middle, apical) at baseline
the subendocardial area of hypoenhancement corresponding and at each level of dobutamine (Fig. 7.12). Data suggest that
to a chronic left ventricular thrombus49,50 (Fig. 7.11). Accurate dobutamine stress CMR is more sensitive for the detection
quantitative evaluation of right ventricular volumes, ejection of coronary artery disease (versus dobutamine stress echo-
fraction, and mass is also a relatively unique attribute of cardiography).55–57 This superiority is directly related to the
CMR.51 For regional assessment of both right and left ven- enhanced ability of CMR to visualize/define all of the myo-
tricular systolic function, myocardial tagging techniques cardial segments.50 A study that compared dobutamine CMR
have been shown to be more sensitive for quantitation of stress with vasodilator CMR stress found dobutamine wall
local dysfunction,52,53 though their clinical role remains to motion CMR to be superior (Fig. 7.13).58 The combination of
be defined. CMR resting left ventricular ejection fraction and inducible
ischemia has prognostic value among patients with known
coronary artery disease.59 Cardiovascular magnetic reso-
nance tagging methods may offer superior sensitivity,60 but
Detection of Coronary Artery Disease they are less commonly used.
Early applications of CMR myocardial perfusion methods
In addition to ventricular volumes and global/regional sys- were limited in ventricular coverage, with current methods
tolic function, CMR offers several approaches for detecting now acquiring data at three to six short-axis levels during
and evaluating patients with known or suspected coronary the first passage of Gd-DTPA (0.05 mmol/kg) administered
artery disease. These include pharmacologic stress testing as a tight bolus into the right antecubital fossa. Both visual
with β-agonists (regional dysfunction), vasodilators (perfu- and quantitative methods (upslope) have been utilized and
sion deficits), viability imaging, and coronary artery validated in animal models.61–63 Comparison studies with x-
imaging. ray angiography and radionuclide imaging are very good.64–66
Due to distortions of the ECG related to the magnetohy- Cardiovascular magnetic resonance protocols of myocardial
drodynamic of pulsatile blood in the aorta, the ECG is unin- perfusion may include assessment of perfusion at rest and

Rest 10 μg/kg/min 20 μg/kg/min 40 μg/kg/min

FIGURE 7.12. Common display used for real-

time monitoring and subsequent interpreta-
tion of dobutamine stress CMR images. Images
at rest and gradations of stress are displayed
simultaneously for review in the short axis (top
two rows) and horizontal long axis (bottom
row).
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 16 9

0.9 100
90
0.8
80
0.7
70
0.6 0%
60 Prevalence
1–25%
0.5 50 Specificity
26–50%
0.4 40 Sensitivity
51–75%
0.3 30 Correct
76–100%
0.2 20
10
0.1
0
0 None 1–24 25–49 50–74 75–100
A B
FIGURE 7.13. (A) Likelihood of functional recovery following hood of recovery. An intermediate finding demonstrates reduced
mechanical revascularization as a function of transmural hyperen- predictive accuracy. (B) Sensitivity, specificity, and accuracy of low-
hancement with delayed-enhancement (DE)-CMR in patients with dose dobutamine for prediction of functional recovery after mechan-
regional systolic dysfunction. Dysfunctional regions without any ical revascularization appears to be superior to DE-CMR, especially
enhancement have a >80% likelihood of functional recovery while for those with 1% to 49% transmural hyperenhancement.
those with >50% transmural hyperenhancement have <10% likeli-

at peak stress or a single peak-vasodilator assessment with this limitation, the feasibility of identifying stenoses in the
normal resting systolic function used as a surrogate for proximal and midcoronary segments has been demonstrated
normal perfusion. Vasodilator perfusion CMR has demon- in several single centers.76,77 At present, some approaches
strated an improvement in myocardial perfusion reserve (free breathing navigator with real-time motion correction)
after a percutaneous coronary intervention67 and impaired remain vendor specific, making multicenter multivendor
subendocardial perfusion in syndrome X.68 trials difficult to perform and interpretation of the literature
more complicated. We continue to prefer a targeted 3D
free-breathing segmented k-space gradient-echo sequence78,79
Native Coronary Artery Disease Integrity using patient specific delay and short acquisition (less
than 90 ms/R-R interval) periods.80 With this approach, high
Cardiovascular magnetic resonance is used routinely for signal intensity (bright blood) represents normal, laminar
evaluation of vascular beds throughout the body, but coro- blood flow, with low signal (signal void) at sites of
nary MRI is more technically challenging due to the small stenosis and focal turbulence (Fig. 7.15). Despite superior
caliber, tortuosity, and motion related to both the respiratory spatial resolution of multidetector CT, a head-to-head
and cardiac cycle. As a result, CMR assessment of native comparison of 3D coronary MRI with 16-slice multidetector
coronary artery integrity continues to be a field of rapid (using quantitative x-ray coronary angiography as the
evolution with recent competition from coronary CTA gold standard) showed similar diagnostic accuracy,81 includ-
methods. The relative strengths of coronary MRI include ing sensitivity and specificity of 75% and 77% for coronary
both the lack of substantial ionizing radiation69 or the need MRI and 82% and 79% for coronary CTA, respectively.
for potentially nephrotoxic/anaphylactic iodinated contrast, A multicenter trial of over 100 patients from seven
or the need to induce bradycardia with beta-blockade. Another international sites demonstrated high sensitivity but only
disadvantage of coronary CTA is the difficulty with lumen modest specificity for identifying focal stenoses, with very
integrity assessment among patients with high risk70 and high accuracy for discriminating between patients with
older patients due to prominent epicardial calcium.71 Pre- multivessel disease and no disease.82 For this reason, we
liminary data suggest that epicardial calcium does not offer coronary MRI as a clinical option for patients
provide the same interference with coronary MRI depiction presenting with a dilated cardiomyopathy in the absence
of the lumen (Fig. 7.14).72 of a history of acute infarction. Preliminary data from a
Since the initial descriptions of 2D breath-hold coronary group of patients with depressed left ventricular systolic
MRI,73–75 the field has advanced to 3D acquisition methods function83 suggest that coronary MRI is superior to DE-
(double-oblique slab or larger axial stack analogous to coro- CMR for discriminating between these two subsets. Tar-
nary CTA) with submillimeter spatial resolution and supe- geted 3D approaches using SSFP methods84 or a “whole heart”
rior reconstruction capabilities. The spatial resolution of 3D SSFP methodology that supports extensive reconstructions
coronary MRI remains inferior to coronary CTA and x-ray (Fig. 7.16),85,86 somewhat analogous to multidetector com-
coronary angiography, thereby precluding quantitative puted tomography (MDCT) acquisitions (though inferior in
assessments, although the magnitude of the local signal void spatial resolution), have been advocated. Comparative data
does correlate with angiographic stenosis.75 Data acquisition suggest longer vessel segments have been identified, with
also remains relatively prolonged at 10 to 20 minutes. Despite improved signal-to-noise ratio (SNR) and contrast-to-noise
 17 0 chapter 7

B
FIGURE 7.15. RCA (A) targeted 3D free breathing navigator coro-
nary MRI and corresponding (B) projection x-ray angiogram in a
patient with a mid-RCA stenosis (arrow).

ratio (CNR) with SSFP whole heart acquisitions,85,86 but

similar diagnostic results.84,86 Preliminary data suggest
similar overall results with 3T coronary MRI.87 It is very
C likely that coronary MRI methods will get faster and more
FIGURE 7.14. Right coronary artery (A) projection x-ray angiogram,
(B) 16-slice multidetector computed tomography (MDCT), and (C) automated with subsequent application of powerful CT ana-
coronary MRI in a patient with prominent epicardial calcium. Note lytic tools to the 3D CMR data sets.
that the ostial right coronary artery (RCA) stenosis (arrow) is visible Although not yet routine due to issues of spatial resolu-
on the x-ray angiogram and the coronary MRI, but not on the tion, another advantage of coronary MRI (vs. coronary CTA)
MDCT.
is the application of phase velocity flow methods to assess
coronary artery blood flow and flow reserve. For patients who
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 171

Ao

graft

FIGURE 7.16. Whole heart coronary MRI reconstruction in a

* graft
patient with a proximal left anterior descending branch (LAD)
stenosis.

have experienced a myocardial infarction, phase velocity

CMR can accurately evaluate the presence of antegrade flow
in the infarct-related artery.88 The noninvasive determina-
tion of patency influences therapy and prognosis in these
patients.
A

Coronary Artery Bypass Graft Patency

B
In comparison with native vessel coronary MRI, CMR of FIGURE 7.17. (A) Targeted 3D free breathing navigator coronary
coronary artery bypass grafts (both saphenous veins MRI and corresponding (B) projection x-ray angiogram in a patient
with a stenosis (arrow) of a saphenous vein graft. Ao, aorta.
and internal mammary arteries) is facilitated by their rela-
tively stationary anterior location, straight and predictable
course, and their greater lumen diameter. Adequate flow is
visualized as a signal void (spin-echo) or as bright signal
(gradient-echo, contrast imaging) in the anatomic location
corresponding to the expected graft position. Identification ing assessment in these regions. These artifacts, which are
of flow in at least two contiguous slices, or obtained at dif- commonly located in very close proximity to the coronary
ferent planes perpendicular to the expected bypass graft arteries or grafts, preclude the assessment of these vessels.
course suggests patency. If flow is suggested at only one level, As mentioned earlier, both drug eluding stents currently
graft patency is considered “indeterminate,” and if there is marketed in the United States are FDA approved for CMR
no evidence of flow in any portions of the graft, the graft is scanning immediately after implantation.
considered “occluded.” Spin-echo (dark blood), gradient-echo
(bright blood), and Gd-DTPA–enhanced 3D coronary MRI
have been reported to have higher sensitivity (95–100%) for Myocardial Viability
patency of both saphenous venous and internal mammary
grafts.89–93 Focal disease can be identified using a 3D coro- Few applications of CMR have been so rapidly embraced
nary MRI sequence94 (Fig. 7.17). The addition of phase veloc- by the clinical community as its ability to characterize myo-
ity imaging of graft flow95 is also useful for discriminating cardial fibrosis and thereby derive prognostic data regarding
vein graft patency, especially for jump grafts. physiologic viability—the likelihood that resting regional
Implanted metallic clips, markers (Fig. 7.2), or intracoro- left ventricular dysfunction will improve with mechanical
nary stents15,96 (Fig. 7.3) will have a local signal void, preclud- revascularization. Extensive correlative CMR and histologic
17 2 chapter 7

studies in animal models have demonstrated that extracel-

lular Gd-DTPA will localize/concentrate to areas corre-
sponding to scar/fibrosis on histology and can be recognized
using delayed enhancement CMR imaging.97,98 Using an
inversion recovery sequence with imaging 10 to 20 minutes
following injection of 0.1 to 0.2 mmol/kg of Gd-DTPA, areas
of hyperenhancement correspond to scar/fibrosis (Fig. 7.11)
with highly reproducible results.99 Delayed-enhancement
CMR studies have demonstrated that the lack of hyperen-
hancement is a very strong predictor of functional viability
(Fig. 7.13), while the presence of more than 50% transmural
hyperenhancement is a powerful predictor for the lack of
functional recovery.100–102 An intermediate finding (1% to
49% transmurality) is less useful. For this group, regional
systolic response to low-dose dobutamine appears superior58
(Fig. 7.13). Delayed-enhancement CMR also compares favor- A
ably with electromechanical mapping103 and clinical posi-
tron emission tomography.104
The DE-CMR method appears to be particularly superior
to wall thinning for the discrimination of viable myo-
cardium. Anecdotal reports105 and preliminary data from
a multicenter series106 reported that 20% of subjects with
thinned, akinetic segments have lack of hyperenhancement
of those segments. Following mechanical revascularization,
these segments demonstrate markedly improved systolic
thickening in addition to local hypertrophy/normalization of
diastolic wall thickness. Delayed-enhancement CMR also
appears to be superior to global left ventricular ejection frac-
tion for identification of patients with underlying substrate
for sustained ventricular tachycardia.107

B
Nonischemic Cardiomyopathies FIGURE 7.18. (A) Cine steady-state free precession (SSFP) short axis
and corresponding (B) DE-CMR in a 17-year-old patient with hyper-
trophic cardiomyopathy. Note the prominent septal hypertrophy
Initial studies suggested that hyperenhancement may be spe-
with an area of hyperenhancement at the juncture of the right ven-
cific for coronary artery disease.108 Subsequent studies have tricular free wall and septum (arrow).
shown that hyperenhancement may occur in a variety of
nonischemic myopathic conditions including hypertrophic
cardiomyopathy109–111 (Fig. 7.18), Fabry’s disease,112 sarcoid-
osis,113 myocarditis,114,115 and Churg-Strauss syndrome.116 A
diffuse pattern of hyperenhancement is seen in amyloid car- important for evaluation of patients with focal/asymmetric
diomyopathy.117 Though not totally specific for myocardial hypertrophy (Fig. 7.18). Both DE-CMR109–111 and investigative
infarction, a subendocardial hyperenhancement correspond- CMR “tagging” methods may assist in the assessment of
ing to a coronary artery distribution is far more common these patients,120 though the latter remains to be more fully
among patients with ischemic cardiomyopathy, while elucidated. Serial CMR examinations may be useful to
patients with nonischemic myopathies more often demon- monitor ventricular remodeling and infarction size follow-
strate a hyperenhancement pattern of the midventricular or ing alcohol ablation.121
epicardial layers that also do not correspond to a coronary In addition to biventricular volumetric and mass data,
distribution.110,112,114–116 Two studies83,118 have suggested that CMR may confirm excess iron deposition122 as the cause of
the pattern may be used to characterize the cause of a dilated depressed systolic function in a patient with suspected hemo-
cardiomyopathy, although 25% of patients with a “coronary chromatosis. Assessment of septal T2* has been shown to
disease” hyperenhancement pattern had a nonischemic reflect myocardial iron stores, with T2* of less than 20 ms
myopathy. Thus, coronary MRI may be superior.83 Among indicating iron overload.123
patients with a dilated cardiomyopathy given carvedilol, the Cardiovascular magnetic resonance’s ability to identify
absence of hyperenhancement predicts a regional improve- focal areas of fat and fibrosis is particularly valuable in the
ment in systolic function, global improvement in left ven- evaluation of patients with suspected arrhythmogenic right
tricular ejection fraction, and decrease in left ventricular ventricular cardiomyopathy. This condition, in which the
cavity size.119 right ventricular free wall myocardium is diffusely or focally
The ability of CMR to acquire images of the entire heart replaced with fatty or fibrous tissue with cavity dilation and
in true tomographic planes makes it ideal for the evaluation focal wall thinning (or aneurysm), is associated with ven-
of patients with hypertrophic cardiomyopathies, especially tricular arrhythmias and sudden death. Spin-echo MRI can
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 17 3
sition of a cine SSFP data set through the plane of the aortic
valve. For now, leaflet thickening, calcification, vegetations,
abscess, and minor degrees of mitral valve prolapse largely
remain the province of echocardiography, though obvious
prolapse and partial leaflet flail are readily identified on cine
CMR imaging.
For the assessment of aortic valve stenosis, two CMR
approaches are utilized: a morphologic/2D assessment with
planimetry of the maximum systolic aortic valve area127 on
orthogonal cine SSFP sequences, and a continuity equation
“equivalent.”128 Difficulties with the anatomic (2D measures)
include orientation of the slice among patients with mark-
edly deformed valves, while difficulties with the continuity
equation approach include orientation of the imaging plane
perpendicular to the maximal velocity jet and dephasing/
artifacts due to turbulence in patients with severe aortic
stenosis. Analogous approaches are used for assessing mitral
stenosis, including 2D planimetry of the mitral valve area as
A defined by a cine acquisition oriented orthogonal to the valve
plane129 and with the use of phase velocity mapping at the
level of the mitral leaflet tips,130 thereby applying a pressure-
half-time equivalent measurement. Difficulties with the
former again include proper orientation orthogonal to flow,
while limitations of the latter include the relatively poor
temporal (vs. Doppler echocardiography) resolution and dia-
stolic artifacts among the many patients with coexistent
mitral stenosis and atrial fibrillation.
The use of CMR for the quantitative assessment of val-
vular regurgitation is much more direct and highly quantita-
tive. Qualitative assessment of mitral and aortic regurgitation
had initially been by qualitative estimate of the flow distur-
bance (signal void) in the receiving chamber in a manner
somewhat analogous to color Doppler. These early studies
showed a good correlation with Doppler echocardiography.131
However, the subsequent introduction of strong gradients
and shorter echo times led to attenuation and near elimina-
B tion of the dephasing artifact.132 This is particularly true of
FIGURE 7.19. (A) Spin-echo CMR. Note the bright signal in the the newer SSFP acquisitions, which have become “standard”
thinned right ventricular free wall (arrow) consistent with fatty at most CMR centers, with the nearly complete elimination
infiltration. (B) Delayed enhancement imaging after administration
of Gd-DTPA with enhancement of the right ventricular free wall. of regurgitant jets. Fortunately, CMR offers a more quantita-
tive approach. Using phase velocity mapping, flow is mea-
sured across the aortic valve (from a practical perspective,
this is often obtained in the axial plane at the level of the
be used to identify transmural or focal fatty infiltration in
bifurcation of the pulmonary artery). Such an assessment
the right ventricular free wall as well as focal wall thinning
includes a direct quantitative assessment of aortic regurgita-
(Fig. 7.19).124,125 Delayed-enhancement CMR with right
tion (Fig. 7.20). For mitral regurgitation, we generally quan-
ventricular free wall hyperenhancement has also been
tify the mitral regurgitant volume as the difference between
described,126 with the clinical history best able to discrimi-
the left ventricular stroke volume (derived from the contigu-
nate hyperenhancement due to right ventricular infarction
ous short axis left ventricular stack) and the forward flow out
from that of a primary cardiomyopathy.
of the aorta. Another option is to directly measure mitral
regurgitation volume using phase velocity mapping at the
Valvular Heart Disease level of the mitral annulus. We have found the latter approach
to be technically more challenging due to the base to apex
The clinical adoption of CMR in the care of patients with motion of the annulus during systole and eccentric, high-
valvular heart disease is expanding. Once almost solely the velocity mitral regurgitation jets, which sometimes lead to
province of 2D and Doppler echocardiography, the unique errors, analogous to some of the limitations of quantitative
quantitative nature of CMR with regard to ventricular Doppler echocardiography.
volumes and function, as well as the ease in calculation of Beyond simple calculation of regurgitant volume, CMR
regurgitant volumes, has brought CMR to the clinical arena provides for the ready determination of regurgitant fraction
for the care of this large group of patients. Valve morphology (regurgitant volume/stroke volume), regurgitant volume
(e.g., bicuspid valve) is easily recognized by CMR with acqui- index (regurgitant volume/end-diastolic volume), and effec-
 174 chapter 7

3D CMR data sets to be reconstructed in any orientation

Haselkorn STR retrospective helps to guide the surgical approach in such situations.
350 Though rarely difficult to diagnose from echocardio-
300 graphic images, benign lipomatous hypertrophy of the inter-
250 atrial septum as visualized on transthoracic echocardiography
Flow (mL/s)

(TTE) or TEE may sometimes lead to the misdiagnosis of an

200
atrial septal “tumor.” The characteristic, very intense signal
150 Asc Ao from fatty tissue134 with suppression using a fat saturation
100 prepulse readily allows for the CMR diagnosis of this benign
RV.5.12mL
50 disorder.
0
0 200 400 600 800 1000 1200
–50
–100
Pericardium
Time (ms)
A The normal pericardium extends around the heart as a thin
black line between visceral and parietal pericardial fat on
Kass STR retrospective 2
spin-echo CMR imaging. Normal pericardial thickness is
700 3 mm or less.135 Among patients presenting with constrictive
600 cardiomyopathy, often following recurrent pericarditis or
500 mediastinal radiation, the pericardium is thickened (Fig.
Flow (mL/s)

400 7.21), a finding that is readily appreciated by ECG-triggered

300 spin-echo CMR. Gradient-echo methods are slightly less reli-
Asc Ao able for pericardial thickness.136 Computed tomography is
200
also valuable in this situation, and is better suited for the
100
specific assessment of pericardial calcifications (see Chapter
0
0 200 400 600 800 1000 1200 67). It should be remembered, however, that while CMR (and
–100
RV:66.77mL CT) will accurately quantify focal pericardial thickening,
–200 the presence of thickened pericardium alone is not diagnos-
Time (ms)
B tic of constrictive physiology, and constriction may be present
FIGURE 7.20. Integrated phase velocity data acquired in the proxi- in the absence of pericardial thickening.137 Cardiovascular
mal ascending aorta (Asc Ao) in a patient (A) without and (B) with magnetic resonance tagging methods demonstrate adherence
severe aortic regurgitation. Note the persistence of “negative” flow
throughout diastole in the patient with severe aortic regurgitation
of the pericardium to underlying epimyocardium.138 Among
with a total of 56 mL of aortic regurgitation. patients with constriction, CMR also frequently demon-
strates thickened pericardium in concert with an enlarged
inferior vena cava alone, right atrial and right ventricular
enlargement,136 and abnormal septal motion (with real-time
tive forward ejection fraction (net forward stroke volume/ CMR). Though echocardiography is generally adequate for
end-diastolic volume). These same measures can be equally circumferential effusions, CMR depicts transudative effu-
well applied for pulmonic and tricuspid regurgitation. sions as areas of high intensity and may be particularly
Another advantage of CMR versus echocardiography and
invasive measures is the ability to easily quantify the regur-
gitant volumes attributable to each valve in the presence of
serial regurgitant lesions (e.g., mitral regurgitation and aortic
regurgitation).

Cardiac Tumors and Masses

Although the high spatial resolution of CMR allows for
depiction of intracavitary tumors/masses (e.g., myxoma),
these intracavitary “masses” are generally well appreciated
and characterized using conventional echocardiography
(transthoracic or transesophageal). However, the sensitivity
and accuracy of transthoracic echocardiography for mural
left ventricular thrombi has recently been called into ques-
tion by an operative series that suggested far superior accu-
racy of DE-CMR (Fig. 7.11).49,50 Cardiovascular magnetic
resonance also has great value for characterizing paracardiac
FIGURE 7.21. Cine four-chamber SSFP image in a 45-year-old man
and extracardiac tumors133 and their extension into the myo- with recurrent pericarditis and symptoms of constriction. Note the
cardium, cardiac chambers, or neighboring mediastinal thickened pericardium with fluid (arrow) and stranding within the
structures (e.g., vena cavae, pulmonary veins). The ability of pericardial space.
 c a r d i o va s c u l a r m a g n e t i c r e s o n a n c e i m a g i n g 175
helpful in the delineation of loculated effusions, especially
in patients with suboptimal echocardiographic windows.
Delineation of hemorrhagic and transudative effusions is
another attribute of CMR.
RCA
MPA
Congenital Heart Disease
An extensive review of CMR applications for congenital L
heart disease is beyond the scope of this chapter. As previ- R
ously mentioned, CMR has great utility for both simple and
complex congenital heart disease. While hemodynamically LA
significant atrial septal defects and ventricular septal defects
are usually identifiable by TTE or TEE, phase-velocity CMR
is highly accurate and valuable for quantifying the pulmo-
nary/systemic flow ratio in patients with known defects139 RV
and characterizing congenital heart disease outside of the
cardiac chambers. These defects include aortic coarctation
(Fig. 7.6), anomalous pulmonary venous drainage (Table 7.1;
Fig. 7.22), and complex congenital heart disease in patients
who have undergone corrective or palliative surgery. For FIGURE 7.23. Reconstruction of targeted 3D free-breathing naviga-
these patients, CMR defines structural components and their tor coronary MRI in a patient with an anomalous right coronary
artery of the “malignant” form originating from the left (L) coronary
relationships, including serial evaluation and planning of cusp. LA, left atrium; MPA, main pulmonary artery; R, right coro-
subsequent surgical interventions. nary cusp; RV, right ventricle.
Coronary MRI for identification and characterization of
anomalous coronary arteries is widely accepted as a clinical
tool. This condition is found in less than 2% of the popula-
tion and is generally benign. However, there is an increased
risk of sudden death and myocardial infarction when the
anomalous vessel courses between the aorta and pulmonary anatomic course of the vessel may be misinterpreted owing
artery (Fig. 7.23). Even among patients with anomalous coro- to the projection method or operator inexperience, especially
nary arteries identified by invasive x-ray angiography, the with the declining routine use of right heart catheterization,
making coronary MRI a preferred approach. Several studies
have now reported on the value of MR in this condition,140–143
including the finding of initial misinterpretation by conven-
tional x-ray angiography.141,143 Though coronary MRI data for
anomalous disease are quite extensive, in the absence of a
strong suspicion, data are not sufficient to support routine
coronary CMR screening among young adults who present
with chest pain. Coronary CTA likely has similar efficacy,
though it has been less well studied and would expose young
adults to potentially harmful ionizing radiation.

Summary
Over the past decade, there has been tremendous clinical
growth in CMR. The recent introduction of high field (e.g.,
3 T) CMR systems144 and application of parallel imaging
RA methods145 in CMR has the potential to dramatically decrease
the time needed for CMR study completion. Moreover, inves-
tigations in the use of CMR for detection of subclinical
disease are ongoing146 and expected to further expand the role
of CMR in clinical care. Finally, the enhancement of real-
time CMR has facilitated the exciting birth of interventional
CMR methods, including placement of percutaneous valves
and atrial septal defect closure devices as well as guidance
for electrophysiologic procedures. Intervention CMR is
FIGURE 7.22. A 3D CE-MRA in a patient with an anomalous pul- expected to have its greatest initial impact in the pediatric
monary vein (solid arrow) entering the superior vena cava (dashed population,147 for which radiation exposure is of greatest
arrow). RA, right atrium. concern.
176 chapter 7

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 8 Computed Tomographic
Cardiovascular Imaging
Matthew J. Budoff

Tomographic Imaging Modalities. . . . . . . . . . . . . . . . . . . 181 Pulmonary Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Noncontrast Computed Tomography Imaging . . . . . . . . 183 Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . 195
Contrast-Enhanced Computed Tomography Electrophysiologic Applications of Cardiac
Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . 196
Pericardial Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Aorta and Aortic Valve Pathology . . . . . . . . . . . . . . . . . . 194

C
ardiac computed tomography (CT) is a robust technol- coronary artery anatomy. The speed of image acquisition is
ogy for the noninvasive assessment of a spectrum of possible due to the fact that the x-ray source is stationary. In
cardiovascular disease processes. This image modal- basic terms, instead of rotating the x-ray tube around the
ity has been used to provide assessment of atherosclerotic patient as conventional scanners do, the EBCT scanner has
plaque burden and coronary artery disease risk through coro- the patient positioned inside the x-ray tube, obviating the
nary calcium scoring. Although the technology has been need to move any part of the scanner during image acquisi-
clinically available for 20 years,1 cardiologists and even radi- tion. The electron beam is emitted from the cathode, which
ologists are largely unaware of its capabilities. This chapter is several feet superior to the patient’s head, and then passes
reviews the current clinical uses and describes some of the through a magnetic coil, which bends the beam so that it
potential for even greater utility in the near future. Advances will strike one of four tungsten anode targets. The magnetic
in spatial and temporal resolution, electrocardiographic trig- coil also steers the beam through an arc of 210 degrees. The
gering methodology, and image reconstruction software have x-ray generated from the powerful electron stream striking
helped in the evaluation of coronary artery anatomy and the tungsten anode target passes through the patient in a
vessel patency, providing the ability to noninvasively diag- fan-shaped beam and strikes the detector array positioned
nose or rule out significant epicardial coronary artery disease. opposite the four anodes.
Cardiac CT allows the three-dimensional (3D) simultaneous Three imaging protocols are used with the electron beam
imaging of additional cardiac structures including coronary CT scanner. They provide the format to evaluate anatomy,
veins, pulmonary veins, atria, ventricles, aorta, and thoracic cardiovascular function, and blood flow. The imaging proto-
arterial and venous structures, with definition of their spatial col used to study cardiovascular anatomy is called the volume
relationships for the comprehensive assessment of a variety scanning mode and is similar to the scanning protocol
of cardiovascular disease processes. This chapter discusses employed by conventional CT scanners. Single scans are
the role of cardiac CT in the assessment of cardiovascular obtained, and then the scanner couch is incremented a preset
pathology, with an emphasis on the detection of coronary distance, usually the width of the scan slice, so that there is
atherosclerosis. no overlap of anatomy. This scanning mode is utilized with
and without contrast enhancement and provides high spatial
resolution of cardiovascular anatomy. This technique is ideal
Tomographic Imaging Modalities for evaluation of the aorta, coronary arteries, and congenital
heart disease. The thinnest slice available is 1.5 mm, which
is not as thin as now available on multidetector scans (which
Electron Beam Computed Tomography
have slice thickness as thin as 0.5 mm by one vendor, and
The tomographic imaging modalities, including electron 0.625 to 0.75 by most others).
beam CT (EBCT), multidetector CT (MDCT), and magnetic The cine scanning protocol acquires images in 50 ms.
resonance imaging (MRI), have advantages and limitations Each scan is separated by an 8-ms delay, which translates to
in the evaluation of cardiovascular disease, depending on the a scanning rate of 17 scans/second per target. Scanning on
particular clinical questions posed. Electron beam CT is a multiple targets simultaneously allows for large volumes of
fourth-generation CT imaging modality that is able to rapidly the heart to be covered with each heartbeat. Scans are
obtain thin tomographic cardiac slices for the evaluation of acquired for the duration of the cardiac cycle. Depending on

181
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the heart rate, up to 8 cm of the heart can be imaged in a ously rotating, the table moves the patient through the
single heartbeat. The images acquired can be displayed in a imaging plane at a predetermined speed. The relative speed
cine loop (literally a movie demonstrating motion of the of the gantry rotation table motion is the scan pitch. The
heart), making assessment of wall motion, segmental thick- smooth rapid table motion or pitch in helical scanning allows
ening, and valve motion possible. Blood pool contrast complete coverage of the cardiac anatomy in 15 to 25 seconds.
enhancement is achieved by injection of contrast medium A major advantage over EBCT is the improved spatial resolu-
boluses via a superficial peripheral vein. The bolus amount tion and contrast resolution, allowing for a more detailed
for each image acquisition period averages 30 mL. The flow look at the coronary anatomy.4
mode imaging protocol acquires a single image gated to the Advances in MDCT technology have led to scanners that
electrocardiogram at a predetermined point in the cardiac can obtain images with a scan rotation of 333 ms, and with
cycle [e.g., end-diastole (peak of the R-wave)]. Images can be partial scanning, image acquisition between 175 and 250 ms.
obtained for every cardiac cycle or multiples thereof. Scan- Furthermore, utilizing portions of each of the images, and
ning is initiated before the arrival of a contrast bolus at an adding data from consecutive detectors, allows for further
area of interest (e.g., left ventricular [LV] myocardium) and is reduction in temporal resolution. Although it is not always
continued until the contrast has washed in and out of the possible, given the heart rate and regularity of the rhythm,
area. Time density curves from the region of interest can be most vendors are now quoting scan times approaching 110
created for quantitative analysis of flow, useful for shunt to 140 ms using this technique (Fig. 8.1).
fraction determinations, as well as timing of boluses for Multidetector CT also possesses greater versatility for
imaging of coronary anatomy in the volume (high resolution) peripheral vascular imaging, as the gantry opening allows
mode. the patient to be inserted from head to foot without reposi-
The ability to rapidly acquire images decreases respira- tioning. This is in contrast to EBCT, where the cone beam
tory and cardiac motion artifacts, making the modality well- limits patient motion, where many peripheral studies need
suited for the evaluation of the coronary vasculature. The to be done in two phases (iliac to popliteal, and then the
entire cardiac structure is imaged during a single approxi- patient is rotated feet first to image popliteal to foot). The
mate 15- to 30-second breath-hold. Electron beam CT smooth rapid table motion or pitch in helical scanning
acquires high-resolution images of the heart with temporal allows complete coverage of the cardiac anatomy in 15 to
resolution of 50 or 100 milliseconds (ms) and prospective 25 seconds. Use of the 64-slice scanner decreases this
gating to the cardiac cycle. This allows imaging during the imaging window to 5 to 12 seconds for cardiac and periph-
diastolic phase, when cardiac motion is minimized.2 The eral imaging.
newest generation of EBCT scanner is the e-speed scanner With MDCT, the limited temporal resolution is due to
(GE Medical Systems, San Francisco, CA), which allow for the design. The mechanical detector head has to rotate
50-ms image acquisition in both the high-resolution and low- around the patient. Present versions complete a 360-degree
resolution modes, and imaging more than one level simulta- rotation in about four-tenths of a second. These scanners’
neously. The faster image acquisition and multiple level exposure times can be decreased to as little as 175 ms by
imaging associated with this device further decreases breath- utilizing only a portion of the 360-degree rotation. Approxi-
hold time, radiation exposure, and motion artifacts. Prospec- mately 210 degrees of rotation is necessary for one image, so
tive gating (identifying the R wave and triggering at a fixed the rotation speed can be multiplied by 0.6 to calculate image
time thereafter to catch early diastole) allows for imaging of acquisition times. For example, a rotation speed of 400 ms
patients with a spectrum of heart rates and rhythms (includ- for a 360-degree image will have a total temporal resolution
ing premature beats and atrial fibrillation).

Snapshot image reconstruction:

Multidetector Computed Tomography Improving effective temporal resolution
Multidetector CT (MDCT) systems were initially capable of
acquiring four levels simultaneously in 2000,3 now can
obtain up to 64 levels of the heart simultaneously with ECG
gating in either a prospective or retrospective mode. The
MDCT differs from single-slice helical or spiral CT systems
principally by the design of the detector arrays and data
acquisition systems that allow the detector arrays to be con- Detector 1
figured electronically to acquire multiple levels of various Detector 2
Detector 3
slice thickness simultaneously. Thus, in the current 16- Detector 4
channel MDCT systems 16 slices can be acquired at nomi-
nally 0.75-mm slice widths for cardiac imaging. In MDCT
systems, like the preceding generation of single-slice helical Burst 2-Sector: ~ 125 ms
scanners, the x-ray photons are generated within a special-
ized x-ray tube mounted on a rotating gantry. Subsecond
MDCT scanners use a rapidly rotating x-ray tube and several FIGURE 8.1. “Burst” technology allowing parts of each image to
be used for reconstruction. In this example, portions of two consecu-
rows of detectors, also rotating. The tube and detectors are tive images were used to allow the temporal resolution of multide-
fitted with slip rings that allow them to continuously move tector computed tomography (MDCT) to be reduced from 265 ms to
through multiple 360-degree rotations. With gantry continu- about 132 ms.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 18 3
of approximately 240 ms. The manufacturers often quote devices such as pacemakers and defibrillators, and shorter
50% of the rotation speed (i.e., 200-ms image acquisition), study times.4
but this only refers to the central point on the scan, and not
the entire image, so this is most often somewhat misleading
to the clinician or user. Simultaneous imaging from multiple Noncontrast Computed Tomography Imaging
detectors (now up to 64) during gantry rotation provides
greater spatial resolution than EBCT (specifically thinner
Coronary Artery Calcium
slices through the heart), but at the expense of temporal reso-
lution (time to image an individual level, presenting more Coronary artery calcium (CAC) is closely associated with
motion artifacts when heart rates are above 60 beats per coronary atheromatous plaque. Arterial calcium deposition
minute).4 Newer EBCT systems quote 9 to 11 line-pairs/cm, occurs in association with atherosclerotic plaque evolution
while MDCT has improved spatial resolution, with 14 to 16 and is regulated by cellular calcification-regulating pro-
line-pairs/cm of resolution. Although EBCT suffers from teins.15 A direct relationship has been established between
decreased signal to noise and gantry design, a disadvantage coronary artery calcium as measured by EBCT and both
of MDCT cardiac scanning is an increase in motion artifacts histopathologic16,17 and in vivo intravascular ultrasound18,19
and radiation exposure.5 For cardiac imaging, there is a nar- studies, which confirm the close correlation between athero-
rower window of acceptable heart rates for scanning with sclerotic plaque burden and extent of CAC.
MDCT compared to EBCT, with many patients requiring Electron beam CT can accurately and noninvasively
pharmacologic decreases in heart rate to less than 60 beats/ quantitate CAC, and several measurements have been used.20
minute to extend diastole to the point of minimizing cardiac Most centers and research studies have reported a calcium
motion (see Multidetector Computed Tomography Angiogra- score measurement (Agatston method)1 that takes into
phy, below). A major current disadvantage of MDCT in account the density and area of the calcification. The score
cardiac scanning is an increase in radiation dose (see is calculated by multiplying the lesion area by a density
below).6 factor derived from the maximal Hounsfield unit (HU) within
In the near term, the development and introduction of this area. The density factor was assigned in the following
MDCT systems with increased detectors is likely. In 2005, manner: 1 for lesions whose maximal density was 130 to
most vendors offer a 64-row system, and the additional detec- 199 Hu, 2 for 200 to 299 Hu, 3 for 300 to 399 Hu, and 4 for
tor rows help to improve temporal resolution, reduce breath- >400 Hu. A total calcium score is determined by summing
hold time, and reduce contrast dose. We will observe individual lesion scores from each of four anatomic sites (left
continued rapid advancement in CT for coronary and periph- main, left anterior descending, circumflex, and right coro-
eral angiography and a series of comparative studies evaluat- nary arteries) (Fig. 8.2). The other measures are volume
ing these new CT techniques with existing measures of
coronary heart disease.

Comparison of Computed Tomography to Magnetic

Resonance Imaging
The strength of magnetic resonance cardiovascular imaging
includes greater definition of tissue characteristics, perfu-
sion, valvular function, lack of x-ray radiation, and lack of
need for potentially nephrotoxic contrast media, compared
to CT technologies. Several studies have been reported com-
paring this modality to coronary angiography.7–9 Limited
temporal and spatial resolution,10 partial volume artifacts,11
reliance on multiple breath holds, and poor visualization of
the left main coronary artery12 all reduce the clinical appli-
cability of MR angiography. Computed tomography angi-
ography offers advantages over MR angiography, including
single breath hold to reduce respiratory motion, higher spatial
resolution, reduced slice thickness, and overall study time of
35 to 50 seconds with CT techniques as compared to 45 to
90 minutes for MR angiography.4,13 Reported sensitivities for
MR angiography range from 0% to 90%.4,7,13 Magnetic reso-
nance angiography remains a technically challenging tech-
nique with certain limitations hindering its clinical use. The
rapidity and ease with which CT coronary angiography can
be performed suggest possible cost advantages compared
with MR angiography and selective coronary angiography.14 FIGURE 8.2. A computed tomography (CT) study (axial image)
demonstrating calcification of the left main and left anterior
In comparison, the strengths of CT include superior descending coronary arteries. The total coronary calcium score was
imaging of coronary arteries, higher spatial and temporal over 1000. Arrow, left anterior descending coronary artery
resolution, ability to scan patients with implantable metallic calcification.
18 4 chapter 8

measurement and mass score. A large criticism directed at with cardiac gating demonstrated a mean variability of 36%
the Agatston method is increased variability (decreased for volume scoring and 43% for Agatston scoring.26
reproducibility) due to image noise (a peak HU of 199 would
multiply the area by a factor of 1; if that increased to 201 on
Calcium Progression
a subsequent scan, it would increase the score twofold, as the
density factor would be two). These small changes in mea- Much interest has been directed at using CAC to measure
surement can double the interscan variability, leading to plaque burden, and then remeasuring at some point in time
other measures to be proposed to allow for more accurate and to assess for progression of disease. Callister et al.21 was one
reproducible measurement of CAC. The volume method of of the first studies to demonstrate a relationship between
Callister et al.21 somewhat resolves the issues of density cholesterol control and atherosclerosis progression. There
measures, slice thickness, and spacing by computing a was a significant net increase in mean calcium-volume score
volume above threshold. This has been shown to be more among individuals not treated with cholesterol-reducing
reproducible, but fewer data are available on the prognostic medications (mean change: 52 ± 36%, p < .001). There was a
values of such scores. A mass score has been introduced, but graded response depending upon the low-density lipoprotein
absolutely no prognostic information is available, and this (LDL) reduction with statin therapy, with those treated to
requires a phantom to make this measure, which has been LDL < 120 mg/dL demonstrating an average diminution of
shown to increase image noise (which worsens reproducibil- coronary calcium (−7% ± 23%), and those individuals treated
ity on individual scans).22 Further research using either less aggressively (LDL > 120 mg/dL) showed a calcium-volume
volume or mass scores will be needed to allow accurate clini- score increase of 25% ± 22% (p < .001 for comparison with
cal guidelines to be written. aggressively treated subjects).
Data regarding calcium score distribution in large Another study evaluated 299 patients who underwent
numbers of asymptomatic persons have been published.23 two consecutive scans at least 12 months apart.27 The average
These tables can be used to classify patients on the basis of change in the calcium score (Agatston method) for the entire
the extent of their atherosclerotic disease compared with the group was 33.2% ± 9.2% per year. Those patients reporting
expected norm. In men, there is a rapid increase in the preva- use of a statin had an annual rate of progression of 15%,
lence and extent of coronary calcification after age 45. Com- compared with 39% annual increase in EBCT score for non-
pared to men, this increase is delayed for 10 to 15 years in statin users.
women. Prospective studies demonstrating a link between CAC
progression and coronary events have recently been reported.
The first study demonstrated, in 817 persons, that EBCT-
Reproducibility of Coronary Calcium Assessment
measured progression was the strongest predictor of cardiac
The reproducibility of the CAC measurement is essential to events.28 This observational study suggests that continued
utilizing this modality for assessment of the efficacy of ther- accumulation of CAC in asymptomatic individuals is associ-
apeutic interventions. Reproducibility was initially a concern ated with increased risk of myocardial infarction (MI) in
for repeated testing, but hardware and software improve- asymptomatic individuals. A second study measured the
ments have reduced interscan variability to a median of 4% change in CAC in 495 asymptomatic subjects submitted to
to 8%.24 In addressing reproducibility issues with coronary sequential EBCT scanning.29 Statins were started after the
calcium, it was noted that the most commonly used trigger initial EBCT scan. On average, MI subjects demonstrated a
time in early studies (80% of the R-R interval) is suboptimal CAC change of 42% ± 23% yearly; event-free subjects showed
due to increased coronary motion during atrial kick (atrial a 17% ± 25% yearly change (p = .0001). Relative risk of having
systole causing the right coronary and circumflex arteries to an MI in the presence of CAC progression was 17.2-fold [95%
move rapidly). This has become particularly important with confidence interval (CI): 4.1 to 71.2] higher than without
the increased use of CT for measurement of progression of CAC progression (p < .0001). In a Cox proportional hazard
atherosclerosis as well as CT coronary angiography (to model, the follow-up score (p = .034) as well as a score change
improve visualization of the coronary arteries without >15% per year (p < .001) were independent predictors of time
motion artifacts). Recent studies suggest that a triggering to MI. The Multi-Ethnic Study of Atherosclerosis will
should be initiated early in diastole rather than near the end measure baseline CAC scores and repeat this measurement
(80%) as has been done in the past with some scanners.2 The after 3.5 years in 6600 patients. Interim events, within the
ideal trigger is, by definition, that which gives the least 3.5 years, will be measured. Future events in the subsequent
cardiac motion, and has been extensively studied for EBCT, 3.5 years (total 7 years follow-up) will be measured.
and found to be at the end of systole (late systole or early
diastole). Studies with MDCT usually conclude that 40% to
Coronary Artery Calcium and Obstructive Disease
50% of the R-R interval (early diastole) is the optimal trigger
for visualization of lumina with least coronary motion. Early In contradistinction to other noninvasive modalities that
diastolic triggering has reduced the variability of CAC to focus on diagnosis of obstructive coronary artery disease
11% to 15%.25 With excellent inter- and intraobserver vari- (CAD), EBCT coronary calcium represents an anatomic
ability (1%), this test can measure plaque burden changes measure of plaque burden.30 Studies comparing pathologic
over time. Multidetector CT reproducibility is currently and EBCT findings have shown that the degree of luminal
higher, although newer scanners (with 16, 32, or 64 detectors) narrowing is weakly correlated with the amount of calcifica-
should help in reducing this measurement error. A study of tion on a segment-by-segment basis, 31 whereas total calcium
537 patients undergoing two studies on four-slice MDCT score is more closely associated with the presence and severity
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 18 5
of maximum angiographic stenosis.32 Detection of coronary surement of atherosclerosis burden in the risk stratification
calcium by EBCT has been demonstrated to be highly sensi- for future cardiovascular events, rather than relying solely
tive for the presence of significant CAD. A report of 1764 on evidence of obstructive coronary artery disease.
persons undergoing angiography and EBCT similarly showed
a very high sensitivity and negative predictive value in men Coronary Artery Calcium Risk Prediction in
and women (>99%).33 Therefore, a calcium score of 0, denoting Symptomatic Individuals
evidence of coronary calcium, can virtually exclude those
Studies have demonstrated that CAC has prognostic signifi-
patients with obstructive CAD, making this test an effective
cance in symptomatic individuals. Margolis et al.46 assessed
screen prior to invasive angiography. Guerci et al.34 studied
the significance of CAC found on fluoroscopy in 800 patients
290 men and women undergoing coronary arteriography for
undergoing coronary angiography. The patients with CAC
clinical indications and concluded that EBCT scanning
had a 5-year survival rate of 58%, compared with a rate of
improved discrimination over conventional risk factors in the
87% for the patients without CAC. A study of 192 patients
identification of persons with angiographic coronary disease.
observed for an average of 50 ± 10 months, after undergoing
An important point in the interpretation of CAC scores
an EBCT study while in the emergency department for chest
relates to the detection of obstructive CAD. A negative test,
discomfort, found that the presence of CAC (calcium score
indicating no evidence of calcified atherosclerotic plaque, can
>0), and increasing absolute calcium score values were
virtually exclude obstructive disease. A positive EBCT study,
strongly related to the occurrence of hard events (p < .001)
indicating the presence of CAC, is nearly 100% specific for
and all cardiovascular events (p < .001).47 The patients with
atheromatous coronary plaque.35 However, since both obstruc-
absolute calcium scores in the top two quartiles had a rela-
tive and nonobstructive lesions have calcification present,
tive risk of 13.1 (95% CI, 5.6–36; p < .001) for new cardiovas-
CAC is not specific to obstructive disease. While increasing
cular events as compared to patients with lower scores. The
calcium scores are more predictive of obstructive CAD, there
annualized cardiovascular event rate was 0.6% for subjects
is not a 1 : 1 relationship between calcification and stenosis.
with a coronary artery calcium score of 0 compared with an
The overall specificity of any CAC for obstructive CAD is
annual rate of 13.9% for patients with a coronary artery
approximately 66%.36 In a study of 1851 patients undergoing
calcium score >400 (p < .001).
angiography and CAC measure,37 EBCT calcium scanning in
A multicenter study of 491 patients undergoing coronary
conjunction with pretest probability of disease derived by a
angiography and EBCT scanning found that higher calcium
combination of age, gender, and risk factors, could assist the
scores were associated with a markedly increased risk of
clinician in predicting the severity and extent of angiographi-
coronary events over the next 30 months.48 In multivariate
cally significant CAD in symptomatic patients. Electron
analysis, the only predictor of a hard cardiac event was log
beam CT is comparable to nuclear exercise testing in the
calcium score, even with coronary risk factors and angio-
detection of obstructive CAD.38,39 As opposed to stress testing,
graphic disease included in the model. In another study of
the accuracy of EBCT is not limited by concurrent medica-
symptomatic patients, EBCT-detected CAC was a stronger
tions, ability to exercise, or baseline electrocardiogram abnor-
independent predictor of disease and future events than a
malities. Moreover, scanning for coronary calcium (CC) does
sum of all of the traditional risk factors combined.49 Keelan
not require injection of contrast medium; therefore, a CT
et al.50 followed 288 symptomatic persons who underwent
technician can perform the study without supervision. The
angiography and EBCT calcium scanning for a mean of 6.9
entire procedure takes less than 10 minutes to perform.
years, and found age and CAC score were the only indepen-
However, cardiac CT does not afford assessment of functional
dent predictors of future hard coronary events.
status of the patient, so many physicians may utilize a tread-
mill test and calcium scan together. This algorithm has been
Coronary Artery Calcium in
shown to improve the diagnostic accuracy of both tests,40
Asymptomatic Individuals
without significantly increasing cost.
Coronary artery calcium is also a useful predictor of cardio-
vascular events in asymptomatic individuals. Unfortunately,
Role of Coronary Calcium in Risk Stratification
at least half of all first coronary events occur in asymptom-
Disease processes related to atherosclerosis are the primary atic individuals who are unaware that they have developed
cause of morbidity and mortality in every industrialized CAD, and often present as sudden death or acute MI.45 Several
nation. The initial manifestation of CAD is a MI or death in lipid-lowering trials have shown that substantial risk reduc-
up to 50% of patients.41 Most cardiac events occur in the tion can be attained with both secondary and primary pre-
intermediate risk population, where aggressive risk-factor vention measures.51
modification is not often recommended or applied. Unfortu- Several prospective trials have demonstrated the prognos-
nately, traditional risk factor assessment helps predict only tic ability of EBCT to identify asymptomatic patients at high
60% to 65% of cardiac risk; therefore, many individuals risk of cardiac events. Arad et al.52 reported 3.6-year follow-
without established risk factors for atherosclerotic heart up of 1173 patients. Asymptomatic individuals were scanned
disease continue to experience cardiac events.42 Acute coro- using EBCT as well as measures of traditional risk factors,
nary occlusion most frequently occurs at the site of mild to and followed prospectively for cardiac events. This study
moderate stenoses (<50% lesion severity) in association with demonstrated CAC to be the strongest predictor of future
the process of plaque rupture.43,44 Therefore, plaque burden, cardiac events, with patients in the highest score category
and not stenosis severity, is a more important marker of over 20 times more likely to suffer a cardiac event (odds ratio
disease.45 These studies emphasize the importance of mea- 22.3, CI 5.1–97.4).
18 6 chapter 8

Wong et al.53 followed 926 asymptomatic patients (mean tional cardiovascular risk factors, and very high scores
age 54 years) for an average of 3.3 years. The presence of CAC (>1000) were associated with a 13-fold increased risk of death
and increasing score quartiles were related to the occurrence as compared to persons with lower scores.
of new MI (p < .05), revascularization (p < .001) and total
cardiovascular events (p < .001). The risk ratio for events in
Coronary Artery Calcium: Guidelines
patients whose absolute calcium score was in the upper quar-
and Applications
tile (score > 271) compared with individuals whose absolute
calcium score was in the lowest quartile (score < 15) was 12 The above-mentioned studies demonstrate the ability of CAC
(relative risk 8.8 and 0.72, respectively; p < .001). to provide risk stratification in asymptomatic and symptom-
Greenland et al.54 published long-term follow-up of the atic populations with incremental prognostic information
South Bay Heart Watch. Coronary artery calcium was found beyond traditional risk factors. Based on the results of these
to be predictive of risk in patients with a Framingham Risk studies, modification of the Framingham Global Risk Score
Score of >10%, with a high CAC score able to predict risk by using a weighted factor based on the patient’s individual
beyond Framingham risk score alone. As compared to a CAC calcium score percentile has been suggested.59 In this modi-
score of 0, a CAC score of >300 was highly predictive of fication, the Framingham Risk Score assigned to a subject
cardiac events (HR 3.9, p < .001). undergoing EBCT screening for asymptomatic CAD is
Raggi et al.55 followed 632 asymptomatic individuals increased if the calcium score is in a high percentile.
with risk factors for CAD for an average of 32 ± 7 months. A The greatest potential for CAC detection could be as a
CAC score of zero was associated with a 0.11%/year event marker of CAD prognosis in asymptomatic persons at risk
rate, compared to 4.8%/year with a score >400. The event of CAD, beyond that detected by conventional coronary risk
rate in patients with calcium scores in the highest quartile factors. Since the 2000 American College of Cardiology
was 22 times the event rate in patients with calcium scores (ACC)/American Heart Association (AHA) expert consensus
in the lowest quartile, significantly outperforming risk document on EBCT noting inconclusive risk stratification
factors in cardiac event prediction. Multiple logistic regres- evidence on CAC scanning,60 a number of studies have
sion analyses demonstrated that calcium score percentile reported that the presence and severity of CAC has indepen-
was the only significant predictor of events and provided dent and incremental value when added to clinical or histori-
incremental prognostic value when added to traditional risk cal data in the measure of death or nonfatal MI. Since those
factors for CAD. early recommendations, the National Cholesterol Education
Larger trials have been reported, demonstrating approxi- Program (NCEP) has made recommendations specifically for
mately 10-fold increased risk with the presence of CAC. the use of EBCT to assist in risk stratification in elderly and
Kondos et al.56 reported 37-month follow-up on 5635 initially intermediate risk patients. The new NCEP guidelines (Adult
asymptomatic low- to intermediate-risk adults. In men, Treatment Panel III)61 support the conclusions of the AHA’s
events (n = 192) were associated with the presence of CAC Prevention Conference V62 and the ACC/AHA report60 that
[relative risk (RR) = 10.5, p < .001), diabetes (RR = 1.98, p = high coronary calcium scores signify and confirm increased
.008), and smoking (RR = 1.4, p = .025), whereas in women risk for future cardiac events, and state, “Therefore, measure-
events (n = 32) were linked to the presence of CAC (RR = 2.6, ment of coronary calcium is an option for advanced risk
p = .037) and not risk factors. assessment in appropriately selected persons. In persons with
A prospective study of 5585 subjects aged 59 ± 5 years, a multiple risk factors, high coronary calcium scores (e.g.,
calcium score ≥100 predicted all atherosclerotic cardiovascu- >75th percentile for age and sex) denotes advanced coronary
lar disease events, all coronary events, and the sum of non- atherosclerosis and provides a rationale for intensified LDL-
fatal MI and coronary death events with relative risks of 9.5 lowering therapy.” New guidelines for prevention of CAD
to 10.7 at 4.3 years.57 The calcium score also predicted events recommend coronary calcium as a method of risk stratifica-
independently of and more accurately than measured risk tion, with positive scores placing individuals at intermediate
factors. The area under the receiver operating characteristic risk by the Framingham model (10–20% 10-year risk) and
curve for event prediction with risk factors alone in this high CAC scores at high risk for future cardiac events.63
study was 0.71, increasing to 0.81 with EBCT testing (p < .01). The absence of CAC in the asymptomatic patient identi-
This prospective study strongly demonstrated the ability to fies a group of patients at very low risk of events over the
utilize this test to rule out patients who do not require next 3 to 5 years. An annual event rate of only 0.11% has
therapy. In this study, only 19% of patients had scores above been reported for patients with scores of zero.55 Both the
the diagnostic threshold (calcium score ≥100), yet relying on ACC/AHA writing group and the Prevention V Conference
this threshold had a negative predictive power of 99.2%. agreed that the negative predictive value of EBCT is very
Thus, clinicians can focus on a smaller, yet higher risk popu- high for short-term events.60,62 Whether a calcium score of
lation (10.7-fold increased risk in this group), for risk reduc- zero will allow therapy to be withheld remains to be prospec-
tion therapy. tively tested.
Shaw et al.58 demonstrated the power of coronary artery Current guidelines suggest that intermediate risk patients
calcium to predict all-cause mortality over the next 5 years. would benefit most from further risk stratification, as most
A cohort of 10,377 asymptomatic individuals undergoing cardiac events occur in this population.61 “Recent work
cardiac risk factor evaluation and CAC measure with EBCT suggests that electron-beam tomography (EBCT) can also
reported a mean follow-up of 5.0 years. In a risk-adjusted improve risk prediction in intermediate-risk patients. Thus,
model, CAC was an independent predictor of mortality (p < with a prior probability of a coronary event in the intermedi-
.001). Coronary calcium was a better predictor than tradi- ate range (>6% in 10 years but <20% in 10 years), a calcium
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 18 7
score would yield a posttest probability in virtually all such beats per minute; at faster heart rates, motion artifacts may
patients greater than 2% per year, that is, a level similar become more prominent.
to that in secondary prevention, or a “coronary risk Protocols are being developed that may reduce radiation
equivalent.” Furthermore, CAC screening with EBCT was doses with MDCT, by attempting to decrease beam current
demonstrated to be a cost-effective screening strategy in during systole, when images are not used for interpretation.
asymptomatic individuals between 45 and 65 years of age.64 New AHA guidelines are being published discussing the
The ability of CAC scoring to identify patients who require advantages and disadvantages of each modality.70 These
aggressive risk factor modification, coupled with effective- guidelines conclude that “some limitations remain for mul-
ness of cholesterol lowering medications, aspirin, and other tidetector CT, including: (1) slower speed of the acquisition
therapies, should allow physicians to focus aggressive pre- (EBCT = 50–100 msec, MDCT = 200–330 msec); (2) higher
ventative treatment on those individuals with underlying radiation dose (EBCT dose = 0.7 mSv, MDCT dose = 1.5–
atherosclerosis who are at highest risk of having cardiovas- 1.8 mSv); and (3) possibly greater interscan variability of mea-
cular events. surement (EBCT = 11–16%, MDCT = 23–35%).” Two ongoing
There are some potential specific applications of CAC trials [multi-ethnic study of atherosclerosis (MESA) trial in
assessment that warrant mention. Based on the fact that a the United States and the Heinz Nixdorf Recall Study in
CAC score of zero is associated with a <1% chance of obstruc- Germany] are examining the value of EBCT and/or MDCT-
tive CAD, the use of EBCT prior to angiography has been derived CAC in the general population, and will provide
recommended for certain persons of low-to-intermediate risk more answers in relation to the role of CAC in the primary
of obstructive CAD. In the symptomatic patient, evidence prevention of atherosclerosis.
suggests that calcium scanning may be more cost-effective
at diagnosing CAD than traditional noninvasive testing, Position of the Professional Societies
especially in women.64,65,66 and Guidelines
Another potential application of cardiac CT relates to the
In 1996, the AHA assembled a writing group on the applica-
triage of chest pain patients. Electron beam CT has been
tion of EBCT coronary calcium scanning. This group con-
shown to be an efficient screening tool for patients admitted
cluded that EBCT CAC was a useful surrogate for
to the emergency department with chest pain to rule out
atherosclerosis, with a negative test most likely associated
myocardial infarction.47,67,68 These studies demonstrate sen-
with normal coronary arteries and a low risk of cardiac
sitivities of 98% to 100% for identifying patients with acute
events in the next 2 to 5 years, and a positive test being
MI, and very low subsequent event rates for persons with
associated with atherosclerosis.33
negative tests. The high sensitivity and negative predictive
Fortunately, the AHA and the ACC have taken responsi-
value may allow early discharge of those patients with non-
ble positions on this issue. Given the strong literature in
diagnostic ECG and negative calcium scans. Exclusion of
support of risk stratification with this tool, the issue of CAC
coronary calcium, therefore, may be used as an effective
scanning is undergoing a current revision and should have
screen prior to invasive diagnostic procedures or hospital
stronger support from both organizations, especially given
admission.
the incremental and independent predictive value found in
In patients with cardiomyopathy, CAC has been shown
all studies to date.
to be useful in determining the etiology of cardiomyopathy.
Recent guidelines and expert consensus documents have
The clinical manifestations of patients with ischemic car-
recommended the use of CAC (or the use of other tests of
diomyopathy are often indistinguishable from those patients
atherosclerosis burden) in clinically selected intermediate
with nonischemic dilated cardiomyopathy. Budoff et al.69
CAD risk patients (e.g., those with a 10% to 20% Framing-
demonstrated in 120 patients with heart failure of unknown
ham 10-year risk estimate) to refine clinical risk predic-
etiology that the presence of CAC was associated with a 99%
tion62,71,72 and to select patients for altered targets for
sensitivity for ischemic cardiomyopathy.
lipid-lowering therapies.61,73

Electron Beam versus Multidetector CT for

Assessment of Coronary Artery Calcium
Contrast-Enhanced Computed
Tomography Angiography
The higher tube currents available with MDCT allow for
images with a better signal-to-noise ratio and higher spatial
Electron Beam Angiography
resolution in comparison to EBCT, but at the expense of
higher radiation exposure and lower temporal resolution. The ability to visualize the coronary artery lumen has revo-
Retrospective gating involves acquiring hundreds of cardiac lutionized CT imaging. An alternative, less expensive, and
image, but only uses those that occurred with appropriate noninvasive test for use as a diagnostic tool before possible
diastolic timing. This retrospective approach markedly intervention could have a major impact on health care prac-
increases the radiation dose, image analysis time, inter- and tice and cost containment.4 Contrast-enhanced CT angi-
intra-reader variability, and interscan variability. A more ography is an emerging technology with the potential for
practical approach is prospective gating, which is similar to obtaining essentially noninvasive coronary arteriograms.
the methods employed by EBCT. This methodology allows Studies have reported contrast-enhanced, electrocardiogram
for image acquisition only at the specified time (diastole), and (ECG)-triggered, 3D-EBCT angiography for detecting and
therefore reduces variability and radiation. For MDCT, the grading coronary stenosis.74,75,76,77,78,79 Coronary electron beam
images are best when the resting heart rate is less than 60 angiography (EBA) was first introduced in 1995,80 and since
18 8 chapter 8

that time has improved due to technology and methodology

advances. Electrocardiogram triggering is employed, so that
each image is obtained at the same point in diastole. Iodin-
ated contrast is administered through an antecubital or
jugular vein with an injection rate of approximately 4 mL/sec
and total volume of 80 to 160 mL, depending on the version
of scanner used. Images are obtained over a single breath-
hold, usually over approximately 30 seconds. This entire
protocol can be performed within 15 to 20 minutes. Image
processing is rapid, with detailed analysis through the assess-
ment of two-dimensional (2D) and 3D views as well as
maximum intensity projections in which serial overlapping
thin slices are viewed in unison (Figs. 8.3 to 8.5).81 As com-
pared to invasive angiography, this modality has been dem-
onstrated to identify significant coronary lumen narrowing
(>50% stenosis) with an overall sensitivity of 87% and speci-
ficity of 91% for the 10 or so studies now reported.4
These early studies, while demonstrating sensitivities
and specificities in the range of 88% to 94%, were somewhat
limited by nonevaluable segments, despite the high temporal FIGURE 8.4. Electron beam angiography demonstrating the obtuse
resolution of EBCT (100-ms imaging). Historically, the most marginal (OM) and circumflex without evidence of obstructive coro-
common trigger time used is 80% of the R-R interval. nary artery disease.
However, this trigger occurs on or near the P wave during
atrial systole. Electrocardiogram triggering at 80% of the R-R
interval (late diastole) used in most prior studies might not coronary angiography. Patients were divided into two groups
be optimal for imaging of the coronary segments near the based on different ECG triggering used: 80% R-R interval
right or left atria, since atrial contraction during end-diastole trigger method (group 1, n = 53) and end-systolic triggering
causes rapid movement of the base of the heart,82 and the (group 2, n = 80). Overall sensitivity (including all segments,
least motion among all heart rates occurs earlier in the not just evaluable segments) to detect a ≥50% luminal ste-
cardiac cycle (late systole).83 A study was subsequently nosis was 69% in group 1 and 91% in group 2 (p = .002);
reported demonstrating a marked improvement in results specificity was 82% and 94% in group 1 and group 2, respec-
with EBCT when using end-systolic triggering rather than tively (p < .001). Nonassessability of coronary segments on
late diastolic triggering. 3D-EBA images was reduced from 35% in group 1 to 9% in
Lu et al.84 studied 133 patients with suspected coronary group 2 patients (p < .001). The number of motion-free coro-
disease with intravenous coronary EBA and conventional nary images increased from 67% to 95% from group 1 to
group 2 (p < .0001).
Another study by Budoff et al.85 reported the improve-
ment with image quality and diagnostic accuracy with newer
triggering techniques was also reported. Eighty-six patients

1st Diagonal

Conus

RV

AM

FIGURE 8.5. Computed tomography angiography demonstrating

FIGURE 8.3. E-Speed (General Electric, San Francisco, CA) electron the left and right coronary arteries, without evidence of obstructive
beam angiography demonstrating the left and right coronary arter- coronary artery disease. The conus artery, as well as the right
ies, without evidence of obstructive coronary artery disease. LAD, ventricular vein and acute marginal branches are well visualized.
left anterior descending coronary artery; RCA, right coronary 1st Diag, first diagonal artery; AM, acute marginal branch of right
artery. ventricle; RV, right ventricular vein.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 18 9
were studied; EBT correctly classified 49 of 53 patients (92%)
as having at least one coronary stenosis. Overall, 103 steno-
ses exceeding 50% diameter reduction were present, and of
these 93 lesions were correctly detected by EBT (sensitivity:
90%; specificity: 93%; positive predictive value: 84%; and
negative predictive value: 96%). Only 5% of vessels could not
be assessed, predominantly due to significant calcification.
Newer advances in both modalities will lead to routine
use of noninvasive angiography. In regard to the EBCT
scanner, newer electron beam technologies are now available
(e-speed, General Electric, San Francisco, CA) that provide
greater spatial and temporal resolution and may provide
greater visualization of smaller branch veins as well as distal
tapering sections of branch veins than the scanner used in
this study.86 Early results from this scanner demonstrate FIGURE 8.6. Quantum 64 (Toshiba Medical Systems) multidetec-
sensitivities of 92% and specificities of 98% for the detection tor CT image demonstrating a multiplanar reconstruction of the
of obstructive CAD.87 right coronary artery (RCA). This allows the entire vessel to be
viewed in one image.

Multidetector Computed Tomography Angiography

Multiple studies with four-slice MDCT have been reported, tively), and high specificities were maintained (94% and
with most studies reported a diminished overall sensitivity. 93%, respectively).
Achenbach et al.88 reporting 68% of vessels interpretable by These studies concluded the MDCT with beta-blocker
angiography, with 32 of 58 high-grade stenoses were detected premedication permits detection of CAD with improved
(sensitivity 55%). All four major coronary arteries could be accuracy. When using MDCT as a noninvasive diagnostic
evaluated in only 30% of patients. The authors note that “its
clinical use may presently be limited due to degraded image
quality in a substantial number of cases, mainly due to rapid
coronary motion.” Giesler et al.89 reported that 115 of 400
(29%) coronary arteries were uninterpretable, and in only
39% of patients were all coronary arteries assessable by
MDCT. Overall, 51 (49%) of 104 stenoses were revealed on
MDCT. Additionally, most studies demonstrate a significant
heart rate interaction. One study demonstrated that overall
sensitivity for stenosis detection decreased from 62% (heart
rate <70 bpm) to 33% (heart rate >70 bpm),89 while in another
sensitivity dropped from 82% (mean heart rate 55.8 bpm) to
32% (mean heart rate 81.7 bpm).90
The use of eight or more detectors improves spatial reso-
lution by decreasing slice thickness, and it allows for a higher
sensitivity and specificity. Average sensitivity and specificity
over the first six studies reported an average sensitivity of
80% and specificity of 86%, when including all segments for
analysis.91 Excluding those with motion artifacts and other
reasons for nonassessability increases the sensitivity and
specificity to approximately 90%. The use of eight 64-slice
MDCT scanners allows for faster and thinner imaging than
the four-slice scanners (Figs. 8.6 to 8.8). Three studies have
recently been reported with 16-level scanners,92,93,94 each
with improved accuracy as compared to prior reports with
4-level scanners. These studies reported a sensitivity of 73%
to 95% and a specificity of 86% to 93%. The most recent
study was a prospective, blinded, standard cross-sectional
technology assessment; analysis of all 530 coronary seg-
ments demonstrated moderate sensitivity (63%) and excel-
lent specificity (96%), with a moderate positive predictive
value of 64% and an excellent negative predictive value of
96% for the detection of significant coronary stenoses. FIGURE 8.7. Volume rendered image of the left coronary system
using a Lightspeed 16 multidetector computed tomography (General
Assessment restricted to either proximal coronary segments Electric, Milwaukee, WI) demonstrating mild, nonobstructive
or segments with excellent image quality (83% of all seg- disease. LAD, left anterior descending artery; OM, obtuse
ments) led to an increase in sensitivity (70% and 82%, respec- marginal.
19 0 chapter 8

FIGURE 8.8. Maximal intensity projection demonstrating signifi-

cant disease at the origin of the left anterior descending artery
(LAD). C, circumflex coronary artery; D, diagonal.

modality to assess advanced CAD, it appears to be manda-

tory to preselect patients (sinus rhythm, lower calcium score, FIGURE 8.9. Noninvasive angiography demonstrating patent saphe-
steady heart rates) in order to achieve reliable results, and to nous vein grafts to the first obtuse marginal (OM) and a patent
use scanners with eight or more detectors. internal mammary artery (white arrows) to the left anterior descend-
ing coronary artery (LAD).

Computed Tomography Angiography

after Revascularization tion for the clinical assessment of the according arterial
segment by EBA, MDCT, and MR angiography. Pump et al.100
Computed tomography angiography may play a role in the
reported a sensitivity of 78% (18 of 23 stenoses detected) and
assessment and follow-up of patients who have undergone
specificity of 98% (189 of 193 stents correctly assessed to be
coronary interventions, potentially replacing some invasive
angiographic procedures. The utilization of EBA to detect
coronary artery bypass graft (CABG) patency has been
reported as early as 1986.95 Saphenous vein grafts, which are
generally of large caliber and have minimal cardiac motion,
are especially well suited for noninvasive imaging with CT
angiography (Figs. 8.9 and 8.10). Using 3D visualization in
post-CABG patients, both MDCT and EBCT can demon-
strate graft stenosis and patency. Recent studies for both CT
techniques demonstrate sensitivities of 92% to 100% and
specificities of 91% to 100% for establishing patency of
saphenous vein grafts as compared to coronary angiogra-
phy.96,97,98 These studies demonstrated sensitivity and speci-
ficity for patency of left internal mammary of 80% to 100%
and 82% to 100%, respectively.
In patients who experience chest pain after stenting or
angioplasty, visualization of the site of angioplasty to assess
for restenosis is often required. A noninvasive method to
visualize the site of angioplasty could potentially be used for
less typical presentations of acute closure (no typical angina
or ECG changes suggestive of ischemia). Computed tomog-
raphy angiography has been shown to permit imaging of the
coronary arteries and detecting high-grade restenosis after
coronary angioplasty. Achenbach et al.99 reported 50 cases in
which a coronary angioplasty was performed without coro-
nary stent implantation. The sensitivity and specificity of
FIGURE 8.10. Noninvasive angiography demonstrating multiple
EBA was 94% and 82%, respectively, to detect severe stenosis closed saphenous vein grafts (black arrows) and a right coronary
(≥70% stenosis). The widespread utilization of metal stents artery (RCA) occlusion with a patent saphenous vein graft to the left
during revascularization procedures provides a major limita- anterior descending artery (white arrow).
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 191
without significant coronary artery stenoses.105,106 However,
segments containing exclusively noncalcified plaque were
identified with a sensitivity of only 53%, and MDCT sub-
stantially underestimated plaque burden. Accuracy for plaque
detection was lower for smaller plaques and in distal versus
proximal vessel segments.
The limitations of soft plaque detection may be much
more significant than a limited sensitivity or underestima-
tion of plaque burden. The reproducibility of the measure has
not been reported. Additionally, there are no prognostic data
assessing whether noncalcific plaque adds any prognostic
information to traditional risk factors, angiographic disease
severity, and calcified plaque quantitation. Finally, this pro-
cedure requires both contrast and radiation, and the risks
may outweigh the benefit in individual patients. These
factors require further investigation in order to define the
possible role and importance of CT coronary angiography as
FIGURE 8.11. Noninvasive angiography using the Lightspeed 16 a noninvasive modality for soft plaque imaging.
multidetector computed tomography demonstrating a stent (black
arrow) in the left anterior descending. It is not possible to determine
whether the stent is patent or partially occluded. Radiation Dose and Cardiac CT
Computed tomography utilizes x-rays, a form of ionizing
radiation, to produce the information required for generating
free of stenosis) for the detection of significant in-stent reste- CT images. One drawback of MDCT as compared to EBCT
nosis by flow measurements. The difficulties in imaging is the potential for higher radiation exposure to the patient,
stents (with scatter from the metal, coupled with motion depending on the tube current selected for the examination.
artifacts and small interior diameters) make CT angiography Hunold et al.6 recently performed a study of radiation doses
very limited in this application currently (Fig. 8.11).101 during cardiac exams. Cardiac scanning was performed with
Although some authors have reported mixed results with CT EBCT and four-slice multidetector CT (Siemens Volume
imaging within stents, current studies are limited, and the Zoom, Ehrlangen, Germany) utilizing prospective triggering
scatter artifact of the metal, coupled with the small diame- to assess patient effective radiation exposure, compared
ters and coronary motion, suggest that invasive coronary to measurements made during cardiac catheterization.
angiography is required to evaluate stent patency accurately.

Assessment of Noncalcified Plaque

Computed tomography angiography’s ability to visualize and
characterize “soft” noncalcific coronary plaque is an emerg-
ing area of interest (Fig. 8.12). Autopsy and coronary intra- 1000
vascular ultrasound (IVUS) studies have shown that
angiographically “normal” coronary artery segments may
contain a significant amount of atherosclerotic plaque;102 400
IVUS allows for a direct, 360-degree visualization of the
coronary atheroma within the vessel wall and identifies both
plaque distribution and composition.103 The utility of coro-
150
nary IVUS over coronary angiography in recognizing these A
smaller plaques is somewhat limited, though, by a higher R
procedural complication rate secondary to its more invasive J
nature. 60
The potential identification of early, nonobstructive coro-
nary plaques with CT angiography requires further investi-
gation. The noncalcified “soft” plaque in coronary arteries –10
is measured as the volume under 130 HU on nonenhanced
images corresponding to filling defects on enhanced images. 100 %
The noncalcified plaque can be divided into low (<0 HU) and
higher-density noncalcified plaques (0–130 HU). A compari-
son study with EBCT and IVUS demonstrated a linear rela-
tionship between coronary segments with calcified and with
FIGURE 8.12. Noninvasive angiography with significant stenosis
noncalcified plaques.104 In comparisons of MDCT with IVUS, consisting of noncalcified plaque (depicted as yellow) in the distal
investigators found a sensitivity of 82% to detect coronary right coronary artery. The red structures represent calcium and the
artery segments containing atherosclerotic plaque in patients green is the contrast.
19 2 chapter 8

Electron beam CT CAC protocols yielded effective doses of evaluating graft patency post-CABG; and for early detection
1.0 and 1.3 mSv for men and women, while MDCT CAC of obstructive CAD in the high-risk person. Given the current
protocols using 100 mA, 140 kV, and 500-ms rotation yielded utility of these techniques, we can expect a rapid growth in
1.5 mSv for men and 1.8 mSv for women. Invasive coronary both the knowledge and experience with noninvasive angi-
angiography yielded effective doses of 2.1 and 2.5 mSv for ography, leading to much wider clinical applications for the
men and women, respectively. The doses obtained for MDCT assessment of obstructive coronary artery disease.
angiography were significantly higher. Since radiation is con-
tinuously applied (retrospective gating) while only a fraction
Ventricular Structure and Function
of the acquired data is utilized, high radiation doses (doses
of 6 to 10 mSv/study) still limit the clinical applicability of Advances in image acquisition and data processing have
this modality.6,107 In females, the effective radiation doses is allowed for characterization of ventricular structures and
another 25% higher than in males, raising the mean dose function with CT angiography, with reproducible quantita-
from 8 mSv in men to 10 mSv per study in women.108 These tive measurement of left ventricular ejection fraction,115,116
radiation doses are two to five times higher than can be ventricular volumes,117,118 ventricular mass,119,120 wall thick-
expected for conventional angiography, and five- to tenfold ness,121 and regional wall motion122 in cardiomyopathic pro-
higher than doses obtained during EBCT angiography (1.1– cesses (Fig. 8.13). These data can be integrated with coronary
1.7 mSv). In two studies of radiation dose comparing EBCT artery assessment for a comprehensive assessment of the role
and four-slice MDCT, the first reported EBCT angiography that coronary artery disease plays in the cardiomyopathic
doses of 1.5 to 2.0 mSv, MDCT angiography 8.1 to 13 mSv, process.
and coronary angiography 2.1 to 2.3 mSv, while another Cine scanning allows for assessment of systolic and dia-
reported EBA doses of 1.1 mSv and MDCT doses of 9.3 to stolic function. The spatial resolution and contrast enhance-
11.3 mSv.6,109 Newer MDCT studies report that radiation ment adequately defines the endocardium of both the right
doses are still significant with newer 16+-level multidetector and left ventricles, so that precise measurement of biven-
scanners,110 and dose modulation should be employed when- tricular cardiac volume and ejection fraction is feasible.
ever possible.111 Rumberger et al.123 have demonstrated the feasibility of eval-
For MDCT, increased numbers of detectors (64-slice uating diastolic performance of the LV. Diastolic filling vari-
systems are now available) will allow for better collimation ables, such as those measured by blood pool scintigraphy, can
and spatial reconstructions. Having more of the heart visual- be determined with EBCT. Application of this technique
ized simultaneously will also allow for reductions in the may prove useful for detecting subtle changes in LV diastolic
contrast requirements and breath holding, further improving function induced by myocardial ischemia.
the methodology. Multisector reconstruction (combining Left ventricular mass can also be quantified. Quantita-
images from consecutive heart beats) and dose modulation tive measurement of regional wall motion and wall thicken-
(to reduce radiation exposure during systole, when images ing can be performed, which is particularly useful for
are not used for reconstruction) are increasingly being evaluating CAD patients. Application of this technique may
applied. prove useful for detecting changes in LV function induced by
myocardial ischemia, as well as accurately diagnosing ejec-
Limitations of CT Angiography
Some limitations are inherent to both CT modalities in
regard to coronary artery imaging. One major limitation is
dense calcification of the coronary arteries, with investiga-
tors citing scores of >500 or >1000 as problematic. Another
limitation of all noninvasive angiography is the relative
inability to visualize collaterals. The main determinant of
false-positive results for diagnosing ≥50% coronary luminal
stenosis was small vessel size, and the diameter of stenotic
segments tends to be underestimated by CT angiography.112

Applications of CT Coronary Artery Angiography

The most common clinical application of CT angiography is
to evaluate patients with symptoms post-CABG surgery and
coronary angioplasty evaluation, assessment of congenital
heart disease and coronary anomalies,113 and measurement
of wall motion, myocardial mass, as well as right and left
ejection fractions.114
Some current uses of noninvasive CT angiography include
the following: after the nondiagnostic stress test; for those
persons with intermediate likelihood of CAD (where the step FIGURE 8.13. Profound thickening of the interventricular septum
to coronary angiography might be premature); for symptom- (IVS) in a patient with hypertrophic cardiomyopathy.
atic persons postcoronary angioplasty and possibly poststent; LV, left ventricle; RV, right ventricle.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 19 3
making as well as approaches to intervention in patients
with dilated and ischemic cardiomyopathy.
Hypertrophic cardiomyopathy can lead to heart failure
symptoms and sudden cardiac death.127 Echocardiography is
RV
the main diagnostic modality for the diagnosis of hypertro-
phic cardiomyopathy, and in addition to anatomy can assess
resting and exercise gradients and associated valve func-
tion.128 The diagnosis can be made by CT angiography (Fig.
8.13)129,130 and MRI,131 which can provide details of regional
LV
wall thickness, indexed ventricular mass, and ejection
fraction.
Assessment of right ventricular structure and function
abnormalities has risen in importance due to the recognition
of significant disease processes involving the right ventricle.
Visualization and assessment of right ventricular function is
difficult by echo and cardiac catheterization. Computed
tomography angiography potentially may be an effective tool
for assessment of right ventricular anatomy and function.132
Right ventricular pathology, such as right ventricular dyspla-
FIGURE 8.14. Severely dilated left ventricle (LV) in a patient with sia, can be difficult to diagnose, and often the initial presen-
ischemic cardiomyopathy. The apical-lateral infarction can be well
tation is sudden death. In terms of visualization of right
visualized by the dark region (lower contrast enhancement due to
infarcted tissue, black arrow). RV, right ventricle. ventricular abnormalities, echocardiography lacks sensitiv-
ity.133 Magnetic resonance imaging has been the modality of
choice for anatomic evaluation of right ventricular dysplasia
tion fraction postinfarction.124 Bicycle exercise can be coupled due to its superior ability to define tissue characteristics such
with CT scanning to detect exercise-induced ischemia. A as myocardial fat deposits, but the variation in fat content
decrease in ejection fraction and development of a new wall and location in patients without this process makes this cri-
motion abnormality have been shown to be accurate for terion only of modest clinical utility.134 Computed tomogra-
detection of ischemia, with data indicating that exercise CT phy angiography has been assessed for the ability to diagnose
may be at least as sensitive and more specific than techne- anatomic features associated with right ventricular dyspla-
tium-99m sestamibi stress testing.125 A study was reported sia, such as epicardial and myocardial fat, low-attenuation
evaluating the diagnostic value of dobutamine stress EBCT trabeculations, and right ventricular free wall scalloping, but
as compared with exercise stress thallium-201 single-photon has not been assessed as a screening tool.132,135,136
emission computed tomography and found comparable sen- Cardiac CT can provide excellent depiction of ventricular
sitivity and specificity for the detection of myocardial aneurysms and pseudoaneurysms (Fig. 8.15). The 3D aspects
ischemia.126
Noninvasive quantitation of myocardial blood flow is
also possible by evaluating flow patterns of iodinated con-
trast on CT. Myocardial blood flow is proportional to the
peak iodine concentration in the myocardium after intrave-
nous injection of contrast medium. The technique is accu- Thrombus
rate for myocardial flows up to 2 mL/min/g. Technical factors
related to Compton scatter and beam hardening may cause
inaccuracies. Further research is necessary, for the develop-
ment of clinically useful methods for accurate quantification
of blood flow measurements. Based on the principle that
blood flow is proportional to iodine concentration during LV
contrast medium infusion, acute MI can be imaged by CT as
a region of little or no iodine (low density, Fig. 8.14). This
technique has been used to detect MI and to quantitate the
infarct size as well as the patency of the infarct vessel, using
both flow and 3D techniques. Complications of myocardial
infarction, including ventricular septal defects, thrombi,
aneurysms, and pericardial effusions, can all be easily visu-
alized by CT.
The ability to document abnormalities of ventricular
structure and function coupled with the ability to assess
coronary artery calcium and angiographic coronary artery
FIGURE 8.15. A patient with a transmural apical infarction dem-
disease make cardiac CT a useful tool in the assessment of onstrating a large thrombus in the apex. The white structure sur-
cardiomyopathic processes. Definition of the etiology of car- rounding the thrombus is calcified myocardium replacing normal
diomyopathy, to quantitate function, can facilitate decision tissue after a large infarction. LV, left ventricle.
19 4 chapter 8

of the aneurysm can be determined, and global and regional sities are similar. However, pericardial fluid, if free in the
function assessed. Ventricular thrombus can also be easily pericardial space, appears as layers, making differentiation
identified. There is some evidence indicating that CT is more from pericardial thickening relatively simple.
sensitive in detecting LV thrombus than transthoracic Cardiac CT is an excellent diagnostic technique for eval-
echocardiography.137 uation of pericardial cysts and tumors.139 Because CT images
the entire thorax and provides clear definition of mediastinal
structures, pericardial involvement by metastatic tumors is
Pericardial Disease easily identified. Congenital anomalies, such as absence of
the left hemipericardium, are well seen by this modality.
The combination of excellent spatial resolution, tomographic
format, and exquisite density differentiation makes EBCT an
ideal tool for diagnosis of pericardial disease. Because the Aorta and Aortic Valve Pathology
normal pericardium is 1 to 2 mm thick, spatial resolution
must be very good for any imaging technique to define this Computed tomography angiography can diagnose aneurysm,
structure. X-ray CT is aided by the fact that epicardial and dissection, and wall abnormalities such as ulceration, calci-
extrapericardial fat often outline the normal pericardium. fication, or thrombus throughout the full length of the aorta
Fat, being of very low density, serves as a natural contrast as well as involvement of branch vessels. The superior tem-
agent. Therefore, even minimal pericardial thickening (4 to poral and spatial resolution of cardiac CT significantly
5 mm) is well recognized by cardiac CT (Fig. 8.16).138 The high improves imaging of the aorta, because motion artifacts are
density of pericardial calcium makes its detection easy. The eliminated. Computed tomography is a superior method for
3D representation of anatomy by CT provides the surgeon identification of aortic dissection (Fig. 8.17).140 The intimal
with precise detail of the extent of calcification and the flap is usually well delineated, even in branches of the aorta.
degree of myocardial invasion. In the flow mode, flow can also be assessed in the true and
In addition to providing an excellent description of the false lumina.
anatomy of pericardial constriction, EBCT also defines the Cardiac CT is also an effective method of imaging aortic
degree of hemodynamic abnormality by describing diastolic aneurysms throughout the extent of the aorta (Fig. 8.18). It
filling from ventricular volume measurements every 50 ms is particularly useful for imaging ascending aortic aneu-
throughout diastole.123 Cine mode images of the right atrium rysms before and after surgical treatment. Accurate mea-
and RV can also detect diastolic collapse when pericardial surements of aortic root diameter can be made easily and the
tamponade is present. Enlargement of the superior and infe- extent of the aneurysm defined. The origin of the coronary
rior vena cavae can also be identified when either constric- arteries is also well visualized. Thrombus within any aortic
tion or tamponade is present. Pericardial effusion is easily aneurysm is easily identified by differences in tissue density
detected by CT. Occasionally, very small effusions cannot during contrast enhancement. The tomographic format of
be distinguished from pericardial thickening, as the CT den- CT provides excellent definition of the relationship of aortic
aneurysms to adjacent structures. Leakage of blood from the
aneurysm may be recognizable with contrast enhancement
of surrounding tissues.

Pericardium
PA

Ao

Pericardium RV D Ao

FIGURE 8.16. Severe pericardial thickening of the anterior and

posterior sections of the pericardium. Normal pericardium is very FIGURE 8.17. Large aortic dissection (black arrows), originating in
thin and barely seen on computed tomographic images. Thickened the ascending aorta (Ao) and ending in the descending aorta (D Ao).
pericardium is quite visible. PA, pulmonary artery; RV, right ventricle.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 19 5

Congenital Heart Disease

Due to advances in surgical management, many patients
with congenital heart disease are living into adulthood. The
ability to assess the 3D relationships among cardiac, arterial,
and venous structures makes CT angiography useful in the
diagnosis and follow-up of patients with congenital heart
disease in its native and postoperative forms.146
Computed tomography angiography is well-suited to the
evaluation of congenital abnormalities of the coronary arter-
ies (Fig. 8.20). A rare but important abnormality relating
specifically to coronary arteries is anomalous origin of the
coronary arteries, with sudden death in young persons during
exertion often being the initial presentation.147 Identification
can be difficult by other modalities. Specific anatomies
are associated with risk of sudden cardiac death including
takeoff of the left coronary artery from the pulmonary
trunk, left coronary artery from the right aortic sinus, and
FIGURE 8.18. An 8-cm ascending aortic aneurysm (Ao) is well right coronary artery from the left aortic sinus.148 Anomalous
delineated by ultrafast contrast-enhanced CT. DAo, descending coronary arteries can be defined noninvasively by CT
aorta; LA, left atrium; RV, right ventricular outflow tract; S, superior
vena cava. angiography,149,150 as well as by MRI151 and transesophageal
echocardiography.152
Considerable experience has been obtained with MRI.153
Pulmonary Arteries Very similar results are now seen with CT high-resolution
scanning.154 The disadvantages of CT are the requirement for
Computed tomography can also be utilized to image the injection of contrast medium and exposure to x-ray. Com-
pulmonary arteries. Large chronic thrombi, presumably puted tomography offers advantages over MRI, including a
resulting from previous embolization, have been success- single breath-hold to reduce respiratory motion, higher
fully detected by this technique (Fig. 8.19).141 The cross- spatial resolution,155 and reduced slice thickness.4 An addi-
sectional view of the main and proximal right and left tional advantage of CT is the overall study time of 1 to 2
pulmonary arteries provides clear delineation of the proxi- minutes as compared to 45 to 90 minutes for MR angiogra-
mal extent of the thrombi, which is essential for successful phy, reducing the time for patients (especially children) to lie
surgical treatment.142 Research has indicated that CT may perfectly still. As many congenital abnormalities are associ-
also be a valid method for diagnosis of acute pulmonary ated with significant conduction abnormalities or ventricu-
embolism.143,144 Accurate measurement of pulmonary artery lar arrhythmias, many patients with congenital heart disease
size may also be useful in estimating the severity of pulmo- have pacemakers or implantable cardiac defibrillators in
nary hypertension.145 place, contraindicating the use of MRI for imaging. However,
MRI may be more applicable to younger patients due to lack

Ao

PA

FIGURE 8.19. Large chronic pulmonary embolism (arrows) is FIGURE 8.20. Anomalous coronary artery with left main coronary
shown by contrast-enhanced ultrafast CT to involve the proximal artery arising from the right coronary cusp [black arrows depicting
right and left pulmonary arteries. Ao, ascending aorta; DAo, descend- the course of the artery between the aorta (Ao) and the pulmonary
ing aorta; PA, pulmonary artery; SVC, superior vena cava. artery (PA)].
19 6 chapter 8

of radiation exposure, but longer study times require a greater

need for anesthesia.156
Computed tomography imaging can almost always be
completed without the need for sedation. The high-resolu-
tion images provide excellent detail of the anatomic struc-
ture of the cardiac chambers and great vessels. The flow
mode can be used to detect and quantitate left-to-right and
right-to-left shunts.157 The cine mode can be used to evaluate
RV and LV function, as well as valvular motion. One of the
great strengths of cardiac CT is its capacity to study cardiac
anatomy, cardiovascular function, and blood flow during a
single study period.
A spectrum of cyanotic and acyanotic congenital anoma-
lies can be visualized and characterized by CT angiography
(Fig. 8.21).158 Studies can assess patency of shunts, pulmonary
hemodynamics associated with shunts, central pulmonary
artery anatomy, anomalous vascular connections, pulmo-
FIGURE 8.21. Secundum atrial septal defect with predominant left nary vein obstruction, partial anomalous pulmonary venous
to right shunting. Right atrial (RA) enlargement and right ventricu- connections, and other associated thoracic abnormalities
lar (RV) hypertrophy are present. Ao, ascending aorta; LA, left
atrium.
such as tracheobronchial abnormalities.159,160,161,162,163 CT
angiography can provide detailed and comprehensive assess-
ment of complex anatomy for surgical planning.164,165 Con-
genital abnormalities of the aorta such as coarctation can be
easily identified and assessed with 3D imaging (Fig. 8.22).166

Electrophysiologic Applications of Cardiac

Computed Tomography

Coronary Veins
The same techniques that allow visualization of coronary
arteries also visualize the coronary veins (Fig. 8.23). The
coronary venous anatomy has become increasingly impor-
tant as many interventional procedures use the coronary
veins to obtain venous access to the left atrium and left
ventricle. Computed tomography angiography is effective for
visualization of the coronary sinus and its tributaries.167,168
Computed tomography angiography can provide detailed

D Ao

CS

Lateral
vein

FIGURE 8.23. The coronary venous system is visualized with iden-

FIGURE 8.22. Coarctation of the aorta. Prominent vertebral artery tification of the coronary sinus (CS) and a large lateral cardiac vein.
vessels are noted entering the descending aorta (DAo). Distances and diameters can easily be measured.
 c o m p u t e d t o m o g r a p h i c c a r d i o va s c u l a r i m a g i n g 19 7
assessment of the coronary venous anatomy, with coronary achieved through software advances to visualize the com-
sinus dimensions, branch vessel locations, diameters, angu- plexity of each pulmonary vein os. Additionally, follow-up of
lations off the coronary sinus/great cardiac vein, and associ- patients for such complications as pulmonary vein stenosis
ated myocardial segment location.169 is extremely important.172 The incidence and time course of
Particular attention has been the focus on coronary pulmonary vein stenosis requires further definition, through
venous anatomy with the increasing application of resyn- serial evaluation of pulmonary vein structure.
chronization therapy. In resynchronization therapy, simulta-
neous biventricular pacing is performed in patients with
dilated or ischemic cardiomyopathy, significant heart failure, Summary
and prolonged interventricular conduction in order to “resyn-
chronize” right and left ventricular activation and contrac- Computed tomography coronary artery calcium assessment
tion. The left ventricular component of pacing is provided by and CT coronary angiography using EBCT or MDCT are
a chronic pacing lead placed in a coronary sinus branch technologies that can provide risk stratification for future
vessel, with placement often being challenging due to the cardiac events and definition of patient populations requir-
need to locate small coronary vein branches for adequate ing aggressive risk factor modification or interventional
pacing sites. As potential left ventricular pacing sites are therapy for CAD. Computed tomography angiography is a
defined by an individual patient’s coronary venous anatomy, robust technology that can identify a spectrum of cardiovas-
detailed anatomic information could potentially play a role cular disease processes and facilitation of invasive cardiac
in the approach to resynchronization therapy. Many patients procedures. Further advances in technology and methodol-
undergoing resynchronization therapy already have devices ogy will broaden the research applications for the under-
in place with upgrade to a biventricular system, precluding standing of cardiovascular pathophysiology and clinical
visualization of anatomy by MRI. applications for diagnosis and treatment of cardiovascular
disease. The availability of many other imaging modalities
Pulmonary Veins and the relatively high cost of CT scanners and limited or
lack of reimbursement have slowed its adoption for diagnosis
Characterization of pulmonary venous anatomy is important by cardiologists, radiologists, and primary caregivers.
to catheter-based therapies for atrial fibrillation. Atrial fibril- However, the technology offers some truly unique capabili-
lation has become a major area of research focus due to its ties, with unmatched prognostic capabilities for cardiac
increasing incidence in an aging population.170 Procedural events and noninvasive imaging of the coronary arteries and
efforts have focused on ablation of the pulmonary vein. Com- veins, and clinicians are increasingly employing this imaging
puted tomography angiography and MRI can provide detailed technique. Cardiac CT is considered by some to be the gold
information on pulmonary vein location, variation, size, and standard in evaluating congenital heart disease, pulmonary
complexity, which are difficult to visualize by other tech- vein anatomy, and coronary venous anatomy. Further experi-
niques; this is important for ablation of pulmonary vein ence and utilization will undoubtedly increase the interest
triggers and electrical isolation of pulmonary veins (Fig. and knowledge of this multifaceted tool.
8.24).171 Endoscopic views of the left atrium can now be
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computed tomographic angiography in neonates and infants Radiol 1997;7:1473–1477.
with complex congenital heart disease. Am Heart J 2000; 167. Gerber TC, Sheedy PF, Bell MR, et al. Evaluation of the coro-
139:654–660. nary venous system using electron beam computed tomogra-
157. Garrett J, Jaschke W, Aherne T, et al. Quantitation of intracar- phy. Int J Cardiovasc Imaging 2001;17:65–75.
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AJR 2001;177:1045–1049. 169. Shinbane JS, Girsky MJ, Mao S, Budoff MJ. Thebesian valve
159. Chen SJ, Li YW, Wang JK, et al. Three-dimensional reconstruc- imaging with electron beam CT angiography: implications for
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beam CT. J Comput Assist Tomogr 1998;22:560–568. 27(11):1566–1567.
160. Lim C, Kim WH, Kim SC, Lee JY, Kim SJ, Kim YM. Truncus 170. Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ.
arteriosus with coarctation of persistent fifth aortic arch. Ann Epidemiology and natural history of atrial fibrillation: clinical
Thorac Surg 2002;74:1702–1704. implications. J Am Coll Cardiol 2001;37:371–378.
161. Taneja K, Sharma S, Kumar K, Rajani M. Comparison of com- 171. Schwartzman D, Kuck KH. Anatomy-guided linear atrial
puted tomography and cineangiography in the demonstration lesions for radiofrequency catheter ablation of atrial fibrilla-
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162. Choe KO, Hong YK, Kim HJ, et al. The use of high-resolution monary vein stenosis after radiofrequency ablation for atrial
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SEC TION II

Congenital Heart
Disease in
the Adult
 9 Normal and
Abnormal Anatomy
Robert H. Anderson and Anton E. Becker

Normal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Abnormal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

Normal Anatomy posterior and descending. It has also led to the atrial and
ventricular chambers being described as “right” and “left,”
To understand the various anatomic abnormalities of the when in truth they are located more anteriorly and posteriorly
heart, we first need to appreciate the structure of the normal (Fig. 9.3B). Because the chambers are not always in their
heart. So as to describe the cardiac components in appropri- anticipated position when the heart is congenitally mal-
ate fashion, it is also necessary to appreciate the location of formed, we will describe them as being “morphologically
the normally structured heart within the thorax. Thereafter, right” and “morphologically left,” meaning that they possess
we can describe the location and morphology of the cardiac the anatomic features expected for the so-called right- and
chambers and arterial trunks, the arrangement of their vas- left-sided structures as seen in the normal heart. With regard
cular supply, and the location of the so-called specialized to the arteries, and other structures within the heart, we will
conducting tissues. follow the anatomic convention, and describe them in attitu-
In the normal individual, with usually arranged organs, dinally appropriate fashion,1 since with the increasing use in
so-called situs solitus, the heart is positioned within the clinical practice of tomographic techniques and three-dimen-
mediastinum, with one third of its bulk to the right and two sional reconstruction, the cardiologists of tomorrow will
thirds to the left of the midline. When projected to the frontal need to understand the structure of the heart within the body,
plane, the cardiac silhouette is trapezoidal, with the apex of not as it is visualized on the autopsy table. Thus, the so-called
the trapezium extending to the left (Fig. 9.1). The trapezium posterior descending coronary artery will be described as
can be divided into atrial and ventricular triangles, which being inferior and interventricular, which is the anatomically
meet one another in the plane of the atrioventricular and accurate terminology (Fig. 9.4).
ventriculoarterial junctions. This plane also represents the The morphologically right atrium (Fig. 9.5) lies predomi-
base of the ventricular mass (Fig. 9.1). According to conven- nantly in front of its alleged left-sided counterpart, although
tion, all structures within the body should be described rela- also somewhat right-sided and inferior, with the atrial septum
tive to the anatomic position, with the subject viewed positioned more or less in the frontal plane. In addition to its
standing upright and facing the observer (Fig. 9.2). The subject well-recognized venous component, it also has a muscular
thus positioned has three orthogonal planes: the first frontal, vestibule, which supports the leaflets of the tricuspid valve,
with right and left borders; the second lateral, with anterior and an extensive appendage. The appendage, the most con-
and posterior borders; and the third in the short axis. Relative stant component of the right atrium, has a broad base, and
to the orthogonal planes themselves, there is any number of is lined throughout by the prominent pectinate muscles,
companion planes. For example, those in the short axis extend which take their origin in parallel fashion from the broad
from the head, which is superior and cranial, to the feet, muscle bundle, the terminal crest, which separates the
which are inferior and caudal. Unfortunately, those describ- appendage from the smooth-walled venous component. The
ing the heart over the years have not followed this conven- appendage forms the entirety of the anterior wall of the right
tion, but instead have described the heart in terms of its own atrium, with the pectinate muscles radiating from the ter-
orthogonal planes, with the heart considered as removed minal crest to reach the vestibule all around the right atrio-
from the body and positioned on its apex (Fig. 9.3A). This leads ventricular junction.
to the unfortunate situation in which the diaphragmatic Entering the superior part of the smooth-walled systemic
surface of the heart, located inferiorly, is usually described as venous component is the superior caval vein, with the infe-
being the posterior part, with the artery irrigating the mid- rior caval vein entering inferiorly, and the coronary sinus
portion of this surface, in reality positioned in inferior and opening inferiorly and posteriorly, having traversed the left
interventricular position (Fig. 9.4), usually described as being atrioventricular groove. The location of the terminal crest is

205
206 chapter 9

Ventricular
Atrial triangle
triangle

A B
FIGURE 9.3. The cast has been made by filling the so-called right
se

heart chambers with red silicon, and the left heart chambers with
Ba

blue silicone. Only when the heart is removed and positioned on

its apex (A) is it possible to see the four chambers in right-left posi-
tion, with the atria above the ventricles. This is wrong. When the
Apex heart is appropriately positioned within the chest (B), the so-called
right chambers are positioned in front of their allegedly “left”
Diaphragmatic surface
counterparts.

marked externally by a prominent groove, the terminal

groove. The sinus node lies in the groove, usually lying just
inferior to the crest of the appendage, although in one tenth
of the population it extends in horseshoe fashion across the
crest. The node is sandwiched subepicardially between the
FIGURE 9.1. The silhouette of the cardiac shadow has been super- musculature of the superior caval vein and the terminal
imposed on the chest radiograph. The silhouette is trapezoidal,
crest. The orifice of the inferior caval vein may be guarded
formed by atrial and ventricular triangles meeting at the base of the
ventricular mass. by a flap-like valve, the eustachian valve, whereas the orifice
of the coronary sinus is often guarded by another flap-like
valve, the thebesian valve. When present, these two valves
come together to form a tendinous structure that extends
from their point of union into the atrial musculature, running
Coronal
Head
Anterior Posterior
Feet
- Sagittal

Transverse Short axis

Right Left
ventricle ventricle
Long axis

FIGURE 9.4. The short axis of the ventricular mass as seen in the
left anterior oblique orientation, and pictured relative to the ana-
tomic landmarks of the thorax. As can be seen, the right ventricle
FIGURE 9.2. The standing anatomic position, facing the observer. is located anterior to the left ventricle, and the so-called posterior
By convention, all structures within the body, including the heart, descending coronary artery (arrow) in reality is positioned in infe-
should be described relative to the three orthogonal planes shown rior and interventricular position, occupying the diaphragmatic
here. surface of the ventricular mass.
 nor m a l a n d a bnor m a l a natom y 207
superiorly and anteriorly within the muscular wall between
the oval fossa and the septal hinge of the tricuspid valve. This
is the tendon of Todaro, which forms the posterior border of
an important triangle, the triangle of Koch (Fig. 9.5). The
atrioventricular node lies at the apex of this triangle.
In the center of the posterior wall of the right atrium is
the oval fossa (Fig. 9.5). The fossa marks the site of the atrial
septum, with obvious borders around its superior, anterior,
and inferior margins, the so-called rims of the oval fossa, or
the superior and inferior limbic bands. The superior rim is
often described as the “septum secundum.” In reality, it is
no more than the deep infolding between the attachments of
the caval veins to the right atrium and the right pulmonary
veins to the left atrium (Fig. 9.6). The atrial septum itself is
the thin fibromuscular floor of the fossa, which overlaps the
margins of the fossa on the left atrial side (Fig. 9.7). The flap
is also described as the valve of the oval foramen. The antero-
FIGURE 9.5. The morphologically right atrium is shown having inferior margin of the foramen is also a true septal structure,
made a cut in the appendage and reflecting the wall to reveal the but the right atrial wall in this location then runs over the
posterior septal surface. Note that the wall of the appendage is base of the ventricular septum to insert into the vestibule of
marked by the multiple pectinate muscles, in contrast to the smooth- the septal hinge of the tricuspid valve. This is the area of
walled contours of the systemic venous component, the vestibule of
the tricuspid valve, and the septum. The location of the triangle of offsetting of the mitral and tricuspid valves identified by the
Koch is marked by the red dotted lines, the mouth of the coronary echocardiographer as one of the features of the normal heart
sinus forming the base of the triangle. (Fig. 9.8).
In the fetus, a channel in the anterior aspect of the oval
fossa provides the extensive and essential interatrial com-
munication. This opening is the oval foramen. In about one
Superior caval vein third of adults, this channel persists as a probe-patent oval

Right
pulmonary
vein

Flap valve

Infolded
superior
rim
Antero-
inferior
rim

Inferior caval vein

FIGURE 9.6. The atrial chambers have been sectioned in so-called

four-chamber fashion to reveal the structure of the atrial septum. FIGURE 9.7. A probe has been passed through the oval foramen,
As can be seen, the so-called septum secundum is no more than the which in this heart is probe patent, and the heart photographed from
deep fold between the attachments of the caval veins to the right the left atrium. The flap valve overlaps the margin of the oval fossa
atrium and the right pulmonary veins to the left atrium. (see also Fig. 9.9).
208 chapter 9

FIGURE 9.8. This four-chamber section is taken through the area

offsetting the attachments of the tricuspid and mitral valves to the
right and left sides of the septum, respectively. The edge of the atrial
wall overlaps the crest of the ventricular mass in the area marked
by the arrows. Note the extension of the inferior atrioventricular
groove separating the muscular walls in this area, and carrying the
artery to the atrioventricular node.

foramen (Fig. 9.9). Potential effects of such patency are dis-

cussed below (see Interatrial Communications).
The valve supported by the vestibular musculature of the
right atrium is the tricuspid valve. It has three leaflets, each
supported by tendinous cords and papillary muscles of the
right ventricle. The right ventricle itself has inlet, outlet, and
apical trabecular components (Fig. 9.10). The inlet portion lies
posteriorly, rightward and inferiorly, while the outlet portion
is located anteriorly, superiorly, and leftward. The coarsely FIGURE 9.9. The right atrial aspect of the probe-patent oval foramen
trabeculated apical part is the most constant component of illustrated from the left side in Figure 9.7. Note how the probe passes
between the margins of the oval fossa and the flap valve, the latter
the right ventricle in congenitally malformed hearts. forming the floor of the fossa. Such probe-patency is present in up
The septal wall of the right ventricle has well-defined fea- to one third of the normal adult population.
tures. At the atrioventricular junction, at the site of the zone
of apposition between the septal and anterosuperior leaflets,
the septum is composed of fibrous tissue, and is known as the
membranous septum. In part, this structure separates the two
ventricles, but because it is crossed by the hinge line of the
septal leaflet of the tricuspid valve, part of the septum inter-
poses between the right atrium and the left ventricle. This is
the fibrous atrioventricular septum (Fig. 9.11).
Superior to the membranous septum is the medial papil- Outlet
lary muscle, also known as the papillary muscle of the conus,
the muscle of Luschka, or the muscle of Lancisi. This receives
tendinous cords from the adjacent portions of the septal and
anterosuperior leaflets of the tricuspid valve. The medial
papillary muscle takes its origin from a prominent muscle
bundle that reinforces the right ventricular aspect of the
muscular ventricular septum. This muscle band takes the Inlet
shape of an inverted Y, with the supraventricular crest, Apical
the muscular wall of the right ventricle interposing between component
the attachments of the tricuspid and pulmonary valves,
inserting between the two limbs of the Y. The Y-shaped
muscle itself is the septomarginal trabeculation, or septal
band. The anterior limb of the Y extends to support the leaf-
FIGURE 9.10. The morphologically right ventricle extends from the
lets of the pulmonary valve, while the stem of the Y extends atrioventricular to the ventriculoarterial junctions (red lines). It is
to the ventricular apex, where it gives rise to the anterior best analyzed in terms of its inlet, apical trabecular, and outlet
papillary muscle of the tricuspid valve. Arising from the components.
 nor m a l a n d a bnor m a l a natom y 209
The right ventricular outlet, or infundibulum, is a cylin-
drical muscular tube that extends from the level of the Y of
the septomarginal trabeculation to support the leaflets of
the pulmonary valve. Part of the infundibulum is formed
by the supraventricular crest, which separates the leaflets of
the tricuspid and the pulmonary valves.
The pulmonary valve is in the most anterior and superior
part of the four cardiac valves. It separates the cavity of the
right ventricle from that of the pulmonary trunk, the latter
being a relatively short vessel that bifurcates into the left and
right pulmonary arteries. The arterial duct of fetal life and
early infancy, which becomes the arterial ligament, connects
the superior aspect of the left pulmonary artery and the
inferior part of the aorta at the junction of its distal arch and
descending portions.
FIGURE 9.11. This section shows the so-called membranous The morphologically left atrium (Fig. 9.13) lies posterior
septum. This is the part of the septum made of fibrous tissue. It is and somewhat to the left and superior relative to the mor-
crossed on its right-sided aspect by the hinge of the septal leaflet of
the tricuspid valve, dividing it into atrioventricular and interven- phologically right atrium. Like the right atrium, it possesses
tricular components. a venous component, a vestibule, and an appendage, but the

anterior margin of the septomarginal trabeculation are a

series of septoparietal trabeculations. One of these crosses to
the anterior papillary muscle, and is known as the moderator
band (Fig. 9.12). Venous component
Appendage

SVC

SMT

Body
Tricuspid
valve

Vestibule Septum
FIGURE 9.12. The right ventricle has been opened to show the
septal surface. The supraventricular crest (SVC) inserts between the
limbs of a prominent septal trabeculation, known as the septomar-
ginal trabeculation (SMT), or septal band. Note the series of septo-
parietal trabeculations (asterisks) extending from the anterior FIGURE 9.13. The left atrium is the most posterior of the cardiac
margin of the strap-like septal trabeculation. One of these septopa- chambers. It has a venous component, a tubular appendage, the
rietal trabeculations (yellow asterisk) extends to the anterior papil- vestibule of the mitral valve, and the flap valve aspect of the atrial
lary muscle. This is the so-called moderator band. septum, and also possesses an extensive body.
210 chapter 9

left atrium also has an extensive body. The venous compo-

nent receives the pulmonary veins at the four corners of its
roof. In most instances, the veins open superiorly and infe-
riorly on the right and left sides, although anatomic varia-
tions in their number are common.
The left atrial appendage joins the body of the atrium
anteriorly and inferiorly relative to the entrance of the left
inferior pulmonary vein. The left atrial appendage is much
narrower than the right atrial appendage, and is often crenel-
lated along its length. The pectinate muscles of the left
atrium are confined within the appendage, so that the pos-
terior atrial wall is smooth throughout the vestibular, body,
and venous component. Although emptying to the right
atrium, the coronary sinus is an integral part of the left
atrioventricular junction (Fig. 9.14). The flap valve of the oval
foramen forms the characteristic left atrial side of the septum,
with its leftward and superior margin overlapping the right
atrial rims of the fossa, albeit without being fused to the rims
in the three tenths of the population that has probe-patency
FIGURE 9.15. The short axis of the ventricular mass is shown as it
of the oval foramen (Fig. 9.9). lies within the body. Although the papillary muscles of the mitral
The left atrial vestibule supports the two leaflets of the valve are usually described as being posteromedial and anterolat-
mitral valve, with the solitary zone of apposition between eral, this reflects the bad habit of describing the heart as if posi-
the leaflets supported at its two ends by tendinous cords tioned on its apex (Fig. 9.3B). In reality, the papillary muscles, as
shown, are positioned inferoanteriorly and superoposteriorly.
attached to the two left ventricular papillary muscles. The
two muscles are usually described as being anterolateral and
posteromedial. When considered in the setting of the heart
within the body, however, the muscles are positioned antero- inferiorly and posterosuperiorly (Fig. 9.15). The free edges of
both leaflets are attached by tendinous cords to the same
papillary muscles.
The left ventricle itself, like the right ventricle, possesses
inlet, outlet, and apical trabecular components (Fig. 9.16).
The apical component is somewhat conical, with its apex
forming the apex of the cone. The left ventricular outflow
tract to the aorta lies behind the right ventricular infundibu-
lum. Unlike the right ventricle, the outlet from the left ven-
tricle is made up in part by muscle, and posteriorly by the

Outlet

Inlet
Apical
component

FIGURE 9.14. The cast shown in Figure 9.3 is photographed to show

its diaphragmatic aspect. Note that the coronary sinus, although
occupying the left atrioventricular groove, opens into the morpho- FIGURE 9.16. As with the morphologically right ventricle, the
logically right atrium. It commences at the union of the great vein left ventricle extends from atrioventricular to ventriculoarterial
with the oblique vein of the left atrium (Marshall’s vein). ICV, infe- junctions, and possesses inlet, apical trabecular, and outlet
rior caval vein. components.
 nor m a l a n d a bnor m a l a natom y 211
area of fibrous continuity between the leaflets of the aortic
and mitral valve (Fig. 9.17). Because of this arrangement, the
leaflets of the mitral valve can conveniently be described as
Pulm.
being aortic and mural. The leaflets of the aortic valve take
trunk
their origin from the muscular ventricular septum and pari-
etal wall of the left ventricle anteriorly and laterally, whereas
posteriorly is found the aortomitral intervalvar fibrous area.
This area is thickened at its right end as the right fibrous
trigone, which joins the membranous septum to form the
so-called central fibrous body (Fig. 9.17).
The mural leaflet of the mitral valve takes its origin from
the left atrioventricular junction, the point of attachment at
the junction often being called the mitral annulus or ring,
although it is rarely a complete fibrous ring. The aortic valve
has three semilunar leaflets, best named according to whether L R
or not the sinus supporting them gives rise to a coronary
artery. Thus, the leaflets are described as being left coronary,
right coronary, and noncoronary (Fig. 9.18). NC
The left and right coronary arteries originate from the
left and the right aortic coronary sinuses, respectively. The
main stem of the left coronary artery is short before its divi-
sion into the anterior interventricular and circumflex coro-
nary arteries (Fig. 9.19). A third branch, sometimes called the FIGURE 9.18. The base of the heart is shown from above, having
intermediate coronary artery, may be present should the removed the arterial trunks. Note that coronary arteries (arrows)
main stem trifurcate instead of bifurcating. The anterior arise from two of the three aortic sinuses, permitting these to be
named as the left (L) and right (R) aortic sinuses. The third sinus is
interventricular artery, also called the anterior descending the noncoronary (NC) sinus.
artery, passes in the anterior interventricular groove toward
the cardiac apex. The circumflex artery runs within the left
atrioventricular groove. The right coronary artery runs in ously as the “posterior descending” coronary artery. This
the right atrioventricular groove toward the posterior and arterial pattern is termed right dominance (Fig. 9.20). In the
inferior aspect of the heart. Most often, it turns abruptly less common left dominant pattern, it is the circumflex
downward in the inferior interventricular groove as the artery, which continues in the left atrioventricular groove to
inferior interventricular artery, usually described errone- give rise to the inferior interventricular artery.

FIGURE 9.17. In this heart, the leaflets of the aortic valve have been
removed, revealing the fibrous triangles (hatched lines) that extend
between the valvar sinuses to the level of the sinutubular junction. Circumflex
The triangle between the right and noncoronary sinuses is continu-
ous with the membranous septum (see Fig. 9.11), the conjoined area
being described as the central fibrous body. This, together with the Anterior interventricular
right fibrous trigone, forms the right end of the area of fibrous con-
tinuity between the leaflets of the aortic and mitral valves, The two FIGURE 9.19. The main stem of the left coronary artery is very
fibrous trigones anchor the area of valvar fibrous continuity in the short (double-headed arrow), branching almost immediately into the
roof of the left ventricle. circumflex and anterior interventricular arteries.
212 chapter 9

Abnormal Anatomy
This section discusses obstructive lesions, lesions promoting
valvar regurgitation, abnormal communications between
the chambers and the arterial trunks, abnormal connections
between the different cardiac segments, combinations of
anomalies, abnormal aortic and arterial branching, and syn-
dromes with cardiac disease.

Obstruction
Congenital obstructions in the cardiovascular system that
are seen in the adult include valvar, paravalvar, and vascular
conditions.

Valvar and Paravalvar Obstructions

FIGURE 9.20. The right atrioventricular junction has been dis- Congenital valvar obstruction may affect any valve, but most
sected to show the course of a dominant right coronary artery. Note
commonly it is the aortic valve that is involved. Lesions
that, at the crux, the artery gives rise to the inferior interventricular
artery, then continuing into the left atrioventricular groove to producing aortic stenosis can be broken down into subvalvar,
supply the diaphragmatic surface of the left ventricle. valvar, and supravalvar entities. There can also be atresia of
any of the cardiac valves. Atresia of the left-sided valves used
to be lethal in early life, but this has now changed with the
increasing use and improvement of the Norwood sequence
of operative interventions. Because of this, patients with
The coronary veins run in the epicardium, either over the so-called hypoplasia of the left heart will now be seen as
ventricles or in the different cardiac grooves, and largely adults with increasing frequency by the cardiologist. With
terminate for the most part in the coronary sinus. As already the success of the Fontan procedure, those with atresia of the
emphasized, the sinus itself, although draining to the right tricuspid valve are already presenting as adults to the cardi-
atrium, is an integral part of the left atrioventricular groove ologist, and atresia of the pulmonary valve can itself be well
(Fig. 9.14). The coronary veins draining the wall of the right tolerated, allowing some patients to survive to adulthood
atrial appendage open directly into the cavity of the right even without surgical intervention.
atrium, as do the smallest coronary veins, known as thebes-
ian veins, some of which may also drain directly into the left AORTIC STENOSIS
atrium. It is the remaining larger veins that drain directly The major cause of obstruction at the aortic valve in the
into the coronary sinus (Fig. 9.21). They are the great cardiac adult is the congenitally bifoliate, or bicuspid, aortic valve.
vein, which accompanies the anterior interventricular artery; Although this condition may be intrinsically obstructive,
the middle cardiac vein running with the inferior interven- this is not usually the case in individuals who reach adult-
tricular artery; and the small cardiac vein, which accompa- hood with a congenitally bicuspid aortic valve. The congeni-
nies the right coronary artery. tally bicuspid aortic valve, nonetheless, has a strong tendency
over time to become calcified and stenotic. It is probable that
an aortic valve with only two leaflets is present in about 1%
to 2% of the adult population.2 Most but not all of these
valves become calcified with time, producing the rigidity
that causes aortic stenosis.3 This type of aortic stenosis in
the adult accounts for approximately half of prosthetic valvar
replacements.4,5 The calcified valve has two leaflets, with one
Oblique vein being the so-called conjoined leaflet. A ridge, or raphe, typi-
cally extends from the sinutubular junction onto the center
of the aortic aspect of the conjoined leaflet (Fig. 9.22). The
conjoined leaflet usually lies anteriorly, with the conjoined
Great sinus supporting it giving rise to both coronary arteries. Less
vein
commonly, the leaflets lie in a lateral orientation, and then
one coronary artery arises from each of the two aortic
Small vein sinuses.
Another anomaly of the aortic valve is the so-called
unicuspid and unicommissural arrangement, in which the
valve has the shape of a keyhole. This valve is intrinsically
Middle vein
Coronary sinus stenotic, the degree of obstruction varying from case to case,
FIGURE 9.21. The venous tributaries that drain to the coronary but is more typically the cause of aortic stenosis in infants
sinus. (See also Figure 9.14.) and children. Occasionally, however, a lesser degree of ste-
 nor m a l a n d a bnor m a l a natom y 213
myocardial disarray. The degree of this change varies quali-
Level of sinutubular junction
tatively and quantitatively, as does its specific location.
Raphe The condition is now well established as a genetically
transmitted condition, characterized by a clinically con-
tinuous spectrum that includes asymptomatic individuals,
symptomatic patients without obstruction to outflow, and
symptomatic patients with typical obstructive lesions.7
Obstruction of the left ventricular outflow tract is caused in
part by the systolic anterior motion of the aortic leaflet of
the mitral valve. As this leaflet of the mitral valve impinges
against the ventricular septum, it not only obstructs the
outflow tract, but also irritates mechanically the septal
endocardium, producing a fibrous imprint over the promi-
nence of the ventricular septum (Fig. 9.24).
Fibrous Subaortic Stenosis. So-called discrete, or
FIGURE 9.22. This congenitally bifoliate aortic valve, photographed fixed, subaortic stenosis is characterized by encirclement of
from above, shows the raphe on the aortic aspect of the conjoined the left ventricular outflow tract with dense fibrous tissue.
leaflet.
The fibrous tissue produces a diaphragmatic shelf that is
attached to the endocardium over the ventricular septum
and the parietal wall of the left ventricle, as well as involving
nosis can be tolerated for years, even into adulthood. Eventu- the ventricular aspect of the aortic leaflet of the mitral valve.
ally, calcification may develop, and the patient with aortic The fibrous tissue not only narrows the left ventricular
stenosis then becomes symptomatic (Fig. 9.23). The calcifica- outflow tract but also often extends to become attached in
tion does not change the caliber of the intrinsically stenotic irregular fashion to the leaflets of the aortic valve (Fig. 9.25).
valve. Because it also allows regurgitation, the increased flow Contracture of this fibrous tissue may lead to aortic regurgi-
through the orifice is responsible for the transformation from tation. The degree of obstruction may increase with age8,9 as
asymptomatic to symptomatic disease.6

SUBAORTIC STENOSIS
Adults exhibit two principal types of subaortic stenosis:
muscular and fibrous. An uncommon third type, tunnel sub- Right ventricle
aortic stenosis, has also been described.
Muscular Subaortic Stenosis. This entity has been
described under myriad names,7 including idiopathic hyper-
trophic subaortic stenosis, muscular subaortic stenosis,
asymmetric septal hypertrophy, and hypertrophic obstruc-
tive cardiomyopathy. Asymmetrical septal hypertrophy is
characterized by asymmetrical hypertrophy of the muscular
ventricular septum associated with histologic features of Septum
Aorta

Parietal
wall Left atrium

FIGURE 9.24. This heart with hypertrophic cardiomyopathy has

been sectioned to replicate the parasternal long axis echocardio-
FIGURE 9.23. This unicuspid and unicommissural valve, seen in graphic section. Note the asymmetric septal hypertrophy, and the
an adult, has become calcified. It is the calcification of the leaflets, ridge on the septal surface facing the aortic leaflet of the mitral
producing immobility that heralds the onset of symptoms. valve.
214 chapter 9

atherosclerosis, with the potential for early manifestations

of coronary arterial obstruction. The intimal aspect of the
aortic lesion may encroach on the orifices of the coronary
arteries. In exceptional cases, the free edge of the aortic
leaflet may be attached along its full length to the sinutubu-
lar junction, thus producing effective coronary arterial
atresia. Infective endocarditis is another potential complica-
tion of the hourglass variant.

PULMONARY STENOSIS
Individuals with isolated, so-called dome-shaped pulmonary
stenosis, even untreated, may survive to adulthood. Although
dome-shaped stenosis of the pulmonary valve can also com-
plicate patients with deficient ventricular septation, when
seen in isolation the ventricular septum is usually intact.
FIGURE 9.25. The subaortic outflow tract has been opened from
There is then major right ventricular hypertrophy. Indeed,
the front to show the typical fibrous diaphragm that produces dis- there may be acquired subpulmonary stenosis secondary to
crete subaortic stenosis. Note that the shelf extends onto the aortic the myocardial hypertrophy. With few exceptions, the valve
leaflet of the mitral valve, and also onto the leaflets of the aortic takes the shape of a truncated cone with a central orifice,
valve. unlike the keyhole arrangement seen in the aortic valve.
Three equidistant raphes are characteristically present at the
initial zones of apposition of the trifoliate pulmonary valve
(Fig. 9.26). In exceptional cases, there may be four raphes,
the result of contracture of the fibrous tissue. In addition,
indicating initial presence of a quadrifoliate valve, or a single
turbulence of the blood flowing through the narrow channel
raphe, indicating stenosis in the setting of a pulmonary valve
may lead to an increase in deposition of fibrous tissue. Among
with two leaflets. Poststenotic dilation of the pulmonary
the significant complications of shelf-like subaortic stenosis
trunk is common, extending more into the left than into the
are major left ventricular hypertrophy and sudden death.
right pulmonary artery.15
Infective endocarditis is a complication seen in the adult,10
When the oval foramen is patent in the setting of pulmo-
and it is more common in fibrous than muscular subaortic
nary stenosis with intact ventricular septum, a right-to-left
stenosis.
shunt may develop at the atrial level. Even though the right-
Tunnel Subaortic Stenosis. The tunnel variant is to-left shunt is minor, such patients may develop cerebral
characterized by a long tubular narrowing in the subaortic
region.11 The orifice of the valve itself is also relatively
narrow, and the valvar leaflets typically show fibrous thick-
ening. Marked left ventricular hypertrophy is the rule, often
with associated asymmetric septal hypertrophy.

SUPRAVALVAR AORTIC STENOSIS Fused leaflets

This is the least common form of congenital obstruction of
the left ventricular outflow tract. There are two major vari-
ants, the tubular and hourglass types, although rarely there
can be a diaphragmatic variant. The tubular variant fre-
quently involves also the pulmonary trunk and arteries. It is
doubtful whether patients with this form survive to adult-
hood. Patients with the hourglass type, nonetheless, cer-
tainly do survive to adulthood,12 and this variant may also
be associated with obstruction of the branches of the aortic
arch and the pulmonary arteries. Experience in children and
adolescents has shown that, in untreated patients, the degree
of obstruction of the left ventricular outflow tract increases
with age, whereas the associated pulmonary arterial stenosis
may become less severe.13,14
One of the significant problems with supravalvar stenosis
is that, in reality, the major level of obstruction is at the
distal attachments of the valvar leaflets to the sinutubular
junction. Thus, the lesion is valvar just as much as it is Narrowed orifice
supravalvar. Because of the involvement of the sinutubular
junction, the coronary arterial orifices lie within the hyper- FIGURE 9.26. This picture, taken in the operating room, shows the
tensive compartment during both systole and diastole. The fused ends of the zones of apposition between the valvar
condition, therefore, is associated with premature coronary leaflets that produces typical pulmonary valvar stenosis.
 nor m a l a n d a bnor m a l a natom y 215
abscess.16 This infectious process is a recognized complica-
tion in instances of chronic right-to-left shunts without a
focus of infection within the heart. In other instances, infec- Arterial ligament
tive endocarditis may develop on the valvar leaflets, or infec-
tious pulmonary arteritis may occur at the area where the
jet-like stream has an impact at or near the pulmonary arte-
rial bifurcation.
In patients treated by adequate pulmonary valvotomy,
right ventricular hypertrophy may remain for years. Sudden
death has occurred in such cases, perhaps as a consequence
of residual myocardial hypertrophy.

M ITRAL STENOSIS
In the past, most cases of mitral valvar stenosis were consid-
ered to be of acquired or rheumatic origin. This is still likely
to be the case in less well-developed countries. In the Western
world, however, cardiologists are increasingly confronted by
adult patients with surgically treated congenital malforma-
tions of the mitral valve.
The so-called parachute valve is among the causes of
congenital mitral stenosis observed in adults. The condition
is characterized by a solitary papillary muscle, into which
all the tendinous cords from both leaflets of the valve con-
verge and insert. It may be associated with three other
obstructive anomalies in the left side of the heart, aortic
coarctation, subaortic stenosis, and supravalvar left atrial
ring, together forming the so-called Shone syndrome.17
Narrowed orifice
T RICUSPID STENOSIS
Seen most frequently in the setting of Ebstein’s malforma-
FIGURE 9.27. The descending aorta is viewed from beneath to show
tion, it is common for patients with this variant of tricuspid the typical curtain formed from the aortic media that produces
stenosis to reach adulthood. Typically, however, Ebstein’s coarctation in the adult.
malformation produces regurgitation as well as stenosis,
with the regurgitation being more common. We will discuss
Ebstein’s malformation, therefore, in greater detail later.
Tricuspid atresia is a relatively common condition in the represent the major channels carrying blood from the proxi-
young, but until recently was rare in adults. Nowadays, mal to the distal compartments of the aorta. Dilation and
however, many patients with tricuspid atresia are becoming tortuosity of the internal thoracic arteries represent part of
the province of the cardiologist as they survive into adult- the subclavian source of blood to the lower body.19 The ori-
hood with the Fontan circulation. We will also discuss the fices of the intercostal and lumbar arteries are also typically
underlying anatomy of this lesion in greater detail later. wider than normal, and the left ventricle is hypertrophied.
A congenitally bifoliate aortic valve is common, reputedly
present in at least half of cases.20 The anterior spinal artery
Aortic Coarctation
may also contribute to the collateral circulation, making it
Among the various arterial obstructive anomalies that allow enlarged and tortuous. It connects with arteries at levels both
patients to survive into adulthood, coarctation of the aorta above and below the coarctation, including branches of the
is the most common. The usual site of coarctation is at the vertebral, intercostal, and lumbar arteries.
union of the arterial duct with the aorta, although in adults The potential complications of coarctation are numerous,
the duct has typically become ligamentous, so it is difficult and include changes in the commonly occurring congeni-
to judge the precise location of the initially obstructing shelf. tally bifoliate aortic valve, such as calcific aortic stenosis,
Externally, in such adults, there is an indentation of the primary aortic valvar regurgitation, and infective endocardi-
superior wall of the aorta at the site of the obstruction. Inter- tis.3 Various aortic complications include saccular aneurysm
nally, this site corresponds to a curtain-like protrusion of the and aortic dissection.21 The latter condition is confined to
aortic media toward the lumen. The curtain extends from the compartment in which it begins. Usually this is the
the anterior, superior, and posterior walls of the aorta but not proximal compartment, leading to the potential for obstruc-
from the inferior aspect, the latter being the site of initial tion of the coronary arteries, and of the brachiocephalic
insertion of the arterial ligament. The position of the medial arteries arising from the aortic arch. External rupture leading
curtain causes the narrowed aortic lumen to lie eccentrically to fatal hemopericardium is usual when a dissecting aneu-
near the inferior wall (Fig. 9.27).18 rysm originates in the proximal compartment. In the aorta
Beyond the obstruction, there is poststenotic dilation of distal to the coarctation, infection may arise at the site of jet
the aorta. The subclavian arteries are typically wide, as these impact of the blood passing through the narrow segment.
216 chapter 9

The infection may lead to a localized mycotic aneurysm. leaflets. Grossly, this yields a line of thrombosis. Such throm-
Rupture of the latter may cause hemorrhage into the left lung bosis may be accentuated when prolapse is associated with
or left pleural space and, uncommonly, into the right pleural calcification of the left atrioventricular junction.
cavity. Mitral valvar prolapse is also associated with a tendency
toward development of chronic obstructive pulmonary
disease. Other sites of potential disease include the aortic
Valvar Regurgitation
and pulmonary valvar leaflets and the aortic media. The
A variety of valvar anomalies may be associated with valvar latter may show cystic medial necrosis, a condition associ-
incompetence. ated with widening of the thoracic aorta. When mitral valvar
prolapse and changes in the aorta and aortic valves coexist,
Mitral Valve one of these conditions is usually dominant and claims the
primary diagnosis. Thus, one may observe primary mitral
Congenital mitral regurgitation in adults is most commonly
valvar prolapse and associated secondary changes in the
caused by prolapsed myxomatous leaflets.22,23 This condition
aorta and its valve. Conversely, the aortic and aortic valvar
is characterized by an increase in the spongy middle layer
changes may be primary, whereas the mitral valvar prolapse
of the valve. Excessive proliferation of the spongy layer
occupies a secondary position.
invades the fibrous layer, which is the part most responsible
for the strength of the leaflets. As the leaflets become weak-
Tricuspid Valve
ened, there is intercordal prolapse (Fig. 9.28), characterized
by intercordal hooding of the leaflets. This feature may be The leaflets of the tricuspid valve may also exhibit prolapse,
responsible for mitral insufficiency. In the myxomatous but typically in association with dominant mitral valvar
valve, other features causing regurgitation include an increase prolapse. When chronic obstructive pulmonary disease is
in the width of the orifice. Another major cause for appear- associated with tricuspid valvar prolapse, the later process
ance or accentuation of mitral regurgitation is rupture of the may be more fully developed than when pulmonary disease
cords. Although this may involve cords attaching to either is absent. The challenge of right ventricular hypertension
leaflet, the most common site involves those attaching to tends to expose the valvar abnormalities when the potential
the central scallop of the mural leaflet. In this situation, the for valvar prolapse exists.
systolic regurgitant stream strikes the atrial septum at the The more typical lesion producing tricuspid regurgita-
same horizontal level as the aortic valve. tion, however, is Ebstein’s malformation. It is characterized
It has been shown that, when the leaflets prolapse, fric- by so-called downward displacement of the hinge points of
tion may develop between the cords of the mural leaflet and the mural and septal leaflets of the valve, the leaflets hinging
the related mural endocardium of the left ventricle.24 The within the ventricular cavity rather than at the atrioven-
secondary effect is the appearance of multiple fibrous thick- tricular junction (Fig. 9.29). The anterosuperior leaflet, in
enings of the mural endocardium. In some cases, the fibrous contrast, usually retains its attachment at the atrioventricu-
lesions may coalesce and bind to the cords, shortening them lar junction, but there is “atrialization” of the inlet of the
further and exacerbating the regurgitation by restraining the right ventricle. The functional disturbance is reduction in
upward excursion of the leaflets. Patients with mitral valvar the effective volume of the ventricular cavity, which is rep-
prolapse experience transient cerebral ischemic attacks, resented only by the apical trabecular and outlet components
probably caused by embolization related to the valvar disease. (Fig. 9.30).25 Minor degrees of tricuspid regurgitation may
One potential source is thrombosis on the contact surface of contribute to the inefficiency of the right ventricle, which
the leaflets. A second site is in the angle between the left tends to develop fibrotic and thinned walls. In the majority
atrial endocardium and the base of the atrial surface of the of cases, there is an interatrial communication, either an
atrial septal defect or a probe-patent foramen ovale, and
therefore some right-to-left shunting. In patients who reach
adulthood, a cerebral abscess may complicate the right-to-
left shunt. Another frequent associated malformation,
reflecting the abnormal formation of the parietal atrioven-
tricular junction, is the presence of accessory atrioventricu-
lar muscular tracts that produce the Wolff-Parkinson-White
variant of ventricular preexcitation.

Aortic Valve
Congenital aortic regurgitation may result from primary
intrinsic disease of the aortic valve, or can be a secondary
event due to disease of the ascending aorta, with secondary
changes in the aortic valvar sinuses. Aortic regurgitation
Prolapsed scallops
may also be associated with a ventricular septal defect.
Primary regurgitation is usually caused by a congenitally
FIGURE 9.28. The mural leaflet of this mitral valve lacks bifoliate valve. In this condition, the conjoined leaflet is
cordal support to the middle scallop, which prolapses into the wider than the opposite single leaflet. In some cases, however,
atrium. the conjoined leaflet is excessively wide and, during ven-
 nor m a l a n d a bnor m a l a natom y 217
tricular diastole, prolapses beyond the single leaflet, thus
permitting regurgitation. Uncommonly, the characteristic
raphe of the congenitally bifoliate valve is represented by a
strand, rupture of which may cause loss of support of the
conjoined leaflet, and either establishment or accentuation
of aortic regurgitation. The congenitally bifoliate valve is
sometimes subject to infective endocarditis, which may be
an indirect cause of regurgitation through destruction of the
tissue of the leaflet.
Abnormal width of the aorta caused by cystic medial
necrosis, either idiopathic26 or associated with Marfan’s syn-
drome,27 may be a primary basis for aortic regurgitation. In
many such cases, the aorta has a tear in the intimal lining
and medial wall in its ascending portion. Such a tear may be
stable and fail to extend, but it can also progress to the begin-
ning of an intramural tract of aortic dissection. Aortic valvar
regurgitation caused by aortic laceration results from loss
of support of the leaflets or widening of the sinutubular

Mural

Valvar orifice
- “keyhole”

FIGURE 9.30. In this specimen with Ebstein’s malformation,

viewed from the ventricular aspect, there is a slit-like keyhole
between the anterosuperior leaflet, which is abnormally tethered in
a linear fashion at the ventricular apex, and the displaced septal
leaflet. This “functional” ventricle is made up of the apical trabecu-
lar and outlet components of the right ventricle.

Septal
junction. Prolapse is an important mechanism that underlies
aortic regurgitation.
Aortic regurgitation may also be associated with defi-
cient ventricular septation. Typically, the defect is doubly
committed and juxtaarterial, lying directly beneath the left
and right coronary aortic leaflets.28 Less commonly, the
defect can be perimembranous, or even muscular (Fig. 9.31).
The basic reason for the aortic regurgitation is that the
portion of the aortic root related to the defect is unsupported.
This allows the involved part of the aorta to move out of line
from its normal position, causing a “tipping” of the related
leaflet or leaflets. The consequence of the tipping is malalign-
ment of the zones of apposition, resulting in incompetence
of the valve.
Thinned wall
Pulmonary Valve

FIGURE 9.29. The right atrioventricular junction has been opened Congenital pulmonary valvar regurgitation is usually associ-
and the diaphragmatic aspect reflected upward to show the essence ated with so-called absence of the leaflets.29 In reality, the
of Ebstein’s malformation. The septal and mural leaflets are both valve is represented by hypoplastic units of valvar tissue
hinged within the right ventricle (dotted lines) rather than at the arrayed in annular fashion (Fig. 9.32). In some instances,
atrioventricular junction (solid line). The anterosuperior leaflet,
however, is normally attached at the atrioventricular junction. Note there are no other associated anomalies. Most cases, however,
the thinning of the myocardium in the inlet component of the right exhibit features of tetralogy of Fallot with mild infundib-
ventricle. ular stenosis. If untreated, congenital pulmonary valvar
218 chapter 9

Abnormal Communications Between the

Chambers and the Arterial Trunks
It is convenient to divide deficiencies of septation into those
in which the communication begins proximal to the atrio-
ventricular junctions and those in which it begins distal to
these junctions.

Pulmonary Proximal to Atrioventricular Junctions

valve
Of the communications that begin proximal to the atrioven-
tricular junctions, the most common is the interatrial com-
munication. Less common are various types of anomalous
pulmonary venous connections. Although anomalous pul-
monary venous connections resemble interatrial communi-
cations in many respects, we consider them in a separate
section.

Muscular INTERATRIAL COMMUNICATIONS

outlet There are several anatomic types of interatrial communica-
Prolapse
defect tion that allow patients to reach adulthood.30,31 Perhaps para-
of aortic leaflet
doxically, not all are positioned within the atrial septum.32
The commonest defect, often called the “ostium secundum,”
is found in the floor of the oval fossa (Fig. 9.33). The less
common sinus venosus type is found at the entrance of either
the superior or inferior caval vein, and is associated with
FIGURE 9.31. In this specimen with a muscular outlet ventricular
septal defect, there is prolapse of one of the leaflets of the aortic
anomalous pulmonary venous connection from the right
valve through the upper margin of the defect. lung (Fig. 9.34). The rarest communication is found at the
site of the mouth of the coronary sinus. It exists because of
effacement of the walls, which usually interpose between
insufficiency does not usually allow survival to adulthood the coronary sinus and the left atrium (Fig. 9.35).
because, in most cases, there is also major dilation of the The other defect that produces an interatrial communica-
pulmonary arteries, extending into the pulmonary paren- tion is the so-called ostium primum defect. This lesion,
chyma. If severe, this complication can prevent surgical however, exists because there is a common atrioventricular
correction in infancy. junction rather than separate right and left junctions.33 It is
part of the spectrum of anomalies with atrioventricular
septal defect in the setting of common atrioventricular junc-
tion. The left atrioventricular valve in this setting is a trifoli-
ate structure, rather than an abnormal mitral valve. Although
Dilated pulmonary arteries the space between the two leaflets attached to the ventricu-
lar septum is often called a cleft, in reality it is the zone of

Rudimentary leaflets

Deviated outlet septum

FIGURE 9.32. This heart has tetralogy of Fallot, with so-called

absence of the leaflets of the pulmonary valve. As can be seen,
however, the valvar leaflets are formed in rudimentary fashion as a
ring of tissue at the ventriculoarterial junction. The symptoms in FIGURE 9.33. In this heart, there is a large hole within the oval
patients such as this are due to the gross dilation of the pulmonary fossa due to deficiency of the flap valve. This gives the so-called
arteries. ostium secundum defect.
 nor m a l a n d a bnor m a l a natom y 219

“Ostium primum”
SCV
Probe thru’
superior rim
of fossa
RPV

Bridging leaflets
Overriding Intact oval fossa
orifice

FIGURE 9.34. In this heart, the mouth of the superior caval vein
(SCV) overrides the upper rim of the oval fossa, which is intact. Note
the anomalous connection of the right pulmonary veins (RPV), and
the probe passed through the intact upper rim of the septum. This Mural leaflet
is the so-called sinus venosus defect, which produces the potential
for interatrial shunting, but outside the confines of the atrial
septum. FIGURE 9.36. The left ventricular aspect of the so-called ostium
primum defect, in reality an atrioventricular septal defect with
common atrioventricular junction, but with a separate trifoliate
valve guarding the left half of the common junction. In this speci-
apposition between two leaflets that bridge the ventricular men, there is a dual orifice in this left valve (arrow).
septum and form the distal extent of the interatrial com-
munication (Fig. 9.36).
In all the patients having an interatrial communication, tion. This complication tends to occur relatively early in
there is a tendency for the increased pulmonary flow to be adulthood, but usually not before the mid-30s.
associated with normal pulmonary arterial pressure for There is marked variation in the histologic features of the
many years. In some patients, obstructive pulmonary vascu- pulmonary vascular bed. In the stage characterized by high
lar disease may develop, followed by pulmonary hyperten- flow of blood to the lungs, but at low pressure, the vascular
sion and right ventricular hypertrophy. The resulting right bed is dilated. Early changes leading to obstructive disease
ventricular hypertrophy is responsible for a difference in the are represented by intimal fibrous proliferation of the pulmo-
filling characteristics of the ventricles, leading to a basis for nary arterioles. Medial hypertrophy of the muscular arteries
right-to-left shunting through the interatrial communica- follows. Ultimately, nonspecific fibrous proliferation may
produce the so-called plexiform lesion. At this stage, right
ventricular hypertrophy has become established. The result-
ing right-to-left shunt may be manifested by delayed cyano-
LSCV sis. Cerebral abscess, in concert with other states in which
Oval fossa a chronic right-to-left shunt is associated, may complicate
the course.
In those patients with pulmonary hypertension compli-
cating an interatrial communication, the wide right and left
pulmonary arteries may become aneurysmal. At aneurysmal
sites, there is a tendency for the development of laminated
thrombus.
The natural history of patients with an interatrial com-
munication was well described in 1970.31 The intent was to
chart the progress of patients having defects in the oval fossa,
but some were included with partially anomalous pulmo-
nary venous connection, and these were likely to be sinus
venosus defects. Of the patients studied, about one quarter
had died before 27 years, over half by 36 years, three quarters
Mouth of sinus by 50 years, and nine tenths by 60 years of age. The mean
FIGURE 9.35. The left atrium of a patient who had so-called unroof- age of death for all patients was no more that 38 years.
ing of the coronary sinus. A persistent left superior caval vein Persistent patency of a competent valve of the oval
(LSCV) drains to the upper corner of the left atrial roof. The walls
that should separate this vessel from the left atrial cavity (lines)
foramen, a feature of about one third of the normal popula-
have disappeared. Because of this, the mouth of the coronary sinus tion,34 although not usually problematic, may have func-
functions as an interatrial communication. tional consequences in certain circumstances. The valve
220 chapter 9

will close the patent oval foramen postnatally as long as left

atrial pressure exceeds right atrial pressure. The potential
exists for a right-to-left interatrial shunt through the patent
foramen ovale if, for any reason during the cardiac cycle,
right atrial intracavitary pressure exceeds left atrial pressure,
and thus opens the valve of the foramen. In addition, with
anatomic patency of the foramen, the valve may enlarge, or
appear to enlarge, creating an aneurysm of the oval fossa.
With such an aneurysm, the floor of the fossa may bulge into
the right or left atrial cavity concomitant with variations in
interatrial pressures such as occur with normal respiration.
In this situation, the interatrial shunt could be either from
left to right, or right to left. If the shunt is from the right to
the left atrium, the potential exists for embolic material
from systemic venous sources to enter the left atrium and
thereby be distributed to the systemic arterial circulation as
a paradoxical embolus. Such an event is recognized to be a
cause of so-called cryptogenic ischemic stroke.35–37

Communications Distal to
Atrioventricular Junctions
Among the abnormal communications beginning distal to
the atrioventricular valves are those hearts with an atrioven-
tricular septal defect with common atrioventricular junction
and the potential for shunting at ventricular level, ventricu-
lar septal defects in the setting of separate atrioventricular
junctions, patency of the arterial duct, aorticopulmonary
window, common arterial trunk, double outlet from the
right or left ventricle, and all forms of functionally single
ventricle. FIGURE 9.37. This section, made to replicate the four-chamber
echocardiographic cut, shows a muscular defect opening between
In all these conditions, it is possible to define two par- the ventricular inlets (double-headed arrow).
ticular subsets of lesions. In one, the communication between
the ventricles or the arterial trunks is narrow and restrictive.
In the other, the communication is wide and nonobstructive.
In the first category, we find those patients with small ven- this can now be achieved using catheterization techniques
tricular septal defects or the classic form of patent arterial without having to resort to open-heart surgery. It is then
duct. The list of those with unobstructive lesions includes important to note that the pulmonary vascular bed will be
those with large ventricular septal defects or widely patent within normal limits in this setting.
arterial ducts, as well as many of those with the other condi- When the ventricular septal defect is large, it is far more
tions listed above. likely to be of the so-called doubly committed and juxtaarte-
The distinction is of significance because, when a ven- rial variety, when the major feature is fibrous continuity in
tricular septal defect or patent duct is small, survival to the roof of the defect between the leaflets of the aortic and
adulthood is usual even in the absence of surgical correc- pulmonary valves (Fig. 9.40), or else a perimembranous defect
tion. The ventricular septal defect itself can be muscular opening between the ventricular outlets with overriding of
(Fig. 9.37), or adjacent to the central fibrous body, the latter the leaflets of the aortic valve but an unobstructed subpul-
now being known as the perimembranous type of defect monary outlet, the so-called Eisenmenger defect (Fig. 9.41).
(Fig. 9.38). Often, both of these types of defect tend to reduce In most patients with these defects, or those with a widely
in size during childhood, or even close spontaneously. When patent arterial duct, or with any of the other conditions pro-
they remain patent but small, the ventricular systolic pres- viding unobstructed communications between the ventricles
sures are different, and the left and right ventricular pres- and the arterial trunks, the pulmonary arterial pressure is
sures are near normal, as is the volume of flow of blood to elevated. The pulmonary and systemic systolic arterial pres-
the lungs. The pulmonary arterial pressure is not elevated. sures are equal. The pulmonary vascular bed is prone to a
Such small ventricular septal defects, or narrow arterial variety of obstructive lesions. Ultimately, the most severe
ducts (Fig. 9.39), nonetheless, also permit a stream of blood forms of pulmonary vascular disease will become estab-
to jet across the communication. This promotes the poten- lished, setting the scene for reversal of the shunt so that it
tial for infection at the sites of impact of the jetlike stream, occurs from right to left, the so-called Eisenmenger reaction.
in the right ventricle in those with a ventricular defect, and In the group of anomalies under consideration, nonetheless,
in the pulmonary artery when there is a narrow but patent there is considerable variation among individuals. Although
arterial duct. Nowadays, however, there is an increasing ten- the majority of patients, if not offered surgical treatment
dency to close such communications even when small, since during the first months of life, will develop major obstructive
 nor m a l a n d a bnor m a l a natom y 2 21

Aortic valve
Ventricular septal defect

Ventricular
septal defect

Mitral
valve

FIGURE 9.40. The ventricular septal defect in this heart is directly

beneath the pulmonary valve, and is roofed by fibrous continuity
between the leaflets of the aortic and pulmonary valves. This is the
so-called doubly committed and juxtaarterial defect.

Tricuspid pulmonary vascular lesions by adulthood, occasional adult

Valvar valve patients do not have significant pulmonary vascular lesions,
continuity and may exhibit different degrees, sometimes large, of left-
to-right shunting.
FIGURE 9.38. This specimen is also cut to replicate the four- A special condition to be considered in this group is the
chamber plane (compare with Fig. 9.37), but in this heart, the roof atrioventricular septal defect with common atrioventricular
of the ventricular septal defect is made up of fibrous continuity junction, but with shunting possible at ventricular level
between the leaflets of the aortic and tricuspid valve. This is the
so-called perimembranous defect. (Fig. 9.42). In uncomplicated cases, survival beyond infancy
or childhood is highly unusual. When this condition is asso-
ciated with the tetralogy of Fallot, however, survival to adult-
hood is common because the subpulmonary stenosis, which
is an integral part of the tetralogy, provides a natural banding
of the pulmonary trunk, thus overcoming the feature of an
unobstructed interventricular communication.38
The congenital aneurysm of an aortic sinus of Valsalva
Pulmonary trunk usually involves either the right or the noncoronary aortic

Arterial duct

Descending aorta
FIGURE 9.41. This heart has been sectioned to replicate the sub-
costal oblique echocardiographic cut. It shows the leaflets of the
FIGURE 9.39. The aortic arch and left pulmonary artery are aortic valve overriding the crest of the ventricular septum in the
viewed from the left side. There is a small persistently patent arte- presence of an unobstructed subpulmonary outlet. This is the so-
rial duct. called Eisenmenger defect. SMT, septomarginal trabeculation.
222 chapter 9

Abnormal Connections
Another group of anomalies that may be seen in adulthood
Atrial
septum by cardiologists is characterized by arteries or veins abnor-
mally joining certain other vessels or chambers.

Bridging Communication of a Coronary Artery with a

leaflet Cardiac Chamber or a Major Thoracic Vessel
Communication of a coronary artery with a cardiac chamber
or a major thoracic vessel not infrequently presents in adult
life. Such fistulas taking their origin from the right coronary
artery are more common than those originating from the left
coronary artery.40,41 In almost nine tenths of such cases, the
fistulous channels drain to the lesser circulation, usually the
right ventricle.42 In such situations, the artery proximal to
the fistulous connection is usually wide, but distal to the
Septal
defect fistula the artery narrows precipitously (Fig. 9.44). The artery
proximal to the fistula may also show aneurysmal dilation.
The fistulous communications can also be the seat of infec-
tious endocarditis, this complication being observed in up to
one tenth of patients.
FIGURE 9.42. This heart has a common atrioventricular junction
and an atrioventricular septal defect. The bridging leaflets of the
common valve, however, are attached to the leading edge of the Discordant Ventriculoarterial Connections
atrial septum. Because of this, shunting through the atrioventricu-
lar septal defect can only take place at the ventricular level.
The situation in which the arterial trunks take their origin
from morphologically inappropriate ventricles is usually
described simply as transposition. But since the lesion
sinus. The fact that the lesion is congenital indicates that involves only a part of the heart, it can obviously be condi-
there may be a congenital weakness in the attachment tioned by further changes occurring at the atrioventricular
between the aortic sinus and the supporting ventricular junctions. The changes at the ventriculoarterial level can be
structures, which in the left ventricle are partly fibrous. This further conditioned by variations in the relationships of the
allows slippage or avulsion of the medial wall of the afflicted arterial trunks themselves, or by variations in infundibular
sinus.39 If this occurs, then the aortic wall is supported only morphology. These different patterns often led to disagree-
by the wall of the right atrium or ventricle. The sinus itself ments in the past as to how best the abnormalities should be
can then become aneurysmal, and may rupture, producing a
shunt from the aorta to either the right atrium or the right
ventricle (Fig. 9.43). When the right aortic sinus is involved,
then frequently the aneurysm is also associated with a ven-
tricular septal defect, which is then either perimembranous Normal coronary artery
or doubly committed and juxtaarterial (see above).

Ends of divided fistula

FIGURE 9.43. In this heart, there is an aneurysm of the right coro-
nary aortic sinus of Valsalva, which has been transilluminated from FIGURE 9.44. This picture, taken in the operating room, shows the
the aortic side, but is photographed from the right side. As can be cut ends of a fistula that extended from the right coronary artery to
seen, if the sinus ruptured, it would communicate with the right the right atrium. Note the caliber of the normal segment of the right
atrium. coronary artery.
 nor m a l a n d a bnor m a l a natom y 223
described and defined.43 Nowadays, however, it is accepted
that the best criterion for definition is the discordant ven-
triculoarterial connections, since it is this feature that deter-
mines the abnormal hemodynamic pattern. It is also the case
nowadays that patients with these lesions undergo surgical
treatment in infancy, and most now survive to adult life. In
one important variant, however, the discordant connections
at the ventriculoarterial level are accompanied by discordant
atrioventricular connections. The two discordancies then
cancel each other out, so that the circulations are congeni-
tally corrected. Patients with such congenitally corrected
transposition can first present to the cardiologist in late adult
life if they have no other associated intracardiac lesions.44
FIGURE 9.46. A so-called congenitally corrected variant of trans-
Regular Transposition position. The essence of the lesion is discordant connections across
both the atrioventricular and ventriculoarterial junctions. As with
The commonest variant of transposition is that in which the the “regular” variant of transposition, the congenitally corrected
atrioventricular connections are concordant, or normal, as pattern can be found with either usually arranged or mirror-image
are the venous connections to the heart (Fig. 9.45). Because atrial chambers. (Abbreviations as for Fig. 9.45.)
of the discordant ventriculoarterial connections, the circula-
tions are then in parallel rather than in series. Without surgi-
cal treatment, this common condition used to cause death
in early life. Nowadays, almost all patients undergo surgical coronary arteries during infancy means that many of these
correction, enabling them to survive to adulthood. patients may develop coronary arterial disease in later life,
Most adult patients presenting at the current time with although thus far there is no evidence to indicate that this
transposition almost certainly have undergone an atrial is happening. Concerns have been raised, however, with
“switch” operation, such as the Senning or Mustard proce- regard to dilation of the initial subpulmonary outflow tract,
dure. Some of these patients may develop obstruction of the which could potentially lead to aortic regurgitation after the
caval venous channels, or the channel of pulmonary venous arterial switch procedure.
flow into the heart. In addition, because of the multiple inci-
sions made in the atrial chambers during the surgical cor- Congenitally Corrected Transposition
rection, many patients suffer atrial arrhythmias, particularly
Because of the presence of discordancies at both the atrio-
sick sinus syndrome. Very soon, patients will be surviving
ventricular and ventriculoarterial junctions, which is the
to adult life after the arterial switch procedure, which
essence of this lesion, the circulations are congenitally cor-
involves detachment of the coronary arteries from the initial
rected (Fig. 9.46). The atrial chambers are typically in their
aortic root, switching of the arterial trunks relative to their
anticipated location but, because of the discordance at the
initial ventricular origins, and reattachment of the coronary
atrioventricular junctions, the ventricles are arranged in
arteries to the arterial root initially supporting the pulmo-
mirror-image fashion, so-called left-handed topology. In
nary trunk. The intricate surgery needed to reattach the
essence, the ventricles are on the “wrong sides” of the heart.
The segmental combination with double discordance, none-
theless, can sometimes be found when the atrial chambers
are mirror-image, so-called situs inversus, but the ventricles
are normally positioned, with so-called right-handed topol-
ogy (Fig. 9.46).
As a result of the two sets of discordant connections, the
circulations of blood are physiologically normal if there are
no associated septal defects or obstructive lesions within the
heart. Patients with uncomplicated corrected transposition,
therefore, may live a normal life, despite the fact that the
morphologically right ventricle is called upon to pump the
blood into the systemic circulation. Some patients with this
condition have first been recognized at autopsy in the eighth
decade of life.44 It is rare, nonetheless, for congenitally cor-
rected transposition to be without associated anomalies.45
When present, it is the associated lesions that determine the
FIGURE 9.45. The segmental arrangements producing the malfor- circulatory effect of the condition. These include a ventric-
mation usually known simply as “transposition.” The atrial cham- ular septal defect, obstruction to the outflow tract from
bers are joined to their appropriate ventricles, but the ventricles give the morphologically left ventricle to the pulmonary trunk,
rise to morphologically inappropriate arterial trunks. As shown, the
segmental combination can be found with the usual arrangement incompetence of the left-sided morphologically tricuspid
of the organs, but also in the mirror-image variant. MRV, MLV, valve, which frequently demonstrates Ebstein’s malforma-
morphologically right and left ventricles, respectively. tion, and congenitally complete heart block.
224 chapter 9

Anomalous Pulmonary Venous Connections

The pulmonary veins may be anomalously connected to a
site other than the left atrium in total or partial fashion.
Totally anomalous pulmonary venous connection, if seen in
uncorrected fashion in the adult, is typically of the type in
which the anomalous termination lies above the diaphragm.
The common connections are with the superior caval venous
system or the coronary sinus (Fig. 9.47). As far as we know,
a totally anomalous infradiaphragmatic connection, which
is almost always to the portal venous system, has not been
reported in adults unless they have undergone surgical cor-
rection during childhood.
A partially anomalous pulmonary venous connection, in
contrast, is by no means rare in adults, although it may not
always be discovered.46 Partially anomalous connection may
either be a random event or part of a syndrome. If only a FIGURE 9.48. The anomalous connection of the right upper pul-
solitary vein is involved, then the anomalous connections do monary veins to the superior caval vein (SCV).
not always introduce a significant cardiovascular burden.
Random connections are exemplified by isolated cases in
which a left or a right upper pulmonary vein joins the left right lung, which has an anomalous arterial supply through
brachiocephalic vein or the superior caval vein (Fig. 9.48). a systemic-to-pulmonary collateral artery. Bronchial anoma-
Partially anomalous connection of a right pulmonary vein lies are also common.50
or veins in association with the sinus venosus type of inter- The so-called polysplenic syndrome,50 now known to be
atrial communication forms a recognized syndrome, the due to isomerism of the organs usually formed on the left
anomalous vein or veins terminating in the superior caval side of the body (Fig. 9.49), including the left atrial appendage,
vein close to its junction with the right atrium (Fig. 9.34). is usually characterized by fewer severe cardiovascular
Indeed, it is the anomalous venous connection that creates anomalies than the asplenic syndrome which is associated
the interatrial communication, which is outside the confines with right isomerism (Fig. 9.50).51 Survival to adulthood,
of the oval fossa.47 therefore, is more common in the former, although now even
There is one other syndrome involving a partially anoma- patients with right isomerism are undergoing conversion to
lous pulmonary venous connection that may first be mani- the Fontan circulation, and will likely present as adults to
fest in adulthood. This is when a vein from the right lung the cardiologist. Among the anomalies that may occur in the
terminates in the inferior caval vein, either above or below setting of left isomerism is connection of pulmonary veins
the diaphragm. The venous anomaly may be the sole condi- to the right-sided atrium, which possesses a morphologically
tion, or part of the so-called scimitar syndrome.49 The syn- left appendage. This may involve all of the pulmonary veins,
drome also typically involves sequestration of part of the or only the right veins.

Supracardiac connection
• to superior caval vein
• via azygos vein

Cardiac connection
• to LSCV & coronary sinus
• direct to right atrium

Infradiaphragmatic &
infracardiac
connection
• to portal venous system
FIGURE 9.49. The essential features of the syndrome often
• to inferior caval vein described as “polysplenia.” In reality, there is duplication of the
FIGURE 9.47. The options for drainage of totally anomalous pul- structures usually found on the left side of the body, in other words,
monary venous connections. LSCV, left superior caval vein. left isomerism.
 nor m a l a n d a bnor m a l a natom y 225

Anomalous Systemic Venous Connection

Major anomalous connections of the systemic veins may
involve the superior caval venous system, the inferior caval
venous system, or both.

INFERIOR CAVAL VENOUS SYSTEM

Congenital union of the inferior caval vein has been reported
with the left atrium, but is usually due to persistence of a
large eustachian valve, which directs the blood across a
patent oval foramen (Fig. 9.51). This can give the impression
that the atrial septum is intact should the eustachian valve
become attached to the margins of the fossa. This situation
is replicated should a surgeon closing a defect in the oval
fossa inadvertently suture the eustachian valve to the
margins of the oval fossa, a mistake that can happen in even
the best regulated of operating rooms.

SUPERIOR CAVAL VENOUS SYSTEM

Persistence of a left-sided superior caval vein is a relatively
common condition. In this condition, there are usually two
superior caval veins. The right-sided vein joins the right
atrium in its usual position, whereas the left-sided vein FIGURE 9.51. The arrangement in which a prominent eustachian
valve directs the return from the inferior caval vein to the left
drains to the right atrium through an enlarged coronary
atrium through a deficient oval fossa.
sinus.52 In about three fifths of patients with this arrange-
ment, there is a bridging brachiocephalic vein between the
two superior caval veins.
Among the variations of this condition is that in which
the right-sided caval vein fails to join the right atrium, with involves “unroofing” of the coronary sinus, with the mouth
the right-sided brachiocephalic vein terminating in a left- of the coronary sinus then functioning as an interatrial com-
sided caval vein that drains through the coronary sinus. munication (Fig. 9.35).53
Much more rarely, a left-sided caval vein can join the left
atrium directly, terminating near the base of the left atrial INFERIOR AND SUPERIOR CAVAL VEINS
appendage. This condition is part of the syndrome that The most common condition involving both caval venous
systems is when the inferior caval vein is interrupted within
the abdomen, the abdominal venous return then reaching
the heart through the azygos system of veins and the superior
caval venous channels, either on the right or the left sides of
the body. This arrangement is typically seen in the setting
of left isomerism, or polysplenia,54 but can also be found as
an isolated anomaly (Fig. 9.52).

Arteriovenous Fistulas
Congenital arteriovenous fistulas may involve either the sys-
temic or the pulmonary vascular bed.

PULMONARY A RTERIOVENOUS FISTULAS

Congenital pulmonary arteriovenous fistulas may be either
solitary or multiple. In the latter instance, the condition may
involve one or more than one lobe of a lung. The individual
lesion is usually characterized by a plexus of intercommuni-
cating arteries and veins within the lung. Because the con-
dition allows desaturated pulmonary arterial blood to be
delivered to the pulmonary venous system, cyanosis and
clubbing of digits may be evident, depending on the volume
of shunt. The condition has a strong hereditary associa-
tion.55,56 The familial Rendu-Osler-Weber syndrome, with
telangiectasia involving various organs and mucous mem-
FIGURE 9.50. The counterpart to left isomerism, often described
branes, is found in about one third of cases.57,58 Cerebral
as “asplenia.” The essential feature of this syndrome is right abscess is a potential complication. Uncommonly, infection
isomerism. may occur at the site of the fistula.
226 chapter 9

arterial system, there is obstruction to pulmonary flow,

Azygos vein either atresia or stenosis. When there is atresia at the pulmo-
Superior caval vein nary outflow tract, then the pulmonary arteries are typically
hypoplastic, represented by atretic cords, or absent in extreme
cases. There is then major variation in the supply of blood to
the lung.

Tetralogy of Fallot
In the adult, tetralogy of Fallot displays the same range of
Morph. right anatomic detail as in the infant or child (Fig. 9.53). The origin
appendage of the aorta from the ventricles varies, as does the degree of
pulmonary stenosis. When the aorta takes its origin primar-
ily from the right ventricle, then the ventriculoarterial con-
nection is such as to make the combination part of the entity
known as double outlet right ventricle.
In terms of the degree of pulmonary stenosis, this also
shows a spectrum, with atresia at some level of the pulmo-
nary arterial channels representing the most severe form
(Fig. 9.54). Survival is not directly related to the width of the
pulmonary arterial channel, but rather to the degree of col-
lateral flow, so that many patients can survive for long
periods with major degrees of pulmonary obstruction.

Hepatic veins
Solitary Arterial Trunk
An extreme in the level of pulmonary arterial obstruction is
that in which is there not only atresia of the right ventricular
FIGURE 9.52. In this heart, with the usual arrangement of the outlet, but also complete absence of the intrapericardial pul-
atrial appendages, the veins traversing the diaphragm from the
monary arteries, including the pulmonary trunk. In this
abdomen carry only the hepatic venous return. The systemic venous
return is to the superior caval vein via the azygos system of veins, setting, a solitary arterial trunk takes its origin from both
with interruption of the abdominal course of the inferior caval ventricles, overriding the crest of the muscular ventricular
vein. septum (Fig. 9.55). In this setting, the pulmonary arterial
supply is derived from systemic-to-pulmonary collateral
arteries. These usually arise from the aorta, principally the
descending aorta, and proceed to the pulmonary hila,
SYSTEMIC A RTERIOVENOUS FISTULAS although one lung may initially have been supplied through
Congenital arteriovenous fistulas involving the coronary a patent arterial duct that has become ligamentous (Fig.
arterial system have been discussed previously. Extracardiac 9.56).
systemic arteriovenous fistulas may occur in any part of the
systemic circulation. Those involving the cerebral circula-
tion are usually covered in treatises concerned with intra-
cranial conditions, but the so-called aneurysm of the vein of Outlet septum
Galen is particularly important in the setting of cardiac
disease. Other congenital systemic arteriovenous fistulas
may involve any part of the body. Multiple arteries com-
monly supply the area of arterial and venous connections.
The main arterial trunks are dilated. When a limb is involved,
the greater length of that limb is characteristic. Infectious TSM
endophlebitis is a recognized complication.

Combinations of Anomalies
Almost any combination of anomalies is possible. The
random association of some anomalies with others has been SMT
discussed previously. In this section, we consider primarily VSD & overriding aorta
the combination of an interventricular communication with
pulmonary stenosis or atresia. The majority of these condi- FIGURE 9.53. In this heart, the subpulmonary outflow tract has
tions are associated with biventricular origin of the aorta and been bisected, showing a narrowed infundibulum (bracket), along
with the leaflets of the aortic valve overriding the crest of a deficient
right ventricular hypertrophy, this combination producing ventricular septum (VSD). This is the tetralogy of Fallot. TSM, sep-
the well-known tetralogy of Fallot. In each case, at some tomarginal trabeculation; SPT, septoparietal trabeculation. (See
level or levels between the right ventricle and the pulmonary also Figure 9.12.)
 nor m a l a n d a bnor m a l a natom y 227

Pulmonary arteries

Aorta

Muscular atresia

FIGURE 9.56. These are the pulmonary hila of the heart shown in
Fig. 9.55. The right lung is supplied through systemic-to-pulmonary
collateral arteries. The left lung was initially fed by an arterial duct,
which has become ligamentous.

Abnormal Aortic and Arterial Branching

Deviated outlet septum
This section discusses variations in branching or origin of
major arteries, including the coronary arteries and the
FIGURE 9.54. In this heart with tetralogy of Fallot, there is mus-
cular atresia of the subpulmonary infundibulum.
aorta.

Coronary Arteries
The anomalies of the coronary arteries59 considered here
include ectopic or anomalous origin of a coronary artery
from the aorta, coronary arterial dominance, and anomalous
origin of a coronary artery from a pulmonary artery, usually
the pulmonary trunk.

ECTOPIC OR A NOMALOUS ORIGIN FROM THE AORTA

In ectopic origin of a coronary artery from the aorta, the
artery typically arises from an inappropriate aortic sinus of
Valsalva, or may arise from an unusually high position, or
Solitary trunk may have an unusually acute angle of origin from the aorta.
In each of these situations, the ectopically arising artery can
run intramurally as it exits from the aorta. This creates a
situation in which the coronary arterial lumen can become
constricted during diastole. Sudden death, especially during
exercise, has occurred in some individuals with such ectopic
coronary arterial origin from the aorta.60 The commonest
pattern is when the circumflex coronary artery arises either
from the proximal segment of the right coronary artery, or
from the right aortic sinus posterior to the normally situated
origin of the right coronary artery. In this pattern, the anom-
alous artery courses behind the aorta to reach the left atrio-
ventricular groove (Fig. 9.57). In other patterns, the anomalous
artery runs between the subpulmonary infundibulum and
the aortic sinuses. This position increases the risk of con-
VSD striction, and poses a significant threat of sudden death.

CORONARY A RTERIAL DOMINANCE

FIGURE 9.55. In this heart, there is complete absence of the intra- The artery that gives rise to the inferior interventricular
pericardial pulmonary arteries, along with failure of formation of
any subpulmonary infundibular structures. The trunk overriding artery is usually designated as the dominant coronary artery.
the ventricular septal defect (VSD) is best described as a solitary In about nine tenths of the general population, this is the
arterial trunk. right coronary artery.
228 chapter 9

coronary artery; anastomoses between the two coronary

Retro-aortic arterial systems; subendocardial myocardial fibrosis (Fig.
circumflex 9.58), including fibrosis of papillary muscles; and large sinu-
artery soids that communicate with the left ventricle in the area of
the distribution of the anomalously arising left coronary
Aorta
artery.

Aortic Arch
The anomalies or variations of the aortic arch system seen
in the adult may occur with either a left arch or a right
arch.
Right
coronary
L EFT AORTIC A RCH
artery
Individuals with left aortic arch have variations from the
classic branching pattern. Among these is a common origin
for the brachiocephalic and left common carotid arteries.
A relatively common variation, seen in up to one tenth of
the population is origin of the left vertebral artery from the
aortic arch. Such an artery arises just proximal to the origin
of the left subclavian artery, and the two arteries commonly
share the same adventitial covering.
Potentially more significant is the arrangement in which
the right subclavian artery arises anomalously from the
distal aortic arch (Fig. 9.59). In this setting, the artery arises
FIGURE 9.57. In this heart, the circumflex artery arises from the
right coronary artery, and then runs behind the aorta to reach the as the fourth branch of the arch, and then runs behind the
left atrioventricular groove. esophagus. Such a vessel occurs in approximately 0.5% of
the population, and can cause problems during swallowing,
although this is not always the case.
In the setting of a congenitally bicuspid aortic valve,
R IGHT AORTIC A RCH
however, about one third of involved persons have domi-
When a right aortic arch is present, it may be either the only
nance of the circumflex artery.
aortic arch or part of a double arch. The double arch is char-
acterized by bifurcation of the ascending aorta into right and
ORIGIN OF A CORONARY A RTERY FROM THE
left arches (Fig. 9.60). Each arch passes over its appropriate
PULMONARY T RUNK
It is usually the left coronary artery that arises from the
pulmonary trunk,61,62 although very uncommonly both coro-
nary arteries can arise from the pulmonary trunk. This situ-
ation leads irrevocably to death in early infancy, unless there
is an associated condition characterized by pulmonary
hypertension.
Usually, the pulmonary arterial segment from which the
coronary artery arises is the pulmonary trunk, although
rarely a coronary artery may arise from one or another pul-
monary artery. Origin of the right coronary artery from the
pulmonary artery is less common than similar anomalous
origin of the left coronary artery. When the right coronary
artery is affected, however, some patients exhibit no evi-
dence of disease. There are reported cases, nonetheless, of
middle-aged persons in whom unexpected sudden death was
associated with anomalous origin of the right coronary artery
from the pulmonary trunk.
If it is the left coronary artery that arises from the pul-
monary trunk, and the condition is left untreated, the major-
ity of individuals die in infancy or childhood. The minority
who survive to adulthood manifest major flow from the nor-
mally arising right artery through the myocardium and then
into the left coronary artery, with the arteriovenous-like flow
FIGURE 9.58. This is the left ventricle of a heart in which the left
terminating in the pulmonary trunk. Some of these patients coronary artery arose from the pulmonary trunk rather than
can die suddenly as adults. In this setting, there are several the aorta. Note the long-standing ischemic changes in the
features in common. These include a large, tortuous, right myocardium.
 nor m a l a n d a bnor m a l a natom y 229

LCCA

RCCA
RSCA LSCA

Arterial
duct
FIGURE 9.59. A picture, from behind, of the aortic arch, in which
the terminal branch is the right subclavian artery (RSCA). Note its Right arch
retroesophageal course. Note also that its origin from the aorta is
dilated—the so-called diverticulum of Kommerell.

bronchus, joining posteriorly to the esophagus to form the Left brachiocephalic

descending aorta. When the arch is right-sided, it may also artery
be associated with a retroesophageal segment. In those Pulmonary trunk
examples lacking a retroesophageal segment, the pattern of
branching, from before it goes backward, is for the arch to
give rise to the left brachiocephalic artery, which divides into
left common carotid and left subclavian arteries, and then
the right common carotid and subclavian arteries (Fig. 9.61).
FIGURE 9.61. In this heart with a right-sided aortic arch, there is
When there is a retroesophageal component, it is the left mirror-image branching of the brachiocephalic arteries [RSCA, right
subclavian artery that is the final branch from the arch, with common carotid artery (RCCA), LCCA, LSCA]. Note the left-sided
the artery passing in a leftward direction behind the esopha- arterial duct, which takes its origin from the left subclavian
gus. This is the mirror image of the arrangement giving ret- artery.
roesophageal origin of the right subclavian artery (Fig. 9.62).
The left subclavian artery, when taking a retroesophageal
course, also usually arises from a diverticulum of the arch,
the so-called diverticulum of Kommerel. It is important to

FIGURE 9.62. The retroesophageal origin of the right subclavian

artery (see Fig. 9.60) is explained on the basis of absorption of the
segment of the double arch (star) between the right subclavian artery
FIGURE 9.60. The essence of the perfect double aortic arch. All (RSCA) and the RCCA. This pattern, in mirror-image format,
known “vascular rings” can be explained on the basis of this explains retroesophageal origin of the left subclavian artery from a
“perfect” arrangement. right aortic arch.
230 chapter 9

note that a double aortic arch, as shown in Figure 9.60, can

exist with an atretic segment between the left common carotid
and subclavian arteries, and can be mistaken for a simple right
aortic arch with a retroesophageal segment (Fig. 9.63).
When the right arch is found in the absence of any retro-
esophageal segment, then this is typically associated with
intracardiac malformations, typically tetralogy of Fallot or
common arterial trunk. When found in this setting, then
usually there is mirror-image branching of the brachioce-
phalic arteries, although aberrant origin of the left subcla-
vian artery or isolation of the left subclavian artery (Fig. 9.64)
can also be found.

Abdominal Aorta
Uncommonly, there can be multiple collateral arteries that
FIGURE 9.64. In this heart, which is associated with a right aortic
arise from the abdominal aorta, or from the nearby lower arch, the left subclavian artery (LSCA) arises from the left pulmo-
thoracic aorta, and lead to a lung, usually the right. This nary artery, being fed though a persistent left arterial duct, but is
pattern is typically seen in the setting of pulmonary seques- isolated because of resorption of the segments of an initially double
tration, as for example, in the so-called scimitar syndrome. arch, specifically between the left common carotid artery (LCCA)
and the subclavian artery, and between the subclavian artery and
the descending aorta (stars).
Syndromes with Cardiac Disease
Congenital malformations of the heart are part of many
syndromes. We discuss only the more common associations
nized as allowing patients to reach adulthood, but the com-
in this section.
bination is now almost always recognized and treated
One recognized association of anomalies is that of aortic
surgically during the first year of life.
coarctation and the congenitally bifoliate aortic valve, the
latter lesion being found in up to half of the patients with
Familial Cardiomyopathy
coarctation.
Patency of the arterial duct is found in up to one eighth At least two forms of familial myopathy are well recognized
of those with a ventricular septal defect. The combination of in the adult: the dilated and hypertrophic variants. To these,
tetralogy of Fallot with atrioventricular septal defect and we now need to add the increasingly well-recognized vari-
common atrioventricular junction was, in the past, recog- ants of so-called arrhythmogenic right ventricular cardiomy-
opathy. The familial dilated variant is similar in terms of its
pathology to apparently acquired congestive cardiomyopa-
thy. The heart is enlarged, with hypertrophied and dilated
Ligamentous remnant ventricles. There are differing amounts, usually small, of
myocardial fibrosis. Congestive failure and sudden major
arrhythmias are common.
Retroesophageal LSCA
Arachnodactyly, or Marfan Syndrome
The laxity of the connective tissues that characterizes
Marfan syndrome commonly affects the cardiovascular
Arterial system. The elastic arteries show foci within their medial
ligament
walls of mucoid, cystlike deposits, shown as cystic medial
necrosis, associated with corresponding interruption and
retraction of fibers. In the aorta, the changes are most com-
monly located in the ascending portion. This leads to general
dilation of the ascending aorta, including the aortic sinuses.
The process of cystic medial necrosis, however, is less evident
beyond the arch than proximally. Aortic valvar regurgitation
and aortic dissection, each with its classic consequences, are
typical complications. Simple aortic regurgitation may result
from dilation of the aorta and coexisting myxomatous
changes in the aortic valvar leaflets. Cystic medial necrosis
may also involve the pulmonary trunk, producing so-called
idiopathic dilation.63 The leaflets of the atrioventricular
FIGURE 9.63. The retroesophageal origin of the left subclavian
artery (LSCA) from a right aortic arch. There is persistence in the valves may also be involved in the myxomatous process,
ligamentous form of the segment that initially joined the artery to this producing prolapse and valvar incompetence. Rarely,
the left arch, along with a ligamentous arterial duct. myxomatous foci can be found in the intimal lining of the
 nor m a l a n d a bnor m a l a natom y 2 31
coronary arteries, and may be responsible for significant 9. Shem-Tov A, Schneeweiss A, Motro M, Neufeld HN. Clinical
obstruction. presentation and natural history of mild discrete subaortic ste-
nosis. Follow-up of 1–17 years. Circulation 1982;66:509.
Holt-Oram Syndrome 10. Morrison RW, Edwards JE. Subaortic stenosis. Report of two
cases, one associated with patent ductus arteriosus, the other
This syndrome is also known as the heart–hand syndrome, complicated by bacterial endocarditis. Int Assoc Med Mus Bull
or the heart–upper limb syndrome. As the names suggest, 1950;31:73.
the syndrome involves the heart and the arms. The usual 11. Maron BJ, Redwood DR, Roberts WC, et al. Tunnel subaortic
cardiac anomaly is an interatrial communication within stenosis. Left ventricular outflow tract obstruction produced
the oval fossa. Skeletal malformations of the arm are by fibromuscular tubular narrowing. Circulation 1976;54:404.
12. Peterson TA, Todd DB, Edwards JE. Supravalvular aortic steno-
characteristic.64
sis. J Thorac Cardiovasc Surg 1965;50:734.
13. Giddins NG, Finley JP, Nanton MA, Roy DL. The natural
Down Syndrome course of supravalvar aortic stenosis and peripheral pulmonary
This syndrome, produced by trisomy of the 21st chromo- artery stenosis in Williams’ syndrome. Br Heart J 1989;62:
some, is accompanied by congenital cardiac malformations 315.
14. Wren C, Oslizlok P, Bull C. Natural history of supravalvular
in two fifths of afflicted patients. The lesions typically
aortic stenosis and pulmonary artery stenosis. J Am Coll
involve the septal structures, with a ventricular septal defect Cardiol 1990;15:1625.
being most common, followed by an atrioventricular septal 15. D’Cruz IA, Arcilla RA, Agustsson MH. Dilatation of the pul-
defect with common atrioventricular junction, although monary trunk in stenosis of the pulmonary valve and of the
afflicted individuals may simply exhibit an enlarged mem- pulmonary arteries in children. Am Heart J 1964;68:611.
branous septum, or an isolated cleft of the aortic leaflet of 16. Parker RL. Pulmonary stenosis: tetralogy of Fallot. Med Clin
the mitral valve.65 Some patients have isolated persistent North Am 1948;32:855.
patency of the arterial duct. 17. Shone JD, Sellers RD, Anderson RC, et al. The developmental
complex of “parachute mitral valve,” supravalvular ring of left
Turner Syndrome atrium, subaortic stenosis, and coarctation of aorta. Am J
Cardiol 1963;11:714.
Turner syndrome is commonly associated with coarctation 18. Edwards JE, Christensen NA, Clagett OT, McDonald JR. Patho-
of the aorta.66 Pulmonary valvar stenosis, or deficiency of the logic considerations in coarctation of the aorta. Proc Mayo Clin
ventricular septum, occur less frequently.67 1948;23:324.
19. Edwards JE, Clagett OT, Drake RL, et al. The collateral circula-
tion in coarctation of the aorta. Proc Mayo Clin 1948;23:333.
Summary 20. Becker AE, Becker MJ, Edwards JE. Anomalies associated with
coarctation of aorta. Particular reference to infancy. Circula-
tion 1970;41:1067.
In this chapter, we have described the salient anatomy of the 21. Edwards JE. Aneurysms of the thoracic aorta complicating
normally formed and congenitally malformed heart. coarctation. Circulation 1973;48:195.
22. Edwards JE. Floppy mitral valve syndrome. Cardiovasc Clin
Acknowledgments 1987;18:249.
23. Lucas RV Jr, Edwards JE. The floppy mitral valve. Curr Probl
This chapter was based on the chapter in the previous edition Cardiol 1982;7:1.
by Jack L. Titus and Jesse C. Edwards. 24. Salazar AE, Edwards JE. Friction lesions of ventricular endo-
cardium. Relation to chordae tendineae of mitral valve. Arch
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25. Schreiber C, Cook A, Ho SY, et al. Morphologic spectrum of
1. Cook AC, Anderson RH. Editorial. Attitudinally correct Ebstein’s malformation: revisitation relative to surgical repair.
nomenclature. Heart 2002;87:503. J Thorac Cardiovasc Surg 1999;117:148.
2. Roberts WC. The congenitally bicuspid aortic valve: a study of 26. Weaver WF, Edwards JE, Brandenburg RO. Idiopathic dilation
85 autopsy cases. Am J Cardiol 1970;26:83. of the aorta with aortic valvular insufficiency: a possible forme
3. Edwards JE. The congenital bicuspid aortic valve. Circulation fruste of Marfan’s syndrome. Mayo Clin Proc 1959;34:518.
1961;23:485. 27. Brown OR, deMots H, Kloster FE, et al. Aortic root dilation and
4. Peterson MD, Roach RM, Edwards JE. Types of aortic stenosis mitral valve prolapse in Marfan’s syndrome. An echocardiog-
in surgically removed valves. Arch Pathol Lab Med 1985;109: raphy study. Circulation 1975;52:651.
829. 28. Kawashima Y, Danno M, Shimizu Y, et al. Ventricular septal
5. Subramaniam R, Olsen LJ, Edwards WD. Surgical pathology of defect associated with aortic insufficiency. Anatomic classifi-
combined aortic stenosis and insufficiency: a study of 213 cation and method of operation. Circulation 1973;47:1057.
cases. Mayo Clin Proc 1985;60:247. 29. Fouget JM, Kelly CE, Pilz CG. Congenital absence of the pul-
6. Edwards JE. Varieties of valvular heart disease. Aortic valvular monic valve. Report of a case in a seventy-three year old man.
disease. Pract Cardiol 1982;8:117. Am J Cardiol 1967;29:732.
7. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertro- 30. Craig RJ, Selzer A. Natural history and prognosis of atrial
phy (ASH): the unifying link in the IHSS disease spectrum. septal defect. Circulation 1968;37:805.
Observations regarding its pathogenesis, pathophysiology, and 31. Campbell M. Natural history of atrial septal defect. Br Heart J
course. Circulation 1973;47:827. 1970;32:820.
8. Somerville J, Stone S, Ross D. Fate of patients with fixed 32. Anderson RH, Webb S, Brown NA. Clinical anatomy of the
subaortic stenosis after surgical removal. Br Heart J 1980;443: atrial septum with reference to its developmental components.
629. Clin Anat 1999;12:362.
232 chapter 9

33. Anderson RH, Ho SY, Falcao S, et al. The diagnostic features 51. Uemura H, Ho SY, Devine WA, et al. Analysis of visceral het-
of atrioventricular septal defect with common atrioventricular erotaxy according to splenic status, appendage morphology, or
junction. Cardiol Young 1998;8:33. both. Am J Cardiol 1995;76:846.
34. Hagen PT, Scholz DG, Edwards WD. Incidence and size of 52. Winter FS. Persistent left superior vena cava. Survey of world
patent foramen ovale during the first 10 decades of life. Mayo literature and report of thirty additional cases. Angiology 1954;
Clin Proc 1984;59:17. 5:90.
35. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneu- 53. Knauth A, McCarthy KP, Webb S, et al. Interatrial communica-
rysm and stroke. A transesophageal echocardiographic study. tion through the mouth of the coronary sinus. Cardiol Young
J Am Coll Cardiol 1991;18:1233. 2002;12:373.
36. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as 54. Moller JH, Nakib A, Anderson RC, Edwards JE. Congenital
a risk factor for cryptogenic stroke. Ann Intern Med 1992;117: cardiac disease associated with polysplenia. A developmental
461. complex of bilateral “left-sidedness.” Circulation 1967;36:789.
37. Petty GW, Khandheria BK, Chu CP, et al. Patent foramen ovale 55. Goldman A. Arteriovenous fistula of the lung: its hereditary
in patients with cerebral infarction. A transesophageal echo- and clinical aspects. Am Rev Tuberc 1948;57:266.
cardiographic study. Arch Neurol 1997;54:819. 56. Armenirout HL, Underwood FJ. Familial hemorrhagic telangi-
38. Tandon R, Moller JH, Edwards JE. Tetralogy of Fallot associated ectasia with associated pulmonary arteriovenous aneurysm.
with persistent common atrioventricular canal (endocardial Am J Med 1950;8:246.
cushion defect). Br Heart J 1974;36:197. 57. Moyer JH, Glantz G, Brest AN. Pulmonary arteriovenous
39. Edwards JE, Burchell HB, Christensen NA. Specimen exhibit- fistula: physiologic and clinical considerations. Am J Med 1962;
ing the essential lesion in aneurysm of the aortic sinus. Proc 32:417.
Mayo Clin 1956;31:407,464. 58. Dines DE, Arms RA, Bernatz PE, Gomes MR. Pulmonary arte-
40. Sakakibara A, Yokoyama M, Takno A, et al. Coronary arterio- riovenous fistulas. Mayo Clin Proc 1974;49:460.
venous fistula. Nine operated cases. Am Heart J 1966;72:307. 59. Vlodaver Z, Neufeld HN, Edwards JE. Coronary Arterial Varia-
41. McNamura JJ, Gross RE. Congenital coronary artery fistula. tions in the Normal Heart and in Congenital Heart Disease.
Surgery 1969;65:59. New York: Academic, 1975.
42. Cooley DA, Ellis PR Jr. Surgical considerations of coronary 60. Mahowald JM, Blieden LC, Coc JI, et al. Ectopic origin of a
arterial fistula. Am J Cardiol 1962;10:467. coronary artery from the aorta. Sudden death in 3 of 23 patients.
43. Becker AE, Anderson RH. How should we describe hearts in Chest 1986;89:668.
which the aorta is connected to the right ventricle and the 61. Wesselhoeft H, Fawcett JS, Johnson AL. Anomalous origin of
pulmonary trunk to the left ventricle? A matter for reason and the left coronary artery from the pulmonary trunk. Its clinical
logic. Am J Cardiol 1983;51:911. spectrum, pathology, and pathophysiology, based on a review
44. Lieberson AD, Schumacher RR, Childress RH, Genovese PD. of 140 cases with seven further cases. Circulation 1968;38:
Corrected transposition of the great vessels in a 73-year-old 403.
man. Circulation 1969;39:96. 62. Smith A, Arnold R, Anderson RH, et al. Anomalous origin of
45. Cumming GR: Congenital corrected transposition of the great the left coronary artery from the pulmonary trunk. Anatomic
vessels without associated intracardiac anomalies. A clinical findings in relation to pathophysiology and surgical repair. J
hemodynamic and angiographic study. Am J Cardiol 1962;10: Thorac Cardiovasc Surg 1989;98:16.
605. 63. Wagenvoort CA, Nenfeld HN, Edwards JE. Cardiovascular
46. Hickie JB, Gimletre TMD, Bacon APC. Anomalous pulmonary system in Marfan’s syndrome and in idiopathic dilatation of
venous drainage. Br Heart J 1956;18:365. the ascending aorta. Am J Cardiol 1962;9:496.
47. Al Zaghal AM, Li J, Anderson RH, et al. Anatomical criteria 64. Holt M, Oram S. Familial heart disease with skeletal malfor-
for the diagnosis of sinus venosus defects. Heart 1997;78:298. mations. Br Heart J 1960;22:236.
48. Kiely B, Filler J, Stone S, Doyle EF. Syndrome of anomalous 65. Spicer RL. Cardiovascular disease in Down syndrome. Pediatr
venous drainage of the right lung to the inferior vena cava. A Clin North Am 1984;31:1331.
review of 67 reported cases and three new cases in children. 66. Palmer CG, Reichmann A. Chromosomal and clinical find-
Am J Cardiol 1967;20:102. ings in 100 females with Turner syndrome. Hum Genet 1976;
49. Halasz NA, Halloran KH, Liebow AA. Bronchial and arterial 35:35.
anomalies with drainage of the right lung into the inferior vena 67. Nora JJ, Torres FG, Sinha AK, McNamara DG. Characteristic
cava. Circulation 1956;14:826. cardio-vascular anomalies of XO Turner syndrome, XX and XY
50. Peoples WM, Miller JH, Edwards JE. Polysplenia: A review of phenotype and XO/XX Turner mosaic. Am J Cardiol 1970;25:
146 cases. Pediatr Cardiol 1983;4:129. 639.
 1 Pathophysiology, Clinical
0 Recognition, and
Treatment of Congenital
Heart Disease
Steven R. Neish and Jeffrey A. Towbin

Left-to-Right Shunt Lesions . . . . . . . . . . . . . . . . . . . . . . . 235 Coronary Artery Anomalies . . . . . . . . . . . . . . . . . . . . . . . 269

Congenital Valve Abnormalities . . . . . . . . . . . . . . . . . . . 247 Aneurysms of the Sinus of Valsalva. . . . . . . . . . . . . . . . . 269
Complex Congenital Heart Disease. . . . . . . . . . . . . . . . . 256 Pregnancy and Congenital Heart Disease. . . . . . . . . . . . 270
Great Vein Malpositions . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Key Points • Subvalvular aortic stenosis has three types: membranous

subaortic stenosis, a fibromuscular tunnel type, and an
• Atrial level communications include any of the follow- idiopathic hypertrophic subaortic stenosis type.
ing: (1) ostium secundum atrial septal defect (ASD), (2) • Pulmonary stenosis may be valvular, supravalvular, or
ostium primum atrial septal defect, (3) sinus venosus subvalvular.
atrial septal defect, and (4) coronary sinus atrial septal • Congenital mitral stenosis in adults is uncommon. Shone
defect. The common ASD among these are the ostium syndrome describes the occurrence of multiple levels of
secundum ASD representing approximately 70% of all obstruction to blood flow into and out of the left ventricle
ASDs. With all of the ASDs, significant pulmonary hyper- and in the aorta. The classic picture includes mitral ste-
tension rarely occurs before the third to fourth decade. nosis with a parachute mitral valve (single papillary
• Fifty percent or more of ventricular septal defects (VSDs) muscle), subaortic stenosis, a bicuspid aortic valve, and
close spontaneously in early childhood, even as late as coarctation of the aorta.
adolescence. The VSDs with large left-to-right shunts • Tricuspid stenosis is generally acquired rather than
may lead to severe pulmonary hypertension with bidirec- congenital and causes include rheumatic heart disease,
tional or right-to-left shunting and cyanosis in the carcinoid syndrome, and right atrial myxoma.
adult. • Ebstein’s anomaly consists of downward displacement
• Patent ductus arteriosus leads to a continuous systolic of the tricuspid valve “atrializing” the inflow tract of
diastolic murmur under the left clavicle and places the the right ventricle. Tricuspid insufficiency, right-to-left
patient at risk for infection at the ductus site, and when shunts at the atrial level, and supraventricular arrhyth-
it leads to a large left-to-right shunt, may cause severe mias often coexist.
pulmonary hypertension. • Coarctation of the aorta as manifested in the adult is
• Aortic valve stenosis in the child and early in adulthood almost always at or just distal to the ligamentum arterio-
is usually caused by a bicuspid or a unicuspid valve. sum and the take-off of the left subclavian artery. This
• Supravalvular aortic stenosis occurs in two settings. often leads to hypertension in the arms and reduced pres-
Williams syndrome is a dysmorphic syndrome caused sures and pulses in the lower extremities sometimes
by a mutation of the elastin gene or chromosome 7, often with some growth retardation in the legs.
associated with hypercalcemia in infancy. The second • Tetralogy of Fallot consists of a large VSD, pulmonary
group of patients with supravalvular aortic stenosis have stenosis, either valvular or infundibular or both, right
a familial form without hypercalcemia, dysmorphic fea- ventricular hypertrophy, and overriding of the ventricu-
tures, or behavioral abnormalities. lar septum by a dilated aorta.

233
234 chapter 10

• Transposition of the great arteries in the adult exists as complication through reparative surgery if they had been
D-transposition, L-transposition, and double-outlet RV. born a decade later.6 Others have been surgically corrected
• Truncus arteriosus exists as three types. Type I has a but may have sequelae related to either their native disease
common trunk, but this gives rise to separate ascending or some complication of therapy. Some remain with signifi-
aorta and pulmonary trunk. In type II, the truncus cant cardiovascular disease because their defect was too
extends up to the right and left pulmonary artery bifurca- complex to repair. And finally, there are patients with condi-
tions. In type III, there is no separate pulmonary trunk. tions that escape detection during routine physical examina-
tion, such as atrial septal defect and bicuspid aortic valve.
In 1897, Maude Abbott wrote her first paper on heart It has become increasingly apparent that patients who
murmurs. The following year she was made curator of the have undergone surgical correction of congenital heart
McGill University medical museum in Montreal. She began disease frequently have complications later in adulthood.
a formal study of congenital heart disease by studying patho- The ligation and division of a patent ductus arteriosus perhaps
logic specimens, encouraged by Sir William Osler. In 1908, comes closest to a complete cure. Even patients with closed
Osler included Abbott’s chapter on congenital heart disease atrial septal defects occasionally are plagued in later life by
in his text called Modern Medicine.1 That chapter was the supraventricular tachyarrhythmias, especially atrial fibrilla-
definitive statement on congenital heart disease in the early tion and atrial flutter. Therefore, most patients seen by car-
20th century. In 1936, Abbott published her classic text, diologists interested in adult congenital heart disease are
Atlas of Congenital Cardiac Disease,2 in which she described those with previously “corrected” congenital heart disease
hundreds of pathologic specimens and provided the frame- who have sequelae later in life. However, a significant minor-
work that allowed congenital heart disease to move past ity consists of those with hitherto undiagnosed congenital
being a curiosity. heart disease, inoperative heart disease, or congenital heart
In 1930, early in her career, Helen Taussig was appointed disease for which the patient has refused surgery. Significant
to head the cardiac clinic at the Harriet Lane home at Johns advances in therapy, including surgery, pacemakers, better
Hopkins Hospital in Baltimore. In a revolutionary way, she treatment modalities for heart failure, and improved man-
began to understand the patterns that differentiated children agement of hyperviscosity syndromes, have increased the
born with various forms of congenital heart disease. She life expectancy of such patients.
recognized that the degree of pulmonary blood flow pro- In earlier eras of congenital heart disease care, the physi-
foundly affected the long-term course of many children with cian who cared for adults could ignore some of the more
more severe congenital heart disease. She began to look for common defects, such as hypoplastic left heart syndrome
a way to apply this observation. In 1941, Alfred Blalock (HLHS), as children with HLHS and some of the other
moved from Vanderbilt University to Johns Hopkins Hospi- complex defects never survived to adulthood. Some defects,
tal and, shortly after Blalock’s move, Taussig approached such as bicuspid aortic valve or ventricular septal defect are
Blalock and proposed that he attempt to attach the subcla- much more common, and survival into adulthood has been
vian artery to the pulmonary artery to augment pulmonary the rule for decades. This chapter concentrates on both the
blood flow in children with critically restricted pulmonary most common congenital heart defects, as well as some of
blood flow. In 1944, the first operation was performed that the rarer defects that have the potential to present on a
came to be known as the Blalock-Taussig operation. The first regular basis to adult cardiology clinics.
three applications of this “B-T shunt” were described in 1945 The incidence of congenital heart disease varies with the
and the door to real therapy for children with congenital population studied and the age of the patients in the study.
heart disease was opened.3 In general, though, the order of frequency for the 10 most
Successful open-heart surgery to correct septal defects in common congenital heart defects is as follows:
humans was ushered in by the pioneering work of C. Walton
1. Ventricular septal defect (VSD)
Lillehei,4 who closed a ventricular septal defect in a 4-year-
2. Atrial septal defect (ASD)
old boy, using the boy’s father for cross-circulation in 1954.
3. Aortic stenosis (AS)
In the early days of open-heart surgery, the results of surgery
4. Pulmonic stenosis (PS)
frequently were uncertain. Also, there were many adults
5. Coarctation of the aorta (COA)
with congenital heart disease who had grown up before the
6. Patent ductus arteriosus (PDA)
development of heart surgery. Congenital heart disease
7. Tetralogy of Fallot (TOF)
clinics were filled with patients with unoperated congenital
8. Transposition of the great arteries (TGA)
heart disease, some of whom had survived into adulthood.
9. Atrioventricular septal defect (AVSD)
Today, most children with significant congenital heart
10. Hypoplastic left heart syndrome (HLHS)
disease have palliative or corrective surgery in infancy or
childhood. Some of these operations are “reparative” while Congenital anomalies of the aortic valve actually are more
others are best described as complex palliations. Today, the common than is represented by the above list, but many, if
cardiologist with an interest in congenital heart disease in not most, patients with a functionally bicuspid aortic valve
adults sees a combination of patients whose course is often are not diagnosed until adulthood.7
characterized by when and where they were born.5 There are The cardiologist treating adults should still be able to
still patients with Eisenmenger’s syndrome (pulmonary diagnose congenital heart disease, or at least to narrow down
hypertension with severe cyanosis due to unrepaired con- the diagnostic possibilities by both clinical and laboratory
genital heart disease associated with chronic shunts), surviv- methods.8 This is equally true in the long-term follow-up of
ing into adulthood, who would have avoided that tragic such patients, especially if they have undergone surgery,
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 235
because the natural history of the disease will have been TABLE 10.1. Paradigm to left-to-right shunts at the atrial level
altered by the operation itself. This demands thorough Electrocardiogram,
knowledge of the operative techniques used at the time of Cyanosis frontal plane axis
surgical intervention—many of which have changed consid- Atrial septal defect, 0 Normal
erably in recent years.8 secundum type
Atrioventricular canal
Ostium primum 0 Left
Left-to-Right Shunt Lesions Common atrium + Left
Complete + Left
Anomalous pulmonary
The most frequent physiologic abnormality caused by con- venous connection
genital heart disease is left-to-right shunting, resulting in
Partial 0 Normal
pulmonary overcirculation.9 The term left-to-right shunt
Complete + Normal
refers to blood in the systemic circulation (i.e., pulmonary
veins, left atrium, left ventricle, or aorta) shunting into the
circulation somewhere after the blood leaves the systemic
capillary bed and before it reaches the pulmonary capillary In practice, the overwhelming majority of atrial septal
bed. Abnormal communications can exist at atrial or ven- defects (ASDs) are ostium secundum ASDs, representing
tricular levels, the shunting can be atrioventricular or aorto- about 70% of all atrial communications. Ostium primum
pulmonary, or the pulmonary veins can connect somewhere ASD is second in prevalence. Sinus venosus ASD is uncom-
other than the left atrium. Such communications result in mon, and coronary sinus ASD is extremely rare. Patients
shunting of blood, the direction of flow being determined by with uncomplicated atrial communications frequently arrive
the pressure gradient or the difference in resistance between at adulthood undiagnosed (Table 10.1).
pulmonic and systemic circulation. Typically, the dominant
direction of flow at these abnormal connections is from the Atrial Septal Defect, Ostium Secundum Type
systemic circulation into the pulmonary circulation (i.e., left
to right) because the impedance of the pulmonary vascula- Atrial septal defect, ostium secundum type, is the most
ture is much lower than the impedance in the systemic common newly diagnosed congenital heart disease in the
circulation. adult, possibly matched only by the bicuspid aortic
A unique physiologic situation exists if the defect results valve.7,9,10,12,13 It is helpful here to review the circulatory phys-
in formation of a common mixing chamber. For example, a iology in the fetus in order to describe how ASDs develop
subset of complete atrioventricular (AV) canal defects con- and physiologically present during life. During fetal life, the
sists of complete absence of the atrial septum (common pressures in the pulmonary artery and the aorta are equal;
atrium). In total anomalous pulmonary venous connection the fetal right ventricle (RV), being adapted for pressure, has
(TAPVC), the right atrium (RA) serves as the common mixing the same compliance as that of the left ventricle (LV). Blood
chamber. In both common atrium and TAPVC, the systemic returning from the placenta (oxygenated blood) flows via the
venous return and the pulmonary venous return mix com- umbilical vein through the ductus venosus and preferen-
pletely at the atrial level, before entering the ventricles. A tially shunts across the foramen ovale. Vestigial preferential
functionally single or common ventricle in which the other right-to-left streaming from the inferior vena cava can be
ventricle is rudimentary would constitute a mixing chamber. demonstrated in adults with atrial septal defects by echocar-
Finally, the septum between the aorta and the pulmonary diography or by indicator dilution techniques; the clinical
artery and the outlet portion of the ventricles may be absent counterpart is paradoxical embolization. At birth, with the
(i.e., truncus arteriosus). In all four of these situations, there infant’s first breath, there is an immediate drop in PVR,
will always be some degree of arterial desaturation, regard- which gradually decreases to normal in the first few months
less of the pulmonary vascular resistance (PVR). of life. At the same time, the RV undergoes regression of
myocardial hypertrophy, gradually changing from its cylin-
drical configuration and thick walls to that characteristic of
Atrial Septal Defect the adult, in which the cavity is more crescentic and the wall
thinner than that of the LV. Therefore, in the fetus, there is
Atrial level communications may include any of the
virtually no left-to-right shunting across the defect. If the
following 9–11:
defect persists, as the PVR falls and the compliance of the
1. Ostium secundum atrial septal defect, representing non- RV increases, left-to-right shunting results and pulmonary
closure of the foramen ovale flow may be two to five times the systemic flow. With time,
2. Ostium primum atrial septal defect, which is a subset of both the RA and the RV enlarge.
AV septal defect or an endocardial cushion defect Significant pulmonary hypertension seldom occurs
3. Sinus venosus atrial septal defect, resulting from failure before the third or fourth decade.12–14 The mechanism by
of the proximal portion of the sinus venosus to be incor- which pulmonary hypertension develops is not well under-
porated into the RA stood. It may rarely start in childhood. Although high flow
4. Coronary sinus atrial septal defect, in which there is a is implicated, it takes many decades for pulmonary hyper-
communication between the coronary sinus and the left tension to develop, and not all patients develop pulmonary
atrium (LA), resulting in flow from the LA to the RA via hypertension.15 Progressive right ventricular enlargement
the orifice of the coronary sinus.5 and hypertrophy may lead to decreased compliance of the RV
236 chapter 10

compared with that of the LV, and therefore, the exclusive

left-to-right shunt also yields some right-to-left shunting.
Right-to-left shunting is not a direct effect of the relative
pressures of the pulmonary artery and of the aorta, but rather
of the compliance of the two ventricles. If left ventricular
compliance also decreases, the atrial pressures rise, and
classic signs of congestive heart failure (CHF) may be present.
The pulmonary artery pressure in atrial septal defects with
shunt reversal is almost always significantly lower than the
systemic pressure. This contrasts with ventricular septal and
aortopulmonary defects, in which shunt reversal and pres-
sure equalization go hand in hand.
Approximately 10% of patients with atrial septal defects
have one or more anomalously connected pulmonary veins.
Mitral insufficiency may coexist in 10% to 20% of these
patients.16 The mitral insufficiency may be due to prolapse
of the posterior leaflet of the mitral valve associated with
secundum ASD and significant right ventricular enlarge-
ment.16 An interesting syndrome has been described (Lutem-
bacher’s syndrome) in which an atrial septal defect coexists
with mitral stenosis;17 in this disorder, patients remain rela-
tively asymptomatic until pulmonary hypertension develops
because the atrial septal defect decompresses the LA, and
therefore the left atrial pressure is not elevated despite sig-
nificant mitral valve obstruction.17–19 Patients with ostium
secundum-type ASDs are seldom symptomatic until they
begin to experience pulmonary hypertension, usually after
the fourth decade,20 if it occurs. It may not occur, however. FIGURE 10.1. Posteroanterior (PA) radiograph in a female patient
Unlike the other atrial communications, there is a 2 : 1 female with a large atrial septal defect. The cardiac silhouette is markedly
to male preponderance in cases of secondary ASD and this enlarged, the pulmonary vasculature is increased, and the main
defect is sometimes familial.21 pulmonary artery is huge. The aorta is inconspicuous, and there is
prominence of the right atrial border.
There is usually a soft systolic flow murmur due to mark-
edly increased pulmonary blood flow. The clinically diagnos-
tic feature, however, is a wide splitting of the second heart
sound (S2), which does not noticeably change with the respi-
described as a “pruned tree” (Fig. 10.2). The ECG is character-
ratory cycle. This wide, fixed splitting of the S2 is variably
ized by an rSR’ in lead V1, usually with a normal QRS axis.
attributed to a variety of theoretical physiologic phenomena.
When pulmonary hypertension develops, electrocardio-
Most likely, it is caused by increased capacitance of the pul-
graphic evidence of right ventricular hypertrophy may
monary arterial circulation and corresponding decreased
become manifest in the form of a tall R wave in lead V1 and
impedance. This increased capacitance leads to a prolonged
a rightward QRS axis.
“hangout interval” at the end of systole. Respiration has a
The echocardiographic picture of ostium secundum atrial
minimal effect on capacitance in this setting, so the splitting
septal defects shows an enlarged RA and RV. The ventricular
of S2 is wide and fixed. The electrocardiogram (ECG) almost
septum moves paradoxically. The atrial septum can be seen
always shows an rSR’ configuration in lead V1. The R’ is
as a “dropout,” especially by transesophageal echocardiogra-
thought to be caused by late activation of the crista supra-
phy. Shunting is demonstrable by color-flow Doppler, and the
ventricularis. This may explain why, after successful closure
pulmonary artery pressure can be estimated if there is tri-
of the atrial septal defect, wide splitting of the second heart
cuspid insufficiency.
sound often persists. The development of pulmonary hyper-
Cardiac catheterization is no longer indicated to confirm
tension accentuates the pulmonary component of the second
the diagnosis of an atrial septal defect. However, it is appro-
heart sound, P2, and ultimately cyanosis appears, at least
priate in middle-aged patients to characterize the pulmonary
with exercise if not at rest.
hemodynamics and to evaluate coexisting coronary artery
disease (CAD) before surgical correction, and also to rule out
Laboratory Findings anomalous pulmonary veins, if they are not accounted for by
echocardiography, for consideration of surgical correction.
Radiographic evaluation of patients with ASDs (Fig. 10.1)
shows an enlarged heart caused by dilatation of the RA and
Prognosis
the RV. The central pulmonary arteries are usually large,
with radiographic evidence of increased pulmonary blood Patients with normal or mildly elevated PVR are usually
flow. When significant pulmonary hypertension develops, asymptomatic, even with vigorous physical activity. They
the radiologic evidence of increased pulmonary flow may have atrial arrhythmias and are at risk for paradoxical
decreases, and the central pulmonary arteries are often embolism. However, the development of significant pulmo-
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 37
However, small ASDs found in childhood may not need
closure. There is some evidence favoring waiting because
about half of such patients have spontaneous closure of the
defect (age 8.4 years).25

PERCUTANEOUS R EPAIR
Open-heart surgery for the closure of defects in the atrial
septum is currently the “gold standard” for treatment of such
patients. The mortality rate for this procedure is close to 0%
in most contemporary reports.26 However, open-heart surgery
is a major procedure, with its attendant morbidity, need for
intensive care, and significant hospitalization. The compli-
cation rates after surgical closure of atrial septal defects in
adult patients can be as high as 13%.27
The pioneering work of King and Mills28,29 resulted in the
development of a double-umbrella ASD device and estab-
lished the feasibility of occluding ASDs with percutaneous
devices. The need for a 23-French delivery sheath and the
cumbersome procedure led to its abandonment. Many other
devices were subsequently developed, including the Rash-
kind single-disk device,30 the Lock USCI “clamshell”
device,31–35 the “buttoned” device, 36–39 the ASDOS device,40–43
the Manodisk device,44 the Das Angel Wings, the Amplatzer
device, the Cardioseal, and a modification of the Cardioseal
FIGURE 10.2. Interatrial septal defect with severe pulmonary
called the Starflex, and the Helex device.45–52 Currently, the
hypertension. Note the increased heart size and the huge central most popular device is the Amplatzer (AGA Medical Corp.,
pulmonary arteries with distal “pruning.” Golden Valley, MN). It is favored for its ease of insertion, low
profile during insertion, and potential for retrievability if the
implantation is unsatisfactory. Investigation of several
nary hypertension causes functional impairment, heart devices is ongoing and it is likely that “full-service” cathe-
failure, and shortened life span, but severe pulmonary hyper- terization services will eventually employ more than one
tension develops only in a minority of patients (<15%). device, depending on the unique nature of an individual
However, there is substantial evidence that the persistence ASD.53 The closure of hemodynamically significant ASDs in
of the larger left-to-right shunt in itself shortens life expec- adults is now becoming the standard of care54 and, when
tancy, with survival beyond age 50 years of age being less compared with surgical closure, performs well from the
than 50%. Factors contributing to this include the develop- standpoint of outcome and cost.55
ment of pulmonary hypertension, which overtaxes the
volume-overloaded RV. The decreased diastolic compliance Late Complications
of the aging LV may further increase the left-to-right shunt-
Occasionally, patients have arrhythmias late, following suc-
ing, and supraventricular tachyarrhythmias and paradoxical
cessful surgical ASD repair or device closure56–60 (Fig. 10.3).
embolism further complicate the course.14,16,22
Sinus node dysfunction often precedes the onset of more
complicated arrhythmias. Sick sinus syndrome may develop
Treatment
with alternating bradycardia and tachycardia. The tachyar-
Because the mortality risk of surgical closure of an un- rhythmias that are common are atrial flutter and atrial fibril-
complicated secundum atrial septal defect is approximately lation. Endocarditis does not occur in cases of isolated ostium
1% or less, and the adverse consequences (i.e., pulmonary secundum ASD.
hypertension, paradoxical embolism, and shortened life In patients in whom closure of an ASD is contraindicated
expectancy) have a higher risk, early closure should be rec- by a high pulmonary vascular resistance, treatment is based
ommended, even when patients are asymptomatic. However, on symptomatic care. Adequate control of the ventricular
when there is severe pulmonary hypertension, especially rate, especially with atrial arrhythmias, and judicious use of
with right-to-left shunting, the pulmonary/systemic flow oxygen are helpful. Anticoagulation with low-dose warfarin
ratio may be closer to 1, and closure would be contraindi- (Coumadin) is advisable to minimize paradoxical embolism.
cated since ASD closure would not be expected to improve Endocarditis does not occur in patients with the secundum
pulmonary hypertension. In such cases, lung transplantation type of defect per se, because flow across the large defect is
with closure of the defect or heart-lung transplantation could at a low pressure. However, if mitral valve prolapse coexists,
be considered.23,24 Closure of the ASD should be recom- the considerations for infective endocarditis prophylaxis
mended, even if patients are asymptomatic; if there is sig- would be those pertaining to isolated mitral valve prolapse.
nificant pulmonary overcirculation. If the Qp : Qs ratio is less Cardiopulmonary transplantation would be a consideration
than 1.3–1.5 : 1, there may not be evidence to support defect in patients with advanced pulmonary vascular disease who
closure, either by surgery or by catheter-placed device. are disabled.
238 chapter 10

I II
III

aVR aVL aVF

V1 V3
V2

FIGURE 10.3. Electrocardiogram of a patient

with an ostium primum defect, severe pulmo-
nary hypertension, and mitral insufficiency
through a cleft anterior leaflet. Note the left-
axis deviation, right ventricular hypertrophy,
V4 V5 V6 and atrial flutter.

Ostium Primum Atrial Septal Defect is very similar to that of a secundum-type ASD unless there
is severe mitral insufficiency, in which case there is evidence
Ostium primum ASD is an endocardial cushion defect in of left atrial enlargement as well. The ECG has the charac-
which the septum primum (i.e., the lower portion of the teristic rSR’ in lead V1, but in addition, the frontal plane QRS
atrial septum) fails to develop, as does the atrioventricular axis is always leftward, and there is often first-degree heart
septum. In this situation, the anterior leaflet of the mitral block (Fig. 10.4). With pulmonary hypertension, the chest
valve is attached to the ventricular septum in a somewhat leads show right ventricular hypertrophy (Fig. 10.5).
lower position than normal and is therefore at the same level Until and unless pulmonary hypertension develops, the
as the tricuspid valve. The anterior leaflet is cleft and, because atrial shunting is left to right, and there is no cyanosis. When
of its lower position, has characteristic angiographic61 and the mitral insufficiency is severe, there may not be a signifi-
echocardiographic20 features. The mitral valve cleft is associ- cant elevation of atrial pressures, because the RA has high
ated with various degrees of mitral regurgitation. Typically, capacitance and the RV is adapted for volume overload and
the hemodynamic disturbance of an ostium primum ASD is accepts the increased left-to-right shunt. However, with a
more severe than an ostium secundum ASD. This is particu- decrease in compliance of a failing RV due to chronic volume
larly true if there is significant mitral valve insufficiency. It overload or a hypertrophied RV because of pulmonary hyper-
is rare for a patient with an ostium primum ASD to reach tension, atrial pressures rise, and the pulmonary venous
adulthood undiagnosed. pressure can be estimated from inspection of the neck
The clinical diagnosis of an ostium primum ASD has veins.
many of the features of those associated with a secundum- The natural history of ostium primum ASDs differs
type ASD (i.e., hyperactive RV; wide, fixed splitting of the significantly from that of a secundum-type ASD. Ostium
second heart sound; and a pulmonary flow murmur). primum defects are susceptible to infective endocarditis of
However, there is usually an additional murmur of mitral the cleft mitral valve. If the mitral regurgitation is severe,
insufficiency. This does not necessarily radiate to the axilla, patients may have dyspnea and left ventricular dysfunction,
because the regurgitant jet is directed more medially than and if the right ventricular compliance is compromised,
toward the free wall of the LA. If the mitral regurgitation is there are signs of both right ventricular and left ventricular
severe or if pulmonary hypertension develops, decreased failure.
exercise tolerance and exertional dyspnea can be expected. Patients with complete AV canal seldom survive to late
Examination finding may also include a left ventricular adulthood without cardiac surgery. The ECG shows left axis
filling sound [the third heart sound (S3) of mitral insuffi- deviation, right ventricular hypertrophy, large P waves, and
ciency] and a fourth heart sound (S4). The chest x-ray result various degrees of AV block (Fig. 10.6).
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 239

V1 V4
1 aVR

2 aVL
V2 V5

3 aVF
V3 V6
FIGURE 10.4. Electrocardiogram of a patient with an ostium primum. Note the left-axis deviation, incomplete right bundle branch block
in V2, and first- and second-degree atrioventricular block.

Laboratory Studies are at the same level. There is mitral insufficiency of varying
degree, an enlarged RV, paradoxical septal motion, and
The echocardiogram classically demonstrates a low-lying enlarged atria. Angiographically, the left ventriculogram
ASD with no continuity between the anterior leaflet of the reveals a “goose-neck” deformity (Fig. 10.7), related to the
mitral valve and the aortic valve, and a cleft in the anterior unusual attachment of the anterior leaflet of the mitral valve,
leaflet of the mitral valve.20 The mitral and tricuspid valves and some degree of mitral insufficiency.61

V1

V2

V3
II

V4

III

V5

aVR aVL aVF

V6

FIGURE 10.5. Electrocardiogram of a patient with an atrial septal patient has slow flutter with varying atrioventricular conduction,
defect of secundum type with severe pulmonary hypertension. Note which resembles “paroxysmal atrial tachycardia with block” and
the right-axis deviation and right ventricular hypertrophy. This may be mistaken for digitalis intoxication.
240 chapter 10

V1 V4
1 aVR

2 aVL
V2 V5

3 aVF
V3 V6
FIGURE 10.6. Electrocardiogram of a patient with an ostium primum. Note the left-axis deviation, incomplete right bundle branch block
in V2, and first- and second-degree atrioventricular block.

Prognosis transcatheter closure, in contrast to the secundum type of

septal defect, because the lower border of the defect is in
The large left-to-right shunt may eventually lead to pulmo-
direct continuity with the anterior leaflet of the mitral valve.
nary hypertension. The cleft mitral leaflets result in increas-
Precautions during surgical closure include not encroaching
ing mitral regurgitation and left ventricular dysfunction and
on or injuring the AV node and the bundle of His. Therefore,
is susceptible to infective endocarditis. Finally, AV block
patching rather than direct suturing is required. The treat-
may develop as part of the natural history of endocardial
ment of the cleft mitral valve depends on the degree of mitral
cushion defects.
regurgitation. However, valvuloplasty is often feasible in
skillful hands. If closure of the cleft in the anterior leaflet of
Treatment
the mitral valve is overly aggressive or if there is insufficient
The definitive treatment for an ostium primum defect is native mitral valve tissue, mitral stenosis may occur. Should
early surgical closure.62 The condition is not suitable for the patient show evidence of advanced second- or third-

FIGURE 10.7. (A,B) Left ventriculogram of a 21-year-old woman detachment of the anterior leaflet of the mitral valve to the ven-
after surgery for closure of an ostium primum defect. Note the usual tricular septum so it is at the same level as the tricuspid valve,
“bite” out of the inferomedial portion of the left ventricle, giving whereas normally it is attached more superiorly.
rise to the so-called goose-neck deformity. This is due to the lower
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 41
degree AV block, biventricular or dual chamber (DDD) pacing difficult in the hands of an experienced operator. The coro-
would be advisable but only after the ASD has been closed, nary sinus yields a rather high oxygen saturation, in contrast
because the electrodes are thrombogenic and paradoxical to the normally very low saturation. It may be difficult to
embolization may occur. distinguish between a coronary sinus ASD and partial anom-
alous pulmonary venous connection to the coronary sinus.
Prognosis However, the coronary sinus ASD is more proximal, and
sampling of the more distal blood in the coronary sinus
The prognosis for ostium primum atrial septal defects that should yield a low saturation, whereas with an anomalous
have undergone surgical closure depends on the degree of pulmonary venous connection to the coronary sinus, there
pulmonary vascular disease, complications associated with is a higher saturation throughout the coronary sinus. This
mitral valve prostheses, and left ventricular function. If the entity is of some clinical importance because the coronary
mitral insufficiency has been relatively severe and long- sinus ostium can be rather large, and there have been rare
standing, even mitral valve replacement may provide only a instances in which the coronary sinus ostium has been mis-
short-term reprieve from eventual failure of the LV. takenly closed for an atrial septal defect.

Common Atrium Partial Anomalous Pulmonary Venous Connection

Common atrium is a variant of AV canal defect. It is char- The connection of one or more pulmonary veins to a struc-
acterized by a total absence of the atrial septum and a cleft ture other than the LA should be considered in patients with
in the anterior leaflet of the mitral valve. The clinical profile clinical or radiographic evidence of left-to-right shunting at
differs from classic AV canal in that these patients invari- the atrial level.66 Partial anomalous pulmonary venous con-
ably have right-to-left shunting at the atrial level. Frequently, nection may occur with no atrial communication.67 It may
patients with a common atrium have some cyanosis, if not coexist in approximately 10% of secundum-type ASDs. The
at rest at least with exercise, because the common atrium insertion may be directly into the superior vena cava; into a
acts as an incomplete mixing chamber. The ECG is essen- vertical vein that goes into the innominate vein and then
tially the same as with an ostium primum atrial septal into the superior vena cava; into the RA directly; to the coro-
defect. The echocardiogram differs in that there is complete nary sinus68; or, rarely, into the inferior vena cava (scimitar
absence of the atrial septum. Because of the pulmonary syndrome)69 (Fig. 10.8). If the cardiologist is alert to the pos-
overcirculation, these patients are symptomatic at an earlier sibility, the echocardiographer who is warned is usually able
age than other atrial septal defects, and surgical creation
of an atrial septum is usually performed in the first year
of life.

Sinus Venosus Atrial Septal Defect

Sinus venosus ASD is an ASD located posteriorly subjacent
to the superior vena cava. It is almost always associated with
the anomalous insertion of at least one pulmonary vein adja-
cent to the superior vena cava. Clinically, it is indistinguish-
able from a secundum type of atrial septal defect. On
echocardiography, the defect is seen posteriorly rather than
in the area of the foramen ovale, and an anomalous pulmo-
nary vein can be identified. Successful surgical closure of
this defect is more difficult because of the presence of an
anomalous pulmonary vein adjacent to the superior vena
cava, and some degree of dehiscence of the patch near that
area is common. As long as the residual left-to-right shunt
is small, it should not cause difficulty.63,64

Coronary Sinus Atrial Septal Defect

A congenital defect may occur between the coronary sinus
and the LA, which results in a left-to-right shunt that physi-
ologically resembles an atrial septal defect.65 The cause of a
coronary sinus ASD is unroofing of the coronary sinus into
the left atrium. This entity can be suspected when echocar-
diography fails to identify an ASD in the presence of clinical
and radiographic evidence of a left-to-right shunt. Cardiac FIGURE 10.8. Posteroanterior radiograph of patient with partial
anomalous venous return to the inferior vena cava (scimitar syn-
catheterization yields an oximetry series that is consistent drome). The heart is normal in size, as is the pulmonary vascula-
with a shunt at the atrial level. A useful maneuver is to ture. The anomalous drainage through a large scimitar vein (arrows)
introduce the catheter into the coronary sinus, which is not is well demonstrated.
242 chapter 10

to identify these. They may also be identified through cardiac The predominant type of congenital isolated VSD seen
catheterization techniques using selective pulmonary arte- in adults is that termed the Eisenmenger complex (i.e., a large
riography (including the levophase) or by means of selective VSD with severe pulmonary vascular obstruction and bidi-
indicator dilution techniques. It is important to be alert to rectional shunting).74
these veins because the closure of an ostium secundum-type
ASD alone only partially decreases the left-to-right shunt if
several anomalous pulmonary veins coexist. Small Ventricular Septal Defect
(Maladie de Roger)
Ventricular Septal Defects Patients with small VSDs are totally asymptomatic. The
volume overload of the LV is minimal to mild. The heart size
Isolated ventricular septal defects (VSDs) are infrequently
remains normal, and pulmonary hypertension does not
seen in adults.70 Fifty percent or more of VSDs close sponta-
develop on the basis of this defect alone. The sole risk is that
neously in early childhood, even as late as adolescence.71,72 If
of infective endocarditis.
the VSD is small, these defects are associated with little or
Rarely, a moderate-size defect may be converted to a
no hemodynamic disturbance of the LV and result in only a
smaller defect by adhesion of the septal leaflet of the tricus-
small left-to-right shunt and no pulmonary hypertension.
pid valve, aneurysm formation of the membranous septum,
Large defects are associated with equalization of pressure in
or prolapse of an aortic cusp. This prolapsed cusp may in
the two ventricles and therefore in the pulmonary artery. In
time become adherent to the VSD, partly occluding it func-
a large VSD, the direction and the degree of shunting are
tionally. The patient may then present with primarily aortic
determined by the relative resistances of the pulmonary
regurgitation and a small VSD.
and systemic circuits. The right-to-left and the left-to-right
The diagnosis of a small VSD is made clinically by the
shunts are more or less balanced if the resistances in the
characteristic holosystolic murmur, starting with the first
systemic and pulmonary circulations are equal. This is the
heart sound. This holosystolic murmur should not be mis-
classic Eisenmenger complex. Large defects with a low to
taken for mitral insufficiency. It is loudest at the left sternal
mildly elevated PVR have large left-to-right shunts with
border but does not radiate to the neck. In mitral regurgita-
severe volume overload of the LV. These are almost invari-
tion caused by a redundant anterior leaflet, the murmur is
ably discovered by a pediatric cardiologist, and the defect is
transmitted to the axilla, whereas if it is associated with a
closed.72 Therefore, in adults, the common forms of congeni-
redundant posterior leaflet, it radiates medially and often is
tal ventricular septal defect are either large ones of the Eisen-
transmitted to the neck. The chest x-ray study and ECG are
menger physiology or those in association with pulmonary
usually normal. The diagnosis is best confirmed echocardio-
stenosis, in which the pulmonary circulation is “protected”
graphically with the color-flow Doppler technique.75,76 It is
from the development of pulmonary vascular disease. Occa-
also readily visualized on the left ventriculogram (Fig. 10.9).
sionally, one may see patients who have a moderate-size
If this is truly a small VSD and not one that has been made
ventricular septal defect, a large left-to-right shunt, and an
small by the prolapse of an aortic cusp, surgery is not indi-
enlarged LV and are symptomatic who present as adults
cated unless there are other unrelated cardiac defects that
(often coming from areas of the world without sophisticated
require surgical correction. The prognosis is good, and the
medical care). Unless there are separate, serious comorbid
chief precaution is the need for prophylaxis against infective
factors, and pulmonary vascular resistance is not severely
endocarditis. If a “small” VSD is associated with significant
elevated, the defect should be closed.
aortic regurgitation due to a prolapsed cusp, the major con-
The most common form of congenital isolated ventricu-
sideration is that of the aortic regurgitation.
lar septal defect is of the so-called perimembranous type,
which is posterior and inferior to the crista supraventricu-
laris, involving what would be the membranous septum and
Large Ventricular Septal Defect
some of the adjacent muscular septum.73 This is situated just
under the septal leaflet of the tricuspid valve and is sub- The rare patient who survives into adulthood with a large
tended by the aortic valve. The bundle of His courses along VSD and a large left-to-right shunt but without severely ele-
the posterior rim of this defect and therefore is not affected, vated pulmonary vascular resistance may exhibit symptoms
but it is vulnerable during surgical closure of the defect. similar to those of patients with significant mitral insuffi-
Single or multiple muscular septal defects may also occur as ciency, both representing examples of left ventricular volume
isolated congenital lesions.73 In early infancy, up to 50% of overload. The chief manifestation is exertional dyspnea as
isolated VSDs are in the trabecular septum. Later, muscular a consequence of elevated left ventricular filling pressure
VSDs are present in about 10% of the cases of VSD. They are causing elevated pulmonary venous pressure. Radiographic
generally multiple and small, so that even in the presence of studies show cardiomegaly, primarily of the LV, and enlarged
large shunts, there is seldom significant elevation of the right central pulmonary arteries with radiologic evidence of
ventricular or pulmonary artery pressure. Although many of increased pulmonary flow. The ECG may show tall voltages
these defects close spontaneously, they may persist and are in the chest leads associated with left ventricular volume
difficult to close completely at the time of surgery because overload. Echocardiography is essential not only to confirm
of heavy trabeculation on the right ventricular aspect of the the large left-to-right shunt but also to determine the type
ventricular septum. The seemingly logical left ventricular and the location.77 Cardiac catheterization is helpful in defin-
approach to closure of the lesion would seriously compro- ing the pulmonary hemodynamics for surgical risk assess-
mise the contractility of the LV. ment and for ultimate prognosis. Left ventricular angiography
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 243

FIGURE 10.9. (A,B) Left ventriculogram of a small ventricular septal defect, best seen in the lateral view (B). Note the normal size of the
left ventricle.

in several views is very helpful. Some of these patients may bundle branch block and left-axis deviation79,80 (Fig. 10.10).
unexpectedly experience a systolic gradient between the RV Rarely in the current era, damage to the conduction system
and the pulmonary artery (Gasul’s phenomenon) without can result in complete AV block, necessitating placement of
having true pulmonary stenosis.78 a pacemaker. There are no extensive data on the late occur-
Surgical closure of VSDs is associated with conduction rence of complete AV block, but it appears to be uncommon.79
abnormalities in as many as 15% of cases, consisting of right These conduction abnormalities are related to the close

6 Sec.

Lead 1 V1 V4

6 Sec.

Lead 2 V2 V5

6 Sec.

Lead 3 V3 V6

Trial rate P-R Interval Patient position

Entricular rate QRS Interval Electrical axis
Hythm Q-T Interval S-T Segment
Waves T Waves
Emarks

aVR aVL aVF

FIGURE 10.10. Electrocardiogram of a patient who underwent part of another entity, such as tetralogy of Fallot. This bifascicular
closure of a ventricular septal defect. Note the left-axis deviation block may uncommonly progress to complete atrioventricular
and right bundle branch block, which are commonly seen after block.
ventricular septal defect closure whether as an isolated defect or as
24 4 chapter 10

proximity of the bundle of His to the posterior wall of the

VSD. Currently, transcatheter device closure of certain VSDs,
particularly certain muscular VSDs and perimembranous
defects, are being used effectively.81–85

Eisenmenger’s Complex
Eisenmenger’s complex is by far the most common presen-
tation of a large VSD in adults.74 These patients exhibit
equalized pressures and resistances in the pulmonary and
systemic circuits from early childhood onward (Fig. 10.10).
At rest, the patients have a bidirectional shunt. With physi-
cal exertion and a decrease in systemic vascular resistance
(SVR), the right-to-left shunting increases, resulting in
increased arterial desaturation and fatigue. There is an
inability to increase pulmonary blood flow with exercise,
so the magnitude of right-to-left shunt increases as systemic
oxygen delivery demands increase with exercise and sys-
temic blood flow increases. Therefore, these patients are
self-restricting and seldom need to have physical restric-
tions arbitrarily imposed. The longevity of such patients is
variable. Causes of death include sudden cardiac death,
infective endocarditis, brain abscess, massive hemoptysis,
and hyperviscosity. By x-ray study, the heart size may
be normal, the central pulmonary arteries are markedly
dilated, and there is no evidence of increased pulmonary
flow (Fig. 10.11).
Echocardiography characteristically demonstrates the
location of a large VSD and bidirectional shunting.86 It can
also differentiate between an isolated VSD with normally
related great vessels from one associated with congenitally
corrected transposition with double-outlet RV.
Cardiac catheterization characterizes the hemodynamics
(i.e., a large VSD through which the venous catheter can be
manipulated into both the aorta and the pulmonary artery),
severe pulmonary hypertension with markedly elevated
PVR, and bidirectional shunting.87
Continued survival of such patients requires careful
follow-up and management.88 The erythrocytosis is a conse-
quence of arterial desaturation, and symptoms of hypervis-
cosity are peculiar to each patient. Most patients have
correlating symptoms, such as visual disturbances, light-
headedness, or a “funny feeling,” at which time it may be
appropriate to phlebotomize them, simultaneously replacing
the blood loss with intravenous saline. It is seldom necessary
to bring the hemoglobin to much below 20 g. The use of
phlebotomy is controversial; it is variably applied at different
adult congenital heart centers. The patients’ symptoms
appear to be a better guide than arbitrary numeric guides. FIGURE 10.11. (A–E) Eisenmenger’s complex (ventricular septal
A word of caution is necessary here, however. Repeated defect with severe pulmonary hypertension and equal resistances
in the pulmonary and systemic circuits). Patient at age 2 (A), at age
phlebotomies without iron supplementation result in an 10 (B), and at age 20 (E). The left ventriculogram (C and D) shows
iron-deficiency anemia that can worsen symptoms of the normally related great arteries and markedly dilated pulmonary
hypervisco-sity due to the effects of iron deficiency on red trunk and left pulmonary artery. Commonly, adults with Eisen-
cell function. In iron deficiency, the red blood cells are small menger’s complex have this physiology from early life.
and more rigid, which increases viscosity. Therefore, iron
supplementation may be necessary. Rapid erythrocyte turn-
over may also lead to folate deficiency, which may require Patients with Eisenmenger’s complex do not progress to
folic acid supplementation. These patients should also be CHF unless other factors supervene, such as ventricular
cautioned to maintain adequate fluid intake during hot dysfunction. The RV is adapted to pressure work, and there
weather and during exertion. is no volume overload. However, injudicious and excessive
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 245
phlebotomies may render the patient relatively anemic, espe- there may be a suggestion of increased pulmonary blood
cially if associated with iron deficiency, and CHF may ensue. flow.
In some patients, moderate pulmonary insufficiency may The echocardiogram shows evidence of flow into the left
develop, creating a volume overload situation that can also pulmonary artery because the ductus is usually between the
lead to CHF. Treatment of CHF in Eisenmenger’s syndrome distal aortic arch and the proximal left pulmonary artery91
is controversial. Historically, digoxin and cautious diuresis shortly after bifurcation. During cardiac catheterization, it
were employed. There is some evidence to support judicious is usually possible to manipulate the venous catheter from
use of afterload reduction, but this therapy has the risk of the proximal left pulmonary artery through the ductus into
increasing the right-to-left shunt and aggravating the cyano- the descending aorta. The pulmonary artery pressure should
sis. If the patient has an iron-deficiency anemia, often owing be measured simultaneously with the systemic arterial
to repeated phlebotomies, cautious transfusion of packed red pressure.
blood cells is sometimes helpful, as is iron replacement.
Current treatment regimens include bosentan, sildenafil, PROGNOSIS
and iloprost, and outcomes appear to be improved.88 The prognosis for PDAs with small-to-moderate left-to-right
Many patients with Eisenmenger’s complex manage to shunt is excellent, the chief risk being endocarditis. Over
do reasonably well, holding down full-time jobs and perform- time, though, the likelihood of endocarditis is significant.
ing many normal activities, although they are not capable of Cardiac catheterization can help to determine the status of
performing strenuous exertion. Ultimately, increasing pul- the pulmonary vasculature.
monary vascular disease with increasing right-to-left shunt- Because the PDA is extracardiac, its ligation and division
ing and increasing erythrocytosis make existence difficult, do not require open-heart surgery, making the surgical risk
and such patients should be considered for heart-lung virtually the risk of anesthesia only. At present, however,
transplantation. there are transcatheter techniques for closure of a patent
ductus, and these are quite suitable for most patients with a
PDA who have persistent patency after the first few months
Patent Ductus Arteriosus of life.92
The ductus arteriosus is the main fetal path through which
oxygenated umbilical cord blood perfuses distal to the aortic Large Patent Ductus
arch of the fetus. With delivery and the baby’s first breath, With normal or even moderately increased PVR, patients
there is an immediate drop in PVR, resulting in a reversal of with large PDAs have a large continuous left-to-right shunt
the shunt through the ductus arteriosus. Usually, the ductus (Fig. 10.12). They are only rarely seen as adults because the
arterious constricts and is functionally closed by 18 hours
after birth. Patency may persist for several weeks without
any consequences. The pathophysiologic consequences of
persistent patency of the ductus arteriosus depend on the size
of the ductus and, to a lesser extent, on the length.89 There
is a continuous left-to-right shunt during systole and diastole
through the ductus as long as the PVR is lower than the
systemic resistance. Predisposing factors for a patent ductus
arteriosus (PDA) are maternal rubella in the first trimester
of pregnancy, prematurity, and high altitude.

Restrictive Patent Ductus Arteriosus

Most patients with restrictive PDA are asymptomatic because
the left-to-right shunt is generally mild to moderate. The
pathophysiology is similar to that of aortic regurgitation, and
there is a rapid run-off with some degree of left ventricular
volume overload. The classic physical finding is the machin-
ery murmur of Gibson,90 heard best in the left subclavicular
region and continuous throughout the whole cardiac cycle.
This is not to be confused with long murmurs in systole and
diastole, such as may occur in combined aortic stenosis and
regurgitation, in which the directional shift in flow is marked
by a short hiatus between the systolic and the diastolic com-
ponents. The murmur is identical to that heard in an AV
fistula, which it in fact resembles physiologically. The radio-
graphic study in patients with a small PDA shows a normal
heart size with normal pulmonary vasculature. There is a FIGURE 10.12. Posteroanterior radiograph of patient with a large
patent ductus arteriosus. There is moderate cardiomegaly, with
tendency, however, for the aortic arch to be somewhat wider increased pulmonary vasculature and marked enlargement of the
than usual for the patient’s age. With a moderate left-to-right main pulmonary artery segment (arrow in prominence of the
shunt, the heart size may increase somewhat over time, and aorta).
24 6 chapter 10

volume overload of the LV and the resultant symptoms betray

the diagnosis in childhood, at which time the defect is cor-
rected. A large PDA seen in adulthood is almost always one
with a PVR slightly less than, equal to, or even greater than
the SVR, with either a small bidirectional shunt or an exclu-
sively right-to-left shunt. In many respects, this resembles
the Eisenmenger complex associated with a ventricular
septal defect (Fig. 10.13).93 The patients experience signifi-
cant exercise limitations because peripheral vasodilation
serves to increase right-to-left shunting and further arterial
desaturation. However, unlike the situation in the Eisen-
menger complex with a ventricular septal defect, the natural
history of a high-pressure, high-resistance PDA may lead to
right-sided CHF if the pulmonary artery dilation results in
significant pulmonary insufficiency. The resulting volume
overload of the RV with an intact ventricular septum can
lead to decompensation.
The clinical history is that of exercise limitation and
sometimes angina-like symptoms with exertion, associated FIGURE 10.14. Differential clubbing in a 23-year-old patient with
with definite cyanosis. Classically, the cyanosis should reversing ductus arteriosus. Note the marked clubbing of the toes
involve the left hand and the feet and not so much the right and of the fingers of the left hand, with normal nails and fingers on
hand, although this is occasionally seen (Fig. 10.14). Far more the right hand. Although classic, this is less common than cyanosis
and clubbing of all fingers and toes in reversing ductus arteriosus.
common, however, is cyanosis and clubbing of all four
extremities, possibly because of reversal of flow in the
ascending aorta during early diastole. Sometimes there is
hoarseness caused by compression of the recurrent laryngeal L ABORATORY STUDIES
nerve, especially if the PDA becomes aneurysmal. Hemop- The chest x-ray evaluation is characterized by a prominent
tysis may occur, presumably because of the pulmonary aortic arch and large central pulmonary arteries. If the PVR
hypertension.94 is high, the peripheral pulmonary vasculature appears
“pruned,” as in the Eisenmenger complex. The heart is
usually of normal size. Examination of the heart may dis-
close only a systolic murmur or no murmur, prominent pal-
pable pulsation of the main pulmonary artery, and a loud P2.
Radiographically, it is possible to see the PDA as a slightly
oblique shadow between the distal portion of the aortic arch
and the pulmonary artery. This is especially evident when
there is calcification of the ductus (Fig. 10.13).
Echocardiographically, a high-pressure PDA is best seen
by the transesophageal technique. Cardiac catheterization is
used to define the pulmonary hemodynamics, and the PDA
can be visualized angiographically for the surgeon.

PROGNOSIS
In a large PDA in which there is still an appreciable left-to-
right shunt and in which the pulmonary/systemic flow ratio
is greater than 1.5 : 1, the ductus can still be divided and
ligated with the anticipation that the pulmonary artery pres-
sure will fall. However, the PVR will remain somewhat ele-
vated. When pulmonary flow and systemic flow are equal, as
are their respective resistances, closure of the PDA is contra-
indicated, and the only treatment would be heart-lung
transplantation.24,95

Endocardial Cushion Defects

The crux of the heart refers to the area where the atrial
septum, the ventricular septum, the mitral valve, and the
FIGURE 10.13. Posteroanterior radiograph of patient with patent tricuspid valve all come together. The structures that make
ductus arteriosus and severe pulmonary vascular disease, as indi-
cated by calcified plaque in the pulmonary arteries (curved white up this part of the heart are formed by endocardial cushion
arrow). The ductus arteriosus itself is also calcified (black arrow). tissue during development as the common atrioventricular
Pulmonary artery segment and aortic knob are markedly enlarged. canal is divided. Defects in this part of the heart have been
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 47
variably referred to as endocardial cushion defects, atrioven- Treatment
tricular canal defects, and atrioventricular septal defects.
Treatment is surgical unless there is irreversible pulmonary
Each nomenclature has a group of passionate defendants. The
vascular disease. If there is severe pulmonary vascular
severity of disease caused by abnormal development and
disease, heart-lung transplantation is the only option. In
division of the atrioventricular canal ranges from minor
earlier eras, patients with Down syndrome were often denied
abnormalities of the mitral valve such as a cleft in the ante-
surgical therapy. More recently, though, this has not been a
rior leaflet to much more severe disturbances such as a
consideration, and children with Down syndrome routinely
complete atrioventricular canal defect or complete atrioven-
do well following surgery. Over the long term, postoperative
tricular septal defect. The anterior leaflet of the mitral valve
morbidity is related to the adequacy of the mitral valve func-
is almost invariably cleft in this group of defects. Deficiency
tion. Repair of the cleft mitral valve in endocardial cushion
of the primum atrial septum at the crux is referred to as an
defects is challenging and patients are almost always left
ostium primum ASD. Alternatively, this abnormality has
with some degree of mitral insufficiency. This can be severe
been referred to as a partial atrioventricular canal defect. The
enough to require a second operation to repair or replace the
combination of an ostium primum ASD and a pressure-
mitral valve. Additionally, if the atrioventricular tissue is
restrictive VSD is conventionally referred to as a transitional
inadequate or the cleft in the anterior leaflet is repaired
atrioventricular canal defect. A large ASD and a large inlet
overaggressively, there can be concomitant mitral stenosis
VSD is referred to as a complete AV canal (septal) defect.
following repair.
Typically, there is a large common AV valve that sits over
both ventricles. This common AV valve has four to six leaf-
lets, including an anterior bridging leaflet and posterior
bridging leaflet that “bridge” the ventricular septum. Defects
Congenital Valve Abnormalities
of the AV septum make up the most common type of defects
seen in Down syndrome. Aortic Stenosis
Congenital obstruction of the outflow tract of the left ven-
Clinical Presentation tricle in the adult is overwhelmingly due to valvar disease
The clinical presentation of ostium primum ASD and its and commonly results from the development of aortic steno-
close relative, common atrium, was discussed earlier. sis because of a congenital bicuspid or unicuspid valve.96,97
Complete AV canal defect in adults may present in asso- The incidence of aortic valve disease is four to five times
ciation with either pulmonary stenosis or pulmonary hyper- higher in males than in females.98 Idiopathic hypertrophic
tension. In the latter case, it has many of the characteristics subaortic stenosis and asymmetric septal hypertrophy, now
of the Eisenmenger syndrome. These patients have a high known as hypertrophic cardiomyopathy (HCM), are different
incidence of cyanosis. The heart is enlarged, and there is a disorders from valvular aortic stenosis and are discussed
loud P2. There is an absent P2 in cases with associated pul- separately.
monary stenosis, and a loud ejection systolic murmur is
heard if pulmonary stenosis is present. Evidence of AV valve Aortic Valve Stenosis
regurgitation may be observed by evaluation of deep jugular In nonelderly adults, aortic stenosis typically develops
pulses. because of a bicuspid (or unicuspid) aortic valve.99,100 This is
sometimes seen in association with coarctation of the
Laboratory Studies aorta.101 In general, the valve causes little or no hemody-
The chest x-ray shows an enlarged heart with a large pulmo- namic disturbance for the first several decades of life and, in
nary arterial tree and, if there is no pulmonary stenosis, fact, may never cause any hemodynamic disturbance at all.
evidence of increased pulmonary blood flow. Both ventricles Progressive aortic regurgitation may develop, especially in
and both atria are enlarged. The ECG may be similar to that young adulthood. It appears that most valves with this abnor-
of an ostium primum ASD (i.e., rSR’ in the anterior chest mality develop progressive thickening and fibrosis after the
leads, left-axis deviation, and often first-degree AV block). third or fourth decade of life. Over time, increasing calcifica-
Echocardiography visualizes the low-lying ASD, a corre- tion and progressively severe aortic stenosis (AS) develops.
sponding VSD, and the characteristic straddling AV valve.20 The presence of mild AS may be associated with progres-
If there is pulmonary stenosis, this can be seen with color- sively severe aortic regurgitation when inadequate coapta-
flow Doppler techniques, and the degree of stenosis can be tion outweighs inadequate opening of the valve.101 Bacterial
estimated. Measurements should be made of the pulmonary endocarditis may also transform the pathophysiologic dis-
hemodynamics with quantification of the left-to-right and turbance from predominant stenosis to predominant
the right-to-left shunts and the respective resistances. regurgitation.
Because of the cyanosis, there is secondary erythrocytosis, The course of the disease, once stenosis begins, tends to
which must be carefully managed as discussed earlier. be relentless but has a highly variable timetable. In general,
the progression to severe AS may take decades, although on
rare occasion may be rapid. After significant AS develops, the
Prognosis
natural history is similar to that of acquired AS. The classic
Long-term survival with a complete atrioventricular septal ominous symptoms are syncope, angina, and CHF. Sudden
defect, without surgery, is uncommon, and such patients death is a threat even when mild symptoms are noted.98,102–104
rarely survive into adulthood. However, evaluation for surgery should be undertaken if
24 8 chapter 10

there has been any subjective change in exercise tolerance or an early diastolic blowing murmur of aortic regurgitation.
in the patient’s general sense of well-being. Most patients The peripheral pulse contour characteristically shows an
with predominant AS have well-preserved left ventricular anacrotic notch. In general, the more severe the stenosis, the
function if exertional syncope is the primary manifestation. more delayed the upstroke and the lower the anacrotic notch
Although angina may occur in severe AS without concomi- on the upstroke.98,112 Classically, the heart is not enlarged.113
tant CAD, CAD is not uncommon in the presence of AS and If the aortic valve is heavily calcified, it can be visualized,
should always be evaluated when surgery on the aortic valve especially in the lateral view of the chest film, and can be
is contemplated.105–107 The appearance of overt CHF is usually readily seen on fluoroscopy. A characteristic associated
of ominous prognostic consequences, although some patients finding is dilation of the ascending aorta (Fig. 10.15).114 This
may recover virtually normal left ventricular function after dilation is asymmetric, anterior, and to the right and is
successful surgery. Approximately 5% of patients with a believed to be due to the direction of the abnormal flow
bicuspid aortic valve (BAV) have associated cystic medial pattern across the bicuspid aortic valve. This “poststenotic
disease of the aorta, which can become the basis of an aortic dilatation” can be observed even when there is no systolic
dissection. Coarctation of the aorta is sometimes associated gradient across the aortic valve. The ECG may be unremark-
with a BAV (it is far more common for coarctation of the able throughout the course of the disease up to the time of
aorta to be associated with a BAV, rather than the reverse), surgery, although it may demonstrate a characteristic “strain”
which has its own inherent natural history and complica- pattern of left ventricular hypertrophy in some patients.
tions.108 Before the aortic valve has become heavily calcified,
the presence of a BAV has classic physical examination find- DIAGNOSIS
ings. The most characteristic feature of a BAV is a loud sys- The clinical diagnosis of aortic valve stenosis is made by
tolic ejection click, which coincides with the doming of the auscultating the characteristic ejection systolic murmur,
aortic valve toward the end of isovolumetric contraction of which is harsh, heard in the upper right sternal border and
the LV.109 In a younger age group, this may be the only physi- suprasternal notch, and radiates to the neck.98 This murmur
cal examination finding, although commonly there is an may be mimicked by mitral insufficiency associated with an
aortic systolic murmur that starts after the ejection sound. “overshooting” of the posterior mitral valve leaflet directing
The ejection click is usually somewhat pronounced, and the regurgitant jet anteriorly and medially, giving rise to a
it is likely that the doming of the aortic valve prolongs the murmur best heard along the left sternal border and some-
phase of isovolumetric contraction.109,110 The aortic systolic times heard in the neck.115–117 Valvar pulmonary stenosis may
murmur, if present, starts with the ejection click and may also be heard in the neck. An aortic ejection sound strongly
be of variable intensity.98,111 suggests the presence of a BAV. With that, many or most such
The second heart sound characteristically preserves both aortic valves become more stenotic.7,118–121 The ejection sound
components (A 2 and P2) until significant AS develops, when may gradually disappear, and its absence is associated with
the second sound becomes single. There may or may not be increasing fibrosis and calcification of the valve leaflets.122,123

FIGURE 10.15. Aortic stenosis on a

congenitally bicuspid aortic valve. Note
the eccentric poststenotic dilatation of
the ascending aorta, with a normal-sized
aortic ring. The ventriculogram illus-
trates the contraction of the severely
hypertrophied left ventricle to a very
small end-systolic volume.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 249
The first heart sound is characteristically soft, and the A 2 59-year-old man 12364016
component of S2 gradually diminishes as the stenosis becomes No aortic systolic gradient
progressively more severe. A soft diastolic murmur of aortic
insufficiency is not uncommon as the cusps become more
rigid. As the stenosis becomes more severe, an S4 becomes
prominent and may sometimes be mistaken for S1. The
peripheral pulses show an anacrotic notch and a somewhat
delayed upstroke. In general, the lower the notch, the more
severe the stenosis. The heart is usually not grossly enlarged
unless there is a significant degree of aortic insufficiency.
Radiographically, the heart is typically of normal size
unless there is significant concomitant regurgitation, possi-
bly with some calcification of the aortic valve and “postste-
notic” dilatation of the ascending aorta, as previously
described (Fig. 10.16). The ECG, even in cases of severe aortic
stenosis, may range from normal to that characteristic of left
ventricular hypertrophy with a “strain” pattern (Fig. 10.17) 67-year-old man 12364016
Severe aortic stenosis, symptomatic
and may not be helpful in the clinical evaluation of severity.
The echocardiogram shows a thickened aortic valve, which
becomes increasingly immobile as it becomes more calcified.
The LV exhibits concentric hypertrophy, and the systolic
gradient across the aortic valve can be estimated by the
velocity of the systolic jet.124,125 Similarly, aortic insufficiency
can be visualized.
On cardiac catheterization, the LV can be entered either
retrograde across the stenotic aortic valve or by transseptal
puncture from the femoral venous approach to the LA and
then the LV. Angiography shows the characteristic postste-
notic dilatation of the ascending aorta, which does not
involve the aortic ring or sinuses. Simultaneous pressures FIGURE 10.17. Electrocardiograms of a patient who developed
severe symptomatic aortic stenosis within less than 8 years. Tight
stenosis and angina were corrected by valve replacement. Note the
absence of significant electrocardiographic changes during this
interval.

across the aortic valve can be measured, and with simultane-

ous measurement of cardiac output, the valve area can be
calculated from the Gorlin formula,126,127 assuming inconse-
quential aortic regurgitation. If the patient has CHF, the
clinical picture must be modified to include left ventricular
dilation, decreased contractility, and a ventricular gallop
rhythm.

T REATMENT
There is no absolute aortic valve area that clearly dictates
intervention. In general, the patient who is normally active,
who has no symptoms, and in whom the clinical signs and
the echocardiogram do not suggest severe aortic stenosis can
be safely watched. Even when the evidence points to signifi-
cant aortic stenosis, the total absence of symptoms should
outweigh the objective measurements of valve orifice size in
continuing careful observation and follow-up.98 However,
with even mild changes in status that can be ascribed to the
heart, together with the physical signs of significant aortic
stenosis that are confirmed by echocardiography and cathe-
terization, surgical replacement of the aortic valve should be
FIGURE 10.16. Posteroanterior radiograph of a patient with con- seriously considered. These changes may involve merely a
genital aortic stenosis. The heart is slightly enlarged and has a left
ventricular configuration. The pulmonary vasculature is normal.
subtle change in well-being or a slight decrease in exercise
There is striking prominence of the ascending aorta (arrow) as a tolerance.128 It is advisable to proceed with cardiac catheter-
result of poststenotic dilatation. ization when it is felt that surgery is imminent, both to
250 chapter 10

confirm the clinical and echocardiographic evidence and to Subaortic Stenosis

visualize the coronary arteries. It is not wise to wait until
Subvalvar aortic stenosis has three types: membranous sub-
major symptoms arise, because the incidence of sudden
aortic stenosis,98,140 a fibromuscular tunnel type,98,141 and an
death rises dramatically.129 In patients with AS and angina,
idiopathic hypertrophic subaortic stenosis type. Discrete
there is a significant incidence of coexisting CAD.105,106
subaortic stenosis may be familial.98,142
Treatment involves surgical replacement of the calcified
Membranous subaortic stenosis or subaortic rings are
valve130,131 by a prosthetic valve, and coronary artery bypass
uncommon in adults. An aortic systolic murmur and often
grafting, if indicated. Even patients older than 80 years of
an aortic diastolic murmur are present, the latter resulting
age may benefit from valve replacement; they have an opera-
from aortic valvar regurgitation. This is postulated to be
tive mortality of 9.4% and a good outcome in 81% of cases
related to damage to the aortic valve caused by the jet of
described. Porcine bioprosthesis is especially suitable in the
blood flowing through the obstructive membrane.143 In
elderly, in whom the longevity of such prostheses is better
patients who have a predominantly muscular ring, a charac-
than when they are implanted in younger patients. Balloon
teristic Brockenbrough’s sign may be observed after prema-
valvuloplasty has been useful in children but disappointing
ture beats (i.e., a fall in the aortic systolic pressure and an
(but improving) in adults, for whom the benefits are of
increase in the ventricular pressure after an extrasystole).
limited duration, especially with a stiff, calcified valve.132–135
Treatment of this condition involves resection of the ring. At
More recently, innovations have occurred including percuta-
surgery, the resection may be incomplete, to avoid damage
neous valve repair and replacement approaches, which appear
to the conduction system or the anterior leaflet of the mitral
to have promise.135,136
valve.143,144
Long-term follow-up on a large cohort of 462 patients
Idiopathic hypertrophic subaortic stenosis is an older
with congenital aortic stenosis (mostly children) showed that
term for one of the findings in some patients with hypertro-
with gradients of less than 50 mm Hg, medical follow-up is
phic cardiomyopathy. This disorder is not discussed in this
appropriate, whereas with gradients of more than 80 mm Hg,
chapter.
intervention is clearly indicated.130

Supravalvar Aortic Stenosis Pulmonary Stenosis

Supravalvar aortic stenosis typically occurs in two set- Pulmonary stenosis (PS) can be valvar, supravalvar, or sub-
tings.137,138 Williams syndrome is a dysmorphic syndrome valvar. Although pulmonary stenosis may occur as an iso-
caused by a mutation of the elastin gene on chromosome 7,139 lated anomaly, it is often associated with an ASD, VSD, or
most typically a deletion. Often, there is hypercalcemia in transposition of the great arteries (TGA).
infancy. Affected people have characteristic facies and char-
acteristic personality traits and limits in learning. As infants, Pulmonary Valve Stenosis
there is often pulmonary artery branch stenosis, which
regresses with time. At the time of diagnosis in infancy, Pulmonary valvar stenosis typically is caused by commis-
there may be no real supravalvar aortic obstruction, but over sural fusion and is associated with a dome-shaped valve.
time the aortic obstruction tends to be progressive. There is Alternatively the valve may be dysplastic.145,146 The conse-
also another group of patients with supravalvar aortic steno- quent obstruction to right ventricular outflow results in
sis that is familial. These individuals appear to have autoso- right ventricular hypertrophy and, when severe, an increase
mal dominant transmission and do not have the findings of in the right ventricular filling pressure. Patients with iso-
dysmorphic features, hypercalcemia in infancy, or behav- lated mild PS usually do well,147–149 whereas those with mod-
ioral abnormalities. On physical examination, there is erate (peak-to-peak systolic gradient of 50 to 80 mm Hg) or
usually no ejection click, but there is a harsh ejection murmur severe stenosis (systolic gradient >80 mm Hg) should be con-
at the right upper sternal border that transmits prominently sidered for intervention.150,151
into the carotid arteries. Additionally, there is a peculiar Multiple peripheral PSs are rare in the adult (Fig. 10.18).
physical examination finding, caused by the Coanda effect. These are almost always associated with one of several clini-
The Coanda effect causes the jet of blood passing through cal syndromes, including the following:
the supravalvar narrowing to track along the greater curve 1. Williams syndrome137–139
of the aorta and into the innominate artery and subsequently 2. Noonan syndrome152,153
into the right subclavian artery. This creates a higher systolic 3. Congenital rubella syndrome154
blood pressure in the right arm than in the left arm or the
legs. While the pathophysiology seems similar to aortic valve In patients who have an associated patent foramen ovale,
stenosis, there are some important differences. The coronary right-to-left shunting at rest may occur during atrial systole
artery origins are proximal to the obstruction. Since coro- (during which the right atrial pressure exceeds that of the
nary flow is most prominent in diastole, coronary blood flow LA) or during exercise or tachycardia, when the pressure in
may be compromised in severe obstruction because blood the RA may exceed that of the LA throughout the cardiac
flow back from the aorta into the coronary arteries is com- cycle, resulting in arterial desaturation. These elevated right
promised. Also, ostial stenosis is often present, causing even atrial pressures result from the decreased compliance of the
more coronary compromise. As the obstruction tends to be hypertrophied RV. The Valsalva maneuver at rest may cause
progressive, treatment typically consists of surgical repair a transient increase in the right atrial pressure relative to
once there is more than mild stenosis. that of the LA during its release.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 51

FIGURE 10.18. Tracing the pulmonary artery pressure as the cath-

eter is being advanced distally. Note the sudden drop in pressure as
the catheter advances. This patient had the clinical pressure of
tetralogy of Fallot with a large ventricular septal defect. The obstruc-
tion to pulmonary flow was in the more distal pulmonary arteries
rather than at the pulmonary valve.

Mild PS (systolic gradient <50 mm Hg) is compatible with

a normal existence, the chief risk being infective endocardi-
tis.155 In increasingly severe degrees of PS, the degree of right
ventricular hypertrophy increases and may result in early
and significant right-to-left shunting at the atrial level if FIGURE 10.19. Posteroanterior radiograph of a patient with valvu-
there is an atrial communication, or right ventricular failure. lar pulmonary stenosis. The heart is normal in size, and there is
This is now an extremely rare eventuality when adequate striking enlargement of the main pulmonary artery (open arrow)
and the left pulmonary artery (solid arrow).
medical facilities are available and early intervention can be
instituted.

DIAGNOSIS
Pulmonary stenosis is always associated with a pulmonary
ejection systolic murmur.111 Pulmonary valve stenosis is
usually loudest at the left upper sternal border and has prom-
inent radiation to the lungs rather than the neck. On auscul-
tation, it may be difficult to distinguish from an aortic
systolic murmur because the pulmonic systolic murmur
may also be heard in the neck. Two subtle auscultatory fea-
tures help to confirm the diagnosis of PS versus AS. In PS,
the ejection systolic murmur should be heard throughout the
duration of right ventricular systole, and thus beyond A 2 and
ending with P2. Furthermore, the pulmonary systolic murmur
is better heard over the left side of the back as opposed to the
right. This phenomenon is related to the anatomy of the
pulmonary arteries; anatomically, the left pulmonary artery
is almost a direct continuation of the main pulmonary artery,
whereas the right pulmonary artery comes off at a right
angle. There is often a systolic ejection sound (click). The
ECG may be normal in mild pulmonary stenosis, but with
increasing severity, the ECG demonstrates an increasing
right ventricular hypertrophy in the chest leads and a ten-
dency to right axis deviation. The chest x-ray is characterized
by a normal heart size with a right ventricular configuration
and a left heart border showing prominence of the main and
left pulmonary arteries (Figs. 10.19 and 10.20). Calcification
of the pulmonary valve is very rare. Patients with only sub-
pulmonary stenosis do not exhibit pulmonary artery dilata-
tion. In patients whose stenosis is far advanced, increasing
cardiomegaly is present owing to enlargement of the RV and
RA. The skilled observer may suspect “decreased pulmonary FIGURE 10.20. Pulmonary stenosis with intact ventricular septum
in a middle-aged man. The cardiac shadow is unusual in that there
blood flow” by the vascular pattern on the chest film. is marked poststenotic dilatation of the main pulmonary artery. The
However, this is more reflective of the decreased pulse pres- cardiomegaly is of right ventricular configuration, typical of long-
sure in the pulmonary arteries than of decreased pulmonary standing significant pulmonary stenosis in this age group.
252 chapter 10

Long-term follow-up of patients with PS shows that the

probability of survival is similar to that of the general popu-
lation after 25 years (95.7%) whether medically or, when
indicated, surgically/catheter treated. Survival is somewhat
shorter when associated cardiomegaly is present.145,167

Subpulmonary Stenosis
Subpulmonary stenosis is relatively uncommon as an iso-
lated lesion but is the more common type of pulmonary ste-
nosis associated with a ventricular septal defect (tetralogy of
Fallot).168 Pulmonary stenosis can be either membranous or
infundibular and may be clinically indistinguishable from
pulmonary valvar stenosis. However, pulmonary valvar ste-
FIGURE 10.21. Electrocardiogram of a patient with severe pulmo- nosis is associated with poststenotic dilatation of the main
nary stenosis. Note the right-axis deviation and severe right ven- pulmonary artery, which is readily seen on chest x-ray, and
tricular hypertrophy. the echocardiogram is definitive. When the condition is
severe, the treatment is surgical, with either resection of the
obstruction or roofing of the outflow tract by patching.169,170
On rare occasion, the “stenosis” may be caused by a tricuspid
flow because it is the same as the cardiac output. The echo- valve aneurysm during systole.171
cardiogram demonstrates a dome-shaped stenotic pulmonary
valve, the severity of which can be gauged by Doppler deter- Mitral Stenosis
mination of the pressure gradient and assessment of coexist-
ing infundibular stenosis. Pulse oximetry can be useful to Congenital mitral stenosis (MS) in adults is uncommon.
detect an associated right-to-left atrial level shunt. Shone syndrome is the term used to describe the occurrence
When stenosis is mild, the ECG is usually normal. With of multiple levels of obstruction to blood flow at levels of
moderate to more severe PS (systolic gradient >50 mm Hg), flow into and out of the left ventricle and in the aorta.172,173
right ventricular hypertrophy is seen in the chest leads, and The classic picture includes MS with a parachute mitral
“P pulmonale” will be increasingly evident (Fig. 10.21). valve (a single papillary muscle), subaortic stenosis, a bicus-
Cardiac catheterization for direct measurement of the pid aortic valve, and coarctation of the aorta. These patients
systolic gradient across the pulmonic valve, combined with typically require intervention in infancy and often repair
simultaneous cardiac output measurements, permits calcu- will be staged with different lesions requiring intervention
lation of valve orifice size by the Gorlin formula.126 The at different ages. In adulthood, the clinical picture may
catheter may cross a probe-patent foramen ovale, and, if so, resemble that of rheumatic mitral stenosis, in that there is a
a comparison of the oxygen saturation of the pulmonary vein long and initially asymptomatic history followed by gradu-
and that of the systemic artery indicates whether a signifi- ally increasing exertional dyspnea and fatigability. Atrial
cant right-to-left shunt is present. Angiography in the RV fibrillation may develop secondary to enlargement of the LA
visualizes the valve and right ventricular outflow tract as a consequence of the stenosis.
stenosis. Cardiac examination does not identify the opening
snap characteristic of rheumatic mitral stenosis, and a dia-
PROGNOSIS stolic rumble may or may not be present. However, there may
In the modern era, the prognosis is usually good because the be signs of pulmonary hypertension associated with a loud
striking murmur demands cardiac evaluation and, when P2 and an active RV. The definitive examination is echocar-
indicated, intervention. However, such patients are always at diography, both transthoracic and transesophageal. However,
risk for infective endocarditis. hemodynamic studies at cardiac catheterization are impor-
tant for the characterization of pulmonary hemodynamics
T REATMENT and for the search for other features of the Shone
Treatment of isolated pulmonary valvar stenosis formerly syndrome.
entailed surgical valvuloplasty, but increasingly, the treat- Treatment consists of excision of the mitral valve with
ment of choice is percutaneous transvenous balloon valvu- valve replacement, and removal of the supravalvar ring if this
loplasty.156–159 This is the noninvasive analogue of the older is significantly stenotic.
Brock procedure (pulmonary valvotomy)160 but with more
adequate dilatation of the valve. Treatment with balloon
Tricuspid Stenosis
valvuloplasty is highly successful and can be repeated if the
dilatation is inadequate or restenosis occurs.161–163 If there is Congenital tricuspid stenosis is extremely rare as an isolated
a coexisting probe-patent foramen ovale, consideration should lesion.174,175 Most cases of adult tricuspid stenosis are acquired,
be given to its closure because late paradoxical embolism is such as those associated with rheumatic fever, carcinoid syn-
possible, but during balloon dilation, it may be protective.164 drome, or right atrial myxoma.
Several devices are now able to close atrial communications Echocardiography provides a definitive diagnosis by dem-
by transcatheter techniques.28–51,165,166 onstrating a stenotic tricuspid valve with an enlarged RA.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 253
Cardiac catheterization is usually unnecessary unless the
coexistence of other anomalies cannot be entirely excluded
by echocardiography.

Atrioventricular Valvar Regurgitation

Atrioventricular (AV) valvar regurgitation, long held to always
be pathologic, is now seen as a phenomenon that may at
times be “normal” under certain conditions when it is
minimal. This has become clear with newer, highly sensitive
echocardiographic techniques. Near-instant closure of the
AV valves is dependent on normal sinus rhythm, an optimal
PR interval, and normal ventricular function. The swiftness
of AV valve closure is greatest when there is sinus rhythm
with a normal PR interval, resulting in a ventricular contrac-
tion that generates the steepest ventricular pressure rise as
a consequence of the presystolic atrial “boost.” Therefore, in
atrial fibrillation, mild valve regurgitation may occur in the
presence of a normal valve. Similarly, in marked first-degree
AV block, mild regurgitation may occur because atrial systole
is not timely. In AV dissociation or third-degree heart block,
mild AV valve regurgitation may be intermittent, depending
on the timing of atrial contraction in relation to ventricular
systole. Normally, one may see mild tricuspid regurgitation,
even with sinus rhythm. Thus, pathologic valvar regurgita- FIGURE 10.22. Posteroanterior radiograph of a patient with
tion entails more than trivial regurgitation in the presence Ebstein’s malformation of the tricuspid valve with right-to-left
of sinus rhythm and a normal PR interval. shunt. The cardiac silhouette is huge. There is prominence of the
right atrial border. The pulmonary artery segment and aorta are
inconspicuous. The pulmonary vasculature is frankly decreased.
Mitral Valve Regurgitation
Isolated congenital mitral regurgitation is rare. Rarely, an
isolated cleft in the anterior leaflet of the mitral valve can
In mild cases of Ebstein’s anomaly, there is little or no
lead to mitral regurgitation. A cleft in the anterior leaflet of
functional disturbance, and the condition is compatible with
the mitral valve usually is in the spectrum of AV canal or
a normal life expectancy. When the condition is severe, the
endocardial cushion defects.
entire inflow tract is functionally atrialized, and there is
little pump function of the RV. There is an associated atrial
Aortic Valve Regurgitation communication, with a patent foramen ovale or an ASD in
50% of patients. If right-to-left shunting occurs, cyanosis and
Congenital aortic valve insufficiency is extremely uncom-
fatigability ensue. The large “atrium” also predisposes to
mon. There have been rare reports of absence of the aortic
atrial fibrillation. The chest x-ray is characteristic and has
valve. These patients have severe aortic valve insufficiency
been described as a “pumpkin” heart (Fig. 10.22).
with severe consequences on cardiac output and ventricular
The diagnosis is made by echocardiography to delineate
function. Patients born with an absent aortic valve require
the tricuspid valve, assess right ventricular function, and
surgical valve replacement, most typically with a homograft
look for right-to-left shunting.177,179
valve, early in the neonatal period.
The ECG may show one of two patterns: Wolff-
Parkinson-White pattern180 or an unusual right bundle branch
Ebstein’s Anomaly block with a “splintered” QRS complex in V1 or V2 (Fig. 10.23).
These patients may have an accessory AV pathway that
Ebstein’s anomaly consists of downward displacement of the
predisposes to supraventricular tachyarrhythmias (SVTs).
tricuspid valve so that the septal and posterior leaflets are
adherent to the right ventricular wall, thus to a greater or
Treatment
lesser extent “atrializing” the inflow tract of the RV.176,177 The
tricuspid valve is deformed and may assume a cribriform No treatment is needed when the condition is mild.181 If there
appearance, and it is invariably associated with tricuspid is considerable atrialization of the RV and some function in
regurgitation. Some evidence has linked this anomaly to the remaining RV, tricuspid valve replacement or reconstruc-
maternal use of lithium.178 tion with closure of the ASD may be indicated.182 Electro-
The physical findings show a characteristic “quadruple physiologic studies are appropriate so that an accessory
cadence” consisting of S1, one or multiple clicks (“sail sound”) pathway can be interrupted at operation. When arrhythmias
produced by the upward motion of the billowing anterior are significant, they require treatment. These include atrial
leaflet, and wide splitting of S2 due to right bundle branch ectopic tachycardia, atrial flutter and fibrillation, atrial
block. reentry tachycardia, and ventricular tachycardia (VT).183
254 chapter 10

presurgical era was ominous with only 10% of patients sur-

viving to age 50 years. Coarctation of the aorta is the most
common congenital cardiovascular disease in Turner
syndrome.187,189

Diagnosis
There are seldom symptoms from hypertension alone.
Because blood flow distal to the coarctation is normal, lower
body development is normal, and claudication is not neces-
sarily a part of the clinical picture. In the adult, no symptoms
occur until one or more complications develop.190 The diag-
nosis is made clinically by the faint or absent pulses in the
FIGURE 10.23. Electrocardiogram of a 24-year-old man with femoral arteries in the presence of hypertension in the arms.
Ebstein’s anomaly. Note the right bundle branch block pattern, with In some instances, the femoral artery pulsations are good,
“splintering” of the QRS complex in the V2 (i.e., R’SS’S).
but simultaneous pressure measurements in the arms and
legs reveal the systolic pressure in the lower extremities to
be somewhat lower than in the arms. A bicuspid aortic valve
is present in more than half the cases.190,191 Sometimes, the
Therapy may include radiofrequency ablation.183 Severe cases
intercostal collaterals are palpable, and murmurs are audible.
of Ebstein’s anomaly, however, do not do well over the long
The chest x-ray study often shows a notch at the site of the
term. In some cases, cardiac transplantation is required.184
coarctation just distal to the aortic arch, the so-called “3”
sign (Fig. 10.24), caused by dilatation of the proximal aorta
Coarctation of the Aorta because of the hypertension and poststenotic dilatation distal
to the coarctation. There is frequently notching of the pos-
By far, the most common congenital aortic obstruction in
teroinferior border of the ribs after the second rib (Fig. 10.25).
adults is coarctation of the aorta (COA, which in adults is
These are not directly due to increased flow per se in the
almost always at or just distal to the ligamentum arteriosum
intercostal arteries but rather to the tortuosity and resulting
and the takeoff of the left subclavian artery. This anomaly
“knuckling” of the arteries from increased flow, the notches
is seen in adults who have hypertension in the arms and in
corresponding to the knuckling. Mild cases of COA are
whom there is a decrease in the pulse pressure of the femoral
sometimes found incidentally in the evaluation of a bicuspid
arteries. It is twice as common in men and is sometimes seen
aortic valve192 (Fig. 10.26).
in patients with Turner syndrome.185–187 Sometimes there is
Echocardiography is useful to assess the anatomy and
a discrepancy between the blood pressure in the two arms.
function of the aortic valve and the degree of left ventricular
This may occur because the coarctation is proximal to the
hypertrophy and to follow the diameter of the ascending
left subclavian artery stenosis or because there is an anoma-
aorta, especially after surgery. Transesophageal echocardiog-
lous origin of the right subclavian artery distal to the coarc-
raphy may or may not visualize the coarctation optimally.
tation or because the origin of the left subclavian artery is
involved in the coarctation and is stenotic.
Physiologically, there is hypertension of the arterial
system proximal to the coarctation and normal blood pres-
sure distal to the COA. Outside of infancy, the decreased or
absent pulses in the distal arteries are due not to low flow
but to a narrow pulse pressure. Invariably, in untreated
adults, the mean pressure in the distal arterial tree is normal.
Flow to the distal aorta is by a number of collaterals via arte-
rial anastomoses involving the internal mammary, intercos-
tal, and superior and inferior epigastric arteries. It has been
well demonstrated by Shepherd188 that flow distal to the
coarctation is normal at rest and in exercise. This is often
not appreciated if it is assumed that impalpable pulses are
associated with low flow. The difference in the systolic pres-
sure between the upper and the lower halves of the body is
determined by the degree of coarctation and by the caliber
and the number of the collateral vessels. Hypertension results
both from mechanical obstruction, and damping of pulsatile
flow distal to the coarctation may affect the renin-angioten-
sin system via the juxtaglomerular apparatus leading to a
high renin state.
FIGURE 10.24. Coarctation of the aorta in a 24-year-old man. Note
Mild COA initially may not be associated with hyperten- the “3” sign just beyond the aortic arch, where the indentation
sion. In general, though, the severity of obstruction is pro- (arrow) is the site of the coarctation with a dilated aortic arch proxi-
gressive and the natural history of unoperated COA in the mal to the coarctation because of the hypertension.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 255
an increased incidence of cystic medial changes in the
aorta,197 which may predispose to aortic dissection, the ini-
tiation of which may be just above the aortic valve or in the
aortic arch.198,199 Aortic rupture may occur as an infrequent
complication of dissection. Infective endocarditis may occur
at the site of coarctation or, more commonly, on the bicuspid
aortic valve. The presence of arterial hypertension from birth
predisposes to premature cerebrovascular disease and CAD
if the hypertension persists into adulthood.186,197 Cerebral
hemorrhage may occur in 20% of cases as a result of a fre-
quently associated berry aneurysm of the circle of Willis.200
In women, pregnancy increases the risk for aortic rupture,
ventricular dysfunction, and increased hypertension.201,202
Most patients who survive childhood reach adulthood
without having symptoms but hypertension, until one of the
complications supervenes.

Treatment
Treatment in adults should be undertaken as soon as the
diagnosis is made. Balloon dilatation is often performed in
the pediatric age group, but recurrence is common in native
coarctation and has limited enthusiasm.203,204 Currently,
stents have been used with better outcomes in adolescents
FIGURE 10.25. Posteroanterior radiograph of a patient with coarc-
and adults.204 In adults, the most common form of coarcta-
tation of the aorta. The heart is not enlarged, and the pulmonary tion is a discrete constriction, which is best resected with
vasculature is normal. The aortic arch is inconspicuous owing to end-to-end anastomosis.205,206 Sometimes significant resteno-
tubular hypoplasia of the distal segment. Rib notching (arrows) is sis occurs, necessitating reintervention. Long tubular coarc-
demonstrated. tation is rare in adults. Cross-clamping of the aorta during
surgery does not usually cause ischemia of the kidneys or
spinal cord, because most of the distal aortic flow is via col-
Magnetic resonance imaging (MRI) has emerged as the most
laterals. Overall, most patients have been treated with
valuable tool to completely outline the anatomy of the aortic
surgery over the years. There appears to be a place for balloon
arch in coarctation.193,194 It can provide important informa-
angioplasty with stent placement as an alternative to surgery
tion that is helpful to direct surgical or interventional cath-
is some patients. After successful correction in the adult,
eterization procedures.195,196
hypertension often persists but is more readily controlled
medically, especially with repair in later adulthood. This
Prognosis
persistent hypertension appears to be related to barometer
The frequently associated congenital bicuspid aortic valve resetting and activation of the renin-angiotensin system.
discussed elsewhere influences prognosis separately if it pro- Patients must be followed clinically throughout their lives
gresses to significant aortic stenosis or reflux.96–98 There is because of the potential complications associated with

FIGURE 10.26. (A,B) Mild coarctation

found incidentally during evaluation of
aortic stenosis on a bicuspid aortic valve.
Note the characteristic poststenotic
dilatation.
256 chapter 10

hypertension and the frequently associated bicuspid aortic

valve.

Complex Congenital Heart Disease

Complex congenital heart disease is a group of diseases in
which more than one cardiac abnormality is present, which
may or may not be associated with cyanosis.

Without Cyanosis
Congenital heart diseases without cyanosis have been alluded
to in separate categories. Their clinical presentation is a
composite of their individual pathophysiology. Such combi-
nations include atrial septal defects with one or more anoma-
lous pulmonary veins,66–69 Shone’s syndrome,172 Williams
syndrome (supravalvar aortic stenosis) and peripheral pulmo-
nary artery stenoses (with characteristic facies), aortic insuf-
ficiency and mitral insufficiency with Marfan syndrome,207
coarctation of the aorta or ventricular septal defect with
Turner syndrome,187 pulmonic stenosis or AV canal defect in
Noonan syndrome,153 and various degrees of AV block with
endocardial cushion defects, from first- to second- to third-
FIGURE 10.27. Posteroanterior radiograph of a patient with trans-
degree AV block. position of the great vessels, ventricular septal defect, and pulmo-
nary stenosis. The heart size is at the upper limits of normal, and
the pulmonary vasculature is slightly accentuated. The main pul-
With Cyanosis monary artery segment is absent.

These conditions involve TGA. Three categories of great

vessel transposition can be seen in the adult: D-
transposition, L-transposition, and double-outlet RV.
sis, either valvar or infundibular, or both.212 The large VSD
results in equal pressure in the two ventricles. The two other
D-Transposition (Complete Transposition) of the features constituting the “tetralogy” are right ventricular
Great Arteries (D-TGA) hypertrophy and overriding of the ventricular septum by the
This form of transposition of the great arteries involves vir- dilated aorta. This malformation is compatible with surviv-
tually a direct switch between the two great arteries so that ing into adulthood.213,214 The more severe the PS, the greater
the aorta arises anteriorly from the RV and the pulmonary the degree of right-to-left shunting at the ventricular level
artery arises posteriorly from the LV208 (Figs. 10.27, 10.28, (Fig. 10.30). The more complete the arterial desaturation, the
10.29). It is evident that without intercommunication, these greater the disability. Such patients not only are prone to the
would be two closed circuits that are incompatible with life. usual complications of cyanotic heart disease (e.g., endocar-
Therefore, there must be a shunt at the atrial level (most ditis, brain abscess, and complications of marked erythrocy-
common) or at the ventricular level, or else a large PDA. In tosis) but may also experience sudden death, which has been
patients with an ASD or VSD, pulmonary stenosis may be attributed to spasm of the infundibulum.215 Lesser degrees of
present, which “protects” the pulmonary vasculature.209 PS result in a lesser degree of right-to-left shunting, with a
Uncorrected D-TGA is compatible with survival into adult- modestly decreased exercise capacity but with the ability to
hood, but patients are invariably cyanotic. Because the dis- perform most normal activities. In some patients, the degree
ability is obvious in childhood, these patients now undergo of PS is such that the patient is not visibly cyanotic at rest
surgery before they reach adulthood. Echocardiography208,210 but only with exercise; such patients are said to have tardive
is the diagnostic modality of choice. Cardiac catheterization cyanosis.216
is essential to characterize the pulmonary vasculature for The usual clinical findings in the adult are cyanosis and
any consideration of surgery. Surgical treatment for this con- clubbing of the digits and a loud, harsh pulmonary ejection
dition has undergone considerable evolution, from “atrial murmur with spilling over A 2 to a very soft P2 of the second
switching” (actually rerouting of venous blood to the appro- heart sound, or P2 may even be absent. This murmur is often
priate ventricle) to present-day methods, including arterial well heard in the neck, and such radiation should not mislead
switching.208,211 one into thinking that this is of aortic origin. Frequently,
there is a systolic ejection sound that arises in the dilated
ascending aorta. A faint blowing diastolic murmur of pul-
Tetralogy of Fallot
monary insufficiency is sometimes heard either starting
Tetralogy of Fallot (TOF) consists of a large ventricular septal with P2 or, when P2 is inaudible, starting after a gap from
defect in the usual position, together with pulmonary steno- A 2.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 257

LPA
RPA
MPA

RV

A Complete transposition, VSD, hypoplasia LPA B

AO PA

Inf
FIGURE 10.28. (A–D) D-transposition
in a 28-year-old man. (D) The completely
switched position of the pulmonary
artery (PA) and the aorta (AO) is evident,
with the aortic valve anterior to the pul-
monary trunk and the pulmonary valve. RV
LPA, left PA; MPA, main PA; RPA, right C D
PA; RV, right ventricle.

FIGURE 10.29. (A,B) Double-outlet

right ventricle in a 25-year-old man with
a supracristal ventricular septal defect
with significant left-to-right shunting.
Note the kyphoscoliosis, which is not
uncommon in cyanotic congenital heart
disease.
258 chapter 10

FIGURE 10.30. This 22-year-old man

had origin of both great vessels from the
right ventricle with the ventricular
septal defect under the pulmonary valve.
(A) In this chest film note the unusual
left-sided heart border caused by the
markedly dilated pulmonary artery (PA).
(B) This ventriculogram shows both
great vessels arising from the right ven-
tricle. This patient had an Eisenmenger
physiology. AO, aorta.

T REATMENT
The first palliative operation for cyanotic congenital heart
The chest x-ray (Fig. 10.31) is characterized by a some- disease with pulmonic stenosis was the Blalock-Taussig
what globular heart of normal size, and on the lateral view anastomosis (B-T shunt), anastomosing the subclavian artery
a prominent RV can be seen “hugging” the sternum. There to the pulmonary artery, resulting in significant functional
may be a right-sided aortic arch, which deviates the esopha- improvement, with many patients reaching adulthood.218
gus and the sternum slightly to the left. If the pulmonary Surgical correction now consists of closure of the VSD and
stenosis is purely valvar and tricuspid, as occurs in about relief of the PS.169,170 If the PS is valvar, the entire procedure
20% of these cases, poststenotic dilation of the pulmonary can be performed transatrially for both the closure of the
trunk and left pulmonary artery occurs.217 With the much VSD and the pulmonary valvotomy. In patients in whom the
more common infundibular stenosis, the left heart border is
concave because the pulmonary trunk is relatively small.
This stenosis usually creates a “third chamber” just subja-
cent to the pulmonary valve.206,207 The ECG shows RV hyper-
trophy (RVH), often with a right bundle branch block pattern.
Echocardiography shows the large VSD, the overriding large
aorta, the pulmonary valvar or infundibular stenosis with
the systolic gradient by Doppler, and RVH. Cardiac catheter-
ization can quantify the pulmonary artery pressure and the
PVR and can measure the systolic gradient between the pul-
monary artery and the RV. By careful catheter withdrawal,
it is possible to quantify the systolic gradient across the valve
and also across the infundibulum, if both coexist. Right
ventriculography can indicate the size and the location of the
ventricular septal defect, and biplanar angiography demon-
strates the extent of the infundibular stenosis, if present (Fig.
10.32). Sometimes, unusual moderator bands can mimic
classic infundibular stenosis.

PROGNOSIS
Patients who reach adulthood with uncorrected tetralogy of
Fallot used to be common, but now the vast majority of such
patients are diagnosed in childhood and undergo surgery.169,170
Patients who have had a surgically placed Potts shunt or a
Waterston anastomosis may experience significant rise in
PVR,169,170 unlike those who have undergone the single
Blalock-Taussig anastomosis,218 in which pulmonary vascu-
FIGURE 10.31. Posteroanterior radiograph of a patient with tetral-
lar changes are exceedingly rare. However, a double Blalock- ogy of Fallot. The heart is normal size and boot shaped in configura-
Taussig anastomosis may result in volume overload of the tion. The pulmonary vasculature is decreased. The esophagus is
LV (Fig. 10.33). displaced toward the left by a right-sided aortic arch.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 259

PA PA

P.V. Inf PA
Inf

AO Inf

RV RV

PA PA
PA
P.V. Im.V.
Inf Inf Inf

VSD
VSD
LV
RV LV RV
RV

FIGURE 10.32. Right ventriculogram of a 40-year-old patient with chamber just under the pulmonary valve (Pulm. V.) and also show
tetralogy of Fallot. In the upper panels are anteroposterior views contrast from the right ventricle (RV) passing through a high ven-
showing the normal relationship of the pulmonary trunk and the tricular septal defect (VSD) into the left ventricle (LV). The ventricu-
ascending aorta (AO). The lower panels show an infundibular lar septum can be clearly seen.

PS is largely infundibular, it may be necessary to expand and Pulmonary Atresia with Ventricular Septal
roof the outflow tract and the pulmonary trunk by incision Defect (Pseudotruncus Arteriosus)
and patching. In general, the postoperative results of such
surgery have been extremely gratifying, with restoration of Pulmonary atresia may be associated with a large VSD and
full functional capacity.169,170,219,220 However, late sequelae is sometimes considered the extreme version of the tetralogy
may include recurrent supraventricular tachyarrhythmias of Fallot.168 A more uncommon situation exists when the
related to the atriotomy, ventricular tachycardias related to pulmonary atresia is seen with an intact ventricular septum
ventriculotomy, and mild right-sided CHF resulting from (PA-IVS) and a small RV that is drained by large coronary
ventriculotomy and pulmonary regurgitation.169,170,219,220 Such sinusoids. The latter is almost never seen by cardiologists
CHF is uncommon, but when it exists, it occurs mostly in treating adults.223
patients who have undergone ventriculotomy, either to close Pulmonary atresia associated with a VSD (PS-VSD) is
the VSD or to open up the infundibular stenosis rather than more usefully thought of clinically as an entity apart from
using the transatrial approach. the tetralogy of Fallot.168 The clinical manifestations and the
Many patients with TOF have a mild degree of aortic surgical considerations are quite different. The pulmonary
insufficiency, which is related more to the dilatation of aortic circulation is derived entirely from large anomalous arteries
root than to intrinsic valvar disease. This is almost never of that arise from the descending aorta, often called bronchial
clinical significance. Over the long term, many problems arteries224 (Fig. 10.34). At the junction of these arteries with
remain in patients who have undergone “total correction”: the pulmonary arteries, it is common to observe significant
impaired right heart function, decreased exercise intoler- stenosis, so that the distal pulmonary arteries may be of
ance, and especially rhythm disorders.169,170,219–222 relatively normal pressure. Pulmonary atresia can range
260 chapter 10

FIGURE 10.33. Tetralogy of Fallot in a

20-year-old woman. (A) A globular and
bulky heart with somewhat increased
pulmonary vasculature after a Blalock-
Taussig anastomosis. (B) Some decrease
in pulmonary flow is due to decreasing
shunt through the anastomosis. (C)
Striking cardiomegaly after a left-sided
Blalock-Taussig anastomosis, demon-
strating the adverse effect of marked
volume overload on the heart. (D)
Decreased heart size after spontaneous
closure of the first anastomosis.

FIGURE 10.34. (A–D) Angiogram of a 30-year-old man with pseudotruncus arteriosus. There is a rather dilated ascending aorta, no pulmo-
nary trunk is seen, and the pulmonary vasculature fills from “bronchial” arteries that arise from the descending aorta.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 61
from mere atresia of the pulmonary valve, which is uncom- ascending aorta. Over the past two decades, the Norwood
mon, to atresia of the pulmonary trunk and often atresia of procedure has become standard therapy in most centers, and
the proximal left and right pulmonary arteries. These patients in the future a cadre of these patients will survive into
are markedly cyanotic. A characteristic feature on clinical adulthood.227–229
examination is the presence of a continuous murmur
throughout the chest, arising from the stenoses of the bron- Double-Outlet Right Ventricle
chopulmonary anastomoses. The chest x-ray demonstrates a
large ascending aorta and aortic arch, and absence of the A double-outlet RV (DORV) is rarely seen in the adult. Both
pulmonary trunk and the left and right pulmonary arteries the aorta and the pulmonary artery arise from the RV.230 The
(Fig. 10.35). There are bronchial arteries arising from the relationship of the great arteries is more or less usual. There
descending aorta. Echocardiography can identify the absence is an obligatory VSD.230 When the VSD is under the aortic
of a pulmonary artery in the presence of a large ventricular valve (Taussig-Bing anomaly), cyanosis is minimal or mild,
septal defect. Cardiac catheterization is essential for the with left ventricular blood flowing preferentially into the
measurement of pressures in the distal pulmonary arteries. aorta and pulmonary flow coming chiefly from the RV. Right
This is a very difficult procedure, which involves cannulat- ventricular blood goes to both great vessels but primarily to
ing the bronchial arteries arising from the descending aorta the pulmonary artery. When the VSD is subjacent to the
and threading the catheter into the distal arteries beyond the pulmonary valve, the situation physiologically resembles
stenoses. All the arteries arising from the descending aorta that of D-transposition of the great vessels with ventricular
that are supplying the pulmonary vasculature should be thus septal defect. Diagnostic confirmation is by echocardiogra-
cannulated. phy230 and by cardiac catheterization and angiography230 for
Arteriography of each of these vessels is also important consideration of surgical correction.231,232
to define the anatomy. If the anatomy is suitable and the PVR
acceptable, some of these patients can be considered for Tricuspid Atresia
staged open-heart surgery to establish continuity between
Tricuspid atresia233 is unusual but is compatible with sur-
the RV and the pulmonary arteries.223 This can be performed
vival to adulthood, providing that there is a coexisting
only in highly selected individuals and carries a significant
VSD.233,234 This anomaly never occurs alone because live
surgical risk.
birth obligates patency of the foramen ovale or, more com-
monly, a secundum type of ASD. In patients who survive to
Hypoplastic Left Heart Syndrome
adulthood, coexisting PS or subpulmonary stenosis is virtu-
Hypoplastic left heart syndrome is an unusual lesion in adult ally always present. About one fourth of the patients also
congenital cardiology clinics. Until the 1980s, this complex will have transposition of the great arteries, with the aorta
was almost universally fatal in the first year of life.225 In arising from a hypoplastic right ventricle. Patients with tri-
1982, Norwood reported his initial experience with a complex cuspid atresia are invariably cyanotic because there is mixing
palliation that has subsequently become known as the at both the atrial and at the ventricular level. The degree of
Norwood procedure.226 Classic hypoplastic left heart syn- disability largely depends on the degree of arterial desatura-
drome (HLHS) consists of mitral atresia or severe mitral ste- tion. This, in turn, depends on the magnitude of pulmonary
nosis, aortic atresia or severe aortic stenosis, left ventricular blood flow. Patients with a large VSD and mild PS will have
hypoplasia which is usually severe, and hypoplasia of the the most pulmonary blood flow and be the least cyanotic

FIGURE 10.35. (A,B) Pseudotruncus

arteriosus in a 24-year-old man. Note
the large ascending aorta and aortic arch
and marked concavity of the left heart
border owing to the absence of the
central pulmonary arteries.
262 chapter 10

FIGURE 10.37. A 34-year-old man with tricuspid atresia and nor-

mally related great vessels. Note the left-axis deviation and the
unusual P waves.

FIGURE 10.36. Tricuspid atresia in a 16-year-old girl. Note that D-TGA. The P waves are often large and bizarre (Figs. 10.37
there is unusual cardiomegaly due to the greatly dilated “right and 10.38). Atrial arrhythmias are common, especially atrial
atrium,” which is actually composed of the true right atrium and
the thin-walled, atrialized right ventricle. fibrillation and atrial flutter (Fig. 10.39). In some patients,
preexcitation or Wolff-Parkinson-White (WPW) syndrome is
notable on the ECG.236
The echocardiogram demonstrates an absence of the
initially. Over time, though, there will be high pulmonary inflow portion of the right ventricle. There is an ASD with
blood flow and pulmonary vascular disease will develop. If obligate right-to-left shunting, a functionally single ventricle
pulmonary vascular disease develops, standard single ven- communicating with a rudimentary ventricle via a VSD, and
tricle palliations such as the Fontan procedure will be often PS. There may be transposition of the great arteries.
impossible.235 Cardiac catheterization provides important information
Clinically, there is always marked cyanosis with club- if a Fontan procedure is contemplated.235 The PVR must be
bing. The characteristic murmur of pulmonary stenosis can carefully quantified and adequacy of ventricular function
be heard. There is some degree of cardiomegaly. On chest x- determined. These can be accurately obtained only with
ray study, the enlarged heart is somewhat bottle shaped, with direct measurements of pressures in the pulmonary artery
normal or somewhat decreased pulmonary vasculature (Fig. and the two atria and measurement of simultaneous flow by
10.36). There may be associated skeletal anomalies, such as the Fick method. Measurement of pulmonary artery pressure
pectus excavatum and kyphoscoliosis. is needed to calculate the PVR. Because even a mild elevation
The ECG shows left axis deviation in patients with nor- of PVR greatly decreased the success of the Fontan proce-
mally related great arteries and normal axis in patients with dure,237 direct measurement is vital.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

RHY THM STRIP: II

25 mm/sec; I cm/mV FIGURE 10.38. A 25-year-old
man with tricuspid atresia. Note
the marked right-axis deviation
in the frontal plane. This patient
had L-transposition of the great
LOC 50000-0006 15569 arteries.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 263

V1
V.P. # 844 379 17
Tricuspid atresia
V2.5
I

V3.5
II

V4
III

V5

aVR aVL aVF

V6

FIGURE 10.39. Electrocardiogram of a V4R

young woman with tricuspid atresia and
chronic atrial flutter.

T REATMENT OF T RICUSPID ATRESIA WITH tions must be met for this to succeed: a virtually passive
PULMONARY STENOSIS pulmonary vascular bed (i.e., an unequivocally normal PVR)
Earlier treatment modalities were directed toward increasing and a completely normal left ventricular filling pressure.245
pulmonary blood flow by creating systemic artery to pulmo- When these conditions are rigidly met, this operation is sur-
nary artery shunts.238–242 The earliest treatment was the prisingly successful and the patients are able to live relatively
Blalock-Taussig anastomosis, originally devised for tetralogy normal lives with normally saturated arterial blood. However,
of Fallot.218 In the Blalock-Taussig operation, a significant the cardiac output response to exercise is somewhat limited
portion of the partially oxygenated arterial blood is recycled and, therefore, so is the maximal exercise capacity.245 The
into the pulmonary vasculature for more complete oxygen- long-term results are uncertain but it appears that a signifi-
ation. The Glenn procedure (anastomosis of the superior cant portion of this increasingly large patient population will
vena cava to the right pulmonary artery) is another palliative require cardiac transplantation.246–249 In adulthood, palliative
modality.243 In the Glenn procedure, no true shunt is involved, shunts should be performed only when the physiologic condi-
because the operation allows the superior vena cava to bypass tions preclude a Fontan procedure and the degree of cyanosis
the right heart and empty directly into the pulmonary artery. is severe.
However, blood from the inferior vena cava continues to
shunt from right to left, so that although there is some clini-
Truncus Arteriosus
cal improvement, the increasing desaturation of the inferior
vena cava blood associated with work by the lower extremi- Truncus arteriosus is an incomplete septation of the ascend-
ties, such as walking and running, results in shunting of ing aorta and the pulmonary trunk.250,251 The semilunar
increasingly desaturated blood and therefore a considerable valve is a single truncus valve, which in most cases consists
limitation of exercise capacity. of three cusps but may be either quadricuspid or bicuspid. It
In 1971, Fontan and colleagues237 devised an ingenious is commonly insufficient, sometimes markedly so, and strad-
procedure to separate the pulmonary and systemic circula- dles a VSD.250 Truncus defects are divided into three types.250
tions. The original procedure entailed closing the ASD, Type I has a common trunk, but this gives rise distally to
closing the stenotic pulmonary valve, and anastomosing the recognizably separate ascending aorta and pulmonary trunk
RA to the pulmonary artery by means of a conduit. A modi- (Fig. 10.40). In type II, the truncus extends up to the right
fication in which the communication between the RA and and left pulmonary artery bifurcations, there being no sepa-
the pulmonary artery is achieved by anastomosing the right rate pulmonary trunk (Fig. 10.41). In type III, the left and
atrial appendage to the pulmonary artery avoids the use of right pulmonary arteries arise from either side of the truncus.
prosthetic material.244 In this arrangement, flow proceeds In adults, the most common type is a type I truncus.252 Such
from the venous system to the LA entirely by the pressure patients have a regurgitant truncal valve, a common mixing
gradient between the RA and the LA. Two obligatory condi- chamber, and Eisenmenger’s physiology. In the very young
264 chapter 10

FIGURE 10.40. Truncus arteriosus in

an adolescent. (A,B) Note the rather
characteristic wide waist of a heart with
a somewhat unusual shape but not
enlarged. The shape is in part influenced
by the presence of pectus excavatum,
which is not infrequently seen in
patients with congenital heart disease.
(C,D) The heart and great vessels, with
injection into the right ventricle. The
truncus artery is clearly seen in both
anteroposterior and lateral views, with
the truncus dividing into a separate
aorta and pulmonary artery. The ven-
tricular septal defect can be seen (D),
where the anterior right ventricle and
the posterior left ventricle are separated
by the ventricular septum.

patient, the PVR may be somewhat less than the SVR, so that pulmonary flow).251 Echocardiography readily visualizes the
surgical correction can be attempted. By adulthood, the PVR truncal arteriosus and the truncus valve and can distinguish
is markedly elevated, and few if any of these patients are the truncus subtype. Cardiac catheterization is important in
candidates for corrective surgery. The remaining possible characterizing the pulmonary vasculature, especially if there
treatment is heart-lung transplantation. When patients are is any consideration of repair, because the PVR would need
operated on in childhood, the results are promising for sur- to be significantly less than the SVR.
vival to adulthood.253 Note should be made of a commonly used term, pseudo-
The clinical examination classically reveals cyanosis and truncus arteriosus, which is really pulmonary atresia with
clubbing.251 There is usually no systolic murmur, but occa- VSD. Despite the single arterial outflow from the two ven-
sionally one may be heard. The early diastolic blowing tricles, this is really not a variant of truncus arteriosus,
murmur of truncal valve insufficiency is characteristic. because the single outflow is the ascending aorta and not a
Depending on the degree of truncal valve insufficiency, the truncus, and the valve is a competent tricuspid aortic valve
heart may or may not be enlarged. Chest radiography is char- rather than a truncal valve. Pulmonary blood flow in this
acterized by a cardiac silhouette with a wide waist, which is lesion is via bronchopulmonary anastomoses, as described
the markedly dilated truncus arteriosus. The pulmonary vas- earlier.
culature is similar to that in Eisenmenger’s complex (i.e., Aortopulmonary window or aortopulmonary septal
large central pulmonary arteries and no evidence of increased defect is a separate entity, different from truncus arterio-
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 265
under the rubric of cyanotic congenital heart disease.255
However, such normal hearts are uncommon, and in such
cases, two common features in the natural history make it
unlikely that these patients will have a normal heart for the
rest of their natural lives. These patients are prone to develop
AV block, which may progress to third-degree block with a
narrow QRS.255,256 Although they may have Adams-Stokes
attacks, this is a less common manifestation, but exercise
tolerance may become limited because of the inadequate
chronotropic response to exercise. Furthermore, the left-
sided AV valve (i.e., the tricuspid valve) is prone to dysplasia
or to Ebstein’s anomaly.254 If the patient survives into adult-
hood, this Ebstein’s anomaly is not apt to be severe, but the
valve becomes insufficient because of systemic pressure in
the arterial ventricle. This may therefore necessitate subse-
quent valve replacement.255,256
In the vast majority of patients who reach adulthood,
there is communication at the ventricular level associated
with pulmonary stenosis. A ventricular septal defect or
sometimes even a functionally common ventricle may be
present. Such patients are always cyanotic but have a pulmo-
nary vasculature that is “protected” against the development
of pulmonary hypertension. The physical examination find-
FIGURE 10.41. Posteroanterior radiograph of a patient with truncus
arteriosus type II. The heart is markedly enlarged, and no main ings are those of severe PS, together with cyanosis and club-
pulmonary artery segment is demonstrated. The right and left pul- bing. The chest x-ray shows a normal heart size, very often
monary arteries are prominent, as is the aorta. The left pulmonary with a straight left heart border, this being the ascending
artery is in an abnormally high position (arrow). aorta (Figs. 10.43 and 10.44). The heart may have an unusual
contour if the inverted RV is prominent (Fig. 10.45). The ECG

sus.254 In this condition, there is a “window” in the septum

between the aorta and the pulmonary trunk. The aorta and
the pulmonary trunk have separate semilunar valves, and
the window does not go down to and involve the semilunar
valves. If the window is large, the adult patient presents with
Eisenmenger’s syndrome (Fig. 10.42). Smaller windows may
protect the pulmonary vasculature and allow closure of the
defect.

Congenitally Corrected Transposition

Numerous attempts at standardizing the nomenclature of
this anomaly have been attempted but none has ever been
completely satisfactory. These include L-transposition of the
great arteries (L-TGA), corrected transposition (CC-TGA),
congenitally corrected transposition, and ventricular inver-
sion. The most precise description is atrioventricular discor-
dance or ventricular inversion. This “inversion” involves
both the AV valves and the semilunar valves, so that the
venous ventricle is the anatomic LV, the arterial ventricle is
the anatomic RV, and the crista supraventricularis is on the
left, as is the tricuspid valve, whereas the mitral valve is the
right AV valve. The AV conduction system goes down the left
side of the heart. The atria are not involved, and therefore
the venous return to both atria and the coronary sinus is in
the normal position. However, the aortic root and the pul- FIGURE 10.42. Posteroanterior radiograph of a patient with
monary trunk do not have an anteroposterior relationship ventricular septal defect and severe pulmonary vascular disease
but rather a side-by-side relationship, so that the aortic root (Eisenmenger’s syndrome). The heart is moderately enlarged, and
the central pulmonary artery is distinctly enlarged, whereas the
forms the left heart border and the pulmonary trunk arises peripheral pulmonary vasculature is normal. The main pulmonary
medially. Were there no other abnormalities, this would be artery is huge (arrow) as a result of long-standing pulmonary
a functionally “normal” heart and therefore would not belong hypertension.
266 chapter 10

shows evidence of right ventricular hypertrophy and first-,

second-, or third-degree AV block (Figs. 10.46 and 10.47).
The echocardiogram is characteristic.255 The inversion of
the ventricles can be identified by the presence of the crista
supraventricularis in the arterial ventricle, the clearly
switched AV valves, and the unusual position of the two
semilunar valves. Because the aorta and the tricuspid valve
are now on the same side, the aortic valve and the left-sided
(tricuspid) AV valve are not in continuity, as would be the
relationship between the aortic and the mitral valves in the
normal heart. Ebstein’s anomaly of the left-sided AV valve
can also be visualized if present. The VSD and PS can be
further identified. For purposes of possible surgical treat-
ment, one needs to know whether the ventricular communi-
cation is a functionally common ventricle or a large VSD.
Cardiac catheterization is important for characterizing
the hemodynamics, including ventricular function, the
degree of pulmonary stenosis, and the PVR. These data are
especially important in patients who have a common ven-
tricle, with the possibility of a modified Fontan procedure as
a therapeutic option. Angiography can quantify the degree of
left AV valve insufficiency and the respective positions of the
FIGURE 10.43. Congenitally corrected transposition in a 35-year- two great arteries. The pulmonary stenosis can be confirmed
old man with ventricular septal defect and no pulmonary stenosis.
Note the straight left-sided heart border, which is formed by the L- as being either valvar or subvalvar. Angiography also helps
transposed ascending aorta and the inverted right ventricle.

FIGURE 10.44. (A–D) An 18-year-old

woman with congenitally corrected
transposition of the great vessels and a
common ventricle. (A,B) The anteropos-
terior views show that the ascending
aorta forms the left-sided heart border
and the pulmonary trunk arises more
medially. (C,D) The lateral views show
that the semilunar valves are more side-
to-side than anteroposterior to each
other.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 2 67

38EC 38EC
R

I aVR
Au
.5

II aVL
3 0.5
F

III aVF
V1 M
1.0

1.0
V1 V4
V2 0.5 1.0

V2 V5
V3 .5 1.0
FIGURE 10.45. Posteroanterior radiograph of a patient with cor-
rected transposition, ventricular septal defect, and pulmonary ste-
nosis. The heart is slightly enlarged, and the pulmonary vasculature
is within normal limits. There is a prominent bulge at the left heart
contour (arrows), representing the inverted right ventricle. The pul- V3 V6
monary segment is absent because the main pulmonary artery lies
centrally within the mediastinum and is no longer border 1.0 1.0
forming.

V1
FIGURE 10.46. Electrocardiogram of a 43-year-old patient with
to detail the anatomy of the coronary arteries, which undergo congenitally corrected transposition with pulmonary stenosis and
a curious “rotation.” ventricular septal defect. Note the absence of Q wave in the lateral
Patients who start out in life with a “normal” heart chest leads. This is because of the ventricular inversion, with the
usually have trouble eventually with the supervention of septum depolarizing from right to left rather than from left to
right.
various degrees of heart block and with insufficiency of the
left-sided AV valve. The prognosis for patients who have VSD
with PS has improved considerably with modern surgical
therapy. However, these patients are still susceptible to infec-
tive endocarditis. Even with correction of the left-sided AV
valve insufficiency, the anatomic RV may not perform opti-
mally over the years.257,258

T REATMENT
The treatment of this lesion is surgical.255,258 Because the
clinical profile of such patients closely resembles that of
tetralogy of Fallot, many of them have undergone a Blalock-
Taussig shunt anastomosis with marked improvement in
functional capacity and arrive at adulthood only mildly cya-
notic.259 Although they may not be functional class I, they
may still be quite functional but receptive to future surgical
procedures.260,261
For patients who have an ventricular septal defect and
FIGURE 10.47. Electrocardiogram of a 54-year-old woman with a
pulmonary stenosis, closure of the VSD and pulmonary val- third-degree heart block. She did well over the years, but eventually,
votomy would seem reasonable. The approach to the defect the inadequate chronotropic response to exercise necessitated a
from the right side in this lesion, however, is technically pacemaker.
268 chapter 10

difficult. Patients with a common ventricle and pulmonary

stenosis may be eligible for a modified Fontan proce-
dure,235,237,244 provided that the PVR and ventricular filling
pressure are normal. This can be accomplished by converting
the heart into one with tricuspid atresia by closing the tri-
cuspid valve and placing a conduit between the RA and the
pulmonary artery.

Great Vein Malpositions

Partial Anomalous Pulmonary Venous

Return (Connection)
Partial anomalous pulmonary venous return (PAPVR) is
physiologically similar to left-to-right shunting at the atrial
level.262 There may be one, two, or three pulmonary veins
that are anomalously connected, and they may drain together
or separately into the innominate–superior vena cava system,
coronary sinus, RA, or inferior vena cava. These constitute
pure left-to-right shunts. When all four pulmonary veins
connect anomalously (i.e., total anomalous pulmonary
venous connection, TAPVC) and drain eventually into the
RA, there is an obligatory ASD, the RA becoming a mixing
FIGURE 10.48. Posteroanterior radiograph of a patient with total
chamber, with right-to-left shunting at the atrial level.
anomalous venous return to the left superior vena cava. The heart
is mildly enlarged, the pulmonary vasculature is increased, and the
dilated left and right portions of the superior vena cava are clearly
Total Anomalous Pulmonary Venous Connection demonstrated (arrows); snowman heart.
Total anomalous pulmonary venous connection is uncom-
mon in the adult.262 The most common form is type I, in
which the pulmonary veins drain via a large ascending verti-
cal vein into the left innominate vein and then to the supe-
rior vena cava. Less common is type II, in which the veins
drain into a left superior vena cava and then into the coro-
or “figure-eight” configuration of the heart and great vessels
nary sinus. In type III, the pulmonary veins join to form a
(Fig. 10.48). The echocardiogram can identify the drainage
long anomalous vein into the inferior vena cava or even into
site of most or all of the pulmonary veins if the echocardiog-
the portal vein. Type III is not seen in adults and, if not cor-
rapher is compulsive in identifying all pulmonary veins or
rected during the first few weeks of life, is usually fatal. One
alerted beforehand to the diagnosis. Sometimes a transesoph-
may also see a combination of connections, with the veins
ageal echocardiogram may be required. Cardiac catheteriza-
draining separately but ultimately into the RA.262
tion is helpful in obtaining the oxygen saturations in all
In all situations, the oxygen saturation in all four cham-
cardiac chambers and in the pulmonary artery and aorta to
bers should in theory be identical, but in fact, this is not
give one a clue as to the likely connections. The anomalous
necessarily so. Drainage into the inferior vena caval system
connections can be individually cannulated, and angiograms
causes the relatively more oxygenated blood to stream pref-
of these anomalous veins and the exact anatomy are
erentially through the ASD so that the left heart chambers
extremely helpful to the surgeon, especially if they drain to
are somewhat more saturated than the right heart chambers.
different sites (Fig. 10.49). It may be necessary to explore the
When the connections are by the superior vena caval system,
superior vena cava and innominate vein, the coronary sinus,
there is apt to be more nearly equal saturation in all four
and the inferior vena cava. Selective indicator dilution curves
chambers. If all four veins drain to the coronary sinus, the
in the four pulmonary arteries or selective angiography of
right ventricle and the pulmonary artery may have a higher
these vessels can help identify the connections if the anoma-
oxygen content than the left side of the heart.
lous veins are not draining together. Today, computed tomog-
Clinically, patients may exhibit cyanosis and clubbing,
raphy (CT) and MRI are increasingly used to identify the
but the cardiac findings are similar to those of the secundum
pulmonary venous anatomy.263
type of ASD, with a wide, fixed splitting of the second heart
sound and a hyperactive LV. The ECG is also similar, with
Treatment
incomplete right bundle branch block with rSR´ in lead V1
and a normal frontal plane QRS axis. The chest x-ray is most The treatment is surgical. The type of connection that is
striking if all four pulmonary veins drain into a venous most readily amenable to surgery is anomalous pulmonary
sinus, then into a common vertical vein and into the innomi- venous connection of the snowman type, by a side-to-side
nate vein, and then to the superior vena cava. The marked anastomosis of the common venous sinus to the LA and liga-
dilatation of this system gives rise to the so-called “snowman” tion of the vertical vein.
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 269

FIGURE 10.49. This 35-year-old patient

had total anomalous pulmonary venous
connection via a large vertical vein to
the superior vena cava. (A) Chest x-ray
shows the characteristic “snowman” or
figure-eight configuration. (B) Angio-
gram shows the large horizontal vein,
being the confluence of the pulmonary
veins, which drains by a vertical vein
into the innominate vein and thence
into a greatly dilated superior vena
cava.

Coronary Artery Anomalies greatly enlarged coronary artery as a “puddle” from which
contrast enters the RV. Fistulas of small coronary arterial
Coronary artery anomalies can be divided into four branches are sometimes seen in routine angiograms and are
types.265–267 The first is anomalous origin of the right coro- of no hemodynamic significance.
nary artery from the left coronary artery, or a branch of the If coronary artery fistulas are asymptomatic, it seems
left coronary artery from the right coronary artery, or if the that they can be safely watched. Although the details of the
left anterior descending coronary artery and the circumflex lifelong mortality risk of such an anomaly are not entirely
artery have separate ostia. These patients are asymptomatic known, the evidence that exists suggests that the mortality
and do well unless they acquire coronary atherosclerosis. risk of such fistulas is extremely small and would not neces-
A second type is an ectopic course of the left coronary sarily warrant surgical intervention.271
artery, so that instead of coursing anterior to the pulmonary Finally, there may be an anomalous origin of a coronary
artery, it goes between the aorta and the pulmonary artery.266 artery from a pulmonary artery.272 In this situation, the effect
Sudden deaths have been reported with this anomaly. It is is that of a large coronary artery steal because the pulmonary
likely that the pathophysiology is not compression of the artery is under low pressure. Therefore, anomalous origin of
coronary artery between the aorta and the pulmonary artery, the left coronary artery from the pulmonary artery is seen
as has been suggested, because the pulmonary artery is less commonly in adults because it is usually symptomatic
essentially a low-pressure vessel. Rather, the course of the or fatal in childhood unless it is treated. Formerly, the recom-
coronary artery shortly after its origin from the aorta is at a mended treatment was ligation of the anomalous artery, but
somewhat acute angle, which, during vigorous exercise, may current treatment involves both ligation of the anomalous
become more acute, with resultant myocardial ischemia. coronary artery at its takeoff from the pulmonary artery and
The other anomaly in this group is myocardial bridging, in bypass grafting. In the adult, anomalous origin of the right
which the epicardial coronary artery dives under the myo- coronary artery from the pulmonary artery is somewhat
cardium and then reemerges. During systole, the vessel more common and is usually asymptomatic, although it has
undergoes compression. Most such cases are asymptomatic, been implicated in sudden death.
but an occasional patient has angina and a positive stress test
result that is relieved when the bridging is unroofed.268,269
A third anomaly involves fistulas between the coronary Aneurysms of the Sinus of Valsalva
arteries and the ventricular cavity.270 A coronary artery may
empty distally directly into a cardiac chamber. This more Congenital aneurysm of the sinus of Valsalva is caused by a
commonly involves the right coronary artery, which drains weakness at the junction of the aortic media and annular
into the RV. More often, the coronary artery drains into a fibrosis of the aortic valve.273 By far the most commonly
telangiectatic structure, which then empties into the RV. involved sinus is the right aortic sinus. The aneurysm
Clinically, such patients are usually asymptomatic, but the usually protrudes into the outflow tract of the RV or, less
physical examination may reveal a soft, continuous murmur commonly, into the RA. Aneurysm of the posterior sinus is
over the precordium, more commonly near the left sternal much less common, and that of the left coronary sinus
border if the right coronary artery is involved. If the shunt is extremely rare. An aneurysm of the sinus of Valsalva is
is large, there may be a “steal” phenomenon, which may asymptomatic until it ruptures, at which time a sudden
rarely cause angina. The treatment may be either surgical or large left-to-right shunt develops into the RV or RA, with
selective embolization of the distal telangiectatic lesion. dyspnea due to pulmonary congestion and even pulmonary
Angiographically, this lesion is seen at the terminus of a edema.274 The physical findings are those of an arteriovenous
270 chapter 10

fistula (i.e., a loud, continuous murmur over the precor- drugs should be reserved for pregnant women who have clear-
dium). The diagnosis is made clinically by the history and cut hypertension that cannot be controlled with salt restric-
physical findings and is corroborated by echocardiography, tion alone.281
which can locate the fistula and visualize the shunt. This In patients who have mechanical cardiac prostheses280 or
can also be accomplished by aortic root angiography. The who might have thromboembolic phenomena caused by
treatment is surgical. secondary erythrocytosis in cyanotic heart disease, use of
The sinus of Valsalva aneurysm itself is a potential site warfarin should be avoided because of its substantial terato-
for infective endocarditis and occasionally is the cause of genicity and fetal wastage. Heparin does not cross the pla-
rupture. cental barrier because of its molecular size and is the drug
of choice for anticoagulation.283 In the presence of erythro-
cytosis, self-administration of subcutaneous heparin is prac-
Pregnancy and Congenital Heart Disease tical.284 For mechanical prostheses, however, more careful
monitoring of the activated partial thromboplastin time is
During pregnancy, there is an increase in intravascular necessary, and intravenous administration of heparin via a
volume starting in the second trimester, reaching a peak at heparin lock may be necessary. It is precisely these consid-
32 weeks, and declining slightly thereafter until term.201,220,275 erations that may make it advisable for women of childbear-
There is a corresponding rise in cardiac output owing to the ing age who have severe congenital valve disease necessitating
increased volume and the vascularity of the gravid uterus.276,277 valve replacement to opt for a bioprosthesis, if they wish to
During the first stage of labor, the hemodynamic alterations bear children, with the full understanding that a second
are intermittent and transient. The pulmonary artery wedge operation will in all likelihood be necessary some years later,
pressure may rise with each uterine contraction and fall after childbearing has been completed.
promptly with relaxation, the rise in pulmonary wedge pres- For cardiac arrhythmias, digoxin has a long history of
sure being due to a sudden increase in intravascular volume safety in pregnancy. Although by itself, it may not be espe-
by up to 500 mm Hg, caused by the contracting uterus. cially effective, in combination with other drugs, it can be
During the second stage of labor, however, vigorous bearing useful.285 In general, quinidine has had a reasonable record
down constitutes a series of giant, prolonged Valsalva maneu- of safety, although rarely it causes damage to the eighth
vers. During the third stage, there is a loss of blood of about cranial nerve of the fetus. Disopyramide, verapamil, meto-
500 mL and a transient rise in cardiac output without a sig- prolol, and labetalol have a reasonable safety record.286,287 The
nificant change in arterial blood pressure, which translates conduct of labor in patients with serious valve disease and
into a lower SVR.277–279 cyanotic heart disease optimally should include Swan-Ganz
Patients with noncyanotic heart disease with left-to-right catheterization for monitoring of the pulmonary artery
shunting and normal to moderately elevated PVRs usually wedge and right atrial pressures, constant blood pressure
tolerate pregnancy well.280,281 Patients with ASD, PDAs, monitoring, and oximetry.288 Vaginal delivery, with shorten-
small-to-moderate VSDs, and mild valvar stenosis or insuf- ing of the second stage of labor by forceps delivery, if neces-
ficiency can also be safely carried through pregnancy. Coarc- sary, is feasible in most patients. However, intractable and
tation of the aorta carries a higher risk during pregnancy serious elevation of the pulmonary artery wedge pressure,
because of possible aortic dissection, aortic rupture, or sub- significant fall in arterial oxygen saturation, or intractable
arachnoid hemorrhage from a berry aneurysm, which is hypertension or hypotension or fetal distress should raise a
sometimes associated with coarctation of the aorta.282 In all serious consideration of cesarean section.
of these situations, salt restriction to prevent a dispropor- The first stage of labor usually does not cause serious
tionate rise in the intravascular volume is of great impor- hemodynamic disturbances, except transiently during con-
tance. It is especially important in coarctation of the aorta, tractions. However, the second stage should be shortened by
in which management of the intravascular volume should forceps if safely feasible, and anesthesia, which minimizes
coincide with control of hypertension, if present. Salt restric- vasodilatation, should be given. The third stage may be dan-
tion may also help to control hypertension. However, if drug gerous in cyanotic patients, in whom the fall in SVR after
therapy becomes necessary, the inevitable question of fetal delivery, combined with blood loss, may suddenly increase
toxicity arises. Verapamil has been used during pregnancy right-to-left shunting. The fall in blood pressure and arterial
to treat fetal tachycardias without documented fetal toxicity. desaturation may cause progressive deterioration, with a
However, nifedipine has been associated with a high rate of fatal outcome. Therefore, every effort should be made to
cesarean section and low-birth-weight infants. The beta- replenish lost intravascular volume and to maintain blood
blockers propranolol and atenolol have been associated with pressure and adequate oxygenation. Such patients should
low birth weight, tachycardia, and hypoglycemia. Metoprolol have been typed and cross-matched, with blood available and
has been well tolerated, as has labetalol. There have been rare arterial vasoconstrictors on hand to maintain the blood pres-
reports of adverse effects on the fetus with angiotensin-con- sure and thus increase the SVR if necessary if sudden hypo-
verting enzyme (ACE) inhibitors. Diuretics have not been tension occurs. Cesarean section itself is not without risk.
shown to be directly deleterious to the fetus, although they There is the risk posed by general anesthesia, the greater
may decrease placental perfusion. The combination of thia- blood loss, and the supine hypotension phenomenon of preg-
zide diuretics and methyldopa has apparently been shown to nancy (postulated to be due to compression of the inferior
be safe and effective. There have been reports, however, that vena cava by the gravid uterus). Therefore, cesarean section
thiazides, which cross the placental barrier, are associated is an option only when it appears that vaginal delivery is
with neonatal thrombocytopenia and hyponatremia. Thus, posing an unacceptable risk.277,289
 p a t h o p h y s i o l o g y, c l i n i c a l r e c o g n i t i o n , a n d t r e a t m e n t o f c o n g e n i t a l h e a r t d i s e a s e 271
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38%, and causes considerable fetal wastage.281 tion 1987;76:1037.
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Myocardial bridging. Eur Heart J 2005;26:1159–1168. 291. Gleicher N, Midwall J, Hochberger B, et al. Eisenmenger’s syn-
270. Levin DC, Fellows KE, Abrams HL. Hemodynamically signifi- drome in pregnancy. Obstet Gynecol Surv 1979;34:721.
cant primary anomalies of the coronary arteries: angiographic 292. Radford DJ, Stafford G. Pregnancy and the Rastelli operation.
aspects. Circulation 1978;58:25. Aust N Z J Obstet Gynaecol 2005;45:243–247.
 1 Echocardiography in the
1 Adult with Congenital
Heart Disease
Julie A. Kovach

Indications for Echocardiography in the Evaluation of Abnormalities of Ventricular Number or

the Adult with Congenital Heart Disease . . . . . . . . 279 Morphology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Indications and General Segmental Echocardiographic Conotruncal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . 296
Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Obstruction to Ventricular Outflow . . . . . . . . . . . . . . . . 300
Abnormalities of Cardiac Septation. . . . . . . . . . . . . . . . . 282 Miscellaneous Congenital Anomalies. . . . . . . . . . . . . . . 303
Abnormalities of Venous Inflow. . . . . . . . . . . . . . . . . . . . 291 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Abnormalities of Ventricular Inflow . . . . . . . . . . . . . . . . 292

Key Points College of Cardiology estimated that over 800,000 adults

with congenital heart defects were living in the United States
• Echocardiography, because of its excellent spatial as of the year 2000.1 Based on birth rates and disease inci-
resolution and ability to assess both anatomy on two- dence, one group of investigators estimated that there are
dimensional imaging and physiology by Doppler, is espe- currently up to 1.33 million U.S. survivors with congenital
cially suited to the diagnosis and follow-up of adults with heart disease born since 1940, 56% with simple lesions, 30%
congenital heart disease. with moderately complex lesions, and 14% with more severe
• Indications for echocardiography in this patient popula- lesions.2 An additional 3 million Americans have bicuspid
tion have been published. aortic valves. Adults, most of whom have undergone some
• In the previously undiagnosed adult with suspected con- operation to repair or palliate their defect, will soon outnum-
genital heart disease, a careful segmental approach to ber children with congenital cardiac defects. The long-term
scanning is required to make a complete diagnosis. clinical course of these patients will be determined by both
• Echocardiography of adults with congenital heart defects their congenital and acquired cardiovascular conditions,
should be performed and interpreted by personnel trained which require accurate diagnosis, diligent ongoing follow-up,
in the care of these patients. and continued management.
• Echocardiography of adults with congenital heart disease Echocardiography plays an essential role in the diagnosis
requires knowledge of the anatomy and natural history and management of patients with congenital heart disease.
of unoperated defects, awareness of the possible palliative For an unselected cohort of children and adolescents referred
or corrective procedures for the defect, and awareness of for evaluation of a cardiac murmur, echocardiography identi-
the potential complications, sequelae, and residua of the fied congenital cardiac lesions in 12% of subjects diagnosed
repair. to have a functional murmur on history and physical exami-
nation performed by experienced congenital cardiologists.
For 152 individuals who underwent auscultation, the diag-
Indications for Echocardiography in the nosis by echocardiography was discordant in 19% of patients,
Evaluation of the Adult with Congenital with a major discordance recorded in 6%.3 In many cases,
Heart Disease echocardiography supplants invasive diagnostic techniques
in patients who proceed to complete repair, palliation, or
Thanks to advances in antenatal and postnatal diagnostic reoperation without the need for cardiac catheterization.
methods, rapid progress in surgical options and technique, Transthoracic echocardiography (TTE) with two-dimensional
improvements in perioperative management, and meticulous (2D) imaging and color4 and spectral Doppler affords accurate
care by pediatric cardiac specialists, over 85% of children and complete characterization of cardiac anatomy and hemo-
born with cardiac anomalies survive well into adulthood. dynamics in the majority of adults with congenital heart
The 32nd Bethesda Conference sponsored by the American disease. For patients with limited acoustic windows due to

279
280 chapter 11

prior operations, body habitus, coexistent lung disease, or knowledge of the echocardiographic features of the isolated
atypical cardiac location within the chest, or those with unrepaired defect, understand the potential repairs or correc-
structures not accessible to TTE, transesophageal echocar- tive operations for each defect (especially since the patient
diography (TEE) provides direct visualization with excellent may not know the nature of his operation), and examine for
resolution.5–8 In the operating room, TEE provides invaluable potential complications, residua, or late sequelae of unoper-
assistance to the surgeon in determining the nature of the ated defects or surgical repair or palliation. Thus, echocar-
surgery, assesses adequacy of repair, and rapidly identifies diography in the adult with congenital heart disease demands
any immediate complications, thus reducing operative mor- a thorough and careful systematic approach.
bidity and mortality.9,10 Interventional cardiologists use TEE This chapter emphasizes the general approach to the
or intracardiac catheter-based echocardiography for guidance examination, outlines echocardiographic features of common
during transcatheter procedures, especially for placement of defects that may first appear in adulthood, briefly reviews
closure devices for atrial septal defects (ASD) or patent the echocardiographic characteristics of lesions that were
foramen ovale (PFO).11–17 Three-dimensional echocardiogra- most likely diagnosed and operated in childhood, presents
phy, a promising technique with rapidly improving image the usual appearance of standard operative (and transcathe-
quality and speed of image acquisition and rendering, has ter) procedures for congenital cardiac anomalies, and dem-
added to the understanding of congenital heart disease, onstrates the echocardiographic findings of the most common
including ASD closure, and facilitated the diagnosis of cor late complications or sequelae of palliation or correction.
triatriatum, an uncommon congenital defect.18–22 Diagnosis Both 2D TTE and TEE have widespread use in these patients
of cardiac abnormalities in utero by fetal echocardiography and are presented in detail. M-mode echocardiography, which
promotes better counseling and education of families. In at one time was utilized for the diagnosis of certain cardiac
addition, fetal echocardiography facilitates earlier planning defects, has minimal clinical application at present and is
of postnatal management by physicians and parents, includ- not discussed. Like pediatric patients, adults with previously
ing possible surgery.23 undiagnosed congenital heart anomalies benefit from a
Adults with previously undiagnosed congenital cardiac sequential, segmental approach for the determination cardiac
defects, many with minimal hemodynamic consequences up anatomy.
to that time, require a similar echocardiographic approach
to that called for in children. It is not unusual for a small
ASD without significant left-to-right shunt to be first diag- Indications and General Segmental
nosed on routine TTE performed for other indications. Echocardiographic Approach
However, important differences exist between most adults
with previously diagnosed or repaired congenital heart The American College of Cardiology/American Heart Asso-
defects and their pediatric counterparts, and these differ- ciation Task Force on Practice Guidelines (Committee on
ences necessitate additional considerations for the acquisi- Clinical Applications of Echocardiography) noted the follow-
tion and interpretation of echocardiographic images in these ing reasons for adult congenital patients to seek care from a
patients. Adults typically have more difficult acoustic cardiologist and for which they might need an echocardio-
windows with less clear images than children owing to gram: (1) an initial diagnosis of congenital heart disease; (2)
larger body size, prior surgeries, and coexisting conditions a previously recognized congenital heart disease that is pres-
that can affect image quality such as lung disease. Echocar- ently inoperable; (3) a progressive clinical deterioration, such
diographic contrast agents may improve diagnostic accuracy as ventricular dysfunction or arrhythmias due to the natural
for assessment of ventricular function and diagnosis of history of their defect; (4) the patient becomes pregnant or
certain anomalies such as apical hypertrophic cardiomyopa- has other stresses such as noncardiac surgery or infection,
thy or noncompaction of the left ventricle in these patients.24 including infective endocarditis; (5) the patient has residual
Age- and body habitus–associated changes in cardiac posi- defects after a palliative or corrective operation; (6) the patient
tion within the chest, cardiac malposition at baseline, or the develops arrhythmias (including ventricular tachycardia,
presence of conduits may require the use of multiple imaging atrial flutter, or atrial fibrillation) that may result in syncope
planes from varied ultrasound transducer positions on the or sudden death; (7) a progressive deterioration of ventricular
chest wall that differ from standard transducer locations. function with congestive heart failure; (8) progressive hypox-
“Adult” cardiovascular diseases like hypertension and ath- emia because of the inadequacy of a palliative shunt or the
erosclerotic coronary or peripheral arterial disease may alter development of pulmonary vascular disease; or (9) the patient
the “typical” physiology of a congenital defect; for example, requires monitoring and prospective management to main-
a small secundum ASD with no significant shunt when the tain ventricular or valvular function or to prevent arrhyth-
patient is 20 years of age may cause right ventricular volume mic or thrombotic complications. The task force recommended
overload at age 50 when blood pressure is higher and ven- that cardiac sonographers and physicians who perform and
tricular compliance is less. Patients with unoperated cardiac interpret echocardiograms for these patients have special
lesions will exhibit expected complications of that defect as competency in congenital heart disease or refer the patient
determined by the underlying lesion. Importantly, adults to a cardiologist (either adult or pediatric) who is trained in
with congenital abnormalities that were “successfully” the care of adults with congenital heart disease. Based on
repaired or palliated in childhood, including adults with these considerations and the available literature, the task
“cured” ASD and coarctation of the aorta, may have residua force issued guidelines for indications for the performance of
or late complications of the repair or sequelae of unrepaired 2D and Doppler echocardiograms in the adult patient with
components of the defect. The echocardiographer must have congenital heart disease (Table 11.1).25
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 2 81
TABLE 11.1. Indications for echocardiography in the adult patient with congenital heart disease
Class I Patients with clinically suspected congenital heart disease, as evidenced by signs and symptoms
Patients with known congenital heart disease when there is a change in clinical findings
Patients with known congenital heart disease for whom there is uncertainty as to the original diagnosis or when the
precise nature of the defect is unclear
Periodic echocardiograms in patients with known congenital heart disease for whom ventricular function and
atrioventricular valve regurgitation must be followed
Patients with known congenital heart disease for whom pulmonary artery pressure is important
Periodic echocardiography in patients with surgically repaired or palliated congenital heart disease with the following:
change in clinical condition, clinical suspicion of residual defects, left or right ventricular function that must be
followed, the possibility of hemodynamic progression, or a history of pulmonary hypertension
To direct interventional catheter valvotomy (or other interventions as necessary) in the presence of complex cardiac
anatomy
Class IIb Annual or biennial follow-up Doppler echocardiographic study in patients with known hemodynamically significant
congenital heart disease and no evident change in clinical condition
Class III Multiple repeat Doppler examinations in a patient with repaired patent ductus arteriosus, atrial septal defect (ASD),
ventricular septal defect (VSD), coarctation of the aorta, or bicuspid aortic valve without change in clinical condition
Repeat Doppler examinations in patients with known hemodynamically significant congenital heart lesions

In general, the echocardiographic approach to the previ- cate atrial situs inversus. Since visceral-atrial discordance is
ously undiagnosed patient is anatomically sequential fol- almost always accompanied by complex congenital defects,
lowing the course of blood flow through a normal heart and it is usual that that diagnosis would already have been made
focusing on the presence or absence and location of cardiac in childhood, so this is of little concern in the previously
structures, with attention to morphology, relationships and undiagnosed adult. Additional clues to the determination of
connections to one another. This approach is summarized atrial situs include the presence of the inferior vena cava
below. The sonographer must recognize that standard draining into an atrium (almost always the right atrium) and
imaging planes may not be helpful and adapt scanning as atrial morphology. Some patients have an absent inferior
necessary. “Unusual” transducer positions, including high vena cava associated with anomalous drainage into the
parasternal, laterally displaced apical, and even right-sided azygous vein in the right chest, so the absence of the inferior
or posterior thorax locations may be required to image vena cava on ultrasound is not helpful in determining atrial
certain structures. Importantly, the ultrasound plane should situs. The right atrium is broad-based and triangular (“puppy
be purposefully aligned to visualize a specific structure of dog’s ear” appearance) and is associated with a eustachian
interest. For previously operated patients, the cardiac sonog- valve while the left atrium is narrow-based, longer (“finger”
rapher must have knowledge of possible types of repairs for appearance), and is not associated with a eustachian valve.
a particular anatomic defect and use whatever clues are In addition, the septal surface of the left atrium contains the
available to examine the repair if the patient does not know flap valve of the fossa ovalis. Rare patients have bilateral
the nature of her surgery. For example, an adult with tetral- right or left atria (isomerism) or have a common atrium with
ogy of Fallot who has an isolated scar on the right lateral no atrial septum.
thorax and no right radial pulse may have been palliated in Second, both systemic and pulmonary venous connec-
childhood with a Blalock-Taussig shunt, and therefore might tions to the atria should be determined. In adults, only three
need a right supraclavicular transducer position with pulmonary veins are generally visualized on TTE (best seen
Doppler to evaluate for shunt obstruction and to estimate in the apical views). The right inferior pulmonary vein is
pulmonary artery pressure. Finally, the examination must not seen. All pulmonary venous drainage into the left atrium
include sufficient views to evaluate all intracardiac and can be easily identified on transesophageal imaging. Third,
extracardiac structures, the normality or abnormality of abnormalities of ventricular inflow such as tricuspid atresia
these structures, and the hemodynamic consequences of or cor triatriatum are assessed. Fourth, ventricular number,
anatomic alterations. The patient should not leave the labo- morphology, relative size, position, and concordance with
ratory until every attempt has been made to answer all the the atria are determined. A ventricle is defined as a chamber
questions. that receives at least 50% of the ventricular “inlet” or
The first step of the examination, especially in the previ- fibrous ring of the atrioventricular (AV) valve. Neither AV
ously undiagnosed patient, is to determine visceral and atrial valve patency nor connection to an outlet is required. Cham-
situs and cardiac position within the chest (normal or levo- bers that do not meet these criteria are termed rudimentary
cardia, dextrocardia, or mesocardia). This is most easily chambers and may or may not have an outlet. The number
accomplished from a subcostal transducer position and of ventricles is determined by the presence or absence of an
transverse imaging plane in the upper abdomen. Since atrial interventricular septum. If only one ventricle is present (e.g.,
situs and visceral situs are usually concordant, a right-sided double inlet left or right ventricle, possibly tricuspid atresia,
liver and inferior vena cava and left-sided gastric bubble and etc.), the morphology of the ventricle should be classified as
aorta are almost always associated with atrial situs solitus, right, left, or indeterminate. Of note, the ventricle is almost
whereas a left-sided liver and right-sided gastric bubble indi- always concordant with the AV valve. That is, a tricuspid
282 chapter 11

valve (three leaflet with chordal attachments to three papil- Abnormalities of Cardiac Septation
lary muscles) regulates flow into a right ventricle, and a
mitral valve (two leaflets with chordal attachments to two
Atrial Septal Defect
papillary muscles) regulates flow into the left ventricle. The
septal leaflet of the tricuspid valve inserts more apically The most commonly diagnosed congenital cardiac defect in
than the anterior leaflet of the mitral valve. The right ven- adulthood, aside from bicuspid aortic valve, is ASD, which
tricle is generally heavily trabeculated while the left ven- accounts for almost 30% of all first congenital cardiac diag-
tricular endocardial surface is smooth. The presence of a noses in adults. It occurs due to failure or incomplete devel-
moderator band defines a right ventricle. Fifth, abnormali- opment of portions of the interatrial septum and is classified
ties of cardiac septation such as ASD, ventricular septal by the embryologic segment of the septum involved by the
defect (VSD), and AV septal defect (AV canal or endocardial defect. The ostium primum ASD, actually a type of endocar-
cushion defect), including direction and magnitude of shunt, dial cushion defect often called a “partial” AV canal, is char-
are assessed. acterized by the absence of the primum septum at the AV
Sixth, ventriculoarterial concordance and great vessel junction or crux of the heart, is usually accompanied by
number and relationships are elucidated. Normally, the mor- abnormalities of the anterior mitral valve leaflet in the form
phologic right ventricle is anterior and to the right of the of a cleft, and represents approximately 15% of ASD in adults.
morphologic left ventricle and gives rise to a pulmonary Approximately 75% of ASDs are of the ostium secundum
artery that is anterior and to the left of the aorta. The mor- type, which is caused by a defect in portions of the membra-
phologic left ventricle gives rise to an aorta that is posterior nous fossa ovalis (secundum septum). The atrial septal aneu-
and to the right of the pulmonary artery. Since the great rysm, which may be congenital or acquired, occurs when the
arteries normally arise in orthogonal planes, their long axes membranous flap of the fossa ovalis protrudes with a “wind-
are perpendicular on echocardiogram. In the parasternal and sock”-like appearance into one or the other atrium and may
subcostal short axis views, the aorta and aortic valve appear demonstrate mobility during the cardiac cycle. Atrial septal
in short axis posterior and to the right of the pulmonary aneurysms may have multiple small fenestrations that are
artery and right ventricular outflow tract, which are visible not visible on color Doppler. Occasionally, especially if a
in long axis, the typical “circle and sausage” appearance. In PFO or multiple fenestrations are present with right-to-left
the two forms of ventriculoarterial discordance (transposi- shunt, an aneurysmal atrial septum may be associated with
tion complexes), the great arteries arise in parallel; thus, paradoxical embolization. Patent foramen ovale, persistence
both appear as “circles” with varied anteroposterior and of the normal embryologic state of an open flap valve of the
lateral relationships in the parasternal short axis and in fossa ovalis, occurs in approximately 20% to 25% of all
longitudinal plane in the parasternal long axis views, respec- adults, is not due to absence of atrial septal tissue, and should
tively. In d-transposition of the great arteries, the atria and not be confused with ASD. As noted previously, PFO, espe-
ventricles are concordant with normal anteroposterior cially in patients with atrial septal aneurysm, may be associ-
and right-left position of the ventricles, but the aorta arises ated with paradoxical thromboembolism. Sinus venosus
anteriorly from the right ventricle. The pulmonary artery ASD, caused by absence of the basal segment of the inter-
arises posteriorly and then bifurcates, an appearance readily atrial septum most commonly at the superior vena cava
identified on echocardiogram and key to differentiating (SVC) and rarely at the inferior vena cava (IVC) junction with
the two great arteries. In l-(congenitally corrected) transposi- the atrium, accounts for 10% to 15% of ASD in adulthood.
tion, there is atrioventricular and ventriculoarterial discor- Sinus venosus ASD is frequently associated with anomalous
dance, so that the morphologic right ventricle lies posterior drainage of one or more pulmonary veins usually into the
and to the left of the left ventricle and gives rise to an right atrium or SVC. The least common type of ASD is the
aorta while the morphologic left ventricle lies anterior unroofed coronary sinus with direct communication between
and to the right and gives rise to a pulmonary artery. This the coronary sinus and the left atrium resulting in a left-to-
often is best thought of as “ventricular inversion” since right shunt.
there is no mixture of deoxygenated and oxygenated blood In the situation of a previously undiagnosed ASD in the
in the isolated form of this defect and patients are not adult, an echocardiogram is typically ordered to evaluate
cyanotic. symptoms of dyspnea, effort intolerance, atrial arrhythmias,
Seventh, the right and left ventricular outflow tracts, or even neurologic symptoms suspicious for an embolic
including subvalvular, valvular, supravalvular, and distal event. Indirect echocardiographic evidence of enlargement
great arteries must be evaluated for the presence of obstruc- and volume overload of the right ventricle may first raise the
tive lesions such as pulmonary valve stenosis, branch pul- possibility of a significant left-to-right shunt from an ASD
monary artery stenosis, discrete subaortic membranes, and and was one of the first characteristics of ASD described on
even coarctation of the aorta. Finally, attention is turned to M-mode and 2D echocardiogram.26–31 In addition to findings
the evaluation of native shunts (e.g., patent ductus arteriosus, of dilation of the right ventricle, the interventricular septum
aortopulmonary windows, ruptured sinus of Valsalva aneu- will be noted to move paradoxically (Fig. 11.1). Motion of the
rysm, or systemic to pulmonary artery collaterals), and post- interventricular septum is dependent on the relative pres-
operative structures (patches, conduits, surgically created sures of the right and left ventricles during systole and dias-
systemic to pulmonary shunts, Fontan circuits, etc.). In some tole. In right ventricular volume overload due to significant
younger adults with excellent acoustic windows, origins of left-to-right shunting through an ASD, the relative pressures
coronary arteries can be identified in the parasternal short in the ventricles equalize in diastole, resulting in character-
axis view. istic diastolic flattening of the septum. The left ventricular
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 283

FIGURE 11.1. (A,B) Parasternal short axis view of the ventricles left ventricle is D-shaped. In systole (B), left ventricular pressure is
demonstrating paradoxical septal motion of right ventricular volume greater than right ventricular pressure and the ventricle resumes its
overload. In diastole (A), right ventricular pressure equals left ven- normal circular geometry.
tricular pressure, the interventricular septum is flat (arrow), and the

cavity assumes a D-shape in diastole as viewed from para- 2D and Doppler echocardiography. In one study, ASD was
sternal short axis view of the 2D echocardiogram. In systole, accurately diagnosed and categorized as primum, secundum,
left ventricular pressure exceeds right ventricular pressure or sinus venosus in 47 of 50 adults using 2D and color Doppler
(the normal hemodynamic state) and the interventricular imaging. Three of five sinus venosus defects proven at surgery
septum resumes its normal circular geometry. In patients were missed on TTE.36 The presence of a secundum ASD
with ASD and pulmonary hypertension, right ventricular may be suggested on the apical four-chamber view by abrupt
pressure will equal left ventricular pressure throughout the dropout of echoes in the area of the fossa ovalis with bright
cardiac cycle and the ventricular septum will remain flat- side lobe artifacts producing an inverted T-shape.37 Because
tened in both diastole and systole, referred to as a right ven- the interatrial septum is parallel to the ultrasound beam
tricular pressure overload appearance.32,33 In children with when the transducer is in the apical position, attenuation of
ASD, 2D and spectral Doppler have been used to quantitate the ultrasound beam and the relative thinness of the mem-
the pulmonary to systemic blood flow ratio (Qp/Qs) with branous part of the septum compared to the muscular portion
fairly good correlation with that determined by cardiac may result in a false-positive diagnosis of secundum ASD by
catheterization.34,35 However, in adults, correlation between 2D TTE. The appearance of a color flow signal from the left
echocardiographic methods of shunt quantification and cath- to right atrium in the apical view can assist in the diagnosis
eterization is poor; echocardiographic shunt quantification of secundum defects. Transesophageal echocardiography is
is not of practical use in adults.36 excellent for localizing the defect (Fig. 11.2). When the ultra-
Most ostium secundum and ostium primum ASDs are sound transducer is in the subcostal location with a trans-
accurately diagnosed with the combination of transthoracic verse imaging plane, the interatrial septum is perpendicular

FIGURE 11.2. (A,B) Transesophageal echocardiogram of an ostium limbus tissue between the superior vena cava (SVC) and the defect
secundum atrial septal defect (ASD) in the long axis plane. The (A). Color Doppler flow imaging (B) shows a large left-to-right shunt.
defect is in the region of the fossa ovalis with a rim of superior LA, left atrium; RA, right atrium.
284 chapter 11

FIGURE 11.3. (A,B) Transesophageal echocardiogram of an ostium (AV) valves (A, arrow). Shunting is primarily left-to-right on color
primum ASD. The defect is seen at the junction of the interatrial Doppler with a zone of flow convergence seen on the left atrial side
septum and ventricular septum at the level of the atrioventricular of the septum (B).

to the beam of the ultrasound and ASDs may be viewed more defect and the distance of the defect from the ultrasound
directly. In 154 adults with documented ASD in whom ade- beam; if seen at all, they are best visualized from the subcos-
quate subcostal views could be obtained, 89% of secundum, tal view in adults. The existence of a sinus venosus ASD is
100% of primum, and 44% of sinus venosus defects were often suggested when no definite secundum or primum ASD
successfully visualized.38 Ostium primum defects are easily is seen on 2D or color Doppler but right ventricular enlarge-
identified on TTE in either the apical four-chamber or sub- ment with right ventricular volume overload motion of the
costal views and on TEE as echo dropout in the lower portion interventricular septum is present. The appearance of micro-
of the interatrial septum at the level of the AV valves (Fig. bubbles in the left atrium shortly after the appearance of
11.3). When a primum ASD is recognized, a cleft in the ante- bubbles in the right atrium subsequent to injection of agitated
rior leaflet of the mitral valve may be seen on the parasternal saline into a peripheral vein further suggests the diagnosis.
short axis view of the ventricle at valve level, and eccentric Saline contrast injections can be used to diagnose all
mitral regurgitation is almost always present on color Doppler forms of ASD. A “positive” saline contrast study with appear-
imaging (Fig. 11.4). It is not unusual to visualize a small ance of bubbles in the left atrium, however, documents only
aneurysm of the inlet portion of the interventricular septum the existence of a right-to-left shunt which could result from
beneath the tricuspid valve that may be formed when some intracardiac shunts other than ASD, including pulmonary
of the septal leaflet of the valve has sealed over a ventricular arteriovenous malformations or systemic to pulmonary
septal defect that was originally part of the endocardial artery collaterals. The appearance of bubbles in the left
cushion defect. atrium occurring six or more cardiac cycles after appearance
Sinus venosus ASDs are frequently missed on 2D TTE in the right atrium should suggest an intrapulmonary right-
and color Doppler because of the posterior location of the to-left shunt. The sensitivity of saline contrast study for the
diagnosis of ASD or PFO can be increased by asking the
patient to perform a Valsalva maneuver to transiently increase
right-sided intracardiac pressures and increase the shunt
during the contrast injection.39–42 More specific for the diag-
nosis of atrial septal defect is a “negative contrast” study in
which a “clear space” appears in the microbubble opacifica-
tion of the right atrium due to left-to-right shunting of
unopacified blood across the ASD (Fig. 11.5).43 False-positive
“negative contrast” effects can occur in the absence of ASD
due to unopacified blood flowing into the right atrium from
the inferior vena cava, coronary sinus, or anomalous pulmo-
nary veins. Both PFO and atrial septal aneurysm (Fig. 11.6)
with PFO can be associated with right-to-left or left-to-right
shunting on contrast study. For the diagnosis of right-to-left
shunt through a patent foramen ovale or atrial septal aneu-
rysm and the detection of a source of cardiac embolus in
patients with unexplained cerebral ischemia, TEE is superior
to TTE.44–52
Because of its close proximity to the interatrial septum
FIGURE 11.4. Color jet of mitral regurgitation in the left atrium on and obviation of most acoustic impediments, TEE generates
apical four-chamber view in a patient with ostium primum ASD. high-resolution images and is ideally suited for the diagnosis
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 285

FIGURE 11.5. (A,B) Saline contrast injection in a patient with negative contrast effect is demonstrated when unopacified blood
ostium secundum ASD. (A) Microbubbles are seen crossing the from the left atrium passes into the right atrium (arrow), creating
interatrial septum from the right into the left atrium (arrow). (B) A an echocardiographic “clear space.”

and characterization of ASD. In studies of patients with preoperatively in 23 of 25 patients, requiring alterations in
known secundum ASD, TEE was superior to TTE for the operative approach.56 In the most common form of partial
diagnosis of ASD.53 Defect size measured by TEE showed anomalous pulmonary venous return, the right upper pulmo-
good correlation with defect size found at surgery.54 Because nary vein is seen entering the atrium at the junction of the
TEE provides complete characterization of the interatrial sinus venosus defect and the SVC with color flow directed
septum, it is the diagnostic procedure of choice for visualiz- into the right atrium, but one or more pulmonary veins may
ing sinus venosus ASD to both the SVC (Fig. 11.7) and the drain into the SVC directly, into the IVC, or into a hepatic
IVC (Fig. 11.8).55 The longitudinal esophageal plane is the vein. Every attempt should be made to identify all pulmo-
most useful for diagnosis of sinus venosus ASD on TEE. In nary venous connections in the patient undergoing TEE for
a study of 25 adults with sinus venosus ASD on TEE, only ASD. Occasionally, anomalous pulmonary veins occur in
three patients had defects that were clearly defined by TTE, patients with secundum ASD, so these should be sought in
though another 11 had venosus ASD suspected on the basis all patients with secundum ASD. In the rare patient with the
of color flow mapping, while another 10 adults were evalu- unroofed coronary sinus defect, TEE may image the connec-
ated to find the cause of unexplained right-heart enlargement tion between the coronary sinus and the left atrium, and
on TTE. The importance of TEE in these patients was further left-to-right shunt may be seen on color flow mapping.
emphasized by the finding of 37 anomalous pulmonary veins Like patients with ostium secundum and ostium primum
ASD, patients with sinus venosus ASD do not require routine
preoperative cardiac catheterization if pulmonary hyperten-
sion is not demonstrated.57,58 For adults with suspected
secundum ASD, TEE provides significant useful information
if transcatheter closure of the ASD is being considered.59
With appropriate experience, the size of the ASD on TEE can
be used to assist in device size selection.60 Closure devices
for ASD require that an adequate “rim” of septal tissue be
present on all edges of the defect to ensure adequate seating
of the device. This can be quantified by TEE or by intracar-
diac echocardiography. Three-dimensional reconstruction of
TEE images of the interatrial septum may provide additional
information to the interventional cardiologist for device
selection and assessment of deployment.61 Also, TEE can
identify multiple defects for which additional closure devices
might be necessary and identify anomalous pulmonary
venous drainage, which might necessitate a surgical rather
than transcatheter approach. Recently, intracardiac echocar-
diography has been used in the catheterization laboratory to
FIGURE 11.6. Atrial septal aneurysm. In the parasternal short axis monitor percutaneous closure of ASD or PFO and may be less
view, a bulging of the interatrial septum with displacement of the expensive than TEE with equivalent success.62–64 On echo-
septum into the right atrium is noted (arrow). A displacement of
1 cm into either atrium is the typical criterion for the diagnosis of cardiography, the ASD occluder device appears as linear
ASA. The ASA may demonstrate mobility with the respiratory bright echoes on either side of the interatrial septum (Fig.
cycle. RA, right atrium; LA, left atrium. 11.9) and should be examined for security of its seating on
286 chapter 11

FIGURE 11.7. (A,B) Sinus venosus ASD to the superior vena cava (arrow) immediately beneath the superior vena cava (A). Color
on transesophageal echocardiography (TEE) in the long axis view. Doppler shows the left-to-right shunt (B). LA, left atrium; RA, right
The defect is visualized in the most superior portion of the septum atrium.

FIGURE 11.8. (A,B) Sinus venosus ASD to inferior vena cava. The defect (arrow) is seen in the inferior portion of the septum adjacent to
the coronary sinus (cs) in (A) with large left-to-right shunt demonstrated in (B). RA, right atrium; LA, left atrium.

FIGURE 11.9. (A,B) An ASD septal occluder device seated on the interatrial septum. The device is seen as parallel linear echoes on either
side of the septum (arrow) on the apical four-chamber view of TTE (A) and TEE (B).
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 287
the septum and residual shunt on color Doppler flow mapping. undermine the aortic annulus, prolapse of an aortic cusp can
Although the frequency of serial follow-up in adults with occur with the development of aortic insufficiency, which, if
corrected ASD has not been established, these patients may more than mild, constitutes an indication for closure of even
develop late atrial arrhythmias or pulmonary hypertension small supracristal VSDs. Rarely occurring in isolation,
and require continued monitoring. defects of the inlet septum occur beneath the septal leaflet
of the tricuspid valve and are often accompanied by defects
of the primum portion of the atrial septum as part of an AV
Ventricular Septal Defect
septal or endocardial cushion defect also known as an AV
The most common congenital cardiac defect diagnosed in canal.
childhood, VSD is much less commonly diagnosed in adults, Because of the complex, curved shape of the ventricular
in large part because 60% of small VSDs close spontaneously septum, multiple transducer locations and imaging planes
before the teenage years. The remainder of VSDs have already with both 2D and color and spectral Doppler must be used
been repaired by adulthood or are large and associated with to interrogate the entire septum. The sensitivity and specific-
fixed pulmonary vascular disease, absence of murmur, rever- ity of echocardiography for the diagnosis of VSD are related
sal of the intracardiac shunt (Eisenmenger’s syndrome), and to the size and location of the defect. The best views of a
cyanosis. A more common scenario is the adult with a loud particular defect occur when the defect is perpendicular to
murmur and small, hemodynamically insignificant VSD. the ultrasound beam. Because a significant length of septum
Rarely, an adult may present with a moderately sized VSD is perpendicular to the ultrasound plane and axial resolution
and symptoms of heart failure. Because small VSDs confer a is best when the transducer is the subcostal location, subcos-
significant risk of endocarditis and larger VSDs are associ- tal views may be helpful, especially in thin adults.65 The
ated with a much higher risk of pulmonary hypertension hallmark of VSD on 2D echocardiography is echo dropout of
than ASDs, the echocardiographic recognition of VSD is the ventricular septum. The finding of a T-sign in the apical
essential for these patients. views increases the specificity for the diagnosis of VSD in
Defects of the ventricular septum are classified by ana- the same fashion as for ASD.66–69 Frequently, the VSD is not
tomic location as viewed from the right septal surface. The well visualized on 2D imaging, but high-velocity turbulent
most common type of VSD, making up 70% of all VSDs, flow in systole on color Doppler provides a definitive
occurs in the membranous septum often with involvement diagnosis.70
of adjacent muscular tissue beneath the crista supraventricu- Surface TTE is approximately 80% to 90% sensitive for
laris when viewed from the right ventricle and under the the diagnosis of perimembranous VSD. Perimembranous
aortic valve when viewed from the left. This defect is more defects are best visualized in the parasternal long axis and
properly termed a perimembranous VSD but is also called a parasternal short axis views. In the parasternal long axis
subaortic VSD and is a type of outlet VSD. Defects in the view, the defect appears immediately below the aortic valve.
muscular portion of the septum are the next most common In small, restrictive perimembranous VSDs, a turbulent sys-
accounting for 20% of VSD and may occur anywhere in the tolic jet passes from the left ventricular outflow tract into
septum from inlet to trabecular to outlet. Muscular VSDs the right ventricle through the defect (Fig. 11.10). It is impor-
may be multiple in which case they are termed Swiss-cheese tant to remember that large VSDs with equalization of right
defects and are the most difficult to identify echocardio- and left ventricular pressure may be seen as a sizable defect
graphically. Defects located beneath the pulmonic valve, with no turbulent systolic flow on color Doppler. In the
another form of outlet VSD, are referred to as supracristal, parasternal short axis view at the level of the aortic valve,
doubly committed, or subpulmonic VSDs and represent the turbulent jet is seen to the left of midline near the inser-
approximately 5% of all VSD. Because supracristal VSDs tion of the tricuspid valve at the 10 o’clock position if the

FIGURE 11.10. (A,B) Perimembranous VSD. The defect in the acterized by turbulent flow from the left to the right ventricle on
region of the membranous interventricular septum is not well seen color flow Doppler (B).
on the parasternal long axis view of the TTE (A, arrow). It is char-
288 chapter 11

FIGURE 11.12. Large inlet VSD. The defect in the interventricular

FIGURE 11.11. Color Doppler in the parasternal short axis view septum (arrow) is seen in the superior septum at the crux of the
showing a turbulent jet immediately inferior to the tricuspid valve heart in the apical four-chamber view.
seen at approximately the 10 o’clock position on the clock face of
the aortic valve (Ao).

aortic valve is considered to be a clock face (Fig. 11.11). Supra- multiple views including parasternal long axis, parasternal
cristal VSDs are also best seen in the parasternal short axis short axis from apex to base, subcostal long and short axes,
view at the base of the heart and appear as a systolic color and apical views if a muscular VSD is suspected. Some mus-
flow jet just beneath the pulmonic valve at the 2 o’clock cular VSDs appear as narrow channels in the ventricular
position on the aortic valve. Small supracristal VSDs may be septum with openings into the left and right ventricles at
missed, especially if careful color Doppler imaging is not different levels on the septum (Fig. 11.13). In adults, it is not
performed. The highest sensitivity of echocardiography in uncommon to find a ventricular septal aneurysm in the
VSD is for inlet defects, which are best seen in the apical region of the membranous septum, which appears as a thin
four-chamber view (Fig. 11.12). For uncomplicated inlet VSD membrane that bulges into the right ventricle, rarely causing
without an atrial component, the septal leaflet of the tricus- right ventricular outflow tract obstruction, and may incor-
pid valve originates from its normal apically displaced posi- porate a portion of the septal leaflet of the tricuspid valve.72
tion relative to the mitral valve. In AV canal-type defects, The septal leaflet can completely or only partially seal the
both AV valves are in the same plane and their chordal perimembranous defect, and this can be best visualized by
attachments must be determined. color Doppler in the parasternal long axis view (Fig. 11.14).
On occasion, the septal leaflet of the tricuspid valve may Although 2D and color Doppler can identify the presence
partially close an inlet VSD, and a rare type of communica- and estimate the size of VSDs, continuous wave spectral
tion between the left ventricle and the right atrium called a Doppler accurately quantitates the pressure gradient between
Gerbode defect may result.71 Muscular VSDs, when small, the left and right ventricles. By measuring systemic pressure
are the most difficult to identify on TTE, with sensitivity as with a blood pressure cuff and subtracting the pressure gradi-
low as 50% for their detection. Color Doppler must be per- ent between the left and right ventricle, the right ventricular
formed of the entire expanse of the ventricular septum in systolic pressure can be estimated. In the absence of pulmo-

FIGURE 11.13. (A,B) Muscular VSD in the midportion of the trabecular septum (arrow) in the apical four-chamber view (A) with high-
velocity color jet from left to right (B). LV, left ventricle; LA, left atrium; RA, right atrium.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 289

FIGURE 11.14. Parasternal long axis view of ventricular septal of the membranous septum (arrow) into the right ventricle (A). Color
aneurysm. Parts of the septal leaflet of the tricuspid valve partially Doppler flow confirms the VSD (B).
seal over a perimembranous VSD. This is seen as a localized bulge

nary outflow obstruction, the pulmonary systolic pressure is integral to the assessment of other complications of VSD
can be inferred from the right ventricular systolic pressure. including evaluation of aortic insufficiency in patients with
With careful alignment of the Doppler cursor with the tur- supracristal VSD who have prolapse of a (usually right) coro-
bulent jet on color flow imaging, the peak velocity of the VSD nary cusp into the defect,78 pulmonary hypertension, or
jet can be measured (Fig. 11.15). Using the modified Bernoulli endocarditis with vegetation79 typically of right heart struc-
equation in the usual fashion, tures at the site of jet impingement. Infrequently, an adult
Peak gradient = 4 × V2 (peak velocity squared) may present who underwent banding of the pulmonary
artery (PA) in childhood to protect from fixed pulmonary
the peak gradient between the ventricles is calculated.73–75 vascular disease, but never proceeded to closure of the defect.
Small restrictive VSDs will have high gradients, often in An example of a PA band in an adult patient with a nonre-
excess of 100 mm Hg, whereas large, nonrestrictive VSDs strictive VSD and pulmonary hypertension is shown in
have low or no gradients, reflecting the fixed pulmonary Figure 11.17. By measuring the systemic blood pressure by
hypertension that is present in most adults with the defect. cuff and subtracting the sum of the peak gradient across the
The normal postoperative appearance of the septum after VSD and the peak gradient across the PA band, PA systolic
surgical closure is typified by a bright linear echo on the pressure can be estimated. A recent development is the
right ventricular side of the defect if a prosthetic patch was closure of perimembranous and muscular VSDs using trans-
used.76 Dehiscence of the patch may be visualized from mul- catheter closure devices.80,81
tiple views by a turbulent systolic jet on color Doppler at the
margin of the patch (Fig. 11.16) or mobility of the echodense
patch into the right ventricle in systole.77 Echocardiography Atrioventricular Septal Defects (Atrioventricular
Canal or Endocardial Cushion Defect)
Atrioventricular septal defects occur due to failure of fusion
of the inferior and superior endocardial cushions to varying
degrees, with abnormalities of the AV junction ranging from
isolated primum ASD with cleft mitral valve (MV) and
isolated inlet VSD (“partial” AV canal with separate AV
valves) to complete AV canal with a spectrum of abnormali-
ties of the AV valves. Echocardiography with color Doppler
can readily determine the size and extent of the septal defects,
the nature of the shunt, and the morphology of the AV valves.82
The extent of the atrial and ventricular components of the
defect is best gauged in the apical four-chamber or subcostal
views. In these views, the nature of the AV valve(s) and attach-
ments should be carefully explored. Some patients may have
a single (common) AV valve (Fig. 11.18). In the patient with
two AV valves in the same plane, chordal attachments of the
valves must be elucidated. The presence of a straddling AV
valve with chordal attachments crossing the septal defect to
FIGURE 11.15. Continuous wave Doppler of restrictive perimem-
branous VSD with peak velocity approximately 5.6 m/sec. The peak
insert into the opposite ventricle makes the surgical repair
pressure gradient between the left and right ventricle is calculated more complex than does an overriding valve that overlies
to be 125 mm Hg by the modified Bernoulli equation. the AV septal defect but has no chordal attachment to the
290 chapter 11

FIGURE 11.16. (A,B) Prosthetic VSD patch dehiscence. In the para- echo dropout of the defect (small arrow) (A). Flow across the defect
sternal short axis view, a bright linear echo is seen on the right is seen on color Doppler (B).
ventricular side of the inferior septum (large arrow) with associated

FIGURE 11.17. (A,B) In the high parasternal view, there is a band band (B) is 20 mm Hg, suggesting that there is insufficient protection
noted on the main pulmonary artery (arrow) just distal to the pul- of the distal pulmonary vascular bed from increased pulmonary
monic valve (A). The peak gradient across the pulmonary artery blood flow through the ventricular septal defect.

FIGURE 11.18. (A,B) Atrioventricular septal defect (AV canal or arrow) and the inferior portion of the ventricular septum (bottom
endocardial cushion defect). In the apical four-chamber view, a large large arrow) is seen (A). The common AV valve is seen in diastole
defect involving the superior portion of the atrial septum (top large (small arrows) in A and in systole (large arrow) in B.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 2 91

FIGURE 11.19. Color Doppler flow image of regurgitation of the AV

valve in a patient with AV septal defect. FIGURE 11.21. Transesophageal echocardiogram of complete
eustachian valve. The eustachian valve is the flap valve of the infe-
rior vena cava (arrow). SVC, superior vena cava; RA, right atrium;
opposite ventricle. In patients with a primum ASD, the asso-
LA, left atrium.
ciated cleft anterior mitral valve leaflet is best directly visual-
ized in the parasternal short axis view, though the eccentric
mitral regurgitation may be appreciated in the apical views.
monary vein. Most often, a persistent left SVC is suspected
Although most patients present after having been repaired in
when a dilated coronary sinus that appears as a large circular
childhood, some adults, particularly patients with Down syn-
structure in the posterior AV groove is noted on the paraster-
drome who were not operated, present with pulmonary
nal long axis view of the TTE. Persistence of the left SVC is
hypertension and cyanosis. Atrioventricular valve regurgita-
the most common cause of a dilated coronary sinus on TTE.
tion (Fig. 11.19) is common in these patients.
The coronary sinus can also be visualized with steep poste-
rior angulation in the apical four-chamber view as a longitu-
Abnormalities of Venous Inflow dinal structure behind the left atrium draining into the right
atrium. In adults, the actual left SVC is not often directly
The most frequent congenital anomaly of systemic venous visualized. Instead, the diagnosis is clinched by injection of
inflow is persistence of a left SVC, which is found in approxi- agitated saline into a peripheral vein in the left arm. In this
mately 0.5% of the general population and up to 10% of instance, bubbles will first be seen in the coronary sinus
patients with other congenital heart defects. Embryologic followed by opacification of the right heart (Fig. 11.20).84–87
resorption of the right-sided SVC in utero is rare in these Injection of agitated saline into a vein in the right arm pro-
patients, and an absent right SVC was seen in only three of duces direct opacification of the right heart without opacifi-
10 patients evaluated by magnetic resonance imaging.83 The cation of the coronary sinus. Although not an abnormality,
left SVC usually drains directly into the coronary sinus and a prominent or “complete” eustachian valve at the junction
then to the right atrium with no physiologic consequences, of the inferior cava extending to a varied degree to the ostium
but on rare occasion will drain into the left atrium or pul- of the coronary sinus warrants mention (Fig. 11.21) because

FIGURE 11.20. (A,B) Persistent left superior vena cava. In the para- injected in a peripheral vein in the left arm, bubbles appear first in
sternal long axis view, a dilated coronary sinus (cs) is seen posterior the coronary sinus and then the right atrium and ventricle (B,
to the left atrium in the AV groove (A). When agitated saline is arrows). RV, right ventricle.
292 chapter 11

it can cause confusion and misdiagnosis as thrombus or The tricuspid valve morphology, chordal attachments,
vegetation. and functional right ventricular size can be accurately
Anomalous pulmonary venous drainage in adults is most assessed using multiple views on TTE.96,97 The degree of
frequently seen in association with a sinus venosus defect, apical displacement of the septal leaflet is best estimated
but may be an isolated abnormality with one or more pul- from the apical four-chamber view. Because some degree of
monary veins draining into the SVC, IVC, right atrium, or apical displacement of the septal leaflet is present in the
hepatic vein. Unrepaired total anomalous pulmonary venous normal heart and may be accentuated by right ventricular
return is not seen in adults. In adults with normal pulmo- enlargement from any cause, echocardiographic criteria have
nary vein anatomy, the right superior, and left superior and been developed to make the diagnosis of Ebstein’s anomaly
inferior pulmonary veins may be identified draining into the in adults. In one study, an absolute value of 20-mm displace-
left atrium in the apical four-chamber view. The right infe- ment of the septal tricuspid leaflet relative to the insertion
rior pulmonary vein is not visualized in adults on TTE. point of the anterior leaflet of the mitral valve was used. In
Often the only clue to the presence of isolated anomalous other studies, a distance of 8 mm/m2 when normalized to
pulmonary veins is enlargement of the right heart with no body surface area provided an accurate diagnosis of Ebstein’s.98
right-to-left shunt on saline contrast injection. Preoperative Tethering of the anterior leaflet should be evaluated in the
identification of abnormal pulmonary vein drainage in apical four-chamber view (Fig. 11.22). Assessment of tether-
patients with ASD is important for defining the approach to ing of the anterior leaflet and functional right ventricular
these patients since a procedure to baffle flow from the vein size may also be performed in the right ventricular “inflow”
to the left atrium will be necessary in addition to repair of view obtained by anterior and medial angulation of the ultra-
the defect. For these patients, TEE is more accurate than TTE sound beam from a left parasternal long axis transducer
for the diagnosis of anomalous pulmonary veins.88–92 Con- position. A functional right ventricle area smaller than 35%
genital stenosis of pulmonary veins is not seen in the adult of the total ventricle and extensive tethering of the anterior
population. However, TEE has proved useful for arrhythmia leaflet portend a less favorable surgical outcome.97 In unoper-
mapping in the pulmonary veins during radiofrequency abla- ated adults with Ebstein’s, the septal leaflet attachment ratio,
tion of atrial fibrillation and diagnosing pulmonary vein defined as the distance from the AV valve annulus to the
stenosis that can occur as a late complication of the distal attachment of the septal leaflet divided by the total
procedure.93,94 ventricular septal length in the four-chamber view at end
diastole, did not correlate with the percent of atrialized area
of the right ventricle. However, a higher index (indicating
Abnormalities of Ventricular Inflow more severe apical displacement) was associated with worse
prognosis for survival.95 Both TTE97 and TEE99 can be used
The most common anomalies involving the inflow tract of to assess suitability for and adequacy of tricuspid valve
the right ventricle are tricuspid atresia or hypoplasia and reconstruction. In Ebstein’s anomaly, there is usually severe
Ebstein’s anomaly. Patients with tricuspid atresia have an tricuspid regurgitation with the origin of the color Doppler
obligate intraatrial communication and usually have associ- jet occurring at the coaptation point of the tricuspid valve,
ated hypoplasia of the right ventricle. Because these patients close to the right ventricle apex (Fig. 11.23).
are generally managed as patients with single ventricle physi-
ology, they will be considered in the section on single
ventricles.
Ebstein’s anomaly, an abnormality of tricuspid valve
development, is characterized by apical displacement of the
insertion of the septal (and sometimes posterior) leaflet of
the tricuspid valve and variable elongation of the anterior
leaflet, designated a “sail” leaflet owing to its resemblance
to the sail of a ship. There is a wide spectrum of tethering
of the anterior leaflet to the ventricle by multiple abnormal
short chords. This abnormality results in apical displace-
ment of the tricuspid valve coaptation point into the right
ventricle with “atrialization” of the inlet portion of the right
ventricle as a consequence. Ebstein’s anomaly, often accom-
panied by a secundum ASD or PFO, most often presents in
childhood with signs of right heart failure or cyanosis and
has a less favorable prognosis in this population. In many
instances, however, Ebstein’s does not present until adult-
hood, even in patients with severe apical displacement of
the tricuspid valve. In one study of 72 adults diagnosed
with Ebstein’s anomaly, the mean age at first diagnosis was FIGURE 11.22. Apical four-chamber view of Ebstein’s anomaly.
24 years.95 In general, suitability for tricuspid valve repair The origin of the septal leaflet of the tricuspid valve (large arrow) is
displaced toward the right ventricle (RV) apex. The anterior “sail
versus replacement is determined by valve morphology, and leaflet” (small arrows) is elongated with multiple chordal attach-
prognosis is related to the size of the functional right ments to the anterior wall of the RV. There is a large area of atrial-
ventricle. ized RV superior to the valve. RA, right atrium.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 293

FIGURE 11.24. Parasternal short axis view of the left atrium

FIGURE 11.23. Color Doppler flow image of Ebstein’s anomaly in showing the membrane of cor triatriatum (arrow). RA, right atrium;
the apical four-chamber view. The origin of the jet of tricuspid LA, left atrium.
regurgitation (arrow) is displaced far toward the right ventricular
apex.

Obstruction to inflow of the left ventricle can take the TEE can provide clear images of the membrane, its attach-
form of cor triatriatum, mitral supravalvular ring, congenital ment to the interatrial septum and lateral wall of the atrium
mitral stenosis, or mitral atresia (usually as part of complex above the atrial appendage, and the nature of the opening,103
left ventricular inflow and outflow obstructive lesions known thus guiding operative resection.103–106 A stenotic supravalvu-
as Shone complex). Shone complex is always diagnosed in lar mitral ring differs from cor triatriatum in that it occurs
infancy and childhood and therefore will not be dealt with at the level of or slightly superior to the mitral annulus, is
here. sometimes adherent to the base of the valve leaflets, but is
Cor triatriatum, caused embryologically by incomplete below the left atrial appendage. Small rings may be difficult
resorption of the floor of the common pulmonary vein as it to image with 2D echocardiography, but may be suggested
merges with the roof of the left atrium, is characterized by if color Doppler demonstrates turbulent inflow to the left
the presence of a perforated membrane that divides the left ventricle above the mitral valve leaflets. The echocardio-
atrium into a superior chamber that receives the pulmonary gram of a patient with a supravalvular ring is shown in
veins and an inferior chamber associated with the left atrial Figure 11.26.
appendage and the mitral valve. In most instances, the Congenital mitral stenosis, usually diagnosed in child-
opening in the membrane is restrictive. Patients present with hood, may be difficult to differentiate from rheumatic mitral
symptoms of left ventricular inflow obstruction with pulmo- stenosis on echocardiogram in adults. Congenital mitral
nary congestion. Asymptomatic adults with cor triatriatum
first identified as an incidental finding on TTE may have a
nonrestrictive membrane. Cor triatriatum is usually readily
identified on TTE.100,101 The membrane is often identified on
TTE in the parasternal views where it is seen in the left
atrium inserting anteriorly at the level of the posterior wall
of the aorta and coursing to the posterior left atrial wall (Fig.
11.24). However, the membrane is best visualized on TTE in
the apical view in the middle left atrium since it is perpen-
dicular to the ultrasound beam (Fig. 11.25). The left atrial
appendage may be identified in the lower chamber. Pulmo-
nary veins can be visualized draining into the superior
chamber and may be dilated if obstruction of the fenestration
is significant.
The site of obstruction in the membrane can be identified
by a turbulent color flow jet in the middle atrium that is
primarily diastolic, but can persist throughout the cardiac
cycle if stenosis is severe. The transmembrane gradient can
be calculated (reflecting severity of stenosis of the orifice)
using the modified Bernoulli equation from the peak velocity FIGURE 11.25. The membrane of cor triatriatum (arrow) is seen
obtained by pulsed or continuous wave Doppler in the apical coursing across the left atrium (LA) in the apical four-chamber
views.102 If the diagnosis is suggested but not clear on TTE, view.
294 chapter 11

FIGURE 11.26. (A,B) A supravalvular mitral ring is noted just supe- the apical four-chamber view (B), the convergence zone for mitral
rior to the mitral valve at the mitral annulus in A (two arrows) in inflow is above the level of the mitral valve signifying obstruction
the parasternal long axis view. On color Doppler flow imaging in at that level.

stenosis is usually the result of abnormal insertion of chordae assessed on color Doppler flow imaging. Multiple complex
tendineae into either a single papillary muscle, the “para- abnormalities are common in these patients. Ventriculoarte-
chute” type of mitral valve, or into multiple small papillary rial discordance with the aorta arising from the anterior
muscles, the “arcade” type. Both types of congenitally ste- outlet chamber and the pulmonary artery arising from the
notic valves can be visualized in apical and short axis views posterior chamber is especially common.
of the ventricle on TTE. An occasional adult will exhibit a Tricuspid atresia results from failure of development of
“double orifice” mitral valve, which has the hallmark of two the tricuspid valve. At birth, an ASD or PFO must be present
separate orifices seen on short axis cross-sectional views of for survival. There is usually significant underdevelopment
the ventricle at valve level. The degree of stenosis of these or hypoplasia of the right ventricle with mixing of oxygen-
valves is variable and dependent on insertion of the chords ated and deoxygenated blood in the left ventricle causing
(usually each orifice inserts into its own papillary muscle cyanosis. Although the small right-sided chamber receives
making this, technically, a double parachute mitral valve) the inlet of the tricuspid valve in the form of a fibrous ring,
and chordal fusion.107–109 and therefore is technically a ventricle, the physiology is
identical to that of other single ventricle complexes.
Patients with this group of defects who survive to adult-
Abnormalities of Ventricular Number hood have usually undergone an operation that establishes a
or Morphology connection between the systemic veins or right atrium and
the pulmonary arteries to provide pulmonary blood flow and
improve oxygenation. In most adults, this connection is
Single Ventricle Complexes
created with one of several variations of a Fontan circuit. In
Many different congenital abnormalities may result in what one common form of Fontan anastomosis, a connection is
is physiologically a single pumping chamber in which oxy- made between the right atrial appendage and the PA either
genated and deoxygenated blood mix before being pumped to by direct anastomosis (Fig. 11.27) or interposition of a conduit.
the body. In single ventricle hearts, a small outlet chamber In other individuals, a conduit may be placed from the IVC
may exist with communication from the main ventricle through the lateral right atrium and connected to the PA, the
through a defect known as a bulboventricular foramen. The so-called lateral tunnel Fontan, with connection of the SVC
rudimentary chamber does not have an inlet and is techni- to the PA in a total cavopulmonary connection. Especially
cally not a ventricle. Echocardiography permits extensive in individuals with elevated pulmonary vascular resistance
evaluation of the wide spectrum of congenital abnormalities prior to surgery, holes or “fenestrations” may be deliberately
resulting in a single ventricle.110 Often, the univentricular placed in the Fontan at the time of surgery to allow the
heart can be classified morphologically as right, left, or inde- circuit to decompress, but at the cost of increased cyanosis.
terminate by its appearance on 2D TTE. The most common These fenestrations may be closed using percutaneous inter-
type of univentricular heart is the morphologic left ventricle ventional techniques at a later time. In other patients, the
and is referred to as a double-inlet left ventricle. Double-inlet conduit may be placed from the IVC external to the right
right ventricles also exist. If the single ventricle is a left atrium to the pulmonary artery, the extracardiac Fontan
ventricle, a rudimentary outlet chamber with connection to circuit.
a pulmonary artery should be sought anterior and superior Echocardiography plays a vital role in the understanding
to the ventricle. The rudimentary chamber in a morphologi- and management of patients with univentricular hearts who
cally right single ventricle is posterior and inferior to the have undergone the Fontan operation. However, the Fontan
ventricle. Patency of the bulboventricular foramen can be connection is often poorly visualized on TTE for many
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 295
variable, a wide spectrum of echocardiographic abnormali-
ties can be seen, ranging from normal right ventricular size
and function, to regional abnormalities with localized
“bulging” of the right ventricular free wall, to marked dila-
tion of the entire right ventricle, a condition termed Uhl’s
anomaly or “parchment” right ventricle. Because the right
ventricle has a complex, crescent shape, complete evaluation
requires the use of multiple ultrasound planes from subcos-
tal, apical four-chamber, and right ventricular inflow trans-
ducer positions. The right ventricle may be incompletely
visualized on TTE. The use of echocardiographic contrast
agents may improve the sensitivity for the diagnosis of ARVD
in these patients.114 The use of tissue Doppler velocity evalu-
ation may also increase the sensitivity for the diagnosis of
early disease.115
In isolated noncompaction of the left ventricle, the devel-
opment of ventricular myocardium is arrested prior to
FIGURE 11.27. A classic Fontan anastomosis of the right atrial condensation and compaction of the myocardium, and, as a
appendage directly to the pulmonary artery is shown on trans- result, some or all of the myocardium has deep trabecular
esophageal echocardiogram. A layer of thrombus, a common finding recesses that communicate with the ventricular endocar-
after Fontan operation in adults, is noted in the atrium (arrows). RA, dium. These adults typically present with heart failure or
right atrium; PA, pulmonary artery.
ventricular arrhythmias. Transthoracic echocardiography
provides the diagnosis in the majority of patients. On 2D
echocardiography, the myocardium appears “spongy” with
reasons including multiple prior surgeries and scarring, mal- deep sinusoids (Fig. 11.29). On color Doppler imaging, color
position of the heart in the chest, and the location of most may be seen entering the sinusoids. With the use of peripher-
connections behind the sternum. In some adults with direct ally injected echocardiographic contrast agents, which may
right atrial anastomosis to the pulmonary artery, the con- be seen entering the sinusoids, noncompaction can be dif-
nection may be visualized on high parasternal views on TTE ferentiated from left ventricular thrombus and hypertrophic
or on TEE. The lateral tunnel Fontan may be seen as a bright cardiomyopathy. In one study with pathologic correlation,
circular prosthetic structure within the atrium. The Fontan four echocardiographic criteria were required to be diagnostic
circuit should also be examined with color Doppler to assess for noncompaction: (1) absence of any other cardiac
for obstruction and with spectral Doppler to establish flow abnormality; (2) echocardiographic appearance of a two-layer
patterns within the circuit. In patients with low pulmonary structure to the myocardial wall, with a compacted thin
vascular resistance, the pattern of flow in the pulmonary epicardial band and a much thicker noncompacted endocar-
artery after Fontan is characterized as biphasic with the dial stripe, and with deep endomyocardial spaces and a
largest peak due to atrial contraction in late diastole and a maximal end-systolic ratio of noncompacted to compacted
smaller late systolic peak. Flow velocity typically increases layer >2; (3) predominant localization of abnormalities in the
during inspiration. In patients with elevated pulmonary vas- midlateral, apical, and mid-inferior regions of the ventricle;
cular resistance or ventricular diastolic pressure, the Doppler
pattern may demonstrate a smaller peak in late diastole with
reduced respiratory variation, or absence of diastolic flow
altogether in extreme cases. Because of low-velocity flow and
enlargement of the right atrium, thrombus can develop
within the circuit, causing obstruction or pulmonary embo-
lism, especially in adults. Fontan thrombus may be identi-
fied on TTE,111 especially in symptomatic patients. However,
TEE is more likely to diagnose thrombus in these patients,112
an important finding since clinically silent pulmonary
embolism has been reported in up to 17% of Fontan patients
and anticoagulation is required (Fig. 11.28).113
Two congenital abnormalities of ventricular myocar-
dium, arrhythmogenic dysplasia of the right ventricle and
isolated noncompaction of the left ventricle, may be first
diagnosed in the adult. Arrhythmogenic right ventricular
dysplasia (ARVD) is a genetic condition, often with autoso-
mal dominant inheritance, characterized pathologically by
fibrofatty replacement of right ventricular myocardium. The
patient usually presents with ventricular arrhythmias of left FIGURE 11.28. Transesophageal echocardiogram of right atrial
bundle branch block morphology. Since the extent of replace- thrombus (arrow) in a patient after Fontan operation. RA, right
ment of ventricular myocardium with fibrofatty tissue is atrium.
296 chapter 11

FIGURE 11.29. (A,B) Apical four-chamber (A) and two-chamber (B) and inferior walls (arrow) of the left ventricle. LA, left atrium; RA,
views of noncompaction of the left ventricle. Areas of “spongy” right atrium.
appearing myocardium with deep sinusoids are seen in the lateral

and (4) color Doppler evidence of deep perfused intertrabecu- Doppler may suggest obstruction by the presence of a turbu-
lar recesses.116 lent jet at the site of the stenosis. Using continuous wave
Doppler through the obstruction, the total gradient may be
calculated, but obtaining individual gradients at each level
Conotruncal Abnormalities obstruction may not be possible. Though most patients with
unoperated tetralogy of Fallot have valvular pulmonic steno-
sis, an infrequent patient may have congenital absence of the
Tetralogy of Fallot
pulmonary valve with severe pulmonary insufficiency.120 In
The most common abnormality of conotruncal development the unoperated young adult who otherwise would not require
seen in adults is tetralogy of Fallot, a defect consisting of a cardiac catheterization, it is important to identify the origin
large subaortic/perimembranous VSD with malalignment of of the coronary arteries in the parasternal long axis view at
the infundibular septum; anterior and rightward displace- the level of the aortic valve.121 In some patients an aberrant
ment of the aortic root, such that the aortic valve “overrides” conus branch or left anterior descending artery can be identi-
the defect; obstruction to right ventricular outflow, which fied crossing the right ventricular outflow tract and could be
may occur at any level from subvalvular to the branch pul- transected if care is not taken during repair.
monary arteries; and right ventricular hypertrophy, resulting Adults with tetralogy of Fallot who present for care have
from the obstruction. The degree of aortic override from generally been repaired in late childhood or adolescence,
malalignment of the septum correlates with the severity of though some adults were palliated with a Blalock-Taussig
infundibular stenosis. The VSD with aortic override is the
most obvious echocardiographic finding in these patients
(Fig. 11.30) and is easily identified in the parasternal long axis
view on TTE.117 Another conotruncal abnormality, the
double-outlet right ventricle (DORV), can be confused with
tetralogy of Fallot on echocardiography if aortic override is
extreme. In DORV, both great arteries arise from the right
ventricle, and there is discontinuity between the posterior
wall of the aorta and the anterior leaflet of the mitral valve.
The diagnosis of DORV is made on TTE if more than 50%
of the aorta is seen to override the right ventricle and there
is aortic-mitral discontinuity, whereas the appropriate diag-
nosis is tetralogy of Fallot if more than 50% of the aorta
overrides the left ventricle and aortic-mitral continuity is
preserved.118,119 Right ventricular outflow obstruction can
occur at many levels, which must be evaluated in the patient
with tetralogy of Fallot.
Infundibular stenosis due to muscle bundle hypertrophy
and anterior displacement of the septum can be visualized
FIGURE 11.30. Parasternal long axis view of tetralogy of Fallot.
in the parasternal and subcostal short axis views at the base The aortic valve (AoV) overrides a large, subaortic VSD (arrow).
of the heart. Valvular stenosis and stenosis of the proximal There is marked hypertrophy of the right ventricle (RV). LV, left
pulmonary arteries can also be evaluated in this view. Color ventricle.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 297

FIGURE 11.32. Transesophageal short axis view of the great vessels

FIGURE 11.31. Color Doppler flow image of the pulmonary valve in a patient with d-transposition of the great arteries. Both semilu-
in the high parasternal short axis view. There is severe pulmonary nar valves appear in short axis. The pulmonary artery (PA) is seen
insufficiency. posterior and to the left of the aorta (Ao). In this transesophageal
image, the top of the sector corresponds to the transducer location
posterior to the heart in the esophagus.
shunt in childhood and never completed the repair. Serial
echocardiography is critical to the appropriate management ously and are shown in Figures 11.32 and 11.33. In d-TGA,
of the postoperative adult with tetralogy of Fallot. Most the aorta is usually anterior and to the right of the PA in
of these patients, in whom repair included incisions across short axis views. Since the anomaly results in parallel cir-
the pulmonary annulus, many with transannular patches, cuits that would not be compatible with life, adult survivors
develop late severe, free-flowing pulmonary regurgitation as have necessarily undergone operations to restore the normal
a result (Fig. 11.31).122 Some patients develop aneurysmal dila- flow pattern and allow oxygenation of systemic venous blood.
tion of the prosthetic patch, which may be associated with In the majority of adults, this procedure consisted of a com-
more severe pulmonary regurgitation. Continued volume plete atrial septectomy with placement of either a pericardial
overload of the right ventricle produces systolic dysfunction or prosthetic baffle in the atrium in the Mustard or Senning
that is unlikely to improve if pulmonary valve replacement operation, also known as the atrial switch procedure. The
is delayed until systolic dysfunction is symptomatic.123 Right interatrial baffle is saddle shaped and routes deoxygenated
ventricular function, though difficult to precisely quantitate blood from the vena cavae through the mitral valve into the
echocardiographically, may be easily followed in a serial left ventricle and out to the pulmonary arteries. Oxygenated
fashion to monitor for the development of systolic dysfunc- blood returns from the pulmonary veins and is routed supe-
tion. Severe pulmonary insufficiency may beget right riorly over the baffle through the tricuspid valve to the right
ventricular dilation and tricuspid regurgitation, further com- ventricle and out the aorta. The interatrial baffle can be
promising systolic function.124 In the patient with severe
valvular stenosis or pulmonary atresia who was repaired
with a right ventricle to pulmonary conduit, TTE and Doppler
may detect valve conduit stenosis due to pannus ingrowth
or valve calcification or conduit insufficiency. Echocardiog-
raphy also detects the sizable subset of adults with tetralogy
of Fallot repaired in childhood who now exhibit progressive
dilation of the aortic root with aortic regurgitation.125 Adults
who have been repaired uniformly exhibit a right ventricular
restrictive diastolic abnormality on spectral Doppler.126
Interestingly, this restrictive abnormality actually shortens
the duration of pulmonary regurgitation and is associated
with improved exercise performance in these patients.

D-Transposition of the Great Arteries

In patients with d-transposition of the great arteries (d-TGA),
there is both atrioventricular concordance and ventriculoar-
terial discordance, with the aorta arising from the anterior
FIGURE 11.33. Transesophageal long axis view of the great vessels
right ventricle and the pulmonary artery originating from in a patient with d-transposition of the great arteries. The axes of
the posterior left ventricle. The echocardiographic features the pulmonary artery (PA) and aorta (Ao) are parallel rather than
of the unoperated patient with d-TGA were outlined previ- orthogonal and the PA is posterior to the Ao.
298 chapter 11

FIGURE 11.35. Continuous-wave Doppler of the stenotic site in the

FIGURE 11.34. Apical four-chamber view of a Mustard baffle in a pulmonary venous limb of the Mustard baffle in the patient with
patient with d-transposition of the great arteries. Stenosis of the d-transposition of the great arteries shown in Figures 11.34 and
pulmonary venous portion of the baffle is indicated by the narrow 11.35. The mean gradient across the baffle stenosis is approximately
color Doppler jet (arrow) from the pulmonary venous atrium (PVA) 8 mm Hg.
toward the tricuspid valve. RV, right ventricle; LV, left ventricle.

directly visualized in the parasternal long axis view and in Transesophageal echocardiography is also used to monitor
the apical views on TTE as a linear echo within the left transcatheter interventions such as closure of baffle leaks
atrium, and must be examined along its length for evidence and stenting of SVC obstruction in these patients.128,129 Most
of leak or obstruction.127 Small leaks of the baffle are common, patients with d-TGA who have undergone the Mustard opera-
and, if not seen on color Doppler imaging, may be revealed tion will exhibit systolic dysfunction of the systemic right
by peripheral injection of saline contrast. The most common ventricle by early adulthood, though most remain asymp-
site of baffle obstruction is within the systemic venous limb tomatic until the fourth decade. Transthoracic echocardiog-
at the SVC, but is unlikely to be visualized in adults by TTE. raphy is used to follow systemic ventricular function and
Obstruction of the pulmonary venous limb of the baffle may monitor for AV valve regurgitation, another fairly common
be suspected by a turbulent jet in the baffle on color Doppler problem in these patients.130 Patients with d-TGA may
or by dilation of the pulmonary veins (Fig. 11.34). The gradi- develop subpulmonic obstruction that can be diagnosed by
ent across the obstruction can be estimated from the dia- Doppler. The arterial switch procedure for d-TGA involves
stolic velocity obtained with spectral Doppler (Fig. 11.35). In transection of the great arteries with reanastomosis to the
adults in whom acoustic windows and image quality are appropriate ventricle and reimplantation of the coronary
poor, TEE clearly visualizes all limbs of the baffle (Fig. 11.36). arteries. The operation restores normal flow direction, with
The systemic right ventricle with the usual curvature of the the left ventricle pumping to the systemic circulation and is
right ventricular septum is seen in Figure 11.37. now the procedure of choice for patients with d-TGA. The

FIGURE 11.36. (A,B) Transesophageal echocardiogram of a Mustard A). A convergence zone is seen on the pulmonary venous atrium
baffle in the same patient with d-transposition of the great arteries side of the baffle consistent with stenosis at that site (B).
and obstruction of the pulmonary venous limb of the baffle (arrow,
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 299

FIGURE 11.37. Parasternal short axis view of the ventricles in an

adult with d-transposition of the great arteries. The right ventricle
(RV) is dilated and the interventricular septum bulges into the left
ventricle (LV).

FIGURE 11.38. Apical four-chamber view of a patient with l-(con-

genitally corrected) transposition of the great arteries. The systemic
right ventricle (RV) with its moderator band (large arrow) and api-
cally placed septal leaflet of the tricuspid valve (small arrow) is to
first successful operation was performed in 1975, which the left of the left ventricle (LV).
means that these patients are now entering their 30s and 40s
and require continued echocardiographic monitoring for Persistent Truncus Arteriosus
supravalvular aortic and pulmonic stenosis and left ventricu-
lar dysfunction due to ostial stenosis of the coronary Persistent truncus arteriosus, an abnormality that results
buttons.131 from failure of partitioning of the conotruncal region of the
heart, is characterized by the presence of a single great vessel
positioned over a large outlet VSD (Fig. 11.40). The truncal
L-(Congenitally Corrected) Transposition valve has numerous, up to six, leaflets and, in adults, is
of the Great Arteries almost always regurgitant. Persistent truncus arteriosus is
In l-transposition of the great arteries (l-TGA), the ventric- classified by the origin of the pulmonary arteries. The pul-
ular loop forms to the left and results in inversion and mal- monary arteries may arise as a single vessel from the truncal
position of the ventricles with atrioventricular and
ventriculoarterial discordance. As in d-TGA, the great vessels
exit the ventricles in parallel, but in l-TGA the aortic valve
is usually anterior and to the left of the pulmonary valve in
short axis views at the base rather than to the right of the
pulmonary artery. Echocardiographically, the diagnosis is
established using multiple views to identify a rightward mor-
phologic left ventricle with smooth endocardium and basally
placed mitral valve and a leftward trabeculated right ventri-
cle with an apically displaced tricuspid valve and a moderator
band (Fig. 11.38). The great vessel exiting the morphologic
left ventricle is seen to course posteriorly and bifurcate into
a pulmonary artery while the aorta exits the anterior left-
sided right ventricle and extend anteriorly. Adult patients
usually have some degree of systolic dysfunction of the sys-
temic right ventricle that should be followed echocardio-
graphically, and most have regurgitation of the left-sided
tricuspid AV valve (Fig. 11.39).132 If a perimembranous VSD,
which occurs in 70% of patients with l-TGA, is not present,
the diagnosis may not be made until adulthood, when sys-
temic AV valve regurgitation and ventricular dysfunction
have already supervened. Because systemic AV valve regur-
FIGURE 11.39. Color Doppler image in the apical four-chamber
gitation is due primarily to morphologic abnormalities of the view of regurgitation of the systemic (tricuspid) atrioventricular
valve similar to Ebstein’s anomaly, operation is more likely valve in a patient with l-(congenitally corrected) transposition of the
to require replacement than repair. great arteries.
300 chapter 11

FIGURE 11.40. (A,B) Persistent truncus arteriosus (TA) is seen in the parasternal long axis view (A). There is a single great artery overriding
a large outlet VSD (arrow). A jet of truncal valve regurgitation is seen on color Doppler of the truncal valve (B).

artery, which then bifurcates, as separate vessels exiting artery pressure can be estimated by subtracting the gradient
from the posterior wall, as separate vessels from the sides of across the stenosis from the right ventricular systolic pressure.
the truncus, or discontinuous from the truncus and fed by After balloon pulmonary valvotomy, pulmonary regurgita-
collaterals from systemic arteries. tion or restenosis can occur and can be diagnosed on TTE.

Left Ventricular Outflow Obstruction

Obstruction to Ventricular Outflow
As with right ventricular outflow obstruction, obstruction of
flow from the left ventricle can occur at any level ranging
Right Ventricular Outflow Obstruction
from the outflow tract beneath the valve, to the valve itself,
Right ventricular outflow tract obstruction can occur at any to the supravalvular region of the ascending aorta or in the
level including the infundibulum, at the pulmonic valve, or descending thoracic aorta. The two least common types of
in the pulmonary arteries, all of which can be investigated outflow tract obstruction in adults are the subvalvular and
with 2D and Doppler TTE.133–137 Obstruction of outflow the supravalvular forms. Subvalvular stenosis in adults is
occurring below the pulmonary valve is a result of a fibro- usually a result of a discrete subaortic membrane or ridge just
muscular ridge or markedly hypertrophied muscle bundles in beneath the valve. Discrete subaortic stenosis may be seen
the infundibulum, an anomaly known as a double-
chambered right ventricle. A double-chambered right ventri-
cle can be difficult to differentiate from severe valvular
stenosis with secondary hypertrophy of the muscle bundles.
In double-chambered right ventricle, continuous-wave
Doppler through the infundibulum will reveal a velocity
spectrum characteristic of dynamic obstruction, with the
peak velocity occurring in late systole and a dagger-like
appearance similar to that seen in hypertrophic obstructive
cardiomyopathy involving the left ventricle. Stenosis of the
pulmonic valve is characterized by thickening and restricted
motion of the tips of the valve leaflets with systolic doming,
which is most clearly seen in the parasternal and subcostal
short axis views at the base of the heart (Fig. 11.41). The bifur-
cation of the main pulmonary artery can be identified from
a high parasternal transducer location to assess for narrowing
of the main pulmonary artery or the branches at their takeoff
from the main pulmonary artery. Stenosis of more distal
branch pulmonary vessels cannot be visualized echocardio-
graphically. The pressure gradient across the stenosis is esti-
mated using the modified Bernoulli equation from the peak
velocity obtained using continuous-wave Doppler (Fig.
11.42).138 In patients with tricuspid regurgitation, the right FIGURE 11.41. High parasternal view of the pulmonic valve (PV)
ventricular systolic pressure can be calculated from the peak in a patient with pulmonic stenosis. The leaflet tips have restricted
velocity of the tricuspid regurgitation jet. The pulmonary motion causing characteristic doming in systole (arrow).
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 3 01
obstructive membranes is not necessary in asymptomatic
patients as was previously recommended to prevent progres-
sion of aortic insufficiency. Two other forms of subvalvular
stenosis, the fibromuscular type and the tunnel type, are
infrequently seen in adults. Supravalvular stenosis may occur
as a discrete membrane typically located at the sinotubular
junction, as an hour-glass deformity of the ascending aorta
(the most common type) associated with “elfin” facies and
hypercalcemia as part of the Williams syndrome, or as diffuse
hypoplasia of the ascending aorta and arch. Two-dimensional
images from a high parasternal and suprasternal notch trans-
ducer locations may be necessary to view these defects.143
Continuous-wave Doppler can accurately estimate the pres-
sure gradient across discrete stenosis, but is unreliable if
serial obstruction exists at multiple levels and in the tunnel
form of supravalvular aortic stenosis.
Congenital aortic valve stenosis in adults is almost
always a result of a bicuspid aortic valve that was normal at
birth and became increasingly stenotic over time. Bicuspid
aortic valves are the most common congenital cardiac
anomaly occurring in 1% to 2% of the general population.
FIGURE 11.42. Continuous-wave Doppler across the pulmonic Restricted motion of the leaflet tips relative to the body of
valve with a peak pressure gradient of 52 mm Hg, consistent with
the leaflet resulting in systolic doming of the valve in the
moderate pulmonic stenosis.
parasternal long axis view may first suggest a bicuspid aortic
valve. Valve morphology and leaflet number can be deter-
in isolation or after surgical repair of congenital heart defects mined on 2D imaging from the parasternal short axis plane
such as the AV canal. The membrane is identified on 2D TTE in most adults.144,145 A true bicuspid aortic valve has two
in the parasternal long axis or apical views as a linear echo cusps (though a raphe may give the illusion of a third cusp)
originating from and perpendicular to the interventricular with two sinuses of Valsalva. Although a raphe may give the
septum (Fig. 11.43). If the membrane itself is not seen, a high- appearance of three cusps in diastole, valve opening in systole
velocity color jet in systole originating just below and directed confirms the diagnosis when the two cusps are clearly seen.
toward the valve may raise suspicion of its existence. Con- This is visualized especially well on TEE (Fig. 11.44). As with
tinuous-wave Doppler permits estimation of severity of ste- the other forms of left ventricular outflow obstruction, trans-
nosis.139–141 Some degree of aortic regurgitation caused by valvular pressure gradients derived from Doppler velocities
aortic leaflet trauma from the high-velocity stenotic jet is can be used to estimate the severity of valvular aortic steno-
seen in up to 80% of patients in one study of 134 adults with sis. Aortic valve area can be calculated using the continuity
the anomaly, but was more than mild in <20% of patients equation.146 A rare abnormality of aortic valve anatomy is the
and did not appear to progress during a follow-up of 4.8 quadricuspid aortic valve, which is more likely to be insuf-
years.142 This suggests that resection of mildly or moderately ficient than stenotic (Fig. 11.45). The other two valve mor-
phologies associated with congenital aortic stenosis, the

FIGURE 11.43. (A,B) Apical five-chamber view in a patient with

discrete subaortic stenosis with aortic regurgitation. A bright linear FIGURE 11.44. Transesophageal echocardiogram of a bicuspid
echo of the ridge of tissue is seen below the aortic valve (arrow, A). aortic valve. There are two cusps and two sinuses of Valsalva in this
A small jet of aortic insufficiency is noted in B. valve.
302 chapter 11

FIGURE 11.45. (A,B) A quadricuspid aortic valve is seen on a transesophageal echocardiogram short axis view in diastole (A) and systole (B).

acommissural valve and the unicuspid, unicommissural of the stenosis on color Doppler.148–150 However, the descend-
valve, are seen in children and rarely in the adult. Aortic ing thoracic aorta distal to the coarctation may not be seen
stenosis in childhood is often treated by percutaneous balloon clearly in adults, thus obscuring the diagnosis. Color-guided
valvotomy, which may result in early or late aortic regurgita- continuous-wave Doppler provides an estimate of the gradi-
tion and late restenosis that is readily diagnosed by 2D TTE. ent across the coarctation with certain caveats: (1) The gradi-
Some children with severe aortic stenosis or insufficiency ent across the narrowing is flow dependent, so it may be
undergo the Ross operation in which the diseased aortic lower when the patient is at rest. Exercise such as treadmill
valve is excised, the native pulmonary valve is transected walking or leg lifts may increase the peak gradient across the
and anastomosed to the aortic annulus, and a pulmonary coarct, but may also cause flow to continue across the ste-
homograft is placed in the pulmonary position. These patients nosis into diastole, a sensitive indicator of more severe ste-
should undergo serial echocardiographic surveillance nosis. (2) The coexistence of a patent ductus arteriosus with
for development of autograft dilation and insufficiency diversion of blood proximal to the coarct to the pulmonary
(Fig. 11.46).147 artery causes the Doppler to underestimate the true gradient
Coarctation of the aorta may take one of several forms, as will the presence of large or numerous collaterals around
but is most commonly caused by a discrete shelf of tissue in the coarctation. (3) Severe aortic stenosis from a bicuspid
the descending thoracic aorta just distal to the ostium of the valve also results in falsely low gradient. A higher gradient
left subclavian artery near the insertion of the ligamentum may be revealed after aortic valve replacement. An example
arteriosum. Approximately 80% to 85% of patients with of continuous wave Doppler of severe coarctation is seen in
coarctation of the aorta have a bicuspid aortic valve, though Figure 11.48. Operative coarct repair in childhood may have
the opposite is not true. The coarct site is most likely to be been done by one of several methods, such as creation of a
visualized by 2D TTE from a suprasternal notch transducer subclavian flap as a patch, excision of the coarct with reanas-
position (Fig. 11.47) with a mosaic high velocity jet at the site tomosis of the proximal and distal aorta, or placement of an

FIGURE 11.46. (A,B) Two-dimensional (A) and color Doppler (B) transesophageal echocardiogram of aortic valve and proximal aorta in a
patient who has undergone the Ross operation. There is severe aortic insufficiency noted in the left ventricular outflow tract.
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 303

FIGURE 11.47. Suprasternal notch view in a patient with coarcta- FIGURE 11.48. Continuous-wave Doppler through the coarctation
tion of the aorta. There is marked narrowing just distal to the site demonstrates a peak pressure gradient of 68 mm Hg.
takeoff of the left subclavian artery (arrow). The ascending aorta
(AAo) is aneurysmal.

interposition conduit. Knowledge of the type of repair is the pulmonary artery directly to the descending aorta bypass-
important to adequately assess for late problems. Potential ing the lungs. In certain individuals, particularly infants
late complications of coarct repair include restenosis of the with other congenital cardiac defects or who are premature,
coarct site and aneurysm of the descending aorta proximal the ductus may remain patent. The right-to-left shunt present
to or just distal to the repair. In addition, aortic stenosis can in utero will reverse as pulmonary vascular resistance drops
develop as can aneurysms of the ascending aorta related to in the first week of life and a left-to-right shunt will ensue.
abnormalities of the media of the vessel wall. Transthoracic The size of the shunt is determined by the diameter of the
echocardiography and TEE can be used to visualize each of vascular connection and the pulmonary vascular resistance.
these complications or sequelae of coarctation of the aorta. In patients with large left-to-right shunts, the development
of fixed pulmonary vascular disease will cause the shunt to
again reverse with resultant differential cyanosis of the lower
Miscellaneous Congenital Anomalies extremities. The ductal vessel is rarely seen directly in adults
on TTE, but may be visualized in children from the supra-
sternal or high parasternal transducer location in the short
Systemic to Pulmonary Artery Shunts
axis view. It may be clearly seen on TEE (Fig. 11.49). In the
The most common native extracardiac left-to-right shunt typical patient with small PDA, a narrow high-velocity con-
seen in adults is the patent ductus arteriosus (PDA). The tinuous color jet may be identified entering the main pulmo-
ductus arteriosus, which normally closes at birth, is a normal nary artery adjacent to the left pulmonary artery directed
structure of the fetal vascular circuit that diverts blood from retrograde to the pulmonary valve (Fig. 11.50). This is best

FIGURE 11.49. (A) A large patent ductus arteriosus (pda) is visualized connecting the descending thoracic aorta (Ao) and the pulmonary
artery (PA). (B) A low-velocity jet is seen on color Doppler.
304 chapter 11

FIGURE 11.51. On transesophageal echocardiogram of the descend-

FIGURE 11.50. Color Doppler of the pulmonary artery in the high ing thoracic aorta (DAo) in the long axis plane, a bright circular
parasternal view shows a narrow jet (arrow) originating just proxi- structure is identified (arrow), which represents the distal aspect of
mal to the bifurcation of the pulmonary artery directed retrograde a coil inserted into this patient’s patent ductus arteriosus.
to the pulmonic valve.

seen in the high parasternal imaging plane.151–153 Continuous- echocardiography may visualize the defect more clearly
wave Doppler of the descending aorta may reveal retrograde than TTE.160
diastolic flow indicating left-to-right shunting through the The most common surgically constructed systemic-to-
ductus. Two-dimensional and Doppler TTE and TEE are also pulmonary shunts seen in the adult population are the Glenn
ideal for monitoring PDA during and after percutaneous anastomosis of the superior vena cava to the pulmonary
closure (Fig. 11.51).154 artery, and the Blalock-Taussig shunt from either subclavian
Rarely, a sinus of Valsalva aneurysm, a result of localized artery to the ipsilateral pulmonary artery. Generally, the
weakening of the media of the sinus, may occur. On TTE, conduit itself is not visualized on 2D imaging in adults;
a sinus of Valsalva aneurysm is characterized by localized however, spectral Doppler can be used to assess the pressure
bulging of the sinus, often into the right ventricle (Fig. across the circuit, and thus estimate pulmonary artery
11.52).155 Color Doppler of unruptured aneurysms may dem- pressure.
onstrate aortic regurgitation due to abnormal geometry
of and failure of valve coaptation in diastole. The aneurysm
Coronary Artery Abnormalities
may rupture into any cardiac chamber; aneurysms of
the right coronary sinus typically rupture into the right Anomalous origin of coronary arteries occurs in approxi-
ventricle and those of the noncoronary cusp rupture into mately 1% of adults undergoing cardiac catheterization. The
the right atrium, resulting in a continuous left-to-right most common type is origin of the left circumflex from the
shunt easily imaged by color Doppler.156–159 Transesophageal right coronary sinus and is usually benign and discovered

FIGURE 11.52. (A,B) Transesophageal echocardiogram in the long has distorted the aortic annulus in the patient in B, who has signifi-
axis plane of a sinus of Valsalva aneurysm. The marked dilation of cant aortic insufficiency noted on color Doppler flow.
the sinus in each patient is noted (arrow, A and B). The aneurysm
 e c hoc a r diog r a p h y i n t h e a du lt w i t h c ong e n i ta l h e a rt di se a se 305
incidentally on coronary angiography. The variants associ- 13. Rhodes JF, Lane GK, Tuzcu EM, Latson LA. Invasive echocar-
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Transthoracic echocardiography and transesophageal echo-
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1979;59:395–402. monary stenosis. Am J Cardiol 1974;34(6):644–651.
118. Henry WL, Maron BJ, Griffith JM. Cross-sectional echocar- 137. Tinker DD, Nanda NC, Harris JP, Manning JA. Two-dimen-
diography in the diagnosis of congenital heart disease. Identi- sional echocardiographic identification of pulmonary artery
fication of the relation of the ventricles and great arteries. branch stenosis. Am J Cardiol 1982;50:814–820.
Circulation 1977;56:267–273. 138. Lima CO, Sahn DJ, Valdes-Cruz LM, et al. Noninvasive
119. Sanders SP, Bierman FZ, Williams RG. Conotruncal malforma- prediction of transvalvular pressure gradient in patients
tions: diagnosis in infancy using subxiphoid 2-dimensional with pulmonary stenosis by quantitative two-dimensional
echocardiography. Am J Cardiol 1982;50:1361–1367. echocardiographic Doppler studies. Circulation 1983;67:866–
120. Di Segni E, Einzig S, Bass JL, Edwards JE. Congenital absence 871.
of pulmonary valve associated with tetralogy of Fallot: diag- 139. Hatle L. Noninvasive assessment and differentiation of
nosis by 2-dimensional echocardiography. Am J Cardiol left ventricular outflow obstruction with Doppler ultrasound.
1983;51:1798–1800. Circulation 1981;64:381–387.
121. Jureidini SB, Appleton RS, Nouri S. Detection of coronary 140. Lima CO, Sahn DJ, Valdes-Cruz LM, et al. Prediction of the
artery abnormalities in tetralogy of Fallot by two-dimensional severity of left ventricular outflow tract obstruction by quan-
echocardiography. J Am Coll Cardiol 1989;14:960–967. titative two-dimensional echocardiographic Doppler studies.
122. Li W, Davlouros PA, Kilner PJ et al. Doppler-echocardiographic Circulation 1983;68:348–354.
assessment of pulmonary regurgitation in adults with repaired 141. Krueger SK, French JW, Forker AD, Caudill CC, Popp RL.
tetralogy of Fallot: comparison with cardiovascular magnetic Echocardiography in discrete subaortic stenosis. Circulation
resonance imaging. Am Heart J 2004;147:165–172. 1979;59:506–513.
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142. Oliver JM, Gonzalez A, Gallego P, Sanchez-Recalde A, Benito 155. Terdjman M, Bourdarias JP, Farcot JC, et al. Aneurysms of sinus
F, Mesa JM. Discrete subaortic stenosis in adults: increased of Valsalva: two-dimensional echocardiographic diagnosis and
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aortic regurgitation. J Am Coll Cardiol 2001;38:835–842. Cardiol 1984;3:1227–1235.
143. Weyman AE, Caldwell RL, Hurwitz RA, et al. Cross-sectional 156. Kiefaber RW, Tabakin BS, Coffin LH, Gibson TC. Unruptured
echocardiographic characterization of aortic obstruction. 1. sinus of Valsalva aneurysm with right ventricular outflow tract
Supravalvular aortic stenosis and aortic hypoplasia. Circula- obstruction diagnosed by two-dimensional and Doppler echo-
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144. Brandenburg RO Jr, Tajik AJ, Edwards WD, Reeder GS, Shub C, 157. Chow LC, Dittrich HC, Dembitsky WP, Nicod PH. Accurate
Seward JB. Accuracy of 2–dimensional echocardiographic diag- localization of ruptured sinus of Valsalva aneurysm by real-
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LM. Noninvasive quantification of stenotic semilunar valve 160. Rubin DC, Carliner NH, Salter DR, Plotnick GD, Hawke MW.
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Doppler echocardiography. Am J Cardiol 1984;53:1473–1475. 165. Velvis H, Schmidt KG, Silverman NH, Turley K. Diagnosis of
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of ductus arteriosus in infants associated with congenital ultrasound and color flow mapping. J Am Coll Cardiol 1989;
anomalies of the heart or great arteries. Am J Cardiol 14:968–972.
1986;56:845–851. 166. Nishiguchi T, Matsuoka Y, Sennari E, et al. Congenital coro-
153. Swensson RE, Valdes-Cruz LM, Sahn D, et al. Real-time nary artery fistula: diagnosis by two-dimensional Doppler
Doppler color flow mapping for detection of patent ductus echocardiography. Am Heart J 1990;120:1244–1248.
arteriosus. J Am Coll Cardiol 1986;8:1105–1112. 167. Samdarshi TE, Mahan EF III, Nanda NC, Sanyal RS. Trans-
154. Bridges ND, Perry SB, Parness I, Keane JF, Lock JE. Transcath- esophageal echocardiographic assessment of congenital coro-
eter closure of a large patent ductus arteriosus with the clam- nary artery to coronary sinus fistulas in adults. Am J Cardiol
shell septal umbrella. J Am Coll Cardiol 1991;18:1297–1302. 1991;68:263–266.
 1 Congenital Heart Disease
2 in the Adult:
Interventional Therapy
Charles E. Mullins

History and General Considerations . . . . . . . . . . . . . . . . 311 Device Occlusion of Miscellaneous Intracardiac

Valvular Stenoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Obstruction of the Great Vessels . . . . . . . . . . . . . . . . . . . 317 Occlusion of Extracardiac Intravascular
Intravascular Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Communications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Coarctation of the Aorta . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Occlusion of the Other Abnormal Extracardiac
Systemic Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Vascular Communications . . . . . . . . . . . . . . . . . . . . . 332
Pulmonary Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Miscellaneous Therapeutic Catheter Procedures . . . . . . 333
Occlusion of Intracardiac Defects . . . . . . . . . . . . . . . . . . 322 Catheter Removal of Foreign Bodies . . . . . . . . . . . . . . . . 335
Occlusion of the Patent Foramen Ovale . . . . . . . . . . . . . 326 Collaborative (Hybrid) Therapeutic Catheterization
Occlusion of Ventricular Septal Defects and Other and Surgical Procedures . . . . . . . . . . . . . . . . . . . . . . . 336
Abnormal Intracardiac Communications . . . . . . . . . 327 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Key Points catheterization with an accurate balloon sizing of the

defect.
• Balloon valvuloplasty and balloon angioplasty now are • The major indications for closing a patent foramen ovale
applied effectively to all four cardiac valves and all major (PFO) are significant right to left shunting through it, and
blood vessels in children with cardiovascular diseases. a documented central nervous system (CNS) embolic
• Aortic valvuloplasty is done in children with valvular event in the presence of a PFO.
aortic stenosis with a systolic gradient greater than or • Interventional cardiologists have been occluding the
equal to 50 mm Hg at rest, or a peak gradient of 40 to patent ductus arteriosus (PDA) nonsurgically for almost
50 mm Hg with symptoms or signs of ischemia. four decades.
• The most typical form of congenital mitral stenosis con-
sists of thickened leaflets and shortened chordae tendin-
eae with decreased interchordal spaces. Other forms History and General Considerations
include supravalve mitral membrane and a parachute
mitral valve. As cardiovascular surgeons have become more technically
• The techniques for relieving congenital or surgically adept at performing surgery for congenital heart disease in
acquired vascular lesions by balloon angioplasty and smaller, sicker, and bluer patients, they have expected and
stents now are routine and employed with variable required better diagnostic information about those same
success for stenoses anywhere within the great vessels. patients. The same surgical interventions for these patients
• The discrete, shelf-like coarctation of the aorta represents stimulated not only the requirement for better angiography
the ideal lesion for successful dilation. and diagnostic cardiac catheterization in these patients
• Obstruction to systemic veins in patients with congeni- by the catheterizing cardiologists but also intensified the
tal heart disease usually is iatrogenic. desire to perform these treatments in the catheterization
• Congenital pulmonary vein stenosis is very rare and laboratory. To accomplish these goals, pediatric interven-
usually occurs with other congenital heart lesions with tionalists have been at the forefront of development of
or without associated surgical intervention. new catheterization techniques and better imaging systems.
• The final suitability of an atrial septal defect for trans- Along with better diagnoses and imaging, there has been
catheter closure is determined by transesophageal an explosion of new therapeutic catheters, devices, and
echocardiography (TEE) and confirmed during cardiac procedures for use in the pediatric as well as the growing

311
312 chapter 12

population of surviving adults with congenital heart to use the specialized catheters and devices. Each procedure
disease. also requires a large inventory of specialized and expensive
Historically, pediatric cardiac catheterization began expendable equipment. In addition to the training in the use
moving from strictly diagnostic to therapeutic catheteriza- of the equipment, the cardiologist performing these proce-
tions in 1966 when Rashkind and Miller1 introduced balloon dures must have training and experience in when to use the
atrial septostomy for babies with transposition of the great various techniques or devices and must know the contrain-
arteries. This procedure was lifesaving for a very limited dications for each device. Obviously, not every center should
number of patients, but of equal importance, it demonstrated plan to perform every type of therapeutic catheterization
that transcatheter intracardiac procedures could be per- procedure on congenital heart patients. However, all cardi-
formed relatively safely in small babies with excellent long- ologists who care for these patients must be aware that these
term results. procedures are available in order to advise their patients most
During the same time period, the development of diag- appropriately of the therapeutic options.
nostic cardiac catheterization was advanced by the introduc-
tion of transseptal left heart catheterization by Cope2 and
Ross et al.3 and Roveti et al.4 This procedure became widely Valvular Stenoses
used in pediatric cardiology when Duff and Mullins5 intro-
duced the long transseptal sheath in 1978. The long trans-
General Considerations
septal sheath encouraged the development of the Park blade
septostomy procedure, permitting the septostomy concept to In the 25 years since Kan et al.8 first introduced the concept
be applied to the older patient with complex lesions.6 of balloon valvuloplasty for the pulmonary valve, techniques
The most recent and dramatic advances in interventional have developed rapidly for the aortic, mitral, and tricuspid
cardiology began in 1978 when Gruentzig and Hopff7 dem- valves. Early in the experience with these techniques, the
onstrated that fixed-diameter cylindrical balloons could be voluntary Valvuloplasty and Angioplasty of Congenital
positioned within a stenosis in a vessel and when inflated at Anomalies (VACA) registry was established. This registry
high pressure the obstruction was relieved. In 1982, Kan et included 28 centers where these procedures were performed.
al.,8 using much larger diameter balloons, applied this tech- This registry was intended to record primarily the basic
nique to pulmonary valvular stenosis in congenital heart results and the complications of dilation procedures.9 The
patients. The results were excellent and were accepted enthu- registry rapidly accumulated information on a large number
siastically by pediatric cardiologists, with rapid extension of of patients with a large variety of lesions undergoing dilation
the technique to the other cardiac valves and to vascular procedures by pediatric cardiologists. Now there are many
obstructions. Balloon valvuloplasty and balloon angioplasty additional reports documenting the results of these proce-
now are applied effectively to all four valves and all major dures in both pediatric and adult patients with congenital
blood vessels and in children with cardiovascular disease. In and acquired heart disease. There is a place for balloon dila-
the relatively short time since its inception, balloon valvu- tion of stenosis of each of the four cardiac valves. These pro-
loplasty has led to a tremendous increase in technology, cedures have special applications in selected adult patients,
including the development and use of balloon-expandable especially women during later stages of pregnancy and in the
stents in conjunction with the dilation of vessels. During elderly.
this same time span, there were dramatic developments in Before a valvuloplasty procedure is performed a complete
transcatheter devices and techniques for closing abnormal or diagnostic cardiac catheterization is performed to document
persistent intracardiac and vascular communications. Ini- the exact anatomy and hemodynamics of the lesion and
tially these devices were only for the occlusion of aortopul- exclude additional congenital or acquired heart disease.
monary collateral vessels, but soon evolved into the closure Angiography is performed to delineate the anatomy of the
of the patent ductus arteriosis and intracardiac septal valve exactly and measure the valve annulus very precisely.
defects. Additional angiography may be necessary to evaluate valvu-
As patients with operated congenital heart disease have lar insufficiency prior to balloon valvuloplasty, particularly
reached adulthood, it has become clear that many have resid- for the left-sided valves. A catheter with calibrated centime-
ual cardiovascular problems, which are particularly difficult ter marks embedded in it, a calibration grid, a large sphere
to approach surgically. Therapeutic cardiac catheterization of known size, or a calibrated centimeter reference system
procedures in many instances now offer alternatives to built into the x-ray system should be used as the reference
surgery for these patients. This chapter discusses therapeutic measurement. Using the diameter of a catheter as the refer-
interventional catheterization techniques, which should be ence for large structures leads to huge calibration errors. The
considered when evaluating the adult with congenital heart reference object must be recorded in the exact plane of the
disease. A brief technical description of each procedure is valve, which is being dilated in order to achieve accurate
included. measurements of the valve.
Each congenital lesion is somewhat different from the
same lesion in another patient. Cardiac catheterization of
Dilation of Pulmonary Stenosis
these patients requires a three-dimensional understanding
and visualization of the anatomy, which in turn, requires With the current safety of this procedure in experienced
biplane fluoroscopic and angiographic visualization. Each hands, the indications for transcatheter intervention for
procedure requires special technical skills and training in pulmonary valvular stenosis are less stringent than the
order to perform the individual catheter manipulations and indications for the comparable surgical valvuloplasty. The
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 313
indications for treatment of pulmonary stenosis include sig- An end-hole diagnostic catheter is advanced through the
nificant right ventricular outflow tract obstruction, any evi- right heart and into the distal left pulmonary artery. It is
dence of right ventricular hypertrophy, and any evidence of important that this catheter passes through the center of the
right ventricular fibrosis or dysfunction.10 The severity of tricuspid valve and not between or through the chordal
pulmonary valvular stenosis correlates quite well with the attachments. A stiff exchange guidewire is passed through
peak instantaneous gradient by echo, but is determined this catheter and into a large distal left pulmonary artery.
definitively at catheterization by the peak systolic gradient With the wire carefully fixed in place, the catheter is with-
across the valve in the presence of normal cardiac output. A drawn and replaced with the previously prepared balloon
gradient of less than 10 mm Hg is considered trivial, 10 mm Hg catheter. The balloon catheter is advanced over the wire until
to less than 30 mm Hg is considered mild, 30 to 60 mm Hg is the balloon is centered across the annulus. This procedure is
considered a moderate obstruction, and greater than 60 mm Hg repeated with a second catheter from a second femoral intro-
is considered severe stenosis. Natural history studies have ductory site for the second balloon.
documented that moderate and severe pulmonary valve ste- Exact centering of the balloons on the valve is important
nosis tend to develop more obstruction with time, whereas so that the balloons are not squeezed forward or backward
mild pulmonary valve stenosis usually does not progress.11,12 out of the valve during inflation. The balloons are inflated
At the time of catheterization, a favorable valve with fused to their designated maximum pressures using inflation
commissures, a peak systolic gradient of 30 mm Hg or more devices that include a pressure manometer. The balloons are
across the pulmonary valve, and association with clinical observed first for the development of a “waist” or circumfer-
evidence of right ventricular hypertrophy or dysfunction ential indentation in the balloons, followed by disappearance
should undergo catheter intervention. of the waists with further inflation. Once the waist disap-
There are a variety of balloons in use for pulmonary val- pears or the maximum pressure of the balloon is achieved,
vuloplasty. These are cylindrical, predominantly polyethyl- the balloons rapidly are deflated, with the entire inflation/
ene balloons that are noncompliant and have parallel walls deflation cycle taking place over less than 10 to 15 seconds.
at the fixed, predetermined diameter at the maximum infla- This process is repeated several times with slight to-and-fro
tion pressure. The balloons are available in a wide range of repositioning of the balloons to ensure their centering across
diameters from as small as 2 mm to as large as 26 mm. When the valve.13 In the presence of a very large annulus, a balloon
inflated to their maximum recommended pressure of dilation using three balloons may be more satisfactory than
between 2.5 and 12 atmospheres, they reach their advertised two very large balloons. Occasionally, only one venous access
fixed diameter and become very rigid.13 The balloon is pre- is available, or an operator chooses to use a single balloon for
pared by purging it of air with repeated flushing and low- a pulmonary valve dilation. When a single balloon is used,
pressure inflations with a solution of contrast, which is the diameter of the single balloon should be 1.3 to 1.4 times
diluted with saline in a 1 : 5 dilution. The same contrast solu- the diameter of the valve annulus.10,13
tion is used to inflate the balloon during the balloon As the first valve to be successfully dilated and with the
valvuloplasty. relatively easy approach to this valve, data on pulmonary
To perform the valvuloplasty, the pulmonary valve, valve valve dilation accumulated rapidly. In 1990 the voluntary
annulus, right ventricular outflow tract, and main and branch VACA registry reported on the results of 784 pulmonary
pulmonary arteries are imaged with a right ventricular valvuloplasties, including 33 neonates, 716 children, and 35
angiocardiogram in the posteroanterior (or cranially angu- adults.15 For the whole group of patients, the gradient across
lated posteroanterior) and lateral views.13 Measurements of the pulmonary valve decreased from 71 ± 33 mm Hg to 28 ±
the valve annulus diameter are obtained using an accurately 21 mm Hg, with an incidence of complications of only 1.3%.
calibrated reference. Preferentially, a double-balloon dilation In the VACA registry, there was no difference in success of
procedure is used for the pulmonary valve. Not uncommonly, the procedure with age, but only nine adults between the
the valve annulus is too large for a single-balloon technique ages of 21 and 79 years were included in the analysis. In 196
(greater than 18 mm in diameter), or the use of a single very of the VACA patients, the residual gradient was subdivided
large balloon would require the introduction of a very large into infundibular (18 ± 24 mm Hg) and transvalvular (16 ±
and traumatic balloon surface profile into the vein. Under 15 mm Hg).15 Unsuccessful procedures were associated with
these circumstances, the double-balloon technique is used.14 dysplastic valves and, remarkably, with the inability to cross
The balloon diameters of the two balloons are chosen so that the valve by less experienced operators. Pulmonary balloon
the sum of the diameters of the two inflated balloons is 1.5 valvuloplasty now is the procedure of choice for children and
to 1.6 times the diameter of the pulmonary valve annulus.14 adults with pulmonary valvular stenosis.
Of equal importance to the size of the annulus being too The experience at Texas Children’s Hospital has been
large for a single balloon, the double balloons allow the very positive and similar to that in the VACA report. Pulmo-
introduction of two much smaller profile balloons, and when nary valvuloplasty was performed in 102 patients including
the two balloons are inflated simultaneously within the three patients who were 51, 71, and 76 years of age.13,16 The
annulus, they provide two persistent lumina adjacent to the mean gradient was reduced by 69% for the whole group, and
inflated balloons within the annulus. For these reasons, the valve angiographically opened significantly more than
the double-balloon technique is preferentially employed, prior to valvuloplasty. There often was an associated dynamic
even when a single larger balloon may be available.10,13,14 The or reactive infundibular narrowing, which often actually
length of the balloons is chosen according to the patient’s increases immediately following the valvuloplasty. The
size. In general, much longer balloons (6 to 8 cm) are used in residual infundibular gradient tends to decrease with
the adult congenital patient. time.13
314 chapter 12

There is less information available for adult patients with inflation helps to stabilize the balloons in the aortic orifice.
pulmonary valvular stenosis because it is relatively rare for Although a single-balloon technique was originally
a patient with this lesion to reach adulthood without prior described,21 many centers have switched to a double-balloon
diagnosis and treatment. Chen and colleagues17 reported technique for the same advantages seen in pulmonary valve
their experience in 53 adolescent and adult patients 13 to 55 dilation.13,14,21 When the double-balloon technique is used,
years of age. With pulmonary balloon valvuloplasty, the sys- the combined diameter of the two balloons is a maximum
tolic pressure gradient across the pulmonary outflow tract of 1.1 to 1.2 times the measured diameter of the aortic valve
decreased from 91 ± 46 mm Hg to 38 ± 32 mm Hg in their annulus.13,14,21 If only one balloon catheter is used, the diam-
patients. There was a further decrease in gradient at follow- eter of the single balloon should be approximately the same
up catheterization in nine patients who were restudied. as the diameter of the aortic annulus.21
Teupe et al.18 reported a similar experience in 24 adult The procedure requires a full cardiac catheterization
patients who were 19 to 65 years of age, 14 of whom had late with complete hemodynamic measurements including
follow-up of 5 to 9 years. In those 14 patients, the mean peak simultaneous measurements of left ventricular and ascend-
systolic gradient prior to valvuloplasty was 82 ± 29 mm Hg. ing aorta pressures along with an assessment of cardiac
Immediately after intervention, the gradient fell to 37 ± output. A transseptal approach allows a transseptal sheath
14 mm Hg, and it was 31 ± 7 mm Hg at a mean follow-up of to be positioned in the left ventricle, and by using a floating
6.5 years. Three patients in this study had a peak systolic balloon catheter one French size smaller advanced through
gradient of more than 100 mm Hg prior to valvuloplasty. All the transseptal sheath and into the ascending aorta, simul-
three had high residual gradients immediately after the pro- taneous left ventricular and ascending aorta pressure
cedure, which were shown to be dynamic in nature. In these measurements are obtained before, during, and after aortic
three patients, the subvalvular hypertrophy resolved by 3 valve dilation without a separate arterial catheterization or
months following the procedure, and they had a permanently exchange of any balloons/catheters. Angiograms are obtained
lower gradient at late follow-up. Both authors felt that balloon in the left ventricle and ascending aorta, and using a large-
valvuloplasty for pulmonary valvular stenosis in the adult is diameter calibrated reference grid or calibrated marker cath-
highly effective and associated with an excellent long-term eter, careful measurements of the diameter of the aortic
outcome.17–19 Now a much better relief of the gradient would valve annulus are obtained. The presence and amount of
be expected. aortic regurgitation must be evaluated initially to assess
appropriateness of valvuloplasty.
Once the catheters are introduced into the left heart,
Dilation of Aortic Stenosis
heparin, 100 U/kg, is administered intravenously. The appro-
Aortic valve dilation was first reported by Lababidi20 in 1984. priate-size balloons are chosen and prepared using a dilute
This technique was slower to gain acceptance than pulmo- solution of contrast and saline (1 : 5). Two end-hole catheters
nary valvuloplasty because of concerns of producing poten- are introduced into separate femoral arteries, and advanced
tial aortic regurgitation. The early and subsequent follow-up retrograde across the aortic valve into the left ventricular
experience has been favorable, without an inordinately high apex. A 180-degree curve is preformed at the transition area
incidence of this complication. The alternative of surgical between the stiff and floppy portions of the distal ends of
valvotomy is not without this complication and often results two Super Stiff exchange wires. One by one, the wires are
in valve replacement, which is best delayed as long as possi- positioned through the end-hole catheters into the left ven-
ble in children and adolescents because of size issues and tricular apex with the floppy tip curled toward the outflow
difficulties with anticoagulation. Children, adolescents, and tract. With both wires fixed securely in position, the end-hole
young adults with congenital aortic valve stenosis now rou- catheters are withdrawn. The two balloon catheters are
tinely undergo balloon valvuloplasty. Indications for balloon advanced retrograde into position across the aortic valve
valvuloplasty of the aortic valve are similar to those for sur- annulus. The balloons are centered side by side across the
gical intervention for aortic stenosis. Although no single set valve, the patient is paced at 200 beats/min, and the balloons
of diagnostic criteria is agreed upon when judging the sever- are inflated until the waist of circumferential narrowing
ity of aortic stenosis, most pediatric cardiologists would disappears. It is important to keep the balloons stable within
agree that in the presence of normal cardiac output, a systolic the valve annulus by the use of stiff wires, rapid [200 to 240
gradient of ≥50 mm Hg at rest, or a peak gradient of 40 to beats per second (bps)] ventricular pacing just before and
50 mm Hg with symptoms and/or signs of ischemia indicate during the balloon inflations, and maintenance of proper
the need for some form of intervention.21 positioning of the wires in order to prevent “shear” trauma
A major contraindication to performing aortic balloon against the leaflets from the balloons moving in and out of
valvuloplasty is the presence of more than 2+ aortic regurgi- the valve. The total inflation/deflation cycle should be com-
tation, as 25% to 30% of patients develop some increase in pleted within 10 to 15 seconds. Balloon inflations are repeated
degree of regurgitation with this procedure.13 as many as four to eight times while repositioning the balloon
The balloon catheters are similar to those used for the catheters within the valve as necessary. After completion of
pulmonary valve, with the exception that longer, 6- to 8-cm the balloon inflations, the balloons are withdrawn to the
balloons are utilized to help stabilize them across the aortic descending aorta, the measurement of the valve gradient is
valve. The longer balloons are less likely to be ejected from performed and angiography in the aortic root is repeated. The
the valve with inflation during systole. In addition to the balloons and the sheaths are withdrawn, and hemostasis
longer balloons, the use of Super StiffTM wires (Boston achieved by careful pressure over the femoral puncture
Scientific, Natick, MA) and rapid ventricular pacing during sites.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 315
It is preferable to delay valve replacement as long as tomatic relief at best, and better overall survival is obtained
possible—optimally well into adulthood and past the child- with direct valve replacement.27,28
bearing years for women. Realizing that both surgical val-
votomy and balloon dilation are palliative, both children and
Mitral Stenosis
younger adults with aortic stenosis that is severe enough to
warrant intervention are offered the alternative of balloon Young adults may have either congenital or rheumatic mitral
valvuloplasty. Although long-term outcome studies of aortic stenosis. Congenital mitral stenosis is a rare form of congeni-
balloon valvuloplasty are just now appearing, it does appear tal heart disease, which is actually a spectrum of abnormali-
that this procedure is comparable to surgical valvotomy for ties. The obstruction may occur in the supravalve area, the
the short- and midterm relief of aortic stenosis. This is sup- annulus, the leaflets, the chordae tendineae, the papillary
ported by reports by Justo and colleagues22 and by the VACA muscle level, or any combination of these. The most typical
registry.23 Justo et al. compared 110 patients with balloon form of congenital mitral stenosis consists of thickened leaf-
valvuloplasty to 103 patients following surgical valvotomy lets and shortened chordae tendineae with decreased inter-
and demonstrated that the left ventricle to aorta pressure chordal spaces.29,30 Other typical forms include supravalve
gradient is reduced equally well in both, with the procedures mitral membrane or a parachute mitral valve.29,30 The diag-
having a similar likelihood of having recurrence of the aortic nosis of mitral stenosis may be delayed or masked in these
stenosis with time. Additionally, their study verified that the patients due to associated lesions, most commonly other
risks of creating aortic valve regurgitation by either surgical obstructions to left heart outflow.31,32
valvotomy or balloon valvuloplasty were equal and equally Intervention is indicated for severe mitral stenosis, par-
unpredictable. ticularly when it causes pulmonary hypertension. Symptoms
The report of the VACA registry, which examined results of severe stenosis include shortness of breath, orthopnea, and
in 606 patients from 23 participating institutions, also dem- marked limitation in exercise tolerance. The presence of
onstrated a comparable relief of obstruction and a similar significant mitral stenosis is confirmed by echocardiographic
incidence of aortic insufficiency.23 In this report, the left evidence of a significant mitral gradient and a prolonged
ventricle to aorta systolic gradient was reduced by a mean of pressure half-time of ≥220 ms. The severity of the mitral
60% ± 23%, with 7.3% (n = 46) developing either severe aortic stenosis is confirmed definitively at catheterization by find-
insufficiency, or an increase in valve insufficiency of equal ings of a high left atrial pressure, a significant pressure gradi-
to or greater than two grades. Independent predictors of ent across the mitral valve with a calculated mitral valve
development of more severe aortic regurgitation included an area ≤0.5 cm2/m2 and secondary pulmonary hypertension.
increased balloon to annulus ratio, larger diameter valves, Surgical mitral valvuloplasty in the congenital lesions is
and the presence of preexisting aortic regurgitation (mild or associated with significant morbidity and mortality. Patients
more), all presumed to signify valves with morphologic with congenital mitral stenosis or even acquired rheumatic
abnormalities that can be exacerbated by valvuloplasty.23 mitral stenosis in young adults frequently have a mitral
Procedure-related mortality for this large cohort of patients annulus that is small, and insertion of a prosthetic mitral
was 1.9%. The procedure could not be performed or com- valve prohibits any further growth of the annulus. In an
pleted in 4.7%, with a suboptimal result in 17%. Both sub- effort to provide symptomatic relief and allow growth of the
optimal outcome and mortality were highly correlated with mitral annulus along with other left heart structures, balloon
young age (<3 months). Midterm follow-up studies continue valvuloplasty is attempted for severe congenital as well as
to suggest that aortic balloon valvuloplasty is an effective rheumatic mitral stenosis in children and young adults.33–36
and relatively safe palliation for children and adolescents Appropriate hemodynamic measurements including the
with valvular aortic stenosis.24,25 simultaneous measurement of left atrial and left ventricular
Balloon valvuloplasty of the aortic valve has outcomes pressures are obtained and angiography is performed in the
for young adults with bicuspid aortic valve that are similar left atrium or the left ventricle in a right anterior oblique/
to those in children,26 and it is utilized in young adults with caudal view and a steep left anterior oblique/cranial view in
significant stenosis. Balloon valvuloplasty is useful particu- order to align the valve “on edge” and obtain accurate mea-
larly in those adults in whom anticoagulation presents an surements of the mitral valve annulus. The diameter of the
increased risk due to lifestyle or employment demands and annulus is measured angiographically by comparing to a
in women who are interested in becoming pregnant (because catheter with special calibration marks (calibrated in centi-
of the known teratogenic effects of warfarin anticoagula- meters) or to another large reference device. The valve
tion). Balloon valvuloplasty of the calcific aortic valve in the annulus diameter also is measured by TTE.
elderly is unlikely to result in any beneficial effect,27,28 and, The InoueTM balloon and technique, which is in wide use
as a consequence, valve replacement is the procedure of for rheumatic mitral stenosis, produces comparable results
choice in the presence of a calcified valve. Lieberman et al.27 with fewer complications and less fluoroscopy time than
evaluated the results in 165 symptomatic adult patients who other types of balloon valvuloplasty in the larger adolescent
underwent balloon aortic valvuloplasty and found that event- and in adult patients with mitral stenosis of rheumatic
free and actuarial survival after this procedure resembles the origin.37 This technique should be considered for larger
natural history of untreated symptomatic aortic stenosis, patients with congenital mitral stenosis in centers where
and is even more dismal for patients who are not candidates this balloon is available and there is a familiarity with the
for aortic valve replacement. Although it has been shown technique.
that balloon valvuloplasty will improve symptoms in very The Inoue balloon is a unique balloon designed specifi-
old patients, this effect provides only a short period of symp- cally for dilation of the stenotic mitral valve. The final
316 chapter 12

inflated balloon is shaped like a fat dumbbell with the central fully controlling the positions of the balloons, particularly
fat waist expanding to a specific diameter with each specific so that they do not move forward into (through!) the left
amount of fluid, which is instilled into the balloon. The ventricular apex or backward toward (and into) the atrial
Inoue balloon catheter is positioned across the mitral valve septum. After repositioning the balloons forward or back-
with the deflated balloon completely within the left ven- ward over the wires in order to re-center them across the
tricular cavity. The balloon then is expanded sequentially valve, the inflation/deflation cycles are repeated until the
with the distal end expanded first well into the left ventricu- circumferential waists no longer appear with the initial
lar cavity. Then the balloon with the distal portion inflated inflation of the balloons. In the event of a significant residual
is withdrawn into the stenotic orifice of the mitral valve with gradient and in the presence of no waist on the balloon and
the inflated portion against the left ventricular side of the no significant mitral regurgitation, the procedure is repeated
valve. Next, the proximal end of the balloon, which now is using larger diameter balloons. At the end of the procedure,
on the left atrial side of the valve, is inflated. Finally, the hemodynamic measurements and angiography are repeated
waist of the dumbbell, which now is fixed in the valve orifice before and after the balloons are removed. 36
by the two expanded ends of the balloon above and below the Other methods are available for the delivery of double-
valve, is expanded exactly in the orifice.38 balloon catheters to the mitral valve, including a combina-
Although the Inoue balloon is available in several sizes tion of transseptal and retrograde, a single atrial puncture for
and each balloon can dilate to several different sizes, all of a double-balloon dilation, and a totally retrograde tech-
the balloons require a 14-French (F) opening in the vein at nique.39–41 None of these techniques appears to have any
the introductory site and a similar-sized puncture through advantage over either the Inoue or the double-transseptal,
the atrial septum. In addition to the large profile of the double-balloon technique, and thus they are not discussed
deflated Inoue balloon/balloon catheter, there are no bal- here.
loons for patients with a valve annulus of less than 20 mm The long-term benefit of mitral valvuloplasty for severe
in diameter, and with multiple levels of left ventricular congenital mitral stenosis is unknown. It is likely that all of
inflow obstruction as seen in many congenital mitral valves, these patients eventually will require a mitral valve replace-
the specific shape of the Inoue balloon would be ment. By delaying operative intervention, this procedure will
unacceptable. delay the need for chronic anticoagulation therapy and may
The double-transseptal, double-balloon technique is pre- allow growth of the annulus, permitting the insertion of a
ferred in smaller patients or in patients whose anatomy is larger prosthetic valve when the inevitable valve replacement
unsatisfactory for the Inoue balloon.36 The double-balloon is necessary. In adults with rheumatic mitral stenosis,
technique is applicable to patients of all sizes. The two bal- balloon valvuloplasty has been proven to be beneficial with
loons are selected and prepared prior to introduction as previ- longer follow-up.42 Although balloon mitral valvuloplasty
ously described using dilute contrast solution. The combined has had limited use in congenital mitral stenosis, this should
diameter of the two balloons should be approximately equal be the initial interventional procedure for most adolescents
to the diameter of the annulus.36 Relatively long balloons are and young adults with severe congenital mitral stenosis.
preferred (5 to 6 cm for larger patients). Two separate trans-
septal punctures are performed for this procedure, preferably
Tricuspid Stenosis
from opposite legs. If a 12 or 14 French MullinsTM transseptal
set is employed, no further dilation of the atrial septum Isolated tricuspid valve stenosis is very rare in either child-
should be necessary in order to pass the dilation balloon hood or in adults. The etiology can be congenital, rheumatic,
catheters into the left atrium. The patient is given heparin, stenosis of a bioprosthetic valve, or acquired with systemic
100 U/kg, as soon as the transseptal procedures are illnesses such as carcinoid. When tricuspid stenosis is present
completed. in children, it is often associated with a hypoplastic tricuspid
To avoid passing through small chordal spaces in the left valve annulus and right ventricle, so that this type is rarely
ventricle, balloon-tipped or “pigtail” end-hole catheters are amenable to surgical or balloon valvuloplasty. The early and
passed through the transseptal sheaths and utilized to cross limited experience with tricuspid valvuloplasty in children
the mitral valve into the left ventricle; 180-degree curves are and young adults for either congenital or acquired tricuspid
formed on the transition portion of two appropriate-sized stenosis has demonstrated that it is possible to achieve some
Super Stiff wires so that the formed curves will fit within dilation of the valve in these patients.
the apex of the left ventricle, while the tips of the wires curve Symptoms of severe tricuspid stenosis include tiring and
back on themselves within the left ventricle and toward the peripheral as well as central edema. These symptoms corre-
left ventricular outflow tract. Once the wires are positioned late with a gradient demonstrated by echocardiography or
securely in the left ventricle, the end-hole catheters are catheterization, although the right atrium is so extremely
removed through the long sheaths and over the wires. Each compliant that the gradient across the tricuspid valve usually
of the balloon catheters is then advanced over the wire is very small. The lesion is usually well demonstrated by
through the transseptal sheath to the left atrium. The bal- right atrial or right ventricular angiography when obtained
loons are subsequently manipulated into position across the in a caudal right anterior oblique view.
valve, centered side by side precisely across the mitral The procedure for tricuspid stenosis is similar to that
annulus, and inflated until the waists on the balloons disap- described for mitral stenosis, although it is slightly safer and
pear or until the maximal advertised pressures of the easier to perform. Due to the large size of the tricuspid
balloons are reached—whichever occurs first. The inflation/ annulus, a double-balloon technique is necessary. The
deflation cycle is performed as rapidly as possible while care- sum of the diameters of the two balloons should match the
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 317
diameter of the valve annulus, and longer, 5.5- or 8-cm To perform dilation of a vascular stenosis, the stenotic
balloons are used. The Super Stiff wires with a long floppy area is crossed with an end-hole catheter. An exchange length
tip can be curled in the apex of the right ventricular, or they stiff or Super Stiff wire is positioned across and as far distal
can be stabilized in the left pulmonary artery. If no waist to the site of stenosis as possible, the diagnostic catheter is
appears in the balloons with the inflation/deflation cycle, removed over the wire, and the appropriate dilation balloon
larger balloons are utilized. The Inoue balloon also has been is advanced over the wire to the area of stenosis. After posi-
used for dilation of tricuspid valve stenosis.43 tioning the balloon precisely in the stenosis, the balloon is
Case reports of successful tricuspid valvuloplasty are inflated to its maximum advertised pressure for several
available in adult patients with rheumatic tricuspid stenosis, seconds or until the circumferential deformity or waist in
often accompanying mitral stenosis.44 This valve has also the balloon disappears on the fluoroscopic screen. The
been successfully dilated during pregnancy to allow comple- balloon is repositioned across the area of stenosis, and the
tion to term.45 The procedure should be attempted for any dilation is repeated to achieve maximum effect. After com-
patient with tricuspid stenosis in whom surgery is being pletion of the dilation procedure, the pressure measurements
considered. and angiography are repeated to assess improvement in vessel
diameter and identify any disruption in the vessel wall.
Balloon angioplasty enlarges stenotic vessels acutely by
Obstruction of the Great Vessels stretching the intima/media and more permanently by
causing a tear in the vessel intima while stretching or tearing
surrounding scar tissue. This is reasonably safe in stenotic
General Considerations for Angioplasty
areas, which are due to previous surgical manipulations
and Stent Placement
where the vessel is supported and surrounded by dense scar
After the original description of balloon angioplasty for coro- tissue, which presumably will prevent more extensive tearing
nary arteries,7 the procedure was soon extended to all other or rupture. Care must be taken to prevent overdilation of
blood vessels by both adult and pediatric cardiologists.46,47 congenital vascular stenosis in native vessels, which have no
The techniques for relieving congenital or surgically acquired surrounding scar tissue. Dilation of these lesions has a
vascular lesions by balloon angioplasty now is routine and greater probability of extending the tear in the vessel wall
is employed with variable success for stenoses anywhere through the media, with the potential for vessel rupture or
within the great vessels.13,48–50 The technique is similar for aneurysm formation. Extreme care is necessary when advanc-
systemic arterial, pulmonary arterial, and systemic venous ing wires, catheters, or balloons across freshly dilated seg-
obstructions. The most common congenital lesions to be ments of vessels, as this may create or extend tears/aneurysms.
dilated are stenoses of branch pulmonary arteries, systemic Other concerns related to specific lesions are discussed with
veins, systemic venous “channels,” and coarctation of the each defect.
aorta. The vessel to be dilated is identified and measured Balloon angioplasty has variable success, depending par-
angiographically using a calibrated measuring system with ticularly on the criteria for success utilized in the report.
large distance reference marks, which are filmed in the same Balloon dilation alone usually expands the stenotic area
planes as the vessel. Both discrete stenoses and longer acutely and usually reduces the obstructive gradient at least
segment lesions can be dilated, and more than one site can a little, producing a satisfactory result, but at the same time
be dilated in the same patient during one catheterization. dilation alone leaves the vessel with some residual obstruc-
The diameter of the balloon selected for angioplasty alone tion even though the stenosis in the vessel was dilated
should be three to four times the diameter of the stenotic acutely to three or four times the size of the original narrow-
diameter, but no more than 1.5 times the diameter of the ing during the balloon expansion. It is not uncommon for
normal pulmonary artery or systemic vein on either side of the postdilation angiogram to be indistinguishable from the
the stenosis.13,47 Systemic arterial lesions are dilated with preintervention study because of the elastic recoil of the
balloons the exact diameter of the adjacent normal vessel.13,47 vessel wall.52 In adult congenital heart patients, balloon dila-
Overdilation of the adjacent normal vessel can result in tears tion alone of vascular stenosis is seldom indicated or
or rupture of the normal vessel. If there are multiple stenoses attempted without the concomitant implant of intravascular
in separate vessels, the most severe obstruction is dilated stents.
first. In general, it is better to perform angioplasty on the
more distal lesions before the more proximal ones in the
same vessel, so that freshly dilated areas are not reentered Intravascular Stents
or crossed repeatedly.
The success of balloon angioplasty of pulmonary branch The implant of intravascular stents into rabbit aortas and dog
stenoses varies from 20% to 70%, depending on the criteria coronary arteries by Palmaz et al.54 in the mid-1980s was
used for success.51,52 Success has been defined as a greater revolutionary for the treatment of vascular stenosis particu-
than 50% increase in diameter of the lumen, or as little as a larly in the face of the dismal long-term results of the dila-
50% drop in the pressure gradient across the stenosed area. tion alone of vascular structures. Palmaz et al. designed a
This degrees of success itself leaves much to be desired in stainless steel mesh stent that could be delivered into the
spite of an incidence of serious complications of greater than vascular system over an angioplasty balloon and expanded
5%.53 Although very long-term follow-up still is not avail- by that balloon to hold the vessel open permanently.54,55 Fol-
able, persistent stenosis or restenosis is reported in as many lowing these reports, Mullins et al.52 in 1988 performed an
as 90% of the vessels dilated successfully originally. animal study in which the feasibility of stent implantation
318 chapter 12

in the pulmonary arteries and systemic veins was docu- them flexible and they do not shrink in length when expanded
mented. As a result of that animal work, a collaborative sequentially. In addition, the open cells allow passage through
investigation of the uses of larger intravascular stents in the side cells of the stent with the capability of dilation of
stenotic pulmonary arteries and systemic veins in humans the side cells up to 12 mm.
was initiated.56 Others reported laboratory successes with Other types of stents are being used in adult vascular
encouraging results.57,58 The excellent results in these series, lesions including self-expanding wire mesh and nitinol
along with the persistent long-term results,59 led to the stents,62 which do not require a balloon angioplasty catheter
acceptance of stents as the standard, approved therapy for for implant. These stents have some theoretical advantages
patients with both native congenital or postoperative vascu- including smaller sheath size and even greater flexibility. No
lar stenoses. experimental and very little clinical information is currently
The PalmazTM balloon expandable stent (Johnson & available on their use in congenital lesions. In congenital
Johnson, Warren, NJ) was the first and initially the only stent heart children, there have been very severe long-term adverse
in the original investigation for treating the vascular steno- sequelae including total obliteration of the vessel by the self-
sis, which occurred in children with congenital heart disease. expanding stents. This may not be a problem in the full-
This stent is manufactured from a stainless steel tube with grown adult congenital heart patient.
staggered longitudinal slots cut along its length, which, In addition to the newer larger stents, there are several
when expanded with a balloon, form diamond-shaped spaces stents with a smaller maximum expanded diameter of 10 to
circumferentially around the expanded tube. The diamonds 11 mm, which are usable only in the more peripheral vessels.
of these tubes of expanded metal proved to be very resistant These stents are available very firmly premounted on deliv-
to collapse and, in turn, to the elastic recoil of the dilated ery balloons, which in turn makes them easier to deliver.
vessel. The intravascular stents have the drawback of each The most readily available of these are the large and medium
particular stent having a finite maximum diameter, which GenesisTM stents (Johnson & Johnson-Cordis Corp.) and the
if not large enough for the vessel at the time of implant, or Express StentsTM (Boston Scientific).
subsequently with growth, will in itself create an obstruc- When the implant of a stent is considered, the hemody-
tion that cannot be dilated further. The Palmaz stents were namic gradients are determined and very precise angio-
the precursor to all of the intravascular stents that currently graphic measurements are performed in the area of stenosis.
are available for use in congenital heart patients. The diameter and the length of the stenotic area along with
The Palmaz iliac stents, which were the most commonly the diameters and length of the adjacent normal vessel both
used, were 18 or 30 mm long and had a nonexpanded external proximal and distal to the site of stenosis in the area where
diameter of 3.4 mm. These stents can be expanded with an the stent is to be placed are measured precisely using a large-
angioplasty balloon to a maximum diameter of 18 mm. With dimension calibration-reference system. Using these mea-
full expansion, the stents shorten by 45% to 50%. Smaller surements, the angioplasty balloon for the stent delivery is
“renal” stents with a 2.4-mm nonexpanded diameter and chosen so that the expanded stent diameter will be the same
lengths of 10 and 20 mm but with a maximum expanded diameter as the contiguous normal vessel. The stent should
diameter of only 10 to 11 mm could be used in the smaller have the capability of dilating to the eventual maximum
peripheral vessels. The renal stents also shortened by 40% to diameter of the vessel after any growth and long enough to
45% at maximum expansion. cover the entire lesion. The balloon length should be the
The diameter of the stent at implant is determined by the same or slightly shorter than the unexpanded length of the
diameter of the angioplasty balloon utilized to deploy the stent. When the balloon is too long, the ends of the balloon
stent. The larger-diameter stents can be implanted initially inflate first, creating a dumbbell configuration. This often
over a smaller angioplasty balloon and then be expanded leads to an uneven expansion of the stent, displacement of
further with a larger balloon up to the maximum diameter the stent during inflation, or perforation of the balloon by
of the stent either during the same catheterization or at a the stent.
much later time.60,61 Two or more catheters are utilized simultaneously for a
During the two decades of the use of stents in congenital stent implant procedure. One catheter is required for the
heart lesions, several additional stents have become available delivery of each stent while an additional catheter is utilized
for use in the larger diameter congenital lesions; however, for precise angiography during the positioning of the balloon/
the techniques for delivery have remained essentially stent(s). The delivery of the large stents is accomplished
unchanged. The P-8 stents (Johnson & Johnson, Warren, NJ) through a Mullins transseptal or other long sheath with a
have been supplemented by the even larger P-10 Series diameter, which is at least two French sizes larger than
stents (Johnson & Johnson-Cordis Corp., Miami Lakes, FL), required for the angioplasty balloon in order to accommodate
which have a maximum expanded diameter of 26 mm for use the combined angioplasty balloon and mounted stent. This
in the larger vessels. The original P-8 stents have been requires a minimum of a 9F to 13F diameter sheath for the
replaced by the Genesis XDTM stents (Johnson & Johnson- implant of stents in the larger vessels.
Cordis Corp.). The Genesis XD stents have small flexible An end-hole diagnostic catheter is advanced as far as pos-
connections between circumferential rows of diamonds and sible beyond the site of stenosis, and a Super Stiff wire is
smoother closed cells at the ends, which gives the stents advanced through the catheter and anchored as far distally
some flexibility and makes them less prone to puncture of beyond the stenosis as possible. The anchoring of the wire
adjacent structures. The Mega XDTM and Maxi XDTM series prevents the dislodgment of the sheath as well as the stent
of larger stents (ev3, Plymouth, MN) have an “open-cell” wall during its subsequent delivery and also helps to maintain a
configuration as well as smooth ends. These features make firm fixation of the stent/balloon within the lesion during
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 319
balloon inflation. The diagnostic catheter is removed over significant right ventricular hypertension, right ventricular
the wire leaving the Super Stiff wire in place. The long failure, unbalanced pulmonary blood flow by perfusion scan,
sheath/dilator set is advanced over the wire until the tip of and excessive pulmonary regurgitation.52,56 In addition, any
the sheath is well distal to the stenosis. Occasionally, the visible discrete pulmonary artery obstruction in a patient
stenosis requires predilation with a smaller balloon in order with a cavopulmonary anastomosis or other modifications
to permit the large-diameter sheath to pass through a very of the Fontan procedure warrants intervention even without
tight lesion. a measured gradient.
The larger stents are mounted on the balloons by force- Balloon angioplasty alone for congenital vascular lesions
fully “crimping” the stent over the balloon by circumferen- is indicated only for those patients in whom delivery
tially and repeatedly compressing the stent between thumb and implant of a stent is not possible. The experience at
and forefinger throughout its length. After the long sheath is Texas Children’s Hospital and other institutions confirms
in place and the stent is mounted on the balloon, the dilator such a high rate of success and low risk of stent implant
is removed from the sheath over the wire and the stent on in patients with native or postsurgical pulmonary branch
the angioplasty balloon is introduced over the wire into the stenosis that angioplasty in these patients prior to stent
sheath. The stent/balloon is advanced over the wire through implant is no longer attempted.56,59 Stent implant should be
the sheath to the desired location. The sheath is withdrawn considered in any patient with important pulmonary branch
just off the balloon/stent and a repeat selective angiography stenoses who is large enough to accommodate the delivery
is performed to confirm proper stent position across the site of the potentially adult-sized stents. The procedure for stent
of stenosis. delivery is described above. Adolescent or adult patients are
The balloon is expanded slowly to its maximum recom- the most ideal for stent implant, as they can tolerate place-
mended pressure, which expands the stent in the stenotic ment of the large sheaths required, and their stents can be
area. Once the stent is fixed in the lesion, the balloon is fully expanded to 15 to 18 mm at the time of initial
deflated, adjusted forward or backward slightly, and the infla- implantation.56,59
tion of the balloon is repeated several times within the The occurrence of significant restenosis after stent
implanted stent in order to ensure full expansion of the stent. implant is extremely low, and residual or restenoses because
The angioplasty balloon catheter is withdrawn into and then of vessel growth can be re-dilated or re-stented.63 For some
out of the sheath, and angiography of the lesion is repeated. patients with multiple lesions, the initial therapy is a com-
If necessary, the stent can be dilated further with a larger or bination of balloon angioplasty and stent implantation. For
a higher-pressure angioplasty balloon. For long-segment ste- example, angioplasty alone may be performed at branch
noses that are longer than the available stents or in a curved points in vessels that are more distal, particularly if the ste-
vessel, overlapping stents are placed sequentially using the nosis is exactly at a distal bifurcation or trifurcation or if
same wire and sheath. stenting of one or even two vessels would lead to occlusion
of a significant branch artery. In the same patient, one or
even a series of stents could be implanted in stenoses of more
Pulmonary Artery Stenosis
proximal and larger vessels. When two important nearby
Branch pulmonary artery stenosis may be an isolated lesion branches are stenotic and when the placement of a single
but more commonly occurs in conjunction with other con- stent likely will block access to a significant neighboring
genital heart lesions such as part of defects as in tetralogy branch, two stents are implanted and bifurcating or “open-
of Fallot or pulmonary atresia. Branch stenoses are also a cell” stents are used.62 To implant bifurcating stents, two
significant part of the heart disease accompanying rubella wires and two long sheaths are placed, one across each vessel,
syndrome, Williams syndrome, and Alagille syndrome. and the two stents are implanted simultaneously.62 Similar
Additionally, branch stenoses occurs frequently following considerations must be made when placing a stent in the
any surgical procedure on or about the pulmonary arteries, orifice of the proximal right or left pulmonary artery or when
including shunt procedures, previous pulmonary artery a single stent would partially occlude or “jail” the contralat-
banding, the arterial switch procedure, and right ventricle to eral pulmonary artery and at the very least make it difficult
pulmonary artery conduit repairs for severe forms of right or impossible to ever reenter the vessel.
ventricular outflow hypoplasia/atresia. Whether congenital Stents are used sparingly in proximal conduits adjacent
or following operative intervention, pulmonary artery branch to the muscular insertion of the conduit because the repeti-
stenosis is a difficult problem for the cardiovascular surgeon. tive compression from the beating heart can lead to stent
The site of stenosis is frequently deep within the lung paren- fracture.64 If right ventricular dilation and failure are already
chyma, distal to the hilus or embedded in scar tissue.52 These present, care must be taken that the implant of a stent will
stenoses occasionally can be improved a small amount and not impinge on the pulmonary or homograph valve and cause
usually transiently by balloon angioplasty alone, but can be increased pulmonary regurgitation. On the other hand,
totally and permanently relieved by the implant of appropri- “crossing stents” placed in proximal branch stenoses at a
ate intravascular stents. The only patients unlikely to achieve distal obstruction in a conduit or homograph relieves the
a correction of their lesion by the implant of pulmonary distal obstruction and can delay further surgery. Whenever
artery stents are those with generalized hypoplasia or mul- large sheaths and stiff wires are placed across a tubular
tiple stenoses throughout the entire pulmonary vascular conduit of prosthetic material, an intimal peel can be lifted
bed, and even these patients often achieve very significant and become obstructive.56 Pressure measurements and angi-
sustained benefit. Indications for stent intervention include ographic assessment are repeated at the end of the procedure
obvious angiographic stenosis with or without a gradient, to document the final results.
320 chapter 12

Coarctation of the Aorta Balloon angioplasty was subsequently performed in chil-

dren and young adults with native coarctation with variable
Coarctation of the aorta is a relatively common form results, including a continued incidence of aneurysm forma-
of congenital heart disease that frequently is seen in the tion.49,72 The original VACA registry report included the mul-
adult population. There is a long surgical experience, and ticenter combined early experience with native coarctation
the late results of surgical repair of coarctation are not in 140 patients with significant complications in 17% includ-
always completely satisfactory, particularly when the patient ing two early and six late aneurysms. In those patients, the
initially was operated on early in infancy. A significant aorta adjacent to the coarctation frequently was dilated to a
number of these patients have persistent or recurrent diameter significantly larger than the aorta in order to
obstruction at the aortic isthmus due to isthmus hypoplasia, achieve a relief of the gradient. To avoid the creation of tears
or at the site of previous coarctation repair.65–67 When the and the development of aneurysms later on, more conserva-
obstruction at the site of previous coarctation repair is a tive dilations are performed, however, with resultant higher
persistence of the original membrane or it is the suture line residual gradients. To achieve an even better relief of the
itself, both are successfully treated either by balloon angio- gradient without any overdilation of the adjacent vessel,
plasty or with stent implant. Dilation of recurrent coarcta- most centers are implanting stents in larger patients during
tion of the aorta was one of the first lesions approached with the initial dilation of any type of coarctation. This is
balloon angioplasty.68 This lesion was thought to be ideal discussed subsequently. Further long-term follow-up is
for this procedure, with the speculation that the extensive necessary to know if this procedure can match the low
surrounding scar tissue would provide extravascular support complication rate of initial operative intervention.
and some safety against bleeding and extension of wall The technique for balloon angioplasty is the same for
tears.56 In 1990 the VACA registry originally reported both native and recurrent coarctation. A complete cardiac
on the multicenter experience with dilation in 200 patients catheterization is performed. This includes measurements of
with residual or recurrent coarctation of the aorta.50 In these gradients and precise, calibrated angiography of the aortic
patients, the peak systolic pressure difference across the arch, the coarctation, and the aorta adjacent to the coarcta-
aortic obstruction was decreased from 41.9 ± 19 to 13.3 ± tion. When large collateral vessels are present, little empha-
12.1 mm Hg and the diameter or the re-coarctation site was sis is placed on gradient across the coarctation and more on
increased from 5.2 ± 2.9 to 8.9 ± 3.4 mm. A residual resting the angiographic appearance of the coarctation itself. To
gradient of <20 mm Hg originally was considered a good or obtain the aortic pressures and precise measurements, a
even excellent result, and this was accomplished in 78.4% catheter is positioned in the transverse or proximal descend-
of patients dilated. Five patients (2.5%) died of complications ing aorta. This preferentially is introduced from a prograde
related to the procedure, which included aortic rupture (n = approach where the left heart is entered via a transseptal
1), sudden death at 6 and 14 hours after the procedure with technique and a catheter is advanced from the left atrium,
probable exaggerated vagal reactions (n = 2), cerebral vascular left ventricle, and into the ascending aorta. This catheter
accident due to carotid occlusion (n = 1), and persistent con- remains just proximal to the coarctation before, during, and
gestive heart failure unimproved by angioplasty (n = 1). The after the dilation and avoids crossing the coarctation site
angioplasty success rate for recurrent coarctation of the even once during or after angioplasty. A calibrated catheter
aorta and relatively low mortality compare well with surgi- or grid is filmed at the time of angiography to obtain very
cal results for reoperation of recurrent coarctation of the accurate vessel measurements.
aorta.50 The discrete, shelf-like coarctation represents the ideal
Balloon angioplasty for native coarctation of the aorta is lesion for successful dilation. Patients with a long tubular
more controversial because of a higher potential for intimal coarctation probably are not candidates for balloon dilation
tears, aneurysm formation, and the potential difficulties in alone.73 The narrowest diameter of the adjacent aorta is the
repairing the coarctation after one of these complications limiting diameter, which determines the diameter of the
plus a successful dilation. Histologic specimens of excised balloon used for dilation and usually is the segment of
human coarctation segments from surgical repairs of native the aorta just proximal to the coarctation. The angioplasty
coarctation demonstrate cystic medial necrosis of varying balloon is selected to be no more than 1 to 2 mm greater than
degrees in virtually all of the specimens, with severe changes the diameter of this area in the larger patient. The patient is
in 67%.69 There is extension of the necrosis into the aorta anticoagulated using 100 mg/kg intravenous heparin for the
proximal or distal to the coarctation in 80%. This has been procedure. A Super Stiff wire with a long floppy tip is posi-
proposed as a part of the mechanism of late aneurysm forma- tioned retrograde across the coarctation, across the aortic
tion after balloon dilation. In 1981, Lock et al.70 performed arch, and preferentially as far into the right subclavian
balloon angioplasty in seven explanted coarctation segments artery as possible. The angioplasty balloon is introduced
using a balloon approximately twice the size of the stenotic through a sheath, advanced retrograde, and centered over the
diameter, and was able to increase the vessel diameter by tightest area of the coarctation. The balloon is inflated until
85%. However, four of the specimens had tears extending it reaches its maximum recommended pressure or until
into the media, and three had complete tears completely the waist (circumferential narrowing in the balloon)
through the media. In vivo studies on an animal model with disappears—whichever occurs first. Following slight repo-
surgically created coarctation found less extensive tears of sitioning of the balloon, the inflations are repeated up to
the media following angioplasty and some healing with the maximum pressure of the balloon until the waist
time.71 disappears.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 3 21
The balloon is withdrawn gently out of the angioplasty Systemic Veins
site so as not to increase trauma to the freshly dilated area.
An end-hole diagnostic catheter is reintroduced over the Obstruction of systemic veins in patients with congenital
Super Stiff wire, and the wire is withdrawn through the heart disease usually is iatrogenic. It can be due to previous
catheter so that the wire itself does not abrade the angio- surgical intervention on or adjacent to the vein, indwelling
plasty site. The gradient is measured with pressures obtained intravenous lines, or cardiac catheterization, but also can
simultaneously through the prograde catheter in the ascend- occur secondary to inflammatory illnesses or tumors. Sys-
ing aorta and the retrograde catheter in the descending aorta temic venous obstruction usually is diagnosed angiographi-
or by a direct pressure withdrawal of the retrograde catheter cally and often incidentally when a catheter will not pass
across the coarctation site. Angiography is repeated to visual- through an expected venous channel. Because of the combi-
ize the result and to ensure that no tear or dissection has nation of the normally low venous pressures, the massive
been created. The patient is maintained well hydrated over- compliance of the systemic venous system, and the extensive
night with supplemental intravenous fluids to minimize any collateral channels, severe degrees of systemic venous
effects of hypovolemia or volume shifts. Persistent back or obstruction usually result in very little or even no gradient
chest discomfort of any type is not normal and should be across the lesion, with no increased velocities detected by
investigated immediately. Both immediate and long-term echocardiography. Treatment is based on the angiographic
patient follow-up are mandatory, and should include mag- appearance of stenosis.
netic resonance imaging or repeat catheterization with angi- The most common venous obstructions encountered
ography within 1 to 2 years after the angioplasty. in the congenital heart patients are the peripheral venous
Morrow et al.74 initially demonstrated that stents that obstruction secondary to prior indwelling lines or prior
were implanted in the normal aorta of juvenile animals then cardiac catheterization. This frequently goes undetected
could be reexpanded after vessel growth. Histopathologic until the patient is to undergo a repeat catheterization, par-
specimens from the aortas did not suggest significant intimal ticularly where a catheter intervention requires the same
or medial injury from either the initial implant or subse- particular venous route! Another more recent and very com-
quent reexpansion of the stents. There was some limited use plicated arrival to the arena of venous stenoses are the ste-
of the P-8 stents in adolescent and adult humans all with noses in the channels/anastomoses of the various types of
good short-term success.75,76 However, because of the con- single-ventricle Fontan repairs. These can be very subtle but
cerns with the placement of fixed-diameter stents with a at the same time cause severe symptoms including protein-
maximum expanded diameter of 18 mm, which is smaller losing enteropathy. Obstruction of one limb of the baffle,
than the adult aorta, there was limited enthusiasm for stent which occurs following either the Mustard or Senning
implant as a definitive therapy for coarctation of the aorta. “venous switch” operation for transposition of the great
It was obvious that the implant of the smaller diameter vessels, is another venous obstruction found in adult con-
stents, which could not be dilated to an adult diameter, genital patients. With severe obstruction of the upper limb
would create an eventual lesion worse than the original. of the baffle, symptoms include upper trunk, head, and neck
Larger diameter P-10TM stents (Johnson & Johnson- swelling and venous distention, headache, and even com-
Cordis Corp.), which are identical to, but larger and sturdier municating hydrocephalus. Some of these patients, however,
than, the P-8 iliac stents and the Maxi LDTM (ev3, have no signs or symptoms, but because of the high incidence
Plymouth, MN), now are available commercially in the of sick sinus syndrome in these patients, many need this
United States. These stents expand to 26 and 25 mm diam- venous channel opened for the implant of a transvenous
eters, respectively. The relief of obstruction with these pacemaker. The inferior limb vena caval of the baffle also
stents has been excellent; however, several cases of aneu- can be obstructed, although this is much less common.
rysms still have been reported following the implant of the Obstruction to inferior vena cava (IVC) flow can cause
P-10 stents. These aneurysms may be related to the marked abdominal ascites or peripheral edema but also may go
increase in diameter of the vessel from a very tight stenosis unrecognized. In most centers, the venous switch repairs of
or due to the circumferential ring of sharp tips that occurs transposition have been replaced by the arterial switch pro-
when the P-10 stents are expanded to their full diameter on cedure, and most patients who survived one of the venous
a single large balloon. When large-diameter stents are switch operations are now adults. Any of these symptoms or
implanted in a very tight lesion, the lesion should be dilated/ signs in a patient who has had a venous switch repair should
stented only partially with the stent at the initial catheter- be investigated with a detailed cardiac catheterization with
ization, or when the lesion is to be dilated to an initial large venous angiography. The surgical approach to these problems
diameter, the stent should be expanded sequentially on a requires complete revision of the baffle, with frequently less
BIBTM balloon (NuMED Inc., Hopkinton, NY). The sequen- than satisfactory results due to the dense adhesions and
tial staged expansion on the BIB balloon prevents the sharp scarring.
flaring of the ends of the stent. The large stents mounted on Although the systemic veins and venous channels usually
a BIB balloon require sheaths between 10F and 14F for intro- tolerate significant overdilation with a balloon, the recoil/
duction. A larger experience with more information about rebound is equally as aggressive and the results of balloon
the cause of the aneurysms and longer follow-up still is nec- dilation alone generally are unsatisfactory. Reports of balloon
essary to document whether the primary implant of a stent angioplasty for superior vena cava (SVC) obstruction follow-
represents the preferable alternative treatment for coarcta- ing the venous switch operation indicated some improve-
tion of the aorta. ment in vessel diameter following this procedure, but the
322 chapter 12

improvement frequently was only temporary.77–79 The use of vein repair has been successfully treated with the implant
intravascular stents in systemic venous and systemic venous of stents and should be considered as the treatment of choice
baffle obstructions now is the accepted standard primary when this problem occurs in adult patients following either
treatment where a permanent result is desired.59,80 Indica- of the venous switch operations.85
tions for stent implant have been expanded to include patients
of all ages with SVC syndrome of any etiology with very
successful results.81 Occlusion of Intracardiac Defects
For implant of stents in systemic veins, the diameter and
length of the stenosed segment as well as of the normal vein
Atrial Septal Defect: Background and
adjacent to the obstruction are measured angiographically.
General Considerations
The obstruction is crossed with an end-hole catheter. In the
cases of complete occlusion, the area is crossed initially by An atrial septal defect (ASD) usually does not cause problems
advancing the end of a GlideTM wire, a radiofrequency wire, in childhood, but when persisting into adulthood may have
or a transseptal needle out of a long dilator to penetrate the serious implications. These include the development of con-
obstruction.79 To direct the wire or transseptal needle accu- gestive heart failure, arrhythmias, paradoxical embolism, or,
rately, biplane fluoroscopy/angiography must be utilized both very rarely, pulmonary vascular disease. The diagnosis of
above and below the obstruction. When puncturing, it also ASD can be missed in childhood because of the low-intensity
is helpful to position a catheter at the opposite end of the murmur and lack of symptoms, only to have the patient
obstruction in the nearest accessible part of the vessel so as present in adulthood with a murmur or arrhythmia, or inci-
to provide a target for the wire or needle from the puncturing dentally as the result of an abnormal study obtained for some
end. Once a wire has been passed across the obstructed area, other reason. Some adult patients with known atrial septal
predilation with a small angioplasty balloon is performed defects have declined surgical repair because of fear and the
before the large-diameter, long sheath for stent implant can lack of symptoms during early life.
be introduced across the obstruction.80 The patient is given Probably due to its frequency, its known eventual late
heparin once the obstruction is crossed. The diameter of the complications, and, at the same time, relative ease of cathe-
angioplasty balloon selected for the stent implant should ter approach, the atrial septal defect was the first intracardiac
approximate the diameter of the adjacent vessel proximal or septal defect to be considered for a transcatheter occlusion
distal to the obstruction, whichever is the smaller diame- device. King et al.86 in 1976 reported on an effective double-
ter.80 The stent is mounted on the angioplasty balloon and umbrella device that was used successfully in a few patients.
delivered as described previously. Following the implant of Because of its very large delivery system and its very rigid
stents in systemic veins, the patient remains on aspirin for frame, its use was limited to patients of adult size and it
at least 6 months. Although extreme long-term hemody- never gained wide acceptance. However, the few patients
namic follow-up for stents placed in systemic veins is not yet who were treated with this device still are doing well and
available, lack of recurrent symptoms as well as continued provide a perspective about the long-term follow-up of the
patency of these vessels by echocardiography and early ASD occluded with a catheter delivered device.
recatheterization for as long as 8 years suggests good long- The next major development in catheter closure of atrial
term results as long as good flow was established through septal defects was reported in 1977 by Rashkind and Cuaso,87
the stent.80 who developed a hooked, six-legged, self-centering, single-
umbrella device [United States Catheter, Inc. (USCI) BARD,
Glens Falls, NY), which could be delivered through a slightly
Pulmonary Veins smaller catheter system. For a very short time this hooked
device was implanted in humans under an investigational
Congenital pulmonary vein stenosis is very rare, and it com- protocol, but its use was discontinued because the tiny hooks
monly occurs with other congenital heart lesions with or often would become attached prematurely to structures
without associated surgical intervention.82,83 Pulmonary within the left atrium before the septum could be engaged,
vein stenosis is becoming increasingly more prevalent with which, in turn, led to erroneous placement. Although aban-
ablation procedures around the orifice of the pulmonary doned even for clinical trials, the Rashkind ASD device
veins. This lesion is the most discouraging of all of the stimulated an almost frantic development of additional
stenotic lesions for both the cardiovascular surgeon and for devices for ASD closure.
the interventional cardiologist. Balloon dilation has been Lock et al.88 used the experience from the already devel-
attempted in many cases with very transient acute success, oped patent ductus arteriosus (PDA) devices to create the
only to find recurrence of the stenosis within weeks or next generation of ASD occlusion devices. First they used a
months.56,83 Stent implant has been similarly unsuccessful larger version of the Rashkind PDA double-umbrella (USCI
in the limited number of pediatric patients in whom it has BARD), which, however, did not clamp onto the septum suf-
been tried.84 This is due not only to the technical difficulties ficiently. They next added hinges or joints to each arm of
of the procedure but predominantly to the progression of both umbrellas and used woven Dacron as the umbrella
underlying sclerotic disease of the affected veins. In the fabric instead of the earlier polyurethane foam. This ASD
failure of all attempted treatments of these lesions the reste- device had the appearance of a clamshell when viewed on
nosis occurs further within the parenchyma of the lung. edge and was marketed as the Clamshell DeviceTM (USCI
Obstruction of the common pulmonary venous channel after BARD).89 The long sheath delivery system and technique
venous switch transposition or total anomalous pulmonary that had been developed for the Rashkind PDA devices were
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 323
used for the Clamshell device and still is employed with Mullins sheath for delivery. A HausdorffTM modification
some of the current ASD occlusion devices.90 The Clamshell (Cook Inc.) of the Mullins sheath with a special compound
ITM ASD occlusion device underwent a Food and Drug Admin- lateral and a rightward curve at the tip now is used for deliv-
istration (FDA) Investigational Device Exemption (IDE) pro- ery to true atrial septal defects.92
tocol clinical trial in five centers and was implanted in 545 The CardioSEAL and STARFlex devices are supplied in
patients, with 97% successful implants. At follow-up, only the open position and must be loaded into the delivery
64% of implanted patients had complete closure of the ASD, sheath. The tips of the distal arms are attached to a pair of
but of the remainder, 34% had only a very small residual sutures that, in turn, pass through a loading device. Like the
shunt.91 Clamshell device, the size of the CardioSEAL/STARFlex
Fractures of the legs of the device were identified inciden- device that is chosen is at least two times the diameter
tally on follow-up x-rays, although the fractures did not result of the ASD but cannot exceed the diameter of the septum
in clinical consequences on long-term follow-up. However, itself. The device is attached to the delivery wire/catheter
four of the asymptomatic patients with a protrusion of a at the center of the proximal umbrella. The CardioSEAL
fractured leg against an adjacent wall developed a mass in device is folded for delivery by drawing it into the loading
the area. This mass led to surgery of the four patients, and device using the sutures attached to the tips of the distal
although the mass turned out to be a benign, fibrous, “callous- arms. Originally the CardioSEAL was loaded for delivery
like” lesion, this finding plus the unknowns of the fractures by withdrawing the folded device from the loading device
led to the withdrawal of the device. into a metal delivery pod at the end of the delivery catheter.
Even though it was removed from clinical trials, the The more recent CardioSEAL and the STARFlex devices
success of the Clamshell device demonstrated unequivocally are “front-loaded” directly from the loader into the preposi-
that most secundum atrial septal defects could be closed tioned long delivery sheath with no delivery pod on the
nonsurgically, both safely and effectively. This stimulated a catheter.
further proliferation of new ideas and designs for devices for In the United States only the CardioSEAL device is avail-
ASD closure, some of which have come and gone but several able and then only for humanitarian use in the PFO follow-
of which still are employed in Europe and one of which has ing a stroke, in surgical fenestrations, in muscular ventricular
FDA approval for routine use. septal defects, and in a prospective IDE clinical trial for PFO
closure. In Europe, both the CardioSEAL and the STARFlex
devices are commercially available for use in both the ASD
CardioSEAL and STARFlex Devices
and the PFO.93,94
The CardioSEALTM device (NMT Medical Inc., Boston, MA) For the delivery of either the CardioSEAL or the
is a further modification of the withdrawn Clamshell device. STARFlex device, a long Mullins sheath is positioned in the
The CardioSEAL is produced by a different manufacturer and left atrium with the tip between the left pulmonary veins
has a new design with an additional hinge on each arm, and and the left atrial appendage. The delivery catheter with the
the arms are manufactured with new MP35n metal alloy, attached device is then introduced from the loader into
which is more flexible and corrosion resistant. The the long sheath and advanced until the folded device is in
STARFlexTM device (NMT Medical Inc.) is a further modifi- the area of the right atrium. The sheath and the delivery
cation of the CardioSEAL device and has four very fine, catheter are fixed in position while the proximal delivery rod
nitinol spring wires extending from the tip of each leg on one is advanced. This advances the wire with the attached device
umbrella of the device to the tip of the nearest apposing leg within the sheath. This and subsequent maneuvers are
on the opposite umbrella of the device. These fine spring observed very closely on both fluoroscopy and transesopha-
wires do not affect folding or delivery but do tend to center geal echocardiography (TEE) or intracardiac echocardiogra-
the device once it is implanted. phy (ICE). The sheath now acts as a curved delivery catheter.
Although the devices themselves were totally new, they As the device is slowly advanced beyond the end of the
initially were delivered using the same technique established sheath, the distal umbrella springs open in the left atrium.
with the Clamshell device. In the in vitro studies, in animal When all of the distal legs are confirmed both by fluoroscopy
trials, and now in extensive clinical use in the patent foramen and by TEE or ICE to be open and not entangled in the left
ovale (PFO), the new material and designs have eliminated atrium, the entire system is withdrawn as a single unit
the clinical problem of strut fractures. The CardioSEAL toward the right atrium. Because of the usual and significant
and STARFlex devices themselves consist of two opposing malalignment of the long axis of the standard delivery sheath
umbrellas made of woven Dacron. Similar to the Clamshell to the perpendicular axis of the septum, the surface of the
device, the two umbrellas are attached to each other at their distal umbrella usually does not align even close to parallel
centers. Each umbrella has four metal arms of MP35n alloy, to the septal surface. The more cephalad arms touch the
but each arm now has two joints along its length in addition septum well before the caudal arms are even near the septum
to the central hinge point. The two umbrellas are attached by echocardiography. During an ASD closure, no attempt is
in their open positions with the concavity of the two umbrel- made to have the more caudal arms approximate the septum,
las facing each other. The two umbrellas fold away from each as any further withdrawal proximally on the device will
other for delivery. Both the CardioSEAL and the STARFlex cause one or more of the more cephalad arms to pull through
devices are available in 17-, 23-, 28-, 33-, and 40-mm diame- the septum.
ters. The 17- and 23-mm devices can be delivered through a Once the initial legs of the left atrial umbrella of the
10 F long MullinsTM sheath (Cook Inc., Bloomington, IN), device touches against the septum, the delivery wire and
whereas the 28-, 33-, and 40-mm devices require an 11 F long delivery catheter are fixed in place while the sheath alone is
324 chapter 12

withdrawn. Because of the length of the collapsed device, tially consisted of a single strand of spring guidewire. After
this allows the proximal legs to spring open on the right the occluder umbrella was positioned on the opposite side of
atrial side of the defect. Once both umbrellas are opened and the septal defect, the center of the counter-occluder was but-
the sheath has been withdrawn, the device usually aligns toned against the center of the occluder umbrella by a very
itself better on the septum and in a relatively secure position. unique, latex, buttoning mechanism—thus its name. The
However, while the device is still attached to the delivery umbrella and the counter-occluder were delivered separately
wire, all of the legs usually do not come in contact with the and sequentially through a single long sheath and over a long
septum. When assured by TEE/ICE and fluoroscopy that all loop of a control suture. Once buttoned together, the delivery
of the legs are on the appropriate side of the septum, the catheter was released from the occluder by withdrawing one
release mechanism is activated. This allows the delivery end of the long control suture from the device mechanism.
wire/catheter to spring away from the device as the device The delivery sheath was then withdrawn.
moves away from the cable and aligns with the septum as it The early generations of this device were very flexible
is released. The proper position of the device on the septum and the polyurethane foam was very compressible, so that
and the degree of closure are confirmed by TEE/ICE. A right the device could be folded into a small diameter and deliv-
atrial angiocardiogram is obtained with the x-ray tubes in a ered through a much smaller sheath than any of the other
four-chamber view. This images the right atrial surface of ASD occlusion devices. The newer generation devices still
the device as well as the left atrial side of the device during are square umbrellas of polyurethane foam, but with a
the recirculation phase of the contrast through the left heart. thicker counter-occluder, which is not as compressible. They
Manipulation of a catheter into the pulmonary artery for now reportedly require 10 F to 12 F sheaths for delivery.99
angiography after the implant is unnecessary and potentially Defect sizing, the ratio of device to defect size, and the deliv-
dangerous because of the possibility of dislodging the newly ery through a long sheath are similar to the other devices.
implanted device. The button device is available in very small sizes suitable for
the small defects, and also in sizes up to 60 mm in diameter
for very large ASDs. Because of the attachment with a suture
Atrial Septal Defect Occluding System and Angel
during delivery and its flexibility after seating on the septum,
Wings Devices
it is easily retrievable until it is released purposefully from
In addition to the Clamshell and CardioSEAL devices, two the control suture and generally retrievable by a catheter
additional atrial septal occlusion devices were developed and technique even after release.
introduced into clinical use but now have disappeared from The earlier generations of Button devices had a high inci-
all use. These were the Atrial Septal Defect Occluding dence of residual and recurrent leaks. There were also reports
System (ASDOS)TM (Osypka Co., Germany) and the Angel of embolization from poor fixation or unbuttoning. Because
WingsTM ASD occlusion device (Microvena Corp., White Bear of these problems, the device underwent several significant
Lake, MN). The ASDOS device underwent investigational changes and it now is in its fifth generation since the initial
clinical trials in Europe and for a short time was commer- FDA pilot study.99 Although the Button device has been used
cially available in Europe,95 whereas the Angel Wings device in many centers throughout the world, there have not been
underwent a successful FDA clinical pilot trial in the U.S. large enough numbers with the same generation of device in
and also was commercially available in Europe for a short any individual center for data analysis. The current-genera-
time.96 However, both devices were found to erode through tion Button device has not undergone an FDA IDE clinical
adjacent structures and were withdrawn from any use.97 trial but is available for commercial use in many countries
There have been preliminary rumors that the Angel Wings outside of the U.S.
device had been modified markedly into an easier to use and
safer Guardian Angel septal occluder, but no medical reports
Helix Device
have been forthcoming.93
A more recent addition to the devices for transcatheter
occlusion of atrial septal defects is the Helix device (W.L.
Sideris Button Occlusion Device
Gore & Associates, Flagstaff, AZ). This device is very differ-
One of the earliest ASD occlusion devices, which did undergo ent from all previous devices. It is manufactured from a
at least one FDA clinical pilot study in the U.S. and currently curtain of polytetrafluoroethylene (PTFE) fabric stretched
is in its fifth generation of modification, is the Sideris But- over a long nitinol wire. The nitinol wire curls into a double
tonTM device (Pediatric Cardiology Custom Medical Devices, circle or helix in its relaxed state. It is loaded and delivered
Athens, Greece). This device has been available outside of as a straightened wire, which, as it is extruded, curls into
the U.S. It has had extensive use in numerous centers around separate disks on each side of the septum. The Helix device
the world and has persisted longer than many of the other is available in multiple diameters (sizes) of the disks in 5-
ASD devices.98 The many modifications that it has under- mm increments up to 35 mm in diameter. Like the other
gone were to correct serious deficiencies in earlier designs devices that rely on the double disks for fixation, it is recom-
that prohibited its general use in the U.S. mended that a Helix device be twice the diameter of the
The Button occluder began as a single square umbrella defect for an ASD occlusion. The Helix device is round, quite
that was cut from a sheet of polyurethane foam and attached flexible, and after being fully implanted is totally retrievable
to a frame consisting of two crossed pieces of spring guide- until a final safety thread is purposefully withdrawn. The
wire. It was held against the septum by a “counter-occluder,” Helix device is available commercially in Europe and it has
which buttoned to the occluder. The counter-occluder ini- completed a successful IDE clinical trial in the U.S. and is
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 325
awaiting an FDA decision for use for ASD occlusions in the the long sheath by pushing it out of the loader and then
U.S. advanced to the ASD through the long sheath.

Amplatzer Atrial Septal Defect Occlusion Device General Procedure for Atrial Septal Defect Closure
The AmplatzerTM atrial septal occluder (AGA Medical Corp., The final suitability of an ASD for transcatheter closure is
Golden Valley, MN) is the one device that has successfully determined by TEE or ICE and confirmed during cardiac
completed European and FDA IDE clinical trials and catheterization with a very accurate balloon sizing of the
now is available commercially throughout the world and defect. The standard transthoracic echocardiogram (TTE) is
since 2002 even in the United States. The Amplatzer ASD useful in screening patients to confirm the diagnosis and
occluder is by far the most effective, easiest to deploy, and location of the defect. It is also useful to rule out a sinus
safest occlusion device to be developed.100 In the 3 years venosus, a primum or a very large ASD, which would be
since its release in the U.S., the Amplatzer ASD occluder totally unsuitable for transcatheter closure, and to exclude
has become the standard accepted treatment for the majority other intracardiac defects. The TTE cannot determine the
of secundum atrial septal defects. The one potential short- precise size or the absolute suitability of the ASD for trans-
coming of this device is a very small but finite incidence catheter closure either accurately or unequivocally. The TEE
of its erosion through the aorta or atrial wall. The incidence and ICE are more accurate for sizing and localizing the ASD,
is probably less than 0.1%, but of the 29 reported cases there but in borderline cases even they do not correlate accurately
have been three permanent neurologic sequelae and five enough with the definitive size found with the stretched
deaths as a result of the erosions.101 The erosions have sizing performed at catheterization to make an absolute
occurred from a few hours to 3 years after implant, and so determination of appropriateness for transcatheter closure
far there are no distinguishing features of the patients without the balloon sizing.
involved. The catheterization procedure is similar for most of the
The concept of this device, again, is different from all of ASD devices currently in use and in trials in the U.S. If a
the previously described devices. The Amplatzer ASD device patient is considered a possible candidate for ASD occlusion,
has two disks that rest on the opposite sides of the atrial strict operating room sterile precautions are observed in
defect; however, it is fixed in place in the defect by a broad the catheterization laboratory. A 9 F sheath is placed in the
central hub that fits exactly and tightly within the defect to right femoral vein and a small cannula or dilator placed
accomplish the occlusion. The central hub, which completely in the femoral artery for monitoring. When TEE is used, a
fills the defect, is the main mechanism of fixation and occlu- 7 F sheath is introduced into the left femoral vein, but when
sion. The entire device is composed of a weave of fine nitinol ICE is to be used, an 11 F sheath is placed in the left femoral
metal wires, which retain their shape as a consequence of vein to accommodate the 10 F ICE catheter. A detailed
the memory of the nitinol metal. In its relaxed state, the wire right heart catheterization is performed to determine the
mesh forms the pair of circular end disks, which are an magnitude of the shunt in order to confirm the significance
extension of the broad circular central hub of the same mate- of the ASD. An angiographic catheter often is introduced
rial. The device is held in place by the central hub expanding and advanced to the mouth of the right upper pulmonary
into the circumferential rim of the atrial defect and tightly vein for angiography. A shallow four-chamber view, with
filling the atrial defect while the two disks stabilize the either x-ray tube at approximately 30 to 45 degrees left
device against each side of the septum. The left atrial disk anterior oblique (LAO) and 25 to 45 degrees cranial angula-
is 14 mm larger and the right atrial disk is 12 mm larger in tion should produce a good on-edge view of the atrial septum,
diameter than the central hub. There are thin polyester disks which can provide additional information about the size
within each of the two nitinol disks and one within the and position of the ASD and help to rule out additional
central hub to promote occlusion. The diameter of the hub defects. If the septum is not cut precisely on edge by the
represents the size of the device. The size of the device (hub) first angiogram, it is repeated using a different angulation
should correspond very closely to the balloon-occluded diam- of the x-ray tube or with the sizing balloon inflated across
eter of the atrial defect. These devices are available in sizes the defect until the septal defect is clearly demonstrated.
between 4 and 38 mm for occlusion of atrial defects up to An appropriate calibration grid or other large diameter
38 mm in diameter.102 reference device for measuring is filmed in the same
In spite of its considerably different design, the Am- plane for accurate measurement of the defect. Heparin,
platzer device is delivered to the left atrium through a long 100 mg/kg, is administered to prevent thrombus formation
sheath in a similar fashion to the original ASD devices. The on the delivery catheter/wires or within the large delivery
delivery of the device is guided with a combination of fluo- sheath.
roscopy and by TEE or ICE. The smaller devices pass through The TEE or ICE echo probe is introduced at this time.
a 7 F sheath, whereas the larger devices require up to a 12 F Images of the defect, the rims around the defect, and the
sheath. The long sheath is positioned across the atrial septum adjacent structures are obtained to assist with defect mea-
with the tip of the sheath free within the body of the left surement and later visualization during implant. An end-
atrium. For delivery, the device is attached to a delivery cable hole catheter is introduced through the right femoral vein
by a very fine screw mechanism. It is then stretched into a sheath and advanced through the right heart, through the
long, thin braid of the nitinol wires by withdrawing it into ASD, and out into a left upper pulmonary vein. With extreme
a loader, which is the same French size as the delivery sheath. care to avoid introduction of air, an exchange length 0.035-
The elongated device is introduced into the proximal end of inch stiff guidewire is advanced through this catheter into
326 chapter 12

the peripheral pulmonary vein and the catheter is withdrawn until visualized in the left atrium within the sheath on fluo-
over the wire. roscopy. As the device reaches the tip of the sheath, it is
Accurate sizing of the atrial defect is performed using extruded slowly out of the end of the sheath by simultane-
a special, very compliant, cylindrical, AmplatzerTM sizing ously advancing the delivery cable into the proximal end of
balloon (AGA Medical Corp., Golden Valley, MN). A 24- or the sheath while withdrawing the tip of the sheath back
34-mm (depending on the estimated size of the defect by toward the right atrium. When the left atrial disk is fully
echo) sizing balloon catheter is advanced over the exchange extruded and expanded, the sheath together with the remain-
wire and is positioned straddling the atrial defect. The der of the device is withdrawn until the left atrial disk aligns
balloon is inflated very slowly with a 1 : 5 dilution of contrast against and parallel to the septum. The position of the distal
until a slight waist appears on the circumference of the disk is confirmed by TEE/ICE and fluoroscopy. The sheath
balloon or until all flow across the defect as visualized by alone is withdrawn, allowing the central hub to expand in
color Doppler is stopped. Once flow through the defect is the defect followed by the right atrial disk opening on the
stopped, the narrowest diameter of the balloon is measured right side of the septum. The length of the folded device
on TEE or ICE and by angiography. The entire circumference allows considerable leeway in the distance for this full extru-
of the balloon is scrutinized by TEE or ICE for adequate rims, sion and requires that the delivery cable be readvanced
additional atrial defects, adequate additional length of the slightly to allow the right atrial device to assume its relaxed
septum for the device, and the proximity of the balloon/ configuration against the septum. Once fully extruded the
defect to adjacent critical structures. If a waist does not entire circumference of the device is scrutinized by TEE or
appear or flow is not stopped with the 24-mm sizing balloon, ICE for the presence of a “sandwich” of tissue circumferen-
the balloon is replaced with the 34-mm sizing balloon and tially between the two disks. To check the security of its
the measurements repeated. The 34-mm balloon often fixation, the device is test wiggled by pushing the delivery
requires a 10 F introductory sheath and can be inflated to a cable forward and backward enough to move the device to
40+-mm diameter with 90+ cc of dilute contrast! and fro slightly. If the Amplatzer device is malpositioned or
An additional right upper pulmonary vein angiogram can pulls through the defect at any stage of the delivery, it can
be performed through the second catheter with the sizing be withdrawn back into the delivery sheath and repositioned,
balloon inflated in the septum. This demonstrates the ade- reimplanted, or removed and a different-size device inserted.
quacy of the sizing, and of more importance verifies any Once confident of the fixation, the device is unscrewed from
additional small ASD or suggests a peculiar shape of the ASD the delivery wire for release by multiple counterclockwise
that could compromise closure. turns.
The sizing balloon catheter is withdrawn over the wire
and replaced with a long sheath/dilator of an appropriate size
for the size of the particular Amplatzer occluder device. The Occlusion of the Patent Foramen Ovale
Amplatzer ASD occluders come with matched sizes of deliv-
ery sheaths (AGA Medical Corp.), which are appropriate in All of the ASD devices have at one time or another been used
size for the various sizes of devices. There are several other to close a PFO. The major indication for such closures is the
long sheaths with specific curves at the distal end of the presence of a PFO with significant right to left shunting
sheath that facilitate the delivery of the Amplatzer ASD through it or a documented central nervous system (CNS)
occluders. The HausdorffTM modification of the 10 F and 11 F embolic event in the presence of a PFO. The potential for this
Mullins sheaths (Cook Inc., Bloomington, IN) and the 8 F SL2 use appears staggering; however, the true risk for embolism
Fast CathsTM (St. Jude Medical, Woodland Hills, CA) both through a PFO has not been documented sufficiently to abso-
have a posterior and a rightward curve at the tips, which lutely justify this use. In the United States, the CardioSEAL
greatly facilitate the alignment of the devices parallel to and PFO device has FDA approval for closure of the PFO only
against the septum during deployment. These sheaths now under a Humanitarian Device Exemption (HDE) in patients
are used preferentially for the delivery of the Amplatzer ASD who have a documented CNS embolic event (stroke) and a
occluders. recurrent CNS event on warfarin therapy or failure of war-
The long delivery sheath/dilator is advanced over the farin therapy. The STARFlex device and the Amplatzer PFO
wire and well into the left atrium. The dilator and then the device are in separate randomized controlled IDE trials for
wire are carefully and slowly withdrawn and the sheath patients with PFO and proven embolic strokes.
(including the hub of the back-bleed valve/flush port) is In addition to the required documented stroke, there are
cleared very meticulously of any air and/or clots preferen- several other strong indications for closure of a PFO that are
tially by passive drainage. To verify the exact position of the not approved for official use in the U.S.103 Deep-sea divers
tip of the sheath in the left atrium and to confirm that it is have considerably more frequent and more serious problems
not entrapped in the atrial appendage or a pulmonary vein, with systemic nitrogen bubble emboli that occur with
there should be a free back flow of fluid or oxygenated blood decompression in the presence of a PFO.104 Patients with a
through the side port. Once the free flow of fluid/blood is PFO and compromised right ventricular function or obstruc-
obtained, a slow hand injection of contrast is performed tive pulmonary vascular disease often develop significant
through the sheath. The position of the sheath passing and debilitating cyanosis.105,106 Orthodeoxia-platypnea is
through the septum should also be clearly identified by fluo- associated with an intermittent but significant and debilitat-
roscopy and TEE or ICE. ing right to left shunting through the PFO.107 Many patients
Once the sheath is in position, the collapsed device is who did have strokes also were noted to have had a history
introduced from the loader into the long sheath and advanced of severe debilitating migraine headaches. It was found, coin-
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 327
cidentally at first, that most of these headaches disappeared septum before opening/releasing the right-sided component.
with the closure of the PFO. There appears to be a strong This makes the delivery procedure significantly easier and
correlation between severe migraine with aura and the pres- safer.
ence of a PFO even without a prior stroke.108 There now is The ASD/PFO occluding devices discussed in this section
one randomized blinded trial of PFO closure for documented are available clinically or are in clinical trials in the U.S.
migraine with aura under way in the United Kingdom. The Most of the devices are available routinely in the rest of the
controlled trials of PFO closure for these various indications world as of 2005. In the same way that the King-Mills device
may be necessary to determine the true indication for this and the original Rashkind ASD device stimulated the devel-
procedure. opment of the current ASD devices, this group of devices has
The PFO is an extremely variable lesion and not just a already stimulated the development of probably more effec-
small, discrete, potential hole in the septum. Although the tive and even safer transcatheter ASD/PFO occlusion devices/
flap of the septum primum may cover the opening com- techniques, which may be in investigational trials by the
pletely, it often also creates a very long tunnel. Most of the time of this publication.
openings of the PFO in patients who have had strokes are
potentially 10 to 20 mm in diameter. The PFO that is associ-
ated with a very redundant aneurysmal septum and is very Occlusion of Ventricular Septal Defects and
mobile appears to have an even higher risk of stroke. The Other Abnormal Intracardiac Communications
majority of the PFO lesions often require the very largest
umbrellas or disks to cover the entire opening and to include Transcatheter closure of muscular ventricular septal defects
the aneurysm. In the presence of a very long and stiff tunnel, (VSDs) was first performed on a compassionate basis using
a transseptal puncture through the septum primum occa- the Rashkind PDA-occluding device.109 The defects attempted
sionally is necessary to implant the devices without signifi- were leaks in patches following prior surgery, an acquired
cant distortion of the device. These represent much more of VSD due to myocardial infarction, and some unoperated
a challenge to implant. native congenital apical and midmuscular ventricular
The equipment and technique for PFO occlusion are defects. The Rashkind device frequently was too small,
similar to those used for ASD closure. The CardioSEALTM leaving significant residual shunting or causing emboliza-
device is used under a humanitarian use approval for patients tion of the device. Once it became available, the Clamshell
with documented recurrent CNS events or intolerance of ASD device next was used under a separate high-risk proto-
warfarin anticoagulation therapy as well as in a randomized col for closure of certain ventricular septal defects.110 As a
controlled investigational trial. There also is a special consequence of a modification of this clinical trial, the Car-
AmplatzerTM PFO occluder (AGA Medical Corp.) for the PFO, dioSEAL device has received an HDE approval for closure
which is in a randomized controlled clinical trial. The Am- of muscular ventricular septal defects. In addition, AGA
platzer PFO occluder is made of the same materials and has Medical Corp. now has the Amplatzer muscular VSD
right and left disks similar to the Amplatzer ASD device; occluder, which is available routinely throughout most of the
however, the right disk in the PFO device is slightly larger world except the U.S.,111 but it has completed clinical IDE
than the left disk and the central hub is very narrow and trials in the U.S. and is awaiting approval from the FDA for
flexible, which makes it more like the CardioSEAL devices. this use. The defects chosen for occlusion are in the middle
The Helix device has been used for PFO closure, and there or apical muscular interventricular septum, away from the
is a reverse-button modification of the Sideris Button device semilunar and atrioventricular valves. The CardioSEAL and
for the PFO. In Europe, there are several other double- the Amplatzer muscular VSD devices are delivered with a
umbrella types of devices for PFO closure. similar technique.
Although not all institutions still perform balloon sizing/ These particular defects are the most difficult for the
shaping of the PFO, this definitely is recommended in essen- surgeons to repair and frequently have unsatisfactory surgi-
tially all PFO occlusions. The sizing balloons from either cal results with significant complications or residual leaks.
NuMED Inc. (Hopkinton, NY) or AGA Medical Corp. (Golden The device closure of muscular septal defects is complicated
Valley, MN) are positioned in the defect/tunnel and inflated and technically challenging for the interventional cardiolo-
at zero pressure until the balloon begins to deform and con- gist; however, the device closure appears safer and more
forms to the shape of the defect. This shape and in particular effective than the comparable surgery.
the long distorted shapes will determine the approach to the The muscular interventricular defects are very difficult
defect. When the long sigmoid distortion is over 15 mm in to cross from the right atrium/right ventricle to the left ven-
length, particularly in an older patient, a transseptal approach tricle with a catheter due to their apical location, the heavy
is recommended and the largest available device will be right ventricular trabeculations in the area, and the high-
used. velocity flow against that direction. The acute and com-
All of the PFO devices except the Helix device are deliv- pound angle created when the septum is approached from the
ered across the septum through long sheaths similar to their IVC, through the tricuspid valve, and to the interventricular
ASD predecessors. When a transseptal puncture through septum at the ventricular apex makes the catheter approach
the septum primum is necessary, all are delivered through from the femoral vein particularly difficult for the subse-
a long sheath. The procedure is controlled with fluoroscopy quent delivery of a fairly rigid device. The jugular venous
and either TEE or ICE. The major difference is in the actual approach with a through-and-through or rail wire system
delivery of the device where the opened left-sided disk/ extending through the left heart is used to overcome these
component is pulled more firmly/securely against the problems.
328 chapter 12

The procedure for VSD closure involves crossing the tive approach is to enter the left ventricle with a retrograde
defect with an end-hole catheter from the left ventricle to the catheter to create this rail from the femoral artery to the left
right ventricle. The left ventricle preferentially is entered ventricle, to the right ventricle, to the right atrium, and out
prograde through an atrial transseptal approach or, alterna- through the jugular vein.
tively, from a retrograde arterial approach. The prograde The jugular venous end of the rail wire is then utilized
transseptal approach provides a better angle toward the left to advance the delivery sheath, catheter, and occlusion device
side of the VSD, better control of the through-and-through through the right ventricle, through the VSD, and into the
wire, and far less operative time and trauma to the systemic left ventricle. Traction to the opposite end of the rail wire
artery. A second smaller retrograde angiographic catheter, frequently is needed during the passage of the sheath and
however, routinely is placed retrograde into the left ventricle dilator combination through the septum, and during the
to allow repeated left ventricular angiocardiograms during advancement of the sheath over the dilator into the left
positioning and delivery of the initial end-hole catheter and ventricle.
eventually the device. The x-ray tubes are positioned to cut The dilator is slowly and carefully removed from the
the ventricular septal defect exactly on edge, usually in a sheath over the wire, and the sheath meticulously is cleared
slight LAO/cranial angulation. A left ventricular angiocar- of all air or clot. After removal of the dilator, the position of
diogram is recorded to serve as a roadmap for the procedure. the tip of the sheath within the left ventricular cavity is
The x-ray tubes are maintained at the same angles for the verified by a left ventricular angiocardiogram and by TEE or
remainder of the procedure. Often the left ventricular side of TTE. If the sheath position is not exactly in position and
the muscular VSD will be broad and single whereas the VSD needs to be advanced to a more secure position, the dilator
will taper into relatively narrow or multiple communica- is reintroduced over the wire and to the tip of the sheath
tions as it approaches the right ventricular side of the before readvancing the sheath. Advancing the sheath alone
septum. will kink the curved portion of the sheath within the right
Entrance into the left ventricular side (end) of the VSD ventricle. Since any movement of the patient or the slightest
also can be quite difficult and often requires a combination traction on the sheath can displace the sheath back to the
of tip deflector wires, torque-controlled catheters, and float- right ventricular side of the septum, the through-and-through
ing balloon end-hole catheters. The use of a balloon end-hole wire is not removed until the device is loaded and ready for
catheter for this catheter passage helps to ensure passage introduction. In addition, it is useful to keep the end-hole
through the largest opening from the left ventricle to the catheter, which was introduced from the left ventricular end,
right ventricle through the VSD. Torque-controlled guide- over the wire and through the defect within the tip of the
wires facilitate wire and catheter guidance to the vicinity of jugular sheath. As the dilator is withdrawn the end-hole
and through the defect once the left ventricular entrance of catheter is advanced into the distal end of the sheath follow-
the defect has been engaged. After the catheter has been ing the tip of the dilator as it is withdrawn. When the device
advanced through the ventricular septum into the right ven- is ready for delivery and the position of the sheath within
tricle, the wire and catheter are maneuvered into the pulmo- the left ventricular cavity still is satisfactory, the through-
nary artery. and-through rail wire is withdrawn from the entire system
A separate venous sheath is introduced into the right but the catheter retrograde into the sheath is left in place.
jugular vein and an end-hole floating SwanTM balloon cathe- The catheter retrograde within the sheath provides an access
ter (Edwards Lifesciences, Irvine, CA) is “floated” through route to replace the rail wire if it is necessary to reposition
the tricuspid valve and into the main pulmonary artery. A the long sheath. As the wire is removed, the sheath is held
floating balloon catheter is used to ensure passage through firmly in place and if necessary adjusted forward very gently
the center of the tricuspid valve orifice en route to the in order to keep the sheath tip well within the left ventricle.
pulmonary artery. A GooseneckTM retrieval snare (ev3, Changes in the position of the tip of the sheath are verified
Plymouth, MN) or an EnSnareTM [MDTECH (Medical Device by small left ventricular angiocardiograms.
Technologies), Gainesville, FL] is advanced through the The device is attached to the delivery catheter/cable and
balloon catheter from the jugular vein or the balloon catheter is withdrawn into its respective loader. The loader contain-
first is replaced in the pulmonary artery with the specific ing the device, which is attached to the delivery catheter/
snare catheter. The free end of the wire, which has passed cable within the loader, is introduced into the prepositioned
through the VSD and into the pulmonary artery, is grasped sheath. The device is advanced carefully out of the loader and
with the snare catheter. into the sheath and advanced to the center of the right atrium.
Once the wire and catheter have been snared, the distal If the retrograde catheter had been introduced into the sheath,
end of the wire is withdrawn back through the tricuspid the catheter is withdrawn proportionately to the introduc-
valve and externalized through the sheath in the right jugular tion of the device into the sheath, keeping the tip of the
vein. The catheter through which the wire was introduced device and the tip of the catheter approximated. The sheath
through the VSD remains the left ventricle to protect the left must be allowed to advance or move slightly in order to keep
heart chambers, valves, and vessels from the cutting effects its tip well within the left ventricle. Advancing the device/
of the bare wire passing through these structures. A through- delivery catheter tends to straighten the sheath and, in turn,
and-through rail wire is created with the wire passing from pulls it back into the VSD or right ventricle. No attempt
the femoral vein, through the atrial septum to the left atrium, should be made to deliver the device unless the tip of the
through the mitral valve to the left ventricle, through the sheath remains completely through the defect, secure there,
VSD to the right ventricle, through the tricuspid valve to the and yet with the very tip free within the left ventricle. If
right atrium, and out through the jugular vein. An alterna- delivery is attempted with the tip of the sheath still within
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 329
the defect, the device will be deployed entirely on the right the use of the CardioSEAL device for these defects under
side of the defect. an HDE use and the use of the Amplatzer PFO occluder
When the device has been advanced to the tip of the for occlusion of the fenestrations in an investigational
sheath well within the left ventricle or against the free wall protocol.
of the left ventricle, the device is advanced very slightly Similarly, the various occlusion devices have been used
while the sheath is withdrawn the same distance. This is in extenuating circumstances for closure of other nonpur-
repeated until the distal legs/disk of the device spring open poseful residual postoperative leaks including peripatch
completely within the left ventricular cavity. Once the left leaks and even a few perivalvular leaks. The uses in these
side has opened completely, the entire system is slowly with- lesions are so rare and so heterogeneous, that each case
drawn into the left ventricular ampulla of the defect. The usually is a new and unique procedure, which is performed
distal left ventricular arms/disk usually conform to the at the discretion of a physician skilled and experienced in
ampulla with a conical folding into the left ventricular side the use of the particular device and after an informed discus-
of the defect. An angiogram is repeated in the left ventricle sion and disclosure with the patient. As these unusual and
to verify proper positioning. In spite of what appears to be rare uses occur, they will become accepted and more and
perfect folding into the defect, the device may still be caught more of these patients will be spared unnecessary redo surgi-
on a rim of the defect and the center or hub of the device still cal procedures.
can be within the left ventricle, which in turn could lead to
embolization of the device. With predominantly angiographic
and occasionally TEE guidance, the device is withdrawn well Occlusion of Extracardiac Intravascular
into the defect in order to be sure that the center of the device Communications
is at the narrowest portion of the defect and all of the proxi-
mal side of the device will open on the right side of the
Patent Ductus Arteriosus
VSD.
The sheath is withdrawn completely off the device to The patent ductus arteriosus (PDA) is a very common lesion
allow the proximal, right-sided arms or disk to spring open. in childhood, and occasionally a PDA will slip by the pedi-
The right-sided arms/disk usually are entangled in the right atric cardiologist and appear in adulthood. Commonly, the
ventricular trabeculae and may not open completely or sym- PDA is small or moderate in size, and the main adverse
metrically; however, the device does fix very securely on the implications for the adult patient are endocarditis and the
right ventricular side. After angiographic confirmation of the eventual consequences of a lifelong left ventricular volume
correct positioning in the defect, the device is released and overload. Although the risk of operative intervention for PDA
the delivery catheter and sheath are removed. Because of the in pediatric patients generally is considered low, it is surgery,
complexity of this procedure, transcatheter closure of the and it involves the pain and morbidity of surgery and even
muscular VSD will certainly be limited to a few centers that an occasional death, particularly in the elderly patient who
are very active in interventional catheterization.112 has more sclerotic vessels, heart failure, pulmonary hyper-
tension, or additional coronary artery disease. Surgery is
complicated further by calcification of the PDA in older
Device Occlusion of Miscellaneous adults.
Intracardiac Communications Interventional cardiologists have been occluding the
PDA nonsurgically for almost four decades. Porstmann
In addition to the previously discussed ASD and VSD occlu- et al.114 first introduced a catheter technique for closure of
sions, many other unusual or often unique intravascular the ductus arteriosus in 1967, following which Rashkind et
communications have been closed with ASD and VSD occlu- al.90 introduced a more clinically useful double umbrella
sion devices, specific vascular plugs, and various coils. The device (USCI BARD, Glens Falls, NY), which began clinical
most notable of this type of use is the closure of the atrial trials in 1981. Despite a successful FDA IDE clinical trial,
communication or fenestrations that are left purposefully in eventual approval by the FDA professional panel, and uni-
the baffles of the caval-pulmonary procedures. A small 3- to versal professional approval for use throughout the rest of
5-mm opening purposefully is created in the atrial baffle of the world, the failure of the bureaucracy of the FDA to
a caval-pulmonary artery repair of a single ventricle. This finally approve the device for use in the U.S. forced the USCI
defect allows a small right to left shunt of blood away from to abandon the device (and all pediatric devices) in 1995.
the pulmonary circuit, which increases the systemic cardiac The Rashkind PDA device is no longer available anywhere
output with this shunted blood. This augmentation is par- in the world.
ticularly important during the immediate postoperative The Rashkind PDA device demonstrated very effectively
recovery period.113 The defect/shunt does leave the patient that a correction of a congenital cardiac defect in the cathe-
cyanotic and with a potential for right to left embolization terization laboratory was possible safely and effectively. With
of particulate material so that once the usefulness of the the Rashkind PDA device the long sheath delivery system
increased systemic output is over, it is desirable to close the for intravascular devices, which is still used today for many
defect. This is accomplished similar to the closure of an devices, was introduced and perfected. Fortuitously, the
ASD. Because of the small size and usually rigid baffle mate- sudden withdrawal of this widely and successfully used non-
rial, the occlusion devices seat securely in these defects surgical cure of a lesion stimulated the imagination of inter-
although during the implant, the device often initially rests ventional cardiologists to develop other devices for occlusion
at a very unusual angle. At the present time, the FDA allows of the ductus as well as other lesions.
330 chapter 12

Coil Occlusion of the coil are extruded out of the tip of the catheter, which
is positioned in the pulmonary artery just at the pulmonary
The first of these devices and techniques for PDA occlusion artery end of the narrowest portion of the ductus. The pusher
that resulted from the void left after the withdrawal of the wire is fixed rigidly in this position against the tabletop while
Rashkind device was the GianturcoTM coil (Cook Inc., Bloom- the catheter alone is withdrawn into the descending aortic
ington, IN) described by Cambier et al.115 for PDA occlusion. off the pusher wire (and coil). This extrudes the remaining
Gianturco coils already were FDA approved for occlusion of two to four loops of coil from the delivery catheter into the
vascular structures.116 The Gianturco coils are lengths of descending aorta/aortic ampulla of the ductus. The closure
spring guidewire that have no safety core but are curled into rate with this technique is up to 97% in some series.123–125
repetitive loops of a fixed diameter and have filaments of Occasionally, there is some residual flow through the ductus,
nylon embedded in the coiled wire along their length. The which necessitates the placement of one or more additional
coils are available in wires of different diameters and with coils after a successful placement of the first coil. The proce-
various diameters of the loops of the coil. Initially and until dure for the additional coils is the same, with particular care
the later introduction of the 0.052-inch coil wire,117 only the taken not to dislodge the first coil during the subsequent
0.038-inch wires were sturdy enough for the occlusion of the catheter manipulations through the ductus. A disadvantage
usual PDA. The coil is straightened into a length of spring of this technique is the lack of control with no ability to
guidewire in a straight metal loader, which is used to intro- withdraw the coil once the extrusion of the coil has just
duce it into the delivery catheter. The straightened coil is started. This leads to occasional coil displacement or embo-
advanced through the catheter by pushing it out of the loader lization. Usually, the coil can be retrieved from the circula-
with a long standard spring guidewire of the same wire tion if the coil is badly placed or embolization occurs.126
diameter as the coil wire. When the coil is extruded out of Modifications of the coil delivery technique include
the end of the catheter, it coils like a small pigtail, forming methods of attaching the delivery wire to the coil to enhance
three to six circular loops depending on the initial length of delivery with the potential for retraction of the coil anytime
the coil wire and its manufactured diameter. Once any part during the delivery if the position is not optimum. Outside
of the coil has been advanced past the tip of the catheter, of the U.S., these JacksonTM coils are standard, approved
there is no way of withdrawing the standard Gianturco coil systems with specifically designed, effective screw attach-
back into the delivery catheter. ment and release mechanisms that have simplified the tech-
The use of Gianturco coil for PDA occlusion along with nique and made it more safe and effective.127 Unfortunately,
multiple modifications of the coil and the techniques for its these exact systems are not available for clinical use in the
delivery118–120 proliferated over a very short period of time, U.S. A different attach/release mechanism for the coils has
and this method now has been accepted as one of the stan- been introduced in the U.S.; however, the coil wires for this
dard therapies for the small to moderate-sized PDA in the system are smaller in diameter and there are fewer fibers on
U.S. and abroad.121 Coil occlusion of the ductus is most appli- each coil. As a consequence, these coils are less robust and
cable when the PDA has an aortic ampulla with a discrete less occlusive and have not gained much popularity.
narrowing toward the pulmonary end. It is less likely to be To increase the occlusion and stability of the coils, they
successful with either the very short or large and tubular have been used with the simultaneous delivery of two (or
PDA. Fortunately, most PDAs are small to moderate with more) coils at the same time through separate catheters.128
some discrete stenosis. The Gianturco coils and techniques The separate catheters can be from the same vessel approach,
offer the advantages of the ready availability of a variety of or one catheter from the artery and one catheter from the
sizes and the low cost of the coils. vein are used. In addition, a thicker, much more robust coil
The standard Gianturco coil can be delivered retrograde of 0.052-inch wire has become available in the U.S. (Cook
from the arterial or prograde from the pulmonary arterial Inc., Bloomington, IN). This coil by itself fixes in the ductus
approach. Very low profile, end-hole-only catheters are used much more securely,117 and along with the bioptome control
for the retrograde approach and allow the delivery of 0.038- technique, which is described subsequently, has become the
inch caliber coils through a 4 F or 5 F arterial sheath. The preferred coil for the PDA occlusion.
retrograde coils usually are delivered using a free, noncon- In the U.S., a snare technique118 and a bioptome attach-
trolled release. When delivered prograde, the same free release release mechanism119 were developed for controlling the
technique is possible, but more often the coil is grasped with coil(s). With the snare technique, the 4 F or 5 F coil delivery
a 3 F bioptome for control and the combination is delivered catheter is passed retrograde through the ductus arteriosus
through a 5 F long sheath.122 into the main pulmonary artery similar to the free release
All techniques for coil occlusion of a PDA require very technique. A snare catheter is advanced from the femoral
careful angiography of the ductus arteriosus with accurate vein into the pulmonary artery and used to snare the very
measurement of the narrowest and the widest diameter as tip of the retrograde catheter in the main pulmonary artery.
well as the length of the ductus. A coil is selected with coil The coil is then advanced through the retrograde catheter
loops that are at least twice the diameter of the narrowest until 1 mm of the tip of the coil is extruded out of the tip of
area of the PDA.115 For the standard retrograde delivery, the the delivery catheter into the main pulmonary artery. The
PDA is crossed from retrograde into the pulmonary artery snare is allowed to slip to the tip of the retrograde catheter
with an appropriate end-hole (only) catheter for the coil deliv- in order to snare the exposed tip of the coil just as the nar-
ery. The coil is advanced through the catheter using a stan- rowed snare loop slips off the tip of the catheter. The coil
dard straight spring guidewire of the same wire diameter as is fixed in its exact position by holding the tip of the coil
the coils as the pusher wire. One-half to three-quarter loops with the snare catheter while the retrograde delivery cathe-
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 3 31
ter is withdrawn off the coil. A half loop of coil is held in at its largest (aortic) end. Except in the very smallest device,
the main pulmonary artery by the snare, and the rest of the the hub tapers 2 mm in diameter from the largest to the
coil is delivered onto the arterial side of the ductus ampulla. smallest end. In the smallest device (the 5-4), the taper of the
If the positioning is not ideal even after the coil is fully hub is only 1 mm. The hub is 5 mm long in the 5 device, 7 mm
extruded, the coil can be pulled further into the ductus or long in the 6 and 8 devices, and 8 mm long in the 8 and 10
removed completely using the venous snare. Angiography is devices. Like the other Amplatzer devices, the PDA device
performed while the coil is still held by the snare catheter. is stretched into a long thin braid of the nitinol material for
If delivery of a second coil is necessary, the retrograde cath- loading and introduction into the delivery sheath.
eter can be repositioned across the ductus and into the main The device also is delivered through a 6 F to 8 F long
pulmonary artery while still having control of the first coil sheath, which previously has been positioned prograde from
already in the ductus with the snare in order to avoid dislodg- the pulmonary artery across the PDA. The retention disk is
ment of the first coil. Once the position of the coils are sat- extruded in the descending aorta, the entire system is with-
isfactory, the snare is opened carefully to release the coil. drawn until the disk is seated in the aortic ampulla of the
Although a little more complex and time-consuming, and ductus and then the sheath is withdrawn off the rest of the
although the procedure adds to the cost of the snare catheter, device to expand and fix it in the ductus.
this technique does allow better control of the procedure at The Amplatzer PDA device used is at least 2 mm larger
all stages. than the smallest diameter of the ductus. The smallest Am-
The use of a 3 F bioptome to grasp the tip of the coil is platzer PDA device is the 5-4 device, which makes the Am-
an even preferable system to control the delivery of the stan- platzer PDA devices suitable for the PDA which is larger than
dard 0.052-inch coil to the ductus.119 The attachment site on 2.5 mm with a characteristic conical configuration. The
the coil is prepared by forcefully grasping the tiny welded tip Amplatzer PDA occluder now represents the standard
of the coil with a forceps and pulling this weld 1 mm away accepted therapy for the PDA that is larger than 2.5 to 3 mm
from the remainder of the coil wire. The weld remains as a in diameter.
small ball 1 mm away from the rest of the coil but attached
by a single strand of the basic fine wire, which makes up the
Gianturco-Grifka Vascular Occlusion Device
coil. The separated tip is grasped by the 3 F bioptome and the
coil is withdrawn out of the original loading tube into a short The Gianturco-Grifka Vascular Occlusion DeviceTM
length of 4 F sheath, which is comparable in length to the (GGVOD) (Cook Inc.) was developed as another modification
loading tube and through which the bioptome has been of the spring coil wire for vascular occlusions. The GGVOD
passed. The short sheath, in which the coil is grasped by the consists of a long predetermined length of flexible spring
bioptome, is introduced into the proximal end of a 4 F or 5 F guidewire that in use is forcefully wadded into a small nylon
long sheath, which previously has been positioned across the bag to form a dense, constrained mass of the coil wire. The
ductus. The long sheath can be positioned retrograde from bags are of different diameters to correspond to the different
the aorta or, preferably, prograde from the pulmonary artery. lengths of wire. All sizes of the GGVOD are delivered through
The appropriate loop (or number of loops) of coil is extruded an 8 F long sheath system.
at one end of the ductus (depending on which direction the The GGVOD is applicable for the occlusion of larger,
long sheath was introduced from), the entire system is with- tubular and higher velocity vascular communications.131 It
drawn into the ductus, and then the bioptome is fixed in has FDA approval for occlusion of vascular structures and
place while the sheath is withdrawn off the remaining loop(s) has had limited use for PDA and other abnormal tubular
of coil at the opposite end of the ductus. Once the coil is in vascular structures. When used for occlusion of the PDA,
the proper position, the bioptome is opened releasing the coil. angiography of the lesion is essential to carefully measure
The bioptome allows the coil to be withdrawn or reposi- both the length and the diameter of the PDA. To use the
tioned any time until the purposeful release from the GGVOD, the diameter of the vascular structure must be
bioptome. 0.5 mm narrower and the length of the vessel 1.5 times the
length of the sack that will be used. The 8 F long sheath is
introduced prograde from the pulmonary artery, through a
AmplatzerTM PDA Occluder
tubular ductus, and the tip of the sheath is positioned well
While the coils and coil delivery techniques were being mod- into the descending aorta. The empty sack is advanced
ified and perfected for occlusion of the PDA, the Amplatzer through the sheath to the aortic ampulla, where it is partially
PDA occluder was developed, introduced into a clinical FDA filled with coil. The sheath and sack are withdrawn into the
IDE trial, and eventually fully approved specifically for PDA tubular portion of the ductus, toward but still within the
occlusion.129,130 This device uses the same nitinol wire mesh pulmonary end of the ductus. The sack is filled completely
and a similar expansion/fixation concept as the Amplatzer with the specific length of spring wire. Once the surgeon is
ASD and VSD occluders. The Amplatzer PDA occluder con- satisfied with the position of the sack as well as the stability
sists of a short, slightly tapered, tubular hub with a thin and occlusion of the PDA, wire and sack are released from
2 mm larger rim or disk at its largest (aortic) end. The disk the delivery catheter by the fairly complex attach/release
creates a retention mechanism to help hold the device in mechanism. The sack is totally removable until this pur-
place. The Amplatzer PDA device is available in sizes of 5-4, poseful release from the delivery catheter. The GGVOD has
6-4, 8-6, 10-8, and 12-10 in the U.S. and two larger 14-12 and proven very effective for the long tubular PDA132 as well as
16-14 sizes outside of the U.S. The larger number of the some other larger tubular abnormal vascular structures
labeled size indicates the diameter in millimeters of the hub including aortopulmonary collaterals.
332 chapter 12

Other Devices for PDA Occlusion with an internal diameter just slightly larger than the diam-
eter of the wire of the coil is positioned within the vessel as
In addition to the Amplatzer PDA occluder, the various mod-
near as possible to the site to be occluded. The Gianturco
ifications of the coil, and the GGVOD, there are other devices
coil occludes the vessel by the creation of a mass of the wire
outside the U.S. specifically developed for PDA occlusion.
and attached strands of nylon thread, which stimulate throm-
One of these is the Nit-OccludTM device [PFM (Produkte fur
bus formation. Ideal vessels for Gianturco coil occlusion
die Medizin AG), Cologne, Germany], which is a more recent
have a discrete narrowing where the coil can be fixed in
modification of an earlier Duct-OccludTM device.133 The Nit-
place. Without a discrete stenosis, the coils have a potential
Occlud device has had favorable results outside of the U.S.
to migrate farther through the vessel, so that care must be
and is in IDE trials in the U.S. at this time. The Nit-Occlud
taken in the measurement of the vessel. Without a distal
device is a stiff, preformed, tight double coil of nitinol wire
narrowing, coils can be used only in vessels that, when dis-
that comes in various sizes to fit various sized and shaped
tended, are less than 7 to 8 mm in diameter. It is often neces-
ductus. It also comes with an elaborate attach/release/
sary to place several coils in a larger vessel to achieve
delivery mechanism that gives total control over the delivery
complete occlusion.135 For vessels that are greater than 7 to
of the device until it is very purposefully released.
8 mm in diameter, coils may be used in conjunction with
In addition to the various vessel occlusion devices previ-
other intravascular occlusion devices, especially where there
ously described, a number of ASD/VSD occlusion devices
is no discrete stenosis.
have been adapted for the closure of the large, atypical PDA
AGA Medical Corp., in its line of Amplatzer occluders,
that add to the armamentarium available for the occlusion
now has an AmplatzerTM Vascular Plug for occlusion of mis-
of the PDA.
cellaneous abnormal vascular lesions.136 These, as the name
implies, are short cylindrical plugs. They are manufactured
from a weave of an even finer nitinol wire and have no reten-
Occlusion of Other Abnormal Extracardiac tion disks at the ends and no polyester material within them
Vascular Communications to enhance thrombosis. The Amplatzer plugs are available
up to 16 mm in diameter. Because of the differences in their
Embolization of abnormal or persistent arterial or arterio- manufacture, the plugs can be delivered through smaller-
venous structures has been performed for over 30 years.116 diameter long sheaths, but must be oversized in order to be
Many materials and devices have been used for these periph- wedged tightly into vessels, and they do not occlude imme-
eral occlusions, including the patient’s own clotted blood, diately. The Amplatzer plugs are FDA approved and are avail-
Gelfoam, colloidal plugs, glues, detachable balloons, and able in the U.S.
coil occlusion devices. These embolization techniques Most abnormal aorta-to-pulmonary communications can
originally were developed and perfected by vascular radiolo- now be occluded with Gianturco coil137 or the Amplatzer
gists to treat abnormal bleeding related to the gastrointes- plug.138 The intracardiac or more specific ASD, VSD, or PDA
tinal tract and CNS, particularly in end artery vessels. occlusion devices occasionally are used in the very large
In patients with congenital heart disease, there frequently vascular communications. Other lesions in which the various
are abnormal aorta-to-pulmonary collateral vessels or per- vascular occlusion devices may be useful include arteriove-
sistent, surgically created, systemic-to-pulmonary artery nous fistulas, systemic coronary-cameral communications,
shunts associated with complex cyanotic lesions. It is ap- and pulmonary arteriovenous fistulas. In these lesions, it is
propriate to occlude these vessels when there is competitive critical to advance the delivery catheter as distally as possi-
flow between the collateral and the normal pulmonary ble beyond branches of the vessel that supply more proximal
blood flow, particularly when the major defect has been or significant or vital tissues before considering device delivery.
is to be corrected.134 These communications historically It is helpful to be able to deliver the occlusion device at a
required surgical division during the corrective procedure stenotic site or vessel to reduce the danger of more distal
or even as a separate surgical procedure. When these embolization through the communication to a vital systemic
communications are closed surgically along with the structure.
intracardiac repair, the closure of these defects significantly In very complex congenital heart lesions and particularly
prolongs the surgery and the recovery of the patient. in the older patient, unusual communications occur that
Occasionally, teenagers and adults with congenital heart require occlusion. These include persistent left SVC to the
disease will develop hemoptysis from spontaneous bleeding left atrium, persistent systemic-to-pulmonary artery shunts
of these abnormal collaterals and will require urgent in patients who had undergone tetralogy of Fallot or pulmo-
intervention. nary atresia repair, recurrent cephalad systemic venous to
The Gianturco coils116 described previously are the most caudal systemic venous shunts in patients who have opera-
commonly used device for occlusion of unwanted aorta-to- tive Glenn procedures, persistent pulmonary venous-to-
pulmonary communications in patients with congenital systemic venous communications in patients who had had
cardiac defects. For occlusion of abnormal tubular vascular some type of caval-pulmonary operations, and persistent
communications, the coil to be used should have a coil diam- atrial communications in patients with right to left shunt
eter that is approximately 1.5 times the diameter of the following repair of complex defects. All of these patients
vessel to be occluded. The delivered coil wire should elongate have symptoms from their abnormal communications and
slightly, and in turn form an irregular mass of wire but not are at significantly greater risk for any further surgical inter-
a straight strand or a tight doughnut circle in the vessel to vention. In any defect of this type, the nonsurgical transcath-
be occluded. To deliver the coil, an end-hole-only catheter eter approach should be considered. Thoughtful and
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 333
innovative interventions in these types of patients can sig- only blade catheter that is sturdy enough for the thicker
nificantly improve their quality and length of life. septum in the adult congenital patient.
Indications for blade septostomy in the adult are patients
with inoperable complex congenital lesions with inadequate
venting of either atrium and patients with cor pulmonale
Miscellaneous Therapeutic secondary to pulmonary vascular disease.139 In the presence
Catheter Procedures of the muscular atrial septum found in the adult, the balloon
pull-through septostomy is impossible to perform, and the
Atrial Septostomy creation of an atrial septal communication always is begun
with the blade septostomy procedure even when a small,
The very first intracardiac therapeutic catheterization proce-
preexisting ASD is present.
dure was the balloon atrial septostomy performed in 1966 by
When a balloon dilation septostomy is performed first or
Rashkind1 using his balloon septostomy catheter. This was
alone, it will stretch only a preexisting restrictive atrial com-
not only the first intracardiac therapeutic procedure to be
munication. When the defect is stretched, it causes a subse-
performed in the catheterization laboratory, but also the first
quent blade to distort and pull through the stretched orifice
therapeutic catheterization procedure, which effectively
and does not produce the desired initial cut. The PBS 300
replaced a surgical procedure. The procedure was crude but
blade septostomy catheter is introduced through a 9 F long
effective in creating an interatrial communication when
Mullins sheath that has been passed into the left atrium
intracardiac mixing of systemic and pulmonary blood was
through either a preexisting atrial communication, or prefer-
critical, and it is still in use today. The actual Rashkind
ably via a separate transseptal puncture adjacent to any pre-
balloon septostomy has no use in the adult patient, but the
existing atrial communication. The location of the blade in
concept of creating atrial communication in the catheteriza-
the left atrium is verified on biplane fluoroscopy. The sheath
tion laboratory is absolutely essential in many adult congeni-
is withdrawn off the blade and well back into the low right
tal patients.
atrium/IVC.
Although the original septostomy procedure is strictly a
With the blade apparatus positioned well into the left
pediatric procedure and has not changed significantly over
atrium, the catheter is rotated until the blade points toward
the past four decades, the procedure has been elaborated on
the anterior chest wall and either to the patient’s right or left.
in order to make the catheter septostomy applicable in adults.
The blade is opened carefully to approximately a 45-degree
The use of the catheter septostomy has been extended
angle while verifying that it is not in the left atrial appendage
to other lesions where mixing is needed through the
or in a pulmonary vein. The blade is locked in the open posi-
atrial septum to sustain life. Such lesions in the adult patients
tion and the blade catheter is withdrawn slowly against the
include patients with failing, single ventricle, caval-
atrial septum. Resistance is felt at the septum, and the blade
pulmonary repairs, inoperable complex lesions, and pulmo-
tends to rotate as it engages the septum. A continued firm,
nary vascular disease. All of these patients benefit from
slow, and controlled withdrawal of the catheter and blade is
an atrial pop-off to improve cardiac output, to decrease
performed until the blade snaps through the septum. Often
pulmonary congestion, or to decrease right heart failure.139
the entire septum (and heart!) is displaced caudally almost
into the IVC before the blade pulls through the septum.
Blade Atrial Septostomy
When the blade pulls through the septum, it is important
The inability to create an adequate atrial communication that the open blade is not withdrawn any further into the
with balloon septostomy in children beyond the newborn IVC after the incision is made. After the successful cut, the
period led to the development of the ParkTM blade septostomy blade apparatus is withdrawn back into the catheter shaft.
catheter (Cook Inc., Bloomington, IN) and the blade septos- The blade catheter is reintroduced into the left atrium, and
tomy procedure.140 Indications for this procedure are similar the blade pull-through is repeated three to five times until
to those for balloon septostomy and have been further no further resistance is felt as the blade is withdrawn through
expanded to include teens and adults. The Park blade septos- the septum. With each withdrawal the right or leftward angle
tomy catheter is designed to initiate a cut in a thicker or of the blade is changed slightly, while at the same time the
tougher atrial septum.141 A small blade at the distal end of blade always is maintained facing anteriorly. After multiple
the catheter is controlled by a sliding wire that runs the withdrawals of the blade are completed, the blade catheter is
length of the catheter lumen from the proximal Tuohy™-type replaced with a balloon dilation catheter that should be sig-
hub to the blade at the distal tip of the catheter. When the nificantly larger than the size of the desired opening. A
control wire is advanced, the blade extends out of the slot in balloon dilation of the atrial septum is performed to enlarge
a metal pod at the end of the catheter and forms a triangle the opening created with the blade.
extending off the shaft of the catheter/pod with the apex of
the triangle away from the catheter and the proximal edge
Balloon Dilation of an Atrial Defect Alone
of the triangle sharpened. When the extended blade is with-
drawn, from left atrium to right atrium, the blade initiates Angioplasty balloon dilation of the atrial defect is used in
an incision in the atrial septum. This incision then is conjunction with a blade atrial septostomy or it can be per-
extended with a balloon dilation procedure. The current Park formed as the primary septostomy procedure in the adult
blade septostomy catheters include the PBS 300, on an 8 F patient. Balloon dilation septostomy also is indicated when
shaft. This catheter has a very sturdy 2-cm-long knife blade there is compromised access from the IVC for a blade septos-
recessed in a slot in the distal end of the catheter. It is the tomy. Balloon dilation of the atrial septum, however, is more
334 chapter 12

effective following an initial blade septostomy because even diameter angioplasty balloon for delivery. The left atrium is
a tiny initial incision will initiate a tear that will be extended entered either through a preexisting opening or a new trans-
by the dilation. septal puncture. A stiff wire is positioned in the left upper
To perform a balloon dilation of the atrial septum, an pulmonary vein, and a long sheath large enough in diameter
end-hole catheter or a transseptal puncture is used to intro- to accommodate the balloon/stent/suture combination is
duce a stiff exchange wire through the atrial septum and out positioned in the left atrium. Often, to pass the large sheath
into a left upper pulmonary vein. An angioplasty balloon is through the tough septum, it is necessary to perform a
chosen with a diameter at least twice the size of the desired predilation of the septum with a smaller high-pressure
opening in the atrial septum. With the wire stabilized in this angioplasty balloon. Once the sheath is positioned in the left
position, the appropriate balloon dilation catheter is intro- atrium, the stent/balloon is advanced into the sheath, cen-
duced over the wire and advanced into the atrial septum. The tered precisely on the septum, and dilated to the maximum
angioplasty balloon is partially inflated to visualize the pressure of the dilation balloon. The stent should be centered
indentation on the balloon made by the restrictive septum. on the septum as accurately as possible using angiograms or
Once the balloon is centered precisely within the septum, a TEE, but because of the restriction at the center of the stent
controlled inflation of the dilation balloon to its maximum and the toughness of the septum, these stents tend to self-
recommended pressure is performed. The balloon should be center with the inflation of the larger balloon. The ends of the
observed closely on fluoroscopy during the inflation to be stent are expanded to the maximum diameter of the balloon,
sure that it is not squeezed out of the tight septum at its full and the balloon is deflated and withdrawn, leaving the dumb-
inflation. The procedure is repeated several times to ensure bell-shaped stent in the septum holding open the septal
the dilation has achieved maximal opening of the septum. opening at the desired restricted diameter.
During the repeat inflations, no waist or indentation should
appear on the balloon even as the balloon is inflated initially.
Catheter Implant of Cardiac Valves
In large adult patients, a single angioplasty balloon may not
achieve an adequate atrial septal defect due to balloon size The most recent and one of the most exciting new therapeu-
and pressure limitations. In these patients, venous access is tic catheterization procedures to appear is the transcatheter
obtained from both groin areas, two separate sheaths are implant of cardiac valves. A large number of adult congenital
introduced, and two stiff wires introduced into the pulmo- heart patients who previously have undergone repair of tetral-
nary veins for simultaneous balloon inflations of two angio- ogy of Fallot, pulmonary atresia with ventricular septal
plasty balloons side by side in the atrial septum. Once defect, or truncus arteriosus now have wide-open pulmonary
completed, the balloon angioplasty catheters are removed valve regurgitation with right ventricular dilation and failure.
and the hemodynamics are repeated to be sure an adequate Many of these patients already have undergone one (or more)
septal opening has been achieved. repeated surgical interventions for the replacement of the
In most of the patients with complex lesions and restric- pulmonary valve with some type of conduit containing a
tive mixing or inadequate venting, an attempt is made to prosthetic pulmonary valve.
create the largest possible ASD by using the large blade and Bonhoeffer et al.,143 working with NuMED Inc. (Hopkin-
double balloons. Occasionally multiple separate punctures, ton, NY), developed a stent-mounted pulmonary valve that,
blade withdrawals, and balloon dilations are performed. At after extensive animal testing, has been successfully
the other extreme, in patients with pulmonary vascular implanted percutaneously in humans. The initial delivery
disease or malfunctioning caval-pulmonary connections, a system was very large but has been modified to a more practi-
very small defect (4 to 6 mm) is created initially, enlarging it cal size. At present the pulmonary stent/valve requires a
in 1-mm increments until the desired minimal systemic somewhat restrictive as well a regurgitant right ventricular
desaturation is achieved. outflow tract in order to hold the valve in place. It is hoped
The final means of creating a more permanent atrial that this stent/valve will enter FDA IDE clinical trials in the
septal communication or a defect of a specific size is to very near future. In addition to Bonhoeffer et al., other inves-
implant an intravascular stent in the atrial septum. For a tigators are in various stages of developing other percutane-
restricted opening, the stent is prepared on the table to ous implants for the pulmonary as well as the aortic valve.
produce an area of restricted expansion.142 This procedure is Cribier et al.144 developed a modification of the stent/
utilized in patients with pulmonary vascular disease and in valve concept for use in the aortic valve. The percutaneous
patients with a single ventricle or a failing Fontan caval- aortic valve is intended for use in the elderly adult with cal-
pulmonary repair who have developed protein-losing enter- cific aortic stenosis/insufficiency. The valve itself, the deliv-
opathy. A short stent with a strong wall and the capacity to ery technique, and the indications for this valve currently
be dilated to a large diameter is necessary. are being modified, but as these are perfected this valve may
A restrictive stent must be prepared by hand on the table. have applicability for the adult patient with congenital aortic
First the stent is expanded on a 10- to 12-mm balloon, the valve disease who has developed dominant aortic regurgita-
balloon is deflated, and a heavy suture is woven in and out of tion secondary to prior surgical or catheter interventions or
the struts/openings around the entire circumference of the just over time.
stent at its center. The stent with the suture around it is The percutaneous implant of cardiac valves is just in its
crimped over a smaller balloon inflated to the diameter of the infancy but should continue to be very exciting over the next
desired septal opening and the suture is tightened over this few years and provide a considerably less traumatic reinter-
balloon. The smaller balloon is deflated, withdrawn from the vention for these patients with severe pulmonary or aortic
stent, and the stent/suture is mounted (crimped) onto a large- valve regurgitation.
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 335

Catheter Removal of Foreign Bodies a wire with the fixed diameter loop. When it is advanced out
of the distal end of the snare catheter, it aligns at a reproduc-
Transcatheter removal of intravascular foreign bodies is an ible acute angle to the shaft of the catheter. The proximal
important part of the armamentarium of the interventional end of the snare wire extends out of the proximal end of the
cardiologist. The need for this intervention has been present catheter for control of the loop from the proximal end.
since the early days of intravascular catheterization145 and The loop of the snare is advanced out of the tip of the
has evolved into an essential and often complex intervention. catheter and manipulated to encircle the foreign body by
The incidence of iatrogenic intravascular foreign bodies has moving the wire at the proximal end in and out while rotat-
increased due to the general increase in the use of indwelling ing the catheter. Once an object is grasped, the snare loop is
catheters and the increased number of therapeutic devices made smaller by advancing the catheter forward over the
being implanted in the catheterization laboratory—all of proximal loop while holding the back end of the wire. With
which have a potential for embolization. Most, if not all, of the infinite memory of the nitinol snare loops, no matter
the foreign bodies within the vascular system are iatrogenic. how many times the loop is advanced to open or is with-
In the past, the majority of these foreign bodies were pieces of drawn back into the catheter, it resumes its original shape
indwelling intravenous tubing from chemotherapy, hyperali- and orientation when reextruded. Another advantage is that
mentation, and neurosurgical shunts that were broken during the snare loop has an offset at an angle from the shaft of the
removal, leaving pieces floating in the circulation.146–148 catheter that has the same memory as the loop. This allows
Now, many of the foreign bodies are a consequence of inter- the loop to pass around the object more easily as the open
ventional procedures, including occlusion coils that have snare is advanced rather than trying to catch it from the side
migrated or embolized, tips of catheters or wires, pieces of as the snare is withdrawn. For a snare to work, there must
balloon dilation catheters, umbrella occlusion devices, and be a free end or piece of the foreign body extending into the
even intravascular stents. Most intravascular foreign bodies lumen of the vessel/chamber so that the loop of the snare
can and should be removed in the cardiac catheterization can encircle it. This snare is most useful for the retrieval of
laboratory. A biplane catheterization laboratory is essential pieces of indwelling lines, pieces of catheters, or wire/coils.
for any foreign body removal, which in turn makes the con- Another frequently used retrieval device is the basket
genital catheterization laboratory particularly well suited for device (Boston Scientific, Natick, MA, and Cook Inc., Bloom-
these retrievals. The key to the successful removal of foreign ington, IN). This is a catheter with a core wire system that
bodies is the ability to localize the foreign body within the has a helix or basket of three or four strands of memory wire
vascular system in three dimensions using biplane fluoros- at the distal end. The basket opens as it is extruded from the
copy. Without the use of the simultaneous fluoroscopic views, catheter. There are several different designs of the baskets,
the retrieval becomes a random “fishing expedition” that each of which are available in various sizes. When extruded
uses inordinate amounts of fluoroscopy time and often ends from the catheter, and as the basket opens, it is rotated as it
unsuccessfully. expands and encircles or entangles the foreign body. Several
There are a variety of catheter devices for the removal of wires of the basket must be able to encircle at least part of
foreign bodies. These devices are commonly inserted through the foreign body in order to trap it. When the catheter is
a long sheath that must be of a sufficient diameter and stiff- advanced over the open basket, the basket compresses as it
ness to allow the grasped foreign body to be withdrawn into retracts into the catheter and in this way grasps the foreign
the sheath before withdrawal from the body. This occasion- body securely. The basket device also is used for the retrieval
ally requires a 14 F or 16 F long sheath. An end-hole catheter of pieces of catheter or other larger foreign bodies that have
is manipulated to a location in the exact same vessel but a free end. The basket will not work unless at least one sepa-
distal to the foreign body. A stiff or Super Stiff exchange rate wire of the basket can encircle or pass through the
length guidewire is advanced and fixed distal to the foreign foreign body and the combination then can be trapped by the
body so that a large long sheath and dilator can be maneu- basket. This technique is essential in the retrieval and extrac-
vered over the wire to a location immediately adjacent to the tion of fractured pieces of embedded transvenous pacing
foreign body. The retrieval device is passed through the long leads. The basket is also useful for embolized occlusion
sheath so that the foreign body can be grasped and with- devices including coils, umbrellas, or even stents—all of
drawn into the sheath for removal. which can be compressed at least partially by the basket.
The mainstay of the retrieval devices is the snare cathe- Another essential retrieval device is the GrabberTM cath-
ter. Several snare catheters are available including simple eter (Boston Scientific, Natick, MA). This 4 F catheter has
homemade snares that use a loop of standard 0.018-inch four tiny metal arms that when extended out of the tip of
spring guidewire looped through an end-hole catheter. The the catheter move away from the center of the catheter as
more sophisticated commercial nitinol snare systems, which small outward arcs positioned 90 degrees away from each
include the GooseneckTM snare (Microvena Corp., White other. Each arm has a small 1-mm 90-degree inward bend at
Bear Lake, MN) and the EnSnareTM (MDTECH, Gainesville, its distal tip, which, when the arms are withdrawn into the
FL) now are used universally. The total and reproducible catheter, are forced together and overlap each other, creating
memory of the nitinol snare loops of the commercially avail- a very tight grip on anything positioned between the arms.
able snares represents significant advantages over the home- The Grabber has the advantage (and disadvantage) of grasping
made snares. The commercial snare catheters are only 4 F or anything directly in front of it and, in turn, not having to
5 F end-hole catheters, which can be inserted through a short encircle a foreign body before grasping it so that it can grab
sheath, a long sheath, or a 7 F end-hole guiding catheter that the side of objects. This makes the Grabber uniquely useful
has been positioned near the foreign body. The snare itself is for grabbing objects embedded in the tissues with no free
336 chapter 12

ends such as occlusion devices and wads of coils. The major cover sharp parts of the device, it never should be withdrawn
disadvantages of the Grabber are that once an object is through the cardiac chambers/structures. When the foreign
grabbed it often cannot be released and the Grabber often body can be drawn into a peripheral vessel, it usually can be
will also grab adjacent tissues and retrieve small pieces of removed by a small cut-down over the peripheral vessel using
tissue along with the foreign body! Fortunately, this does not local anesthesia, rather than requiring a thoracotomy. Even
appear to cause any permanent sequelae. when a large foreign body has embolized to the lung, is
A cardiac Bioptome can be used as an alternative to grasp grasped and freed from its distal site, but cannot be with-
foreign objects in some circumstances. The advantage of a drawn sufficiently into the sheath to be drawn through the
bioptome is that it also can be used to grasp a side as well as heart, it can be maneuvered to and held in the main or proxi-
the ends of a small object. A limitation of the bioptome is mal branch pulmonary arteries where the surgeon has easier
that it must be manipulated so that its jaws open perpendicu- access to it. All of these possibilities should be considered in
lar to the object to be grabbed. The bioptome jaws also may preparation for foreign body removal.
not open widely enough to accommodate larger foreign
bodies, and once the object is grabbed, often the bioptome is
not strong enough to hold and withdraw the object. Another
Collaborative (Hybrid) Therapeutic
disadvantage of the bioptome is the difficulty and patience
Catheterization and Surgical Procedures
(and fluoroscopy) it takes to grab a small, moving object with
An added bonus to the new therapeutic catheterization pro-
such a small jaw.
cedures has been an increased collaboration between pediat-
A unique use of the bioptome is to grasp a part of a foreign
ric cardiologists and many of the more forward-thinking
body in order to free or stabilize it while it is being grasped
pediatric cardiac surgeons in the development of staged,
by a sturdier device. The bioptome is useful to grasp the
collaborative repairs of complex defects.110,149–151 One of the
center of a piece of catheter or wire that extends across a
earliest examples of this preplanned cooperation was the
vessel or chamber when no free end of the catheter/wire is
fenestrated Fontan patients, in whom the immediate surgical
accessible. Although retrieval may not be accomplished with
morbidity was reduced by purposefully leaving a residual
the bioptome, at least one end can be pulled free to allow it
ASD that could be closed in the catheterization laboratory
to be grasped by one of the stronger retrieval devices.
once the patient had recovered from the surgery.113 Another
Another retrieval device is the vascular retrieval forceps
notable example of this type of multistaged collaboration is
(Cook Inc., Bloomington, IN). This device has a very tiny
in patients with pulmonary artery atresia and VSD. Early in
angled and serrated jaw that extends out from one side near
the course of management, the surgeon creates a right ven-
the distal end of a very small 3 F catheter. It is operated much
tricle to pulmonary artery connection rather than the simpler
like the jaw operation on the CookTM bioptome catheter. This
to perform systemic to pulmonary shunt. The right ventricle
tiny device can be passed into or through a mass of foreign
to pulmonary artery connection provides the interventional
body that is wedged distally in a vessel. The grasping jaw is
cardiologist with early access to the pulmonary vessels in
opened and closed within or beyond the mass to catch part
order to dilate the small, deformed, pulmonary arteries and
of the object and pull it partially free, if not out of the vas-
to perform intrapulmonary stent implants in preparation for
cular system. The tiny tip and catheter also can be passed
the eventual more definitive repair.
under the middle of a catheter or wire that is against a vessel
The most extensive and notorious example of this col-
or chamber wall and used to pull the foreign material away
laborative effort is the proposed cardiology/surgery collabora-
from the wall. This device is useful both for small foreign
tion to complete the final IVC to pulmonary artery connection
objects and to dislodge or move larger objects initially into
of the caval-pulmonary single ventricle repair in the cathe-
more favorable positions for grasping with sturdier retrieval
terization laboratory rather than in the operating room.152
systems.
This requires the surgeon to do a preceding Glenn procedure
The AmplatzTM deflector wires (Cook Inc.) can be used in
(SVA to pulmonary artery anastomosis) in a very specific
a similar manner to the small jaws device to encircle, grasp,
manner to prepare the pulmonary artery for the eventual
and dislodge or secure foreign bodies that have no free ends.
completion of the IVC tunnel in the catheterization labora-
The tip of the straight deflector wire is advanced outside of
tory. This type of cooperation and its complementary benefi-
the end of the catheter and passed between the foreign body
cial results for the patient contribute to a far better outcome
and the vascular wall. The deflector system is activated,
for many of the extremely complex lesions.
which results in the foreign material being encircled by the
360-degree loop of the deflected tip of the wire. This loop of
wire is not very strong and is more useful for holding or Summary
securing the foreign body while it is grasped with a stronger
retriever. The therapeutic cardiac catheterization procedures dis-
The type and size of the foreign body, its location, the cussed in this chapter represent some of the greatest
time it has been in place, and the adequacy of access vessels advances in the treatment of patients with congenital heart
all will determine the success of foreign body retrieval. The disease since the advent of the first surgical corrections. The
larger foreign bodies certainly can be grasped within the procedures are performed with less immediate risk and cer-
vascular system but may be too large to be withdrawn into tainly far less acute trauma to the patient than from repeated
a sheath or otherwise completely out of the vascular system. surgical interventions. Even with the additional expense of
If a large, jagged foreign body such as an open occlusion the specialized catheters and devices and the added cost
device cannot be withdrawn into the large sheath enough to of the more extensive catheterization procedure, the direct
 c ong e n i ta l h e a rt di se a se i n t h e a du lt 3 37
costs of the therapeutic catheterization procedure are sig- 17. Chen CR, et al. Percutaneous balloon valvuloplasty for
nificantly less than the costs for the comparable surgical pulmonic stenosis in adolescents and adults. N Engl J Med
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132. Grifka RG. Transcatheter PDA closure using the Gianturco- 144. Cribier A, et al. [Percutaneous artificial heart valves: from
Grifka vascular occlusion device. Curr Intervent Cardiol Rep animal experimentation to the first human implantation in a
2001;3(2):174–182. case of calcified aortic stenosis]. Arch Mal Coeur Vaiss 2003;
133. Le TP, et al. Duct-Occlud for occlusion of patent ductus arterio- 96(6):645–652.
sus. Curr Intervent Cardiol Rep 2001;3(2):165–173. 145. McSweeney WJ, Schwartz DC. Retrieval of a catheter foreign
134. Sharma S, et al. Systemic-to-pulmonary artery collateral body from the right heart using a guide wire deflector system.
vessels and surgical shunts in patients with cyanotic congeni- Radiology 1971;100(1):61–62.
tal heart disease: perioperative treatment by transcatheter 146. Ramondo AB, Favero L, Chioin R. Percutaneous retrieval of a
embolization. AJR 1995;164(6):1505–1510. broken catheter from the left atrium in an adult. J Intervent
135. Lane GK, et al. Percutaneous coil occlusion of ascending Cardiol 2002;15(5):417–419.
aorta to pulmonary artery shunts. Am J Cardiol 1998; 147. Savage C, et al. Percutaneous retrieval of chronic intravascular
81(11):1389–1391. foreign bodies. Cardiovasc Intervent Radiol 2003;26(5):
136. de Giovanni JV. The use of Amplatzer devices to occlude vas- 440–442.
cular fistulae. J Intervent Cardiol 2001;14(1):45–48. 148. Liu JC, et al. Percutaneous retrieval of 20 centrally dislodged
137. Schmaltz AA, et al. [Interventions in congenital heart Port-A catheter fragments. Clin Imaging 2004;28(3):223–229.
disease and their sequelae in adults]. Herz 1999;24(4):293– 149. Trivedi KR, Azakie A, Benson LN. Collaborative interventional
306. and surgical strategies in the management of congenital heart
138. Hijazi ZM. New device for percutaneous closure of aorto- lesions. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu
pulmonary collaterals. Catheter Cardiovasc Intervent 2001;4:185–207.
2004;63(4):482–485. 150. Bacha EA, et al. New therapeutic avenues with hybrid pediatric
139. Nihill MR, O’Laughlin MP, Mullins CE. Effects of atrial cardiac surgery. Heart Surg Forum 2004;7(1):33–40.
septostomy in patients with terminal cor pulmonale due to 151. Waight DJ, Hijazi ZM. Pediatric interventional cardiology: the
pulmonary vascular disease. Cathet Cardiovasc Diagn 1991; cardiologist’s role and relationship with pediatric cardiotho-
24(3):166–172. racic surgery. Adv Card Surg 2001;13:143–167.
140. Park SC, et al. A new atrial septostomy technique. Cathet 152. Maher KO, et al. New developments in the treatment of hypo-
Cardiovasc Diagn 1975;1(2):195–201. plastic left heart syndrome. Minerva Pediatr 2004;56(1):41–49.
 1 Surgical Treatment
3 Magdi Habib Yacoub, Anselm Uebing,
Rosemary Radley-Smith, and
Michael A. Gatzoulis

General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Specific Congenital Defects in the Adult . . . . . . . . . . . . 341

D
uring the 1980s and 1990s, there was a determined as the result of turbulence or failure of development and
effort to “correct” congenital heart disease during growth due to chronic reduction in flow. The pulmonary
infancy, usually within the first few days or weeks vascular changes caused by an increase in flow and pressure
of life,1–5 in an attempt to prevent secondary functional and include medial hypertrophy and reactivity of smooth muscle
anatomic changes in the heart and other organs and to avoid cells, functional and structural intimal changes,20 and even-
the stress of repeated hospitalization and surgery in older tual development of irreversible plexogenic lesions.21,22 The
children and adults. Despite this, a significant proportion of rate at which such changes occur varies among different
patients with uncorrected congenital heart disease grow to conditions and among individual patients. Other changes
adulthood because of the relatively “benign” nature of the that may occur are the direct result of previous surgery,
condition or because they were not offered or they refused which can produce distortion of vessels on intracardiac
surgical treatment. In addition, a number of patients who shunting. Cerebral, hepatic, and renal function may be
have undergone palliative or supposedly corrective opera- affected by hypoperfusion, cyanosis, or embolism. Accurate
tions require further surgical treatment in adulthood. The characterization of the extent and reversibility of secondary
increasing number and the specific nature of these opera- changes is of special importance in planning the time and
tions have created a new subspecialty of surgery for congeni- type of surgical intervention in adults with congenital heart
tal heart disease.6–9 This chapter considers some of the disease.
general features and specific conditions of congenital heart
surgery in the adult.
Specific Congenital Defects in the Adult
General Considerations Aortic Valve Stenosis
Congenital heart defects produce progressive changes in Congenital bicuspid aortic valve commonly results in pro-
cardiac form and function, as well as secondary effects gressive stenosis due to thickening and calcification of the
resulting from chronic systolic or diastolic overload10 that cusps (Fig. 13.1). Accurate measurement of the amount and
can involve myocardial cells,11 the connective tissue frame- localization of calcification in the aortic valve can be made
work of the heart,12–14 or the microvasculature and endocar- using electron beam computed tomography.23,24 The amount
dium.15 These abnormalities are qualitatively different for of calcium in the valve has been shown to be a predictor of
systolic and diastolic overload. Although many of these progression of the disease25 as well as an independent prog-
changes initially have the potential to be reversed,16 they nostic indicator.26 Valve-conserving surgery is rarely possible
may become irreversible if left uncorrected. Other cardiac in adults, and therefore valve replacement is the most com-
effects may involve progression or development of new monly performed surgical procedure. Advances in myocar-
obstructive lesions, such as that observed in tetralogy of dial protection and other intraoperative techniques have led
Fallot,17 ventricular septal defect (VSD), or aortic outflow to a reduction in the perioperative mortality rates for both
obstruction in double-inlet ventricle with malposition of the initial and successive surgery to approximately 1% to 3%.27
great arteries.18,19 Continued blood turbulence may affect the The most important issue is the choice of a valve substitute,
structure and function of the atrioventricular (AV) or semi- which should match the characteristics of the valve to the
lunar valves, with thickening or calcification of the cusps or requirements of the patient.
dilatation of the annulus. Poststenotic changes in the great Although a considerable amount of information is avail-
arteries can lead to either dilatation or arterial wall changes able about the performance and suitability of the different

3 41
342 chapter 13

FIGURE 13.1. Severe aortic stenosis of congenitally bicuspid

valve.

FIGURE 13.2. A stented xenograft valve: porcine bioprosthesis.

valve substitutes, this information is often incomplete, and

other factors, such as the experience, predictions, and bias of
the surgical team, cardiologist, and patient, can influence
the choice. There is increasing evidence that the normal
aortic valve performs a series of extremely sophisticated tion32 can lead to a small but significant morbidity and mor-
functions that depend on the biologic properties of their tality incidence,33 particularly in women during the
components.27–29 The use of a living valve substitute capable childbearing years.34 Stented xenografts offer the advantage
of reproducing most or all of these functions can result in of predictability, ease of insertion, and low incidence of
clinical benefit in terms of both survival and quality of life. thromboembolic complications. However, their durability is
The only current valve procedures capable of preserving limited, particularly in patients younger than 35 years. In
aortic valve viability in the long term are valve repair and addition, the stent can become obstructive (Fig. 13.2), which
the Ross operation. Recent evidence strongly suggests that has negative implications for hemodynamic performance
both survival and exercise capacity are enhanced after the and possibly for long-term left ventricular (LV) function.
Ross operation when compared to other valve substitutes.30 Homograft valves are inserted in the subcoronary position
Recent progress in tissue engineering31 holds the promise of either via a two-suture-line technique 35,36 (Fig. 13.3) or as a
making available a fully viable human valve in the not very root replacement (Fig. 13.4) with reimplantation of the coro-
distant future. The available substitutes include prosthetic nary arteries.37,38 These valves have excellent hemodynamic
valves and stented or unstented xenografts. Prosthetic valves performance (Fig. 13.5), are virtually free of thromboembolic
are the most commonly used valve substitutes and have the complications, and have greater durability than xenografts,
advantages of ease of insertion and superior durability. particularly in children. However, their insertion is some-
However, the need for continuous postoperative anticoagula- what technically demanding, they are less readily available,

FIGURE 13.3. Homograft aortic valve replacement: the two-suture-

line technique.
 su rgic a l t r e atm e n t 343

FIGURE 13.4. Homograft aortic valve replace-

ment with reimplantation of the coronary
ostia.

and they must be replaced after a period of time.39,40 Pulmo-

PCG nary autografts make use of the patient’s pulmonary valve
ECG to replace the aortic valve, with insertion of a pulmonary or
aortic allograft in the pulmonary position (Fig. 13.6).41–43 The
autograft is inserted in the aortic position using a two-suture-
line technique or as a root replacement. The latter technique
is more predictable with regard to achieving immediate com-
100 mmHg petence, but there is some concern about the late dilatation
AOP
of the autograft root. This problem, however, can be largely
LVP
0
prevented by technical modifications, particularly in rela-
tion to the lower suture line43 and the use of hypotensive
drugs during the immediate and early postoperative period.
Aortic stenosis
After aortic valve replacement Stenosis of the pulmonary homograft in the right ventricular
A using homograft outflow tract requiring reoperations occurs in 5% to 10% of
PCG patients following the Ross operation. However, this is com-
ECG pensated for by the considerable advantages of enhanced sur-
vival and quality of life mentioned earlier.

AOP
100 mmHg Subaortic Stenosis
Subaortic stenosis may be caused by muscular or fibromuscu-
0 LVP lar tissue, which may be mild at birth but can progress during
adulthood (Figs. 13.7 and 13.8).44–47 Adequate relief of obstruc-
tion can be achieved in almost all cases with transaortic exci-
sion of the obstructing tissue, starting from a point below the
After aortic valve replacement midportion of the right coronary cusp and extending laterally
Aortic stenosis using stented bioprosthesis
B toward the left fibrous trigone, clearing the angle between the
FIGURE 13.5. Simultaneous left ventricular pressure (LVP) (solid- muscular septum and the anterolateral attachment of the
state catheter) and M-mode echocardiogram show left ventricular anterior mitral leaflet with mobilization of both fibrous
wall movement and transventricular peak systolic gradient imme-
diately after aortic valve replacement with homograft (A) and stented trigones (Fig. 13.9) and thus restoring the dynamic nature of
xenograft (B). AOP, aortic pressure; ECG, electrocardiogram; PCG, the subaortic region (Fig. 13.10).48 Subaortic obstruction due
phonocardiogram. to hypertrophic obstructive cardiomyopathy (HOCM) can be
 Homograft

FIGURE 13.6. Pulmonary autograft

replacement in the aortic position; two-
suture-line technique. Pulmonary auto-
grafts as a root replacement (see Fig.
1. Excise pulmonary valve 2. Pulmonary valve to aorta 3. Homograft to pulmonary artery 13.4).

FIGURE 13.7. Left ventricular outflow tract obstruction due to subvalvular

muscular hypertrophy. IVS, interventricular septum; PW, posterior wall; i,
inferior; s, superior.

FIGURE 13.8. Echocardiogram shows the anterior component of the subaortic stenosis (A), post-
operative transesophageal echocardiogram of the left ventricular outflow tract (LVOT) during
systole and diastole (B), and the mobilized hinge mechanism of the right and left fibrous trigones
(C). Ao, aorta, LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle.
 su rgic a l t r e atm e n t 345

FIGURE 13.9. Diagrams show the dif-

ferent steps of surgical relief of fixed sub-
aortic stenosis with mobilization of the
fibrous trigones (see text for details).

relieved by percutaneous alcohol ablation49 or with transaor- Coarctation of the Aorta

tic wide excision of the obstructive muscle. Currently, surgi-
cal myectomy is considered the gold standard for relief of Uncorrected and recurrent coarctation56,57 or complications
obstruction in HOCM.50 Mobilization of the fibrous trigones related to previous repair,58 such as false aneurysms or hyper-
may be necessary in some of these patients.48 A very small tension, can present in adult life. In these patients, an accu-
minority of patients with tunnel-type obstruction requires rate diagnosis of the exact anatomic lesion is necessary.
more radical procedures.51–53 Magnetic resonance imaging or alternatively high-resolution
computed tomography is the preferred noninvasive imaging
technique to delineate the anatomy of the entire aorta (Fig.
Supravalvular Aortic Stenosis
13.13). Magnetic resonance imaging provides information
Supravalvular aortic stenosis is usually associated with not only on the anatomy but also on the pressure gradients
hypoplasia of the ascending aorta. This condition can be across the coarctation and collateral blood flow.59–62 The use
adequately treated by the insertion of a bifid (Fig. 13.11)54 and of patch angioplasty has resulted in a high incidence of late
trifoliate (Fig. 13.12)55 patch of autogenous pericardium or false aneurysms. The operation of choice is excision of the
Dacron. lesion with direct end-to-end anastomosis; in some patients,
On the right side, isolated infundibular stenosis can however, interposition of a Dacron graft or the use of a bypass
usually be relieved through the pulmonary valve or through graft from the proximal to the distal segment may be neces-
a transverse ventriculotomy. sary, and possibly safer.

Muscular septum Membranous

septum

FIGURE 13.10. Diagrams show the

interaction between the mitral and aortic
orifices (B and C), with the two fibrous
trigones acting as a hinge mechanism for
the movement of the subaortic curtain Left fibrous
and anterior leaflet of the mitral valve trigone Right fibrous
during different phases of the cardiac Subaortic trigone
cycle and the structures surrounding the curtain
left ventricular outflow tract (A). A B C
346 chapter 13

as treatment of choice for native or recurrent coarctation in

the adult.64 Furthermore, interventional implantation of an
endovascular stent graft has the potential to avoid repeat
surgery for para-coarctation aneurysms and is offered in spe-
cialized tertiary centers (Fig. 13.14).
However, there are ongoing concerns about balloon
angioplasty and stenting for young pediatric patients relating
to the common complication of aneurysm formation and the
relative narrowing of the stent with respect to somatic
growth, respectively.

Aortic Regurgitation
Severe aortic regurgitation in adults may be secondary to
congenital abnormalities of the aortic sinuses, sinotubular
junction, or cusps, and may be associated with VSD. Valve-
preserving reparative procedures are possible in a high pro-
portion of these patients65–71 and depend on a thorough
understanding of the anatomic and functional components
of the particular condition, factors that influence progression
and evolution of safe, predictable methods of surgical repair.
These principles are exemplified in repair of the syndrome
of dilatation of the right coronary sinus, VSD, and aortic
regurgitation67 (Figs. 13.15 and 13.16), as well as aortic regur-
FIGURE 13.11. (A,B) Repair of supravalvular aortic stenosis with a
patch of autologous pericardium. gitation due to dilatation of the aortic sinus or sinotubular
junction in patients with connective tissue disorders, such
as Marfan’s syndrome72–75 (Fig. 13.17), or after the correction
Over the past one to two decades interventional tech- of certain congenital malformations, such as truncus
niques have been developed both for pediatric and adult arteriosus.76
patients with congenital heart disease.63,64 In many centers Cusp extension with the use of fresh autologous or glu-
primary stent implantation has nowadays replaced surgery taraldehyde-treated or homologous pericardium dura mater

FIGURE 13.12. (A) The aorta is tran-

sected just distal to the area of maximal
stenosis. (B) Three incisions are made,
one into each sinus of Valsalva. (C) Res-
toration of normal aortic root geometry
by insertion of three patches. (D) End-to-
end anastomosis of the reconstructed
root of the ascending aorta. (E) En-
largement of the ascending aorta by an
additional patch.
 su rgic a l t r e atm e n t 3 47

A B C
FIGURE 13.13. Magnetic resonance imaging of an adult patient with native aortic coarctation showing the anatomic details (A–C) of the
aorta and collateral arteries.

FIGURE 13.14. Magnetic resonance imaging

of severe aortic coarctation before (left) and
after (right) primary stent implantation in an
adult patient.

FIGURE 13.15. Hemodynamic forces

that influence progression of the syn-
drome during early systole (A), late
systole (B), and diastole (C).
348 chapter 13

FIGURE 13.16. (A,B) Section in the

aortic root illustrates the placating
sutures used to close the ventricular
septal defect, elevate the annulus, reduce
the size of the sinus, and restore compe-
tence of the aortic valve.

A B

D
E

FIGURE 13.17. (A–E) Operative technique of the

valve-sparing operation used in this series (see text).
 su rgic a l t r e atm e n t 349
has been used with good initial results (Fig. 13.18).77–79 the anterior cusp or to cusp prolapse (Fig. 13.19) caused by
Although this technique can be used to tide patients over for myxomatous degeneration.80–85 Valve repair is the procedure
a period of time, relatively fast degeneration of the cusp of choice for these lesions and is appropriate for the majority
extension, especially in young individuals, limits its wider of patients. Accurate characterization of the anatomic lesion
use. The development of more durable materials, possibly is usually achieved with intraoperative echocardiography
through tissue engineering, is needed for this method to (Fig. 13.20). Intraoperative testing of the mitral valve, using
reach its potential. a technique that subjects the valve to physiologic pressures
with a beating heart, allows selective repair of the responsi-
ble lesion (Fig. 13.21).
Mitral Valve Disease
Congenital mitral stenosis secondary to a parachute
Congenital abnormalities of the mitral valve can present in valve almost always presents in infancy or childhood. A
adulthood with severe regurgitation secondary to a cleft in supravalvular membrane attached to the upper surface of the

C
A B D E

F G I J

A B H

C D

FIGURE 13.18. (A–H) Surgical tech-

nique of aortic cusp extension with
fresh autologous pericardium. G H
350 chapter 13

FIGURE 13.21. Intraoperative testing of mitral valve repair. Note

use of bifurcated coronary line directing blood into the left ventricle
via the apex and into the aortic root proximal to the cross-clamp.
The mitral valve can be safely inspected in the beating heart.

mitral valve can present in late childhood or early adulthood

(Fig. 13.22).86 We have observed the progression of supraval-
vular membranes in adulthood. Although the membrane is
commonly fused to the atrial surface of the mitral valve
cusps, it is usually possible to excise it with preservation of
the valve. The left AV valve in ventriculoarterial discordance
FIGURE 13.19. Top: Short-axis cut at the level of the left ventricular
outflow tract (LVOT) in a patient with an isolated cleft in the anterior
is usually abnormal, with resulting progressive regurgitation
mitral valve leaflet. Note the cleft, indicated by two arrows pointing in adult life.87,88 These valves usually require replacement
toward the outflow tract, and not the right ventricle (RV). LA, left and are very rarely suitable for repair. Furthermore, after
atrium. Bottom: Short-axis cut at the level of the mitral valve (MV). surgery, the regurgitation is usually associated with varying
Note again the cleft indicated by the arrows, pointing toward the degrees of dysfunction of the systemic morphologic right
outlet of the heart and not the right ventricle. A, anterior; IVS, inter-
ventricular septum; L, left; MV, mitral valve; P, posterior; R, right; ventricle.
RVOT, right ventricular outflow tract.

FIGURE 13.20. (A,B) Typical features of mitral valve prolapse (MVP) as shown by intraoperative transesophageal echocardiography. AL,
anterior leaflet; LA, left atrium; LV, left ventricle; RA right atrium; RV, right ventricle.
 su rgic a l t r e atm e n t 3 51
13.23).89,90 In patients with advanced RV dysfunction in the
presence of severe LV dysfunction, a total cavopulmonary
shunt can be considered. In patients with advanced RV and
LV dysfunction, cardiac transplantation is indicated.

Pulmonary Valve
Isolated pulmonary valvular stenosis occasionally presents
for the first time in adult life. Although the valve is thicker
and may be calcified, open valvotomy is usually possible.
Pulmonary valve replacement is rarely necessary. Recurrent
or residual pulmonary valvular dysfunction after previous
repair or angioplasty is uncommon except in patients with
tetralogy of Fallot who have received transannular patches
or previous insertion of a valve conduit for correction of a
variety of complex congenital anomalies.91 In these patients,
FIGURE 13.22. Congenital stenosing supravalvular membrane the calcified conduit could be adherent to the sternum and
attached to the atrial side of the mitral valve (mv). Note that in
contrast to the situation in cor triatriatum, the pulmonary veins
therefore at risk of being injured during sternotomy. To avoid
and left atrial appendage enter the left atrium (LA) proximal to or this, profound hypothermia with femorofemoral cannulation
above the supravalvular membrane. AO, aorta. may be used. The preferred valve at both the first and second
operation is a pulmonary homograft, although both aortic
homografts and xenografts have been used with varying
degrees of success. Alternatively, percutaneous valve replace-
ment could be used.92
Tricuspid Valvular Disease
The most common congenital defects of the tricuspid valve
Percutaneous Valve Replacement
presenting in adulthood are the less severe forms of Ebstein’s
anomaly, with displacement of attachment of the posterior This is a rapidly progressing area that has captured the
and septal leaflets into the right ventricle, resulting in imagination of both clinicians and patients. Several strate-
varying degrees of tricuspid regurgitation, as well as RV and gies are being developed for all four valves.92 The most
LV dysfunction. Repair is possible in approximately two successful to date is pulmonary valve replacement utilizing
thirds of the patients, with a variety of techniques (Fig. a stent bearing a bovine jugular vein valve (Fig. 13.24).

FIGURE 13.23. Surgical technique. I:

Operative view. A, Anterior leaflet; C,
atrialized chamber; P, posterior leaflet;
S, septal leaflet. II: Anterior leaflet and
adjacent portion of posterior leaflet are
detached from the annulus. Leaflet
tissue is mobilized by cutting fibrous
bands attached to the ventricular wall.
Interchordal spaces are fenestrated if
obliterated. III: Longitudinal placation
of right ventricle by simple sutures
passed through the septal and posterior
leaflet remnants. Tricuspid annulus and
right atrium are plicated. IV: Anterior
and posterior leaflets are sutured to the
tricuspid annulus after clockwise rota-
tion (arrow) to cover the entire orifice
area. V: Prosthetic ring is inserted to
remodel the orifice and to reinforce
repair. Atrial septal defect is closed.
352 chapter 13

FIGURE 13.24. Pulmonary angiogram before percutaneous valve injection into to the pulmonary artery documents normal function-
replacement showing significant pulmonary regurgitation (upper ing of the new valve.
panels). After implantation of the valve (lower panels), contrast

The immediate and short-term results are good and the pro- (AGA Medical Corp., Golden Valley, MN), is established as
cedure offers the great advantage of avoiding or delaying a safe and effective alternative to surgical closure.93,94
repeat surgical procedures in young patients. The long-term However, transcatheter closure is not feasible if the ASD is
results of these procedures, however, are still unknown but too large (without a sufficient rim around the defect) or if the
could be greatly enhanced by advances in experience and ASD is of sinus venosus or primum type. Therefore, ASDs
technology including the development of tissue engineered still need surgical closure with a pericardial or Dacron patch
valves that, at least in theory, could provide semipermanent to avoid tension on the slightly rigid tissues. The sudden
solutions. postoperative drop in flow through the markedly enlarged
pulmonary arteries may lead to intravascular thrombosis,
which may be prevented by postoperative anticoagulation for
Septal Defects and Anomalous Pulmonary Veins
a period of 1 month to 1 year, depending on the size of the
pulmonary arteries. Defects with echocardiographic evi-
Secundum Atrioseptal Defect
dence of right heart dilatation, a pulmonary/systemic flow
Secundum atrioseptal defect (ASD) can present in adulthood ratio of more than 1.5, or both, should be closed electively to
and may be associated with atrial fibrillation, marked enlarge- prevent long-term complications. Even in older patients
ment of the right ventricle and pulmonary arteries (Fig. 13.25), (above 40 years) with large ASDs, closure of the defect
and occasionally mitral valve prolapse. Varying degrees of improves mortality from cardiovascular events such as pul-
pulmonary vascular disease may occur later in life. monary or systemic embolism, deterioration or heart failure,
Nowadays, the majority of secundum ASDs can be closed and overall mortality, and improves functional class.95
with a transcatheter approach. The latter, which is most However, older patients remain at the risk of persistent or
commonly performed with the Amplatzer septal occluder™ newly developing postoperative arrhythmia (Fig. 13.26), and
 su rgic a l t r e atm e n t 353
volume overload with secundum ASDs, with the additional
hazard of left AV valve regurgitation. Patients with more
severe forms of left AV valve regurgitation tend to present
earlier. Repair of partial AVSD in adulthood, combined with
elective left AV valvuloplasty, carries a low operative risk
with an excellent long-term outcome and may reduce the
need for reoperation on the left AV valve.99
Patients with complete AVSDs, in contrast, develop
early pulmonary vascular disease, and although they may
still survive to adulthood without an operation, they develop
the Eisenmenger complex. Occasionally, the pulmonary
circulation in the older patient with complete AVSD is
protected by natural pulmonary stenosis or the early inser-
tion of pulmonary artery banding. Ideally, complete AVSD
should be corrected during the first year of life, including
those with tetralogy of Fallot, unless there are specific
contraindications.100
After repair of the AVSD, a significant number of patients
develop progressive left AV valve regurgitation. This is
usually secondary to separation of the two repaired compo-
nents of the reconstructed septal leaflet of the new left AV
valve and can be repaired by inserting extra sutures (Fig.
13.27). Occasionally, valvular tissue is deficient, necessitat-
ing valve replacement with a low-profile valve to prevent LV
outflow obstruction by the prosthetic valve. Subaortic steno-
sis can develop late after repair of AVSD. This is usually due
to turbulence produced by the abnormal attachment of the
FIGURE 13.25. Right ventricular enlargement associated with a
left AV valve, resulting in the development of a discrete
secundum atrial septal defect presenting in adult life. fibrous shelf. Radical excision of the fibrous tissue is usually
sufficient to relieve the obstruction (see Subaortic Stenosis,

for this reason, additional procedures targeting the arrhyth-

mia (maze procedure) should be considered at the time of
surgical closure of the defect.96–98

Atrioventricular Septal Defect

Patients with partial atrioventricular septal defects (AVSDs)
share the same hemodynamic burden of chronic right heart

FIGURE 13.26. Meier survival curve of freedom from late post- FIGURE 13.27. Reattachment of the two components of the recon-
operative atrial flutter/fibrillation. structed septal leaflet of the left atrioventricular valve.
354 chapter 13

above). Occasionally, more complex forms of reconstruction Patent Arterial Ducts

are required.
Small patent ductus arteriosus diagnosed in adulthood
Anomalous Pulmonary Veins carries a relatively high risk for endarteritis (about 1% to 2%)
because of the turbulence created, which may produce endo-
Anomalous drainage of one or more pulmonary veins is occa- thelial damage and infection; therefore, these defects should
sionally encountered in adult life. This may be isolated or be electively closed. In middle-aged patients, calcification
associated with a small ASD or specific syndrome of right and aneurysmal dilatation around the area of the duct may
pulmonary hypoplasia (scimitar syndrome) (Fig. 13.28). As necessitate the use of cardiopulmonary bypass to handle the
in isolated ASD, the need for correction depends on the size additional lesion. The presence of a large patent ductus arte-
of the left-to-right shunt. riosus in adults in usually associated with severe pulmonary
vascular disease, which may require heart-lung or double-
Ventricular Septal Defect lung transplantation.
Small VSDs may be diagnosed in adulthood during routine
medical examination or during repeated episodes of infec- Coronary Artery Anomalies
tious endocarditis involving the tricuspid valve on the RV
Anomalies of the mode of origin or course of the proximal
wall. The defect may be closed after adequate treatment of
coronary arteries can have a profound effect on myocardial
the endocarditis with intravenous antibiotics. Emergency
blood flow and can lead to severe ischemia or sudden death.
excision of the infected tissue and repair of the VSD during
Although these anomalies are uncommon, familiarity with
the acute stage are indicated in patients with uncontrolled
the different anatomic types and with the exact mechanisms
infection or uncontrolled heart failure. There still is no
involved in ischemia is essential if the treating clinician is
agreement about the management of small defects diagnosed
to recognize and effectively treat these potentially correct-
during routine medical examination. The risk for death or
able conditions before they produce irreversible damage.
major complications (i.e., endocarditis) is very small and
In addition, recognition of benign coronary anomalies
probably equal to the risk of surgical correction. Occasion-
and aberrant vessels is important in planning surgical repair
ally, small defects present with RV outflow obstruction or
of congenital heart disease. Anomalies occur in 10% to 30%
aortic cusp prolapse and aortic regurgitation. Resuspension
of cases of tetralogy of Fallot—most commonly, a prominent
of the right coronary or noncoronary cusp often reveals a
conus artery arising from the right coronary artery or the
larger VSD—partially occluded by the cusp—and may pre-
left anterior descending coronary or circumflex artery aris-
serve the aortic valve.67 Patients with large unoperated defects
ing from the right aortic sinus or right coronary artery. If
present with advanced pulmonary vascular disease and are
the aberrant vessel crosses the RV outflow tract, it may be
considered for heart-lung transplantation or double-lung
jeopardized at the time of surgical repair. There are several
transplantation, and repair of the defect (see later).
surgically important variations of coronary anatomy in
transposition of the great arteries (AV concordance, VA
[ventriculo-arterial] discordance) to be considered when per-
forming the arterial switch operation in an infant.101

Anomalous Origin of the Coronary Arteries From

an Inappropriate Aortic Sinus
Origin of the left coronary artery from the right coronary
sinus and, less commonly, the right coronary artery from the
left coronary sinus102 is known to produce sudden death or
episodic ischemia. The exact mechanism responsible has
been debated and was originally thought to be compression
of the proximal coronary artery by the pulmonary artery.
However, the most probable cause is compression of the
intramural segment of the anomalous coronary artery that
runs inside the aortic wall superficial to the intercoronary
commissure of the aortic valve. Clinical diagnosis of the
anomaly may be difficult, because objective evidence of isch-
emia may be lacking unless the patient undergoes repeated
stress exercise testing to reproduce the exact conditions nec-
essary to produce ischemia. Surgical treatment involves
removal of the intramural course of the artery by laying it
open into the lumen of the aorta, with careful reattachment
of the intima.102 This technique is effective, but there is a
risk of damaging the aortic valve or producing coronary dis-
section or obstruction by the intimal flaps. Alternatively, the
FIGURE 13.28. Hemianomalous pulmonary venous drainage in coronary artery can be bypassed, preferably using an arterial
association with right lung hypoplasia (scimitar syndrome). graft.
 su rgic a l t r e atm e n t 355

Anomalous Origin of the Left Coronary Artery may also be required. Survival after surgical repair depends
From the Pulmonary Artery on the amount of ischemic myocardial damage and degree of
mitral regurgitation.
This rare condition usually presents in infancy when pulmo-
nary vascular resistance decreases, with myocardial isch-
emia and LV failure. However, 10% to 15% of patients survive Coronary Artery Fistulas
into adulthood because an adequate circulation is established Coronary artery fistulas consist of a heterogeneous group of
between the right and left coronary arteries via intercoro- anomalies characterized by the presence of a fistulous tract
nary collateral vessels.103–105 Adults may be asymptomatic or between part of the coronary artery tree and a low-pressure
present with myocardial ischemia or mitral regurgitation chamber such as the right ventricle (40% of cases), the right
due to papillary muscle dysfunction. Even if there is no atrium (25%), the pulmonary artery (15%), and rarely, the
resting myocardial ischemia and ventricular function is left atrium, pulmonary veins, or superior vena cava. In almost
normal, repair is warranted because such patients remain at all of these conditions, survival to adulthood is usual, but
risk of ischemia, syncope, and sudden death. Although longevity could be reduced. The evolution of the anomaly
several surgical strategies for treating this condition have and its clinical importance depend on several factors, includ-
been described,106–110 the operation of choice is to create a ing the initial size and the exact location. Small fistulous
two-coronary artery system by transplanting the anoma- communications between the proximal left anterior descend-
lously arising vessel from the pulmonary artery. A reliable ing or right coronary artery on one side and the pulmonary
technique of anatomic correction of this anomaly with aortic artery on the other side usually cause trivial shunts and no
transfer of the coronary ostium to the middle of the left coro- significant coronary steal and appear to remain very small
nary aortic sinus has been developed.111,112 The exact location and therefore require no treatment. In contrast, large fistu-
of the coronary ostium in the sinus could have important lous tracts between one of the aortic sinuses near the coro-
implications for coronary flow.113 The technique consists of nary orifice or from one of the large coronary arteries usually
limited mobilization of the pulmonary artery button bearing continue to grow in size and length, becoming progressively
the coronary orifice, followed by threading it through the more tortuous.
transverse sinus into the lumen of the aorta after making a The relationship between the fistulous tract and the coro-
circular hole in the aortic sinus. The anastomosis is per- nary artery system can be complex in that the portion of the
formed from inside the aorta (Fig. 13.29). Mitral valve repair coronary artery proximal to the origin of the fistula can
markedly enlarge and appear to be part of the fistulous tract
but can be distinguished by the fact that it gives origin to
coronary artery branches and, to some extent, by its location,
which follows the normal course of the particular artery
affected. Definition of the exact location of the coronary
arteries to the fistulous tract is essential in planning the
appropriate corrective procedure. The objective is to remove
the fistulous tract in its entirety while preserving coronary
artery supply without ectatic segments. Attempts at defining
the exact cause of the fistulous tract and the associated coro-
nary orifice in relation to the fistulous tract can be deter-
mined at the time of operation after opening the fistulous
tract. Restoration of near-normal coronary anatomy (after
excision of the fistulous tract) can be accomplished via
various reconstructive procedures involving anastomosing a
flap or a button carrying the main coronary artery back to
the aorta, occasionally combined with arterial grafts to the
distal coronary branches. Distal interruption of the fistulas
is inadequate because it could result in recurrence through
rupture of the blind end into the same or another chamber
or progressive thrombosis involving some of the coronary
artery branches. Similarly, transcatheter closure may be
accompanied by such complications.114

Cyanotic Heart Disease

Tetralogy of Fallot
Uncorrected tetralogy of Fallot encountered in adulthood is
usually associated with many secondary changes, including
FIGURE 13.29. Technique of anatomic correction of an anomalous various degrees of RV fibrosis, acquired calcification or
left coronary artery with transfer of the coronary ostium to the atresia of the pulmonary valve, aortic valvular abnormalities
middle of the left coronary aortic sinus. (regurgitation or annular calcification), and, occasionally,
356 chapter 13

dilatation of the aortic root and ascending aorta. In addition, corrected before they produce irreversible changes. Pulmo-
the possibility of coronary artery disease should be excluded nary regurgitation secondary to transannular patches, mal-
by angiography. Late repair is usually feasible but carries a functioning monocusp, or complete conduit is well tolerated.
slightly higher risk.115–117 Such patients do not tolerate well Pulmonary regurgitation, however, in the long term may
free pulmonary regurgitation, and the use of a valve in the lead to reduced exercise capacity, RV dysfunction, arrhyth-
pulmonary position under these circumstances is advisable. mia, and possibly sudden death.122 QRS duration from the
Previous palliative procedures, such as shunts, must be taken surface electrocardiogram relates to RV size; when it exceeds
down, with repair of any distortion or narrowing of the pul- 180 ms, it becomes a sensitive and specific marker of sus-
monary arterial tree produced by the shunt. The shunts of tained ventricular tachycardia and sudden death late after
Waterston and Pott require separation of the aorta from the repair of tetralogy of Fallot.
pulmonary artery, with reconstruction of both vessels, which Restoration of right ventricular outflow competence with
may be extensive in some patients. The use of extracardiac pulmonary valve implantation, therefore, should be consid-
conduits to relieve the RV outflow obstruction is required ered when progressive RV dilatation and early dysfunction,
more often than in the pediatric age group. Pulmonary or new-onset tricuspid regurgitation, or arrhythmia occurs or
aortic homografts118,119 are the preferred types of conduits the patient becomes symptomatic. Timely pulmonary valve
because of their superior hemodynamic performance and implantation leads to an improvement of right ventricular
durability compared with other types of conduits, such as function and clinical status.123
stented porcine xenografts,120 pericardial valve conduits, or Magnetic resonance imaging has been established as the
prosthetic valves.121 method of choice for the noninvasive assessment of right
Residual or recurrent hemodynamic lesions leading to ventricular size, function, and mass and for quantifying pul-
RV dilatation are not uncommon in the adult patient with monary regurgitation. It can be used for serial assessment of
previous repair of tetralogy of Fallot. These lesions should be the patient (Fig. 13.30).123–125

A B 600

PA 400
Flow volume (mL/s)

200

0
0 200 400 600 800 1000 1200
RV
–200

–400
Trigger delay (ms)
A B

RV
* RPA

RVOT

LV LV

C D
FIGURE 13.30. (A) Diastolic right ventricular outflow tract cine pulmonary regurgitation (35%). (C) Four-chamber cine image
MRI image in patient with repaired tetralogy of Fallot with late showing dilated, hypertrophied right ventricle and tricuspid regur-
pulmonary regurgitation. (B) Flow map from through plane pulmo- gitation (arrow). (D) Cine image showing discrete right pulmonary
nary artery velocity map in the same patient showing significant artery stenosis (below asterisk).
 su rgic a l t r e atm e n t 357
If degeneration of an implanted homograft in the pulmo-
nary position occurs leading to pulmonary stenosis and
again regurgitation, nonsurgical percutaneous insertion of a
new pulmonary valve is now an option in selected special-
ized centers,126 as mentioned earlier (Fig. 13.24).
Progressive aortic root dilatation potentially leading to
aortic regurgitation can occur in a subset of Fallot patients,
operated and unoperated and may warrant aortic valve and/or
root replacement.127 There is fresh evidence that this is
caused by marked histologic abnormalities in the wall of the
aortic root and the ascending aorta.128

Tetralogy of Fallot with Pulmonary Atresia

A significant number of patients with tetralogy of Fallot with
pulmonary atresia survive into adulthood when there is pul-
monary blood supply through a set of true pulmonary arter-
ies supplied by a patent ductus arteriosus, a previously
constructed shunt, or multiple aortopulmonary collateral
arteries (MAPCAs). The intracardiac anatomy is usually
identical to that found in tetralogy of Fallot with atresia or
absence of the RV outflow tract. Aortic root dilatation is
often marked in these patients and may predispose to aortic
root rupture and sudden death.
Management of this condition depends largely on the
anatomy of the pulmonary circulation. The blood supply to
the different segments may be absent or may be taken by a
transpulmonary artery (connected to a central pulmonary
artery derived from the sixth arch), by an MAPCA, or by a
combination (dual blood supply).129 Accurate definition of all
the branches supplying the lung (Fig. 13.31) is essential to the
formulation of a plan for surgical treatment, consisting of FIGURE 13.32. Repair of pulmonary atresia with homograft conduit
one or, usually, more multiple stages of unifocalization130–132 from the right ventricle to the central pulmonary artery.
of the pulmonary arteries by direct anastomosis of the differ-
ent branches or interposition of segments of azygos vein or
Gore-Tex shunt combined with ligation of MAPCAs supply-
ing segments with dual blood supply. Total correction is per-
formed by closing the VSD and inserting a homograft conduit
from the right ventricle and the reconstructed pulmonary
artery tree (Fig. 13.32). In some patients with absent central
pulmonary arteries, unifocalization is not a real option; for
these patients, lung or heart-lung transplantation may be the
only recourse.

Transposition of the Great Arteries

Uncorrected transposition is incompatible with survival into
adulthood unless there are additional lesions that ensure
adequate mixing of blood and possible protection against
pulmonary vascular disease. The most common such addi-
tional abnormalities are large VSDs with or without pulmo-
nary stenosis. Patients with transposition and large VSDs
develop severe pulmonary vascular disease at an earlier age
than those without transposition.133 In severely symptomatic
patients, heart-lung transplantation is the only treatment
option.134,135 The combination of transposition of the great
arteries, VSD, and pulmonary stenosis can be treated with
the Rastelli operation,136 which consists of redirection of
blood through the VSD to the RV outflow tract into the aorta
and insertion of an extracardiac conduit from the right ven-
FIGURE 13.31. Aortopulmonary collateral arteries in a patient tricle to the transected pulmonary artery (Fig. 13.33). The
with tetralogy of Fallot and pulmonary atresia. Lecompte operation [redirection entre ventriculaire (REV)]
358 chapter 13

Senning) may present with arrhythmia or symptoms due to

stenosis of the systemic or pulmonary venous pathways or
RV dysfunction. Relief of baffle obstruction can be achieved
Pledgets with baffle revision, enlargement of the pulmonary venous
atrium, or both.
Right ventricular dysfunction is common in adults after
atrial switch operation as the RV has to sustain systemic
pressure permanently. It seems that progressive structural
deterioration of the right ventricular myocardium takes
place after the atrial switch procedure. Fibrosis of the sys-
temic right ventricle detectable by late gadolinium enhance-
ment magnetic resonance imaging could be found especially
in older patients and relates not only to RV dysfunction but
also to clinical events such as arrhythmia or syncope, sug-
gesting prognostic importance of this finding (Fig. 13.35).138
Anatomic correction (takedown of the Mustard or
Senning procedure combined with an arterial switch) after
pulmonary artery banding (to retrain the left ventricle for the
systemic circulation) has been considered a “conventional”
Pledgets
option for patients with failing systemic right ventricles.139
FIGURE 13.33. Use of a right ventricle to pulmonary artery conduit
in the Rastelli operation.
However, there are very limited data on the use of this
approach in this group of patients. The future application of
this strategy will depend on the timing of the operations and
possibly on the use of strategies to induce physiologic hyper-
constitutes an alternative approach (Fig. 13.34).137 Incomplete trophy as suggested by experimental studies.140 Deterioration
or L-transposition of the great arteries is usually associated in RV function can ultimately affect LV structure and func-
with AV and ventriculoarterial discordance (corrected trans- tion through ventriculoventricular interaction.141
position). In these patients, surgical treatment is commonly
required for left AV valve regurgitation and associated anom-
Tricuspid Atresia and Double-Inlet Ventricle
alies such as VSD and pulmonary outflow obstruction.
Adults with transposition of great arteries who have The conditions of tricuspid atresia and double-inlet ventricle
undergone a previous atrial switch procedure (Mustard or are characterized by severe hypoplasia or absence of one of the

FIGURE 13.34. Correction of transposi-

tion of the great arteries with ventricular
septal defect and pulmonary stenosis.
(A) View from right ventricular infun-
dibulectomy of the ventricular septal
defect and the portion of the interven-
tricular septum to be excised. (B) The
infundibular septum has been resected.
(C) The intraventricular baffle has been
sutured into place. (D) The pulmonary
bifurcation is passed anterior to the
ascending aorta. (E) The posterior rim of
the distal pulmonary trunk is sutured to
the top of the infundibulectomy. (F) An
anterior patch is sewn over the pulmo-
nary outflow tract.
 su rgic a l t r e atm e n t 359

A B

C D

FIGURE 13.35. Magnetic resonance imaging of a patient after right ventricle is severely dilated (A,C). There is extensive fibrosis
Mustard repair for transposition of the great arteries. Cine images of the right ventricular free revealed by late gadolinium enhance-
show thin myocardium of the right ventricular free wall and the ment magnetic resonance imaging (white areas in B and D).

ventricular chambers, rendering biventricular repair impos- tunnel) or by an extracardiac conduit. The extracardiac total
sible or impractical. These patients are considered for opera- cavopulmonary connection has become the Fontan modifi-
tions that direct systemic venous return to the lung.142–144 cation of choice in patients older than 3 years of age. This
The original Fontan operation142 consisted of anastomosing technique preserves147,148 the hemodynamic benefits ascribed
the right atrium to the pulmonary artery with interposition to the total cavopulmonary anastomosis, yet avoids the
of homograft values. These operations can be considered only potential disadvantages of aortic cross-clamping and compli-
if pulmonary vascular resistance is low, the pulmonary arter- cations related to the intraatrial placement of baffles or
ies are of adequate size, ventricular function is not signifi- tunnels, including leaks, stenoses, arrhythmias, and throm-
cantly impaired, and there is no AV valvular dysfunction. boembolic complications in the systemic circulation.147,148
Directing systemic venous return to the lung can also be In patients with marginally elevated pulmonary vascular
achieved by total cavopulmonary shunt,145,146 which avoids resistance, the addition of a fenestration between the sys-
the use of the atrium as a pumping chamber. This approach temic venous channel and the atrium has added substantially
has many advantages. to the safety of the operation.149 The fenestration can then
A total cavopulmonary connection (TCPC) can be estab- be closed by transcatheter insertion of an umbrella device,
lished by connecting the superior vena cava to the pulmo- providing balloon occlusion of the orifice does not cause
nary arteries (bidirectional cavopulmonary anastomosis) and excessive rise in systemic venous pressure (>15 mm Hg).
diverting the inferior vena cava return to the pulmonary In addition, protagonists of the extracardiac Fontan opera-
arteries either by a baffle within the right atrium (lateral tion have advocated that the need for fenestration be
360 chapter 13

assessed after cardiopulmonary bypass is discontinued, when

hemodynamics can be accurately evaluated.149 Another
approach that we have used is the creation of a temporary
“fenestration” by a cruciate incision in the baffle that closes
spontaneously after a period of several weeks or months.
The judicious use of the Fontan operation has provided
good palliation for a large number of patients. There are still
concerns, however, regarding the very long-term results of
this procedure.150–152 Complications late after the Fontan
operation include atrial arrhythmias, decreased ventricular
function, increasing cyanosis, intraatrial thrombus forma-
tion, protein-losing enteropathy, liver dysfunction, and
finally multiorgan failure and premature late death. Many of
these complications are related to surgical pathways, atrial
distention, and unfavorable fluid dynamics mainly in atrio-
pulmonary connections. Fontan conversion to a total cavo-
pulmonary connection with concomitant arrhythmia surgery
is an option for these patients with a failing Fontan circula-
tion and can improve clinical status and exercise tolerance
and reduce arrhythmia propensity.153
Some patients can be adequately palliated by systemic-
to-pulmonary artery shunts, a Glenn anastomosis, or both
as a long-term solution.154 Survival rates for such selected
patients with definitive non-Fontan palliations may compare
favorably with those from published Fontan series. Arrhyth-
mia is a major cause of morbidity for these patients and
relates to both ventricular dysfunction and death. Another
serious complication of a Fontan-type operation is protein
losing enteropathy.155,156 This condition may respond to con-
version of the Fontan operation to total cardiopulmonary
correction or could necessitate heart transplantation.156

Heart-Lung Transplantation for Congenital

Heart Disease
Transplantation constitutes an effective form of treatment
for patients with congenital heart disease who develop irre-
versible myocardial damage or advanced pulmonary vascular
disease. These patients can experience specific anatomic and
functional changes related to congenital heart disease or
secondary to complex or less complex surgical treatment.
This point must be addressed if transplantation is to be suc-
cessfully accomplished.
Abnormalities of situs, such as situs inversus or situs
ambiguus, can be treated through technical modifications of
the transplant procedure (Fig. 13.36).157 Similarly, abnormal
pulmonary or systemic venous return, malposition of the
great arteries, and aortic artery anomalies can be corrected
with the use of donor tissue.
In patients with marginally elevated pulmonary vascular
disease (three to five units), cardiac transplantation can lead
to severe and acute failure of the thin-walled normal donor
right ventricle. In patients with potentially reversible pulmo-
nary vascular disease, such as those with long-standing pul-
monary venous hypertension due to chronic heart failure,
tests of reversibility, using pulmonary vasodilators158 such as
prostacyclin or inhaled nitric oxide, can be of value in decid-
ing whether orthotopic heart transplantation should be con-
sidered. In these patients, a large heart or a heart from a FIGURE 13.36. Technique of heart implantation in recipients with
abnormalities of situs inversus (A) and situs ambiguous (B).
domino procedure159 for a patient who requires heart-lung
transplantation for a condition causing some degree of pul-
 su rgic a l t r e atm e n t 3 61
monary hypertension can be valuable. Alternatively, hetero- 13. Doering CW, Jalil JE, Janiki JS, et al. Collagen network
topic heart transplantation can be considered if the recipient remodelling and diastolic stiffness of the rat left ventricle
heart has a relatively healthy pulmonary ventricle capable of with pressure overload hypertrophy. Cardiovasc Res 1988;22:
supporting the pulmonary circulation.160,161 686–695.
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SEC TION III

Valvular Heart
Disease
 1 Valvular Heart Disease:
4 Anatomic Abnormalities
Hugh A. McAllister, Jr., L. Maximilian Buja,
and †Victor J. Ferrans

Floppy Valve (Myxomatous Degeneration) and Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

Connective Tissue Dyscrasias . . . . . . . . . . . . . . . . . . 369 Prosthetic Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Endocrine and Metabolic Valvular Diseases. . . . . . . . . . 370 Conduits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Collagen Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . 372 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Congenital Valvular Heart Disease . . . . . . . . . . . . . . . . . 375

Key Points surface area of the affected leaflets (Fig. 14.1), which are
voluminous, hooded, and white; however, they transillumi-
• Floppy mitral valve is due to myxomatous degeneration
nate with ease, especially before fixation. On sectioning, the
and can occur as an isolated entity or as a component of
myxomatous consistency of the center of the leaflet is often
Marfan’s syndrome or other connective tissue dyscrasias.
apparent on gross examination. Small foci of ulceration with
• Endocrine and metabolic conditions producing valvular
occasional superimposed thrombi may be noted on the atrial
dysfunction include carcinoid heart disease, cardiac amy-
surface of the affected mitral leaflet.1 The chordae tendineae
loidosis, ochronosis, mucopolysaccharidoses, lipid storage
often are elongated and thin; however, some localized thick-
diseases, hyperlipidemias, and gout.
ening may be present at their insertions into the valve leaf-
• Collagen vascular diseases that produce valvular heart
lets (Fig. 14.2). Rupture of the chordae tendineae is common
disease include rheumatic valvulitis, rheumatoid valvu-
in myxomatous degeneration of the mitral valve: less fre-
litis, lupus erythematosus valvulitis, and other related
quently, myxomatous degeneration may result in aneurys-
conditions. Postinflammatory valvular disease is mani-
mal dilatation and rupture of a mitral leaflet. Commissural
fested by fibrosis and commissural fusion leading to
fusion is not a feature of the floppy valve. Because these
incompetence and stenosis.
valves are predisposed to infective endocarditis, gross evi-
• The most common congenital malformation of heart
dence of this complication must be sought by the surgical
valves is the bicuspid aortic valve; these valves are prone
pathologist, so that appropriate sections can be obtained for
to progressive fibrosis, calcification, and stenosis.
culture before fixation of the valve.
• Infective endocarditis can develop on previously diseased
Microscopically, the spongiosa contains stellate cells
or normal valves and produce valvular incompetence and
embedded in a matrix rich in proteoglycans. Characteristi-
embolization of infected thrombi.
cally, there is focal to extensive replacement of the normal
• Complications of prosthetic heart valves include throm-
dense, homogeneous collagen of the fibrosa by this myxoma-
bosis of mechanical valves and degeneration and calcifi-
tous tissue. This histologic pattern is in contrast to that seen
cation of bioprostheses.
in most valvular heart diseases, in which the spongiosa of the
leaflets is partially or completely replaced by dense fibrous
Floppy Valve (Myxomatous Degeneration) tissue. The collagen in the chordae tendineae may show
and Connective Tissue Dyscrasias changes similar to those in the fibrosa. The atrialis of the
leaflet generally contains a variable degree of fibroelastic pro-
Although myxomatous degeneration has been described in liferation, and superficial ulceration with microscopic fibrin
tricuspid, aortic, and pulmonary valves, the mitral valve is deposition is not uncommon. Unless there is superimposed
most commonly involved, and the posterior leaflet is affected infective endocarditis, there is no evidence of inflammation
more often and more severely than is the anterior leaflet. or vascularization. Ultrastructurally, there is focal loss of the
Grossly, the most outstanding feature is marked increase in normal orderly cross-banding of collagen fibers. Microscopi-
cally, small areas of myxomatous degeneration may be found
†
Posthumously, Dr. Ferrans remains an author of this chapter. Dr. near the free edges of normal or diseased valves and should not
Ferrans died in October 2001. be confused with the diffuse findings in floppy valves.

369
37 0 chapter 14

mitral valve appear to be more common in type III, the

benign hypermobile form.2 The most common valvular
lesion in osteogenesis imperfecta is aortic regurgitation;
mitral regurgitation and combined aortic and mitral regurgi-
tation are less common. The aortic regurgitation results from
dilatation of the aortic root and deformity of the valvular
leaflets, which become abnormally translucent, weak, and
elongated. Aneurysms of the sinuses of Valsalva also occur.
The mitral annulus is dilated, the mitral leaflets are attenu-
ated and redundant and tend to prolapse, and the chordae
tendineae may rupture.2 In cutis laxa, the most common
cardiac lesions involve the aorta, pulmonary artery, and pul-
monary veins; less commonly, there may be myxomatous
degeneration of the aortic or mitral valves.2 The aortic and
mitral valves are the cardiac valves most commonly involved
in relapsing polychondritis. Lesions may be microscopically
FIGURE 14.1. Floppy mitral valve. The most outstanding feature is identical to those in the other connective tissue
a marked increase in the surface area of the leaflets. They are volu- dyscrasias.1
minous, hooded, and white; however, they transilluminate with
ease. Commissural fusion is not a feature of the floppy valve.

Endocrine and Metabolic Valvular Diseases

Myxomatous degeneration of the cardiac valves, with In carcinoid heart disease, there is either focal or diffuse
resulting insufficiency, often occurs in connective tissue plaque-like thickening of valvular and mural endocardium
dyscrasias such as Marfan’s syndrome, osteogenesis imper- and, occasionally, of the intima of the great veins, coronary
fecta, cutis laxa, and relapsing polychondritis. This group of sinus, pulmonary trunk, and main pulmonary arteries. The
diseases may also be associated with cystic medial degenera- fibrous tissue is atypical and limited in the majority of
tion of the aorta. Adults with Marfan’s syndrome most com- instances to the right side of the heart. When the pulmonary
monly have myxomatous degeneration of the aortic valve; in valve is involved, deposition is almost exclusively on the
children, however, the mitral valve is more commonly arterial aspect of the valve cusps (Fig. 14.3). When the tricus-
involved.2 The affected mitral and aortic leaflets contain an pid valve is involved, however, the fibrous tissue is located
accumulation of myxoid material mainly in the spongiosa. predominantly on the ventricular aspect, often causing the
Recent studies have shown the importance of matrix metal- leaflets to adhere to the adjacent ventricular wall.4 Similar
loproteinases in the pathogenesis of these lesions in the lesions may be observed in the mitral and aortic valves in
Marfan syndrome.3 The Ehlers-Danlos syndrome is a hetero- patients with a patent foramen ovale or a functioning bron-
geneous group of several genetically distinct disorders of chial carcinoid tumor.5 In some patients with predominant
connective tissue synthesis, which differ in major clinical right-side carcinoid heart disease, the mitral and aortic valves
features, inheritance patterns, and biochemical defects. Car- also may be involved to a lesser degree. Microscopically,
diovascular lesions have been described in types I to IV; these lesions contain fibroblasts, myofibroblasts, and smooth
however, myxomatous degeneration and prolapse of the muscle cells embedded in a distinctive stroma, which is rich
in collagen and proteoglycans but lacking in elastic fibers.
Blood vessels, often thick-walled, may be immediately adja-
cent to the valve leaflets. Lymphocytes and plasma cells are
frequently located adjacent to these blood vessels.
Histologically, similar valvular and endocardial lesions
have been described in patients taking methysergide6 and
ergot7; however, the mitral and aortic valves are most com-
monly involved in these cases. Similar valvular lesions have
been described in patients taking fenfluramine and phenter-
mine for appetite suppression.8
The heart valves are involved in 50% of patients with
cardiac amyloidosis. Valvular involvement is usually
minimal, but discrete nodules measuring from 1 to 4 mm in
diameter are occasionally present on the valves either in the
cusps or in the annulus.2 Rarely, valvular involvement is
diffuse, resulting in thick, rigid cusps and stenotic or regur-
gitant orifices (Fig. 14.4). The four cardiac valves are affected
with almost equal frequency.
FIGURE 14.2. Floppy mitral valve. The chordae tendineae are often All heart valves and valvular annuli, especially the mitral
elongated and thin; however, some localized thickening may be and aortic valves, are sites of heavy pigment deposition in
present at their insertion into the valve leaflets. patients with ochronosis.2 Although the pigment deposition
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 371

FIGURE 14.4. Amyloid valve disease. Valvular involvement is

usually minimal; however, diffuse involvement, as illustrated in
this heart, can occur, resulting in thick, rigid cusps and stenotic or
regurgitant orifices.

extremely soluble and difficult to preserve. In addition, small

granular cells are present, which contain membrane-limited
electron-dense material associated with fragments of colla-
gen fibrils. The valve thickening is due to the presence of the
cells and to an increase in the amount of fibrous connective
FIGURE 14.3. Carcinoid heart disease, pulmonic valve. Heavy
tissue.
deposition of collagen, lacking in elastic fibers, occurs almost exclu-
sively on the arterial aspect of the valve cusps, resulting in pul- In Fabry’s disease, the glycosphingolipid is deposited
monic stenosis (Movat pentachrome, ×25). within the cardiac valves, occasionally resulting in valvular
dysfunction.2 The mitral and aortic valves are the two valves
that most commonly present clinical problems. There may

is most prominent at the bases of the mitral and aortic valves

and annulus fibrosus, the edges of the cusps may be rough-
ened and fused for 1 to 2 mm at their bases; the cusps may
be focally calcified. The ochronotic pigment appears blue-
black on gross examination and yellow-tan in histologic
sections. Infective endocarditis may occasionally be super-
imposed, especially when the valves are heavily calcified.
The cardiac valves may be involved in any of the muco-
polysaccharidoses, most frequently in Hurler’s syndrome
(mucopolysaccharidosis I).2 The valves are considerably
thickened, particularly the mitral valve; right-sided cardiac
valves are less severely affected than those in the left side of
the heart (Fig. 14.5). The valvular thickening is most pro-
nounced at the free margins, which have an irregular, nodular
appearance. The commissures are not fused. The chordae
tendineae of the atrioventricular valves are moderately short-
ened and thickened. Calcific deposits occur in the angle just
beneath the basal attachment of the posterior mitral leaflet
(mitral annular calcification), in the mitral leaflets, and in
the aortic aspect of the aortic valve cusps. The valves contain
FIGURE 14.5. Hurler’s syndrome, mitral valve. The valvular thick-
large, oval or rounded connective tissue cells (Hurler cells) ening is most pronounced at the free margins, which have an irregu-
filled with numerous clear vacuoles, which are the sites of lar, nodular appearance. The commissures are not fused. The
deposition of acid mucopolysaccharide.2 This material is chordae tendineae are moderately shortened and thickened.
37 2 chapter 14

be thickening of the valves with interchordal hooding, or the atrioventricular valves and on the ventricular surface of
there may be attenuation of the chordae with thickening and the semilunar valves.4 Occasionally, a few verrucae may be
ballooning of the mitral valve. Commissural fusion is not a distributed elsewhere over the cusps. They are also charac-
feature of Fabry’s disease. teristically present on the chordae tendineae, especially
Type II hyperlipoproteinemia (familial hypercholesterol- those of the mitral valve, and not infrequently, they extend
emia) exists in homozygous and heterozygous forms, which over the posterior leaflet of the mitral valve onto the endo-
differ in the severity and age of onset of clinical symptoms. cardium of the left atrium. The verrucae tend to conglomer-
Aortic valvular disease is frequent in homozygous patients ate on the corpora arantii of the aortic valve and extend in a
but does not usually occur in heterozygous patients. The row along the semilunar cusps. Diffuse thickening of the
aortic valve may be markedly stenosed by fibrous tissue, valves, except the pulmonary, is a less conspicuous but fre-
deposits of foam cells, and cholesterol crystals in the cusps. quent gross alteration.
Thickening of the mitral valve, which results in both steno- Microscopically, the verrucae may have the appearance
sis and regurgitation, and thickening of the pulmonary valve of either thrombi, formed by the deposition of platelets and
and endocardium by foam cells also occur.2 fibrin on the surface of the valve, or extruded collagen that
Patients with gout most commonly develop dysfunction has undergone fibrinoid degeneration. The region immedi-
due to hypertension secondary to renal damage; however, ately adjacent to the vegetation shows marked proliferation
tophi occasionally may be present in the heart, most com- of fibroblasts, as well as edema and numerous lymphocytes.4
monly in the mitral valve and the endocardium of the left The inflammatory process is observed most frequently in the
ventricle and, less frequently, in the mitral annulus and auricularis layer of the atrioventricular valves and the ven-
aortic and tricuspid valve leaflets.2,9 To establish the diagno- tricularis layer of the semilunar valves. A nonspecific inflam-
sis histologically, appreciable amounts of uric acid must be matory process, which may involve the entire valve and ring,
identified in the tophi to distinguish them from small consists of edema, increased numbers of capillaries, and a
amounts of uric acid that my be deposited on previously variety of inflammatory cells (mainly lymphocytes; occa-
existing fibrocalcific lesions. Urate deposits are histochemi- sionally polymorphonuclear leukocytes predominate).
cally identifiable by fixation in absolute ethanol, followed by Plasma cells, fibroblasts, and other mononuclear cells are
staining by the De Galantha method. often present in variable numbers. Usually the valve also
contains Anitschkow and Aschoff cells, which may be
arranged in nodules or in rows and often surround foci of
Collagen Vascular Diseases eosinophilic fragmented collagen, fibrinoid, or both. Aschoff
cells may be multinucleated.10 These lesions are typically
accompanied by characteristic Aschoff nodules in the
Rheumatic Valvulitis
myocardium.4,10,11
Acute rheumatic fever produces a pancarditis; however, val- Gross alterations of the cardiac valves become more pro-
vular involvement is responsible for the most important nounced as a result of recurrent rheumatic valvulitis. Thick-
long-term consequences. In the acute phase of rheumatic ening, irregularity of the surfaces, and gross vascularization
valvulitis, the most conspicuous lesions are minute, translu- are usually present. This thickening is usually most pro-
cent nodules (verrucae) along the lines of closure of the valve nounced in the distal third of the valve leaflets.4 The chordae
cusps (Fig. 14.6). These are most frequently observed in the tendineae become thicker and shorter, with especially prom-
mitral and aortic valves, less often in the tricuspid, and rarely inent thickening at their insertions into the valve leaflets.
in the pulmonary valve. They vary in diameter from less Verrucae in various stages of activity and healing may be
than 1 mm to 3 mm and are located on the atrial surface of observed. In addition to being thickened, the aortic cusps
may be considerably shortened, with their free margins rolled
and inverted toward the sinus pocket. Fibrous adhesions
are commonly present at the commissures, and verrucae in
various stages of activity may extend across the commis-
sures of aortic cusps. In recurrent valvulitis, there is a higher
incidence of verrucae on the valves of the right side of the
heart, and microscopic observation reveals considerable
fibrosis, an apparent increase in elastic tissue, and inflam-
matory changes in various stages of activity.4,11 The fibrosis
and inflammation involve the rings as well as the leaflets.
This histologic pattern differs from that of acute valvulitis,
in which the thickening of the valves is the result only of
edema and inflammation. Also in contrast to the appearance
of acute valvulitis are numerous arteries with thick muscu-
lar walls in the ring and proximal portion of the valve.
In chronic rheumatic valvulitis, the alterations described
in recurrent valvulitis are most advanced. Usually, the
FIGURE 14.6. Acute rheumatic valvulitis, mitral valve. Fibrinoid
diffuse thickening and fibrosis of the valves have resulted in
necrosis is represented by minute, translucent nodules (verrucae), 1 loss of elasticity and in narrowing of the orifice (Fig. 14.7).
to 3 mm in diameter, along the lines of closure. Thickening, fusion, and shortening of the chordae tendineae
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 37 3
fibroblasts and collagen fibers. As chronicity progresses, the
number of fibroblasts decreases, and the verrucae become
dense, hyalinized scars.

Rheumatoid Valvulitis
Rheumatoid granulomas may occur in any of the cardiac
valves but are most common in the mitral and aortic valves.12
Involvement may be focal or diffuse and is usually most
prominent in the midportion or base of the valve (Fig. 14.9).
The chordae tendineae are usually uninvolved, but occasion-
ally, they may be fibrotic and shortened. Commissural fusion
is rare. Rheumatoid nodules are most commonly located
within the valve leaflets and are enclosed by fibrous tissue;
rarely, a rheumatoid nodule may erode the surface of the
valve, so that the necrotic center of the nodule communi-
FIGURE 14.7. Chronic rheumatic aortic stenosis. Diffuse thicken- cates with a cardiac cavity (Fig. 14.10). In these unusual
ing and fibrosis of the valves with commissural fusion resulting in occurrences, there may be superimposed thrombus or infec-
marked aortic stenosis. Also note the extensive poststenotic dilata- tive endocarditis. Verrucae of fibrinoid necrosis, common in
tion of the ascending aorta. rheumatic valvulitis and systemic lupus erythematosus, are
not a feature of pure rheumatoid valvulitis.

of the mitral valve are usually pronounced (Fig. 14.8). In

addition, focal deposits of calcium salts may be present.
Lupus Erythematosus Valvulitis
These deposits may be extensive and may project to the atrial Lupus erythematosus valvulitis (atypical verrucous endocar-
and ventricular surfaces, causing further distortion. Ossifi- ditis of Libman and Sacks) is recognized as a specific valvular
cation, complete with hematopoiesis, may occur, causing abnormality occurring in systemic lupus erythematosus.
further distortion.11 Verrucae are less frequent in chronic Any valve may be involved, but the mitral and tricuspid
valvulitis than in recurrent valvulitis and are broad and flat. valves are most often affected (Fig. 14.11). The verrucae may
Active inflammation is less pronounced in chronic than in be located on either side of a valve cusp but most frequently
recurrent valvulitis and usually consists of scattered foci of are present on the ventricular surface of the posterior mitral
perivascular cuffing with lymphocytes. The grossly apparent leaflet or in the valve ring; involvement of the anterior mitral
thickening is due to an increase in fibrous and elastic tissue leaflet is infrequent. The lesions have no special tendency to
throughout the entire leaflet including the rings and the tips occur along the free edge of the valves and may be scattered
of the valves. The fibrous connective tissue is usually homo- on the chordae tendineae and atrial or ventricular mural
geneous and hyaline. These valves are vascularized by capil- endocardium. The lesions are small, usually ranging in size
laries and thick-walled vessels, which are most numerous in from 1 to 4 mm in diameter, but rarely may reach a diameter
the superficial layers. The verrucae no longer consist of mate- of 8 to 10 mm. They are sterile, dry, granular pink vegetations
rial showing fibrinoid necrosis, but are organized and contain that may be single or multiple in conglomerates.4 Histologi-
cally, the verrucae consist of a finely granular, eosinophilic,

FIGURE 14.8. Chronic rheumatic mitral stenosis. Note the thick-

ening, fusion, and shortening of the chordae tendineae, as well as FIGURE 14.9. Rheumatoid valve disease, mitral valve. Involvement
diffuse thickening and fibrosis of the valves, with commissural may be focal or diffuse, as in this case, and is usually most promi-
fusion. The left atrium is enlarged and contains a mural nent in the midportion of the base of the valve. The chordae tendin-
thrombus. eae are usually uninvolved, and commissural fusion is rare.
374 chapter 14

both diseases, the cardiac valves most commonly involved

are the mitral and the aortic.12 Valvulitis is most unusual in
Wegener’s granulomatosis. The mitral valve is most com-
monly involved by the inflammatory process, which may
result in subsequent fibrosis with commissural fusion resem-
bling rheumatic mitral stenosis.13 Primary valvulitis is not a
feature of dermatomyositis. Diseases that may result in val-
vulitis but are manifested most commonly by aortitis include
syphilis, ankylosing spondylitis, psoriatic arthritis, Reiter’s
syndrome, and granulomatous aortitis.

Lesions Resembling Collagen Vascular

Disease Valvulitis
Although not collagen vascular diseases, three entities that
may result in fibrous thickening of the cardiac valves and
thickening and fusion of chordae tendineae are Whipple’s
disease, endomyocardial fibrosis with eosinophilia, and radi-
ation-induced disease. In Whipple’s disease, the valve most
commonly involved is the mitral, and then the tricuspid and
the aortic valves.14 The gross deformity closely resembles
that seen in chronic rheumatic heart disease, with diffuse
thickening and fibrosis of the valve leaflets and chordae ten-
dineae and rolling of the free edges of the leaflets (Fig. 14.12).
Microscopically, the valve substance contains large macro-
phages filled with granules that are positive for the periodic
acid-Schiff reaction; these granules are identical to those
found in the epithelial cells of the small intestine in patients
with this disease. Proliferating fibrous tissue and chronic
inflammatory cells are commonly associated with the peri-
odic acid-Schiff–positive macrophages. Scattered rod-shaped
bodies, measuring 1.5 to 2.0 μm in length and 0.2 to 0.4 μm
in diameter, are present intracellularly and extracellularly.
FIGURE 14.10. Rheumatoid valve disease, mitral valve. Rheuma- These bodies, as well as membrane-bound masses of fibrillar
toid granulomas with extensive contiguous fibrosis involve the base material within the macrophages, are identical to those
and midportion of a mitral valve. Another rheumatoid granuloma is described in jejunal biopsies of patients with Whipple’s
present in the adjacent subvalvular myocardium (Hematoxylin and
disease14 and are thought to represent bacteria (Tropheryma
eosin, ×75).

fibrinoid material, which may contain hematoxylin bodies.

In a general sense, these hematoxylin bodies are the tissue
equivalent of the lupus erythematosus cell of the blood and
bone marrow.4 The verrucous endocardial lesions result from
degenerative and inflammatory processes of the endocar-
dium and deeper layers of the valves. An intense valvulitis
is present, which is characterized by fibrinoid necrosis of the
valve substance and is often contiguous with the vegetations.
Exudative and proliferative cellular reactions are present in
the deeper layers of the valve. Healing of these lesions may
produce foci of granulation tissue, which develop into focal
fibrous thickening in the valves or in the mural endocar-
dium. Rarely, bacterial endocarditis may be superimposed on
the Libman-Sacks lesions.12

FIGURE 14.11. Lupus erythematosus valvulitis (atypical verrucous

Other Collagen Vascular and Related Diseases endocarditis of Libman and Sacks), mitral valve. The lesions repre-
Valvular lesions in scleroderma are distinctly rare; the most sent fibrinoid necrosis as sterile, dry, granular vegetations that may
be single or multiple in conglomerates. They have no special ten-
common lesion is nonbacterial thrombotic endocarditis. In dency to occur along the free edge of the valves and may be scattered
patients with thrombotic thrombocytopenic purpura, non- on the chordae tendineae and atrial or ventricular mural
bacterial thrombotic endocarditis frequently is present. In endocardium.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 375
Commissural fusion is usually minimal, involves only one
commissure, and is only rarely extensive.17,20 Another
common reason for surgical excision of a bicuspid aortic
valve is infective endocarditis. The moderately high inci-
dence of infective endocarditis in patients with bicuspid
aortic valves is well known. Therefore, each of these valves
must be examined closely by the surgical pathologist for
superimposed infective endocarditis, and if suspicious lesions
are noted, sections must be taken for microbiologic culture
before fixation.
The quadricuspid aortic valve is far less common than
the bicuspid valve. The most frequent indication for surgical
excision of these valves is aortic insufficiency. Most com-
monly, one of the cusps is rudimentary; however, the gross
and microscopic appearance of the valves is usually other-
wise normal.21 Quadricuspid pulmonary valves rarely cause
cardiac dysfunction unless there is associated dysplasia of
FIGURE 14.12. Whipple’s disease, mitral valve. The gross defor- the valve or a coexisting congenital cardiac defect. As in
mity closely resembles that seen in chronic rheumatic valve disease,
with diffuse thickening and fibrosis of the valve leaflets and chordae
quadricuspid aortic valves, the fourth cusp is usually small
tendineae and rolling of the free edges of the leaflets. and rudimentary, with the remaining cusps appearing mor-
phologically normal.21
Valve dysplasia may affect any of the cardiac valves, most
frequently the aortic valve; however, 25% of patients have
whippelii), which are known to be associated with this multiple valve involvement.22 The dysplastic changes may be
disease.15 In endomyocardial fibrosis with eosinophilia, the severe and extensive, so that the entire valve is distorted, or
valves most commonly involved are the mitral and the tri- mild and focal, so that valve function is not impaired. A
cuspid, with a lesser incidence of aortic valve involvement. dysplastic stenotic pulmonary valve is frequently present in
There is fibrous thickening of endocardium, with superim- patients with Noonan’s syndrome. The dysplastic semilunar
posed fibrin thrombus beneath either the posterior mitral valve may be unicuspid, bicuspid, or tricuspid; failure of
leaflet or the posterior or septal tricuspid leaflet. These leaf- development of the commissures also may occur, resulting
lets become adherent to the underlying mural endocardium, in a dome-shaped valve. Stenosis is secondary to the marked
which results in regurgitation.16 The aortic valve cusps are thickening of the individual valve cusps. The spongiosa of
occasionally thickened by vascularized fibrous tissue, which the dysplastic valve is quite cellular and composed primarily
is superimposed on the ventricular aspects of the cusps. The of small spindle cells resembling fibroblasts, set in an acid
commissures of the aortic valve may become fused by fibrous mucopolysaccharide matrix and haphazardly arranged
tissue with superimposed fibrin thrombus. Eosinophilic leu- bundles of collagen.1 This loose connective tissue encroaches
kocytes in varying numbers are usually present at the periph- on and often replaces the ventricularis and fibrosa of the
ery of the fibrous lesions. valve cusps. The majority of involved cusps consist entirely
Rarely, patients receiving mediastinal irradiation may of this loose connective tissue; however, remnants of the
develop lesions of the cardiac valves.17,18 The valves most ventricularis and fibrosa, interrupted by accumulations of
commonly involved are the tricuspid and the mitral, fol-
lowed by the aortic and the pulmonary. The fibrous valvular
thickenings are focal, and the anterior tricuspid leaflet and
the anterior mitral leaflet are usually more markedly involved
than are the posterior leaflets. The chordae tendineae also
may be focally thickened by fibrous tissue.

Congenital Valvular Heart Disease

The most common congenital malformation of heart valves
is the bicuspid aortic valve. Unless it is the site of associated
dysplasia, this valve is not inherently stenotic, although it
frequently becomes stenotic in later life. Stenosis is second-
ary to fibrosis and calcification of the cusps and usually not
to fusion of the commissures, as is seen in rheumatic aortic
stenosis.19 Classically, the calcific deposits form nodules at
the base of the cusps in the sinuses of Valsalva and extend
FIGURE 14.13. Bicuspid aortic valve. Stenosis is secondary to fibro-
to, but frequently do not involve, the free edge of the valve sis and calcification of the midportion and hinge of the cusps and
cusps (Fig. 14.13). In addition, there are foci of calcification usually not to fusion of the commissures, as is seen in rheumatic
and extensive fibrosis within the substance of the cusps. aortic stenosis.
376 chapter 14

abnormal loose connective tissue, are often found at the base valves. Rarely, infections are due to other organisms, such as
of the cusps. Inflammation and calcification are not features meningococci, pneumococci, gonococci, Brucella, Hae-
of the dysplastic valve. The abnormal valve tissue of the mophilus, Corynebacterium, mycobacteria, rickettsiae, and
dysplastic or incompletely differentiated valve resembles the Aspergillus and other fungal species.24 Fungal vegetations, in
embryonic connective tissue of the cardiac valves in 8- to particular, tend to be large and friable, with a tendency to
12-week-old fetuses.22 produce embolization. Because fungal endocarditis is fre-
quently indolent clinically, it is important for the surgical
pathologist to obtain appropriate special stains on any throm-
Infective Endocarditis boembolus removed from a systemic artery. Any valve
removed surgically that has gross lesions suggestive of infec-
The relative frequency of involvement of the cardiac valves tive endocarditis should have sections taken for microbio-
is similar for infective endocarditis and rheumatic heart logic culture before fixation. Merely taking a swab of the
disease: mitral, aortic, aortic and mitral, combined tricuspid, surface of the valve for culture is not adequate. Indeed, even
and pulmonary valves, in decreasing order of frequency. The if the valve appears grossly normal, patients in whom the
tricuspid and pulmonary valves are not commonly involved, clinical history or physical findings suggest the possibility
with the notable exception of intravenous drug abusers. In of infective endocarditis should have sections of the valve
many cases of combined aortic and mitral involvement, the taken for culture.
anterior leaflet of the mitral valve appears to be infected by Healing of vegetations may occur as a result of therapy
regurgitation-induced deposition of organisms from the or spontaneously, without antimicrobial therapy.23 These
aortic vegetation. Lesions usually originate on the atrial healed vegetations often result in multiple, calcified, polyp-
surface of the atrioventricular valves and the ventricular oid lesions on the surface of the valve. Contracture of scar
surface of the semilunar valves and vary from tiny granular tissue may further reduce the surface area of the valve. The
or flat vegetations to large polypoid masses. They may be healed vegetations in the heart valves or chordae tendineae
single or multiple and may be firm or soft, but are usually are similar in gross appearance to those with active infec-
friable. Grossly, they may appear yellow-white to red or tion.23 Occasionally, well-circumscribed defects with smooth
brown.23 The affected valve exhibits destruction and loss of edges remain in the heart valve after the healing of perfora-
tissue. Valvular ulceration, perforation, or formation of aneu- tions that resulted from infective endocarditis. Usually, the
rysm of the valve may occur. Rupture of chordae tendineae etiology of these morphologic abnormalities cannot be iden-
is common. Infection may spread into the contiguous struc- tified, especially if there is no known antecedent infection.
tures, resulting in annular or myocardial abscesses or aneu- Histologic study rarely helps to resolve these issues because
rysms of the sinuses of Valsalva. Microscopically, the the alterations resulting from the healing of the inflam-
vegetations are composed of masses of necrotic tissue, fibrin, matory process tend to be similar in their end-state
platelets, erythrocytes, leukocytes, and organisms. Classi- appearance.23
cally, there is a superficial zone of fibrin, organisms, and
leukocytes; an intermediate zone of amorphous necrotic
material; and a basal zone of granulation tissue extending Prosthetic Heart Valves
from the substance of the valve. Small foci of calcification
are common.
Types
Bicuspid aortic valves or valves with acquired deformities
are most frequently involved in infective endocarditis; Prosthetic heart valves in current use can be classified into
however, the disease may develop in previously normal two major groups: rigid-framed (mechanical) valves and
valves, including the pulmonary and tricuspid valves, espe- tissue valves (bioprosthesis). Rigid-framed valves are of three
cially in patients over 60 years of age. In previously normal types: (1) valves with a centrally placed occluder (ball or
valves, the lesions tend to be larger, and tissue destruction disk), which moves up and down in a metal cage and allows
is more extensive. Staphylococci and gram-negative organ- only lateral blood flow; (2) valves with a tilting disk, which
isms are more likely to be the etiologic agents than in the permits semicentral flow; and (3) valves with two hinged,
case of infection of deformed valves, in which Streptococcus semicircular plates (St. Jude type), which allow central flow.
viridans is the most common organism encountered. Infected Tissue valves include (1) fresh and variously treated homo-
but previously normal valves often show marked necrosis grafts, (2) human dura mater or fascia lata valves, (3) bovine
and inflammation, which are less common findings in pericardial valves, and (4) porcine aortic valves. The metal
infected, previously scarred valves. and plastic mounting frames and the preimplantation chemi-
Although streptococci and staphylococci are the most cal treatments vary from one type of tissue valve to another.
common microorganisms responsible for infection, a wide Tissue valves without supporting frames (unstented porcine
variety of bacteria and fungi have been recovered from and human homograft valves) also are being used clinically.
patients with infective endocarditis. Candida species in par- Knowledge of the frames and treatments is necessary to
ticular are recovered from addicts and patients with pros- interpret morphologic findings in tissue valves. Radiographs
thetic heart valves. Gram-negative bacilli account for only a may be useful in the identification and evaluation of
small percentage of infections, despite the relative frequency explanted valves.25–27 Essential for the evaluation of any pros-
of gram-negative bacteremia, and are more likely to be thetic valve is knowledge of the length of time the valve was
encountered in addicts or in patients with prosthetic heart in place and the specific reason for its removal.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 37 7

Complications extension of the thickening into the coronary arterial ostia.

Degeneration (variance) of the silicone rubber poppet was
Certain complications are common to all types of prosthetic common in the caged-ball prostheses implanted before 1967.
heart valves. Among these are thrombosis, embolization, This complication, which resulted from surface abrasion and
infection, dehiscence of the valvular ring, paravalvular leak, lipid infiltration, has not been reported in the metallic hollow
disproportion, turbulent flow, and hemolysis. Complications poppet. Wear of a caged disk, causing “grooving” and disk
limited to rigid-framed prostheses28,29 are related to wear and cocking, has been described in most caged-disk prostheses.
fracture of mechanical components, resulting in interference Disk cocking remains a potential problem with all caged-
with proper motion of the occluder (and sometimes also in disk valves, and it may be totally unrecognized as a cause of
embolic phenomena), whereas complications peculiar to fatalities. Wear of the cloth covering on the struts and the
tissue valves28,29 are related to calcification or breakdown of orifice occurred in some of the older models of completely
the prosthetic tissue leaflets. Degenerative changes also cloth-covered caged-ball prostheses, but strut cloth wear has
develop in homograft human tissue valves.30,31 not been reported in the newer Starr-Edwards model with
metal tracts. Dislodgment of caged disks and poppets has
Complications Common to All Types of been reported in association with wear of these components
Prosthetic Valves or with fracture of struts.
Thrombus formation in mechanical prostheses is most
common at the base of the struts forming the cage. From this Complications Limited to Bioprosthetic
area, thrombi can spread and interfere with motion of the (Tissue) Valves
occluder, with seating of the occluder on the orifice, or with
The various types of bioprosthetic heart valves developed
blood flow. These thrombi can undergo organization, become
since the 1970s have the following characteristics in common:
infected, or be sources of emboli. Ball valves with cloth-
collagen is their major structural component; they are
covered cage struts are less likely to form thrombi than are
mounted (except for some of the homografts) on metal and
those with uncovered struts. Tissue valves are least likely to
plastic stents; the incidence of clinical episodes of thrombo-
form large thrombi, although aggregates of platelets do
embolism is lower with these valves than with rigid-framed
develop on their surfaces. Thrombi can splint the cusps of
valves; and they have problems of long-term durability
bioprostheses and render them stenotic.32,33 Thrombi removed
because they can become stenotic as a result of calcification
from prosthetic heart valves must be examined (by histology
or regurgitant due to alterations in collagen.34
and by culture) for evidence of infection.11 Dehiscence of a
valvular ring must be regarded as due to infection until
proved otherwise. Paravalvular leaks most frequently result Porcine Aortic Valves
from a prosthesis having been sutured to a ring that is heavily
calcified or weakened (as occurs in patients with Marfan’s Porcine aortic valves treated with a low (<1%) concentration
syndrome or other connective tissue disorder). Anemia and of glutaraldehyde (to crosslink tissue protein, to sterilize the
renal hemosiderosis are typical findings in hemolysis pro- tissue, and to eliminate problems of antigenicity) and
duced by prosthetic heart valves. mounted on flexible stents have become a widely used type
Disproportion is caused by prosthetic heart valves that of valvular bioprosthesis. During the first 5 years after
are too large for the chambers in which they are placed. This implantation, these values usually have excellent function,
can result in interference with movement of the poppet, as although they can de velop extensive anatomic changes.
in the case of large ball valves placed in a small ascending After the first 5 years, appreciable incidences of calcification
aorta (particularly in patients with combined mitral and and cuspal damage become evident. Calcific deposits develop
aortic valve disease in whom the aortic root is usually not more frequently and earlier in children and young adults
dilated) or in a small left ventricle (as in patients with com- than in older individuals and also are more frequent in
bined mitral and aortic stenosis in whom the left ventricle patients with chronic renal disease.22,32 Cuspal perforations
is hypertrophied but not dilated). If a porcine bioprosthesis have no relation to patient age.
is improperly placed in the mitral orifice, one of its struts A bioprosthetic heart valve removed because of dysfunc-
may obstruct the left ventricular outflow tract. In the case tion should be first examined for evidence of infection, per-
of the double valve replacement, the prosthetic mitral valve foration, or calcification, and cultures should be taken as
may be inadvertently placed in such a way as to interfere indicated by clinical or anatomic findings; then it should be
with proper seating of the poppet of the prosthetic aortic radiographed and photographed before the cusps are detached
valve. Disproportion also may result from normal growth of from the frame for histologic sectioning. These valves are
the heart of a child in whom a small prosthetic valve was fragile and should be handled only by the mounting frame to
implanted at an early age. avoid producing artifactual damage to the cusps. Connective
tissue stains and stains for calcium are useful in evaluating
these valves. Transmission electron microscopy provides the
Complications Limited to Rigid-Framed
best method for studying the collagen, and scanning electron
(Mechanical) Prosthetic Valves
microscopy is the method of choice for examining the
Turbulent blood flow produced by caged-ball prostheses may surfaces.
lead to diffuse endocardial fibroelastotic thickening and to Histologically, porcine aortic valves are composed of the
intimal proliferation in the ascending aorta, sometimes with following three layers, which also are recognizable in the
37 8 chapter 14

bioprosthesis even after having been in place for long periods the cusps. Their use has been completely discontinued.
of time: (1) the ventricularis, which faces the ventricular Human dura mater valves preserved by glycerol treatment
cavity when the valve is in its anatomic position and which have been used extensively in Latin America. Bioprostheses
contains collagen and abundant elastic fibers; (2) the spon- made of glutaraldehyde-treated bovine pericardium have also
giosa, which is the proteoglycan-rich middle layer, and (3) been used as substitute cardiac valves. Both dura mater and
the fibrosa, which contains densely packed collagen but only pericardium consist of dense collagenous sheets with sparse
small, scanty elastic fibers and which faces the aortic wall. elastic fibers. Their layered structure is easily distinguish-
Proteoglycans are lost from the spongiosa during commer- able histologically from that of porcine aortic valves. Com-
cial processing and soon after implantation of the biopros- plications of pericardial and dura mater valves are similar to
thesis, leaving empty spaces that gradually are filled with those of porcine valves, consisting mainly of calcification
deposits of plasma proteins. The surfaces of porcine valvular and cuspal dehiscence.28
bioprostheses usually do not become endothelialized,
although they may be covered by macrophages, multinucle-
ated giant cells, platelet aggregates, and small fibrin deposits. Conduits
Polymorphonuclear leukocytes are very scanty or absent
unless infection is present. Macrophages show little ten- Conduits composed of various synthetic materials have been
dency to invade the bioprosthetic tissue, and there is no used to correct hypoplasia or atresia of the pulmonary artery.
evidence that immunologic rejection plays a role in its Valveless conduits were first used; subsequently, conduits
deterioration. containing mechanical (Björk-Shiley) valves were employed
Calcific deposits usually develop in association with col- but were found to be prone to valvular thrombosis. More
lagen in foci of loss of proteoglycans and with surface recently, extensive use has been made of pulmonic conduits
thrombi, especially in the region near the commissures; they with bioprosthetic (porcine or pericardial) valves; in addition,
form yellow, plaque-like or raised lesions.35 Calcific deposits left ventricular apical-aortic conduits have had limited use
also develop in the aortic wall just adjacent to the cusps and for correction of tunnel aortic stenosis.28 The most frequent
in cardiac muscle cells in a muscular shelf extending from complication of conduits is obstruction, which can result
the ventricular septum into the base of the right coronary from one or more of the following causes: (1) muscular com-
cusp of the porcine aortic valve. This cusp is larger than the pression of the proximal end of the conduit during ventricu-
others, and its base is less translucent. Calcific deposits can lar systole, (2) accumulation of thrombotic or fibrous material
also be associated with perforations, perhaps because colla- (fibrous peel) in the wall of the conduit, (3) compression of
gen adjacent to those deposits undergoes severe mechanical the conduit by the sternum, (4) calcific or thrombotic steno-
stresses.35 The collagen in bioprostheses undergoes a time- sis of the bioprosthesis, and (5) stenosis at the distal end (the
dependent process of degeneration, which may be related to most common cause of obstruction) because of the small size
material fatigue and many result in perforation of the cusps. of the artery at the anastomotic site.
Perforations in porcine valves occur most frequently near the
basal attachment of the cusps. In pericardial valves, particu-
larly those implanted in the mitral position, cuspal tears are Summary
likely to involve the free edge near the attachment to the
post. It has been suggested that such tears begin at the attach- Valvular heart disease can result from a spectrum of degen-
ment suture. Infection of porcine valvular bioprostheses erative and inflammatory conditions. Floppy mitral valve
differs from that of rigid-framed valves; it is likely to involve due to myxomatous degeneration occurs as an isolated entity
the cusps (rather than the sewing ring), is less likely to result or as a component of Marfan’s syndrome or other connective
in formation of a ring abscess, and usually extends into the tissue dyscrasias. Several endocrine and metabolic condi-
collagen in the cusps.34 The incidence of infection in the two tions can produce valvular diseases, including carcinoid
types of valves appears to be similar. heart disease and cardiac amyloidosis. Collagen vascular dis-
eases commonly produce valvular heart disease, and these
Other Bioprosthetic Valves include rheumatic valvulitis, rheumatoid valvulitis, lupus
erythematosus valvulitis, and other related conditions. The
Fresh, antibiotic-sterilized, freeze-dried, and chemically bicuspid aortic valve is the most common form of congenital
treated aortic valve homografts (allografts) have been used valvular heart disease. Infective endocarditis can develop on
infrequently in the United States. However, cryopreserved previously diseased or normal valves. Prosthetic heart valves
aortic valve allografts have been used more extensively in include mechanical valves and bioprostheses. Characteristic
recent years.30,31 In contrast to glutaraldehyde-treated bio- pathologic changes influence the suitability of the different
prostheses, allografts tend to become covered with a fibrous prostheses for individual patients.
sheath of host origin. These valves become completely acel-
lular, and apoptosis has been shown to play an important role
in the loss of the valvular cells.36 Complications of allograft References
valves include calcification, cuspal rupture, and fibrous 1. Pomerance A, Davies MJ. The Pathology of the Heart. Oxford:
retraction of the edges of the cusps. Autologous fascia lata Blackwell Scientific, 1975.
valves implanted without any chemical treatment have had 2. Ferrans VJ. Metabolic and familial diseases. In: Silver MD, ed.
a very poor record of durability and a high incidence of degen- Cardiovascular Pathology. New York: Churchill Livingstone,
eration, thrombosis, calcification, and fibrous contraction of 1991:1973.
 va lv u l a r h e a r t d i s e a s e : a n a t o m i c a b n o r m a l i t i e s 37 9
3. Segura AM, Luna RE, Horiba K, et al. Immunohistochemistry aortic valves without commissural fusion. Am J Cardiol
of matrix metalloproteinases and their inhibitors in thoracic 1978;42:102–107.
aortic aneurysms and aortic valves of patients with the 20. Fenoglio JJ, McAllister HA Jr, DeCastro CM, et al. Congenital
Marfan’s syndrome. Circulation 1998;98(suppl II):II331–II337. bicuspid aortic valve after age 20. Am J Cardiol 1977;
4. Baggenstoss AH, Titus JL. Rheumatic and collagen disorders of 39:164–169.
the heart. In: Gould SE, ed. Pathology of the Heart and Blood 21. Davia JE, Fenoglio JJ, DeCastro CM, et al. Quadricuspid semi-
Vessels. Springfield, IL: Charles C. Thomas, 1968:701. lunar valves. Chest 1977;72:186–189.
5. McAllister HA Jr. Pathology of the heart in endocrine disor- 22. Hyams VJ, Manion WC. Incomplete differentiation of the
ders. In: Silver MD, ed. Cardiovascular Pathology. New York: cardiac valves. A report of 197 cases. Am Heart J 1968;76:
Churchill Livingstone, 1991:1181. 173–182.
6. Redfield MM. Ergot alkaloid heart disease. In: Hurst JW, ed. 23. Titus JL. Infective endocarditis, active and healed. In: Edwards
New Types of Cardiovascular Diseases: Topics in Clinical Car- JE, Lev M, Abell MR, eds. The Heart. Baltimore, MD: Williams
diology. New York: Igaku-Shoin Medical, 1994:63–76. & Wilkins, 1974:176.
7. Redfield MM, Nicholson WJ, Edwards WD, Tajik AJ. 24. Freedman LR. Endocarditis updated. Dis Mon 1970;26(3):
Valve disease associated with ergot alkaloid use: echocardio- 1–71.
graphic and pathologic correlations. Ann Intern Med 1992; 25. Silver MD, Datta BN, Bowes FV. A key to identify heart valve
117:50–52. prostheses. Arch Pathol 1975;99:132–138.
8. Connolly HM, Cresy JL, McGoon MD, et al. Valvular heart 26. Steiner RM, Flicker S. The radiology of prosthetic heart
disease associated with fenfluramine-phentermine. N Engl J valves. In: Morse D, Steiner RM, Fernandez J, eds. Guide to
Med 1997;337:581–588. Prosthetic Cardiac Valves. New York: Springer-Verlag,
9. McAllister HA Jr. Pathology of the cardiovascular system in 1985:53.
chronic renal failure. In: Lowenthal DT, Pennock RL, Likoff W, 27. Butany J, Ahluwalia MS, Munroe C, et al. Mechanical heart
et al., eds. Management of Cardiovascular Disease in Renal valve prostheses: identification and evaluation. Cardiovasc
Failure. Philadelphia: FA Davis, 1981:1. Pathol 2003;12:1–22.
10. Ferrans VJ, Butany JW. Ultrastructural pathology of the heart. 28. Lefrak EA, Starr A. Cardiac Valve Prostheses. East Norwalk,
In: Trump BF, Jones RT, eds. Diagnostic Electron Microscopy, CT: Appleton & Lange, 1979.
vol 4. New York: Churchill Livingstone, 1983:319. 29. Zeien LB, Klatt EC. Cardiac valve prostheses at autopsy. Arch
11. McAllister HA Jr, Ferrans VJ. The heart and blood vessels. In: Pathol Lab Med 1990;144:933–937.
Silverberg SJ, ed. Principles and Practice of Surgical Pathology. 30. Dagenais F, Cartier P, Voisine P, et al. Which biologic valve
New York: Churchill Livingstone, 1991:787. should we select for the 45- to 65-year-old age group requiring
12. McAllister HA Jr. Collagen diseases and the cardiovascular aortic valve replacement? J Thorac Cardiovasc Surg 2005;129:
system. In: Silver MD, ed. Cardiovascular Pathology. New 1041–1049.
York: Churchill Livingstone, 1991:1151. 31. Koolbergen DR, Hazekamp MG, de Heer E, et al. The pathology
13. Fauci AS, Wolff SM. Wegener’s granulomatosis and related dis- of fresh and cryopreserved homograft heart valves: an analysis
eases. Dis Mon 1977;23(7):1–36. of forty explanted homograft valves. J Thorac Cardiovasc Surg
14. McAllister HA Jr, Fenoglio JJ. Cardiac involvement in Whip- 2002;124:689–697.
ple’s disease. Circulation 1975;52:152–156. 32. Platt MR, Mills LJ, Estrera AS, et al. Marked thrombosis and
15. Eck M, Muller-Hermelink HK, Harmsen D, Kreipe H. Invasion calcification of porcine heterograft valves. Circulation 1980;
and destruction of mucosal plasma cells by Tropheryma whip- 62:862–869.
pelii. Hum Pathol 1997;28:1424–1428. 33. Croft CH, Buja LM, Floresca MZ, et al. Late thrombotic obstruc-
16. Olsen EGJ, Spry CJF. The pathogenesis of Loffler’s endomyocar- tion of aortic porcine bioprosthesis. Am J Cardiol 1986;57:
dial disease, and its relationship to endomyocardial fibrosis. 355–356.
Prog Cardiol 1979;8:281. 34. Ferrans VJ, Tomita Y, Hilbert SL, et al. Evaluation of opera-
17. Roberts WC, Dangel JC, Bulkley BH. Nonrheumatic valvular tively excised prosthetic tissue valves. In: Waller BF, ed. Pathol-
cardiac disease: a clinicopathologic survey of 27 different ogy of the Heart and Great Vessels. New York: Churchill
conditions causing valvular dysfunction. Cardiovasc Clin Livingstone, 1988:311.
1973;5:333–446. 35. Hilbert SL, Ferrans VJ, McAllister HA Jr, Cooley DA. Ionescu-
18. McAllister HA Jr, Hall RJ. Iatrogenic heart disease. In: Cheng Shiley bovine pericardial bioprosthesis: histologic and ultra-
TO, ed. The International Textbook of Cardiology. New York: structural studies. Am J Pathol 1992;140:1195–1204.
Pergamon, 1986:871. 36. Hilbert SL, Luna RE, Zhang J, et al. Allograft heart valves: the
19. Cheitlin MD, Fenoglio JJ, McAllister HA Jr, et al. Congenital role of apoptosis-mediated cell loss. J Thorac Cardiovasc Surg
aortic stenosis secondary to dysplasia of congenital bicuspid 1999;117:454–462.
 1 Aortic Valve Disease
5 Blase A. Carabello

Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 Obesity Drugs, Valvular Heart Disease, and

Diagnostic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . 389
Aortic Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Key Points Aortic Stenosis

• Calcific disease is the major cause of aortic stenosis.
• Bicuspid aortic valves lead to aortic stenosis in approxi-
Etiology
mately one half of patients who are born with them.
• The classic symptoms of valvular aortic stenosis, angina, The causes of aortic stenosis (AS) and our understanding of
syncope, and dyspnea represent a major inflection in the them have evolved substantially over the past four decades.
natural history of the disease and indicate the need for Although rheumatic heart disease was once a major cause of
surgical correction, and in the absence of surgical therapy aortic stenosis in the developed world, today rheumatic
an increased risk of sudden death. disease is exceedingly rare in those countries. Instead cal-
• The mainstay of diagnosis of valvular aortic stenosis cific disease is now the major cause of AS. Previously con-
is the echocardiogram, which, together with Doppler, sidered to be a degenerative disease, it is now clear that the
provide an excellent estimate of the severity of valvular process is much akin to atherosclerosis.1–3 The initial plaque
aortic stenosis. of AS resembles that of coronary artery disease (Fig. 15.1).1
• Patients with low cardiac outputs and some valvular Risk factors such as hyperlipidemia, hypertension, and evi-
aortic stenosis and those with severe valvular stenosis dence of systemic inflammation are held in common by both
and reduced left ventricle (LV) function can often be AS and coronary disease.2 The presence of aortic sclerosis,
distinguished by a dobutamine infusion test with the earliest phase of AS in which no hemodynamic distur-
echocardiography. bance is yet present, is associated with increased cardiac
• Aortic regurgitation is caused by pathology of the aortic mortality.4 Since the valve abnormality is too slight to cause
valve leaflets or of the aortic root. untoward events, it is presumed that the aortic sclerosis pre-
• An Austin Flint murmur (apical diastolic rumble) indi- sages subsequent coronary events. Finally a body of data is
cates severe aortic insufficiency. amassing that shows that hepatic hydroxymethylglutaryl
• Vasodilators may reduce LV volume or delay the develop- coenzyme A (HMG CoA) reductase inhibitors (statins), com-
ment of symptoms in patients with aortic regurgitation monly used agents in treating coronary disease, are also
(AR). beneficial in retarding the progression of AS.5,6 Results of
• Surgical correction of AR is needed when the amount randomized clinical trials are pending.
of regurgitation is severe and either symptoms of conges- Another common cause of AS is bicuspid aortic valve.
tive heart failure (CHF) or angina develop or with evi- This common congenital abnormality, which occurs in about
dence of decline in LV function, for example, a fall in the 1% of the United States population, leads to AS in about half
LV ejection fraction (LVEF) below 0.55 or the LV is unable the patients born with it. When AS occurs in such patients
to contract down to 50 to 55 mm Hg at the end of it usually develops in the fifth and sixth decades of life, 20
systole. to 30 years earlier than occurs in previously normal tricuspid
• Acute AR, such as occurs following perforation of an aortic valves. It is thought that in both bicuspid and tricuspid
aortic leaflet by infective endocarditis, is a potentially valves, the etiology of AS, when it occurs, is similar to that
life-threatening emergency that often requires very early of atherosclerosis.
surgical correction. Occasionally, congenital aortic stenosis is detected for
• Appetite-suppressant drugs may cause pulmonary hyper- the first time in adulthood. This disease differs somewhat
tension and left ventricular valvular lesions, including from the acquired disease discussed above. In congenital AS,
aortic and mitral valve insufficiency. there is usually extensive concentric hypertrophy and

3 81
382 chapter 15

Disruption of endothelium
and basement membrane on
aortic side of leaflet

Lipide
Lipide
Lipide Lipide
T cells
Macrophages Lipide Lipide
Lipide
Lipide
Lipide Lipide Lipide

Lipide
Displacement of Fibrosa
elastic lamina Lipide
Fine, stippled
mineralization Ventricularis

FIGURE 15.1. A schematic representation of

the early lesion of aortic stenosis emphasizes
the presence of macrophages and lipids similar
Ventricular side of leaflet (intact endothelium) in nature to the plaque of coronary disease.

supernormal ejection performance.7 Sudden death is possibly malizing afterload, concentric LVH helps to maintain normal
more frequent in the absence of symptoms in congenital ejection performance. Paradoxically, LVH may be pathologic
versus acquired AS, although data to support this are sketchy. instead of compensatory. In general, in heart disease, LVH is
Finally, because the leaflets are joined at the commissures associated with adverse events.12–14 In addition, LVH may also
instead of being heavily calcified, balloon valvotomy may
produce excellent relief of congenital AS,8 a result rarely seen
in acquired AS.

Pathophysiology and Its Relation to Symptoms

As discussed below, the development of the classic symp-
toms of AS—angina, syncope, or dyspnea (and other symp-
toms of heart failure)—represent a dramatic inflection in the
natural history of the disease with little risk of sudden death
in the asymptomatic state and extreme risk once symptoms
have developed. Thus an understanding of the intertwining
of symptoms with the disease’s pathophysiology is key in
understanding the disease.

Pressure Overload
Normally the aortic valve offers little resistance to forward
flow. Once open, pressures on both sides of the valve are
virtually identical (Fig. 15.2A).9 Near equalization of systolic
pressures in the left ventricle (LV) and aorta remains until
the aortic valve area becomes less than half of its normal 3
to 4 cm2. However, as valve stenosis worsens, a pressure gra-
dient between LV and aorta develops (Fig. 15.2B). This gradi-
ent represents the additional pressure work (pressure
overload) that the LV must develop in order to propel blood
across the narrowed valve.
Although occasionally debated, there is general consen-
sus that a major compensatory mechanism for accommodat-
ing the pressure overload is the development of left ventricular
hypertrophy (LVH). Left ventricular ejection performance is
determined by preload, afterload, and contractility. One
expression for afterload is wall stress (σ) = p × r/2th, where p
is the LV pressure, r is the LV radius, and th is the LV thick-
ness. As the pressure term of this Laplace equation increases FIGURE 15.2. (A) Simultaneous left ventricular and aortic pressure
in the numerator, it can be offset by concentric LVH that tracings from a normal subject are shown. (B) The pressure gradient
increases the thickness term in the denominator.10,11 By nor- across a stenotic aortic valve.
 a o r t i c va lv e d i s e a s e 383
be responsible in part for some of the symptoms of AS, symp- Congestive Heart Failure
toms that presage morbidity and mortality.
Heart failure is often classified as deriving from systolic
dysfunction, diastolic dysfunction, or both. In AS both por-
Angina
tions of the cardiac cycle are usually abnormal. Diastole is
When angina occurs, it indicates myocardial ischemia that usually divided into the isovolumic relaxation phase, the
develops when myocardial oxygen demand outstrips oxygen rapid filling phase, and atrial contraction. All may be abnor-
supply. As noted above it would be expected that many AS mal in AS. In AS and in conditions causing concentric LVH
patients would also have coronary artery disease, and this is in general, the isovolumic relaxation phase is delayed.20
so in about half of AS patients.15,16 However, many patients During this active phase of myocardial relaxation, calcium
with AS who experience angina have normal epicardial is pumped back into the sarcoplasmic reticulum reducing
arteries invoking another cause for angina. In part, angina actin-myosin interaction. Calcium removal is slowed in
in such patients is due to diminished coronary blood flow LVH, presumably due in part to reduced SERCA 2 activity.21
reserve.17 Normal subjects can increase coronary blood flow In turn this delays the onset of the early rapid filling phase,
six- to eightfold during stress, an increase necessary to meet shortening the filling time.
the oxygen demands of increased workload. However, patients During active filling, the pressure-volume relationship is
with AS have reduced coronary blood flow reserve of only shifted upward and to the left (Fig. 15.3).20,22 Thus for any
two- to threefold, a deficit related to LVH. The exact mecha- given filling volume, filling pressure is increased, reflecting
nism of this deficit is unknown but is thought to be second- the increased stiffness of the hypertrophied chamber. Stiff-
ary to the reduced capillary density per gram of myocardium. ness is increased because the left ventricular wall is thicker
A second mechanism of reduced flow reserve in LVH is that than normal and because the collagen content of the myo-
elevated filling pressure that often accompanies it com- cardium is increased. Slowed early relaxation together with
presses the endocardium during diastole (when coronary a stiffer myocardium result in increased LV filling pressure
blood flow occurs), in turn impeding blood flow.18 While that is referred to the lungs, resulting in pulmonary conges-
reduction in coronary blood flow reserve must in some way tion. Increased myocardial stiffness also results in greater
play a role in the angina of AS patients, it is not the complete than normal dependence on atrial contraction for adequate
explanation because many patients with severe LVH do not ventricular filling. Thus patients with AS are especially
have angina. In fact, wall thickness, valve area, pressure dependent on their left atrial “kick” and may decompensate
gradient, and other hemodynamic factors have failed to rapidly if atrial fibrillation occurs.
predict when patients with AS will develop angina. The Systole is also often abnormal in patients with AS. The
measurable hemodynamic parameter best associated with major determinants of systole are preload, afterload, and
angina occurrence is diastolic filling time.19 During every contractility. The last two of these properties are often
cardiac cycle the heart expends energy during systole when disordered in AS. As noted above, LVH is thought to be a
coronary blood flow ceases incurring an oxygen debt. This compensatory mechanism that helps normalize afterload,
debt is repaid by coronary blood flow during diastole. The enhancing LV systolic performance. If the amount of hyper-
ratio of systolic ejection period (debt period) to diastolic trophy that developed were just enough to offset the increased
filling time (repayment period) appears to be the best predic-
tor of when angina might develop.

Syncope
100
Syncope is the temporary loss of consciousness. Cardiac
syncope occurs when blood flow to the brain is inadequate to
maintain satisfactory perfusion. The mechanism of syncope 80
in AS is not well established, although many theories abound.
Stress (kdyne/cm2)

When syncope does occur in AS it almost always does so

during exercise. In normal subjects and in those with AS, 60
exercise causes vasodilatation and reduced total peripheral
resistance. Blood pressure is the product of total peripheral 40
controls
resistance and cardiac output. In normals, cardiac output
AS pre
increases more than total peripheral resistance falls during
20 AS early post
exercise so that blood pressure increases. However, it is
AS late post
thought that in patients with AS who develop syncope, cardiac
output is restricted by the narrowed aortic valve. Thus periph- 0
eral resistance decreases during exercise while cardiac output 0 0.3 0.4 0.5 0.6 0.7
is fixed so that blood pressure must fall, in turn leading to Strain
syncope in some cases. In other cases, because pressure gradi- FIGURE 15.3. Myocardial stiffness (stress vs. strain) is shown for
ent is proportional to the square of the cardiac output, high control subjects and aortic stenosis patients before, and early and
LV pressure during exercise is postulated to cause a vasode- late after aortic valve replacement (AVR). Prior to surgery, myocar-
dial stiffness is greater in aortic stenosis (AS) than in normal sub-
pressor response, in turn leading to syncope. In still other jects. Early after AVR stiffness increases because the muscle
cases, exercise-induced atrial or ventricular arrhythmias may elements of the myocardium regress more quickly than the stiffer
cause reduced cardiac output and syncope. collagen elements. Eventually, stiffness returns to normal.
384 chapter 15

pressure term in the Laplace equation, ejection performance Onset severe

should be normal, and frequently it is. However, in some 100
symptoms
Angina
cases the LVH is inadequate to normalize wall stress and Synope
thus afterload increases, reducing ejection fraction (Fig. Latent period Failure
80 (increasing obstruction,
15.4),23 in turn leading to congestive heart failure. Interest-

% survival
myocardial overload)
ingly, in some cases (especially in children and older women) 0 2 4 6
60
the hypertrophy that develops seems in excess of that needed Average survival (yr)
to normalize wall stress, stress is reduced, and ejection frac-
40
tion is actually increased.7,24 Although this phenomenon is
beneficial for systolic performance, the increased wall thick-
20
ness impairs diastolic filling. Average death
Although in some cases, reduced systolic performance is age
due to increased afterload, noted above, in other cases con- 40 50 60 70 80
tractility is reduced.23 Currently, the exact mechanisms Age (yr)
responsible for reduced contractility in the face of concentric FIGURE 15.5. The natural history of AS is shown, demonstrating
LVH are uncertain. Myocardial ischemia due to reduced a dramatic reduction in survival once symptoms develop.
coronary blood flow,16 abnormal calcium handling,25 and
abnormalities of the myocardial cytoskeleton 26 have been
implicated.

of such patients succumb in 5 years. If syncope occurs, 50%

Natural History survival is 3 years, whereas the patient with dyspnea or other
As shown in Figure 15.5, the onset of symptoms in AS is a symptoms of heart failure has a 50% survival of only 2 years
critical turning point in the natural history of the disease.27–29 without aortic valve replacement. Thus a careful probing
The asymptomatic patient has a nearly normal prognosis, yet history is crucial in managing the patient with AS.
once the classic symptoms of angina, syncope, or dyspnea
develop, survival is abruptly reduced. In fact, taken as a
Physical Examination
whole, once these symptoms develop, mortality is about 2%
per month. Following the development of angina, about 50% The physical examination of the patient with AS is quite
instructive as to the severity of the disease. The apical
impulse is usually not displaced but is sustained and force-
ful. The carotid upstrokes are classically delayed and reduced
in volume (parvus et tardus; Fig. 15.6).30 By placing one hand
on the patient’s forceful apical beat with the other hand on
the patient’s reduced carotid upstroke, the examiner can
deduce the severity of the obstruction between left ventricle
and the vasculature. The murmur of aortic stenosis is a sys-
.6 tolic ejection murmur radiating to the neck. Thus S1 is heard
followed by a short quiet period as the LV develops enough
pressure to initiate ejection at which time the murmur com-
mences. As the severity of AS worsens, the murmur peaks
.5
progressively later in systole until it becomes maximal just
Ejection fraction

before S2. In some cases the murmur is loudest in the aortic

area, decreases over the sternum, and increases again over
.4 the LV apex (Gallavardin’s phenomenon), misleading the aus-
cultator into thinking that two murmurs, one of AS and a
second of mitral regurgitation, are present. The murmur of
AS may be quite loud and accompanied by a thrill. Paradoxi-
.3
cally, as the disease severity worsens, the murmur becomes
softer as less stroke volume is delivered to the valve by a
progressively impaired LV.31 Thus a soft murmur by itself
.2 should not be taken to indicate that the disease is mild. In
most cases the second heart sound becomes single as the
aortic component from a dysfunctional valve is lost. Today,

150 200
250 300 350 400 450
σ dynes × 10 3/cm 2
FIGURE 15.4. Afterload (wall stress,σ) is plotted against ejection
fraction for aortic stenosis patients in heart failure. In some cases
Carotid pulse
(circles) the reduction in ejection fraction is accounted for by
increased stress. In other cases (×’s) ejection fraction is reduced more tracing
than can be accounted for by elevated afterload, implying reduced FIGURE 15.6. A normal carotid upstroke (left) is compared to the
contractility. carotid upstroke of a patient with aortic stenosis (right).
 a o r t i c va lv e d i s e a s e 385
detection of AS usually occurs before severe LV dysfunction only indication for medical therapy in this disease is in the
develops. Thus paradoxic splitting of S2 due to delayed emp- case of symptomatic patients in whom surgery cannot be
tying of a severely weakened LV, which was noted in older performed because of existing comorbidities. In such cases
texts, is now rare. diuretics can be used with caution to treat congestive heart
failure, and nitrates may be used to relieve angina. Vasodila-
tors may be helpful in severe heart failure but must be used
Diagnostic Testing with extreme caution to avoid hypotension.36 In a recent
study, nitroprusside improved hemodynamics in patients
The electrocardiogram (ECG) and chest x-ray may give clues
with pulmonary edema. This agent is believed to be useful
to the presence of AS, but these modalities are rarely diag-
not because it reduces afterload (which is fixed by the ste-
nostic. The ECG typically demonstrates the pattern of LVH,
notic valve) but by reducing LV end diastolic pressure. This
although severe AS may exist without such evidence. The
action of the agent may improve coronary blood flow, enhanc-
chest x-ray may show a boot-shaped heart consistent with
ing LV function.
concentric LVH. Occasionally the calcified aortic valve is
seen in the lateral view. However, the mainstay of diagnosis
is the echocardiogram with Doppler interrogation of the Timing of Surgery
aortic valve. While in severe disease two-dimensional (2D)
echo demonstrates a thickened, immobile, heavily calcified Asymptomatic patients with severe AS have a good prognosis
valve, it is the Doppler examination that can fairly precisely with a minimal risk of sudden death or other complications
quantify stenosis severity. Because flow equals the area until symptoms develop.27–29 Thus as noted above, the onset
times the velocity, bloodstream velocity must increase when of symptoms represents a crucial demarcation point in the
it reaches the narrowed aortic valve. Sound waves transmit- natural history of the disease and indicates the need for
ted from an ultrasound transducer collide with the accelerat- prompt AVR because AVR dramatically improves outcome.37
ing red blood cells that compress the sound waves, increasing In some patients symptomatic status may be hard to ascer-
their frequency. This increase is detected by the transducer tain even after obtaining a careful history. In such patients
that now acts as a receiver, converting the difference between a carefully performed exercise test may be quite helpful38,39
the frequency sent and the frequency received into a velocity in confirming symptom status. While exercise testing is
that in turn can be converted into a pressure gradient or valve clearly contraindicated in symptomatic patients, the proce-
area. dure is becoming more widely accepted in patients in whom
Because almost all patients with AS are old enough to be symptomatic status is uncertain. Such patients are likely to
at risk for coronary disease and because AS and coronary exercise anyway, and the development of symptoms during
artery disease hold risk factors in common, most patients formal testing or evidence of less than expected exercise
with AS should undergo cardiac catheterization to perform tolerance indicates a high risk for requiring AVR in the near
coronary angiography prior to aortic valve replacement future.
(AVR), although this test may be replaced by multislice com- When symptoms are present, the question arises as
puted tomography (CT) scanning in the future. While several to whether the patient’s AS is severe enough to be their
studies have examined the use of nuclear imaging as a non- cause. While no “critical” valve area is agreed upon, because
invasive test to detect the presence of coronary disease, symptoms appear at a wide variation in the valve area,40 in
nuclear studies in the presence of AS have not been accurate general, if the valve area is <1.0 cm2 or if the mean gradient
enough to supplant angiography prior to AVR.32,33 In most exceeds 50 mm Hg or if peak jet velocity exceeds 4.0 m/s,
cases the severity of the AS has been assessed accurately severe AS is usually present and the patient’s symptoms
noninvasively prior to catheterization, obviating the need to are logically attributable to it. Because reduced cardiac
obtain a pressure gradient using simultaneous recording of output reduces gradient, severe AS may be present in patients
LV and aortic pressure (Fig. 15.2). However, in a minority of with heart failure and lower gradients. However, in most
cases, AS severity is still unclear at the time of catheteriza- such patients, the ratio of outflow tract velocity to velocity
tion, necessitating evaluation of the valve invasively. In that at the aortic valve is <0.25, another index of severe aortic
case, valve area is calculated using the Gorlin formula,34 stenosis.
employing measured cardiac output and direct pressure mea-
surement. In recording the gradient it is crucial that the Asymptomatic Patients with Severe
catheters be placed in the proper position with one catheter Aortic Stenosis
well inside the body of the LV and the second catheter placed
Although stenosis severity is important in the progression to
in the ascending aortic to avoid errors in pressure measure-
symptoms, no valve area or gradient has been shown to cause
ment.35 However, the need to use two catheters can be
symptoms by itself. Not surprisingly, then, some patients
avoided by using instead a double-lumen or double-trans-
develop severe asymptomatic AS. While the short-term prog-
ducer catheter or by a carefully recorded catheter pullback
nosis in such patients is excellent without surgery, there is
in patients in sinus rhythm.
still a small but definite risk of sudden death.29,41 Obviously
there is also a small but definite risk of morbidity and mor-
Medical Therapy
tality related to aortic valve replacement and to complica-
For asymptomatic patients with AS, no medical therapy is tions resulting from the presence of a prosthetic valve.42–47
indicated other than antibiotic prophylaxis for bacteremia- Thus the clinician is faced with a dilemma. Whether the
causing procedures. Once patients develop symptoms, strategy is surgery in the absence of symptoms or watchful
surgery is necessary to prevent death (see below). Thus the waiting, there is a small but definite risk. While there is no
386 chapter 15

definite solution to the problem, one strategy is to use the Patient survival (%)
results of exercise testing as noted above. For the truly
100
asymptomatic patient who performs well on the treadmill,
there is no compelling reason to proceed with AVR. If symp-
toms are manifest during the test, or if there is hypotension Group I, valve replacement
75
or arrhythmia, early AVR should be considered. The diffi-
culty in knowing how best to manage the asymptomatic
patient with severe AS has led to an interest in biomarkers. 50
Recent studies have found elevated B-type natriuretic peptide Group II, valve replacement
(BNP) in some asymptomatic patients with severe AS. In one
20 Group I, medical treatment
study elevated BNP greatly increased the risk of symptom
onset in the year following the initial test.48
Group II, medical treatment
0
Aortic Valve Replacement in Patients with
Reduced Ejection Fraction 0 50 100
Follow-up (months)
As shown in Figure 15.4, in some AS patients with low ejec-
FIGURE 15.7. The outcome of low-gradient, low-ejection fraction
tion fractions, reduced ejection performance is due to the patients is shown. Patients with inotropic reserve treated with AVR
afterload excess caused by high systolic LV pressure and had the best results by far.
limited hypertrophy inadequate to normalize wall stress. In
such patients AVR causes a prompt reduction in afterload,
ejection fraction returns to or toward normal, and prognosis
revascularization also has AS. When the AS is severe, obvi-
is excellent.23 However, in other patients, those with a low
ously both are corrected during the same surgery. A more
transvalvular gradient, ejection fraction is depressed below
problematic situation arises when the patient requiring
that which can be attributed to afterload mismatch. In this
bypass surgery has milder AS, AS of severity that by itself,
case there is severe LV muscle dysfunction and outcome fol-
would not be a reason to perform AVR. On the one hand,
lowing AVR is much less favorable. However, some such
concomitant AVR adds surgical risk and exposes the patient
patients may improve dramatically following AVR,49–51 and
to the risks of harboring a prosthetic valve. On the other
the obvious clinical challenge is to judge which low gradient,
hand, leaving significant valve disease behind at the time of
low ejection fraction patients are likely to benefit from
coronary revascularization may result in a second operation
AVR.
in the near future if the patient’s AS progresses rapidly. It
The first task is to divorce true aortic stenosis from a
appears that for patients with moderate AS and a gradient of
condition sometimes referred to as aortic pseudostenosis. In
>30 mm Hg or an aortic valve area of <1.3 cm2, AVR should
the former case severe valve disease has led to severe LV
be performed at the time of coronary (or other heart) surgery.57
dysfunction, a low output, and a low gradient. In the second
For gradients of <10 mm Hg, AVR should be avoided. In the
condition, a ventricle weakened from another cause such as
middle ground, with gradients between 10 and 30 mm Hg,
coronary disease is unable to open a mild to moderately ste-
valve morphology at echocardiography may be helpful, pro-
notic valve to its full aperture. In both cases the valve area
viding an impetus toward AVR for heavily calcified immo-
at rest will be quite reduced. However, in true stenosis, when
bile appearing valves.
cardiac output is increased by exercise or inotropic infusion,
the gradient increases in tandem and the valve area increases
only slightly.52–55 In pseudostenosis when cardiac output is The Elderly Patient with Aortic Stenosis
increased, the gradient does not increase proportionately and
It is well known that elderly patients, even those in their
as a consequence calculated valve area increases substan-
nineties, may have an excellent result following AVR. Indeed
tially, often to >1.0 cm2. Because such patients do not have
age-corrected survival following AVR for AS is normal for
severe aortic stenosis as the cause of their heart failure, they
patients over the age of 65.58 Nonetheless, the elderly patient
are unlikely to benefit from AVR.
is subject to a host of comorbidities that affect outcome.59–61
For the patients with severe aortic stenosis and low gradi-
In recommending AVR for the elderly patient, the co-pres-
ent and low ejection fraction, response to dobutamine infu-
ence of coronary disease, neurologic deficits, and renal and
sion is an important indicator of prognosis. As shown in
pulmonary dysfunction all worsen prognosis and must be
Figure 15.7, if dobutamine infusion increases cardiac output
taken into consideration. Especially in this age group, the
by >20% (with inotropic reserve, group I), prognosis follow-
patient’s expectation of outcome and lifestyle must be con-
ing AVR is much better than similar patients treated medi-
sidered in choosing AVR therapy.
cally and much better than those patients without inotropic
reserve (group II) treated medically or with AVR.56
The Percutaneous Approach to Aortic Stenosis
The Patient with Mild to Moderate Aortic
Although balloon aortic valvotomy (BAV) is useful in chil-
Stenosis Undergoing Coronary Revascularization
dren with congenital AS, the calcified lesion of acquired AS
As noted above, AS and coronary disease are likely to be in the adult does not respond well to BAV. After a modest
manifestations of the same pathologic process and thus often acute reduction in stenosis severity,62,63 restenosis recurs
coexist. Not infrequently, a patient who requires coronary usually within 6 months and BAV has not been shown to
 a o r t i c va lv e d i s e a s e 387
alter the high mortality of symptomatic AS.64 Thus BAV is defect may lead to aortic regurgitation. In such cases there
reserved only as a palliative measure for patients in whom is usually concomitant dilatation of the proximal aortic root
AVR is impossible because of comorbid conditions. leading to valve cusp separation and incompetence. While
Percutaneous aortic valve replacement is being examined such expansion was often labeled “poststenotic” dilatation
as a therapy for AS. After the native valve is dilated by expan- when even mild AS was present, it is now recognized that
sion of a large balloon, a stented bioprosthesis is deployed abnormalities inherent in root composition are responsible
into the aortic annulus. Although residual calcium deposits for its dilatation.66 Such dilatation (annuloaortic ectasia) may
existing from the native valve may restrict seating, leading also be seen in patients with tricuspid aortic valves and is
to mild aortic regurgitation, the initial results in patients in associated with aging and hypertension. Other causes of
whom surgical AVR was contraindicated are promising.65 aortic regurgitation include infective endocarditis aortic dis-
section, Marfan syndrome, rheumatic fever, and collagen
vascular disease, especially ankylosing spondylitis. Appe-
Aortic Regurgitation tite-suppressant drugs have also caused both aortic and
mitral valvular insufficiency (see later in the chapter).
Etiology
Pathophysiology and Its Relation to Symptoms
Aortic regurgitation (AR) is caused by pathology of either the
valve leaflets or the aortic root. As noted above, bicuspid As shown in Figure 15.8,67 AR imparts a volume load on the
aortic valve is a common congenital abnormality often asso- left ventricle, as the cardiac output that regurgitates into the
ciated with aortic stenosis. However, in other cases this same LV during diastole must be compensated for by an increase

AOP 120/80
AOP 130/70
60 cc

Forward 100 cc
stroke Forward
EDV = 150 cc stroke EDV = 170 cc
volume
100 cc volume ESV = 50 cc
60 cc 120 cc EF = 0.71
ESV = 50 cc RF = 0.50
EF = 0.67
LVEDP = 10 mm Hg
LVEDP = 50 mm Hg

A B

100 cc AOP 190/60 75 cc AOP 170/60

Forward Forward
stroke EDV = 250 cc stroke EDV = 300 cc
volume 200 cc ESV = 50 cc volume 150 cc ESV = 150 cc
100 cc EF = 0.80 75 cc
RF = 0.5 EF = 0.50
RF = 0.50

LVEDP = 12 mm Hg LVEDP = 25 mm Hg

C D
FIGURE 15.8. The pathophysiologic stages of aortic regurgitation forward stroke volume and LV filling pressure. The large total stroke
(AR). Normal physiology (A) is contrasted with acute AR (B). In acute volume results in a wide pulse pressure that is responsible for many
AR little left ventricle (LV) dilatation has occurred so that total of the signs of AR. (D) Muscle dysfunction has developed, resulting
stroke volume and forward stroke volume are reduced. The large in increased end systolic volume, reduced forward stroke volume,
filling volume due to the AR is thrust into a small LV resulting in and elevated LV filling pressure. LVEDP, left ventricular end-
high LV filling pressure. (C) Compensatory left ventricular hyper- diastolic pressure.
trophy (LVH) has developed. Cardiac enlargement now allows normal
388 chapter 15

in total stroke volume. However it must be recognized that is sitting upright and leaning forward. A diastolic rumble
this large compensatory total stroke volume increases pulse may also be heard at the apex. This murmur (Austin Flint)
pressure and systolic pressure. Thus the volume overload of arises from the mitral valve. Its origin is thought to be due
AR is also associated with a significant pressure overload. In to either relative mitral stenosis, as LV filling from the aorta
fact, systolic wall stress in AR may be as high as occurs in tends to close the mitral valve in diastole, or the aortic jet
AS and the lesion more typically thought of as a pressure striking and vibrating the mitral valve. In either case the
overload.68,69 Accordingly, LV wall thickness in AR is greater presence of an Austin Flint murmur usually indicates severe
than normal as the ventricle remodels to accommodate the AR.
increased pressure demands on the LV.70 This combined pres- The large total stroke volume and widened pulse pressure
sure and volume overload causes LV mass in AR to be the of AR generate myriad signs. These include de Musset’s sign
greatest of all the valvular heart diseases. (bobbing of the head in cadence with the heartbeat), Duro-
Aortic regurgitation may be tolerated in the compensated ziez’s sign (a to-and-fro bruit over the femoral artery when it
state for years. Compensation is provided by ventricular is compressed by the bell of the stethoscope), Quincke’s pulse
remodeling (Fig. 15.8) whereby the enlarged LV can pump (plethora and blanching of the nail bed when traction is
enough extra stroke volume to maintain adequate perfusion placed on the nail), and Corrigan’s pulse (rapid upstroke and
even during exercise. At the same time the enlarged LV can brisk downstroke of the carotid pulse). Perhaps the most reli-
accommodate the increased filling volume of the LV at fairly able indicator or severe AR is Hill’s sign, which is augmenta-
normal filling pressure, preventing pulmonary congestion. tion of systolic pressure in the leg by >40 mm Hg more than
Eventually, however, eccentric hypertrophy fails to compen- in the arm.
sate for the volume overload and concentric hypertrophy fails
to normalize systolic wall stress, both acting in concert to
reduce cardiac output. In turn, increased residual LV volume Therapy
and diastolic dysfunction lead to elevated LV filling pressure.
At this point in the course of the disease, CHF symptoms Medical Therapy
may appear. As noted above, aortic regurgitation increases left ventricular
While much less common in AR than in AS, angina may afterload. Thus it is logical that afterload reduction therapy
occur with normal epicardial coronary arteries. Angina is pre- might be advantageous. In fact several studies have shown
sumed to be caused by the reduced coronary flow of reserve either reduction in LV volume or a delay to onset of symp-
of LVH together with reduced diastolic aortic pressure for toms when vasodilators were added to the regimen.71–74 In
driving coronary flow. This same reduction in diastolic pres- most cases vasodilators were administered to asymptomatic
sure may occasionally be associated with syncope. patients with normal LV function. Recently nifedipine
Rare symptoms of AR include flushing episodes, carotid administered to patients already manifesting LV dysfunction
artery pain, and an annoying awareness of the heartbeat. provided a long-term mortality benefit following AVR even
though the drug had been discontinued following surgery.75
Physical Examination The mechanism of this benefit is unknown. Which vasodila-
tor is the best agent to use is unknown because no direct
The physical examination of the patient with AR is rich with comparison of chronically used agents has ever been made.
dynamic findings. Palpation of the precordium finds an While use of vasodilators in this disease of high afterload is
active point of maximum impulse, displaced downward and logical, such use should be weighed against preliminary
to the left. The diastolic blowing murmur typical of AR is reports of failed long-term benefit.76
heard best over the left upper sternal border when the patient
Surgical Therapy
Aortic regurgitation, like all valvular heart diseases, is a
mechanical problem that requires a mechanical solution.
100 Although a minority of regurgitant aortic valves can be
Percent of patients asymptomatic

repaired, for the most part the mechanical solution for AR

80 is AVR. Thus as with AS, surgery should be timed to avoid
with normal LV function

unnecessary patient-years of risk from a prosthetic valve

complication, but must be timed early enough to avoid the
60
risk of persistent LV dysfunction following AVR. The natural
history of several AR is shown in Figure 15.9.77 The average
40 risk of developing symptoms or asymptomatic LV dysfunc-
Sudden death tion is about 4.5% per year. Thus many patients can tolerate
20 Onset of symptoms severe AR for a decade or more without negative sequelae.
Onset of asymptomatic
LV dysfunction
However, once more than mild symptoms occur78 (Fig. 15.10)
or if LV dysfunction develops and is allowed to persist, the
0
6 0 82 4
10 12 prognosis is reduced.79–83 While the exact definition of LV
Time (years) dysfunction is unclear, the prognosis diminishes when LV
FIGURE 15.9. The natural history of AR is shown. The onset of ejection fraction falls below 0.55 or when the LV is unable to
symptoms or LV dysfunction occurs at a rate of about 4.5%/year. contract down to 50 to 55 mm Hg at the end of systole. It is
 a o r t i c va lv e d i s e a s e 389
100
82 ± 5%

Overall survival (%)

80 73 ± 7%

60
Class 40 ± 8%
40 I-II 40 ± 9%
III-IV
20
p < .0001 p = .023
FIGURE 15.10. Outcome of patients 0
with AR and reduced ejection fraction 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
(left panel) and normal ejection fraction Years
(right panel) is shown. In either case,
advanced symptoms greatly reduced I-II n = 99 95 95 93 91 85 71 67 57 47 35 45 41 41 41 40 34 31 25 20 15 14
survival following AVR. III-IV n = 54 47 42 42 39 36 31 26 19 14 10 51 45 43 40 38 32 24 21 20 12 11

presumed that these benchmarks represent evidence of sig- vigilance for the earliest evidence of heart failure must be
nificant LV dysfunction. Thus AVR should be performed in practiced, and steps toward AVR must be initiated as soon as
AR patients if even mild symptoms occur or if there is evi- such evidence is recognized.
dence of LV dysfunction as noted above. Following surgery,
reduction in afterload allows LV ejection fraction to improve,
especially if LV dysfunction has been present for less than Obesity Drugs, Valvular Heart Disease,
15 months.78,84 and Pulmonary Hypertension

Acute Aortic Regurgitation Fenfluramine and Phentermine

Acute severe aortic regurgitation (AR), such as might occur The appetite-suppressants dexfenfluramine and the combi-
following the perforation of an aortic leaflet by infective nation of fenfluramine and phentermine (Fen/Phen) have
endocarditis, is a potentially life-threatening emergency that been associated with an unanticipated outbreak of valvular
is often underrecognized. Treated medically, this disease has heart disease associated with their administration.88 Pulmo-
up to 75% mortality while surgical intervention reduces risk nary hypertension occurs in association with another appe-
to 25% or less. Recent analysis clearly favors early surgery tite suppressant, aminorex fumarate.89 Aminorex (Menocil)
in such patients.85 In acute severe AR, the unprepared small resembles epinephrine and amphetamine in chemical struc-
LV must accept a large regurgitant volume, in turn increas- ture, and its toxic effects have been attributed to the release
ing LV diastolic filling pressure. At the same time, diastolic of norepinephrine and other catecholamines.90 Aminorex
aortic pressure falls due to increased run-off of blood into the became available in 1965 in Austria, Germany, and Switzer-
LV. The net result is reduced driving pressure for coronary land, and in the next 7 years the incidence of pulmonary
blood flow, potentially leading to myocardial ischemia, hypertension increased by approximately 10-fold.89 Pulmo-
setting up a vicious cycle of reduced coronary flow leading nary hypertension in humans associated with aminorex use
to reduced LV function leading to reduced coronary flow, etc. often progresses, but it may regress when the drug is discon-
Of concern is that this pernicious physiologic state is diffi- tinued. Fen/Phen usage has also been associated with the
cult for the clinician to recognize. As noted above, the physi- development of pulmonary artery hypertension.91
cal examination of the patient with chronic AR is very In the mid-1990s, more than 18 million prescriptions
dynamic, based on increased total stroke volume and pulse were filled for Fen/Phen, mainly for overweight women.91
pressure. However, in acute AR, there has been no time for There had already been occasional reports of pulmonary
LV dilatation; thus most of the findings of chronic AR are hypertension in association with the use of fenfluramine92
absent. Instead the murmur of AR is short and unimpressive and phentermine alone.93 Connolly et al.88 from the Mayo
because rapid LV filling at high pressure reduces the gradient Clinic had already published a series of patients taking Fen/
for AR. Also rapid LV filling from AR causes early closure of Phen who had developed left ventricular valvular lesions,
the mitral valve so that s1 is soft. Yet if preclosure of the most frequently aortic insufficiency, but also mitral insuffi-
mitral valve is confirmed echocardiographically, the progno- ciency that was sometimes severe enough to require surgical
sis without AVR is dire.86 While medical therapies to stabi- valve repair or replacement. The cardiac valve lesions in
lize the patient are often attempted, they usually fail. patients who have taken Fen/Phen are very similar to those
Vasodilators used to decrease the amount of AR also reduce seen in patients with metastatic carcinoid tumors, and both
systemic blood pressure in patients who are often hypoten- appear to be a consequence of very high serotonin concentra-
sive to begin with. Pressor agents with vasoconstrictor prop- tions in the blood.93,94 It appears that selected appetite sup-
erties increase the amount of AR and thus are deleterious. pressant drugs, such as Fen/Phen, diminish the ability of the
On the other hand, delay in performing AVR because of fear lungs to extract serotonin from the circulation.95 It has been
that the replacement valve will become infected is unjusti- speculated that (1) an inherited susceptibility to aminorex
fied because reinfection even with valve insertion within 48 and fenfluramine predisposes individuals to vasoconstric-
hours of a positive blood culture is extremely rare, especially tion and obliterative pulmonary vascular lesions predomi-
when a homograft is inserted.87 Thus in acute AR, extreme nantly in the precapillary muscular arteries and arterioles of
390 chapter 15

the lungs; and (2) impaired clearance by the lungs of biologi- sudden cardiac death after coronary artery occlusion in con-
cally active substances, such as serotonin, enables toxic con- scious dogs. Circulation 1982;65:1192–1197.
centrations of the agent to reach and damage LV heart valves, 14. Orsinelli Da, Aurigemma GP, Battista S, Krendel S, Gaasch
leading to aortic or mitral valvular regurgitation.91 WH. Left ventricular and mortality after aortic replacement
for aortic stenosis. A high risk subgroup identified by preopera-
Based on data showing the prevalence of abnormal valve
tive relative wall thickness. J Am Coll Cardiol 1993;22:
regurgitation of approximately 30% in 291 patients treated 1679–1683.
with dexfenfluramine, dexfenfluramine phentermine, or fen- 15. Vandeplas A, Willems JL, Piessens J, De Geest H. Frequency
fluramine-phentermine as compared to 2% in controls, fen- of angina pectoris and coronary artery disease in severe
fluramine and dexfenfluramine were withdrawn from the isolated valvular aortic stenosis. Am J Cardiol 1988;62:
market in 1997.96,97 Efforts to identify the incidence of aortic 117–120.
or mitral valve regurgitation in patients using dexfenflura- 16. Garcia-Rubira JC, Lopez V, Cubero J. Coronary arterial disease
mine have suggested that 7.6% of patients using dexfenflu- in patients with severe isolated aortic stenosis. Int J Cardiol
ramine and 2% of controls develop at least aortic or mitral 1992;35:121–122.
insufficiency, with mild AR being the most frequent lesion.96 17. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL.
Decreased coronary reserve: a mechanism for angina pectoris
Other factors also related to the development of valvular
in patients with aortic stenosis and normal coronary arteries.
heart disease in these patients include older age, higher blood N Engl J Med 1982;307:1362–1366.
pressure, and shorter time from discontinuation of the 18. Rajappan K, Rimoldi OE, Dutka DP, et al. Mechanisms of coro-
drug.96 nary microcirculatory dysfunction in patients with aortic ste-
nosis and angiographically normal coronary arteries. Circulation
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 1 Pulmonary and Tricuspid
6 Valve Disease
Otto M. Hess, Urs Scherrer, Pascal Nicod, and
Blase A. Carabello

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Medical/Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . 395

Key Points increase in right atrial pressure. Severe tricuspid stenosis is

present if valve area is less than 1 cm2. Under these circum-
• Pulmonary regurgitation secondary to dilatation of the
stances, right atrial pressure increases to 10 mm Hg or greater,
valve ring in patients with severe pulmonary hyperten-
and venous congestion with peripheral edema and ascites
sion and in those with severe mitral valve disease is the
occurs.
most common pulmonary valvular abnormality.
Tricuspid regurgitation can be relative or organic. By far,
• Tricuspid stenosis is usually rheumatic in origin, but it
the most common cause is relative tricuspid regurgitation
is also seen in patients with carcinoid heart disease.
secondary to dilatation of the right ventricle (RV) and the
• Tricuspid regurgitation is seen with dilatation of the
tricuspid annulus, often associated with pressure or volume
right ventricle, tricuspid annulus, right atrial myxoma,
overload of the RV. Organic tricuspid regurgitation is usually
endocarditis, carcinoid syndrome, Ebstein’s anomaly, and
more severe and may be caused by right atrial myxoma,
myxomatous degeneration of the tricuspid valve leaflets
endocarditis, carcinoid syndrome, Ebstein’s anomaly, or
and supporting structures.
myxomatous degeneration of the tricuspid valve leaflets and
supporting structures.
Physiologic pulmonary or tricuspid regurgitation in
Pathophysiology normal individuals is common and can be found in 80%
(pulmonary) to 95% (tricuspid valve) of all subjects.
Acquired pulmonary valve disease is extremely rare. Occa-
sionally, rheumatic inflammation may be seen, but this
rarely leads to serious deformity. Infective endocarditis and Physical Examination
leaflet destruction of the pulmonic valve may be observed in
drug addicts. Thickening or retraction of the pulmonary
Pulmonary Valve Disease
valve leaflets has also been described in patients with carci-
noid syndrome.1 Finally, low-pressure pulmonary regurgita- Physical findings of pulmonary regurgitation vary according
tion may be observed in patients with dilatation of the to the presence or absence of pulmonary hypertension. The
valvular ring, as in idiopathic dilatation of the pulmonary carotid pulse is usually normal unless cardiac output is
artery, in connective tissue disorders, or after valvotomy for decreased. Jugular venous pressure may be normal or
pulmonary stenosis. increased when tricuspid valve disease or RV failure is
By far the most common disorder is pulmonary regurgita- present. A prominent A wave can be seen with pulmonary
tion secondary to dilatation of the valvular ring in patients hypertension. A parasternal RV impulse may be present, and
with pulmonary hypertension or severe mitral valve disease. a pulsatile pulmonary artery may be felt in the second left
This disorder, called high-pressure pulmonary regurgitation, intercostal space. On auscultation, the pulmonary compo-
is usually overshadowed by the underlying disease and is nent of S2 is usually normal and delayed, causing variable
characterized by a high-pitched diastolic murmur (Graham wide splitting of S2. If significant pulmonary hypertension
Steell’s murmur). is present, P2 becomes louder with narrow splitting of S2.
Tricuspid stenosis is usually rheumatic in origin and is An ejection click and an S3 may be heard. The regurgitant
typically accompanied by mitral stenosis. It is also seen in murmur, in the absence of pulmonary hypertension, follows
patients with carcinoid syndrome. A reduction in tricuspid S2 in a crescendo-decrescendo pattern with a medium pitch
valve area to less than 1.5 cm 2 is usually associated with an and is best heard in the third and fourth left intercostal

393
394 chapter 16

spaces.2,3 When pulmonary hypertension is present, the

murmur becomes decrescendo and has a higher pitch, similar
to that of aortic insufficiency.
When pulmonary stenosis is associated with pulmonary
regurgitation, a thrill may be felt in the second left intercos-
tal space. An ejection click is usually not heard in acquired
mixed pulmonary stenosis and regurgitation. A systolic cre-
scendo-decrescendo murmur is found in the second left para-
sternal intercostal space, with delayed peaking. Typically,
murmurs of pulmonary valve disease increase with inspira-
tion or with inhalation of amyl nitrite.

Tricuspid Valve Disease

Tricuspid Stenosis
The physical findings of tricuspid stenosis are often obscured
by the concomitant presence of stenosis or regurgitation of
other valves. The most prominent finding is the presence of
a large A wave in the jugular veins of patients who are in
sinus rhythm (Fig. 16.1).4 The distinction from pulsating
carotid arteries can be made by concomitant palpation of the
upstroke of the carotid pulse, which follows the jugular A
wave. In patients with atrial fibrillation, jugular turgescence
may be accompanied by a slow y descent, owing to an impair-
ment of RV filling in early diastole.5
Palpation is usually normal unless associated valvular
disease is present. Occasionally, a thrill may be felt over the
left lower sternal border, and pulsation of the right atrium
may be detected in the right parasternal area. FIGURE 16.2. (A) Right-sided venous pulse pressure (VP) in a 39-
S2 may be narrowly split, with little respiratory variation year-old patient with tricuspid regurgitation. There is a prominent
V wave, followed by a rapid y descent. A phonocardiogram (Phono)
as a result of impaired RV filling. An opening snap is often reveals a holosystolic murmur. (B) Right-sided venous pressure in a
difficult to differentiate from that of mitral stenosis but may 26-year-old patient without heart disease. The A wave is typically
occur later in diastole. The diastolic murmur after the taller than the V wave. Both the x and the y descents can be seen.
opening snap is usually of low frequency, or on occasion, of ECG, electrocardiogram.
higher frequency and decrescendo. It is maximal over the

lower left sternal border. In patients with sinus rhythm, a

presystolic murmur may be heard and can be differentiated
from that of mitral stenosis by an earlier appearance, a
crescendo-decrescendo pattern, and termination before S1.4
The murmur of tricuspid stenosis and the opening snap
typically increase in intensity with deep inspiration (Car-
vallo sign). All other maneuvers that cause an increase in
cardiac output, such as leg raising, exercise, and inhalation
of amyl nitrite, also increase the intensity of the murmur
and the opening snap, whereas the Valsalva maneuver and
sudden standing position decrease their intensity.

Tricuspid Regurgitation
Tricuspid regurgitation is often associated with pulmonary
hypertension or other valvular lesions. Prominent jugular V
waves may be seen in the neck (Fig. 16.2).5–7 They should be
differentiated from the A wave of tricuspid stenosis by their
slower upstroke and their appearance after the carotid pulse
FIGURE 16.1. Right-sided venous pulse pressure in a 39-year-old and in association with the second heart sound. They may
patient with tricuspid stenosis. The A wave is predominant, and the
y descent is decreased. On the phonocardiogram, a diamond-shaped
be accompanied by a pulsatile liver and signs of RV failure.
presystolic rumble can be appreciated. P waves on the electrocardio- The y descent is also present. The RV impulse may be promi-
gram are suggestive of right atrial enlargement. nent and hyperdynamic. A systolic right atrial impulse may
 p u l m o n a r y a n d t r i c u s p i d va lv e d i s e a s e 395

Medical/Surgical Treatment
Mild tricuspid or pulmonary valvular insufficiency does not
require specific therapy other than antibiotic prophylaxis
against subacute bacterial endocarditis before dental work or
surgery. Hemodynamically significant tricuspid or pulmo-
nary insufficiency in the presence of pulmonary hyper-
tension is best treated with vasodilators and unloading
interventions, such as angiotensin-converting enzyme inhib-
itors, nifedipine, hydralazine, and prazosin, with or without
FIGURE 16.3. Phonocardiographic recording (Phono) in a patient nitrates. In the absence of important pulmonary arterial
with tricuspid regurgitation. There is a marked inspiratory increase hypertension, the use of the same vasodilators with an ino-
of the intensity of the murmur (Carvallo sign), followed by a third tropic agent, such as cardiac glycosides, may be useful, espe-
heart sound. The right atrial (RA) pressure recording shows no cially if atrial fibrillation is present. With severe tricuspid or
inspiratory fall in pressure, whereas right ventricular (RV) systolic
pressure increases during inspiration. ECG, electrocardiogram.
pulmonary valvular insufficiency and RV failure, surgical
replacement or repair of the leaking valve may be required.
Hemodynamically important valvular pulmonic or tricuspid
stenosis with associated limiting symptoms is treated by
valvuloplasty or sometimes by surgical replacement or repair
of the valve.
rarely be felt in the right parasternal area. On auscultation, The reader is referred to the Web sites of the American
P2 may be increased in presence of pulmonary hypertension. College of Cardiology (ACC) (www.acc.org) and the Ameri-
A prominent S3 that increases with inspiration may be heard. can Heart Association (AHA) (www.americanheart.org) for
The murmur is usually holosystolic and located in the lower the ACC/AHA Guidelines for the Management of Patients
left parasternal area but may be heard over the lower sternum with Acute Myocardial Infarction.
and the subxiphoid area. Occasionally, it may be early sys-
tolic, particularly in the presence of acute tricuspid regurgi- Acknowledgments
tation, or limited to midsystole or even late systole.
Sometimes, a diastolic flow rumble may be heard, as a result This chapter was adapted from the corresponding chapter in
of increased diastolic flow across the tricuspid valve. the previous edition.
The murmur typically increases with deep inspiration
(Carvallo sign) as a result of increased venous return (Fig.
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latter. Saunders, 1997.
 1 Mitral Valve Diseases
7 Maurice L. Enriquez-Sarano and
Robert L. Frye

The Normal Mitral Valve . . . . . . . . . . . . . . . . . . . . . . . . . 397 Mitral Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Mitral Valve Prolapse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402

Key Points free edge and a central clear zone toward the base. The ante-
rior leaflet occupies only one third of the circumference of
• The predominant cause of mitral stenosis is rheumatic
the annulus but is longer than the posterior leaflet so that
heart disease.
the leaflet apposition (coaptation) is along an upward concave
• The most frequent ECG abnormality with mitral stenosis
curve resembling a smile. The anterior leaflet is attached by
is atrial fibrillation.
a fibrous connection to the aortic annulus (intervalvular
• The occurrence of atrial fibrillation (or atrial flutter) in
fibrosa). The posterior leaflet is attached to the mitral annulus
the patient with atrial fibrillation requires anticoagula-
above which the valve tissue is a continuation of left atrial
tion initially by heparin followed by coumadin and often
endocardium. The separations between leaflets (the commis-
of treatment aiming at control of rapid ventricular
sures) are anterolaterally and posteromedially positioned.2
response using digoxin, beta-blockade, and calcium-
The posterior leaflet is composed of three scallops, antero-
channel blockade.
lateral (P1), medial (P2), and posteromedial (P3). The anterior
• Guidance by transesophageal echocardiography (TEE) is
leaflet has no scallops but the zones coapting with the pos-
useful to rule out atrial thrombus before cardioversion.
terior scallops are similarly called A1 to A3. The leaflets are
• Prolapse of the mitral valve is a fall below its normal
thin, pliable, and have no inertia so that full opening is
position, and billowing (bulge beyond its normal place) of
obtained immediately in diastole. The leaflets are attached
the mitral valve is an abnormal movement of the mitral
to chordae tendineae by their tip (primary) or their body
valve during systole beyond its normal position and into
(secondary). The chordae are attached to the two papillary
the left atrium.
muscles (anterolateral and posteromedial), which provide
• Often mitral valve prolapse is a progressive disease with
chordae to both leaflets at and around each commissure.3
flail leaflets and chordal rupture being found in older
The papillary muscles are attached to the left ventricle (LV)
patients.
wall. The mechanisms ensuring competence of the mitral
• Mitral insufficiency is an organic mechanism if there is
valve are the preclosure following atrial contraction, which
intrinsic mitral valve disease or a functional mechanism
allows the leaflets to approximate before the ventricular con-
if the valve is structurally normal but regurgitates due to
traction; the orientation of the anterior leaflet, parallel to the
an extravalvular abnormality.
flow, which slides on its ventricular surface in systole; and
• Surgical correction of mitral regurgitation (MR) is indi-
the coaptation on rough zones of the atrial surface, creating
cated in patients with severe MR and symptoms or with
strong but passive friction resistance when the leaflets are
reduced LV systolic function.
apposed. The leaflets are composed of four layers: auricularis,
• Prevention of infective endocarditis using the appropriate
spongiosa, fibrosa, and ventricularis.
antibiotic prophylaxis is necessary in patients with MR.
The auricularis is composed of collagen and elastic tissue
• The most frequent cause of mortality after surgical cor-
and is continuous with the endocardium of the left atrium.
rection of MR is left ventricle dysfunction due to chronic
The spongiosa is situated between the auricularis and fibrosa
irreversible myocardial damage.
layers and is formed by a loose connective tissue. The fibrosa
constitutes the basic support for the leaflet and is composed
The Normal Mitral Valve of thick collagen. This layer is continuous at its base with
the mitral annulus and the intervalvular fibrosa and at its
The mitral valve has two leaflets (Fig. 17.1) attached at their free edge with the chordae tendineae. The ventricularis is a
bases to a fibrous annulus and by their free edges to their thin layer of collagen and elastic tissue that covers the ven-
chordae tendineae.1 Each leaflet has a rough zone toward the tricular aspect of the fibrosa and is continuous beyond the

397
398 chapter 17

increase markedly with sustained exercise. When the mitral

orifice is <1.5 cm2 (moderately severe to severe MS), LA pres-
sure is augmented at rest, and pressure gradients of more
than 10 mm Hg can be observed. Such patients have often
reduced cardiac output and dyspnea during mild exercise or
even at rest. For any given orifice area, previously asymptom-
atic patients may suddenly become symptomatic if they
become pregnant, infected, or anemic or develop atrial fibril-
lation with rapid ventricular response.
Left atrial response to MS with chronic elevation of LA
pressure is characterized by LA dilatation, which in turn is
a compensatory mechanism normalizing LA compliance12
and activating natriuretic peptides.13 However, LA dilatation
may also have deleterious consequences with reduced blood
flow and increased local coagulability,14,15 which may lead to
FIGURE 17.1. Anatomic ventricular view of a normal mitral valve. thrombus formation and with reduced electrical stability
The commissures (C) are closed by a narrow band of valvular tissue. which may lead to atrial fibrillation. Also, increased LA
Ant Leaf, the anterior leaflet, the longest and narrowest; Post Leaf, transport function plays an important hemodynamic role in
the scallops of the short but widest posterior leaflet; PM, the two MS. Left atrial contraction augments end-diastolic mitral
papillary muscles situated in regard to the commissures and distrib-
uting chordae to the corresponding parts of both leaflets. Chordae blood flow and maintains stroke volume despite reduced
are indicated by arrows. orifice area. Occurrence of atrial fibrillation, even with
acceptable ventricular response, is responsible for approxi-
mately a 20% decrease in cardiac output. Therefore, mainte-
nance of sinus rhythm is important for the well-being of
posterior leaflet with the left ventricular endocardium and patients with MS. Conversely, left ventricular dysfunction is
is part of the fibrosa.4 not a major concern in MS. Although ejection fraction may
be reduced, it is mostly an unloading phenomenon, is usually
not progressive, and has modest effects on outcome.16
Mitral Stenosis
Pulmonary vascular response to chronically elevated LA
pressure leads to increased pulmonary vascular resistance
Pathophysiology
and excessively elevated pulmonary pressure, which in turn
The predominant cause of mitral stenosis (MS) is rheumatic may lead to right ventricular dilatation, tricuspid annular
heart disease. The valvular lesions produced by the rheu- dilatation, and functional tricuspid regurgitation, and ulti-
matic process in patients with MS are characterized by com- mately may lead to global heart failure.17
missural fusion, which directly cause the stenosis.5 There is Mitral stenosis is a progressive disease with progressive
also tissue retraction of leaflets and chordae tendineae, fusion commissural fusion leading to a reduced valve area, which
of chordae, and ultimately postinflammatory calcification, is amplified by periorificial calcifications and by subvalvular
which combined determine the feasibility of interventional obstruction to flow due to chordal fusion and retraction.18
or surgical treatment.5 The commissural fusion is responsible
for the reduction of mitral orifice size during diastole and
Natural History
also for the loss of physiologic valvular reserve (larger open-
ing with larger flow) characterized by fixed mitral orifice The natural history from the initial rheumatic fever episode
irrespective of blood flow.6,7 The major hemodynamic con- to the development of MS is reputed to be slow, taking a
sequence of MS is left atrial (LA) pressure elevation, which decade or much longer in developed countries, whereas in
when greater than 25 to 30 mm Hg is responsible for transuda- developing countries19 the disease may progress more
tion of fluid into the pulmonary interstitial space. Left atrial rapidly,20,21 and severe MS may already be present in early
pressure is determined by the transmitral diastolic pressure adolescence.22 This difference may be due to differences in
gradient, governed mostly by the orifice area and also by dura- utilization of antibiotics, recurrent carditis, virulence of bac-
tion of diastole and stroke volume transported through the terial strains, or genetic factors, but is attested to by differ-
orifice.8,9 Tachycardia decreases diastolic time and for a given ences in age at intervention in various world regions. This
stroke volume augments transmitral diastolic flow rate, pres- reduced MS development in developed countries has resulted
sure gradient, and LA pressure.10 Increased stroke volume for in a major decline in the prevalence of MS requiring medical
any given diastolic filling period (such as with pregnancy or attention.
anemia) increases transvalvular velocity linearly with flow, The natural history of patients with established MS and
but as pressure gradient is a square function of velocity, may medically managed has been defined by retrospective studies
lead to marked LA pressure elevation.11 conducted in the 1950s and 1960s.23,24 Mitral stenosis is a
When the mitral orifice (normally 4 to 6 cm2) is reduced progressive disease with a slow, lifelong course that is ini-
to 2 to 2.5 cm2 (mild MS), LA pressure is normal under resting tially asymptomatic and subsequently punctuated by acute
conditions, but may increase abnormally with excess blood complications or evolving into symptoms development.
flow or heart rate changes. With orifices of 1.5 to 2.0 cm2 Once mitral stenosis has become symptomatic, it takes
(moderate MS), LA pressure, mildly elevated at rest, may approximately 5 to 10 years for most patients to progress
 m i t r a l va lv e d i s e a s e s 399
from mild to severe disability. In these natural history patients with markedly reduced cardiac output. The time
studies, survival has been analyzed according to the develop- interval between A 2 and the opening snap is an indicator of
ment of symptoms, but information regarding the influence LA pressure and is most often 0.08 second with mildly ele-
of mitral valve area, LA size, or pulmonary pressure is vated LA pressure. Intervals <0.06 and >0.10 second suggest
lacking. Ten years after diagnosis in asymptomatic or mini- respectively severe and minimal LA pressure elevation.
mally symptomatic patients, rates of mortality and of new Thus, the A 2 opening snap interval, best measured by pho-
symptoms are 20% and 40%, respectively. In the presurgical nocardiography (or estimated at the bedside on physical
era, 5-year mortality rates were 38% in mildly symptomatic examination), is an indirect measure of MS severity. A dia-
patients and 85% in severely symptomatic patients. The stolic rumble can be best heard while the patient lies on the
cause of death in these series was heart failure in 60% to left side; it follows the opening snap and decrescendo, and
70% and thromboembolism in 20% to 30%. displays presystolic accentuation in sinus rhythm. With a
smaller mitral valve area the rumble is more holodiastolic,
and with a higher gradient it is more intense. However, a
Clinical Evaluation
holodiastolic rumble may be present in mild mitral stenosis
The diagnosis of MS may be based on abnormal physical and tachycardia. The diastolic rumble may be difficult to
examination or Doppler echocardiography with symptoms hear with increased heart-skin distance (obesity or emphy-
either absent or nonspecific, such as fatigue or chest pain. sema) but may be of low intensity with low cardiac output-
Most patients are diagnosed with MS because of exertional low gradient. With markedly reduced output in patients with
dyspnea and more rarely because of complications such as calcified leaflets of reduced mobility, MS may be silent, and
pulmonary edema, hemoptysis, global heart failure, atrial the only clue to the presence of MS may be a faint opening
fibrillation, or an embolic event (Table 17.1). snap. Systole is usually silent, but a systolic murmur (apical,
The general appearance of patients with critical MS, the early systolic with mild mitral regurgitation or xiphoid with
“facies mitralis” with malar cyanosis, is now exceptionally inspiratory accentuation with tricuspid regurgitation) may
observed. Inspection of jugular veins may show prominent be heard. An associated diastolic murmur may be heard
A waves in patients with pulmonary hypertension and in along the left sternal border either due to pulmonary insuf-
sinus rhythm or large V waves in patients with severe func- ficiency (Graham Steell’s murmur) with severe pulmonary
tional tricuspid regurgitation. Jugular vein distention, periph- hypertension or due to the frequently associated aortic regur-
eral edema, and liver enlargement appear in patients with gitation. Thus, it is usually possible to obtain a strong clini-
heart failure. Precordial palpation may reveal a right ven- cal impression of severe MS with loud and holodiastolic
tricular heave in patients with right ventricular dilatation, a rumble with a thrill, short A 2-opening snap interval, loud S2,
palpable S2 with severe pulmonary hypertension, and at the and tricuspid regurgitant murmur, but all these signs can be
apex a palpable S1 and rarely a diastolic thrill found while observed with moderate stenosis and increased cardiac
the patient lies on the left side. output due to pregnancy, infection, or anemia.
Auscultation reveals25,26 a characteristically S1 accentu- The most frequent ECG abnormality is atrial fibrillation.
ated (due to the mitral thickening and wide closure move- In sinus rhythm a prolonged P wave is due to LA enlarge-
ment with elevated LA pressure), but which may be normal ment. With pulmonary hypertension, a P pulmonale (tall P2,
or reduced with decreased leaflet mobility. S2 is usually P2 > P3 > P1), a right axis deviation of QRS, and a tall R wave
normal, but with pulmonary hypertension accentuation of in V1 with negative T’s in V1 to V3 may be observed.
the pulmonary component may be noted. An opening snap The chest radiography may show LA dilatation, creating
follows S2, is best heard at the apex, and is usually high- a double contour, widening of the carina, and LA appendage
pitched but may be attenuated when valve excursion is dilatation along the left sternal border. While the heart
limited by thickening or calcification. However, it rarely size is usually normal, marked LA, right atrial, and ventric-
disappears and it may be the only auscultatory finding in ular dilatation may result in frank cardiomegaly. With

TABLE 17.1. Clinical syndromes of mitral stenosis (MS) presentation

Edematous MS Fibrotic MS Silent advanced MS

Presentation 20–30-year-old; no symptoms 40–50-year-old; mild dyspnea 70–90-year-old

until pulmonary edema with exertion Class IV CHF
Physical examination Loud S1 and OS Audible S1 and OS Soft OS
Loud rumble Moderate rumble No rumble, decreased S1
Pulsatile liver
ECG Sinus; LA enlargement Atrial fibrillation Atrial fibrillation
Chest x-ray Small heart; LA enlarged Marked LA and RA enlargement Marked cardiomegaly
Echo-Doppler Small MVA, large gradient; Small MVA, modest gradient at Critical MS with massive calcification
no MR; no calcification rest, MR present; commissural Severe pulmonary hypertension and TR
calcifications
Follow-up Balloon mitral valvuloplasty PBMV or surgery depending on MVR
MR and calcification
LA, left atrium; MR, mitral regurgitation; MS, mitral stenosis; MVA, mitral valve area; OS, opening snap; PBMV, percutaneous mitral balloon valvuloplasty;
RA, right atrium; TR, tricuspid regurgitation.
400 chapter 17

FIGURE 17.2. Echocardiographic long-axis view of the mitral valve FIGURE 17.4. Doppler measurement of mitral transvalvular gradi-
in a patient with mitral stenosis. The large arrows indicate the ent in a patient with severe mitral stenosis in sinus rhythm. The
leaflet tip thickening, typical of rheumatic mitral involvement and transvalvular velocity is in excess of 2 m/sec and the mean gradient
the small arrows indicate the diastolic hockey-stick deformation is calculated at 13.8 mm Hg.
due to the restriction of movement of the anterior leaflet due to
commissural fusion. Left atrium (LA) is markedly enlarged with
normal left ventricular (LV) size suggestive of severe stenosis. Ao,
aorta. Note the associated thickening of the aortic valve, suggestive short axis view is simple but requires delicate positioning at
of rheumatic disease.
the tip of the mitral funnel.28–30 The value of three-dimen-
sional echocardiography is currently being evaluated,31 and
may improve with enhanced image quality. Second, Doppler
pulmonary hypertension, pulmonary trunk and branch dila- allows measurement of the transvalvular gradient (Fig. 17.4)
tation and cephalization of the pulmonary circulation are and the pressure half-time method of measurement of the
present and often associated with interstitial markings of mitral valve area (Fig. 17.5) uses the velocity decay in early
pulmonary edema and pleural effusion. diastole and is most frequently used,32 but may be affected
Doppler echocardiography is the core test allowing posi- by associated aortic regurgitation33 or alterations of LV and
tive diagnosis and assessing the severity and morphology of LA compliance, particularly after balloon valvuloplasty.34
MS. Imaging shows the features of rheumatic disease (Fig. Third, the continuity equation measures the orifice area as
17.2) with valvular thickening (predominant early on leaflet the ratio of the aortic stroke volume to the mitral stenotic
tips), retraction, and reduced mobility (particularly of poste- jet time velocity integral by Doppler. It may be affected by
rior leaflet). Mitral stenosis diagnosis is based on doming of underestimation of stroke volumes or by frequent presence
the anterior leaflet, direct planimetry of the stenotic mitral of aortic regurgitation. Fourth, the proximal isovelocity
orifice, and increased diastolic velocity (and gradient) through
the mitral valve.27 Assessing MS severity can rely on several
methods. First, mitral orifice planimetry (Fig. 17.3) in the

Area = 1.5 cm2

Scale
RV

LV

Planimetered
mitral orifice

FIGURE 17.3. Echocardiographic short-axis parasternal view in a FIGURE 17.5. Doppler measurement of the mitral valve area by the
patient with mitral stenosis. The image is obtained at the leaflet tip pressure half-time method. The slope of deceleration of the trans-
to allow planimetry of the mitral orifice. RV and LV, right and left mitral velocity indicates a pressure half-time of 223 ms, which
ventricle. calculates a mitral valve area of 1.0 cm 2.
 m i t r a l va lv e d i s e a s e s 4 01
surface area (PISA) method uses color flow imaging of the
flow convergence proximal to the mitral orifice to measure C(17) LV C(9) 0.5m/s LV
transvalvular flow (Fig. 17.6), the ratio of which to transval- D(9) PCWP D(8)
vular velocity provides the orifice area.35,36 Complex angular
50 50
correction tends to limit its accuracy and reproducibility.
Because all of these methods have a notable range of error, it
is prudent to use two or more methods and average them to LA
estimate the mitral diastolic valve area.
An important measure of MS severity is the mean trans-
valvular gradient, measured by continuous-wave Doppler 0 0
(Fig. 17.4) as the average of multiple beats. The mean gradient
should be interpreted carefully depending on cardiac output
(lower gradient with reduced output) and heart rate (increased FIGURE 17.7. Pressure curve tracing obtained by catheterization
gradient with higher rate). If necessary, assessment of mean with simultaneous continuous-wave Doppler recording. The left
gradient with exercise (using a graded recumbent bike proto- curves show a gradient measured simultaneously between the pul-
monary capillary wedge pressure (PCWP) and left ventricular (LV)
col)37 or dobutamine stress38 shows rapid and marked gradi- pressure. The gradient by catheterization (C), overestimates the
ent increase related to the heart rate and output increase in Doppler (D) gradient. The right curves show a gradient obtained
severe MS. Assessing MS morphology relies on the complete between the left atrial (LA) and LV pressures. The gradient by cath-
description of leaflets, commissures, chordae, and papillary eterization and Doppler are identical.
muscle.39 The valve score is a number between 4 and 16 (from
lightest to most severe alteration) obtained by summing the
scores between 1 and 4 for the leaflets’ thickening, lack of
mobility, and calcification, and for subvalvular alteration.40 which is degenerative without commissural fusion and
Scores above 8 to 10 are usually considered as precluding cannot be treated by balloon valvuloplasty.
balloon valvuloplasty.41 Calcification location and severity Cardiac catheterization, which was the first method to
assessment is crucial, because minor or unicommissural cal- measure mitral valve area,46,47 is now rarely necessary for the
cifications do not limit valvuloplasty, while bicommissural, diagnosis or for severity assessment of MS.48 It is usually part
diffuse, or severe calcifications usually preclude good results of pre–balloon-valvuloplasty assessment. It allows direct
of valvuloplasty.42,43 Presence and severity of mitral regurgi- verification of mitral gradient between LA and LV (Fig. 17.7)
tation (MR) are assessed by color flow imaging, if necessary of pulmonary pressures and resistance and of MR severity
using transesophageal echocardiography (TEE) in patients by LV angiography. Coronary angiography may be performed
with uncertain transthoracic assessment. The presence of LA depending on the patient’s age and symptoms, particularly if
thrombus, particularly in the appendage, is assessed by TEE surgery is considered.
before valvuloplasty and in patients with recent thromboem-
bolic complications.44,45 Echocardiography should also dif-
Management
ferentiate true MS with commissural fusion from mitral
obstruction due to protrusive mitral annular calcification, Mitral stenosis is a mechanical obstruction to mitral inflow,
which should be relieved by a mechanical intervention
(balloon valvuloplasty, commissurotomy, or valve replace-
ment), indicated when the MS is severe and the patient pre-
sents with overt clinical consequences of the MS. As LV
dysfunction is not a major outcome issue in MS, interven-
tions in asymptomatic patients are rarely needed.
Medical management aims at avoiding symptoms and
complications. Appropriate rheumatic fever and infective
endocarditis prophylaxis are needed. Limitation of physical
activity and of salt intake, combined with low-dose diuretic
administration, allows maintenance in a minimally symp-
tomatic status sometimes for years. Patients with symptoms
associated with marked tachycardia10 with activity can
benefit from beta-blockade.49,50 The occurrence of atrial fibril-
lation (or flutter) requires administration of anticoagulation
initially by heparin followed by Coumadin51 and often of
treatment aiming at control of rapid ventricular response
FIGURE 17.6. Doppler echocardiographic measurement of the
mitral valve area using the proximal flow convergence (proximal using a combination of digoxin, beta-blockade, and calcium-
isovelocity surface area, PISA) method in a patient with mitral ste- channel blockade. Cardioversion covered by anticoagulation
nosis. The color flow image (left) is obtained with an upward shift may be required urgently in patients with poor tolerance and
of the baseline allowing the measurement of the radius of the flow is otherwise considered in patients with recent (<3 months)
convergence (double-head arrow), which allows calculation of the
diastolic transvalvular flow. Measurement of the transvalvular
arrhythmia and without major atrial dilatation. Guidance
velocity using continuous-wave Doppler (right) facilitates calculat- by TEE is useful to rule out atrial thrombus before car-
ing the mitral valve area as the ratio of flow to velocity. dioversion. As atrial arrhythmias are markers of disease
402 chapter 17

progression, recurrence should lead to the consideration of

mechanical intervention rather than repeated cardioversion.
Atrial fibrillation, even paroxysmal or a history of embolic
events, requires permanent anticoagulation.
Interventional treatment using percutaneous valvulo-
plasty with Inoue balloon (Fig. 17.8), or more rarely commis-
surotomy,52 opens the commissural fusion mostly unilaterally
and is the mainstay of mechanical obstruction relief cur-
rently. The most frequent approach is through transseptal
catheterization with preprocedural TEE to rule out the pres-
ence of atrial thrombus, and echo guidance to progressively
open the mitral orifice (Fig. 17.9) without inducing new
mitral regurgitation.53 Procedural mortality is <1% in high
volume centers, and good results (orifice area >1.5 cm2 with
MR <2+) are obtained in ≥85% of patients,54–56 and these
results are identical to those of surgical commissurotomy.57–
59 FIGURE 17.9. Echocardiographic examination post–balloon valvu-
Postprocedural MR is often the result of valvular tears60 loplasty in short axis view. RV, right ventricle: mv, mitral valve.
and may require urgent surgical intervention.54,61 The proce- Note the large mitral orifice with the large commissural opening of
dure is indicated in patients with MS with a valve area the medial commissure indicated by the arrow. The cross indicates
<1.5 cm2, with class III or IV symptoms, or transient heart the orientation (A, anterior; P, posterior; L, left; R, right).
failure without atrial thrombus and with acceptable valvular
anatomy (valve score ≤8, no bicommissural calcification, and
MR <2+). Symptoms or severe exertional limitations may be
unveiled by exercise testing in patients with “asymptom-
atic” MS62 but with notable pulmonary hypertension. Patients ary degradation.66 Long-term restenosis following surgical or
who complain of no dyspnea but who present with embolic percutaneous commissurotomy may benefit from repeated
events and severe MS are also candidates for intervention percutaneous intervention if the anatomic characteristics
after anticoagulation. The quality of the immediate result is remain adequate.55 Percutaneous valvuloplasty may be per-
mostly dependent on valvular anatomy,54,63,64 while that of formed during pregnancy with minimal irradiation and with
long-term result depends on age, heart failure at presenta- good maternal and fetal clinical results.67,68 At 10 years the
tion, baseline anatomic characteristics, and the quality of event-free survival after percutaneous valvuloplasty is 56%,
the immediate result.19,65 Patients with advanced valve score implying that after the procedure continued careful follow-
may have short-term benefit but incur a high rate of second- up is necessary.19
Surgical treatment, which has been lifesaving in the
initial phase of commissurotomy development,69–71 is rarely
indicated currently and is reserved for patients in whom
percutaneous intervention is considered contraindicated.
Open-heart commissurotomy may be performed in patients
with MS with severe subvalvular alterations requiring papil-
lary muscle splitting or with MR that may require associated
repair. However, most patients with advanced anatomic
alterations or MR ≥2+ require mitral valve replacement.
Because of the small but definite risk of interventional
or surgical treatment, patients with asymptomatic MS and
without embolic complications, even those with severe MS,
are rarely considered candidates for “preventive” interven-
tions. Asymptomatic patients with pulmonary hypertension
should be carefully evaluated, particularly with exercise
testing, to avoid underestimation of the functional limita-
tions. Therefore, indications for interventions are based on
comprehensive evaluation integrating clinical symptoms,
history of embolism, comorbidity, functional capacity, hemo-
dynamics, severity, and morphology of MS.

FIGURE 17.8. Percutaneous balloon valvuloplasty using the Inoue Mitral Valve Prolapse
balloon and the transseptal approach. The sequence is as follows:
upper left, the positioning of the balloon through the mitral orifice; The prolapse (fall below its normal position) or billowing
lower left: inflation and pull back of the distal component of the
balloon; upper right: partial inflation showing the marking of the
(bulge beyond its normal place) of the mitral valve is an
mitral orifice on the balloon; lower right: complete inflation for abnormal movement of the mitral valve during systole,
commissural opening. beyond its normal position and into the LA.72 Confusion has
 m i t r a l va lv e d i s e a s e s 403
surrounded mitral valve prolapse (MVP) because of terminol- based studies,79–82 and is usually sporadic but may be famil-
ogy (the use of the word prolapse to describe the movement ial; linkage analysis mapped loci on chromosome 11, 16, or
and its cause) and because of diagnostic criteria (the saddle X associated with MVP.83–85
shape of the mitral annulus led to a false appearance of pro- Secondary prolapse of mitral leaflets can be seen with
lapse and to excessive diagnoses of MVP in the 1980s). An diseases, such as rheumatic disease, with the initial rheu-
ensemble of etiologies causes this abnormal mitral move- matic insult or later after rupture of chordae; endocarditis
ment by a variety of mechanisms, with a variable extent and complicated by ruptured chordae; coronary disease compli-
variable consequences, so that MVP is a highly heteroge- cated by elongation or rupture of the papillary muscles;
neous condition.73 hypertrophic cardiomyopathy, with ruptured mitral chordae;
posttraumatic chordal or papillary muscle rupture; and con-
nective tissue disorders (e.g., Marfan’s disease).
Etiology and Mechanisms
A mitral prolapse movement requires, isolated or grouped,
Pathophysiology
any of the following mechanisms: excessive leaflet tissue,
chordal elongation or rupture, or papillary muscle elongation Mitral valve prolapse, although due to permanent valve
or rupture.74 The etiology can be primary or secondary. lesions, is a dynamic condition. Because the length of the
Primary MVPs have in common myxomatous degeneration, mitral apparatus is constant, the MVP often does not occur
which is diffuse or localized and is characterized by leaflet in early systole while LV volume is close to the end-diastolic
redundancy and thickening due to an increase in spongiosa volume. With ventricular emptying, the papillary muscles
thickness with increased hydric content,75 accumulation of move toward the heart’s base and center, and at a specific LV
proteoglycans, and collagen alterations.74,76 The detailed volume the length of valve and chordae allows one or two
mechanisms of myxomatous degeneration are uncertain, but leaflets to billow into the LA.86 The occurrence of the pro-
alterations of matrix metalloproteinase expression in the lapse causes a sudden tension of chordae, producing a sound
spongiosa suggest that the process of degradation-regenera- (click) and may be followed by MR (end-systolic murmur).87,88
tion of the matrix support tissue is dysfunctional.77 Primary Even for MVPs with sufficient chordal elongation (or rupture)
MVPs (also called floppy mitral valve) present in two forms: to produce holosystolic regurgitation, LV emptying causes an
(1) diffuse myxomatous degeneration (also called Barlow’s aggravation of the prolapse and the MR increases throughout
disease), in addition to the prolapse present with extensive systole (Fig. 17.11) to culminate with the largest regurgitant
valvular hooding, chordal elongation, and annular dilatation orifice at end-systole.89,90 Thus maneuvers that increase LV
(Fig. 17.10), and (2) localized myxomatous degeneration, volume (recumbent position, increased afterload) tend to
which is observed in older patients with chordal rupture delay the occurrence of the prolapse, while maneuvers that
causing flail leaflets. Whether the myxomatous degeneration decrease LV volume (standing, vasodilators) lead to an earlier
causes the chordal rupture or is the consequence of the prolapse in systole. Thus, the consequence of MVP, regarding
tension on the flail leaflet is unknown, but the tissue in MR severity in individual patients, is variable during the
patients with flail leaflets is characterized by chordae of cardiac cycle and under the influence of changes in loading
lower stiffness and failing at lower stress.78 However, chordal conditions due to the magnitude of the loss of coaptation
rupture may also complicate the diffuse form of myxoma- owing to the prolapse. Similarly, MR complicating MVP is
tous valve disease. Primary MVP has a prevalence between widely different between patients due to differences in the
0.6% and 3.5% in various echocardiographic population- coaptation abnormality.73
Mitral valve prolapse is a progressive disease. The lesions
of simple MVP without flail leaflets are encountered mostly
in young patients,73 whereas flail leaflets and chordal rupture
are diagnosed mostly in older patients.91 The mechanism of
anatomic progression of MVP is unknown but it leads to
progressive MR, in particular because of the occurrence of
new ruptured chords and also because of progression of
annular dilatation.92 The overload due to MR induces LA and
LV overload and dysfunction.

Natural History
Mitral valve prolapse has been reported as carrying a high
risk of complications in hospital-based studies. More recently,
population and community studies provided a more balanced
view of the clinical outcome of MVP.73 The lifetime progres-
sion and complication rates of affected patients have not been
defined, but outcome according to initial presentation at
diagnosis is now better defined. Patients younger than 50
FIGURE 17.10. Anatomic posterior view of a heart showing the
mitral, tricuspid aortic and pulmonary valves, and extensive mitral with MVP but no other complication display an excellent
valve prolapse. Note the extensive billowing with hooding and outcome (no excess mortality and low morbidity), showing
thickening involving both leaflets. that myxomatous degeneration of the mitral valve, in and of
404 chapter 17

FIGURE 17.11. Sequential measurement of

the regurgitant orifice throughout systole in a
patient with mitral valve prolapse showing the
progressively increasing mitral regurgitation.
The upper images show the flow convergence
diameter measurement while the lower images
show the corresponding continuous-wave
velocity, from early systole (left) to middle
systole, to mid-late systole, to late systole
(right). From early to late systole, the effective
regurgitant orifice increased from 0.52 to 0.58
to 0.78 to 1.27 cm2.

itself, is a generally benign condition.73,81,93 The major primary whereas those with major risk factors incur excess mortality
risk factors and determinants of outcome are severe degree and high rates of morbidity (18.5% per year) and MVP-related
of MR or of LV dysfunction. Risk factors of lesser severity events (15% per year) even if they are asymptomatic at diag-
(secondary risk factors) are age ≥50, slight MR, LA enlarge- nosis (Fig. 17.13).73 Thus, MVP is a highly heterogeneous
ment >40 mm, atrial fibrillation, and the presence of a flail condition spanning from a benign finding to a severe
leaflet (Fig. 17.12). Patients without major risk factors but disease.
with two or more minor risk factors incur no excess risk of The role of valve thickness in outcome is controversial.
mortality but a high risk of cardiovascular morbid events Thickened valves have been considered as a marker of poor
(6.2% per year) and of MVP-related events (1.7% per year), outcome in the pre-Doppler era,94 probably related to the

Overall survival Cardiac survival Cardiovascular morbidity

100 p(exp) = .17 100
100 No or 1 secondary RF
95 ± 2 ≥2 secondary RF
90 80 Primary RF
84 ± 5
CV morbidity (%)

p(exp) = .20
Survival (%)

87 ± 4
80
60
70
70 ± 5 No or 1 secondary RF 40 ± 4
≥2 secondary RF 40
60 p(exp) = .01 Primary RF 66 ± 10
p(dif) < .001 55 ± 2 p(dif) < .001 20
50 6±2
0 62 8 4 10 2 4 6 8 10
Years after diagnosis 0
0 4 2 6 8 10
FIGURE 17.12. Survival after diagnosis of asymptomatic mitral
valve prolapse in the community according to the presence of Years after diagnosis
primary and secondary risk factors at baseline. The left graph rep- FIGURE 17.13. Cardiovascular morbid events after diagnosis of
resents the overall survival; the right graph represents survival free asymptomatic mitral valve prolapse in the community according to
of cardiovascular death; p(dif), p value for comparison of the three the presence of primary and secondary risk factors at baseline. Note
curves; p(exp), p value for comparison of overall survival to the the wide difference in morbidity according to this classification,
expected survival. Note the excess mortality in patients with with the group with no or one secondary risk factor incurring little
primary risk factors, essentially mitral regurgitation, moderate or morbid events, where those with two or more secondary risk factors
severe, and note the very low mortality of patients with no or one incur frequent morbidity and those with primary risk factors incur
secondary risk factor. almost inescapable morbidity.
 m i t r a l va lv e d i s e a s e s 405
Lifetime risk Medical management A risk of sudden death associated with MVP has been
30 suggested by autopsy studies99 and has been a concern because
Expected of arrhythmias associated with MVP. However, these arrhyth-
Observed mias are most prevalent with severe MR,100 and longitudinal
Stroke rate (%)

20 p < .001 p = .009 studies showed that young patients with no or minimal MR
exhibit no excess risk of mortality,73 whereas older patients
with severe MR display excess mortality and notable risk of
10 sudden death especially in patients with symptoms or LV
7±1 dysfunction.101
3 ± 0.7 5±1
2±1 Bacterial endocarditis is rare but may complicate MVP
and it justifies prophylaxis, particularly in patients with
0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
MR.
Years Years
FIGURE 17.14. Cerebral ischemic event rates after diagnosis of Clinical Evaluation
mitral valve prolapse in sinus rhythm in the community. The left
graph represents the event-rate throughout follow-up including after Presentation is rarely motivated by symptoms related to MR,
cardiac surgery. The right graph indicates the event rate under con- such as dyspnea, arrhythmia, or heart failure (Table 17.2).
servative management only. The solid line represents the expected Most often presentation is for nonspecific symptoms, fatigue,
rate of ischemic stroke in patients in sinus rhythm of same age and
sex in the same community. The dashed line represents the observed atypical chest pain, or palpitation, or diagnosis is made after
rate of events. Both graphs show the modest but significant excess discovery of auscultatory abnormalities during a general
risk of ischemic stroke in patients with mitral valve prolapse. medical examination. Abnormal autonomic function leading
to clinical presentation in patients with MVP has received
attention but is controversial.102 Increased catecholergic
activity and reduced vagal response have not been confirmed
consistently.103
severity of MR. More recently, it was shown that mitral Physical examination may find marfanoid characteristics
thickening (≥5 mm) is not independently linked to mortality with arched palate, pectus excavatum, and rarely kyphosco-
or cardiac morbid events.73 However, mitral thickening is liosis. Examination may reveal signs of mild or more severe
associated with a small but significant excess risk of cerebral MR, and the radiation of the murmur suggests specific leaflet
ischemic events.95 involvement. Radiation from the apex to the base suggests a
The contribution of MVP to the occurrence of stroke is prolapse predominant or isolated from the posterior leaflet,
controversial. Case-control studies reported discordant find- whereas in patients with anterior or bileaflet prolapse, the
ings.96,97 However, in the community-dwelling population, murmur tends to radiate to the axilla and sometimes the
MVP is associated with a small but definite lifetime risk of back. The typical findings of MVP are the midsystolic click
stroke or transient ischemic attack (Fig. 17.14).95 The major and end-systolic murmur.87 The click is a high-pitched sound
determinants of strokes in patients with MVP are linked to occurring in midsystole, and is well separated from S1 and
the MR complicating the MVP, that is, the need for cardiac S2. As a result, these clicks are classified as nonejectional and
surgery and the occurrence of atrial fibrillation.95 The link are quite different from ejectional clicks, which mimic a
between the occurrence of stroke and mitral thickening, split S1. Mitral clicks are best heard between the apex and
irrespective of the need for surgery, is consistent with the left sternal border as superficial sounds. Not infrequently,
reported observation of clots on thickened myxomatous leaf- there are multiple systolic clicks. Maneuvers that increase
lets.98 Other morphologic characteristics (location of MVP or ventricular volume, such as squatting, phenylephrine admin-
flail segment) do not appear to determine stroke incidence. istration, and leg raising, shift the click later in systole,
However, the risk of stroke is only notable in patients older whereas maneuvers that decrease LV volume, such as stand-
than 50, and thus MVP is not a significant contributor to ing, amyl nitrate inhalation, or Valsalva maneuver, shift the
strokes in young patients.97 click earlier in systole. These changes explain the day-to-day

TABLE 17.2. Clinical syndromes of mitral valve prolapse (MVP) presentation

Incidental MVP Barlow’s syndrome Flail leaflet

Symptoms None; incidental finding by echo Chest pain Sudden dyspnea

Physical examination Normal Midsystolic click Loud murmur with basal radiation
End-systolic murmur
Pectus excavatum
ECG Normal ST-T change LA enlargement LVH
Chest x-ray Normal Cardiomegaly Enlarged LA
Echo-Doppler MVP of 2-mm depth with no or Bileaflet MVP Flail posterior leaflet; large ERO
trivial MR Moderate late systolic MR
Follow-up In 5 years In 1–2 years Consider valve repair
ERO, effective regurgitant orifice; LA, left atrium; LVH, left ventricular hypertrophy; M, mitral regurgitation; MVP, mitral valve prolapse.
406 chapter 17

variability in the detection and timing of the click. The

murmur in late systolic, immediately follows the click, and
changes in duration with the maneuvers that change the
timing of the click. The intensity and character of the
murmur are variable, but it is usually soft, blowing, and best
heard at the apex. The murmur may be confused with that
of hypertrophic cardiomyopathy because both murmurs
increase with standing and decrease with squatting. However,
the murmur of hypertrophic cardiomyopathy becomes louder
after amyl nitrate inhalation, whereas that of MR does not.
Postextrasystolic potentiation in murmur intensity in hyper-
trophic cardiomyopathy contrasts with the lack of change in
LV
MVP. Also, in patients with MVP and notable MR the RV
murmur will tend to predominate at end-systole, a recogniz-
able feature different from the “rectangular” shape of the
murmur in other forms of MR (e.g., rheumatic MR).
The electrocardiogram (ECG) is usually normal but may
show flattening or inversion of the T waves in leads II, III, RA
and aVF, which may mimic ischemia in the inferior territory.
Premature ventricular contractions are frequently observed,
are sometimes bigeminal, and have been attributed to the
LA
traction of the chordae on the papillary muscle. Atrial fibril-
lation is rare and is more frequent in patients with larger FIGURE 17.16. Echocardiographic four-chamber view of a patient
degrees of MR and atrial dilatation. Chest radiography shows with a flail posterior mitral leaflet. The arrow indicates the flail
segment with a ruptured chordae attached. LV, left ventricle; LA,
no specific feature of MVP.
left atrium; RV, right ventricle; RA, right atrium.
Doppler echocardiography is the mainstay of diagnosis,
and of assessment of the MVP’s extent and of the severity of
MR and of LV and LA overload and function. The diagnosis
of MVP has been a source of confusion,88 as normal mitral
valves may appear to billow in certain views, particularly the define the “classic” MVP but is not indispensable to the
four-chamber apical view because of the saddle shape of the diagnosis.81 It is important to note the uni- or bileaflet nature
mitral annulus.104–106 Therefore, the current criteria require a of the MVP and the leaflet’s segments affected (using the A1–
systolic movement beyond the plane of the annulus of at least A3, P1–P3 classification). Timing of the prolapse (holosystolic
2 mm of the body or the tips of one or both mitral leaflets vs. midsystolic) may be noted on 2D or M-mode echocardiog-
detected in long-axis views (Fig. 17.15).105 With this criterion, raphy.88 The presence of a flail leaflet or ruptured chords can
the detected prevalence of MVP is considerably lower than be detected by transthoracic echocardiography (Fig. 17.16), but
initially reported, and false-positive diagnoses were elimi- sensitivity is higher by TEE, which is indicated in a minority
nated. Thickening of mitral leaflets beyond 5 mm is noted to of cases depending on the therapeutic implications of these
findings.107 Mitral regurgitation severity is assessed using the
criterion of the American Society of Echocardiography.108 The
size of the LA and LV is measured using 2D-directed M-mode
diameters or better using LA and LV volumes measurements.
The associations of tricuspid valve or more rarely aortic valve
prolapse are also examined.
Cardiac catheterization is used only as a preoperative
test. It may contribute to the assessment of MR and hemo-
dynamics and to defining the coronary anatomy. Left ven-
tricle angiogram may also observe large mitral prolapse.

Management
Mitral valve prolapse is a heterogeneous condition and man-
agement should be guided by the individualized risk strati-
fication, in which the degree of MR plays a central role.
Although the risk is low, endocarditis prophylaxis is recom-
mended for all patients. There is no medical treatment that
affects the course of the mitral tissue myxomatous degenera-
tion, and treatment focuses on the consequences of the
FIGURE 17.15. Echocardiographic long axis parasternal imaging in
systole showing a posterior leaflet prolapse. A solid line marks the MVP.
annulus plane from which the depth of the prolapse is measured. Low-risk patients do not require close follow-up and may
LV, left ventricle; LA, left atrium; Ao, ascending aorta. be reevaluated at 5-year intervals unless new symptoms or
 m i t r a l va lv e d i s e a s e s 4 07
100 AL-MVP 100 PL-MVP approaches. With improved understanding of the natural
87% ± 2% 85% ± 2% history of MR, and most importantly with major advances
80 80 in conservative surgery, the management of MR has become
63% ± 5% 70% ± 3%
far more proactive.
Survival (%)

60 74% ± 4% 60
65% ± 5% Etiology and Mechanism
40 40 Mitral regurgitation is an organic mechanism if there is an
49% ± 4% 49% ± 5%
p = .003 p = .0004 intrinsic valve disease or a functional mechanism if the
20 Repair 20 Repair valve is structurally normal but regurgitates due to an extra-
Replacement Replacement valvular abnormality. Mitral regurgitation of ischemic etiol-
0 0 ogy may be organic (ruptured papillary muscle) or functional
5 0 10 15 0 5 10 15 (LV dysfunction). Nonischemic MR may be organic (e.g.,
Years after surgery Years after surgery
rheumatic) or functional (e.g., cardiomyopathy). The Carpen-
FIGURE 17.17. Survival after surgical correction of mitral valve
tier classification of MR mechanisms is as follows: type I,
prolapse (MVP) with severe mitral regurgitation, and with exclusive
posterior leaflet (PL) prolapse (right graph, PL-MVP) or anterior normal valvular movement (such as that seen with annular
leaflet (AL) involvement (left graph, AL-MVP). Survival of patients dilatation); type II, excessive movement (such as that due to
who underwent valve repair is indicated with a dashed line, whereas MVP or flail leaflets); type III, restrictive motion; type IIIa,
that of patients who underwent valve replacement is indicated with diastolic restriction (such as in rheumatic diseases); and type
a solid line. Note that irrespective of the location of the mitral valve
prolapse, valve repair provides an improved survival as compared to IIIb, systolic restriction (such as ischemic functional MR).
valve replacement and should be the preferred mode of correction Rheumatic MR is rarely pure, and in most cases is associ-
of mitral valve prolapse with mitral regurgitation. ated with stenosis and fusion of the commissures. Severe
rheumatic MR requiring surgical correction is still frequent
in developing countries but is now rare in developed coun-
tries.116 The underlying lesion is retractile fibrosis of leaflets
and chordae causing loss of coaptation (Fig. 17.18). Secondary
events develop. Patients with palpitations may benefit from dilatation of the mitral annulus tends to further decrease the
beta-blockade for symptom’s relief. The role of aspirin in contact between leaflets. Elongated or ruptured chords are
preventing embolic complications in patients with thickened infrequent.
leaflets is not established.109 Medium-risk patients, in par- Degenerative MR is often associated with MVP and rep-
ticular with mild or moderate MR, require more frequent resent the most frequent cause leading to surgery for severe
follow-up as the degree of MR tends to progress. Vasodilators, MR.116 Degenerative MR can be categorized as follows:
particularly with angiotensin blockade, are not yet confirmed
• Primary MVP with diffuse myxomatous infiltration
in stabilizing the degree of MR but are justified in treating
• Degenerative primary ruptured chordae, which involve
hypertensive patients.110 Atrial fibrillation should lead to
more often the posterior than the anterior leaflet and
reevaluation of the degree of MR and requires anticoagula-
occur more often in men than in women (Fig. 17.19).
tion.111 A limited number of patients with atrial fibrillation
There is usually no excessive tissue, but enlargement of
with uncontrolled ventricular response and moderate MR
the annulus may occur as in any MR. The involved leaflet
benefit from surgical treatment combining a Maze procedure
and mitral repair.112,113 Patients with severe MR are at high
risk. These patients are immediate candidates for surgery if
they are symptomatic or have LV dysfunction. For asymp-
tomatic patients there is no agreement on the need for early
surgery, but in the hands of surgeons skilled in reparative
procedures these patients can benefit from valve repair in
85% to 90% of cases, which implies a low operative risk and
excellent long-term outcome (Fig. 17.17). Therefore, delaying
surgery until severe symptoms or congestive heart failure
occurs compromises survival and should be avoided, justify-
ing a trend for proceeding with valve repair without waiting
for the occurrence of these severe complications.114,115

Mitral Regurgitation
Mitral regurgitation is characterized by an abnormal, reversed
blood flow from the LV to the LA. The etiologic profile of MR
is now dominated by degenerative and ischemic causes in
FIGURE 17.18. Anatomic posterior view of the left atrium and
developed countries. The development of noninvasive assess- mitral valve in a case of rheumatic mitral regurgitation. Note the
ment with Doppler echocardiographic methods, particularly wide orifice despite the presence of limited commissural fusion and
for quantitation of MR, has transformed diagnostic note the tissue retraction leaving a wide-open orifice.
408 chapter 17

FIGURE 17.19. Anatomic long-axis view of

the heart (left panel) and mitral valve (right
panel) in a case of degenerative mitral regurgi-
tation with flail posterior leaflet and ruptured
chordae. Note the thickening of the flail
segment of the posterior leaflet, whereas the
anterior leaflet is of normal thickness.

shows myxomatous infiltration,117 but the other leaflet Ischemic and functional MR, that is, due to LV wall
usually remains normal. Calcification of the mitral dysfunction secondary to ischemia, scarring, aneurysm,
annulus or systemic hypertension may precede the occur- cardiomyopathy, or myocarditis, have in common the same
rence of the ruptured chordae. Isolated ruptured chord mechanism. The coaptation of intrinsically normal leaflets
may occasionally be due to blunt thoracic trauma and is incomplete (Fig. 17.21).118 Rupture of papillary muscle pro-
endocarditis (secondary forms). duces MR because of the flail leaflet and involves in 80% of
• Degenerative MR without prolapse, which is usually cases the posteromedial papillary muscle and is most often
mild and due to valve sclerosis or isolated annular calci- associated with infarction of the adjacent ventricular wall.119
fication, in which regurgitation is secondary to deforma- It is the rarest form of heart rupture and of ischemic MR.
tion of the valves or annulus. Complete rupture is rapidly fatal without surgery, and partial
or single-head rupture of the papillary muscle more often
Infective endocarditis accounts for about 5% of cases of
allows emergency surgery.119
severe MR. Vegetations may produce mild MR by interposi-
There are numerous other causes of MR. It is observed
tion between leaflets. Severe endocarditic MR is usually
frequently with color flow imaging, even in patients without
related to ruptured chords and less frequently to destruction
of mitral tissue involving either the leaflet’s edges or a per-
foration (Fig. 17.20).

FIGURE 17.21. Anatomic view of the heart and mitral valve in a

case of functional mitral regurgitation due to ischemic heart disease
FIGURE 17.20. Anatomic ventricular view of the mitral valve in a (with septal and anterior wall thinning and scarring). The mitral
case of endocarditic mitral regurgitation with perforation of the valve is structurally normal. Traction by the papillary muscle and
anterior leaflet. Note the large perforation with inflammatory chordae tether the leaflets within the LV cavity. Note the enlarged
borders. and spherical LV and LA.
 m i t r a l va lv e d i s e a s e s 409
cardiac disease. Clinically significant MR may be found the potential energy (elevation of atrial pressure). The typical
in (1) connective tissue disorder: Marfan syndrome, Ehlers- LA pressure change is the V wave,127 which is also deter-
Danlos syndrome, pseudoxanthoma elasticum, osteogenesis mined by LA compliance.127 In acute MR, the LA is smaller
imperfecta, Hurler’s disease, systemic lupus erythematosus, and less compliant than in chronic MR, and a similar RVol
and anticardiolipin syndrome; (2) penetrating or nonpenetrat- produces a higher V wave and LA pressure, which in turn
ing cardiac trauma; (3) myocardial disease: hypertrophic minimizes the LV-LA gradient. Thus, for any ERO,123 acute
cardiomyopathy or sarcoidosis; (4) endocardial lesions due to MR translates into more potential energy (LA pressure) with
eosinophilic syndrome, endocardial fibroelastosis, carcinoid smaller RVol (and murmur) than chronic MR. When MR
tumors, ergot toxicity, radiation toxicity,120 and diet or drug becomes chronic, the LA dilates, and the V wave is less
toxicity121; (5) congenital lesions, such as cleft mitral valve prominent and does not limit the regurgitant volume, and
isolated or associated with persistent atrioventricular canal; the LA pressure may be normal even with severe MR.128 At
corrected transposition with or without Ebstein abnormality that stage, usually the cardiac output is decreased but the
of the left atrioventricular valve may also cause MR; and (6) pulmonary pressures are often normal. Pulmonary hyper-
cardiac tumors. tension in MR is poorly understood, and observed mostly in
elderly patients.
Pathophysiology
Left Ventricle Function
The abnormal coaptation of the mitral leaflets creates a
With MR the LV is dilated but less so than in aortic regurgi-
regurgitant orifice during systole and is measured as the
tation of comparable degree.129 End-diastolic LV volume and
effective regurgitant orifice (ERO), which represents the
wall stress are increased,129 and its shape becomes spherical.
lesion severity. The systolic pressure gradient between
End systolic volume is increased in chronic MR, but end
the LV and LA is the driving force of the regurgitant flow,
systolic wall stress is usually normal.130 The myocardial
which accumulates into a regurgitant volume (RVol). The
mass is increased proportionately to LV dilatation.131 Left
RVol is responsible for the volume overload, by entering the
ventricle function is difficult to characterize because of the
LA in systole and the LV in diastole, modifying LV loading
changes in preload and afterload. It has been suggested that
and function.
normalization of ejection fraction to the preload would
provide an appropriate assessment of LV function. Afterload
Chronology of Regurgitation
is more difficult to assess because the MR may decrease the
The pressure gradient between the LV and atrium begins instantaneous impedance to ejection, but the measure of
with mitral closure (simultaneous to S1) and persists after afterload provided by end systolic wall stress is within the
closure of the aortic valve (S2) until the mitral valve opens.122 normal range.130 However, the usual inverse correlation
Thus, timing of regurgitant flow is determined by that of the between end systolic wall stress and ejection fraction is also
regurgitant orifice and is most often holosystolic. Various observed in MR.132 Complex indices using the afterload such
dynamic changes in regurgitant orifice can be observed as the end systolic wall stress,133 or maximum elastance,130
depending on its cause.90 With small regurgitant orifices, the normalized to the LV volume, have been proposed and may
regurgitant orifice declines, with the ventricular volume be sensitive to subtle changes in function. Left ventricle
tending to limit regurgitation to early systole.122 Conversely, dysfunction is a frequent and dismal complication of MR.134,135
in valve prolapse the regurgitant orifice appears or increases The mechanism of LV hypertrophy is a reduction in protein
late in systole, and variations of regurgitant flow throughout degradation, but the mechanisms leading to interstitial fibro-
systole are the complex results of combined effects of changes sis and LV dysfunction remain mysterious. Experimentally,
of regurgitant orifice and gradient.89,90 LV dysfunction is not due to changes in coronary blood flow.
The changes in myofiber contractility parallel those in LV
Degree and Consequences of Regurgitation function136 and are associated with reduced myofiber
content,137 but the cause of the myofiber dysfunction and the
The degree of volume overload depends on three factors: the
explanation of its high incidence have not been clarified.
area of the regurgitant orifice,123 the regurgitant gradient, and
During diastole LV relaxation is prolonged, but chamber
the regurgitant duration. The volume overload is usually less
stiffness is reduced.138 Age and decreased systolic function138
severe in mitral than in aortic regurgitation, despite the
are associated with increased chamber stiffness. The signifi-
usually larger regurgitant gradient and orifice.123 Such differ-
cance of the diastolic abnormalities is unclear.
ences are related to a shorter duration of MR during the
cardiac cycle in mitral than in aortic regurgitation.123 The
Ischemic and Functional Mitral Regurgitation
degree of MR is not fixed and may vary with interventions.
Vasodilators improve the clinical status of patients with The pathophysiology of ruptured papillary muscles is poorly
acute regurgitation,124 and the mechanism of improvement known but it represents the most typical form of acute MR
is a decline in ERO area rather than that of the ventricu- with large ERO, low RVol, and often inaudible murmur but
loatrial gradient. In functional125 and organic MR,126 the ERO severe clinical consequences due to the LA pressure eleva-
increases with increased afterload or ventricular volume and tion. In chronic ischemic MR (IMR) or functional MR (FMR),
decreases with decreased afterload or improved contractility, the primary disease involves the LV, which is often poorly
but is not influenced by changes in heart rate.126 The regur- contracting while the mitral valve is intrinsically normal.
gitant energy is produced by the LV and is transformed in The classically invoked mechanisms of MR, that is, papillary
two components: the kinetic energy (regurgitant volume) and muscle dysfunction and annular dilatation, have been shown
410 chapter 17

the predominance of IMR after inferior myocardial infarc-

tion.142 Therefore, similar degrees of LV enlargement or dys-
Ao function may be associated with quite variable degrees of
IMR due to the variability in the local remodeling. The
LV importance of chordal tethering in generating tenting and
FMR or IMR has been demonstrated experimentally, by
inducing papillary muscle repositioning143 or by secondary
T
chordae cutting,144,145 which resulted in disappearance of the
MR. Cardiomyopathic versus ischemic LV dysfunction shows
slight differences in the distribution of chordal tethering and
LA tenting that are often predominant on the medial commis-
sure in IMR due to the frequent association with inferior
myocardial infarction. In functional versus organic MR,
RVol is usually smaller,146 and LV and LA dilatation are in
excess to the degree of MR.123 Nevertheless, MR is associated
with elevated LA pressure,123 poor outcome,147 and is a marker
of sensitivity to vasodilators.

Hormonal Activation in Organic

FIGURE 17.22. Echocardiographic long-axis view of the mitral Mitral Regurgitation
valve in a patient with ischemic mitral regurgitation (MR). The LV
is enlarged and demonstrates thinning of the inferolateral wall Natriuretic peptides are activated in experimental148 and
consistent with an inferior myocardial infarction. The mitral valve clinical149 studies. The main determinant of elevation of
is protruding forward and the tenting area (T) under the mitral valve A-type natriuretic peptide is the elevation of atrial pres-
up to the annulus (solid line) is large, preventing coaptation of the sures,149 but also atrial arrhythmias, which result in dispro-
mitral leaflet although they are structurally normal. The LA is
enlarged.
portionate elevation of this natriuretic peptide. Thus, B-type
natriuretic peptide (BNP) has been the focus of increasing
interest. Pilot studies suggested that BNP reflected the sever-
ity of symptoms. Its activation is weakly linked to the degree
of MR and is more notably determined by the consequences
to contribute little to functional MR. The occurrence of MR of MR, LA enlargement, LV dysfunction, and the degree of
is due mostly to mitral valve tenting.139 Tenting is a systolic heart failure associated with the MR in particular. In that,
deformation of the leaflets, which protrude forward in the LV it appears as a promising marker of outcome. The catechol-
and thus cannot appose their rough zone on each other (Fig. amine activity is increased in MR with norepinephrine
17.22). Other valvular contributors to the lack of coaptation release rates increased compared to controls, even in asymp-
are the loss of annular contraction and the low ventricular tomatic patients150 and similar to those measured in cardio-
pressure pressing on mitral leaflets.139 Tenting as the main myopathy.151 Alterations in adrenergic activity and receptor
determinant of IMR and FMR is in turn the consequence of density are strongly correlated to the degree of LV over-
tethering by excessive traction on the secondary chordae due load152,153 and dysfunction154,155 and to hormonal activation.156
to localized LV deformation (Fig. 17.23) with apical and infe- Importantly, in long-term experiments with MR due to rup-
rior displacement of papillary muscles,139–141 which explains tured chords, similar to the most frequent human form of

FIGURE 17.23. Echocardiographic apical long-

axis view with two-dimensional imaging of
papillary muscles (left) and with color flow
imaging of the left atrium (right). Left, the ver-
tical arrows show the tips of the papillary
muscles tensing the secondary chordae inserted
on the body of the leaflet (horizontal arrows)
and pulling the leaflets apically, away from the
annulus (arrowheads), resulting in tenting.
Right, the tenting results in a large jet of mitral
regurgitation.
 m i t r a l va lv e d i s e a s e s 411
MR, bradycardia induced by beta-blockers provides recovery 100
of LV function.157 Activation of the renin-angiotensin system
is also noted. In dogs with organic MR, systemic activation Class I-II
80
of the renin-angiotensin system is rare,158 but tissue levels of

Survival (%)
angiotensin II are markedly elevated.159,160 The role of tissue 60 67% ± 7%
angiotensin activation in the development of hypertrophy
and fibrosis is not fully clarified. Beta-1-blockade prevents 40
angiotensin-II–mediated tissue catecholamine release,161 but
the therapeutic role of hormonal modulation in human MR Class III-IV
20
is not yet defined. 21% ± 11% p < .0001

0
Natural History 0 1 2 5 3 6 4 7 8 9 10
Years
Because organic and functional MR occur in very different FIGURE 17.25. Natural history of mitral regurgitation due to flail
contexts, it is important to analyze their natural history leaflets: survival after diagnosis under medical management accord-
separately. ing to symptomatic status at baseline. The patients presenting in
New York Heart Association class III or IV incur considerable mor-
tality under medical management (solid line). Those presenting in
Organic
New York Heart Association class I or II display a better survival,
From the presurgical era to the 1980s, assessment of the but note that one third die within 10 years under medical manage-
ment (dotted line).
degree of MR has remained qualitative and imprecise, so that
the natural history of MR was ill-defined. Patients with mild
rheumatic MR appeared to have a good prognosis,162 whereas
in those with more severe MR higher mortality has been
noted.91,163 In patients with unoperated and clinically signifi- population. These combined data suggested that survival
cant MR, long-term survival was reported as high as 60% at under medical management is determined by the degree of
10 years164 or as low as 46%165 or even 27%166 at 5 years. In MR. This hypothesis was supported by the study of MVP in
our experience with flail mitral leaflets, at 10 years, survival the community, which showed that the degree of MR due to
was 57%, which represents an excess mortality as compared MVP was the strongest determinant of survival after diag-
to the expected survival (Fig. 17.24).91 A notable component nosis, even in asymptomatic patients.73 This hypothesis was
of sudden death has been noted. Such a devastating complica- confirmed in a prospective study of organic MR with degree
tion occurs more often if the ventricular function is of MR quantified using modern Doppler echocardiographic
decreased167 but may also occur in patients with normal ejec- methods and stratified according to guidelines of the Ameri-
tion fraction who are asymptomatic.163 In our experience, can Society of Echocardiography.168 The ERO area proved to
sudden death in patients with MR due to flail leaflets occurs be the strongest predictor of survival after diagnosis (Fig.
at a rate of 1.8% per year.101 The rates are higher in patients 17.27) and patients with ERO ≥40 mm2 incurred excess mor-
with symptoms (Fig. 17.25) or reduced ejection fraction tality as compared to expected mortality. Importantly, the
(<60%; Fig. 17.26), but even in the absence of these risk
factors sudden death rate is 0.8% per year,101 or approximately
the double of the expected rate of sudden death in the general

100

80 EF ≥ 60%
100
Survival (%)

60 61% ± 8%

80 40
Survival (%)

65% EF < 60% 40% ± 12%

20 p = .001
60 Expected
Observed 0
57% 0 1 2 5 3 6 4 7 8 9 10
p = .016
Years
40 FIGURE 17.26. Natural history of mitral regurgitation due to flail
0 2 4 6 8 10 leaflets: survival after diagnosis under medical management accord-
Years ing to echocardiographic ejection fraction at baseline. The patients
FIGURE 17.24. Natural history of mitral regurgitation due to flail presenting with ejection fraction (EF) <60% incur considerable mor-
leaflets: survival after diagnosis under medical management. The tality under medical management (solid line). Those presenting
expected survival for age and sex is indicated by a dashed line. The with EF ≥60% display a better survival but note that almost 40%
observed survival indicated by a solid line is significantly lower. die within 10 years under medical management (dotted line).
412 chapter 17

patients with moderate MR (ERO 20–39 mm2) displayed 62% ± 8%

mortality that was initially low but increased markedly after
60
3 years. ERO 1–19 mm2
Morbidity in patients with severe MR is also high. In

Cardiac events rate (%)

50 ERO 20–39 mm2
patients who were initially asymptomatic, approximately
ERO ≥40 mm2
10% per year develop symptoms,169 which may be hastened 40% ± 7%
40
by atrial fibrillation. In patients with flail leaflets, heart p < .01
failure occurred in 63% within 10 years of diagnosis.91 Atrial
30
fibrillation occurred at a rate of 5% per year in patients
diagnosed in sinus rhythm and was associated after its
20
occurrence with increased mortality under conservative 15% ± 4%
management.111 Left atrium enlargement is a strong predictor
10
of occurrence of atrial fibrillation.111 Quantitation of MR
provides important predictors of outcome, and cardiac events
0
(cardiac death, heart failure, new atrial fibrillation) occur at
0 1 3 2 4
a rate almost six times higher in patients with ERO ≥40 mm2 5
Years
than in those with ERO <20 mm2 (Fig. 17.28).168 Finally, FIGURE 17.28. Natural history of mitral regurgitation quanti-
surgery is almost unavoidable in patients with severe MR. tatively defined: cardiac events (cardiac death, heart failure, or
Indeed, 10 years after diagnosis of MR due to flail leaflets, new atrial fibrillation) after diagnosis under medical management
90% of patients underwent surgery or died before surgery according to Doppler-echocardiographic effective regurgitant orifice
(ERO) at baseline. The patients presenting with ERO <20 mm2 incur
could be performed,91 whereas in patients with any etiology minimal morbidity (solid line). Those presenting with ERO ≥40 mm2
of MR and ERO ≥40 mm2 the rate of death or surgery is 86% display a considerable mortality, higher than the expected mortality
at 5 years.168 (dashed line). The patients with ERO ≥20 mm2 and <40 mm2, or the
The predictors of poor outcome in patients medically moderate MR as per the American Society of Echocardiography
classification (dotted line) show initially little morbidity but after 3
treated are (1) severe symptoms [New York Heart Association
years the event rate markedly increases.
(NYHA) class III–IV],165 even if the symptoms are transient91;
(2) pulmonary hypertension; (3) markedly increased LV end-
diastolic volume or arteriovenous difference in O2170; (4)
reduced ejection fraction91; (5) marked LA enlargement; and
(6) ERO area ≥40 mm2.168 Comparison of prognosis in medi-
valve repair display a considerable reduction of mortality
cally and surgically treated patients shows a trend in favor
with restoration of life expectancy.168
of the surgical treatment,163 especially early surgery,91 with
The progression of LV dysfunction in patients with
definite improvement of outcome of patients with decreased
organic MR medically treated is not well defined. Progres-
systolic LV function.170 Asymptomatic patients who undergo
sion of the degree of MR is usually slow, with progression of
regurgitant volume of 7 to 8 mL per year, but it reaches 20 mL
per year in patients with new flail leaflets.92 The mechanism
of progression of MR is an increase in ERO without change
100 in gradient. The major determinant of regression of MR is a
91% ± 3% reduction in afterload, whereas increase in annular size and
new flail are major determinant of progression of MR.92 The
90
progression of the degree of MR is the probable mechanism
by which patients with moderate MR (ERO 20–39 mm2) expe-
Survival (%)

80 66% ± 6% rience a marked increase in risk within a few years after

diagnosis.
ERO <20 mm2
70
ERO 20–39 mm2
Functional
ERO ≥40 mm2
60 Data on the natural history of functional MR are limited.
p < .01
58% ± 9% Functional MR complicating cardiomyopathy appears to
50 contribute to the poor outcome of this disease.171,172 Recently,
0 1 2 3 4 5 more compelling information has been gathered on IMR,
Years which is noted in approximately one patient in five post–
FIGURE 17.27. Natural history of mitral regurgitation quantita- myocardial infarction,147,173 irrespective of the presence of ST
tively defined: survival after diagnosis under medical management elevation.173 The presence of IMR is associated with more
according to Doppler-echocardiographic effective regurgitant orifice
(ERO) at baseline. The patients presenting with ERO <20 mm2 incur severe clinical presentation167,173,174 and severity of LV remod-
minimal mortality, not different from the expected mortality (solid eling.175 During follow-up, IMR (Fig. 17.29) is associated with
line). Those presenting with ERO ≥40 mm2 display a considerable increased mortality (approximately doubling of the mortality
mortality, higher than the expected mortality (dashed line). The risk) even after adjustment or matching for the associated
patients with ERO ≥20 mm2 and <40 mm2, or the moderate MR as
per the American Society of Echocardiography classification (dotted
LV alterations,147,173,174 and revascularization by surgery176 or
line) show initially little mortality but after 3 years mortality mark- interventional procedures.177 Furthermore, IMR is linked to
edly increases. subsequent occurrence of heart failure,173 even in patients
 m i t r a l va lv e d i s e a s e s 413
100

0.8 p < .0001

61% ± 6% 80
68% ± 12%

Incidence of CHF (%)

0.6 Controls
Survival

ERO, mm2
60 ≥20
0.4 38% ± 5% 46% ± 9%
MR 1–19
0
40
0.2
p < .0001 18% ± 5%
0.0 20
0 1 2 4 3 5 6 7
Years
FIGURE 17.29. Natural history of ischemic mitral regurgitation: 0
survival after diagnosis in patients with Q-wave myocardial infarc- 0 1 2 3 4 5 6
tion matched for age, sex, and EF with (solid line) and without FIGURE 17.31. Natural history of ischemic mitral regurgitation:
(dashed line) ischemic mitral regurgitation. Note that patients with occurrence of congestive heart failure after diagnosis in initially
ischemic MR incur a considerably higher mortality despite similar asymptomatic patients with Q-wave myocardial infarction and
ejection fraction. quantified MR, matched for age, sex, and EF between those without
MR (dashed line) and with MR and effective regurgitant orifice
(ERO) 1 to 19 mm2 (dotted line) or ≥20 mm2 (solid line). Note that
patients with larger ERO due to ischemic MR incur a considerably
higher rate of congestive heart failure despite asymptomatic status
and similar ejection fraction at baseline.

who were asymptomatic at baseline.178 Importantly, it appears

that even a degree of IMR that would be labeled as mild or
moderate is associated with adverse outcomes. Indeed, in the
SAVE study in which severe MR was an exclusion criterion,
IMR severely affected the outcome.147 This concept of lower Clinical Evaluation
thresholds for “severe” IMR has been confirmed in quantita- Sex distribution of disease has changed in parallel to the
tive studies, which showed that patients with ERO ≥20 mm2 changes in etiology of MR. With the decrease in rheumatic
incur a considerable risk of mortality (Fig. 17.30),174,179 and heart disease, severe MR is now predominantly seen in males
heart failure (Fig. 17.31).178 Thus, it is essential to evaluate (65–75%). Prevalence of MR increases with older age,182 and
IMR with specific criteria of severity. Ischemic MR is more therefore, patients with severe MR most often present in the
dynamic than organic MR, and an exercise-induced increase sixth decade of life.91 Clinical presentation is determined by
in IMR degree180 may portend a high risk of subsequent mor- the degree, rapidity of development, and cause of MR.
tality179 and heart failure.181 Therefore, current information Patients with mild MR usually have no symptoms. Severe
suggests that IMR has a poor outcome. MR is diagnosed most often because of the murmur when
no or minimal symptoms are present.91 Fatigue and mild
dyspnea on exertion are the most usual symptoms and are
rapidly improved by rest. The administration of diuretics and
progressive self-limitation of physical activity may prevent
the occurrence of more severe symptoms. Severe dyspnea on
100 exertion or, more rarely, paroxysmal nocturnal dyspnea,
frank pulmonary edema, or even hemoptysis, may be
80
observed later in the course of the disease. Such severe symp-
toms may be triggered by new onset of atrial fibrillation, an
61% ± 6%
Survival (%)

increase in the degree of MR, the occurrence of endocarditis

60
or ruptured chord, or a change in ventricular compliance or
function.
40 ERO 47% ± 8%
0 With severe MR of acute onset, symptoms are usually
1–19 29% ± 9%
more dramatic, such as pulmonary edema and congestive
20
heart failure, which may subside with administration of
≥20 p < .0001
diuretic and increased LA compliance, an improvement that
0
should not falsely reassure, as such patients remain at high
0 1 2 3 4 5
Years risk even after symptoms have improved.91 A syndrome of
FIGURE 17.30. Natural history of ischemic mitral regurgitation: sudden onset of atypical chest pain and dyspnea may occur
survival after diagnosis in patients with Q-wave myocardial infarc- with abrupt chordal rupture. Rupture of papillary muscle
tion and quantified MR, matched for age, sex, and EF between those usually has a dramatic presentation with cardiogenic shock
without MR (dashed line) and with MR and effective regurgitant
orifice (ERO) 1 to 19 mm2 (dotted line) or ≥20 mm2 (solid line).
or a severe pulmonary edema. Pulmonary edema may be also
Note that patients with larger ERO due to ischemic MR incur a observed in transient severe papillary muscle dysfunction.
considerably higher mortality despite similar ejection fraction. Sudden death as the initial presentation of MR is rare.167
414 chapter 17

Physical examination usually finds a normal blood pres-

sure and brisk carotid upstroke. Cardiac palpation may show
laterally displaced, diffuse, and brief apical impulse. An
apical systolic thrill is characteristic of severe MR. A right
ventricular heave (left sternal border lift) is observed with
right ventricular dilatation and may be difficult to distin-
guish from a LA lift due to the dilated, expansive LA, which
is usually lower.
S1 is included in the murmur and usually normal but may
be increased in rheumatic disease. S2 is usually normal but
may be paradoxically split if the LV ejection time is markedly
shortened. The presence of a third heart sound is directly
related to the volume of the regurgitation in patients with
organic MR.183 It is often associated with an early diastolic
rumble due to the increased mitral flow in diastole even
without mitral stenosis. The S3 and diastolic rumble are
low-pitched sounds and may be difficult to detect without
careful auscultation in the left lateral decubitus position.
The S3 increases with expiration. In ischemic-functional
MR, S3 corresponds more often to restrictive LV filling. An
atrial gallop is heard mainly in MR of recent onset and in
ischemic/functional MR in sinus rhythm. Midsystolic clicks
are markers of valve prolapse.
The hallmark of MR is the systolic murmur, most often
holosystolic and including first and second heart sounds. If
an opening snap or S3 are mistakenly interpreted as S2, the FIGURE 17.33. Chest radiography in a patient with mitral regurgi-
murmur may appear midsystolic. A careful examination tation. There is mild cardiomegaly with LA enlargement.
beginning at the base of the heart to identify S2 and progress-
ing toward the apex will facilitate recognizing the origin of
the murmur. The murmur is blowing but may be harsh, lels the degree of MR.185 Murmurs of shorter duration usually
especially in valve prolapse. Maximum intensity is usually correspond to mild MR; they may be mid-late systolic in
apical with radiation to the axilla in rheumatic or anterior MVP or early systolic in FMR.
leaflet prolapse MR. In posterior leaflet prolapse, the jet is However, with myocardial infarction and in general in
usually superiorly and medially directed and the murmur functional MR, severe MR may be totally silent.186 Indeed,
radiates toward the base of the heart.184 The murmur may be the intensity of murmur is usually low and does not parallel
heard in the back, in the neck, and sometimes on the skull. MR severity,185 so that the presence and intensity of murmur
When the murmur radiates to the base, it may be difficult to is a poor detector of FMR or IMR.147,173
distinguish from that of aortic stenosis or obstructive cardio- The ECG’s most frequent feature is atrial fibrillation,
myopathy, and pharmacologic maneuvers showing that the found in approximately 60% to 75% of earlier series and
murmur decreases with amyl nitrite and increases with now present in approximately 30% to 50% of surgically
methoxamine, strongly suggest MR. Murmur intensity does corrected MR.187 Patients in sinus rhythm may present
not increase with postextrasystolic beats and usually paral- with signs of left atrial enlargement (Fig. 17.32). Left
ventricle hypertrophy is more rarely seen and may be associ-
ated with secondary ST-T abnormalities.188 Right ventricular
hypertrophy is uncommon. The ECG, especially in acute
MR, may be entirely normal. In ischemic MR, Q waves in
the inferior leads or left bundle branch block are often
noted.
Chest roentgenogram often shows cardiomegaly in
chronic organic MR or in ischemic/functional MR. Left
atrium body and appendage dilatation is frequent, but giant
LA is rare and usually seen in severe mixed valve disease
(Fig. 17.33). Although valvular calcifications are rare, annular
calcification is seen as a C-shaped density below the posterior
leaflet and is frequent. Because LA pressure is frequently
normal, even with severe MR, signs of pulmonary hyperten-
sion or pulmonary edema are rarely observed.
The clinical, ECG, and radiographic signs are often
FIGURE 17.32. Electrocardiogram in a patient with mitral regurgi-
tation and sinus rhythm. The prolonged duration and morphology
grouped into specific clinical syndromes suggestive of the
of the P wave is consistent with LA enlargement. The deep S wave diagnosis and are schematically separated in four syndromes
in V2 is consistent with borderline left ventricular hypertrophy. summarized in Table 17.3.
 m i t r a l va lv e d i s e a s e s 415
TABLE 17.3. Clinical syndromes of mitral regurgitation (MR) presentation
Sclerotic MR Chronic MR Acute MR Ischemic/functional MR

Symptoms None; incidental diagnosis Fatigue Pulmonary edema CHF

Physical examination Early systolic murmur Loud murmur S3 Loud murmur S4 Soft Murmur S4, S3
ECG Normal Atrial fibrillation Normal Q waves, LBBB
Chest x-ray Normal Cardiomegaly Normal heart size Cardiomegaly, pulmonary
Pulmonary edema edema
Echo-Doppler Jet may be large but is Enlarged LA Jet eccentric and thin Severe LV dysfunction
purely early systolic Incipient LV “Normal” mitral structure
dysfunction
Clinical pitfall Overestimate MR on the Ignore the LV Underestimate MR Ignore the silent but
jet basis alterations clinically important MR
CHF, congestive heart failure; LA, left atrium; LBBB, left bundle branch block; LV, left ventricle; MR, mitral regurgitation.

Doppler echocardiography is the mainstay of the diagno- The assessment of severity of MR is based on the criteria
sis of MR, of the morphologic assessment to determine the defined by the American Society of Echocardiography. The
etiology and mechanism of MR, and of the quantitation of guiding concepts are that the entire Doppler echocardio-
MR and of its consequences. graphic information is gathered (lesion, color-flow, pulsed
The morphologic features of the most common causes are and continuous wave Doppler) but that specific signs for each
discussed below. grade of MR are preferred, and that in the analysis of color-
Rheumatic MR is characterized by thickening of the leaf- flow imaging vena contracta measurements are preferred to
lets and chordae. The posterior leaflet has reduced mobility, jet analysis, and that overall, as often as possible, quantita-
whereas the anterior leaflet may be doming if commissural tive methods should be preferred.108 The methods facilitating
fusion is associated. A valvular prolapse is usually not present collecting these specific signs and the gradation scheme for
unless a ruptured chordae or active rheumatic carditis is MR are delineated below.
present. Similar lesions are observed in lupus or anticardio- Color-flow imaging defines the origin and direction of the
lipin syndrome in which transesophageal echocardiography jet, related to etiology (Figs. 17.35 and 17.36). Jet length, jet to
may also show small vegetations. left atrial area ratio, or more simply jet area193 shows rough
In degenerative MR, prolapse is observed with the passage correlations to MR severity. Small jets consistently corre-
of valvular tissue beyond the annulus plane in long-axis view spond to mild MR.146 However, color-flow imaging has sig-
(as indicated in the MVP section). Localization of the leaflet nificant limitations intrinsically related to the nature of
involved (most often the posterior) is confirmed by the initial regurgitant jets. The extent of a jet is determined by its
direction of the jet. A large mitral annular calcification may momentum, and thus as much by regurgitant velocity as by
represent a limitation for conservative surgery if extensive regurgitant flow. Also jets are constrained by the LA and
and severe. Flail segments appear as a complete eversion of expand more in a large LA.146 The eccentric jets of valve
the segment with or without the small floating echo of prolapse194 impinge on the LA wall and tend to underesti-
ruptured chordae (Fig. 17.34).107 mate MR.146 Central jets of functional MR expand markedly
The mechanism of MR due to bacterial endocarditis is in the enlarged LA and tends to overestimate MR.146
most often flail leaflets (due to the ruptured infected chordae),
which are relatively easy to diagnose.107 Perforations are more
difficult to diagnose. Mitral annular abscesses are rare and
are best detected by transesophageal echocardiography. Veg-
etations can be seen on leaflets or on ruptured chords with
superior sensitivity by transesophageal echocardiography.189
To diagnose IMR or FMR, a dilated annulus,118,190 is non-
specific,146 but annular contraction is reduced. The features
of ischemic heart disease may be observed as regional wall
motion abnormalities (Fig. 17.22).118 The leaflet tissue is
normal. The mitral tenting is due to the abnormal traction
by the secondary chordae on the leaflets,139 which deforms
the leaflets with a typical mid-leaflet tethering and the jet of
MR is central (Fig. 17.23).118,190 Rarely, the tethering predomi-
nates on one leaflet and the other leaflet overshoots in systole
beyond the tethered leaflet (but without prolapse) and the jet
is eccentric. Short axis views may reveal the origin of MR
on the medial commissure in IMR due to inferior myocardial
infarction.191 With papillary muscle rupture,119 MR is due to
the flail leaflet. The diagnosis is based on visualization (if FIGURE 17.34. Transesophageal echocardiography showing a flail
necessary by TEE) of a small mass of muscle attached to posterior leaflet (arrowheads) with ruptured chord (long arrow). Note
chordae and floating freely during the cardiac cycle.192 the normal thickness of the anterior leaflet and the enlarged LA.
416 chapter 17

FIGURE 17.35. Eccentric jet of mitral regurgi-

tation associated with a flail posterior leaflet.
(Left) An echocardiographic four-chamber view
of the flail leaflet (arrow). (Right) A jet directed
superiorly in the left atrium, remaining thin
and wall-attached (Coanda effect) to the bottom
of the LA.

Transesophageal echocardiography usually shows larger jets pulmonary venous reversal may be absent or asymmetric
but does not suppress these limitations of color-flow imaging. in severe MR.198
The vena contracta is the region of the regurgitant flow The goal of the quantitative methods is to measure the
immediately below the flow convergence through the regur- volume overload expressed as the regurgitant volume (differ-
gitant orifice.195 Therefore, direct measurement of the vena ence between the total and forward stroke volume) or frac-
contracta width provides a surrogate of the regurgitant orifice tion (proportion of LV ejection volume regurgitated in the
area. The vena contracta width is simple, appears superior to LA). The lesion severity is expressed as the effective regurgi-
jet measurements, and can be obtained either through trans- tant orifice (ERO) area and calculated as follows123,199:
esophageal195 or transthoracic echocardiography.196
ERO = regurgitant flow/regurgitant velocity, or
Pulsed-wave Doppler assessment of pulmonary venous
ERO = regurgitant volume/regurgitant TVI
velocity profile is useful to assess the degree of MR.197 Sys-
tolic reversal in pulmonary veins is a specific sign of severe where regurgitant TVI is the time velocity integral of the
MR (Fig. 17.37) and is related not only to MR severity but regurgitant jet.
also to jet direction and LA pressure.198 Consequently, Quantitation of MR can be performed using various
methods:
• Quantitative Doppler is based on the calculation of the
mitral and aortic stroke volumes (Fig. 17.38) using pulsed
wave Doppler.200 The principle is simple and applicable

D
.50

n/s

.50

FIGURE 17.37. Pulsed-wave Doppler recording of pulmonary

FIGURE 17.36. Central jet of mitral regurgitation (apical long-axis venous flow in a patient with severe mitral regurgitation. The early
view) in a patient with functional mitral regurgitation. Despite a forward systolic flow is blunted and followed by a late systolic flow
small regurgitant volume the jet is large and fills most of the LA. reversal (S). The diastolic flow (D) is normal.
 m i t r a l va lv e d i s e a s e s 417

FIGURE 17.38. Quantitative Doppler

measurement of the mitral regurgitant
volume. The lower images show the
measurement of annular diameters and
the upper tracings the measurement of
pulsed-Doppler velocity at the annular
levels. On the left the mitral stroke
volume is measured, and on the right the
aortic stroke volume. The difference
between these volumes is the regurgi-
tant volume, 81 mL in this example.

in most cases, but the measurement of the mitral stroke ing the flow convergence proximal to the regurgitant
volume is technically demanding with a significant orifice and is based on the principle of conservation of
learning phase.200 mass. Because color flow mapping allows precise deter-
• Quantitative two-dimensional echocardiography is of mination of velocity in the flow convergence region, the
similar principle, but is based on measurement of LV regurgitant flow can be calculated. Using regurgitant
volumes for total stroke volume calculation.201 flow and velocity, regurgitant orifice (Fig. 17.39) and
• The proximal isovelocity surface area (PISA) method, volume can be calculated.199 This method is simple and
conversely directly measures regurgitant flow by analyz- accurate if the assumptions are respected.

FIGURE 17.39. Proximal flow conver-

gence (PISA) measurement of the mitral
effective regurgitant orifice. (Left) The
color flow imaging of the flow conver-
gence with down shifting of the color
baseline so that the blue-yellow aliasing
velocity reaches 53 cm/s. The flow con-
vergence radius of 0.94 cm allows calcu-
lation of regurgitant flow at 294 mL/s.
(Right) The continuous-wave Doppler Flow = 294 mL/sec. MR velocity = 557 cm/s
measurement of the peak regurgitant
velocity at 557 cm/s. The ratio of flow to
velocity calculates the effective regurgi-
ERO = flow/velocity = 0.53 cm2 or 53 mm2
tant orifice at 0.53 cm2.
418 chapter 17

TABLE 17.4. Signs used for MR severity assessment by Doppler-echocardiography

Mild Moderate Severe

Specific signs • Small central jet <4 cm or <20%

2
Signs of MR > mild present, • Vena contracta width ≥0.7 cm with
of LA area but no criteria for severe MR large central MR jet (area >40% of
• Vena contracta width <0.3 cm LA) or with wall-impinging jet of any
• No or minimal flow convergence size, swirling in LA
• Large flow convergence
• Systolic reversal in pulmonary veins
• Prominent flail MV leaflet or
ruptured papillary muscle
• Dense, triangular CW Doppler MR jet
Supportive signs • Systolic dominant flow in Intermediate signs, findings • E-wave dominant mitral inflow
pulmonary veins (E >1.2 m/sec)
• A-wave dominant mitral inflow • Enlarged LV and LA size (particularly
• Soft density, parabolic CW when normal LV function is present)
Doppler MR signal
• Normal LV size

Quantitative parameters
RVol (mL/beat) <30 30–44 45–59 ≥60
RF (%) <30 30–39 40–49 ≥50
ERO (cm2) <0.20 0.20–0.29 0.30–0.39 ≥0.4

The gradation schemes in mild, moderate, or severe MR

for specific and supportive signs are presented in Table 17.4.
Importantly, RVol ≥60 mL and ERO area ≥40 mm2 (or 0.40 cm2)
are thresholds representing severe organic MR,202 and are
associated with excess risk under medical management.168 It
is also important to note that smaller RVol and ERO are
markers of IMR with severe clinical consequences,174,178 and
therefore that differential grading for organic and FMR
should be used.
Assessment of left ventricular and atrial function is most
often based on guided M-mode diameters, with assessment
of LV size, mass, and wall stress.187,203,204 The LV volumes can
be reliably measured by two-dimensional echocardiogra-
phy.205,206 The ejection fraction can be calculated 207 or esti-
mated.208 M-mode diameter or volume can assess the LA size
by two-dimensional echocardiography.209

Cardiac Catheterization
Cardiac catheterization is rarely performed for the diagnosis
of MR but may assess the hemodynamics, MR severity, and
LV function if Doppler echocardiographic imaging is poor or
ambiguous, and allows assessment of coronary anatomy
preoperatively.
The major hemodynamic consequences of MR are reduc-
tion of cardiac output and elevation of pulmonary artery
wedge pressure. Marked pulmonary hypertension is rarely
present. The large V wave of the LA or pulmonary wedge
pressure (Fig. 17.40) is more frequent in acute than in chronic
MR,210 but can be observed in either disease with reduced
left atrial compliance without MR.211
The assessment of MR degree can be obtained by LV
selective angiography and can be qualitatively graded in
three or four grades on the basis of the degree and persistence FIGURE 17.40. Cardiac catheterization with simultaneous record-
of opacification of the LA.212 Although time honored, this ing of the LA and LV pressure and of the transmitral continuous-
wave Doppler. Note the large V wave on the LA pressure tracing
method has limitations similar to all qualitative methods.213 reflected on the Doppler tracing by the triangular shape of the sys-
Quantitation of MR can be obtained by comparing the tolic jet signal revealing the ventriculoatrial equalization of pres-
angiographic stroke volume to the forward stroke volume sure at end-systole.
 m i t r a l va lv e d i s e a s e s 419
calculated by the Fick or thermodilution methods214 to cal- ment with angiotensin-receptor blockade.226 Because there
culate RVol. The angiographic stroke volume usually overes- are no results of long-term randomized studies, vasoactive
timates the true stroke volume, and corrections have been therapy is not yet recommended for chronic treatment of
used to minimize the overestimation of RVol. Subtraction of MR.110,217 Despite interesting animal data,157,227,228 beta-block-
two stroke volumes introduces a potentially high range of ade in chronic organic MR remains unproven in human
error, which cannot be verified by combined methods or by subjects.
repeating the measurements, and therefore this method is Conversely in IMR and FMR there is a strong body of
rarely utilized. evidence suggesting that medical treatment improves the
The assessment of LV function can be performed using degree and consequences of MR. Angiotensin-converting
quantitative angiography. Left ventricle volumes correlate enzyme inhibitors or angiotensin receptor blockers decrease
strongly with the regurgitant volume, duration, and etiology afterload and remodeling and improve MR.229 Furthermore,
of MR and LV function. The most frequently utilized indices beta-blockade also improves LV remodeling and decreases
of LV function are end-systolic volume and ejection fraction, the degree of FMR with subsequent improvement in
which are useful prognostic indices.135,215 High-fidelity pres- survival.230–233 Therefore, these drug therapies are considered
sure recording with LV angiography allows calculation of standard in patients with ischemic and functional MR.
more complex indices of LV distensibility in diastole,138 and Interventional treatment remains currently experimen-
of wall stress, maximum LV elastance, and LV systolic stiff- tal. Devices that allow percutaneous suture between the
ness. The additional value of these complex measurements mitral leaflets,234,235 similar to the surgical Alfieri suture236
has been investigated in small groups of patients and remains or annular cinching,237,238 mimicking annuloplasty, are under
to be defined in larger populations. initial evaluation. Great hopes of new therapeutic avenues
Selective coronary angiography allows definition of coro- are yet to be confirmed.239
nary anatomy. Obstructive coronary atherosclerosis contin-
ues to be frequent even in the absence of angina,216 and
Surgical Treatment
coronary angiography is performed ordinarily in patients
older than 40 to 50 years before surgery.217 The approach to surgery can be the traditional median ster-
notomy or the more recently used “minimally invasive”
approaches, which range from port-access surgery to small
Management
sternotomy to thoracotomy.240 These new techniques appear
interesting but their long-term outcome remains uncertain.
Medical Treatment
There are two main valvular surgical options: mitral valve
Prevention of infective endocarditis using the appropriate repair and valve replacement.
prophylaxis is necessary in patients with MR.218 Young Mitral valve repair is possible in >85% of patients with
patients with rheumatic MR should receive rheumatic fever MR, when the intervention is performed in advanced repair
prophylaxis. In patients with atrial fibrillation, rate control centers by surgeons with considerable experience with mitral
is achieved using Digoxin or beta-blockers. Long-term main- surgery.168 Nationally, valve repair is performed in approxi-
tenance of sinus rhythm after cardioversion in patients with mately 50% of patients operated for mitral valve diseases.
severe MR or enlarged LA is usually not possible in patients The frequency with which valve repair can be used varies
medically managed. However, return to sinus rhythm after with the experience of the operating team and the spectrum
surgery is possible in patients with atrial fibrillation of short of the underlying valve disease; repair is more often feasible
duration.219 Oral anticoagulation should be used in patients with degenerative than with rheumatic or endocarditic valve
with atrial fibrillation. Diuretic treatment is useful for the disease.107
control of heart failure and for the chronic control of symp- Valvular procedures involve plication or more often exci-
toms, especially dyspnea. However, these efforts should not sion of a valve segment with prolapse (Fig. 17.41).241 However,
delay consideration of surgical repair in patients who are the resulting reduction in area of the leaflet could reduce
otherwise candidates for surgical therapy. coaptation and induce residual MR; therefore, annuloplasty
Acute afterload reduction may decrease the degree and is usually a routine part of the repair.242 This type of repair
consequences of MR.124 This effect is achieved by reducing is most successful with posterior leaflet prolapse. However,
the LV systolic pressure but also by decreasing the effective postoperative systolic anterior motion of the mitral valve and
regurgitant orifice area.125 Acute utilization of sodium nitro- LV outflow tract obstruction may be observed.243 This com-
prusside in unstable patients with severe MR, especially in plication is due mainly to hypovolemia and excessive use of
the context of myocardial infarction, may be lifesaving in inotropes.244 However, extensive myxomatous disease of the
preparation for surgery.124 posterior leaflet with excessive leaflet length may lead to
Chronic afterload reduction is more controversial. persistent systolic anterior motion, which can be prevented
Hydralazine has positive acute effects,220 but this drug is by sliding repair, which reduces the leaflet length.245 With
often poorly tolerated chronically. The effects of angiotensin- anterior leaflet prolapse, because of the limited width of the
converting enzyme inhibitors have been analyzed in small leaflet, the risk of residual MR is higher with plication or
series,221–223 and their long-term efficacy is not defined. Fur- resection.114,244,246 Other highly repairable leaflet abnormali-
thermore, discrepancies between series are noted regarding ties include congenital clefts and acquired perforation, which
the effect on the degree of MR 224 and on LV remodeling.225 may be closed by using a patch. New procedures extended
In a nonrandomized open series, we observed positive results the armamentarium of valvular procedures used to correct
on MR severity, LV volumes, and LA enlargement of treat- lesions traditionally not considered repairable. In patients
420 chapter 17

repair cannot be achieved, it is preferable to replace the

valve immediately. To assess the adequacy of mitral repair
(residual stenosis, regurgitation, or systolic anterior motion),
TEE, which does not interfere with the surgical procedure,
is performed routinely.244
Valve replacement must be performed when mitral repair
is impossible or is unsuccessful. The choice is between a
mechanical valve of potentially excellent durability but with
a hazard of thromboembolism and a biologic valve with
undefined long-term durability261 but less tendency to cause
thromboembolism. With atrial fibrillation, chronic antico-
agulant therapy is necessary even with a bioprosthesis, so
that avoiding anticoagulation is not relevant in choosing a
prosthesis. An important component in maintaining LV
function postoperatively is chordal preservation during valve
replacement.262,263
Postoperative outcome after surgery for organic MR is
essential to determine the appropriate indications. Valve
repair, by preserving the normal valvular tissue, is preferable
to valve replacement. Compared to prosthetic replacement,
valve repair has a lower operative mortality.264,265 Direct com-
parison of the results of valve repair and replacement is dif-
ficult265 because patients undergoing valve repair are usually
at a less advanced stage of the disease than patients undergo-
ing valve replacement.264 However, survival and LV function
after valve repair are better than after insertion of a pros-
thetic valve,264,266,267 even in patients with anterior leaflet
FIGURE 17.41. Schematic representation of the mitral valve repair prolapse (Fig. 17.17).246 Better ventricular function with val-
technique in a patient with flail posterior leaflet (upper left) with
triangular resection of the flail segment (upper right), reapproxima- vuloplasty may be due to preservation of chordae and papil-
tion of the leaflets segments left in place and restoration of an lary muscles.268 Durability of valve repair for degenerative
appropriate coaptation line. disease is excellent if no more than mild residual MR
is accepted intraoperatively,114,246 even very long term after
surgery.269 Some centers noted, despite superior survival,
higher rates of recurrent MR and lesser durability after valve
with leaflets retraction, mitral leaflet augmentation with a repair,270 suggesting that the results of each individual center
pericardial patch may be helpful.247,248 Similar approaches should be analyzed in indicating mitral repair. However,
have been proposed in ischemic MR.249 valve repair has the same low rate of reoperation than valve
Subvalvular procedures are often necessary. In patients replacement.246,264 Mitral regurgitation postrepair is attrib-
with elongated chordae, chordal shortening was intended to uted in two thirds of the cases to new lesions and in one
ensure appropriate coaptation of leaflets, but the durability third to an inadequate primary correction.271 Therefore, valve
of this procedure is limited.114 Major recent improvements repair is the preferred procedure for surgical correction of
were the use of transposition of chordae or of artificial organic MR.
chordae,250–252 which have made anterior leaflet prolapse Operative mortality has been reported between 5% and
repair almost as feasible and as durable as posterior leaflet 12%261 in earlier series, but most patients had prosthetic
prolapse repair.246 valve replacement rather than reconstruction. The operative
Annular dilatation, almost constantly associated with risk is lower in the current era, around 1% in patients younger
MR, is treated by reduction of mitral circumference, i.e., than 75 years with organic MR whether they had valve repair
annuloplasty.253 A rigid ring was originally developed by Car- or replacement,187 and around 2% to 3% above that age. Left
pentier, but flexible annuloplasty rings have been developed ventricle function is not a predictor of operative mortality,
to preserve the normal systolic contraction of the mitral and patients with organic MR even with markedly depressed
annulus,254 and even simple bands have been proposed to function have a reasonable chance of surviving surgery.187
support the repaired leaflet. No definitive differences have Age, symptoms, and coronary disease are the most impor-
been demonstrated between the various rings. In ischemic tant predictors of operative mortality.187 The operative mor-
and functional MR, restrictive annuloplasty has been advo- tality is notably higher in ischemic MR even after valve
cated,255 because standard annuloplasty leads to frequent repair.272,273
recurrence.256 Although early experience with this approach Long-term postoperative survival has considerably
appears interesting,257 the effect on survival is uncertain.258 improved, and survival after valve repair is close to expected
Intraoperative assessment of valve repair259 is essential to survival, whereas it is reduced compared to expected sur-
assess the adequacy of mitral valve reconstruction before vival after valve replacement.114,246,264,269 Another important
completion of the operation,260 and is a significant compo- determinant of long-term postoperative outcome is the
nent of improved results of mitral repair. When satisfactory preoperative symptomatic status. Patients with severe
 m i t r a l va lv e d i s e a s e s 4 21
100 relationships between pre- and postoperative LV func-
p < .0001 p = .18
tion,130,131,134,135,215 and between preoperative LV function and
80 postoperative survival,133,187,203 underline the fact that LV dys-
function is most often already present preoperatively. Because
Survival (%)

60 of the modified loading conditions, multiple and complex

Observed
indices of LV function have been proposed.130,132,133 Despite
40 Expected
these altered loading conditions, preoperative ejection frac-
tion is an acceptable independent predictor of postoperative
20 NYHA III–IV NYHA I–II ejection fraction131,134,135 and survival.187 In general, one can
estimate that the postoperative ejection fraction likely will
0
decrease by approximately 10% early after valve replace-
40 26 8 10 0 2 4 6 8 10
Years Years
ment.131,134,135 However, there is a significant individual varia-
FIGURE 17.42. Long-term postoperative outcome according to pre- tion, and more decline is observed with markedly increased
operative symptoms in patients with isolated mitral regurgitation. end-systolic diameter,134,203 volume,135,215 or wall stress134 or
The left graph shows that observed postoperative survival (dotted in patients with severe symptoms, prolonged duration of MR,
line) in patients presenting with New York Heart Association class or coronary disease.134 A markedly reduced preoperative ejec-
III or IV is significantly lower than the expected survival (solid line).
The right graph shows that observed survival in patients operated tion fraction (<50%) is associated with a high late mortality
with no or minimal symptoms (class I or II) is identical to the (Fig. 17.43),187 but nevertheless surgery provides a better
expected survival consistent with restoration of life expectancy by outcome than medical treatment.170 Even a “borderline”
mitral surgery in patients operated at that stage. ejection fraction (50% to 60%) is associated with an excess
late mortality.187 Therefore, signs of overt LV dysfunction in
MR are LV diameter ≥45 mm or ejection fraction <60%.217
Nevertheless, the end-systolic diameter rarely and belatedly
reaches 45 mm,278 and the best outcome of surgery is obtained
preoperative symptoms, NYHA class III or IV, incur indepen- in patients with both end-systolic diameter <45 mm and
dently of all baseline characteristics, in particular age, ejec- ejection fraction ≥60%.134,187,278
tion fraction, and the type of surgery performed, an excess Atrial fibrillation when chronic preoperatively usually
operative and long-term mortality despite their postoperative persists postoperatively, unless it is of brief duration.219 The
symptomatic improvement.274 Importantly, patients preop- association of a Maze procedure with mitral valve repair can
eratively in class I or II incur a very low operative risk 274,275 be accomplished with minimal risk; it maintains sinus
and an excellent long-term survival, identical to the expected rhythm279 and may reduce the embolic risk. Even patients
survival (Fig. 17.42).274 These results have been confirmed by operated in sinus rhythm incur a notable risk of postopera-
comparing outcome after diagnosis of organic MR between tive atrial fibrillation, determined in particular by LA
patients operated early and conservatively managed, showing enlargement.280 Postoperative atrial fibrillation increases the
that the early surgical approach not only provides a survival risk of postoperative heart failure or stroke, suggesting that
advantage,276 but also results in restoration of life expectancy surgery before excessive LA enlargement should be consid-
in patients asymptomatic at diagnosis.168 These data suggest ered. Differences in thromboembolic risk after valve repair
that in centers and patients at low operative risk, early repair
of organic mitral regurgitation in asymptomatic patients
suppresses the ominous consequences of severe MR and
restores life expectancy.
After mitral surgery for symptoms, most patients improve 100
symptomatically by at least one functional class and some
become asymptomatic. However, with time postoperative
80 73%
heart failure and symptomatic deterioration tend to occur at
a progressively increasing rate (38% at 10 years in operative
Survival (%)

survivors) and is most often (two thirds of the cases) due to 60 53%
residual LV dysfunction.277 Valvular or prosthetic dysfunc-
tions explain heart failure in approximately one third of EF ≥60%
40
cases.277 EF 50–60%
The most frequent cause of mortality after surgical 32%
20 EF <50%
correction of MR is LV dysfunction187 due to chronic irrever-
sible myocardial damage.131,134,135 Left ventricle dysfunction p = .0001
occurred in our experience in approximately one third of 0
patients with organic MR.134 The majority of patients dem- 0 2 4 6 8 10
onstrate a decrease in ejection fraction after successful valve Years
replacement.131,134 This decline may be the result of several FIGURE 17.43. Postoperative survival (after mitral regurgitation
factors: cumulative permanent myocardial damage, occa- surgery) according to preoperative ejection fraction (EF). Consider-
able mortality is observed when EF is <50% preoperatively, whereas
sional myocardial insult sustained at the time of operation, excess mortality is lesser but significant with pseudo-normal EF
diminished preload, and probably an increase in impedance (50–60%) and the best survival is obtained in patients with EF
to ejection after elimination of the MR. However, the ≥60%.
422 chapter 17

and valve replacement have been variably estimated 264,265 but • Low operative risk: Both the operative mortality in the
appear to favor valve repair. In addition, because following institution where such an indication is contemplated and
valve repair anticoagulation is recommended permanently the operative risk for the individual patient involved
only if atrial fibrillation persists, the occurrence of bleeding should be minimal (1% to 2%).
is less common than following prosthetic replacement.264 • Reparability: The valvular lesions as determined by
Postoperative outcome after surgery for functional MR echocardiography should be in all probability repairable
(or IMR) is less well known. Patients present with a more and the surgeon performing the intervention should
advanced clinical situation, with more heart failure, more have a high degree of experience with all forms of valve
reduction of LV function, and comorbid conditions such as repair.
reduced renal function. The operative mortality is higher • Intraoperative TEE should be performed by experienced
than in patients with organic MR, and long-term survival is physicians, to monitor the repair procedure and help with
reduced.281 Valve repair superiority to valve replacement is decisions warranted by an imperfect result.287
uncertain and may be limited to patients with the least • Quantitation of MR should be performed systematically
severe condition.272 Furthermore, valve repair is complicated in these patients preoperatively using multiple noninva-
by more frequent recurrence of MR than in organic sive techniques to determine objectively the degree of
MR.256,282,283 Therefore, the indications of surgery in IMR and MR and affirm that surgery is warranted.
FMR remain uncertain but recent improvements145,249,257,284,285
Therefore, despite the considerable progress recently accom-
suggest that more aggressive indications for repair may be a
plished, currently not all patients and not all institutions
future consideration.
are candidates for these early indications of surgical correc-
tion of organic MR, but surgery should be considered early
Indications for Surgery in the course of MR when severe MR has been thoroughly
For ischemic MR, recognized rescue indications of surgery documented.
address patients with severe symptoms and severe IMR or
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430 chapter 17

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 1 Rheumatic Fever
8 Y.S. Chandrashekhar and Jagat Narula

The Global Burden of Rheumatic Fever . . . . . . . . . . . . . 431 Clinical Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 Laboratory Investigations . . . . . . . . . . . . . . . . . . . . . . . . . 436
Mechanisms of Damage . . . . . . . . . . . . . . . . . . . . . . . . . . 432 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Streptococcal Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

Key Points The Global Burden of Rheumatic Fever

• Streptococcal group A β-hemolytic pharyngitis mediates
acute rheumatic fever (ARF). Acute RF (ARF) was a major problem in the U.S. until
• Cardiac involvement in ARF involves pericardium, myo- the 1960s, and in fact was a common cause of disqualifica-
cardium, and endocardium. tion among young men and women being considered for
• The “pathognomonic” histopathologic finding in the the military. Since then, RF has largely disappeared as
myocardium is the Aschoff nodule. a major cause of illness in the U.S.5 Improved socioeco-
• Arthritis is often the earliest manifestation of ARF and nomic status, reduced crowding, the advent of antibiotics,
brings the patient to clinical attention. and the widespread treatment of streptococcal throat
• Carditis is the only manifestation of ARF that results in infections have contributed to this decline. Unfortunately,
permanent deformity. Clinically detectable cardiac invol- ARF continues to be rampant in the developing world.
vement occurs in a significant proportion of patients with The World Health Organization (WHO)6 reported an inci-
ARF. dence of ARF of fewer than 1 case per 100,000 population
per year in the industrialized world, compared to 100 to
Rheumatic fever (RF) is a delayed, noninfectious consequence 150 cases per 100,000 population in some areas of the
of pharyngitis caused by group A β-hemolytic streptococci eastern Mediterranean, the western Pacific and China.
(GABHS). While it is rare in the developed world, RF remains Acute RF remains a cause of much morbidity in the young.
a major problem worldwide.1 However, RF still continues to Rheumatic heart disease (RHD), a long-term sequela of
show up unexpectedly even in the First World as evidenced RF, continues to be the most common cause of cardio-
by occasional outbreaks in the United States.2 Furthermore, vascular complication and death in young persons in
given the magnitude of international travel and immigration, the developing countries. Surveys in school-age children
clinicians everywhere are likely to encounter RF or its dev- show an RHD prevalence as high as 78 per 1000 in some
astating cardiac sequelae. Finally, the cause of the rise and developing countries.7 It accounts for more than one third
fall of RF in the developed world has not been fully explained of cardiovascular admissions to hospitals in developing
at a time when GABHS carrier rates have not been signifi- countries and constitutes a major indication for cardiac
cantly diminished.3 This raises the possibility of a sudden, surgery.8 Thus, RF and RHD impose a significant economic
unexpected resurgence, and RF thus remains an important burden on the total health budget in developing countries.
disease to understand. Acute rheumatic fever affects multiple Having said that, RF continues to show up all over the
organ systems, which makes it a difficult diagnosis in regular world, and several outbreaks have occurred in the U.S. in
practice; most commonly it presents as a combination of portions of Utah and Ohio and at U.S. Naval Training
arthritis, carditis, chorea, erythema marginatum, and/or Centers.9 Many of these outbreaks have involved middle-
subcutaneous nodules, and valvular heart disease remains class suburbs, less crowded communities, and people
a major long-term sequela. It has thus been aptly said that with access to excellent health care—a situation entirely
“rheumatic fever licks the joints, but bites the heart.” This unlike the developing world, where socioeconomic
chapter briefly discusses the pathogenesis, recognition, treat- issues are thought to be responsible for RF outbreaks.
ment, and prevention of acute RF. The reader is referred This once again emphasizes our limited understanding
elsewhere4 for more in-depth treatment of this topic. of RF.

4 31
432 chapter 18

Etiopathogenesis rheumatogenic streptococci and the concept that only throat

infection can cause ARF is not universally accepted17 and
The pathogenesis of rheumatic fever and RF-induced cardiac awaits further study.
damage is not well understood. The lack of a good clinical
model for RF is an important limitation. However, there is
a significant body of data to suggest an autoimmune process. Mechanisms of Damage
The salient features involved in the pathogenesis include (1)
a human host who harbors “RF susceptibility factors,” which Despite some claims of direct injury by streptococci, viruses,
are thought to increase the proclivity to developing ARF; (2) or toxins, most data suggest that RF is an autoimmune injury.
pharyngitis (and interestingly, not other sites of streptococ- Antibodies (cross-reactive and polyspecific) that react to
cal infection) with certain strains of GABHS with rheumato- shared antigens between streptococci and human tissue
genic potential; (3) the presence of an immune response (molecular mimicry) are thought to underlie this process.
against specific streptococcal antigens; the magnitude of Rheumatogenic streptococci contain multiple antigenic
this response correlates with the occurrence of subsequent determinants that partially mimic normal human tissue
ARF; and (4) an interval of 1 to 5 weeks between GABHS antigens.10 Thus the hyaluronate capsule, the streptococcal
pharyngitis and the development of ARF that presumably membrane, and the M-proteins share similarity with valve
allows time for mounting an immune-mediated injury. glycoproteins, myocardial sarcolemma, and cardiac contrac-
tile proteins, respectively. Following streptococcal pharyngi-
tis, these antigens, which are recognized as foreign by the
Host Factors susceptible host, induce a hyperactive humoral and cellular
Only a few individuals with group A streptococcal infection immune response that damages native tissues bearing similar
develop RF,10 and the genetic makeup of the host may convey antigen. The type of damage is then partly the result of which
differing susceptibility to ARF. The putative “susceptibility tissue shows what kinds of mimicry. For example, antibodies
factor” remains unclear so far, and indeed there may be many to the N-acetylglucosamine moiety of group A polysaccha-
such factors. Identifying these factors is likely to help us ride cross-react with the heart valve tissue,18 and this is
target preventive measures and is the focus of intense study. thought to mediate valve damage; indeed such antibodies are
Certain racial characteristics (e.g., Samoans in Hawaii and increased in patients with rheumatic heart valve disease.19
Maori in New Zealand) and a history of previous episodes of Breakdown of tolerance is an important component in
RF increased the susceptibility to RF after GABHS pharyn- the pathogenesis of ARF. The M-protein epitopes not only
gitis. Another factor may be the differing ability to mount a can trigger heart cross-reactive antibodies and T-cell
vigorous antibody response since this correlates with the responses20 but also can act as superantigens.21 This might
occurrence of ARF. Familial or genetic susceptibility to explain the widespread immune response overriding the his-
RF has been postulated.11,12 Acute RF risk correlates with tocompatibility barrier. In fact, both humoral and cellular
the increased prevalence of human leukocyte antigen (HLA) immune responses are more vigorous in patients with ARF
DR4 in the U.S.12 and Saudi Arabia13 and with the increased than in normal subjects and might be related to superanti-
prevalence of DR3 and DQw2 in India.14 However, these genic property of streptococcal M protein. A significant T-
associations were obtained with older serologic methods cell infiltration is also observed in the valvular tissue, and
and have to be confirmed with newer methods of typing. T cells isolated from valvular tissue of patients with rheu-
Some other markers, such as B-cell alloantigen D8/17, have matic heart disease respond to streptococcal M5 protein and
shown a strong association with susceptibility to RF15 in U.S. also cross-react with cardiac myosin.22 This homology with
populations, but these perform less efficiently in North cardiac myosin can be expected to decrease tolerance and
Indian populations where other markers seem to perform may enhance T-cell–mediated inflammatory damage.23
better. Finally, target organ sensitivity may also be geneti-
cally determined in rheumatic fever, and this kind of sensi-
tivity may determine which tissues get deposited with Pathology
antibodies.16
The cardiac and noncardiac tissues differ in how they react to
ARF. The inflammatory process in the skin, joints, and brain
Factors Within Streptococci
tends to regress spontaneously without any significant resid-
Among the various serotypes of group A streptococci, only ual effects. There is swelling with serous effusion in the
some appear more likely to initiate acute RF (M-types 1, 3, joints. Inflammatory infiltration and edema are evident in
5, 6, 14, 18, 19, 24, 27, and 29), whereas some other strains the synovial membranes. A fibrinoid exudates frequently
are not commonly associated with ARF (M2, 4, and 28). lines the membranes. The blood vessels in the articular and
Furthermore, only throat and not skin infections mediate periarticular areas are often inflamed and show infiltration
ARF. The exact mechanism by which GABHS initiates RF with lymphocytes and polymorphonuclear leukocytes. On
is unclear, and it is also not known why throat infections the other hand, the subcutaneous nodules have a center of
and not other streptococcal infections lead to RF. In general, fibrinoid necrosis with peripheral inflammatory reaction of
the RF strains tend to be rich in M protein, provoke an lymphocytes and occasional polymorphonuclear leukocytes.
intense M-type–specific immune response, and probably Cardiac involvement in RF affects all three layers: peri-
share epitopes with human tissue. However, the concept of cardium, myocardium, and endocardium. The pericarditis is
 r h eum at ic fev er 433

A
A

B B
FIGURE 18.1. (A,B) Pericarditis. Gross pathologic specimens
obtained from a patient who died of rheumatic fever. The outer, or
parietal, layer of the pericardium has been partially reflected away,
revealing the epicardium, which is covered with shaggy fibrinous
exudates as if a buttered sandwich had been pulled apart—hence the
term bread-and-butter pericarditis.

typically fibrinous (Fig. 18.1). The histopathologic findings in

myocardium include the “pathognomonic” Aschoff nodule
(Fig. 18.2).24 The Aschoff granuloma consists of a central area
of fibrinoid necrosis surrounded by cells of histiocytic-
macrophage origin (Anitschkow cells), which show a typical
owl’s eye–shaped nucleus. These cells are usually found in
the subendocardial or perivascular regions in the myocar-
dium. There is surprisingly little histopathologic damage to C
the myocardium, even in patients with florid clinical carditis FIGURE 18.2. (A) Low-power microscopic intramyocardial view
and heart failure.25,26 Myocyte necrosis is uncommon, and shows Aschoff bodies. Note the nodular aggregate of Aschoff cells
immediately adjacent to a coronary arteriole (Hematoxylin and
the cellular infiltrate is confined to the interstitium. This eosin, ×120). (B,C) High-power microscopic view of an Aschoff body
correlates with the lack of troponin leaks even in patients illustrates the characteristic “owl-and-caterpillar” nuclei (H&E,
with frank rheumatic myocarditis.27 The conduction system ×250).
shows little pathology even in the presence of clinical
conduction defects.
The valves bear the brunt of the disease. The valves are
inflamed and thickened during the acute stage of the rheu- of the leaflets (Fig. 18.3), that are not associated with throm-
matic activity. The surface of the valves develops small, boembolic sequelae. A mild degree of inflammation leads to
sterile vegetations or verrucae, particularly along the edges fusion of the cusps while more severe inflammatory reaction
 434 chapter 18

be gradual, and patients with acute RF may be seen without

evidence of aortic valve affliction only to develop aortic
regurgitation at a later date. Mitral and rarely aortic stenosis
are late sequelae that result from scarring and inflammatory
fusion of leaflet cusps.

Clinical Features

Joint Symptoms
Arthritis is the earliest manifestation of RF and frequently
brings the patient to clinical attention.28 Arthritis occurs in
at least two thirds of patients, and is more common in older
patients. Although larger joints of the extremities are com-
A monly involved, occasional involvement of smaller joints in
the hand and feet may be seen; hips, spine, or axial joints are
rarely affected. The joints are swollen, hot, red, and tender.
The joints are inflamed at different times and for various
intervals to impart a migratory character to joint pains.
Monoarticular arthritis is not common. Arthritis usually
resolves in 3 to 4 weeks even without treatment but responds
instantly to aspirin therapy, and does not lead to permanent
damage. Arthralgia without objective signs of inflammation
is common in younger patients, in the presence of carditis,
particularly in rheumatic recurrences and in RHD patients
in the developing countries.29 Some forms of polyarthritis
after streptococcal pharyngitis may represent a reactive phe-
nomenon. Poststreptococcal arthropathy is characterized by
recurrent, severe, prolonged polyarthritis in adults that is not
very responsive to nonsteroidal antiinflammatory agents.
B Although other manifestations of RF are not associated with
arthropathy, some patients end up with residual heart
disease.30 Prophylaxis in reactive arthropathy remains
similar to that for patients with RF, but very little data are
available to provide definite recommendations.

Cardiac Involvement
Carditis is the only manifestation of RF that results in per-
manent deformity.31 The cardiac involvement in RF has been
reported to occur in nearly one third of almost all cases in
various studies and in up to one half of cases in a prospective
series. Clinical carditis was seen in 72% of patients in a
resurgence of RF in Salt Lake City,2 which is similar to the
prevalence in the early part of the 20th century in the United
States.32 Subclinical carditis is being increasingly detected
C
FIGURE 18.3. Valvulitis. (A) Gross appearance of the mitral valve
with modern imaging methods; evidence of valvular regur-
shows characteristic tiny, wartlike verrucae or vegetations on its gitation was seen in 19% of additional cases with the use of
inflow side (atrial surface). (B) Similar verrucae on the ventricular echocardiography. Active rheumatic carditis can present in
surface of the aortic valve. The verrucae are sterile and small and a number of ways, including subclinical cardiac involve-
only rarely result in embolization (unlike vegetations of bacterial ment, acute or even fulminant congestive heart failure, and,
endocarditis). (C) Microscopic appearance.
occasionally, chronic ongoing carditis. Younger patients
often present with carditis, whereas joint involvement is
more common in older patients.28 Although episodes of car-
ditis occur less frequently in older patients, they present
extends into the subvalvular apparatus as well. This can more often with unexplained worsening of congestive heart
result in early mitral or tricuspid regurgitation, caused partly failure. The clinical findings may be suggestive of pericar-
by leaflet prolapse as well as annular dilatation. Aortic ditis, myocarditis, and valvulitis, and the guidelines for
incompetence also occurs as a consequence of thickening the diagnosis of rheumatic carditis are summarized in
and distortion of the valve leaflets. The scarring process may Table 18.1.
 r h eum at ic fev er 435
TABLE 18.1. Simplified schema for the diagnosis of acute rheumatic carditis*
Criteria First attacks Recurrences

Valvulitis New onset apical systolic murmur or aortic regurgitation murmur Change in murmur
Carey-Coombs murmur New-onset murmur
Myocarditis Unexplained cardiomegaly Worsening cardiomegaly
Unexplained congestive heart failure/gallop sounds Worsening congestive heart failure
Pericarditis Pericardial rub Pericardial rub
Pericardial effusion Pericardial effusion
Miscellaneous Conduction disturbances or unexplained tachycardia†
Echocardiographic imaging‡
Nuclear imaging‡
Morphology evidence at surgery
Histologic evidence at biopsy or pathology
* Supportive evidence is required for the presence of acute rheumatic fever according to the Jones criteria. In patients with known rheumatic heart disease,
acute rheumatic fever can be diagnosed with minor criteria along with evidence of antecedent streptococcal infection.
† These would be considered soft criteria.
‡ The significance of these methods is controversial.

Endocarditis of rheumatic carditis. The presence of pericarditis usually

indicates severe carditis.31
Endocardial inflammation most commonly affects the mitral Rheumatic pericarditis is almost always associated with
and aortic valves, and the clinical diagnosis of rheumatic findings of valvular involvement. A pericardial rub can
endocarditis is based on the demonstration of mitral or aortic sometimes mask the underlying valvular murmurs. However,
regurgitation murmurs, or both. Mitral valve disease is seen other causes need to be considered if no valvulitis-related
in approximately 70% of patients, mitral and aortic valve murmur is audible after the resolution of pericarditis.31
disease occurs in an additional 25%, and isolated aortic valve Rheumatic pericarditis is often associated with a mild-to-
disease occurs in 5% to 8%. Clinical tricuspid or pulmonary moderate serosanguineous effusion, and the development of
valve involvement is rare in the first attack of RF. The use pericardial tamponade is rare.
of echocardiography has clarified the mechanism of valve
regurgitation in RF.33 Although mild-to-moderate mitral
regurgitation is due to left ventricular dilatation with mild Sydenham’s Chorea
or no annular dilatation, more severe degrees of mitral regur- Chorea is a late manifestation of RF that is characterized by
gitation are associated with marked annular dilatation, a series of involuntary movements that commonly involve
chordal elongation, and anterior mitral leaflet prolapse.34 the face and extremities associated with emotional lability.28
Rarely chordae may rupture, to result in flail leaflets and It commonly affects children between the ages of 7 and 14
severe regurgitation. Because mitral regurgitation frequently years, and occurs more frequently in girls; it is rarely seen
disappears on follow-up,28,35,36 it is likely that a functional in adults. Chorea is often associated with carditis and sub-
mechanism rather than a permanent structural alteration in cutaneous nodules, but it appears several weeks after an
the valve or annulus underlies the development of mitral acute attack of RF and when the acute manifestations have
regurgitation. Inflammatory changes in the aortic valves and disappeared. The patients thus do not fulfill the Jones criteria
the aortic ring result in aortic regurgitation; aortic valve at this time. The course of chorea is rather gradual as the
prolapse may contribute occasionally. patient appears increasingly nervous, becomes dysarthric,
makes grimacing gestures, develops difficulty in writing,
Myocarditis and shows characteristic purposeless movements of the arms
and legs, which may be associated with muscular weakness.
Myocardial involvement is generally associated with new- The chronic movements are exaggerated in effort or excite-
onset cardiomegaly, an interval increase in cardiac size, or ment but subside during sleep. Chorea is usually a self-
the development of congestive heart failure.26,31,37 The left limited condition and resolves without residual damage but
ventricular systolic function and myocardial contractility the associated carditis can leave behind valvular damage.
indexes are normal in patients with rheumatic carditis, and
only minimal myocyte damage is pathologically seen in
rheumatic carditis. It is has been thought that hemodynami- Skin Manifestations
cally significant valvular lesions lead to the development of Subcutaneous nodules and erythema marginatum are two
congestive heart failure.37 important skin manifestations of RF. Subcutaneous nodules
occur late in the course of rheumatic fever. They are observed
in up to 20% of patients, and their presence is usually associ-
Pericarditis
ated with carditis. Subcutaneous nodules occur on bony
Clinical rheumatic pericarditis occurs in up to 15% of prominences, vertebral spinous processes, or extensor
patients during the acute stage of RF, and the presence of an tendons, and are painless. They usually appear in crops,
evanescent pericardial friction rub in this setting is evidence are variable in size, and disappear within 2 to 3 months.
436 chapter 18

Erythema marginatum can be an early or a late manifesta- degrees in other systemic illnesses, leading to the potential
tion. It occurs in fewer than 15% of patients and is present for misdiagnosis. For example, streptococcal infection is
on the trunk and proximal extremities as a serpiginous, relatively common, and an elevated ASO titer indicates only
macular, nonpruritic, and evanescent rash. previous infection. Similarly, arthralgia is prevalent in asso-
ciation with several viral syndromes, and carditis may occur
as a consequence of Coxsackie B virus, Lyme disease, or
Clinical Diagnosis Kawasaki’s infection. The early manifestations of other col-
lagen diseases, such as systemic lupus erythematosus, may
There is no single diagnostic test or pathognomonic sign that also lead to confusion in diagnosis when they are associated
allows an absolute diagnosis of RF, and the condition is rec- with inflammatory abnormalities of the heart valves, par-
ognized through a constellation of signs and symptoms in ticularly the mitral valve. Rheumatoid arthritis may produce
the setting of recent GABHS pharyngitis. In 1944, Jones38 aortic regurgitation, and inflammatory reaction within the
described the clinical manifestations of RF and categorized pericardium or conduction system may result in pericarditis
them as major and minor. Since that time, the Jones criteria or heart block. There may be an erythema multiforme type
have been modified several times under the auspices of the of rash and laboratory evidence of an elevated erythrocyte
American Heart Association. More recently, modifications sedimentation rate (ESR), anemia, and marked leukocytosis.
have been suggested by the WHO1 (Table 18.2). Various com- For these reasons, rheumatoid arthritis is easily confused
binations of major and minor criteria are used for diagnosing with RF. In a patient who has streptococcal infection and
ARF. The major manifestations include the presence of carditis, particularly with evidence of migratory polyarthri-
carditis, chorea, subcutaneous nodules, migratory arthritis tis, the diagnosis of RF should be assumed until proved
involving large joints, and the skin rash known as erythema otherwise.
marginatum. The minor manifestations include fever, pro-
longed joint pains, prolonged electrocardiographic PR inter-
val, laboratory indicators of inflammation, and acute phase Laboratory Investigations
reactants. An elevated antistreptolysin O (ASO) titer or other
evidence of preceding streptococcal infection is considered a Evidence of preceding streptococcal infection is a prerequi-
prerequisite. site for the diagnosis of RF. Because RF is a postinfectious
Although the Jones criteria remain the cornerstone of immunologic complication, microbiologic evidence is
diagnosing ARF, they are continually changing to balance limited, and the evidence for recent streptococcal infection
sensitivity/specificity, address different forms of presenta- is usually obtained with the antistreptococcal antibody tests.
tion, accommodate a variable diagnostic armamentarium in The most commonly used antibody assays include ASO and
different regions of the world, and reflect new information. antideoxyribonuclease B (anti-DNase B), and other antibody
The most current WHO iteration has many clinically impor- tests such as hyaluronidase, streptokinase, and nicotinamide
tant distinctions: (1) First attacks of RF and recurrent attacks adenine dinucleotidase are occasionally used.39 The antibody
in patients with no evidence of previous established RHD response to various streptococcal antigens develops within
still need to adhere to the Jones criteria. (2) To diagnose recur- the first month and remains detectable up to 3 to 6 months
rence in patients with established RHD requires only two after the infection. ASO titers are determined by an aggluti-
convincing minor manifestations plus evidence of a recent nation test or a hemolytic inhibition test, and in healthy
streptococcal infection. (3) Evidence for recent streptococcal adults the titers are usually less than 85 Todd units/mL,
infection is not required in rheumatic chorea and insidious whereas school-age children can have ASO titers up to 170 U.
onset of clear rheumatic carditis. It should be remembered Generally, an ASO level of more than 240 U in adults or more
that these guidelines are general expert opinion and have not than 330 U in children is used for diagnosis, but a better
been prospectively tested for operating characteristics. diagnostic specificity is obtained by the demonstration of an
Although Jones criteria provide an excellent set of guide- interval increase in ASO in two serial samples. Because ASO
lines for the diagnosis of RF, it is also important to remember titers rise and fall more rapidly, the anti-DNase B test can be
that similar manifestations may be present in varying performed if ASO is nondiagnostic. A rapid slide agglutina-
tion test that looks at antibodies against several (five) strep-
tococcal antigens, the streptozyme test, has been proposed
TABLE 18.2. Jones criteria for diagnosis of acute fever* to improve the detection of streptococcal infection.
Major criteria Minor criteria
The electrocardiogram may be normal in a patient with
ARF. In patients who have cardiac involvement, ST-segment
Carditis Arthralgia change may signal pericarditis, and repolarization abnor-
Polyarthritis Fever malities, including QT prolongation and T inversion, may
Chorea Elevated erythrocyte sedimentation rate occur in myocarditis. In addition, there may be associated
Subcutaneous nodules Positive C-reactive protein arrhythmias with extrasystoles, supraventricular tachycar-
Erythema marginatum Leukocytosis dia, and atrioventricular blocks. First-degree atrioventricular
Prolonged PR interval block is commonly seen in patients with RF but is equally
* Two major criteria or one major plus two minor criteria are required for the common in patients with or without carditis. The chest
diagnosis of rheumatic fever. Supportive evidence of recent streptococcal radiograph has been traditionally used to evaluate cardio-
infection is also required for all diagnoses. Chorea, indolent carditis, and
poststreptococcal arthritis may not fulfill Jones criteria at the time of megaly and is an inexpensive way to study the evolution of
diagnosis.59 the patient under treatment.
 r h eum at ic fev er 4 37
Echocardiography has become the tool of choice in diag- the universal use of echocardiography in RF episodes are
nosis and monitoring cardiac structure and function. Current likely to be enormous. Therefore, the detection of subclinical
echocardiographic techniques were not available during carditis in this population not only is very costly but also
many of the major RF epidemics, and thus its role has probably will not change the management strategy very
remained unclear. However, with newer data that are avail- much; none of the RF therapies available to date modify the
able, it might be time to selectively include this modality in natural history of carditis, and the initial period of prophy-
the Jones criteria. An echocardiogram will quickly resolve laxis is no different in patients without and with mild car-
whether a clinically undetectable murmur is truly absent ditis.43 In this population, the presence of RHD is a reason
and will protect patients with clinical carditis from being for lifelong prophylaxis, and echocardiography could be per-
grouped with noncarditic patients, who have a more benign formed at the time of discontinuation of prophylaxis. The
prognosis and require shorter secondary prophylaxis regimen. absence of heart disease at this time should allow the with-
Indeed there are emerging data indicating that echocardiog- drawal of prophylaxis, whereas the presence of valvular
raphy can detect valve regurgitation more often than clinical disease should prompt lifelong prophylaxis. It is interesting
exam alone40; this advantage is greater with aortic valve to note that adding echocardiography to the initial workup,
involvement. More importantly, these kinds of data also did not seem to make prophylaxis more rigorous in the devel-
suggest that echo detectable valve regurgitation can persist oped world; only a small proportion of patients were taking
in a significant number of patients despite adequate prophy- prophylaxis on long-term follow-up. Finally, the natural
laxis, suggesting that echo detectable cardiac involvement history of echo detectable carditis is just being evaluated, and
might represent clinically important cardiac damage. A there may be merit in exercising caution45 about making
strategy to incorporate echocardiography into the Jones echocardiography the cornerstone of diagnosing carditis.
criteria is undoubtedly very appealing.41 Until there is a convincing body of data that demonstrates
However, the Jones criteria are meant to have widespread the need to detect subclinical carditis and the possibility of
applicability, and this transition to incorporating echocar- actually modifying its natural history, echo detectable car-
diography should be achieved with multiple caveats. There ditis may divert scarce and valuable prophylaxis resources
is a concern that echocardiography may lead to the over- from more proven entities that need these urgently. There-
diagnosis of rheumatic carditis, and some investigators feel fore, echocardiography should be selectively recommended
that the application of echocardiography should be some- for the investigation of RF in developing countries.43 Of
what dependent on the regional practice environment. Echo- course, the role of echocardiography in the detection and
cardiography should be routinely used to detect carditis in management of established RHD is unquestioned in any
the developed world. It is widely available, first attacks are population.
common, and the detection of carditis may be easy through Computed tomography or magnetic resonance imaging
echo. Subclinical cardiac involvement is quite common. may also be useful in myocarditis but their role in RF remains
Overdiagnosis, while possible, is avoided if strict criteria are unclear.46 Endomyocardial biopsies have been performed in
applied for the exclusion of physiologic valvular regurgita- persons with acute rheumatic carditis. Aschoff nodules,
tion.42 Even if echocardiography inappropriately detected which are pathognomonic features of rheumatic carditis, are
subclinical carditis, serial echocardiographic studies will observed in 40% of subjects, thereby offering a test of limited
resolve the significance of such valve dysfunction. There- sensitivity.25 However, because the biopsy results are mostly
fore, the detection of subclinical carditis and even mis- normal in patients with chronic RHD or noncarditic mani-
labeling a minority of patients with RF as having carditis festations of RF, the specificity of the test is very high. In
for a short period of time until their clinical situation is addition, various radionuclide imaging approaches have been
resolved should not adversely affect the overall management evaluated in rheumatic carditis with variable success47; these
strategy. include imaging with indium 111 (111In)-labeled antimyosin
On the other hand, the clinical situation is quite different antibodies, radiolabeled leukocytes, and gallium 67 (67Ga)
in the developing world,43 where the incidence of recurrent scintigraphy. However, there needs to be more study about
RF and the prevalence of RHD are very high and access to the role of such procedures, and they should be considered
medical care is limited. First attacks are rarely witnessed, research at this time.
and patients present with recurrences and usually with
established heart disease. Physical examination is the most
commonly used method to detect patients with and without Natural History
cardiac involvement. Moreover, there is some evidence,
albeit controversial, that echocardiography in advanced A major problem with understanding the natural history of
disease does not demonstrate any incremental diagnostic RF is that most data are old and have not been reevaluated in
benefit in endemic areas; this is probably due to a cumulative the current diagnostic and therapeutic milieu. It appears that
effect of multiple, clinical and subclinical recurrences. 33 In the natural history of RF has changed significantly with the
another study, most of the echo detectable carditis was also advent of prophylaxis, better recognition of antecedent strep-
clinically detectable within a short period of follow-up.44 tococcal infections, social changes, and evolution in strepto-
Recurrences are common and medical records are sparse; coccal virulence. Rheumatic fever appears to behave
thus one cannot be sure if trivial regurgitation is new carditis differently in the developing versus the developed world.
or residua of previous episodes in patients with streptococcal Patients in the latter regions, probably due to conducive socio-
pharyngitis. Echocardiographic facilities are not widely economic factors, demonstrate multiple recurrences and a
available, and the cost and additional workload imposed with particularly aggressive course.48 However, it is heartening
438 chapter 18

that even in this situation, regular prophylaxis favorably combinations of current immunosuppressive therapies. A
modifies this bleak natural history. short course of steroids is commonly used in patients with
First attacks of RF in children characteristically occur severe carditis. Prednisone at 1 to 2 mg/kg/day is given for a
between the ages of 5 and 15 years. Rheumatic fever rarely period of 3 weeks with a tapering schedule once the acute
occurs in children younger than 2 years, and first attacks symptoms resolve. There are no definitive end points for
after the age of 40 years are also less common. Individuals discontinuing antiinflammatory therapy in RF. General
who have RF are susceptible to recurrences of the disease, indicators include the absence of clinical symptoms and
but this again diminishes with time. Rheumatic fever can signs of rheumatic activity, in addition to normalization of
recur with various manifestations at intervals of weeks, acute-phase reactants, usually ESR. Too rapid reduction can
months, or years, with apparent inactivity between these be accompanied by a symptomatic rebound. The steroid taper
episodes. The presence of congestive heart failure (CHF) is a is occasionally covered with salicylates to prevent a relapse.
seriously adverse prognostic indicator; failure of cardiomeg- If heart failure continues to persist despite steroid therapy,
aly and congestive cardiac failure to improve with treatment surgical repair of mechanical lesions should be considered
are associated with the worst prognosis. Patients with the instead of prolonged trials with high-dose steroids. There is
initial syndrome of Sydenham’s chorea have a lower mortal- little data on newer forms of immunosuppressive therapy.
ity and morbidity rate. It was long believed that surgery should not be under-
In patients who have no major valvular damage, the pre- taken during an acute inflammatory state, because earlier
vention of recurrent attacks leads to a significantly better studies had showed increased surgical mortality rates in
prognosis with regard to overall survival and freedom from patients with acute RF. However, this is changing. Essop and
heart disease. If there is valvular involvement, the scarring associates37 reported no deaths among patients with mitral
process may lead to long-term impairment of valve function or mitral and aortic valve replacement during active carditis,
that progresses over 10 to 30 years, with various combina- and surgery was associated with rapid and remarkable
tions of stenosis and regurgitation. Perhaps the most insidi- improvement, including a reduction in left ventricular
ous of these is mitral stenosis, which may develop very dimensions. A subsequent series with a much longer follow-
late—as long as 20 years after the onset of the acute infec- up period has shown that surgery during acute rheumatic
tion—often with no symptoms until the onset of atrial fibril- carditis may be associated with a somewhat less favorable
lation. The onset of arrhythmias can be the beginning of outcome of mitral valve repair, and surgical option during
rather rapid deterioration or thrombotic complications. the acute episode should be reserved for subjects who are
Patients with valve dysfunction remain at risk for subacute refractory in medical therapy.51 In this study of Skoularigis
bacterial endocarditis and should receive prophylactic and colleagues,51 there was a relatively higher incidence of
antibiotics prior to procedures as indicated by consensus valve failure (27%), and the presence of acute carditis was
guidelines. the strongest predictor of reoperation. Cardiac surgery has
been used with greater success in chronic RHD. It appears
that there may be a significant degree of repairable valves,52,53
Treatment and valve repair can be undertaken, albeit with some risk of
reoperation.
The primary objective in the treatment of the patient with The third important objective in the treatment of RF
acute RF is the elimination of offending streptococci with is to prevent recurrences of rheumatic activity.54 This is
appropriate antibiotic therapy; penicillin remains the agent achieved by long-term antibiotic prophylaxis to prevent
of choice. There is a long list of choices for this purpose but GABHS pharyngitis. A secondary prophylaxis program
it is important to remember that some of the more com- should begin during the acute episode of RF and is essentially
monly used ones may not be as effective as others in prevent- based on the ability to prevent streptococcal pharyngitis.
ing recurrent ARF.49 The second objective of treatment of Rheumatic fever is a recurrent disease, and patients with
acute RF is to eliminate the inflammatory state, particularly carditis in previous attacks have a higher recurrence rate per
that involving vital organs such as the heart. Salicylates, streptococcal infection than those without previous cardi-
predominantly aspirin, have been used for many years as tis.55–57 The likelihood of risk of recurrence per streptococcal
antiinflammatory agents in RF. They are very effective and infection may range up to 40% to 60% in young patients
the diagnosis of RF is suspect if high-dose salicylates do not with established RHD, and every recurrence further damages
significantly resolve joint pain and inflammation within 48 the heart. Rheumatic fever recurrences can be prevented by
hours. Relatively high doses are needed: up to 8 to 10 g/day chemoprophylaxis of streptococcal infections, which results
(100 mg/kg/day) for a period of 3 to 4 weeks. A gradual taper in an eventual reduction in the prevalence of residual heart
is recommended to avoid rebound worsening. Salicylates do disease,36,54–57 reduced need for operations, and a possible
not alter the natural history of the disease. Corticosteroids subsequent reduction in mortality rates due to RHD. The
are used in patients with severe carditis and heart failure. duration of prophylaxis is dependent on the anticipated risk
Steroids rapidly suppress the toxic state, subside inflamma- of a recurrence of RF with each throat infection with Strep-
tion, help prevent the appearance of new murmurs, help tococcus, and is determined by the presence of carditis in the
murmurs disappear faster, allow faster resolution of pericar- index RF episodes and the likelihood of acquiring streptococ-
dial effusions, and may be lifesaving in critical illness.50 cal infection. The recurrence of RF is likely to be higher in
Similar to other therapies in RF, they do not alter the long- patients with carditis or residual heart disease, multiple pre-
term natural history.50 However, most of the studies are old, vious attacks, and younger age, whereas the risk decreases
have serious methodologic problems, and have not studied with the interval after the last attack. Streptococcal
 r h eum at ic fev er 439
TABLE 18.3. Secondary prevention of rheumatic fever
Agent Dose Mode Duration

Benzathine penicillin G* 1.2 million U IM Every 4 weeks†

Penicillin V‡ 250 mg b.i.d. PO Daily
Sulfadiazine§ PO Daily
<27 kg (60 lb) 500 mg
≥27 kg (60 lb) 1000 mg
With penicillin and sulfa allergy
Erythromycin 250 mg b.i.d. PO Daily
* Use drug at room temperature and with procaine penicillin to reduce pain.
† Consider three times weekly in high-risk situations, including in Third World countries.
‡ May interfere with oral contraception.
§ Avoid use in pregnancy. More effective than oral penicillin.

infections are more common in schoolchildren, their parents, and synovium), diverse M-type streptococci in a population,
teachers or health personnel in contact with children, and and the cyclical nature of prevalent organisms.61 The N-ter-
persons living in closed quarters or in crowded housing. The minal sequence (which is devoid of possible homology with
recommendations for the choice of antibiotics and duration human myocardial tissue) from all putative strains that
of prophylaxis are listed in Tables 18.3 and 18.4.1,54 The need could cause RF in a community can be used in a multivalent
for prophylaxis should be reassessed periodically. In all situ- streptococcal vaccine. One of the current vaccines includes
ations, the decision to discontinue prophylaxis should be an octavalent antigenic peptide,62 and the other contains
made after discussing the potential risks and benefits with recombinant M-protein fragments linked to Escherichia
the patients. While it is obvious that this program has the coli–labile toxin.63 The advantage of antibodies against the
potential to significantly reduce morbidity with ARF, the C-terminal region is that it is useful against multiple strep-
success rates of optimally adhering to these guidelines has tococcal strains. Non–M-protein moieties have also been a
remained dismal.58 This illustrates the immense number of focus of vaccine development. Intranasal immunization of
challenges in controlling rheumatic fever. mice with a defective form of the streptococcal C5a pepti-
dase (which demonstrates excellent structural similarity in
Streptococcal Vaccine most streptococci) reduced the colonizing potential of several
different streptococcal M serotypes.64 C5 peptidase antibod-
The most effective way to reduce the global burden of RHD ies presumably help clearance of streptococci with the added
would be the development of an antistreptococcal vaccine.59 advantage of a less likelihood of cross-reactive antibody for-
The main target has been the streptococcal M protein, the mation. A similar benefit might accrue from including a
principal virulence factor in group A streptococci since anti- streptococcal extracellular protease in a vaccine form. Mice
bodies to M protein are long lasting and protective.60 These passively or actively immunized with the streptococcal pyro-
approaches have been centered on either the type-specific genic exotoxin B (SpeB) lived longer than nonimmunized
N-terminal region (which protects against specific serotype) animals after infection with group A streptococci.65 There is
or the highly conserved carboxy-terminal region (which pro- a major push toward finding an effective vaccine; some vac-
tects against multiple serotypes and also reduces coloniza- cines are undergoing clinical testing, and an effective strep-
tion). In general vaccine strategies need to address the risk of tococcal vaccine is likely to be available soon. A successful
cross-reactive epitopes (cross-reactivity against human heart vaccine could change the face of RF worldwide.

TABLE 18.4. Duration of secondary rheumatic fever prophylaxis*

Risk of streptococcal infections†

Not high

Category High <40 yrs of age ≥40 yrs of age‡

RHD Lifelong Until 40 yr‡ None‡

History of carditis Until 40 yr of age‡ Until 21 yr of age‡ or 10 yr since last attack¶ None||
and no RHD§
RF and no carditis Until 21 yr of age‡ or 10 yr from last attack¶ Until 21 yr of age|| or 5 yr since last attack¶ None||
RF, rheumatic fever; RHD, residual rheumatic heart disease of any severity.
Patients from developing countries, with large RF burden, should be considered at high risk for recurrent infections.
* Each case is judged individually after considering the clinical situation and patient wishes.
† Modify prophylaxis in epidemic situations, especially if virulent streptococci reemerge.
‡ Should be at least 10 years since last attack and should not have history of multiple attacks.
§ Use echocardiography if possible to prove or disprove RHD.
|| Should be at least 10 years since last attack and should not have history of multiple attacks.
¶ Whichever is longer in duration.
440 chapter 18

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 1 Infective Endocarditis
9 Walter R. Wilson and Eddy Barasch (Second Edition),
revised for The Third Edition by

Layne O. Gentry and Temple W. Williams, Jr.

Incidence, Anatomic Considerations, Evidence-Based Scoring System . . . . . . . . . . . . . . . . . . . . 447

and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Medical Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Clinical Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Treatment of Complications . . . . . . . . . . . . . . . . . . . . . . . 452
Microbiologic Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Prosthetic Valve Endocarditis . . . . . . . . . . . . . . . . . . . . . . 457

Key Points by the same spectrum of microorganisms responsible for

native valve non–addiction-associated endocarditis.
• Patients with acute fulminant bacterial infective endo-
carditis (IE) caused by Staphylococcus aureus, Strepto- The term infective endocarditis (IE) describes infection of
coccus pneumoniae, or Neisseria gonorrhoeae, often the endocardium caused by a microorganism. Endocarditis
present with fever, metastatic abscesses, rapid valvular most often involves the heart valves but may involve septal
destruction, and the sudden onset of congestive heart defects, mural endocardium, arteriovenous shunts, or a
failure. patent ductus arteriosus. The terms acute and subacute were
• Patients with subacute or chronic IE often have viridans used previously to classify patients with IE. These terms
streptococci, enterococci, or gram-negative bacilli of the were based on the progression of untreated patients and are
HACEK group (Haemophilus species, Actinobacillus primarily of historic interest. Most authorities now use the
actinomycetemcomitans, Cardiobacterium hominis, term infective endocarditis rather than subacute or acute
Eikenella species, and Kingella kingae) as etiologies. bacterial endocarditis to describe endocardial infection.
• Vegetations of >2 mm in size are readily detected by In the preantibiotic era, the fact that patients recovered
transesophageal echocardiography (TEE), which may from serious bacterial infections is testimony to the major
detect vegetations of smaller size, prosthetic valve vege- role played by host defense mechanisms in controlling or
tations, and perivalvular extension of infection. eradicating bacterial infection. This is not the case with IE;
• A history of a preceding dental procedure, genitourinary host defense mechanisms play little role in the control of IE,
manipulation, or urinary tract infection is present in and the mortality rate among untreated patients is virtually
20% to 30% of patients with viridans streptococcal or 100%. In no other infectious diseases is cure so dependent
enterococcal endocarditis. on the administration of appropriate bactericidal antimicro-
• The frequency of negative blood cultures in patients bial agents. The successful management of patients with IE
with suspected IE ranges from 5% to 25%. The adminis- is based on (1) recognition of the syndrome consistent with
tration of antimicrobial agents before blood cultures are IE, (2) recovery of microorganisms from blood or cardiac
obtained increases the likelihood of negative blood cul- valve vegetation cultures, (3) administration of appropriate
tures and is the most common cause of culture-negative antimicrobial agents, (4) management of complications, and
endocarditis. (5) adequate prophylactic measures.
• Although virtually any microorganism is capable of
causing IE, at least 75% of non–addiction-associated
cases are caused by streptococci or staphylococci. Incidence, Anatomic Considerations,
Addiction-associated IE is most often caused by S. and Pathophysiology
aureus, S. epidermidis, gram-negative bacilli, or Candida
species. A population-based study in Olmsted County, Minnesota,
• Prosthetic valve endocarditis can be divided into early showed the estimated age- and sex-adjusted incidence of IE
onset (within 2 to 6 months postoperatively) and late to be 4.9 per 100,000 person years.1 Males (rate ratio 2.51) and
onset (>6 months postoperatively). Coagulase-negative advanced age (rate ratio 8.81 for age ≥65 years compared with
staphylococci or gram-negative bacilli most often cause <65 years) were associated with higher rates of endocarditis.
early-onset PVE, whereas late-onset PVE cases are caused In another study, endocarditis accounted for approximately

4 43
444 chapter 19

1 case per 1000 hospital admissions.2 The cardiac valve originating from the focus of infection, such as the skin,
involved with endocarditis varies among reported series. The musculoskeletal system, or genitourinary tract. Although
rate of infection of the mitral valve alone ranged from 24% the pathophysiology of IE in these patients is poorly under-
to 45%; for the aortic valve alone, the rate was 5% to 36%; stood, it may be related to the high magnitude of bacteremia,
and for the aortic and mitral valves combined, the rate was virulence of the microorganisms, and possibly binding to
0% to 35%.3–6 specific receptors on the surface of endothelial cells.
The aortic valve is more commonly involved among male
patients, and mitral valve infections dominate in female
patients. Tricuspid valve involvement ranged from 0% to 6%, Clinical Recognition
and pulmonary valve involvement was less than 1%. Tricus-
pid valve endocarditis has increased in incidence since about
Physical Examination
1980 because of the large number of addicts who abuse intra-
venous drugs. In the United States, mitral valve prolapse The clinical manifestations of IE may involve any organ
(MVP) with regurgitation is the most common underlying system and are largely dependent on the infecting microor-
cardiac defect predisposing to IE; previously, rheumatic val- ganism. Patients with acute fulminant IE caused by S. aureus,
vular heart disease was the most common predisposing con- S. pneumoniae, or N. gonorrhoeae usually present with fever,
dition. Underlying congenital heart disease has been reported metastatic abscesses, rapid valvular destruction, and the
in 6% to 24% of patients with IE. However, as many as 40% sudden onset of severe congestive heart failure (CHF) and
of patients develop IE with no demonstrable underlying val- have a high mortality rate. More commonly, patients present
vular heart disease.5 Presumably, these patients are at risk with a subacute or chronic form of IE that is usually caused
because of calcified mitral or aortic valves or other degenera- by viridans streptococci, enterococci, or fastidious gram-
tive cardiac diseases or because of infection with virulent negative bacilli of the HACEK group (Haemophilus species,
microorganisms that infect previously normal cardiac Actinobacillus actinomycetemcomitans, Cardiobacterium
valves.7 hominis, Eikenella species, and Kingella kingae). The history
Pathophysiologic events that result in IE involving a of a preceding dental procedure, genitourinary tract manipu-
normal cardiac valve differ from those affecting a previously lation, or urinary tract infection is present in 20% to 30%
abnormal valve. Endocarditis affecting a previously abnor- of patients with viridans streptococcal or enterococcal endo-
mal cardiac valve results from a series of factors or events. carditis.5 Initial symptoms are nonspecific and include
Valvular insufficiency, congenital cardiac lesions such as anorexia, weight loss, fatigue, fever, headaches, myalgias,
septal defects, or other valvular abnormalities produce tur- and arthralgias. This condition may be confused with a
bulent blood flow and a jet effect that traumatizes the endo- number of other chronic febrile illnesses, such as lymphoma,
thelial surface and results in deposition of a fibrin-platelet other malignancies, other chronic infectious diseases, and
matrix called nonbacterial thrombotic endocarditis. 8 Tran- collagen vascular disorders. The duration of symptoms in the
sient bacteremias occur frequently, often in association with subacute or chronic form ranges from 1 to 2 weeks to more
procedures such as dental extraction, tooth brushing, or than 1 year.
chewing or as a result of manipulations of the urogenital Although fever is present in virtually all patients with
system, gastrointestinal tract, or oral respiratory tract. Colo- IE, it may be absent in patients who have received antimi-
nization of nonbacterial thrombotic lesions during transient crobial therapy. A cardiac murmur is present in at least 85%
bacteremia results in IE. Once colonization occurs, vegeta- of patients but may be absent in patients with right-sided
tions enlarge through further deposition of fibrin, platelets, endocarditis. A change in a preexisting murmur or the devel-
and bacteria. The dense fibrin-platelet matrix provides a opment of a new regurgitant murmur is an important finding.
sanctuary for bacteria against host defenses and impairs pen- Peripheral embolic or hypersensitivity phenomena occur in
etration of antibiotics into the vegetation. Certain micro- at least 60% of patients with the subacute or chronic form
organisms, such as viridans streptococci, enterococci, of IE.5 Osler nodes occur in 10% to 25% of patients and are
staphylococci, and Pseudomonas aeruginosa, are more adher- characterized by small, tender, slightly nodular lesions
ent to cardiac valve endothelium than other microorganisms usually located on the palms of the hands and soles of the
not commonly associated with IE.9 The adherence of strep- feet. Osler nodes are thought to occur as a result of the depo-
tococci may be, in part, related to the extracellular produc- sition of circulating immune complexes or, possibly, micro-
tion of a polysaccharide called dextran.10 Platelets may also emboli of vegetations that contain bacteria. Roth spots occur
play a role in the pathophysiology of IE. Staphylococci and in about 10% of patients with IE and are characteristically
streptococci stimulate platelet aggregation, and these aggre- present in the retina. Approximately 10% of patients develop
gates may have an increased affinity for nonbacterial throm- macular, nontender, erythematous lesions on the palms and
botic lesions.11 soles, known as Janeway lesions. Splenomegaly occurs in
Nonbacterial thrombotic endocarditis probably does not 25% to 60% of patients with IE, and myalgias and arthralgias
play a major role, if any, in the pathophysiology of IE involv- occur in at least 40%. Large systemic emboli have been
ing normal cardiac valves. The organisms responsible for IE observed in 10% to 30% of patients and are more often asso-
involving previously normal cardiac valves, such as Staphy- ciated with infection caused by nutritionally variant viri-
lococcus aureus, Streptococcus pneumoniae, Neisseria gon- dans streptococci, members of the HACEK group, group B
orrhoeae, and Streptococcus pyogenes, differ from those that streptococci, and fungal endocarditis. Headaches have been
usually infect an abnormal cardiac valve. Infective endocar- reported in up to 60% to 80% of patients with IE.12,13 Approx-
ditis in the former patients is usually caused by bacteremia imately 20% to 40% of patients develop neurologic manifes-
 in fectiv e en doca r ditis 445
tations, including ataxia, aphasia, alterations in mental TABLE 19.1. Proposed new criteria for the diagnosis of infective
status, or other changes resulting from cerebral emboli or endocarditis
hypersensitivity phenomena.13 Intracranial mycotic aneu- Definite infective endocarditis
rysms are documented in approximately 1% of patients with Pathologic criteria
IE; they may be asymptomatic or present with catastrophic Microorganisms: demonstrated by culture or histology in a
vegetation, or in a vegetation that has embolized, or in an
complications resulting from rupture and hemorrhage.12 intracardiac abscess, or
Pathologic lesions: vegetation or intracardiac abscess present,
confirmed by histology showing active endocarditis
Laboratory Examination Clinical criteria, using specific definitions listed in Table 19.2
Two major criteria, or
Because patients with IE may present with a chronic, non-
One major and three minor criteria, or
specific febrile illness that may mimic a wide variety of other Five minor criteria
diseases, clinicians must be alert to the possibility of IE. This Possible infective endocarditis
is especially true for patients who have received partial treat- Findings consistent with infective endocarditis that fall short of
ment with antibiotics that has rendered blood cultures nega- “definite” but not “rejected”
tive and temporarily eliminated the fever. It therefore may Rejected
be necessary in these patients to observe them after the Firm alternate diagnosis for manifestations of endocarditis, or
withdrawal of antibiotic therapy and to periodically obtain Resolution of manifestations of endocarditis, with antibiotic
therapy for 4 days or less, or
blood cultures. No pathologic evidence of infective endocarditis at surgery or
The diagnosis of IE depends on recognition of the clinical autopsy, after antibiotic therapy for 4 days or less
syndrome and the recovery of bacteria or fungi from two or
more cultures of blood obtained at intervals during a 48-hour
period. In most cases, bacteremia associated with IE is con-
tinuous, and if any blood culture is positive, most of the other
specimens cultured will also be positive. Therefore, it is
community acquired or without an apparent primary focus.
usually unnecessary to obtain more than three sets of blood
These bacteremias have the highest risk of being associated
cultures within a 24-hour period on 2 consecutive days. Col-
with IE. A second major criterion includes evidence of endo-
lection of blood for culture during temperature elevations
cardial involvement demonstrable by echocardiography or by
does not increase the likelihood of a positive blood culture.
the development of a new valvular regurgitation. Echocardio-
However, cases of IE caused by nutritionally variant viridans
graphic findings associated with IE are clearly defined by the
streptococci or members of the HACEK group may have
Duke criteria (Table 19.2).
intermittently positive blood cultures. The recovery of these
Six common but less specific findings of IE are catego-
microorganisms from more than one blood culture has such
rized as minor criteria according to the Duke strategy (Table
a high association with IE that this diagnosis must be con-
19.2). The validity of the Duke criteria in establishing the
sidered even in the absence of physical findings suggestive
diagnosis of IE has been confirmed in at least 11 published
of IE.
studies that include approximately 1700 patients.15 Based on
Durack and colleagues14 from Duke University (Duke
these studies, patients suspected of having IE should be eval-
criteria) proposed a new diagnostic strategy to define cases
uated clinically using the Duke criteria as the primary diag-
of IE. The Duke criteria combine important traditional diag-
nostic schema.
nostic parameters, such as persistent bacteremia, newly
Most other laboratory findings for patients with IE are
developed valvular insufficiency, and peripheral manifesta-
nonspecific. Anemia is often present and is that of chronic
tions, with echocardiographic findings. According to the
disease, with normochromic, normocytic indices. In the sub-
Duke criteria, patients suspected of having IE may be classi-
acute form, the leukocyte count is usually normal. Rheuma-
fied into one of three categories: definite, possible, or rejected.
toid factor is present in 40% to 50% of cases.5 Circulating
Definite cases of IE are defined by clinical criteria (Table 19.1)
immune complexes may be detected in the majority of
or by pathologic diagnosis at surgery or autopsy. Possible
patients with IE, but they are also present in patients with
cases of IE are those not meeting the criteria for definite IE,
bacteremia without endocarditis.5 The erythrocyte sedimen-
and rejected cases are those with no pathologic evidence of
tation rate (ESR) is usually elevated. Urinary sediment abnor-
IE or a rapid resolution of signs and symptoms with either
malities are common, reflecting renal involvement caused
no treatment or short-termed antimicrobial therapy or the
by deposition of circulating immune complexes. Microscopic
determination of an alternative diagnosis.
hematuria and erythrocyte casts are frequently present. Elec-
According to the Duke criteria, cases of definite IE may
trocardiographic abnormalities are nonspecific in patients
be diagnosed by the presence of two major criteria or one
with IE; heart block may occur in association with infections
major and three minor criteria or five minor criteria (Table
involving the cardiac conduction system, and atrial or ven-
19.2). Among the major criteria, the presence of certain
tricular ectopy is often noted in patients with intramyocar-
microorganisms in blood culture, such as viridans strepto-
dial abscesses.
cocci or members of the HACEK group, is rarely seen in
patients without IE. In contrast, bacteremia in patients
Role of Echocardiography in Diagnosis
caused by S. aureus or enterococci may be associated with
IE or non-IE infections. According to the Duke criteria, bac- Echocardiography is useful to detect valvular vegetations,
teremia with staphylococci or enterococci is considered myocardial abscess, valvular dysfunction, or prosthetic valve
likely to be associated with IE only when such bacteria are dehiscence in patients with IE. However, either transthoracic
446 chapter 19

TABLE 19.2. Specific definitions of major and minor criteria

Major criteria
Positive blood culture for infective endocarditis
Typical microorganism for infective endocarditis from two separate blood cultures
Viridans streptococci,* Streptococcus bovis, HACEK group, or
Community-acquired Staphylococcus aureus or enterococci, in the absence of primary focus, or
Persistently positive blood culture, defined as a recovery of a microorganism consistent with infective endocarditis from:
1. Blood cultures drawn more than 12 hours apart, or
2. All of three or a majority of four or more separate blood cultures, with first and last drawn at least 1 hour apart
Evidence of endocardial involvement
Positive echocardiogram for infective endocarditis
1. Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets, or on implanted material, in the
absence of an alternative anatomic explanation, or
2. Abscess, or
3. New partial dehiscence of prosthetic valve, or
4. New valvular regurgitation (increase or change in preexisting murmur not sufficient)
Minor criteria
Predisposition: predisposing heart condition or intravenous drug use
Fever: ≥38.0°C (100.4°F)
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival
hemorrhages, Janeway lesions
Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
Microbiologic evidence: positive blood culture but not meeting major criterion as noted previously† or serologic evidence of active
infection with organism consistent with infective endocarditis
Echocardiogram: consistent with infective endocarditis but not meeting major criterion as noted previously
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae.
* Including nutritional variant stains.
† Excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

(TTE) or transesophageal (TEE) echocardiography should be who have a relatively low risk for IE such as those with bac-
performed in all patients suspected of having IE as shown in teremia due to enterococci or other organisms with an
Figure 19.1.15 TTE has a high specificity for valvular vegeta- obvious portal of entry. However, in patients with obesity,
tions (98%), but the sensitivity is less than 60%. Vegetations chest wall deformities, chronic obstructive lung disease, or
of more than 2 mm are readily detected with TEE. Transtho- a prosthetic cardiac valve, TTE may be inadequate to accu-
racic echocardiography is adequate to exclude IE in patients rately detect valvular vegetations or other abnormalities
associated with IE. In these patients, TEE has a higher sen-
sitivity for the detection of vegetations and cardiac complica-
tions of IE. Compared with TTE, TEE has a higher sensitivity
Infective endocarditis suspected
High initial patient risk,+
(80% to 100%) and specificity (94%) for the detection of
Low initial patient risk†
and low clinical suspicion moderate to high clinical perivalvular extension of infection. The use of TEE is prefer-
suspicion or difficult imaging
candidate able to the use of TTE in patients with a high risk for the
Initial TTE Initial TEE complications of IE (Table 19.3).15
– + – +
The role of TEE in patients with bacteremia caused by S.
Increased
aureus is somewhat controversial. Patients with S. aureus
Low Rx High Look for
suspicion suspicion suspicion other source
Rx bacteremia are at risk of IE. Transthoracic echocardiography
persists during High-risk echo No high-risk persists of symptoms
clinical
course
features* echo features* may not be adequate to detect small valvular vegetations or
– + other cardiac complications of S. aureus bacteremia, whereas
Repeat
TEE
TEE TEE for No TEE unless Alternative
detection of clinical status + – diagnosis
complications deteriorates established
– + Look for
Rx other
source
Look for Rx TABLE 19.3. Clinical situations constituting high risk for
other Follow-up TEE or TTE to
source reassess vegetations, complications for infective endocarditis
complications or Rx response
as clinically indicated Prosthetic cardiac valves
FIGURE 19.1. An approach to the diagnostic use of echocardiogra- Left-sided infective endocarditis
phy. *High-risk echocardiographic features include large or mobile
Staphylococcus aureus infective endocarditis
vegetations, valvular insufficiency, the suggestion of perivalvular
extension, or secondary ventricular dysfunction (see the text). †For Fungal infective endocarditis
example, a patient with fever and a previously known heart murmur Previous infective endocarditis
and no other stigmata of infective endocarditis. +High initial patient
Prolonged clinical symptoms (≥3 months)
risks include prosthetic heart valves, many congenital heart dis-
eases, previous endocarditis, new murmur, heart failure, or other Cyanotic congenital heart disease
stigmata of endocarditis. Rx, antibiotic treatment for endocarditis; Patients with systemic to pulmonary shunts
TEE, transesophageal echocardiography; TTE, transthoracic
Poor clinical response to antimicrobial therapy
echocardiography.
 in fectiv e en doca r ditis 4 47
TEE has a higher sensitivity and specificity in these patients.16 TABLE 19.4. Microbiologic cause of native valve, non-addict-
Not all patients with S. aureus bacteremia should undergo associated infective endocarditis
TTE or TEE. However, those with signs of persistent infec- Microorganism Patients (%)
tion or persistent bacteremia or who develop other signs of Viridans streptococci 48
IE should undergo TEE.
Enterococci 15
Negative results on TTE or TEE do not definitively
Staphylococcus aureus 18
exclude the diagnosis of IE. Among patients in whom the
Coagulase-negative staphylococci 6
clinical diagnosis of IE persists after an initial negative echo-
cardiographic study, repeat TTE or TEE may be justified. The HACEK 9
timing of the repeat study depends on the clinical status of Other microorganism 1
the patient and should be individualized for each patient. Negative blood cultures 3
Total 100

Patients with Suspected Endocarditis and HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella species, and Kingella kingae.
Negative Blood Cultures
The frequency of negative blood cultures in patients with
suspected IE ranges from 5% to 25%. The administration of
antimicrobial agents before blood cultures are obtained Microbiologic Etiology
increases the likelihood of negative blood cultures and is the
most common cause of culture-negative endocarditis. The Although virtually any microorganism is capable of causing
duration and type of prior antimicrobial therapy and the IE, at least 75% of non–addiction-associated cases are caused
susceptibility of the microorganism determine the duration by streptococci or staphylococci (Table 19.4).17,18 Addict-asso-
and time that blood cultures will be negative. In these ciated IE is most often caused by S. aureus, S. epidermidis,
patients, after the discontinuation of antimicrobial agents, gram-negative bacilli, or Candida species. Prosthetic valve
blood cultures may remain negative for a few days or for endocarditis (PVE) can be divided into early onset (within 2
weeks. Among patients with suspected IE who are stable to 6 months postoperatively) and late onset (>6 months post-
hemodynamically and who do not appear toxic, it is prefera- operatively). Early-onset PVE is most often caused by coagu-
ble to delay the onset of empiric antimicrobial therapy until lase-negative staphylococci S. aureus or gram-negative bacilli,
a specific microbiologic diagnosis is made. Many of these whereas late-onset PVE cases are caused by the same spec-
patients have been ill for weeks to months, and in these trum of microorganisms responsible for native valve non–
stable patients it is preferable to delay the onset of empiric addiction-associated endocarditis.
therapy for a few days in an attempt to establish a specific
microbiologic diagnosis.
Patients with suspected IE who have not received prior Evidence-Based Scoring System
antimicrobial therapy and in whom blood cultures remain
negative after 48 to 72 hours of incubation should be The American College of Cardiology/American Heart Asso-
suspected of having infection caused by fastidious micro- ciation evidence-based scoring system was first introduced
organisms that are not readily recovered from standard into the American Heart Association’s Guidelines for Endo-
blood-culturing systems. For example, HACEK microorgan- carditis in June 2005 (http://circ.ahajournals.org/manual_
isms and nutritionally variant viridans streptococci (Abio- IIsteps6.shtml). The system is based on a classification of
trophia species) account for 5% to 10% of cases of endocarditis. recommendations and the level of evidence. Such a system
These microorganisms may require prolonged incubation assists clinicians in the interpretation of these recommenda-
and specialized subculture techniques for identification. tions and aids in treatment decisions. Use of this system is
Other causes of endocarditis, such as Brucella species or meant to support clinicians’ decision making in the treat-
Legionella species, require special blood-culturing tech- ment and management of endocarditis.
niques, and communication with the microbiology labora-
tory is essential in these cases. Aspergillus is an uncommon
Classification of Recommendations
cause of endocarditis or prosthetic valve endocarditis and is
rarely, if ever, recovered from blood cultures. The identifica- Class I: Conditions for which there is evidence, general
tion of Aspergillus may result from an examination of patho- agreement, or both, that a given procedure or treatment
logic specimens, such as a large peripheral embolus. is useful and effective.
Other microbiologic causes of endocarditis, such as Coxi- Class II: Conditions for which there is conflicting evidence,
ella burnetii or Bartonella species, may be diagnosed by a divergence of opinion, or both, about the usefulness/
serologic techniques or from tissue culture-based techniques. efficacy of a procedure or treatment.
Polymerase chain reaction performed on blood may be useful Class IIa: Weight of evidence/opinion is in favor of
for the diagnosis of IE caused by Tropheryma whippelii, usefulness/efficiency.
Bartonella species, or other unusual causes of IE. In all cases Class IIb: Usefulness/efficacy is less well established by
of suspected IE with negative blood cultures, the microbiol- evidence/opinion.
ogy laboratory should be consulted for advice regarding spe- Class III: Conditions for which there is evidence, general
cialized techniques to recover fastidious or uncommon agreement, or both, that the procedure/treatment is not
microbiologic causes of IE. useful/effective and in some cases, may be harmful.
448 chapter 19

Level of Evidence to use the same dosages of gentamicin required for the treat-
ment of patients with gram-negative bacillary infections.
Level of evidence A: Data derived from multiple randomized The concentrations of gentamicin necessary to act synergis-
clinical trials. tically with penicillin against streptococci or staphylococci
Level of evidence B: Data derived from a single randomized are relatively low (3 μg/mL). Therefore, patients with penicil-
trial or nonrandomized studies. lin-susceptible streptococcal endocarditis who have normal
Level of evidence C: Consensus of opinion of experts. renal function should receive low-dose gentamicin therapy
(1 mg/kg body weight every 8 hours or 3 mg/kg body weight
Medical Treatment in a single daily dose). Subsequent dosages of gentamicin can
be readjusted to achieve a 1-hour concentration in serum of
It is important to establish the microbiologic diagnosis, if 3 μg/mL and a trough concentration of 1 μg/mL of gentami-
possible, before the initiation of antimicrobial therapy. Most cin. The use of low-dose gentamicin therapy in these patients
patients with IE have been ill for weeks and in some cases significantly reduces the risk of gentamicin-associated neph-
for as long as 1 year. There is usually no urgent need to rotoxicity or cranial nerve VIII toxicity.18 Patients with an
initiate antimicrobial therapy in these patients. Failure to extracardiac focus of infection, a myocardial abscess, a
identify the microbiologic cause may lead to prolonged hos- mycotic aneurysm, or preexisting nephrotoxicity or cranial
pitalization and increased costs, multiple iatrogenic compli- nerve VIII abnormality should not be treated with the 2-week
cations related to inappropriate therapy, progressive cardiac regimen; they should receive therapy with penicillin G or a
valvular damage with the development of CHF, and possible cephalosporin administered alone for 4 weeks.17
relapse of infection. Conversely, patients with the acute Ceftriaxone administered in a single daily dose of 2 g for
septic form of IE or those in whom the microbiologic diag- 4 weeks is effective therapy for patients with penicillin-sus-
nosis has been established should receive antimicrobial ceptible streptococcal endocarditis.19 The advantage of cef-
therapy promptly. Antimicrobial therapy should not be triaxone therapy is that patients who are hemodynamically
delayed pending the results of in vitro susceptibility tests or stable can be discharged from the hospital to complete anti-
additional diagnostic studies. Antimicrobial regimens that microbial therapy on an outpatient basis. Another advantage
have been established as effective therapy for IE are given in is that ceftriaxone can be administered intramuscularly,
the following sections and tables.17 which further facilitates outpatient therapy. Patients unable
to tolerate penicillin or ceftriaxone should be treated with
vancomycin for 4 weeks.17
Penicillin-Susceptible Streptococci
The antimicrobial therapy for patients with IE caused by
The majority of patients with penicillin-susceptible viridans viridans streptococci with a minimum inhibitory concentra-
streptococcal or Streptococcus bovis IE can be treated suc- tion of more than 0.1 pg/μL of penicillin but less than 0.5 pg/
cessfully for 2 weeks with aqueous penicillin G or ceftriax- mL of penicillin is shown in Table 19.6.17 When IE is caused
one together with gentamicin (Table 19.5).17 It is not necessary by viridans streptococci with a minimum inhibitory concen-

TABLE 19.5. Suggested regimens for therapy of native valve endocarditis due to penicillin-susceptible viridans: streptococci and
Streptococcus bovis (minimum inhibitory concentration £0.1 m g/mL)*
Antibiotic Dosage and route Duration (weeks) Comments

Aqueous crystalline penicillin G 12–18 million U/24 h IV either 4 Preferred in most patients older than 65 yr and
sodium continuously or in six equally in those with impairment of the eighth nerve
or divided doses or renal function
Ceftriaxone sodium 2 g once daily IV or IM† 4
Aqueous crystalline penicillin G 12–18 million U/24 h IV either 2 When obtained 1 h after a 20–30 min IV infusion
sodium continuously or in six equally or IM injection, serum concentration of
divided doses gentamicin of approximately 3 μg/ml is
With gentamicin sulfate‡ 1 mg/kg IM or IV every 8 h 2 desirable; trough concentration should be
<1 μg/ml
Vancomycin hydrochloride§ 30 mg/kg per 24 h IV in two 4 Vancomycin therapy is recommended for patients
equally divided doses, not to allergic to β-lactams (see text); peak serum
exceed 2 g/24 h unless serum concentrations of vancomycin should be
levels are monitored obtained 1 h after completion of the infusion
and should be in the range of 30–45 μg/mL for
twice-daily dosing
* Dosages recommended are for patients with normal renal function.
† Patients should be informed that IM injection of ceftriaxone is painful.
‡ Dosing of gentamicin on a mg/kg basis will produce higher serum concentrations in obese patients than in lean patients. Therefore, in obese patients, dosing
should be based on ideal body weight. Ideal body weight for men is 50 kg + 2.3 kg per inch over 5 feet, and ideal body weight for women is 45.5 kg + 2.3 kg per
inch over 5 feet. Relative contraindications to the use of gentamicin are age >65 years, renal impairment, or impairment of the eighth nerve. Other potentially
nephrotoxic agents (e.g., nonsteroidal antiinflammatory drugs) should be used cautiously in patients receiving gentamicin.
§ Vancomycin dosage should be reduced in patients with impaired renal function. Vancomycin given on a mg/kg basis will produce higher serum concentra-
tions in obese patients than in lean patients. Therefore, in obese patients, dosing should be based on ideal body weight. Each dose of vancomycin should be
infused over at least 1 h to reduce the risk of the histamine-release “red man” syndrome.
 in fectiv e en doca r ditis 449
TABLE 19.6. Therapy for native valve endocarditis due to strains of viridans streptococci and Streptococcus bovis relatively resistant to
penicillin G (minimum inhibitory concentration >0.1 mg/mL and <0.5 mg/mL)*
Antibiotic Dosage and route Durationt (weeks) Comments

Aqueous crystalline 18 million U/24 h IV either continuously 4 Cefazolin or other first-generation

penicillin G or in six equally divided doses cephalosporins may be substituted
sodium for penicillin in patients whose
With gentamicin 1 mg/kg IM or IV every 8 h 2 penicillin hypersensitivity is not of
sulfate† the immediate type
Vancomycin 30 mg/kg per 24 h IV in two equally 4 Vancomycin therapy is recommended
hydrochloride‡ divided doses, not to exceed 2 g/24 h for patients allergic to β-lactams
unless serum levels are monitored
* Dosages recommended are for patients with normal renal function.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.

tration of at least 0.5 pg/μL of penicillin or PVE caused by Enterococci

viridans streptococci or S. bovis, appropriate antimicrobial
therapy is as shown in Table 19.7.17 Approximately 5% to 7% Enterococci (Streptococcus faecalis, Streptococcus faecium,
of cases of viridans streptococcal IE are caused by nutrition- Streptococcus durans) are inhibited but not killed in vitro
ally variant viridans streptococci (Abiotrophia species). by penicillin or vancomycin alone. Successful therapy of
These organisms require pyridoxal-supplemented media for enterococcal endocarditis requires the administration of
growth. Infective endocarditis caused by these microorgan- penicillin, ampicillin, or vancomycin together with an ami-
isms has a higher relapse rate after 2 weeks of therapy with noglycoside, usually gentamicin. The most important factor
penicillin and gentamicin or 4 weeks of single-drug therapy. in the outcome of patients with enterococcal endocarditis is
Therefore, patients with IE caused by nutritionally variant the duration of symptoms before the initiation of effective
viridans streptococci should be treated for 4 weeks with antimicrobial therapy. Patients with symptoms of infection
a combination of penicillin and low-dose gentamicin for more than 3 months have significantly higher relapse and
(Table 19.7).17 mortality rates than do those with a shorter duration of
Patients with pneumococcal IE often present with an illness.18 Patients with symptoms for less than 3 months can
acute fulminant course. These patients should receive be treated successfully for 4 weeks with penicillin or ampi-
therapy with penicillin G, a cephalosporin, or vancomycin cillin, together with gentamicin (Table 19.7).17 Patients ill for
administered for 4 weeks. Few data are available concerning more than 3 months and those with PVE should receive 6
the optimal therapy for IE caused by group B streptococci. weeks of therapy. Concentrations of gentamicin in serum
Most authorities recommend 4-week therapy with penicil- should be monitored closely to ensure that the 1-hour con-
lin, a cephalosporin, or vancomycin, combined with low- centration is 3 μg/mL and the trough concentration is 1 μg/
dose gentamicin for the first 2 weeks of treatment. mL. The administration of higher dosages of gentamicin does

TABLE 19.7. Standard therapy for endocarditis due to enterococci*

Antibiotic Dosage and route Duration (weeks) Comments

Aqueous crystalline 18–30 million U/24 h IV either 4–6 4-wk therapy recommended for patients with
penicillin G sodium continuously or in six equally symptoms <3 mo in duration; 6-wk therapy
divided doses recommended for patients with symptoms
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6 >3 mo in duration
Ampicillin sodium 12 g/24 h IV either continuously 4–6
or in six equally divided doses
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6
Vancomycin hydrochloride†‡ 30 mg/kg per 24 h IV in two 4–6 Vancomycin therapy is recommended for
equally divided doses, not to patients allergic to β–lactams; cephalosporins
exceed 2 g/24 h unless serum are not acceptable alternatives for patients
levels are monitored allergic to penicillin
With gentamicin sulfate† 1 mg/kg IM or IV every 8 h 4–6
* All enterococci causing endocarditis must be tested for antimicrobial susceptibility to select optimal therapy (see text). This table is for endocarditis due to
gentamicin- or vancomycin-susceptible enterococci, viridans streptococci with a minimum inhibitory concentration of >0.5 μg/mL, nutritionally variant viri-
dans streptococci, or prosthetic valve endocarditis caused by viridans streptococci or Streptococcus bovis. Antibiotic dosages are for patients with normal
renal function.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
450 chapter 19

not improve efficacy or enhance synergy with penicillin. Staphylococci

However, it does significantly increase the risk for
nephrotoxicity. S. aureus (Methicillin Susceptible)
The treatment of enterococcal endocarditis is becoming
increasingly complicated because of the development of Patients with S. aureus native valve left-sided endocarditis
resistance of enterococci to multiple antimicrobial agents. or PVE should receive 6 weeks of therapy with nafcillin,
Enterococci are uniformly resistant to the cephalosporins. oxacillin, a first-generation cephalosporin (e.g., cefazolin), or
Since the late 1980s, strains of enterococci have been re- vancomycin (Table 19.8).17 In in vitro and in animal model
covered with high-level resistance in vitro to gentamicin, studies of experimental endocarditis, the combination of naf-
streptomycin, and other aminoglycosides; penicillin and cillin and gentamicin was more effective than either drug
ampicillin; and vancomycin. Enterococci that are highly alone.20,21 The administration of nafcillin for 6 weeks com-
resistant to an aminoglycoside are not killed synergistically bined with gentamicin for the first 2 weeks of therapy did
by combinations of either penicillin or vancomycin together not improve survival rates or reduce complications compared
with that aminoglycoside. Moreover, vancomycin-resistant with patients treated with nafcillin alone.22 However, the
strains of enterococci frequently exhibit high-level resistance combination of nafcillin and gentamicin did significantly
to aminoglycosides and often to penicillins. Currently, no shorten the duration of S. aureus bacteremia compared with
bactericidal regimen is available for the treatment of patients patients who received therapy with nafcillin alone. If clini-
with enterococcal IE caused by these multiply resistant cians prefer to use the combination of nafcillin and genta-
microorganisms. A small number of patients with multiply micin, the dosage of gentamicin could be the same as that
resistant enterococcal IE have been treated successfully with for patients with viridans streptococcal endocarditis, and the
a combination of imipenem and ampicillin. Quinupristin- duration of gentamicin therapy should not exceed the initial
dalfopristin (Synercid) and linezolid (Zyvox) have been effec- 3 to 5 days of treatment. Antimicrobial therapy for S. aureus
tive treatment in some patients with IE caused by is shown in Table 19.9.17 Intravenous drug abusers with right-
vancomycin-resistant strains of S. faecium. The treatment of sided methicillin-susceptible S. aureus IE who do not have
patients with infections caused by strains of multiply resis- extrapulmonary or extracardiac foci of infection can be
tant enterococci should be performed in collaboration with treated successfully with a combination of nafcillin and low-
an infectious disease specialist and a cardiothoracic surgeon.17 dose tobramycin or gentamicin for 2 weeks.23 Addicts who
Cardiac valve replacement may offer these patients the only do not qualify for the 2-week regimen should receive therapy
hope of survival. for 4 to 6 weeks.

TABLE 19.8. Therapy for endocarditis due to staphylococcus in the absence of prosthetic material*
Antibiotic Dosage and route Duration Comments

Methicillin-susceptible staphylococci
Regimens for non-β-lactam-allergic patients
Nafcillin sodium or oxacillin sodium 2 g IV every 4 h 4–6 weeks Benefit of additional
aminoglycosides has not
been established
With optional addition of gentamicin sulfate† 1 mg/kg IM or IV every 8 h 3–5 days
Regimens for β-lactam-allergic patients
Cefazolin (or other first-generation 2 g IV every 8 h 4–6 weeks Cephalosporins should be
cephalosporins in equivalent dosages) avoided in patients with
immediate-type
hypersensitivity to
penicillin
With optional addition of gentamicin† 1 mg/kg IM or IV every 8 h 3–5 days
Vancomycin hydrochloride‡ 30 mg/kg per 24 h IV in two 4–6 weeks Recommended for patients
equally divided doses, not allergic to penicillin
to exceed 2 g/24 h unless
serum levels are monitored
Methicillin-resistant staphylococci
Vancomycin hydrochloride‡ 30 mg/kg per 24 h IV in two 4–6 weeks
equally divided doses, not
to exceed 2 g/24 h unless
serum levels are monitored
* For treatment of endocarditis due to penicillin-susceptible staphylococci (minimum inhibitory concentration ≤0.1 μg/mL), aqueous crystalline penicillin G
sodium (Table 19.5, first regimen) can be used for 4 to 6 weeks instead of nafcillin or oxacillin. Shorter antibiotic courses have been effective in some drug
addicts with right-sided endocarditis due to Staphylococcus (see text). See text for comments on use of rifampin.
† For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
‡ For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
 in fectiv e en doca r ditis 4 51
TABLE 19.9. Treatment of staphylococcal endocarditis in the presence of a prosthetic valve or other prosthetic material*
Antibiotic Dosage and route Duration (weeks) Comments

Regimen for methicillin-resistant staphylococci

Vancomycin hydrochloride† 30 mg/kg per 24 h IV in 2 or 4 ≥6
equally divided doses, not
to exceed 2 g/24 h unless
serum levels are monitored
With rifampin‡ 300 mg PO every 8 h ≥6 Rifampin increases the amount of warfarin
And with gentamicin sulfate∫ || 1.0 mg/kg IM or IV every 8 h 2 sodium required for antithrombotic therapy

Regimen for methicillin-sensitive staphylococci

Nafcillin sodium or oxacillin 2 g IV every 4 h ≥6 First-generation cephalosporins or vancomycin
sodium should be used in patients allergic to
With rifampin‡ 300 mg PO every 8 h ≥6 β-lactam; cephalosporins should be avoided
And with gentamicin sulfate∫ || 1.0 mg/kg IM or IV every 8 h 2 in patients with immediate-type
hypersensitivity to penicillin or with
methicillin-resistant staphylococci
* Dosages recommended are for patients with normal renal function.
† For specific dosing adjustment and issues concerning vancomycin (obese patients, length of infusion), see Table 19.5 footnotes.
‡ Rifampin plays a unique role in the eradication of staphylococcal infection involving prosthetic material (see text); combination therapy is essential to prevent
emergence of rifampin resistance.
∫ For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
|| Use during initial 2 weeks.

S. aureus (Methicillin Resistant) HACEK Group

Patients with methicillin-resistant IE should be treated for 6 Endocarditis caused by the HACEK group of microorganisms
weeks with vancomycin (Table 19.8).17 The only effective accounts for about 5% of non–addiction-associated cases.
alternative is cotrimoxazole therapy (trimethoprim/ Previous studies have shown that these patients can be
sulfamethoxazole). treated successfully with 3 weeks of intravenous ampicillin
therapy.26 However, occasional strains of Haemophilus para-
Coagulase-Negative Staphylococci (S. epidermidis) influenzae produce β-lactamase. Susceptibility tests are dif-
ficult to perform on the HACEK group of microorganisms.
Native valve IE caused by coagulase-negative staphylococci
Therefore, they should be considered to be β-lactamase pro-
is relatively uncommon, and most strains are susceptible to
ducers until shown otherwise. Ceftriaxone administered in
nafcillin. These patients should be treated with the same
a single dose of 2 g/d for 3 weeks is effective treatment for IE
therapy used to treat methicillin-susceptible left-sided S.
caused by this group of microorganisms (Table 19.10).17
aureus endocarditis. Patients with infective endocarditis
caused by methicillin-resistant strains should receive vanco-
Other Gram-Negative Bacillary Microorganisms
mycin therapy for 6 weeks. Coagulase-negative staphylococci
are the most common cause of early-onset PVE.24,25 Most of Non–addiction-associated native valve IE caused by gram-
these strains are resistant to nafcillin or cefazolin. The most negative bacilli other than the HACEK group is rare. Most
effective therapy for patients with coagulase-negative staphy- cases of native valve gram-negative bacillary endocarditis
lococcal PVE is a combination of vancomycin and rifampin occur in addicts and are most often caused by P. aeruginosa,
administered for 6 weeks with low-dose gentamicin therapy Serratia, and Klebsiella. The choice of effective antimicro-
for the first 2 weeks of treatment (see Table 19.9).17 bial therapy should be based on in vitro susceptibility tests,

TABLE 19.10. Therapy for endocarditis due to HACEK microorganisms*

Antibiotic Dosage and route Duration (weeks) Comments

Ceftriaxone sodium† 2 g once daily IV or IM† 4 Cefotaxime sodium or other third-generation

cephalosporins may be substituted
Ampicillin sodium‡ 12 g/24 h IV either continuously or 4
in six equally divided doses
With gentamicin sulfate§ 1 mg/kg IM or IV every 8 h 4
HACEK, Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae.
* Antibiotic dosages are for patients with normal renal function.
† Patients should be informed that IM injection of ceftriaxone is painful. For patients unable to tolerate β-lactam therapy, consult text.
‡ Ampicillin should not be used if laboratory tests show β-lactamase production.
§ For specific dosing adjustment and issues concerning gentamicin (obese patients, relative contraindications), see Table 19.5 footnotes.
452 chapter 19

and the selection of a specific antimicrobial agent should be Functional class Sudden onset Functional
the least toxic, most active agent in vitro. In general, therapy III or IV of severe aortic class ≤II
heart failure insufficiency heart failure
should be administered for 4 to 6 weeks.
Gram-negative bacilli are the second most common cause Treat medically Treat medically
of early-onset PVE. The same principles of therapy for the
selection of an antimicrobial agent or a combination of agents
Responsive Unresponsive Urgent cardiac Deterioration Stable
used for addiction-associated IE should be applied to patients after 24–48 valve to class
with gram-negative bacillary PVE. The duration of therapy hours replacement III or IV

should be 4 to 6 weeks. Complete course

of antimicrobials
Complete course
of antimicrobials

Fungal Endocarditis
Cardiac valve
replacement
Endocarditis caused by Candida should be treated with if necessary
amphotericin B or, if susceptible, with fluconazole. After 7 FIGURE 19.2. Diagram of our approach to the management of
to 10 days of therapy, the infected cardiac valve should be patients with infective endocarditis and heart failure. Class II, III,
excised. There are few documented cases of cure of fungal and IV are the New York Heart Association functional
endocarditis with medical therapy alone. Aspergillus endo- classification.
carditis most often occurs in association with cardiac valve
replacement surgery. Aspergilli are relatively resistant to
valve IE is associated with a higher mortality rate than is
amphotericin B and other antifungal agents. Therapy should
mitral valve infection.28 Our approach to the management of
be initiated with amphotericin B, followed by early surgical
patients with CHF caused by IE is shown in Figure 19.2.30
intervention. Fungal endocarditis is associated with the for-
The most important factor in the decision to proceed with
mation of large cardiac valve vegetations, and embolization
cardiac valve replacement and the timing of surgical inter-
to systemic vessels is common. The mortality rate associated
vention is the hemodynamic status of the patient. Among
with fungal endocarditis, especially that with prosthetic
patients with severe CHF who fail to respond to medical
valve infection, is high.
therapy after 24 to 48 hours, consideration should be given
to prompt surgical intervention regardless of the duration of
Culture-Negative Endocarditis
preoperative antimicrobial therapy. In these patients, pro-
Culture-negative endocarditis most often occurs in patients crastination in cardiac valve replacement in an attempt to
who have received recent antimicrobial therapy. Unless the complete the course of antimicrobial therapy preoperatively
need for antimicrobial therapy is urgent, it is preferable to usually results in death from CHF. The operative mortality
withhold therapy for a few days until positive blood cultures rate of patients who undergo cardiac valve replacement owing
establish the microbiologic diagnosis. For patients with acute to CHF caused by IE is directly related to the degree of CHF
fulminating IE or those in whom blood cultures remain present at the time of surgery. In a 13-year study done at the
negative, therapy should be started with a combination of Mayo Clinic, the operative mortality rate was highest in
vancomycin and low-dose gentamicin. As described earlier, patients with class IV disability preoperatively, and the oper-
patients with culture-negative endocarditis should be ative mortality rate in patients with or without IE was
evaluated for Q fever, chlamydia, mycoplasma, or fungal remarkably similar when the degree of heart failure was the
endocarditis. Patients with nutritionally variant viridans same as that at the time of operation.31
streptococcal IE and those with HACEK endocarditis may Echocardiography is useful in the management of patients
have intermittently positive blood cultures, and prolonged with IE and heart failure. Assessment of valvular dysfunc-
incubation may be required before results are positive. tion and hemodynamic status by echocardiography is impor-
tant in decision making concerning the necessity and timing
of surgical intervention.5,32–35
Treatment of Complications Echocardiography is used to define ventricular function,
size, and wall motion, and valvular insufficiency may be
The complications of IE that are considered here are those quantified. Progressive increase in ventricular size, elevation
that involve the heart and adjacent structures or those that of pulmonary artery pressure, and wall motion abnormalities
are extracardiac, and those that occur most commonly and on serial echocardiography suggest the onset or worsening of
are accessible to diagnosis and treatment. heart failure and suggest the need for surgical intervention
(Table 19.11).15 Reportedly, there is a higher frequency of com-
plications, including CHF and need for cardiac valve replace-
Cardiac Complications
ment, myocardial abscess, and death, among patients with
IE in whom vegetations were detected on echocardiography
Heart Failure
compared with patients without echocardiographic evidence
Heart failure caused by valvular insufficiency is the most of vegetation. Patients with larger vegetations (Fig. 19.3) were
common serious complication of IE and is the leading cause also reportedly at high risk for complication in some
of death. Patients with moderate to severe CHF caused by IE studies,33,36,37 but not in others.32,38 On the basis of these
who are unresponsive to medical therapy alone have a higher observations, some authorities have recommended early sur-
mortality than do patients with CHF who are treated with a gical intervention if valvular vegetations are detected by
medical regimen and cardiac valve replacement.27–31 Aortic echocardiography.39–42
 in fectiv e en doca r ditis 453
TABLE 19.11. Echocardiographic features suggesting potential
need for surgical intervention*
Vegetation
Persistent vegetation after systemic embolization
Anterior mitral leaflet vegetation, particularly with size
>10 mm†
One or more embolic events during first 2 weeks of
antimicrobial therapy†‡
Two or more embolic events during or after antimicrobial
therapy
Increase in vegetation size after 4 weeks of antimicrobial
therapy

Valvular dysfunction
Acute aortic or mitral insufficiency with signs of ventricular
failure‡
Heart failure unresponsive to medical therapy‡
Valve perforation or rupture‡

Perivalvular extension
Valvular dehiscence, rupture, or fistula‡
New heart block‡
Large abscess, or extension of abscess despite appropriate FIGURE 19.3. Transthoracic echocardiogram, apical four-chamber
antimicrobial therapy‡ view. A highly mobile linear echodensity (arrow) suggestive of a
vegetation is seen within the left atrium (LA) and is attached to the
* See text for more complete discussion of indications for surgery based on mitral valve (MV) anterior leaflet. LV, left ventricle; RV, right ven-
vegetation characterizations. tricle); RA, right atrium.
† Surgery may be required because of risk of embolization.
‡ Surgery may be required because of heart failure or failure of medical
therapy.

rior mitral valve leaflets, premature closure of the mitral

valve, chordal (Fig. 19.4) or cusp rupture, or Doppler ultra-
Although these studies reported a high incidence of CHF sound evidence of moderate to severe valvular regurgitation
in patients with echocardiographic detection of vegetations were at higher risk for the development of CHF and the need
compared with those without vegetations, Lutas and associ- for cardiac valve replacement.41–45
ates38 reported that the presence or size of vegetations on Echocardiographic imaging is operator dependent and is
echocardiography did not significantly increase the incidence influenced by such factors as obesity, chest wall deformity,
of CHF or the need for cardiac valve replacement. O’Brien trauma, recent thoracic surgery, and the use of ventilating
and Geiser43 reported that 50% of patients without vegeta- equipment. Not surprisingly, considerable variability is
tions on echocardiogram developed heart failure. Patients reported for the incidence of complications and the need for
whose echocardiograms demonstrated fluttering of the ante- cardiac valve replacement associated with the presence of

A B
FIGURE 19.4. Transesophageal echocardiogram, four-chamber (arrowheads). (B) The mass lesion appears more extensive during
view during diastole with mechanical mitral valve prosthesis open prosthetic valve closure (arrowheads). Prosthesis shadowing and
(A, arrows) and during systole with mechanical prosthesis closed reverberation artifacts obscure the left ventricle (LV) and the right
(B). A complex mobile mass lesion consistent with vegetation par- ventricle (RV). RA, right atrium; LA, left atrium.
tially occupies the left atrial appendage (LAA) and valve inflow zone
454 chapter 19

vegetations detected on echocardiography. Medical regimens First relapse

and indications for cardiac valve replacement differ among
institutions, and the detection of vegetations by echocardiog-
raphy may have in itself influenced the decision to intervene Staphylococci Other microorganism
Gram-negative bacilli
surgically. or other microorganism
In summary, we do not believe that patients should be resistant to multiple drugs
Q fever endocarditis Re-treat with
subjected to cardiac valve replacement only on the basis of antimicrobials
echocardiographic detection of cardiac valve vegetations.
The mere presence, location, size, or persistence of vegeta- Cardiac valve
Cure Second relapse
tions visualized by echocardiography do not necessarily replacement

imply that all of these patients will develop CHF. The hemo-
dynamic status of the patient and the response to medical
Gram-negative bacilli or Enterococci
therapy are the most important factors in the decision for unusual microorganisms Streptococci
surgical intervention. Echocardiography is useful as a means moderately resistant Penicillin-sensitive
to antimicrobials Nutritionally variant
to closely monitor patients with endocarditis during and Other highly antibiotic-
after the completion of antimicrobial therapy. Patients with sensitive microorganism

torn aortic cusps that produce severe aortic regurgitation and Cardiac valve
replacement
premature closure of mitral valve or ruptured mitral valve Re-treat with
antimicrobials
chordae that produce severe mitral regurgitation are at higher
risk for CHF and should be followed closely for early detec-
tion of left ventricular dysfunction and CHF so that prompt Cure Third relapse
surgical intervention can be performed.
Cardiac valve replacement can be performed successfully
in patients who have active IE and severe heart failure.46–49 Cardiac valve
Previously, we described 11 patients with active IE who replacement

underwent urgent cardiac valve replacement; eight of these FIGURE 19.5. Diagram of an approach to management of patients
patients had positive blood cultures within 48 hours preop- with relapse of infective endocarditis.
eratively.49 Three of the 11 patients died—two of complica-
tions of sudden-onset severe aortic regurgitation and one of
coagulase negative staphylococcal PVE. The risk of valve
relapse despite adequate antimicrobial therapy should be
dehiscence in PVE may be higher in patients with active IE
considered for cardiac valve replacement, especially if a
at the time of operation than in those who have completed
second relapse occurs and if no metastatic focus of infection
a course of antimicrobial therapy preoperatively, but this risk
to account for the relapse is identified.
is justified by the excessively high mortality rate in patients
Patients with penicillin-susceptible streptococcal IE or
with severe CHF who do not undergo early cardiac valve
enterococcal IE are usually responsive to antimicrobial
replacement. For patients with sudden-onset severe aortic
therapy, and relapses, when they occur, are usually cured by
insufficiency, urgent cardiac valve replacement offers the
a second course of antimicrobial therapy.
only hope for survival.
Perivalvular Extension of Infection, Myocardial
Relapse Abscess, Myocardial Conduction Defects,
Infarction, and Pericarditis
In a series of 629 consecutive cases of endocarditis in patients
seen at the Mayo Clinic, relapse occurred in 4%.1 All patients The extension of infection involving cardiac valves beyond
with IE should be evaluated carefully to determine the portal the valve annulus may result in conduction defects, myocar-
of entry of infection. If a source of infection is identified, it dial abscess, increased risk of valve dehiscence, and the
should be eliminated while the patient is receiving antimi- development of heart failure and is associated with a higher
crobial therapy for IE. Because the oral cavity and urinary mortality rate and need for cardiac surgery. In aortic valve
tract are the most frequently identified portals of entry, urine IE, infection may extend from the annulus into the membra-
culture, urologic evaluation if necessary, and assessment of nous septum and involve the atrioventricular node, resulting
dentition and any necessary dental procedures should be in myocardial abscess or heart block. Perivalvular extension
performed. Metastatic infection is most likely to occur in of infection is more likely to occur in aortic valve IE than in
patients with S. aureus IE, and a diligent search for possible mitral or tricuspid valve IE. Prosthetic valve endocarditis is
metastatic foci of infection, especially located intraabdomi- especially susceptible to perivalvular extension of infection
nally, using imaging techniques should be conducted. and valvular dehiscence. Persistent bacteremia despite appro-
Our approach to the management of patients with relapse priate antimicrobial therapy, recurrent emboli, or the devel-
of IE is shown in Figure 19.5.30 We believe that in all patients opment of heart block or worsening valvular insufficiency or
with bacterial IE who are stable hemodynamically and who dehiscence suggests perivalvular extension of IE. The use of
have not had recurrent multiple large emboli, at least one TEE is more sensitive and specific than TTE for the detection
attempt should be made to sterilize the infected valve by of perivalvular extension of infection.50 Moreover, TEE com-
antimicrobial therapy before cardiac valve replacement is bined with spectral and color Doppler echocardiography
considered. Patients with S. aureus IE who experience a may demonstrate fistulas, pseudoaneurysms, or myocardial
 in fectiv e en doca r ditis 455
abscess associated with perivalvular extension of infection. Extracardiac Complications
Accordingly, TEE is the procedure of choice for the diagnosis
of perivalvular extension of infection in patients with IE. Emboli
Some patients with perivalvular extension of infection
may be successfully treated without surgical intervention; The frequency of clinically apparent emboli in patients with
these patients include those without heart block, echocardio- IE has been reported to be from 22% to 50%.32,51 The highest
graphically demonstrated progression of abscess during percentage of patients with major embolic events occurs in
appropriate antimicrobial therapy, or valvular dehiscence. association with S. aureus or those infections that produce
These patients should be monitored closely with serial echo- large bulky vegetations, such as those caused by the HACEK
cardiography during and after the completion of antimicro- group of microorganisms, nutritionally variant viridans
bial therapy. streptococci, group B streptococci, or fungi (especially Asper-
At the Mayo Clinic, doctors have observed patients with gillus).52,53 Because embolic events may result in irreversible
presumed myocardial abscess diagnosed by echocardiogra- organ dysfunction or death, prevention is a desirable goal.
phy in which antimicrobial therapy alone resulted in disap- Elective cardiac valve replacement has been recommended
pearance of the abscess. In addition, autopsies performed on for patients who have recurrent emboli or who are at high
patients with previously healed endocarditis may demon- risk for additional emboli.40,54
strate healed abscess cavities after medical therapy alone. The relationship between echocardiographically visual-
Therefore, the detection of an abscess by echocardiography ized cardiac valve vegetations, systemic embolization, and
is not an absolute indication for surgical intervention. the need for cardiac valve replacement is controversial. Val-
Daniel and colleagues50 reported their experience in vular vegetations have been detected by echocardiography in
patients with myocardial abscesses documented at surgery 13% to more than 78% of patients with endocarditis,32–34 and
or autopsy. Transesophageal echocardiography in these their presence has been reported to increase the risk of embo-
patients detected abscesses in 87% of cases, whereas only lization in some studies,33,40,42–44,55 but not in others.32,56–59
28% were identified by two-dimensional echocardiography Large, mobile vegetations detected by echocardiography,
(p < .001). In this study, patients with PVE had a higher per- especially those in excess of 10 mm in diameter, have also
centage of abscesses than did those with native valve IE. In been reported to increase the risk of embolization in some
patients with IE, we believe that two-dimensional echocar- reports,33,42,60 but not in others.32,38,44,58,59,61 The results of
diography should be performed initially, followed by TEE if these studies led to the controversial recommendation that
necessary. The two procedures complement each other and elective cardiac valve replacement be considered in patients
are not mutually exclusive. Patients with myocardial with vegetations detected by echocardiography on the pre-
abscesses diagnosed by echocardiography should be followed sumption that the presence of vegetations is predictive of
closely for signs of extension of the abscess, valve dehis- future embolic events.
cence, development of heart block on electrocardiography, At the Mago Clinic, doctors reported the incidence of the
CHF, or persistence of infection despite adequate medical first embolic event after the onset of effective antimicrobial
therapy. Patients who exhibit one or more of these complica- therapy in more than 200 patients with left-sided native
tions of myocardial abscess should receive prompt surgical valve IE.32 Vegetations were detected by echocardiography in
intervention. 38% of patients and were absent in 40%. In the remaining
Cardiac rhythm disturbances or heart block may result patients, vegetation status was indeterminate. We observed
from involvement of the cardiac conduction system by exten- no statistically significant difference in the incidence rate of
sion of IE. Patients with conduction defects should be moni- embolic events among patients with definite valve vegeta-
tored closely and may require the insertion of a transvenous tions compared with those with absent or indeterminate
pacemaker or other surgical intervention. The goal of surgi- vegetation. Moreover, no increased rate of embolization was
cal intervention in patients with perivalvular extension of IE noted with increasing vegetation size from 3 to 30 mm in
is eradication of infection, correction of hemodynamic abnor- diameter, nor was there a statistically significant difference
malities including cardiac valve replacement, drainage of in the rate of emboli among patients with vegetations greater
abscess, and debridement and closure of fistulous tracts. In than 10 mm in diameter compared with those with smaller
patients with perivalvular infection who require cardiac vegetations. There was no significant effect of vegetation size
valve replacement, the use of aortic homografts may be asso- on the rate of embolization in subsets of patients with aortic
ciated with a lower risk of persistence of infection than the or mitral valve involvement except in patients with strepto-
use of an artificial prosthesis. coccal IE who had a higher rate of embolization. The inci-
Myocardial infarction results from vegetations that dis- dence rate of emboli decreased over time during antimicrobial
lodge and embolize to the coronary arteries. In our experi- therapy (p < .001). The incidence of embolic events among all
ence, the frequency of myocardial infarction associated with patients fell from 13 per 1000 patient-days during week 1 of
IE is 3%. Patients with myocardial infarction associated antimicrobial therapy to fewer than 1.2 per 1000 patient-days
with IE should be treated similarly to those with infarction after week 2 of therapy (Fig. 19.6).
associated with atherosclerosis. Pericarditis is most often Many studies, including those cited earlier,32 have
associated with S. aureus IE. Echocardiography is useful in attempted to identify patients with IE who are at high risk
the detection of pericardial fluid, but the diagnosis of puru- of emboli who might benefit from surgical intervention to
lent pericarditis must be established by pericardiocentesis. avoid embolization. Mitral valve vegetations reportedly are
Purulent pericarditis should be treated with prompt surgical more likely to result in peripheral embolization (25%) than
drainage and antimicrobial therapy. in aortic valve vegetations (10%). The highest rate of
456 chapter 19

20 rysm can be made early before massive hemorrhage occurs.

Definite vegetations A severe unremitting localized headache or a homonymous
Embolic rate/1000 pt-days

All patients hemianopsia is a finding that is highly suggestive of intra-

15
Absent vegetations cranial mycotic aneurysm. Contrast-enhanced computed
tomography scanning may detect an intracerebral bleed in
10 90% to 95% of instances and may indirectly suggest the
locations of a mycotic aneurysm.l5 Magnetic resonance angi-
5 ography may be useful for the diagnosis of intracranial
mycotic aneurysm, but its sensitivity for the detection of an
aneurysm of less than 5 mm is less than that of cerebral
0 angiography. Accordingly, cerebral angiography remains the
1 2 3 4
diagnostic procedure of choice. Cerebral angiography should
Week of antimicrobial therapy
be performed in these patients.
FIGURE 19.6. Incidence of embolic events in patients (pt) with
infective endocarditis. Although many authorities believe that most intracra-
nial mycotic aneurysms will rupture if untreated, Bingham64
reported that the outcome of patients with intracranial
mycotic aneurysm is similar in those administered adequate
antimicrobial therapy compared with those treated with
embolization (37%) was observed when the vegetations were
both antibiotics and surgical excision of the aneurysm.
located on the anterior leaflet rather than the posterior leaflet
Some patients with mycotic aneurysm require both
of the mitral valve.62,63 This higher rate may be related to the
cardiac valve replacement surgery and ligation of an intra-
mechanical effects of the abrupt excursion of the anterior
cranial mycotic aneurysm. The more life-threatening
mitral valve during the cardiac cycle, which subject vegeta-
problem dictates the surgical procedure to be performed
tions located on the anterior leaflet to fragmentation and
first. The use of a bioprosthetic cardiac valve that does
embolization. The risk of emboli is greater when associated
not require the administration of anticoagulant therapy may
with an increase in vegetation size demonstrable by TEE
be preferable to mechanical valve prosthesis in these
during 4 to 8 weeks of antimicrobial therapy. The risk of
patients.
emboli in these patients was twice that of patients in whom
Most, if not all, intrathoracic and intraabdominal mycotic
vegetations remained unchanged or decreased in size during
aneurysms will rupture if not excised. Peripheral mycotic
therapy.
aneurysms are most accessible to early diagnosis and are
The American Heart Association published guidelines
associated with the best prognosis. The risk of rupture of an
suggesting the potential need for surgical intervention in
untreated peripheral mycotic aneurysm is high, and prompt
patients with valvular vegetations demonstrable by echo-
surgical intervention is imperative. Most authorities believe
cardiography (Table 19.11).15 Antimicrobial therapy reduces
that the treatment of choice for patients with peripheral
the risk of embolization during the first 2 weeks of therapy.
mycotic aneurysm is ligation and excision and that it is
Accordingly, benefit from surgery to prevent embolic events
preferable to sacrifice the limb, if necessary, rather than the
is highest early in the course of antimicrobial therapy. In
life of the patient.
selected patients, surgical intervention may prevent a
primary or recurrent serious embolic event. The decision
for surgical intervention to prevent embolization should Splenic Abscess
be individualized in each patient. Surgery should be con-
Splenic infarction is a common complication of left-sided IE
sidered when large vegetations are detected on the mitral
(approximately 40% of cases); however, only about 5% of
valve, especially the anterior leaflet, and in patients
patients with splenic infarction develop splenic abscess.15
whose vegetation increases in size after 4 weeks of anti-
Viridans streptococci or S. aureus is the most common cause
microbial therapy or in patients who have one or more
of splenic abscess. Patients with persistent left upper quad-
embolic events during the first 2 weeks of antimicrobial
rant pain and those with persistent or recurrent bacteremia
therapy or two or more embolic events during or after anti-
or fever despite appropriate antimicrobial therapy should be
microbial therapy.
suspected of having splenic abscess. Abdominal computed
tomography or magnetic resonance imaging is the most sen-
sitive test for the diagnosis of splenic abscess. Differentiation
Mycotic Aneurysm
of splenic abscess from infarction may be difficult with these
Mycotic aneurysm is a rare complication of IE. During a 16- imaging tests. Persistent sepsis, positive blood cultures, or
year period at the Mayo Clinic, we were able to identify only enlargement of the splenic defect on computed tomography
32 patients with mycotic aneurysm among 628 patients with or magnetic resonance imaging suggests an abscess rather
IE (5%).12 Intercranial mycotic aneurysms are associated with than an infarction. Percutaneous drainage of splenic abscess
higher morbidity and mortality rates than mycotic aneu- has been performed successfully15 and, in experienced hands,
rysms located elsewhere. Patients with intracranial mycotic has replaced splenectomy as the treatment of choice. In
aneurysms may be asymptomatic, and the diagnosis is patients with splenic abscess who require cardiac valve
usually made after a sudden massive, often fatal subarach- replacement surgery, splenectomy should be performed before
noid or intracerebral hemorrhage. Our experience suggests, valve replacement surgery because of the risk of bacteremia
however, that the diagnosis of intracranial mycotic aneu- and infection of the valve prosthesis.
 in fectiv e en doca r ditis 457

Metastatic Infection Microbiology

Patients with metastatic infection are at risk for relapse of Early-onset PVE (≤2 months postoperative) is most often
IE, which most often occurs in patients with staphylococcal caused by staphylococci (Staphylococcus epidermidis and
endocarditis. Imaging techniques such as computed tomog- other coagulase-negative staphylococci, frequently methicil-
raphy, magnetic resonance imaging, and radioisotope scan- lin-resistant as well as S. aureus, including many isolates
ning may be helpful in localizing occult metastatic foci of that are methicillin resistant).70,74
infection. The persistence of fever, localized pain or tender- After staphylococci, gram-negative bacilli and fungi are
ness, persistently abnormal liver function tests, and break- the etiology of early PVE. Prosthetic valve endocarditis
through bacteremia suggest the diagnosis of metastatic occurring late (≥12 months postoperative) is caused by
abscess. the same organisms that cause IE on native valves
(Table 19.4). There is also an increased incidence of entero-
Central Nervous System Abnormalities cocci and coagulase-negative staphylococci as pathogens in
late PVE.
Central nervous system abnormalities have been reported to
occur in 9% to 80% of patients with IE; these include head-
ache, confusion, stroke, meningoencephalitis, brain abscess,
and mycotic aneurysm.12,13 The management of patients with
Clinical Picture
mycotic aneurysms or embolic events was discussed earlier. Any patient with a prosthetic heart valve and fever should
Most patients with central nervous system abnormalities be assumed to have PVE until proven otherwise. The clinical
show improvement with supportive care and appropriate features of PVE are quite similar to those found in IE except
antimicrobial therapy. Patients with a large solitary brain for the relative absence of signs of peripheral emboli early in
abscess may require stereotactic or open surgical drainage, the course of the illness to help the physician make a clinical
but most patients with small abscesses do not require neu- diagnosis at the bedside.
rosurgical intervention. In patients with brain abscess, the The presentation of PVE, like that of IE, can vary from
duration of antimicrobial therapy should often be extended an indolent subacute picture (more common in late PVE) to
beyond that usually required for the treatment of uncompli- fulminant sepsis and septic shock (more common with early-
cated IE. onset S. aureus infection).

Prosthetic Valve Endocarditis Diagnosis

The Duke Criteria14 using echocardiographic data in addition
Incidence to clinical and laboratory findings may be used in the diag-
nosis of PVE75, as well as IE (Tables 19.1 and 19.2).
Prosthetic valve endocarditis (PVE) continues to be a rare but
The diagnosis of PVE is based on the clinical picture,
life-threatening complication of cardiac valve surgery. The
laboratory tests, and results of the echocardiogram. The clin-
prevalence is reported to be between 15% and 30% of all
ical suspicion must be confirmed with positive blood cul-
cases of endocarditis.66–68
tures. The bacteremia in PVE is more or less continuous, so
The risk of infection of a prosthetic heart valve is highest
blood cultures can be obtained without regard to timing
within the first year after surgery (1% to 3%), particularly
them with chills or fever spikes. In patients who are not
within the first 3 months postoperatively.69 After the first 6
critically ill with sepsis or heart failure, it is preferable to
to 12 months, the rate stabilizes at 0.4% per year.70
withhold antibiotic therapy until a microbiologic diagnosis
Although there seems to be no difference in overall risk
has been established. Most blood cultures obtained off anti-
for infection of these valves, there is an increased incidence
biotics will be positive. The importance of having the organ-
of PVE in the first 6 months with mechanical valves,71 and
ism isolated before treatment is that it is necessary to have
an increase after 5 years with bioprosthetic valves.72
the organism for antibiotic sensitivity testing. Both PVE and
IE require a truly bactericidal antibiotic regimen for a cure,
Pathogenesis and this can be designed only if you have reliable sensitivity
data.
After cardiac valvular replacement, fibrin and platelets
attach at the operative site, particularly the sewing ring/
annulus area, producing a sticky bed for adherence of micro-
Echocardiography
organisms reaching the bloodstream. Early postoperative
bacteremia is frequently associated with line sepsis or wound Echocardiography is critical in the diagnosis and manage-
infections.69,73 ment of PVE. In this infection, TEE is superior to TTE both
As this operative site heals and as the area becomes for initial diagnosis and then serially for early recognition of
endothelialized, the risk of infection is less. Late infections serious complications which may require surgical interven-
mimic the pathogenesis of IE where valvular abnormalities tion: annular abscesses, malfunction of the prosthetic valve
result in turbulence of blood flow with resulting formation due to large vegetation, or early dehiscence of the prosthetic
of the platelet-fibrin bed known as nonbacterial thrombotic valve.75,76
endocarditis. Organisms attach to this during bacteremia, The sensitivity of the TEE in patients with PVE is reported
leading to IE and PVE. to be as high as 86% to 94% with a specificity of 88% to
458 chapter 19

100%. The negative predictive value of a TEE in PVE also Prevention

reaches 95%.
When the initial TEE is negative in a patient with clinical The American Heart Association publishes recommenda-
and microbiologic data suggestive of PVE, simply repeat the tions for IE as well as PVE prevention. These recommenda-
TEE after a week of antibiotic treatment. tions are found in Tables 19.12 to 19.15.
Another important aspect of prevention of PVE is the role
of the cardiologist in reeducating each patient on an annual
Antimicrobial Therapy basis regarding the hazard of PVE in every patient with a
prosthetic valve. Patients need to be instructed that it is the
Once the infecting organism for sensitivity testing has patient’s responsibility to avoid PVE by alerting physicians
been isolated, the antimicrobial treatment becomes straight- and dentists about the presence of a prosthetic valve before
forward. Treatment for IE has been discussed in detail for any manipulation is performed that could cause bleeding in
IE in this chapter. Table 19.9 is a summary for treatment of any area of the body normally colonized with bacteria, par-
staphylococcal PVE. The recommendations concerning ticularly the teeth, mouth, trachea/bronchi, esophagus, and
treatment of other bacteria and fungi that can cause IE gastrointestinal and genitourinary tracts. The cardiologist
also apply to the treatment of these pathogens when they must also be mindful of the following:
cause PVE. (See Tables 19.5 through 19.7 and Table 19.9 for
staphylococcal PVE, and Table 19.10 for the other organisms 1. Patients must be discouraged from treating febrile
causing IE and PVE and the recommended antibiotic illnesses at home. Medical evaluation and antibiotic
treatment.) treatment should be sought early rather than after an
To convert these tables to regimens appropriate for PVE infection is allowed to progress to the point of producing a
treatment77 there are two corrections. In the duration of bacteremia with the hazard of infection of the prosthetic
treatment column always use the longer duration when a valve.
range is given, or add 2 weeks if no range is given. In the 2. Patients must be discouraged from manipulating any
dosage column, always use the highest dose when a range is pustular of infected skin lesions including carbuncles, furun-
given. cles, or even styes on the eyelid. These lesions contain staph-
Other less frequent pathogens causing IE and PVE and ylococci and can lead to transient bacteremia if manipulated
their treatment are discussed earlier in this chapter, as is the or drained without appropriate antibiotic coverage before and
approach to culture negative IE and PVE. after drainage procedures.

Surgical Treatment
The treatment of PVE should be a combined effort of cardiol- TABLE 19.12. Dental procedures and endocarditis prophylaxis
ogy, cardiovascular surgery, and infectious disease. This is
Endocarditis prophylaxis recommended*
particularly true in the decision concerning the need for
surgery and the type of surgery to be performed. Dental extractions
Periodontal procedures including surgery, scaling and root
Most of the complications of PVE are associated with planing, probing, and recall maintenance
spread of infection from the valve ring into perivalvular and Dental implant placement and reimplantation of avulsed teeth
adjacent myocardial tissue. Perivalvular/annular abscesses Endodontic (root canal) instrumentation or surgery only beyond
are common sources for persistent bacteremia in the face the apex
Subgingival placement of antibiotic fibers or strips
of appropriate antibiotic therapy. Valvular dehiscence and
Initial placement of orthodontic bands but not brackets
fistula formation or valvular obstruction or malfunction due Intraligamentary local anesthetic injections
to a large vegetation can result in severe heart failure. New Prophylactic cleaning of teeth or implants where bleeding is
conduction abnormalities can result from extension of infec- anticipated
tion to involve the conduction system.
Endocarditis prophylaxis not recommended
All of these complications are indications for surgical
Restorative dentistry† (operative and prosthodontic) with or
intervention.
without retraction cord‡
In addition, surgery is indicated in the management of Local anesthetic injections (nonintraligamentary)
any infecting organism for which there is no bactericidal Intracanal endodontic treatment; postplacement and buildup
antibiotic regimen and in all fungal PVE since there are no Placement of rubber dams
truly cidal antifungal agents. Postoperative suture removal
Placement of removable prosthodontic or orthodontic appliances
Relapse of infection after an appropriate course of antibi- Taking of oral impressions
otic treatment also requires valvular replacement and another Fluoride treatments
full course of antibiotic therapy. Taking of oral radiographs
Timing of surgery must be individualized for each patient, Orthodontic appliance adjustment
Shedding of primary teeth
but the most important factor is the hemodynamic status of
the patient. Early surgery as soon as one of these complica- * Prophylaxis is recommended for patients with high- and moderate-risk
cardiac conditions.
tions is recognized will lower the mortality. Mortality is
† This includes restoration of decayed teeth (filling cavities) and replacement
reported to be proportional to the degree of preoperative of missing teeth.
congestive heart failure, hemodynamic instability, and end- ‡ Clinical judgment may indicate antibiotic use in selected circumstances
organ dysfunction, particularly renal failure. that may create significant bleeding.
 in fectiv e en doca r ditis 459
TABLE 19.13. Other procedures and endocarditis prophylaxis recommended
Respiratory tract Endocarditis prophylaxis not recommended
Tonsillectomy and/or adenoidectomy Respiratory tract
Surgical operations that involve respiratory mucosa Endotracheal intubation
Bronchoscopy with a rigid bronchoscope Bronchoscopy with a flexible bronchoscope, with or without biopsy†
Gastrointestinal tract* Tympanostomy tube insertion
Sclerotherapy for esophageal varices Gastrointestinal tract
Esophageal stricture dilatation Transesophageal echocardiography†
Endoscopic retrograde cholangiography with biliary Endoscopy with or without gastrointestinal biopsy†
obstruction Genitourinary tract
Biliary tract surgery Vaginal hysterectomy†
Surgical operations that involve intestinal mucosa Vaginal delivery†
Cesarean section
Genitourinary tract In uninfected tissue
Prostatic surgery Urethral catheterization
Cystoscopy Uterine dilatation and curettage
Urethral dilation Therapeutic abortion
Sterilization procedures
Insertion or removal of intrauterine devices
Other
Cardiac catheterization, including balloon angioplasty
Implanted cardiac pacemakers, implanted defibrillators, and
coronary stents
Incision or biopsy of surgically scrubbed skin
Circumcision
* Prophylaxis is recommended for high-risk patients; it is optional for medium-risk patients.
† Prophylaxis is optional for high-risk patients.

TABLE 19.14. Prophylactic regimens for dental, oral, respiratory tract, or esophageal procedures
Situation Agent Regimen

Standard general prophylaxis Amoxicillin Adults: 2.0 g; children: 50 mg/kg PO 1 h before procedure
Unable to take oral medications Ampicillin Adults: 2.0 g IM or IV; children: 50 mg/kg IM or IV within
30 min before procedure
Allergic to penicillin Clindamycin or Adults: 600 mg; children: 20 mg/kg PO 1 h before procedure
Cephalexin† or cefadroxil† or Adults: 2.0 g; children: 50 mg/kg PO 1 h before procedure
Azithromycin or clarithromycin Adults: 500 mg; children: 15 mg/kg PO 1 h before procedure
Allergic to penicillin and unable Clindamycin or Adults: 600 mg; children: 20 mg/kg IV within 30 min before
to take oral medications procedure
Cefazolin† Adults: 1.0 g; children: 25 mg/kg IM or IV within 30 min
before procedure
* Total children’s dose should not exceed adult dose.
† Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins.

TABLE 19.15. Prophylactic regimens for genitourinary/gastrointestinal (excluding esophageal) procedures

Situation Agents* Regimen

High-risk patients Ampicillin plus gentamicin Adults: ampicillin 2.0 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed
120 mg) within 30 min of starting procedure: 6 h later, ampicillin 1 g IM/
IV or amoxicillin 1 g PO
Children: ampicillin 50 mg/kg IM or IV (not to exceed 2.0 g) plus
gentamicin 1.5 mg/kg within 30 min of starting the procedure; 6 h later,
ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally
High-risk patients allergic Vancomycin plus gentamicin Adults: vancomycin 1.0 g IV over 1–2 h plus gentamicin 1.5 mg/kg IM/IV
to ampicillin/amoxicillin (not to exceed 120 mg): complete injection/infusion within 30 min of
starting procedure
Children: vancomycin 20 mg/kg IV over 1–2 h plus gentamicin 1.5 mg/kg
IM/IV; complete injection/infusion within 30 min of starting procedure
Moderate-risk patients Amoxicillin or ampicillin Adults: amoxicillin 2.0 g PO 1 h before procedure, or ampicillin 2.0 g
IM/IV within 30 min of starting procedure
Moderate-risk patients Vancomycin Adults: vancomycin 1.0 g IV over 1–2 h; complete infusion within 30 min
allergic to ampicillin/ of starting procedure
amoxicillin Children: vancomycin 20 mg/kg IV over 1–2 h; complete infusion within
30 min of starting procedure
* Total children’s dose should not exceed adult dose.
† No second dose of vancomycin or gentamicin is recommended.
460 chapter 19

3. In addition, early postoperative bacteremia can lead 14. Durack DT, Lukes AS, Bright DK, et al. New criteria for diag-
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ment of infective endocarditis and its complications. Circula-
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tion 1998;98:2936.
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course of antibiotic treatment will not cure the PVE, and 17. Wilson WR, Karchmer AW, Dijani AS, et al. Antibiotic treat-
relapse will occur within 24 to 48 hours of stopping the ment of adults with infective endocarditis due to streptococci,
antibiotics. enterococci, staphylococci, and HACEK microorganisms.
JAMA 1995;274:1706.
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tions for prophylaxis of IE for patients with cardiac valve cal endocarditis with a single daily dose of ceftriaxone sodium
abnormalities, congenital heart disease, intercardiac pros- for 4 weeks: efficacy and outpatient treatment feasibility.
thesis, or other cardiac abnormalities (Tables 19.12 to 19.15).65 JAMA 1992;267:264.
It is important for clinicians to be aware of the indications 20. Sande MA, Courtney KB. Nafcillin-gentamicin synergism in
for prophylaxis regimens. Patients should be provided with experimental staphylococcal endocarditis. J Lab Clin Med
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can Heart Association.
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 2 The Assessment and
0 Therapy of Valvular
Heart Disease in the
Cardiac Catheterization
Laboratory
Paul Sorajja and Rick A. Nishimura

Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . . 464 Prosthetic Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477

Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 Balloon Mitral Valvotomy. . . . . . . . . . . . . . . . . . . . . . . . . 478
Mitral Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Balloon Aortic Valvotomy . . . . . . . . . . . . . . . . . . . . . . . . . 480
Valvular Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 Percutaneous Valve Replacement and Repair . . . . . . . . . 481

Key Points pressures. Thus, there has been a shift in the evaluation of
patients with valvular heart disease, with the initial diag-
• The approach to catheterization should be individualized
nostic approach consisting of a comprehensive two-dimen-
for each patient, with knowledge of the clinical presenta-
sional and Doppler echocardiogram following the history
tion to facilitate the planning of the procedure and the
and physical examination. When the clinical and echocar-
acquisition of the relevant data.
diographic findings are concordant, catheterization is needed
• Determination of valve gradients may require direct
only to assess the status of the coronary arteries.
measurement of chamber pressures. The use of surrogate
Cardiac catheterization, however, still remains essential
measurements (e.g., femoral artery for central aorta; pul-
for many patients with valvular heart disease. Although
monary capillary wedge for left atrial pressure) may lead
echocardiography can diagnose the presence and severity of
to significant errors in the assessment of valve gradients.
valvular lesions, there are limitations to its accuracy. Thus,
• It is important to critically examine the absolute pressure
the major indication for further assessment with hemody-
in each chamber, its contour, and the relation between
namic catheterization is when there is a discrepancy between
each of the pressures examined.
clinical and echocardiographic findings. Absolute intracar-
• Among patients with a discrepancy between the clinical
diac pressures cannot be assessed by Doppler echocardiogra-
history and resting hemodynamic findings, exercise
phy, and cardiac catheterization needs to be performed when
testing with pressure measurements in the laboratory
this information is necessary. Finally, there has been the
can be helpful.
evolution of catheter-based therapies for patients with valvu-
• Valve morphology is the primary determinant of outcome
lar heart disease, which in many cases obviates the need for
in patients who undergo percutaneous mitral balloon
open-heart surgery.
valvuloplasty.
As the cardiac catheterization laboratory has focused
In the 1960s, cardiac catheterization emerged as the princi- increasingly on acute and chronic coronary syndromes, less
pal diagnostic modality for the evaluation of the patient with attention has been focused on the proper performance and
valvular heart disease. Two-dimensional echocardiography understanding of the hemodynamic assessment of patients
subsequently allowed visualization of valve morphology and with valvular heart disease. The patients with valvular heart
motion as well as the assessment of the ventricular response disease currently being evaluated in the catheterization labo-
to the valvular lesions. The advent of Doppler echocardiog- ratory are now those with more complex problems, since
raphy in the 1980s provided a noninvasive method for deter- patients with straightforward valvular lesions can be assessed
mination of valve gradients, valve areas, and intracardiac primarily with noninvasive methods. Thus, accurate and

463
464 chapter 20

clinically relevant data from invasive catheterization has niques for measurement of cardiac output in the catheteriza-
become increasingly important for patients with valvular tion laboratory. If available, simultaneous echocardiography
heart disease. with measurement of the left ventricular outflow tract diam-
eter and Doppler-derived stroke volume also may be used.
The indicator dilution method uses a bolus infusion of
Principles and Techniques an indicator into the circulation with measurement of its
concentration over time at some point downstream from the
General Approach to the Patient with Valvular injection. The area under the concentration versus the time
Heart Disease in the Catheterization Laboratory curve is inversely proportional to the cardiac output. This
method requires the presence of a mixing chamber between
The approach to the hemodynamic assessment of valvular
the injection and sampling chambers. In most laboratories,
heart disease should be individualized for each patient. The
this method is performed using cold saline injected into the
invasive cardiologist performing the study should have full
right atrium and sampling in the pulmonary artery using a
knowledge of what tests has been performed previously, what
thermodilution balloon-tipped catheter. Indocyanine green
information is known, and what clinically relevant informa-
dye also can be used as the indicator, with injection into the
tion is required from the study. A comprehensive differential
left atrium or pulmonary artery and sampling in the aorta.
diagnosis of the patient’s problems is needed and facilitates
The Fick principle utilizes the difference in oxygen
the planning of the procedure. Before proceeding, the vascu-
content in the arterial and venous system to measure flow.
lar access sites and approach to gathering data should be
In the absence of an intracardiac shunt, the saturation in the
delineated fully.
pulmonary artery and the saturation in the systemic circula-
While all patients should be fasting for the catheteriza-
tion can be used to determine the systemic cardiac output.
tion procedure, intravenous fluids should be administered to
Each gram of hemoglobin carries 1.34 mL of oxygen. Thus,
patients who have a long waiting period between their last
the oxygen content is the saturation · hemoglobin · 1.34. The
oral intake and the procedure. This prevents the hemody-
calculation of cardiac output by Fick also requires that either
namic measurements from being taken during a low-output,
direct measurement of the oxygen consumption or an
low-volume state. Patients can be lightly sedated, but should
assumed number for oxygen consumption (derived from body
be awake to simulate the hemodynamic milieu of their out-
mass and heart rate) be obtained. The formula for cardiac
patient state with close approximation of the heart rate and
output by Fick is as follows:
blood pressure that occurs in their usual daily activities. No
parenteral oxygen should be administered prior to the proce- Cardiac output (L/min)
dure to allow measurements of oxygen saturations.
Oxygen consumption (mL/min)
Accurate measurement of intracardiac pressures with =
fluid-filled catheters requires the use of large-bore, rigid cath- (A − VO2 ) ⋅ 1.34 mL/g ⋅ Hgb(g/dL) ⋅ 10(dL/L)
eters with minimization of the tubing length between the where A − V O2 is the difference in oxygen saturation between
catheter and pressure transducer. Attention to potential the arterial and venous circulation.
errors of measurement due to damping, catheter whip, entrap- There are advantages and disadvantages for each of the
ment, and other artifacts is always necessary during an inva- different methods used. Cardiac output using the indicator
sive hemodynamic study. Fluid-filled catheters can reliably dilution method is inaccurate in the presence of low or high
measure mean and absolute intracardiac pressures. However, heart rates, significant valvular regurgitation, and irregular
for analysis of pressure waveforms, instantaneous recordings rhythms. The Fick method overcomes these limitations, but
with high-fidelity micromanometer-tip catheters should be its accuracy requires a steady state and thus it cannot be used
utilized (Millar Instruments, Houston, TX). If possible, con- for measurement of acute changes (e.g., during pharmaco-
tinuous recording of all hemodynamic pressures should be logic interventions). Furthermore, the Fick method requires
made to allow retrospective review of these pressures simultaneous measurement of oxygen consumption or its
throughout the entire study. assumption with one of several methods. Even under ideal
All hemodynamic measurements should be made before conditions, variability in cardiac output may approach 20%
any contrast injections, as iodine contrast may affect the when using thermodilution and 10% to 15% when using the
hemodynamic milieu. Equilibration periods of at least 10 Fick method. If possible, both methods should be performed
minutes should be used to allow hemodynamic stabilization in an individual study to identify outlier results.
whenever there is any change in the hemodynamic state.
This equilibration period always should be applied to mea- Valve Area Determination
surements taken following infusion of a drug or other inter-
The severity of a stenotic valve lesion is measured directly
vention such as exercise. Spontaneous changes in heart rate
by the gradient across the valve. However, the gradient is
and blood pressure should always be noted during the proce-
proportional not only to the severity of stenosis but also to
dure and documented on the record.
the flow across the valve. It is for this reason that a calculated
“valve area” is required for further assessment of severity.
Calculations
The formula for calculation of stenotic valve areas was origi-
nally derived by Gorlin and Gorlin1 in 1951. This equation
Cardiac Output Calculation
is based on two fundamental hydraulic principles: (1) Torri-
Indicator dilution (using thermodilution or indocyanine celli’s law, which states that the area of an orifice is inversely
green dye) and the Fick method constitute the main tech- proportional to velocity of flow for a given amount of total
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 465
flow across that orifice; and (2) the pressure gradient across culation using the Gorlin equation is 0.2 cm2. However, this
the orifice is directly proportional to the velocity of flow. The error increases significantly in patients with bradycardia or
Gorlin equation is as follows: tachycardia. Furthermore, the Gorlin equation is inaccurate
for patients with significant coexistent regurgitation because
Flow (mL/sec )
(
Valve area cm2 = ) 44.3 ⋅ C ⋅ ΔP
the regurgitant flow is not factored into the measurement of
flow.
where ΔP is the mean transvalvular pressure gradient (mm Hg) A simplified version of the Gorlin equation has been
and C is an empirical constant that encompasses two coef- derived.3 In the derivation of this formula, Hakki and cowork-
ficients: a coefficient of orifice contraction, which corrects ers observed that the product of heart rate, forward flow, and
for the area of a jet through an orifice being smaller than the the Gorlin constants approximated 1 for most calculations.
true area of the orifice, and a coefficient of velocity, which The Hakki equation is as follows:
accounts for the energy loss as pressure energy is converted Cardiac output (L/min )
to kinetic (or velocity) energy. For mitral valve area calcula- (
Valve area cm2 = ) ΔP
tions, C was derived to be 0.85.2 For all other valve area cal-
culations, C is assumed to be 1.0. Flow refers to absolute As in the Gorlin equation, the mean pressure gradient is used
forward flow across the valve expressed in millimeters per for calculation of the valve area using the Hakki equation.
second and is derived from the cardiac output and the dura- Because the proportions of diastolic and systolic flow vary
tion of forward flow, which is the diastolic filling period for with heart rate, the major limitation of the Hakki equation
the mitral valve and the systolic ejection period for the aortic occurs in patients with bradycardia or tachycardia. Errors
valve (Fig. 20.1). In general, the total error in valve area cal- also occur in patients with coexistent regurgitation.

Techniques

Right and Left Heart Catheterization

Right and left heart catheterization is the mainstay of the
hemodynamic assessment of the patient with valvular heart
disease. Although each patient requires an individualized
approach, there is a standard methodology that comprises
the basis for these procedures. Proper performance of the
right heart catheterization involves screening oximetry
for detection of intracardiac shunts, saturation confirmation
of pulmonary capillary wedge readings, cardiac output
determination, and calculation of the pulmonary arteriolar
resistance. For measurement of absolute pressures, a large
bore, single end-hole balloon wedge catheter is preferred for
the right heart catheterization. For patients who require
measurements of acute changes in pressure and simultane-
ous assessment of cardiac output, the multiport balloon-
tipped catheter with thermodilution capability may be used.
The left heart catheterization should include measurement
of ascending aortic pressure, left ventricular pressure, and
arterial saturation. These pressures may be obtained with a
pigtail or multipurpose catheter. If intraventricular pressure
gradients are suspected, an end-hole catheter should be used.
The Judkins coronary catheter should not be utilized for
obtaining left heart pressures.
A standard approach to left and right heart catheteriza-
tion begins with obtaining arterial and venous access. In
most situations, the femoral sites can be utilized. However,
in the presence of severe tricuspid regurgitation with large
right-sided chambers, the internal jugular approach enhances
FIGURE 20.1. Calculation of transvalvular flow and gradient. This the performance of the right heart catheterization. Also, the
patient had both aortic and mitral stenosis. The forward flow rate is
derived from systolic ejection period (SEP) for calculation of aortic internal jugular approach should be used when an endomyo-
stenosis and the diastolic filling period (DFP) for calculation of cardial biopsy is required. Once vascular access has been
mitral stenosis. The diastolic filling period encompasses the entire obtained, the right heart catheter is used to acquire oxygen
duration of mitral valve opening, including periods of diastasis. saturations in the inferior and superior vena cavae for calcu-
Shaded areas indicate areas for mean gradient across the aortic valve
(A) and mitral valve (B). Ao, aortic pressure; C, Gorlin constant; CO,
lation of mixed venous oxygen content and to screen for
cardiac output; DFP, diastolic filling period; LA, left atrial pressure; intracardiac shunts. The right atrial pressure is measured
LV, left ventricular pressure; SEP, systolic ejection period. with the catheter in the midportion of the right atrium and
466 chapter 20

turned to its lateral wall to avoid prolapse across the tricus-

pid valve. Ascending aortic pressure is then measured by
placement of the left heart catheter, followed by advance-
ment of the catheter into the left ventricle to measure simul-
taneous left ventricular and right atrial pressures. The right
heart catheter is then advanced into the right ventricle to
measure simultaneous right ventricular and left ventricular
pressures. Finally, the right heart catheter is placed into the
pulmonary artery. This sequence of catheter placement and
advancement allows prospective examination of the relation
between the pressures of the left ventricle and right-sided
chambers, which may be particularly helpful in patients who
may have concomitant pericardial disease, restrictive cardio-
myopathy, or other diastolic dysfunction. With the catheter
in the pulmonary artery, simultaneous saturations from the
pulmonary artery and left ventricle are obtained for calcula-
tion of cardiac output by the Fick method. Finally, the pul-
monary artery wedge pressure is obtained with confirmation
of the oxygen saturation. Pulmonary arteriolar resistance
should then be calculated from these measurements.
In the presence of elevated pulmonary arteriolar resis-
tance, prognostic information may be obtained using phar-
macologic interventions. Several agents have been used for
this purpose. In general, selective pulmonary arteriolar
dilators (e.g., prostacyclin) are useful in determining the
response of the patient with pulmonary hypertension to
vasodilator therapy. These selective vasodilators should not
be used in patients with elevation of left atrial pressure
because of the potential for pulmonary edema. In these
instances, agents with capability for dilating both the pul-
monary and systemic vascular beds (e.g., nitroprusside)
should be utilized. The response of the pulmonary arteriolar
resistance to pharmacologic interventions is useful for pre-
dicting chronic response to vasodilator therapy, reduction of FIGURE 20.2. Landmarks for transseptal puncture. (Top left) The
pulmonary pressure with left-sided interventions, and candi- target puncture site is located at the intersection of these two lines
(A and B) on frontal fluoroscopy as described in the text. (Top right)
dacy for cardiac transplantation. In general, the target site is located two thirds of the distance (C)
between the aortic valve and posterior border of the left atrium.
(Middle left and right) Advancement of the assembly into the left
Transseptal Puncture atrium. (Bottom left and right) Rotation of the Mullins sheath coun-
terclockwise results in its placement into the left ventricle.
The main indications for transseptal puncture are direct
measurement of left atrial pressure, assessment of the left
ventricle to avoid catheter entrapment from a transaortic
approach, access to the left ventricle with an aortic valve
prosthesis, and performance of percutaneous mitral balloon tion of a horizontal line (M-line) from the tricuspid annulus
valvotomy. The ideal puncture site is the fossa ovalis. The to the lateral border of the right atrium and a vertical line
location of the puncture should be assessed by either biplane that divides the left atrium into anterior and posterior halves
fluoroscopy or echocardiography to avoid injury to adjacent (Fig. 20.2). On lateral fluoroscopy, the puncture site is located
structures (aorta, coronary sinus, tricuspid valve) (Fig. 20.2).4 two thirds of the distance from the aortic valve to the pos-
If fluoroscopy is used, a catheter in the ascending aorta terior border of the left atrium. Of note, in patients with
should be placed to ensure that the puncture is posterior to vertical hearts, the ideal puncture site may be superior to the
the aortic root. Both a Mullins sheath as well as a preformed horizontal M line. In patients with an enlarged left atrium,
Brockenbrough needle are tools that aid in proper perfor- the medial left atrial border may protrude beyond the right
mance of this technique. atrial free wall, thus precluding the use of the M line for
After venous access is obtained, a 0.032-inch straight landmarks. The atrial septum may lie in a more horizontal
wire via the right femoral vein is used to place an 8-French plane in patients with a large left atrium.
(F) Mullins sheath and dilator in the superior vena cava. The With the transseptal needle fixed inside the dilator, the
Brockenbrough needle is inserted into the dilator with the assembly is rotated posteromedially (around 4 o’clock on the
tip just within the end of dilator. The location of the aortic direction indicator) and moved inferiorly from the superior
valve is marked with an arterial diagnostic catheter, and vena cava to the atrial septum. The assembly will move
biplane fluoroscopy is used to guide the approach. On frontal rightward (toward the patient’s left) as it passes into the right
plane fluoroscopy, the puncture site is located at the intersec- atrium and as it moves over the superior limbus of the fossa
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 4 67
ovalis. Slight flexion of the catheter tip with gentle advance- assessment of the severity of the stenosis, mainly from poor
ment of the catheter assembly will occur against the limbus alignment of the Doppler signal with the aortic jet, which
when it is located in the fossa ovalis. Advancement of the results in underestimation of the gradient. When there is a
assembly across the atrial septum is accomplished with discrepancy between the clinical and echocardiographic
gentle pressure and slight protrusion of the Brockenbrough findings in these patients with aortic stenosis, invasive aortic
needle beyond the introducer tip. The location of the assem- valve assessment is indicated.
bly in the left atrium is confirmed with pressure transduc-
tion, oximetry, or contrast injection. Anticoagulation with
Gradient Determination
heparin is administered once access into the left atrium has
been obtained. Following advancement of the sheath into the The assessment of the severity of aortic stenosis requires
left atrium, the introducer and needle are removed with accurate measurement of the left ventricular and ascending
counterclockwise rotation of the sheath, resulting in an ante- aortic pressures and of cardiac output. The left ventricular
rior direction and facilitating access into the left ventricle. and ascending aortic pressures should be measured simulta-
The sheath is vigorously aspirated and then flushed with neously, either via two arterial accesses or a single arterial
heparinized saline. Injury of adjacent structures and cardiac access and a transseptal puncture for left ventricular pres-
perforation with tamponade are the main complications sure. The mean aortic gradient should be measured from
of transseptal puncture; these occur in less than 3% of these two simultaneous pressures, using the average of three
patients.5,6 consecutive beats. In the presence of irregular rhythms, at
least eight to 10 sequential beats should be measured. The
Direct Apical Left Ventricular Puncture mean aortic valve gradient alone can be used to help define
(Brock Procedure) the severity of aortic valvular stenosis in patients with a
normal cardiac output in the absence of significant aortic
The Brock procedure is reserved for patients who require regurgitation (mild, <25 mm Hg; moderate, 25 to 49 mm Hg;
direct measurement of left ventricular pressure, such as severe, ≥50 mm Hg).
those who have both mitral and aortic mechanical valve The pullback of a single catheter from the left ventricle
prostheses that prohibit transvalvular access. The puncture to the aorta may sometimes be performed to determine the
site is at the left ventricular apex, which is located by fluo- peak-to-peak systolic gradient. However, this method is
roscopy or echocardiography. Following location of the site subject to error because variation in the beat-to-beat pressure
and scrubbing and draping it, local anesthesia is used to can occur due to respiration changes and variations in the
infiltrate the region at a location superior to a rib. An 18- or R-R interval. Importantly, the peak-to-peak gradient is not
21-gauge needle with a multihole sheath and inner stylet is physiologic because it is derived from nonsimultaneous
advanced over the superior rib border and parallel to the long recordings (Fig. 20.3). The peak-to-peak gradient may approx-
axis of the left ventricle. Premature ventricular beats fol- imate the true mean aortic valve gradient in some circum-
lowed by pulsatile flow after removal of the stylet indicate stances, particularly at high-pressure gradients (>50 mm Hg).
access into the left ventricle. The sheath itself can then be However, the peak-to-peak gradient does not accurately
used to measure pressures. Complications of apical puncture reflect lower aortic valve gradients, and may be erroneous in
include tamponade or pneumothorax in 3%, pleuritic chest patients with low cardiac output or irregular arrhythmia.
discomfort in 10%, vagal-mediated hypotension in 5%, and In some laboratories, the femoral artery pressure obtained
lower incidences (<1%) of hemothorax, ventricular fibrilla- from the sidearm of the sheath is substituted for the ascend-
tion, and coronary artery laceration.7,8 ing aortic pressure. Errors in aortic valve assessment with
this method occur because of the time delay for the pressure
wave to travel from the ascending aorta to the periphery, and
Aortic Stenosis because of the overshoot phenomenon that is characteristic
of peripheral artery pressures (Fig. 20.4). Pressure overshoot
is due to amplification of the pressure wavefront as it travels
Overview
from a large channel (i.e., aorta) to smaller conduits without
Due to the aging population, senile degenerative aortic ste- a proportional decrease in flow, and is especially prominent
nosis has emerged as a common etiology of patients present- in elderly patients with poorly compliant arteries. While
ing with symptomatic severe valve disease requiring various methods have been proposed to adjust for the poten-
intervention. The classic presentation of the triad of dyspnea, tial errors from the use of femoral artery pressure, they are
angina, and syncope in conjunction with a harsh, late- prone to inaccuracy and cannot be applied to an individual
peaking murmur on auscultation provides the clinician with patient.9 Although the femoral artery pressure should not
the suspicion of critical aortic stenosis. Two-dimensional be used for determination of an aortic valve gradient, this
echocardiography can identify the calcified stenotic aortic femoral artery pressure may be examined for the Carabello
valve, and Doppler echocardiography reliably estimates the sign, in which peripheral pressure increases during catheter
severity of aortic stenosis in the majority of patients. pullback from the left ventricle to the aorta.10 This phenom-
When the noninvasive assessment demonstrates a high enon is believed to be due to partial obstruction of the aortic
mean aortic valve gradient (>50 mm Hg) that correlates with valve orifice by the catheter, which resolves during its pull-
the physical examination, no further hemodynamic assess- back into the aorta. A significant rise in femoral artery pres-
ment is needed, as severe aortic stenosis is unequivocally sure (>10 mm Hg) following catheter pullback has been
present. However, errors may occur in the noninvasive associated specifically with aortic valve areas of <0.6 cm2.
468 chapter 20

200 200
Overshoot

150 150
LV
Ao
FA
100 100
Delay

50 PA 50

LA LA
0 0
FIGURE 20.4. Central aortic and peripheral arterial pressure trac-
ings from one patient with aortic stenosis. (Left) Simultaneous left
ventricular (LV), left atrial (LA), pulmonary artery (PA), and femoral
artery (FA) recordings. There is a temporal delay in the femoral
artery tracing because of the transmission of pressure from the
central aorta to the periphery. This delay can lead to under- or over-
estimation of the gradient and erroneous calculation of the aortic
valve area. Also, due to the femoral artery overshoot, there does not
appear to be a “peak-to-peak” gradient. (Right) Simultaneous left
ventricular (LV), ascending aortic (Ao), and left atrial (LA) recordings
from the same patient. Note the presence of the aortic valve gradient
that was not evident on the tracings on the left-hand side.

Aortic Valve Area

FIGURE 20.3. Aortic valve gradients. Maximum instantaneous
gradient is the maximum pressure difference at any time between The gradient across the aortic valve is dependent not only on
the left ventricle and aorta. “Peak-to-peak” is a nonsimultaneous the severity of obstruction but also on the flow through the
measure of the aortic and left ventricular pressure difference. Shaded
area is the area of planimetry for calculation of mean valvular gradi-
valve. Thus, calculation of the aortic valve area provides
ent. Ao, aortic pressure; LA, left atrial pressure; LV, left ventricular incremental information to the mean gradient. Based on the
pressure. Gorlin equation, the aortic valve area is calculated from the
following formula:
CO ÷ [SEP ⋅ Heart rate ]
Valve area cm2 = ( ) 44.3 ⋅ ΔP
Single arterial access has been used for measurement of
the aortic valve gradient. One method utilizes an 8F double- where CO is the cardiac output in mL/min, SEP is the sys-
lumen pigtail catheter that is advanced retrograde into the tolic ejection period in seconds per beat, and heart rate is in
left ventricle.11 This catheter contains a side hole located beats per minute. The systolic ejection period is the time
10 cm proximal to the distal end hole, enabling simultaneous duration from the aortic valve opening to the dicrotic notch
measurement of the left ventricle and aortic pressures. Care (Fig. 20.1). Normal aortic valve areas range from 3.0 to 4.0 cm2.
must be taken to ensure location of the proximal side hole In general, severe aortic stenosis is less than 1.0 cm2 (Table
above the aortic valve during pressure measurement. 20.1). In patients with a large or small body size, the valve
Damping of the pressure may occur due to the small lumen area may be normalized to body surface area (m2). In these
of the catheter, resulting in erroneous gradient determina- circumstances, severe aortic stenosis is commonly defined
tions. Another technique utilizes a 0.014-inch pressure wire as an indexed valve area of less than 0.5 cm2/m2.
(RADI Medical Systems, Uppsala, Sweden) that has a high- The Hakki equation can be used to calculate aortic valve
fidelity, wire-mounted pressure sensor in its distal end.12 The area in the absence of significant bradycardia, tachycardia,
calibrated pressure wire is placed into the left ventricle or a low output state. This method uses the mean gradient
through a retrograde diagnostic catheter. The catheter is across the aortic valve, and is usually within 10% of the valve
then withdrawn into the ascending aorta with the pressure area calculated from the Gorlin equation.3 In both equations,
wire remaining in the ventricle for simultaneous aortic and
ventricular pressure measurements. While this method has TABLE 20.1. Severity of aortic stenosis
been examined in a small series of patients,13 validation Mild Moderate Severe
of the pressure wire technique against other standard
Valve area >1.5 cm2
1.0 to 1.5 cm 2
<1.0 cm2
methods of aortic valve gradient assessment has not yet been
Mean gradient <30 mm Hg 30 to 50 mm Hg >50 mm Hg
performed.
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 469
concomitant aortic regurgitation causes an overestimation who had contractile reserve (>20% increase in stroke volume
of the true valve area. with dobutamine) had a lower perioperative mortality and a
lower incidence of progressive heart failure and late mortal-
Aortic Valve Resistance ity following aortic valve operation.
An alternative method of evaluating the patient with
Valvular resistance has been proposed as an adjunct measure low-output, low-gradient aortic stenosis utilizes nitroprus-
for determining the clinical severity of aortic stenosis.14,15 side to augment forward output, which leads to higher cal-
Laminar, nonviscous flow through a planar orifice is a limit- culated valve areas in patients without severe aortic stenosis.18
ing assumption of the Gorlin equation, which theoretically This may be potentially useful in patients with systemic
can be overcome by calculation of valvular resistance. The hypertension or resting tachycardia, in whom intravenous
formula for aortic valve resistance is as follows: dobutamine may be contraindicated.
Mean gradient (mmHg ) ⋅ 1.33
( )
Resistance dynes ⋅ sec ⋅ cm−5 =
Systolic forward flow (mL/sec) Levels of Outflow Obstruction
In patients with normal systolic function, a valve resistance Not all patients with left ventricular outflow tract obstruc-
of >250 dynes · sec · cm−5 has been associated with clinically tion have valvular aortic stenosis. The level of obstruction
significant aortic valvular stenosis, whereas a value of <200 may be subvalvular, valvular, or even supravalvular. Sub-
dynes · sec · cm−5 likely indicates minimal obstruction. valvular obstruction may be fixed (discrete subaortic steno-
However, the calculation of aortic valve resistance has not sis, abnormally high profile mitral prosthesis) or dynamic
been shown to provide incremental information to the mean (hypertrophic cardiomyopathy). Although the level of
gradient and valve area.16 obstruction should be diagnosed at echocardiography, these
other types of obstruction may be missed when there are
suboptimal echocardiographic images or limited Doppler
Caveats
interrogation.
Other types of outflow tract obstruction should be sus-
Low-Output, Low-Gradient Stenosis
pected whenever there is a high outflow tract gradient
There is a subset of patients who present with left ventricular without a heavily calcified aortic valve on fluoroscopy. In
systolic dysfunction and a low-output, low-gradient state. the catheterization laboratory, the diagnosis of subvalvular
The valve area will calculate to be in the range of severe obstruction is made by a pullback of the catheter from the
aortic stenosis. Some of these patients have severe aortic left ventricular apex to the left ventricular base to the aorta,
stenosis and secondary left ventricular dysfunction due to preferably with the use of a single end-hole catheter. In
the long-standing severe pressure overload on the left ven- patients with subvalvular obstruction, a systolic gradient is
tricle. However, other patients have a primary depression in present without a change in diastolic pressure when moving
left ventricular systolic dysfunction and concomitant mild the catheter from the left ventricular apex to the left ven-
aortic stenosis. These patients with only mild aortic stenosis tricular base. This finding may be missed if the pullback is
have an overestimation of the severity of stenosis due to the performed too quickly or when a pigtail catheter with mul-
flow dependency of the Gorlin equation in conjunction with tiple side holes is utilized.
inadequate opening of the aortic valve from decreased ino- Attention to the aortic pressure contour may provide a
tropic forces. It is essential to determine the true severity of further clue to the presence of other types of outflow tract
the aortic stenosis, as only patients with severe aortic steno- obstruction. The aortic pressure contour of aortic stenosis is
sis will benefit from surgical intervention. distinctly different from that seen with the dynamic outflow
Dobutamine challenge has been used to differentiate tract obstruction of hypertrophic cardiomyopathy (Fig. 20.6).
the two pathophysiologic processes in these patients with In patients with significant valvular aortic stenosis, the rise
low-output, low-gradient aortic stenosis.17 Dobutamine (5 to in aortic pressure is delayed with a late systolic peak, in
40 μg/kg/min) is infused to normalize the cardiac output contrast to the spike-and-dome configuration of obstructive
during hemodynamic measurements of aortic valve gradient. hypertrophic cardiomyopathy. A fall or failure to augment
Figure 20.5 illustrates representative hemodynamic tracings the pulse pressure on a beat following a premature ventricu-
from three patients with low-output, low-gradient aortic ste- lar contraction (Brockenbrough response) is diagnostic of
nosis who underwent dobutamine infusion. If the cardiac dynamic outflow tract obstruction (Fig. 20.7).
output normalizes and the valve gradient exceeds 40 mm Hg,
severe aortic stenosis is present. Alternatively, in those
patients with normalization of cardiac output and no increase Mitral Stenosis
in mean gradient (less than 30 mm Hg), only mild aortic ste-
nosis is present. Finally, there is a subset of patients who are
Overview
not able to increase the cardiac output with dobutamine
infusion due to the lack of contractile reserve. This lack of The primary etiology of mitral stenosis is rheumatic heart
contractile reserve portends a very poor prognosis irrespec- disease. As the incidence of rheumatic disease has decreased
tive of therapy. In one study, all patients with a final valve in industrialized countries, mitral stenosis has become less
area of <1.2 cm2 and a mean gradient >30 mm Hg at peak common. Nonetheless, mitral stenosis is still prevalent in
dobutamine infusion were found to have surgically con- parts of the United States, particularly in areas with immi-
firmed, severe calcific aortic stenosis.17 Furthermore, patients grant populations.
47 0 chapter 20

A B
Base Dobutamine
Base Dobutamine

AVA Mean LV
Mean
0.8 cm2 24 mm Hg AVA Mean 20 mm Hg
0.8 cm2 47 mm Hg
AVA Mean AVA
0.6 cm2 17 mm Hg 0.7 cm2
100
Ao 100

100 100
Ao Ao
Ao
LV LV
LA

LA
LA LA

0 0 0 0

C
Base Dobutamine
AVA Mean AVA Mean
0.9 cm2 37 mm Hg 0.7 cm2 26 mm Hg
LV LV
100 100
Ao
FIGURE 20.5. Representative hemodynamic findings from three
Ao LA patients demonstrating three different responses to dobutamine. (A)
LA There was an increase in both cardiac output and gradient in
response to dobutamine. The valve area remained 0.8 cm2. The
patient had severe aortic stenosis at operation and was in New York
Heart Association (NYHA) class I following surgery. (B) There was
an increase in cardiac output but only a mild change in the gradient.
This represents mild aortic stenosis. (C) There was no change in
cardiac output, a decrease in the valve gradient, and hypotension
0 0 occurred during the study. Severe aortic stenosis was found at opera-
tion, but the patient died of heart failure 2 years later.

In contrast to aortic stenosis, the hemodynamic assess- Transmitral Gradient

ment of mitral stenosis can be accurately and reliably assessed
with Doppler echocardiography, since the Doppler beam can Proper assessment of the severity of mitral valve stenosis at
be directed parallel to the stenotic jet in nearly all patients.19 catheterization requires simultaneous left ventricular and
The transmitral gradient obtained by Doppler echocardiog- left atrial pressure recordings to obtain the mean transmitral
raphy should be considered a “gold standard” in the evalua- gradient. The pulmonary capillary wedge pressure from a
tion of these patients. Cardiac catheterization for the right heart catheterization has been used for an indirect mea-
hemodynamic severity of mitral stenosis is indicated only surement of the left atrial pressure. The mean pulmonary
when there is a discrepancy between a patient’s symptoms capillary wedge pressure accurately reflects mean left atrial
and lesion severity by echocardiography. The additive infor- pressure in the absence of pulmonary veno-occlusive disease
mation from the results of the catheterization include the or cor triatriatum. However, there is a significant overestima-
measurement of absolute left ventricular, left atrial, and pul- tion of the transmitral gradient (>50% in some cases) when
monary pressures as well as the response of these pressures using the pulmonary capillary wedge pressure and left ven-
to exercise. The severity of concomitant mitral regurgitation tricular pressure (Fig. 20.8). This overestimation may occur
also may need to be determined by cardiac catheterization. in part because of the time delay (usually 50 to 70 ms) for the
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 471

200 200

150 150

100 100

50 50

0 (200) 0
LV Subaortic Aortic
A
FIGURE 20.6. Left ventricular outflow tract obstruction. (A)
Single-catheter pullback from the left ventricle (LV), across the left
ventricular outflow tract (LVOT), and into the ascending aorta (Ao)
in a patient with subaortic stenosis. (B) Similar pullback in a
LV Aortic
patient with aortic valvular stenosis. B

LV

150 mm Hg Ao 150 mm Hg

Ao

LA

RA
0 mm Hg 0 mm Hg

FIGURE 20.7. Pressure tracings after a premature ventricular beat the premature ventricular beat in the patient with hypertrophic
in a patient with a fixed obstruction due to aortic stenosis (left) and cardiomyopathy (i.e., Brockenbrough response) that does not occur
dynamic outflow tract obstruction due to hypertrophic cardiomy- in the patient with aortic stenosis.
opathy (right). Note the decrease in aortic pulse pressure following

FIGURE 20.8. Simultaneous Doppler echocardiography and invasive

catheterization measurement of the transmitral gradient in a patient
with mitral stenosis. (Left) There is excellent correlation of the trans-
mitral gradient by Doppler echocardiography with that obtained by
direct catheterization because the Doppler transducer is easily lined
parallel to the mitral inflow. (Right) There is overestimation of the
true transmitral gradient when the pulmonary capillary wedge pres-
sure is used as a surrogate for left atrial pressure in patients with
mitral stenosis. Dopp, Doppler gradient; LA, left atrium; LV, left ven-
tricle; PCWP, pulmonary capillary wedge pressure.
47 2 chapter 20

A B

FIGURE 20.9. Hemodynamic evalua-

tion of a patient with mitral stenosis. (A)
The mean pressures are obtained by the
pulmonary capillary wedge pressure
(PCWP) and left atrial recordings are the
same. However, note the significant
time delay and blunting of the y descent
C D in the PCWP tracing in comparison to
direct measurement of LA pressure.
These effects can lead to significant
errors in calculation of the mitral gradi-
ent and valve area. (B) Gradient between
PCWP and LV indicated by dark-shaded
area (false mitral valve gradient =
13 mm Hg). (C) Gradient between LA and
LV indicated by light-shaded area (true
mitral valve gradient = 8 mm Hg). (D)
Simultaneous recording of the LA,
PCWP, and LV pressures. Dark shade
indicates area of the false gradient; light
shade indicates area of the true
gradient.

pressure transmission from the left atrium to the pulmonary The diastolic half-time is a semiquantitative, adjunctive
capillaries (Fig. 20.9).19 Phase shifting to align the v-wave measure for assessing the severity of mitral stenosis.20 Its
peak of the wedge pressure curve to coincide with the relax- principle is based on the observation that the rate of decay
ation phase of the left ventricular pressure tracing may be in the transmitral gradient is exponentially and inversely
performed to help correct for the temporal delay. However, related to the degree of valvular obstruction.21 Diastolic half-
even with proper temporal alignment of the wedge pressure, time is calculated as the time in which the peak transmitral
there is a blunting of the y descent, which results in a 20% gradient declines by 50% (Fig. 20.10). Since the rate of pres-
to 30% overestimation of the transmitral gradient. Thus if sure gradient fall is not dependent on transmitral flow, the
catheterization is required for an accurate assessment of the diastolic half-time can be used to estimate the severity of
transmitral gradient, a transseptal approach is necessary to stenosis in patients with mitral regurgitation and irregular
obtain a direct measurement of left atrial pressure. arrhythmia (i.e., atrial fibrillation). The primary determi-
nants of diastolic half-time are the peak transmitral gradient
and the relative compliance between left atrium and left
Mitral Valve Area and Diastolic Half-Time
ventricle. Thus, the half-time may be inaccurate when used
As with aortic stenosis, the mean transmitral gradient is in patients with severe abnormalities of ventricular compli-
dependent not only on the severity of the stenosis but also ance, such as restrictive or hypertrophic cardiomyopathy, or
on the flow through the mitral valve. Thus, a mitral valve after interventions that result in acute changes in net atrio-
area should be calculated as part of the hemodynamic assess- ventricular compliance, such as percutaneous or surgical
ment of a patient with mitral stenosis. Based on the Gorlin valvotomy.22,23 Severe aortic regurgitation also abbreviates
equation, the mitral valve area is calculated from the follow- the diastolic half-time. Values of diastolic half-time for
ing formula: grading the severity of mitral stenosis are as follows: 100 ms,
mild; 200 ms, moderate; and 300 ms, severe.
CO ÷ [DFP ⋅ heart rate ]
( )
Mitral valve area cm2 =
44.3 ⋅ 0.85 ⋅ ΔP
Exercise Testing
where DFP is the diastolic filling period (seconds per beat).
The diastolic filling period is measured from the entire For any given orifice area, the transmitral gradient is propor-
period of mitral valve opening to closure. The normal mitral tional to the square of the transvalvular flow rate. Thus,
valve has an area of 4.0 to 5.0 cm2. Exertional symptoms may some patients who have relatively mild hemodynamic abnor-
occur in patients with mitral valve areas of <2.5 cm2. Severe
mitral stenosis is usually defined as a valve area of ≤1.0 cm2, TABLE 20.2. Severity of mitral stenosis
when transmitral gradients >10 mm Hg are present with a Mild Moderate Severe
normal cardiac output (Table 20.2). An accurate invasive
Valve area >1.5 cm2
1.0 to 1.5 cm2
<1.0 cm2
assessment of valve area requires an accurate measurement
Mean gradient <5 mm Hg 5 to 10 mm Hg >10 mm Hg
of transmitral gradient, which at catheterization is possible
Pressure half time <100 ms 100 to 300 ms >300 ms
only with direct left atrial pressure measurements.
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 47 3
artery, left atrial or pulmonary capillary wedge, and left
ventricular diastolic pressures at rest and during exercise.
The optimal approach for exercise hemodynamics is to
utilize exercise that simulates physiologic stress, such as a
supine or upright bicycle. Other approaches have utilized
arm ergometry or pharmacologic stress, but these techniques
provide less relevant clinical information than exercise.
Arterial or ventricular pacing (if atrial fibrillation is present)
can be used to increase heart rate and decrease the diastolic
filling period, which is a primary determinant of the gradient
in patients with mitral stenosis.
FIGURE 20.10. Diastolic pressure half-time (PHT) measurement in The objective of the exercise hemodynamic study is
a patient with mitral stenosis.
twofold. The first objective is to measure the transmitral
gradient at rest and exercise. A rise in transmitral gradient
to that exceeding 20 mm Hg during exercise associated with
malities at rest may experience symptoms related to their symptoms may be considered an indication for percutaneous
mitral stenosis with exertion.24 For patients whose symp- or surgical relief of mitral obstruction.29 The second objective
toms are out of proportion to the resting hemodynamics, is to examine the rise in absolute pressures and their relation
formal exercise testing with hemodynamics may be war- during exercise. In some patients, the left ventricular dia-
ranted. Testing may be done invasively with right- and left- stolic pressure will rise significantly in conjunction with
heart catheterization or noninvasively with Doppler only a mild increase in transmitral gradient, indicating left
echocardiography.25–28 The advantages of invasive catheter- ventricular diastolic dysfunction as an etiology for symp-
ization are the ability to directly measure the pulmonary toms (Fig. 20.11). In other patients, there will be a rise in

FIGURE 20.11. Representative hemodynamic

tracings from two patients with mitral stenosis
illustrating two different responses to exercise.
(Top) This patient had marked exercise intolerance
but resting hemodynamics were consistent with
mild mitral stenosis. With an increase in heart
rate to 120 bpm, there was a significant increase in
the transmitral gradient (shaded area). (Bottom)
This patient also had symptoms of exercise intol-
erance. With exercise, there was a mild increase in
the transmitral gradient (shaded area). However,
there were marked increases in the left ventricular
(LV) diastolic pressure with relatively rapid filling
(arrows), as well as in the left atrial (LA), and pul-
monary artery (PA) pressure. The increases in LV,
LA, and PA pressures were proportional to the
increase in systemic hypertension, consistent
with exercise-induced diastolic dysfunction. Ao,
aortic pressure.
474 chapter 20

pulmonary artery pressure out of proportion to the rise in ings (clinical exam, two-dimensional echo findings compat-
the left atrial or pulmonary capillary wedge pressure, sup- ible with severe regurgitation, color flow Doppler findings of
porting a pulmonary etiology for the symptoms. severe regurgitation), further invasive evaluation is war-
ranted. This information obtained at cardiac catheterization
includes pressure measurements of the hemodynamic
Caveats
consequences of the valve regurgitation, as well as assess-
The valve area calculation derived by cardiac catheterization ment of the severity of valve regurgitation by contrast
may not be accurate in several circumstances. First, the valve angiography.
area calculation is dependent on accurate measurement of
the transmitral gradient. Thus, significant errors will occur
Pressures and Pressure Contours
when the pulmonary capillary wedge pressure is used, fre-
quently leading to an overestimation of the transmitral gra- The severity of regurgitant valvular lesions can be assessed
dient and a falsely small valve area. The calculation of mitral indirectly by examination of pressure contours. In patients
valve area using the Gorlin equation also is highly dependent with severe mitral regurgitation, the left atrial or pulmonary
on accurate measurement of transvalvular flow (i.e., cardiac capillary wedge pressure tracing may have a large v wave due
output). Since patients with mitral stenosis may have atrial to a rise in left atrial pressure from systolic regurgitation
fibrillation and tricuspid regurgitation, cardiac output back into the left atrium (Fig. 20.12). However, the height of
assessed by the thermodilution method may not be accurate the v wave is also inversely related to atrial compliance and
in such patients. Concomitant mitral regurgitation precludes directly proportional to cardiac output and systemic vascular
accurate measurement of the mitral valve area due to the resistance.30,31 Thus, there may be a large v wave in the
increased flow across the mitral valve. A large transmitral absence of severe mitral regurgitation in patients with severe
gradient with a short half-time may be an indicator of severe diastolic dysfunction. Severe mitral regurgitation also may
mitral regurgitation. not produce a v wave if there is a compliant atrium. There-
An elevation in pulmonary pressures that is out of pro- fore, the finding of a large v wave is consistent but not diag-
portion to the transmitral gradient and mitral valve area nostic of severe mitral regurgitation.
should alert the physician to the presence of concomitant The pulmonary pressure is also an indirect measurement
disorders such as pulmonary disease, mitral regurgitation, or of mitral regurgitation. Although it may be elevated due to
other causes of elevated left-sided diastolic pressures (Fig. a number of other reasons, an indication for intervention on
20.11). The pulmonary artery end diastolic pressure should the patient with few or no symptoms and severe mitral regur-
approximate the left atrial pressure. If the pulmonary artery gitation is the presence of pulmonary hypertension. Thus an
end diastolic pressure exceeds the left atrial pressure by accurate measurement of the pulmonary pressure is helpful
10 mm Hg, intrinsic pulmonary disease should be suspected. for decision making regarding the timing of operation in
Long-standing severe mitral stenosis may lead to pulmonary patients with mitral regurgitation.
arteriolar disease, in which the pulmonary pressure will Patients with chronic severe aortic regurgitation usually
be elevated out of proportion to the elevation of left atrial have a widened aortic pulse pressure from augmented stroke
pressure. volume during systole and a large regurgitant volume during
diastole resulting in a rapid decline in aortic diastolic pres-
sure (Fig. 20.13). There will be a rapid rise in left ventricular
Valvular Regurgitation diastolic pressure, especially in patients with a decompen-
sated left ventricle. In patients with acute aortic regurgita-
tion, a widened aortic pulse pressure may not be present, but
Overview
there will be a rapid elevation of left ventricular diastolic
The workup of the patient with aortic and mitral regurgita- pressure.
tion requires an assessment of the etiology and severity of In all patients with severe tricuspid regurgitation, the
the valve regurgitation as well as the ventricular response to right atrial pressure will be elevated. There usually is a large
the volume overload. This is especially important in the v wave in the right atrial pressure tracing, which rises early
asymptomatic patient, as early valve operation is now being (i.e., cv wave) and, in extreme cases, may resemble the contour
recommended to prevent the detrimental long-term conse- of the right ventricle. When there is a high compliance of the
quences of the volume overload on left ventricular function. right atrium and adjacent vena cava, the cv wave due to tri-
Two-dimensional and Doppler echocardiography have cuspid regurgitation may be blunted (Fig. 20.14). Early rapid
become standard for assessing the etiology of the valve lesion filling in the right ventricular pressure tracing (i.e., dip-and-
and the status of the left ventricle. However, there are major plateau) occurs in severe tricuspid regurgitation due to
limitations to the Doppler assessment of the severity of the volume overload and a decreased effective operative compli-
regurgitation by current methods using only color flow ance of the right ventricle. Pericardial restraint occurs if
imaging. there is severe right ventricular enlargement, resulting in
In the patient with clinically severe mitral regurgitation elevation and equalization of diastolic pressures in the left
and definitive noninvasive evidence of severe mitral regurgi- and right ventricular traces, which can simulate the hemo-
tation (e.g., an unsupported mitral leaflet on echocardiogra- dynamic findings of restrictive cardiomyopathy and con-
phy and a large eccentric jet of mitral regurgitation on color strictive pericarditis (Fig. 20.15). The right atrial–right
flow imaging), no other hemodynamic information is ventricular gradient during diastole should be examined in
required. However, in the absence of any of these three find- these patients to rule out concomitant tricuspid stenosis,
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 475

100

LV
100

50
50 PA
LA
LA

0
0

FIGURE 20.12. Pressure recordings before and after percutaneous balloon mitral valvuloplasty, acute severe mitral regurgitation
balloon mitral valvuloplasty. (Left) At baseline, there is a mean occurs. The v wave in the left atrial tracing is markedly augmented
transmitral gradient of 8 mm Hg. (Right) Following percutaneous with a height that approaches 60 mm Hg.

particularly in patients with rheumatic disease. Patients

with tricuspid stenosis have large a waves and blunting of
the y descent on the right atrial pressure curve.

Angiographic Severity
Assessment of valvular regurgitation may be performed
with injection of contrast into the chamber or great vessel

FIGURE 20.13. Simultaneous ascending aortic and left ventricular FIGURE 20.14. Right atrial pressure recordings from two patients
pressure recordings in a patient with severe aortic regurgitation. with severe tricuspid regurgitation. (Top) Large cv waves due to
Note the early rapid rise in left ventricular (LV) diastolic pressure severe tricuspid regurgitation. (Bottom) In contrast to the patient in
(arrows) and the concomitant fall in aortic diastolic pressure, which the top figure, this patient also had severe tricuspid regurgitation
approaches the LV pressure at end-diastole. but much less prominent v waves.
476 chapter 20

120

120

LV
80 LV
80
Ao

40
40
RV RV

FIGURE 20.15. Pericardial restraint from tricuspid regurgitation sure tracing from a patient with severe tricuspid regurgitation. Note
mimicking constrictive pericarditis. (Left) Right ventricular and left the early dip-and-plateau with equalization of pressures between
ventricular pressure tracing from a patient with constrictive peri- the right ventricle and left ventricle in the diastolic phase.
carditis. (Right) Right ventricular (RV) and left ventricular (LV) pres-

just distal to the regurgitant valve. Biplane angiography [60 this method has been used as the standard by which surgical
degrees left anterior oblique (LAO), 30 to 40 degrees right decisions have been made for decades, and current outcome
anterior oblique (RAO)] is preferred to allow two views of the data for patients with valve disease is based on this method.
receiving chamber. Contrast volume and injection rates typi- Similar angiographic methods are used to grade the severity
cally are 40 to 50 mL at 12 to 15 mL/sec for mitral or tricuspid of aortic regurgitation and tricuspid regurgitation.
regurgitation, and 50 to 60 mL at 20 mL/sec for aortic regur-
gitation. It is important to use a large-bore catheter to avoid
Regurgitant Fraction and Regurgitant Volume
“whip” of the catheter during the injection. In patients with
mitral and tricuspid regurgitation, a 6F or larger pigtail or Calculation of regurgitant fraction and regurgitant volume
Rodriguez catheter is recommended. A 5F or larger pigtail provide a more quantitative method for determining the
with a large bore is recommended for aortic root injections. severity of regurgitation. However, this is a method that can
When performing left ventriculography for mitral regur- be reliably performed only in laboratories that have expertise
gitation, it is important set up the RAO projection to ensure in this measurement, and thus is not routinely done in con-
that the left atrium and descending aorta do not overlap, as temporary practice. Regurgitant fraction is the proportion of
this overlap may mask the entry of dye into the left atrium. the volume of regurgitation to the total amount of blood
This setup may require increasing the RAO angle to 40 to ejected from the left ventricle. The total amount of blood
45 degrees. It is critical to position the catheter to avoid
ventricular ectopy during the injection. A pigtail catheter
should be placed at the base of the heart with the curve of
the pigtail away from the septum on the LAO view. Test
injections during deep inspiration are used to ensure optimal
position of the catheter without ectopy or catheter-induced
mitral regurgitation during the contrast injection. TABLE 20.3. Severity of mitral regurgitation (Sellers criteria) 32
The Sellers criterion for regurgitation severity is the stan- 1+ Contrast does not completely fill left atrium
dard for semiquantitation of valve regurgitation (Table 20.3).32 2+ Contrast completely opacifies left atrium but does not reach
The degree of opacification of the receiving chamber by con- the intensity of the contrast in the left ventricle
trast is dependent not only on the severity of regurgitation 3+ Contrast completely opacifies left atrium and reaches
but also on the amount of contrast injected, rate of injection, intensity of the contrast in the left ventricle after four heart
ventricular function, and size of the heart chambers. The beats
severity of regurgitation cannot be assessed if there is ven- 4+ Contrast completely opacifies left atrium and reaches
tricular ectopy produced during the injection. Although intensity of contrast in the left ventricle within two or three
beats
there are many limitations to this angiographic technique,
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 47 7
ejected (i.e., total volume) is derived from a left ventriculo- across the valve.33 The high velocities within the prosthetic
gram by subtracting left ventricular end-systolic volume valve detected by Doppler echocardiography will lead to an
from end-diastolic volume. Forward flow volume, the net overestimation of the true effective gradient. The amount of
amount of blood moved to the systemic circulation, can be pressure recovery that occurs is directly related to the ratio
derived from cardiac output obtained by the Fick method. of the effective orifice area to the aortic area at the level of
The regurgitant fraction calculation is as follows: the prosthesis, as smaller ratios predispose toward the devel-
opment of flow eddies that dissipate the blood flow and result
Forward flow volume = Cardiac output (from Fick equation)
in loss of the kinetic energy. The pressure recovery phenom-
÷ Heart rate
enon is particularly prominent in patients with small bileaf-
Regurgitant volume = Total volume − Forward flow volume let prosthesis (19 to 21 mm) and with small aortas (diameter
<3.0 cm).
Regurgitant fraction = Regurgitant volume ÷ Total volume
In general, valvular regurgitation is graded as mild for regur-
Approach to Cardiac Catheterization
gitation fraction <20%, moderate for 20 to 40%, moderately
severe for >40 to 60%, and severe for >60%. A regurgitant In patients with suspected prosthetic valve obstruction,
fraction also cannot be used when both significant aortic and cardiac catheterization accurately determines the true
mitral regurgitation are present. The major limitation of severity of obstruction, as the catheterization gradient is
regurgitant fraction is its reliance on ventriculography for not affected by pressure recovery. However, cardiac catheter-
accurate volume assessment. Unless the laboratory has an ization in the patient with suspected prosthetic valve
expertise in reliable reproducible measurement of ventricu- malfunction can be challenging, given the obstruction to
lar volume, this method should not be used. access that may be presented by the prosthesis. Catheters
should not be placed retrograde across mechanical prosthe-
ses. Such placement causes hemodynamic alterations in
Prosthetic Valves patients with ball-cage and disk prostheses from catheter-
induced regurgitation. In addition, placement of a catheter
may result in entrapment of the catheter, particularly if it is
Overview
placed in the minor orifice of the tilting disk prosthesis.
The implantation of a prosthetic valve is a lifesaving proce- Retrograde catheterization should be avoided even with the
dure for the patient with severe valvular heart disease. older tissue prostheses, due to calcific deposits on the valve
Prosthetic valves may eventually malfunction, either with leaflets, which may become dislodged by the catheter. The
obstruction (from thrombosis or pannus formation) or regur- pulmonary capillary wedge pressure should not be used to
gitation (periprosthetic or through a prosthesis). The nonin- determine the transmitral gradient in patients with mitral
vasive assessment of prosthetic valve malfunction is more valve prosthesis. Thus the hemodynamic assessment of valve
difficult than with native valves. Thus, the catheterization prostheses may require alternative procedures, such as a
laboratory plays a major role in the hemodynamic evaluation transseptal approach or a Brock procedure. It is particularly
of the patients with suspected prosthetic valve malfunction. important in this assessment to obtain simultaneous proxi-
However, the invasive evaluation of a patient with a pros- mal and distal pressures as well as an accurate measurement
thetic valve itself can be very challenging as the prosthesis of cardiac output. Both the gradient as well as a calculated
itself may prohibit access to the cardiac chambers. effective orifice area should be obtained when obstruction is
The two-dimensional echocardiographic evaluation of suspected.
the patient with a suspected prosthetic malfunction is Fluoroscopy of the prosthetic valve is a useful adjunct to
limited by acoustic shadowing that is produced by the pros- the assessment of mechanical prosthetic valve dysfunction
thesis. This shadowing decreases the ability to visualize disk in the cardiac catheterization laboratory. This should be
or poppet motion, and prevents assessment of prosthetic done on all patients to assess proper seating of the valve
valve regurgitation by color flow Doppler imaging. This is prosthesis, and to assess disk or poppet motion. Proper fluo-
particularly pertinent in patients with regurgitant mitral roscopic evaluation requires alignment of the x-ray beam
prostheses, in whom imaging of color flow jets in the left perpendicular to the valve ring and valve disks to permit
atrium is severely hampered by the acoustic shadowing of measurement of the opening, closing, and travel angles of
the prosthesis. the leaflets. Normal values of these angles for each specific
As with native mitral valve stenosis, the Doppler trans- valve type and size have been published (Table 20.4).34–37
mitral gradient in the patient with a mitral valve prosthesis Prosthetic dysfunction is usually defined as an opening angle
is reliable and accurate. The transmitral gradient by Doppler less than two standard deviations of the angles derived from
is more accurate than that obtained by conventional cardiac a normal prosthesis.
catheterization using a pulmonary capillary wedge pressure, In patients with suspected prosthetic valve regurgita-
due to the inherent problems of the wedge pressure as previ- tion, contrast angiography may be necessary. Aortic root
ously described. However, the Doppler evaluation of an aortic angiography in patients with aortic prosthesis and left
prosthetic valve may not accurately reflect the true degree of ventriculography in patients with mitral prosthesis may
obstruction, due to the phenomenon of pressure recovery. be a required diagnostic modality. As with native valve
This phenomenon refers to the recovery of kinetic energy of regurgitation, the upstream pressures may be of additional
blood into a pressure head following its acceleration through value in determining the hemodynamic consequence of the
the prosthetic orifice, which reduces the net pressure loss regurgitation.
47 8 chapter 20

TABLE 20.4. Fluoroscopic characteristics of normal prosthetic heart valves35–37

Valve model Closing angle (degrees) Opening angle (degrees) Disk movement (degrees)

Sorin tilting disk 0 60 60

Björk-Shiley (spherical) 0 60 60
Björk-Shiley (convexo-concave 60 degrees) 0 60 60
Björk-Shiley (convexo-concave 70 degrees) 0 70 70
Björk-Shiley (Monostrut) 0 70 70
Medtronic Hall
Aortic 0 75 75
Mitral 0 70 70
Lillehei-Kaster 18 80 62
Omniscience 18 80 62
St. Jude Medical 10–13 120–124*; 130–135† 54–56.5*; 57.5–62.5†
CarboMedics 23–27 128–136 51.0–55.0
Sorin Bicarbon 20–25 136–141 56.5–60.0
Jyros 20–24 108–115 42.0–46.5
Edwards-Duromedics
Aortic 25–29 148 59.0–61.5
Mitral 32–38 148 55.0–58.0
* Valve ring 19–25 mm. † Valve ring 29–33 mm.

Balloon Mitral Valvotomy are assigned according to the morphologic characteristics of

the mitral valve and summated (Table 20.5). A score of ≤8 is
indicative of a pliable, noncalcified valve without significant
Overview subvalvular fusion and has been shown to be predictive of
The pathophysiologic abnormality in the patient with mitral procedural success and long-term event free survival.39–41
stenosis is obstruction to inflow due to fusion of the mitral In addition to the Abascal score, it is necessary to also
valve commissures. The treatment of mitral stenosis has determine the presence or absence of calcification in the com-
been either surgical valvotomy to split the commissures or missures, since it is the splitting of these commissures that
mitral valve replacement. Percutaneous balloon mitral val- is the dominant mechanism by which balloon valvotomy
votomy was first introduced in the 1980s as an alternative leads to relief of mitral stenosis. Calcification of the commis-
treatment for patients with isolated mitral stenosis. Because sures may result in tearing of the valve leaflets during balloon
of the significant improvements in its technique and the
equipment over the years, percutaneous balloon mitral val-
votomy presently is the procedure of choice for selected
patients with severe mitral stenosis.38 TABLE 20.5. Abascal scoring system 39,40
Leaflet mobility
Patient Selection and Indications 1 Highly mobile valve with restriction of only leaflet tips
2 Reduced mobility of the midportion and base of leaflets
The success of balloon mitral valvotomy relies on splitting 3 Valve leaflets move forward in diastole mainly at the base
of the valve commissures without acute disruption of the 4 No or minimal forward movement of the leaflets in diastole
valve leaflets on the remaining supporting apparatus. Thus, Valvular thickening
assessment of the valve morphology is crucial in the proper 1 Near normal (4–5 mm)
2 Mid-leaflet thickening with marked thickening of the margins
selection of patients for this technique. Several methods for
3 Thickening extends through entire leaflets (5–8 mm)
examining the morphology of the mitral valve have been 4 Marked thickening of all leaflet tissue (>8–10 mm)
proposed.39–41 The primary goal of these methods is to deter- Subvalvular thickening
mine the mechanism of commissural fusion and the pliabil- 1 Minimal thickening of chordal structures below the valve
ity of the mitral valve, both of which directly correlate with 2 Chordae thickening extending less than one third of chordal
procedural success rate, acute complication rates, and long- length
3 Thickening extending to the distal third of chordae
term outcome. It is also important to assess the subvalvular
4 Extensive thickening, chordae shortening extending to papillary
apparatus, as retraction, shortening, and fusion of the chordae muscle
and papillary muscles will preclude an adequate result from Valvular calcification
balloon dilatation. 1 Single area of increased echo brightness
The Abascal score is a well-accepted semiquantitative 2 Scattered areas of brightness confined to leaflet margins
system that assesses the suitability of the valve morphology 3 Brightness extending into midportion of leaflets
4 Extensive brightness through most of the leaflet tissue
for this procedure.40 In this scoring system, one to four points
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 47 9
inflation due to the differential stress effects of the inflated Technique
balloon. The presence of commissural calcification is more
predictive of adverse events than the Abascal score.41 The 3- The most common technique for balloon mitral valvotomy
year survival free of death, mitral valve replacement, or repeat employs a transvenous, antegrade approach with a single
percutaneous mitral balloon valvotomy is 86% ± 4% among Inoue balloon system. Retrograde, transarterial approaches
patients without commissural calcium versus 40% ± 11% for have been utilized to obviate the need for a transseptal punc-
those with such calcium (p < .001) (Fig. 20.16). While the ture, but this technique is technically challenging with
Abascal score also is predictive of final mitral valve area and higher complication rates.43 A double-balloon technique was
long-term outcomes, patients with high Abascal scores may initially used in which two balloons are inflated across the
still have a successful balloon valvotomy if there is no heavy mitral valve. However, as compared to the Inoue balloon, the
calcification of the valve commissures. double-balloon technique is associated with higher compli-
Candidates for balloon mitral valvotomy are those cation rates of clinically significant atrial septal defects and
patients with symptoms due to moderate or severe mitral left ventricular perforation, due to the movement of the bal-
stenosis (mitral valve area <1.5 cm2) and a pliable valve that loons during inflation.
is considered suitable for the procedure. Asymptomatic The majority of centers now use the specially designed
patients with moderate or severe mitral stenosis also may be Inoue balloon. This hourglass-shaped balloon is made so that
considered is there is favorable valve morphology, especially increasing inflation pressures will first inflate the distal end
if there is pulmonary hypertension or new onset of atrial of the balloon in the left ventricle, followed by the proximal
fibrillation. In pregnant patients, balloon mitral valvotomy end of the balloon in the left atrium to ensure centering and
has been used successfully to treat increasing symptoms of fixation of the balloon across the mitral valve. Full inflation
heart failure.42 of the balloon inflates the center of the balloon, which dilates
In patients with heavily calcified immobile mitral valve the mitral valve. Comparable reduction in the mitral valve
leaflets with significant subvalvular fusion, percutaneous gradient occurs with either the double- or single-balloon
mitral balloon valvotomy is associated with higher compli- (Inoue) method.44–47 A major advantage of the single-balloon
cation rates (mainly due to severe mitral regurgitation) and Inoue system over the double-balloon method is the ability
lower acute success rates. There is a poorer long-term outcome to gradually up-size the balloon, less fluoroscopy time during
due to a high restenosis rate. In these patients the increased positioning of the balloon, and the self-centering nature of
risk of this procedure must be weighed against the risks of the Inoue balloon.48,49
a mitral valve replacement. The technique of performing a successful procedure
Ineligible patients are those with moderate or severe requires a transseptal puncture directly through the fossa
mitral regurgitation because of the potential for worsening ovalis. Transseptal punctures superior or inferior to the fossa
of regurgitation that may occur with valvuloplasty. Patients ovalis may result in difficulty crossing the mitral valve with
should all have a transesophageal echocardiogram prior to the balloon catheter. Once the transseptal puncture is per-
procedure to rule out a left atrial thrombus. If a left atrial formed, anticoagulation with heparin, and baseline assess-
thrombus is present, patients may be reconsidered for mitral ments of the mitral valve area, gradient, cardiac output,
balloon valvotomy following anticoagulation with warfarin pulmonary blood pressure, and severity of mitral regurgita-
and resolution of the thrombus. However, a persistent throm- tion are performed. Selection of Inoue balloon size is deter-
bus is a contraindication to percutaneous mitral balloon mined by the patient’s height according to the following
valvotomy. formula:

Balloon size (mm) = [height (cm) ÷ 10] + 10

Each Inoue balloon catheter is prepared and examined for

accuracy of inflation size prior to insertion. A heavy-duty
100 Abascal score ≤ 8 100 Calcification absent spring coil guidewire is placed through the transseptal sheath
into the left atrium. The transseptal sheath is exchanged
Probability of survival (%)

80 80 for a 14F long dilator, which is used to dilate the interatrial

septum. The Inoue balloon is elongated, passed over the
Abascal score > 8 guidewire into the left atrium, and then shortened. The
60 60
spring coil guidewire is exchanged for a J-tipped stylet, which
40 40 Calcification present is used to guide the balloon through the mitral orifice with
care to avoid entanglement of the device and the subvalvular
apparatus.
20 20
Following removal of the stylet, the distal part of the
balloon is inflated in the left ventricle and pulled back to
0 0 appose the mitral valve. Sequential inflation of the proximal
0 1 2 3 0 1 2 3
compartment and midsection of the balloon follows, facili-
Years from procedure Years from procedure tating commissural splitting. During the procedure, repeat
No. at risk assessment of the transmitral gradient, severity of mitral
46 33 22 59 45 31
regurgitation, and pulmonary pressures with echocardiogra-
28 22 15 14 10 6
FIGURE 20.16. Survival according to the presence of commissural phy or invasive monitoring is performed. Repeated or subse-
calcium in patients undergoing balloon mitral valvuloplasty. quent dilatation with larger inflation sizes with the Inoue
480 chapter 20

Before PMBV After PMBV single-balloon system, ventricular perforation in 0.5% to 4%,
systemic embolization in 0.5% to 3.0%, myocardial infarc-
tion in 0.3% to 0.5%, and mortality in <2%. Given the com-
plexity of the procedure, acute outcomes also have been
DOPP 10 mm Hg –20 mm Hg directly correlated with operator experience.48,52,53 Overall, in
20 mm Hg DOPP 4 mm Hg patients with favorable morphology, the success rate in expe-
rienced hands is greater than 90% with a complication rate
of less than 3%.
Event-free survival (freedom from death, repeat valvot-
omy, or mitral valve replacement) over 3 to 7 years is 50% to
70% overall, but exceeds 90% in those with favorable valve
Mean 11 mm Hg Mean 4 mm Hg morphology. Randomized, albeit small, investigations have
demonstrated comparable clinical outcomes of balloon mitral
0 mm Hg –0 mm Hg
valvotomy and surgical mitral commissurotomy for selected
FIGURE 20.17. Acute hemodynamic effects of percutaneous mitral patients with mitral stenosis.54–58 These investigations
balloon valvotomy (PMBV). Dopp, Mitral gradient by Doppler enrolled primarily young patients (mean age <30 years) with
echocardiography. favorable valve morphology) and are summarized in Table
20.6.
balloon can be performed in a stepwise fashion in 1- to 2-mm
increments until the desired mitral valve area is achieved. Balloon Aortic Valvotomy
After successful dilatation, the balloon is elongated in the
left atrium to prevent an atrial septal defect during with-
drawal of the balloon back into the right atrium. Following Overview
removal of the balloon catheter, an oxygen saturation run is Percutaneous balloon aortic valvotomy was introduced by
performed to exclude significant left-to-right shunting, and Lababidi et al.59 in 1984 and has become the treatment of
residual mitral regurgitation is assessed by either echocar- choice for noncalcified congenital aortic stenosis in children
diography or left ventriculography. and young adults. In the mid-1980s, Cribier et al. generated
great enthusiasm when they successfully performed this pro-
Outcome cedure in three elderly patients with critical aortic stenosis
Valve morphology is the predominant determinant of due to calcific degenerative disease. Although there was an
outcome and complications after balloon valvotomy. Other acute improvement in hemodynamics and symptom relief in
factors that are associated with the success rate include age, these critically ill patients, subsequent follow-up studies
functional class, ventricular diastolic pressure, severity of have shown a high restenosis rate and no improvement in
stenosis, and cardiac output.50 In general, there is a doubling survival in these critically ill elderly patients. Thus percuta-
of the mitral valve area (usually 1.0 cm2 to 2.0 cm2) and a 50% neous aortic balloon valvotomy in adults now has limited
to 60% reduction in the transmitral gradient (Fig. 20.17). indications and is rarely performed. The following discussion
Procedure success has been defined as a final mitral valve focuses on aortic balloon valvotomy in the older adult.
area >1.5 cm2 and decrease in left atrial pressure to <18 mm Hg
Patient Selection
in the absence of complications, and it occurs in 70% to 95%
of patients, depending on the underlying valve morphology.51 Patients with stenosis due to congenital abnormalities of the
Complications include acute severe mitral regurgitation in aortic valve and no significant calcification may have signifi-
2% to 10%, large residual atrial septal defect (Qp/Qs > 1.5) cant relief of obstruction due to splitting of the commis-
in 12% with the double-balloon technique and <5% with the sures.60–62 However, in patients with senile degenerative aortic

TABLE 20.6. Clinical trials of percutaneous and surgical mitral commissurotomy

Mitral gradient MVA
Mean No. of Average Freedom from NYHA
Study follow-up Procedure patients score Pre Post Pre Post Restenosis reintervention FC I

Patel et al. Immediate PMBV 23 6.0 12 ± 4 4±3 0.8 ± 0.3 2.1 ± 0.7
(1991)54 CC 22 6.0 12 ± 5 6±4 0.7 ± 0.2 1.3 ± 0.3
Turi et al. 8 mo PMBV 20 7.2 18 ± 4 10 ± 2 0.8 ± 0.2 1.6 ± 0.2
(1991)57 CC 20 8.4 20 ± 6 12 ± 2 0.9 ± 0.4 1.7 ± 0.2
Arora et al. 22 mo PMBV 100 23 ± 5 5±3 0.9 ± 0.3 2.4 ± 0.9 5%
(1993)55 CC 100 26 ± 3 6±4 0.8 ± 0.2 2.2 ± 0.9 4%
Reyes et al. 3 yr PMBV 30 6.7 0.9 ± 0.3 2.4 ± 0.6 10% 72%
(1994)56 OC 30 1.0 0.9 ± 0.3 1.8 ± 0.4 13% 57%
Ben Farhat 7 yr PMBV 30 6.0 0.9 ± 0.2 2.2 ± 0.4 7% 90% 87%
et al. OC 30 6.0 0.9 ± 0.2 2.2 ± 0.4 7% 93% 90%
(1998)58 CC 30 6.1 0.9 ± 0.2 1.6 ± 0.4 37% 50% 33%
CC, closed commissurotomy; MVA, moral valve area; NYHA FC I, New York Heart Association Functional Class I; PMBV, percutaneous mitral balloon
valvotomy.
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 4 81
stenosis, the mechanism of aortic valvotomy is annular observed an increase in the aortic valve area from 0.5 cm2 to
stretching and fracture of calcific deposits, resulting in only a 0.8 cm2, a decrease in the gradient from 60 mm Hg to
modest reduction in gradient. Restenosis occurs in nearly 30 mm Hg, and little increase in cardiac output.
100% of patients after 6 to 12 months and may cause acceler- For patients with degenerative aortic stenosis, complica-
ated symptoms. Thus, the current main indication for aortic tions are a major limitation of balloon aortic valvotomy. These
balloon valvotomy is limited to patients who are hemody- occur in approximately 20% of patients, including stroke in
namically unstable as a bridge to aortic valve replacement. 1.4% to 5.5%, emergency aortic valve replacement in 1.2%,
Occasionally, aortic balloon valvotomy may be used as pallia- ventricular perforation in 1.4% to 3.6%, local vascular injury
tive therapy in those with significant comorbid conditions in 4.1% to 10.0%, and procedural death in 1.8% to 7.5%. Pro-
and a limited life span, but this should not be considered a cedural complications are a strong predictor of in-hospital
primary indication for this procedure. Ineligible patients are mortality, occurring most commonly in patients with coro-
those with moderate or severe aortic regurgitation because of nary atherosclerosis, severe functional class, and those who
the potential for worsening of regurgitation with valvotomy. are female. Other important variables associated with in-hos-
pital mortality are left ventricular dysfunction, the severity of
aortic stenosis at baseline, and the final valve area.70
Technique
Restenosis of the aortic valve, defined as 50% reduction
The retrograde aortic approach from femoral artery access is in the acute gain in valve area, occurs in 50 to 65% of these
most commonly used for balloon aortic valvotomy. Initial patients at 6 months and reaches nearly 100% at 1 year.71
measurements are made with one catheter in the left ventri- There also is a continued high rate of late mortality that is
cle and the other in the ascending aorta. Following baseline not different from untreated patients, likely due to the severe
hemodynamic assessment, the left ventricular catheter is comorbidities that are present in these highly selected
exchanged for a 0.038-inch heavy-duty, exchange length patients. Thus, balloon aortic valvotomy remains a palliative
(300 cm) guidewire with a “pigtail” curve made at the end of measure rather than an alternative to aortic valve replace-
the wire. The prepared, deflated balloon catheter is then ment in patients with calcific aortic stenosis.
advanced over this guidewire to straddle the aortic valve
using the proximal and distal balloon markers. In general, a
balloon diameter less than 120% of the annulus size mea- Percutaneous Valve Replacement and Repair
sured on echocardiography is utilized.63 Most operators start
with a 20-mm balloon, but smaller sizes (15 or 18 mm) may Surgical operation remains the standard approach for valve
be used for patients with smaller body surface area (<1.8 m2). replacement. Percutaneous valve replacement was first
The balloon is inflated slowly with pressure on the catheter attempted several decades ago, but significant technical
to maintain stable positioning across the aortic valve, fol- hurdles hindered its progress.72,73 Nonetheless, in 1992, Ander-
lowed by rapid inflation with the appropriate necessary force sen and coworkers74 demonstrated the feasibility of the percu-
to reach its maximum diameter. Inflation is usually less taneous approach by attaching a porcine bioprosthesis to a
than 10 seconds, using the disappearance of a “waist” on the wire-mounted stent, and successfully implanting the device
balloon as a sign that the valve has been adequately dilated. in various aortic positions. Subsequently, Bonhoeffer and
Transient myocardial ischemia, as measured by coronary coworkers75,76 tested a bovine valve mounted on an expandable
sinus flow and metabolites, occurs during balloon inflation stent in animals, and then successfully implanted the device
that resolves immediately with deflation.64 Both the myocar- into the pulmonary position in a 12-year-old boy.
dial ischemia and the increased afterload imposed by balloon In the first reported series in humans, Cribier and cowork-
inflation lead to depression of ventricular function. Systolic ers77 performed percutaneous aortic valve implantation with
blood pressure usually decreases modestly, but can be pre- a 23-mm prosthesis (Cribier-Edwards) in six nonsurgical
cipitous in patients with left ventricular dysfunction. In the patients (mean age, 75 years) with end-stage calcific aortic
event that the desired aortic valve area has not been achieved, stenosis. This prosthesis consists of three bovine pericardial
inflations can be repeated following a period of stability with leaflets mounted on a 15-mm balloon-expandable stainless
larger balloon (23 mm), or, in some instances, double bal- steel stent (Edwards Lifesciences, Irvine California) delivered
loons (i.e., two 15- or 18-mm balloons). The double-balloon via an antegrade approach (Fig. 20.18). Successful delivery
approach allows venting during inflation as an attempt to occurred in five patients with an increase in the effective
improve patient tolerance.65–67 aortic valve area from 0.5 ± 0.1 cm2 to 1.70 ± 0.1 cm2, a
decrease in the gradient from 38 ± 11 mm Hg to 7 ± 3 mm Hg,
and an increase in left ventricular ejection fraction from 24%
Outcome
± 10% to 41% ± 12% at follow-up. Complications included
Several registries have documented the acute hemodynamic one death due to early migration and severe paravalvular
benefits, complications, and long-term outcomes with regurgitation in two, but coronary artery patency was pre-
balloon aortic valvotomy. The Mansfield balloon aortic valve served in all patients. Other percutaneous aortic valve pros-
registry reported on 492 patients who underwent the proce- theses include the CoreValve self-expanding prosthesis,
dure at 27 institutions from 1986 to 1987 in the United States which has been implanted in two patients in Europe. Tech-
and Europe.68 The National Heart, Lung, and Blood Institute nological development of suitable prostheses is ongoing, with
(NHLBI) Balloon Valvotomy Registry examined the out- targeting of the major obstacles to successful percutaneous
comes of 674 patients from 24 institutions in the United treatment of aortic stenosis. These challenges include
States from 1987 to 1989.69 Overall, these investigations (1) accurate placement within the native valve without
482 chapter 20

FIGURE 20.19. The Cardiac Dimensions (KirKland, Washington)

device for percutaneous mitral annuloplasty.

have been two main approaches, both of which emulate sur-

gical techniques. The first method employs one or two metal-
lic clips (Evalve Inc., Redwood City, CA) through an antegrade
approach. The clips attach the free edges of the midportions
of the anterior and posterior mitral valve leaflets to each
other, creating a double-orifice valve and reducing mitral
regurgitation similar to the surgical Alfieri repair.78,79 In a
FIGURE 20.18. The Cribier-Edwards percutaneous aortic valve. report of the multicenter Endovascular Valve Edge-to-Edge
Repair Study (EVEREST) Phase 1 study, Feldman and cowork-
ers80 successfully deployed the Evalve clip in 17 symptomatic
patients with grade ≥3+ mitral regurgitation. There was a
significant reduction in mitral regurgitation with 13 of the
obstruction of the native coronary arteries; (2) minimizing patients having residual regurgitation of grade 2+ or less.
the risk of embolization of the prosthesis and native valve The second method emulates surgical mitral annulo-
debris; (3) retention of the prosthetic position without para- plasty by implanting devices in the coronary sinus, whose
valvular regurgitation; and (4) long-term durability. course roughly parallels the plane of posterior mitral annulus.
While balloon valvotomy has become the preferred These devices, when deployed, foreshorten the coronary
therapy for selected patients with mitral stenosis, ongoing sinus and thereby plicate or straighten the posterior annulus,
studies are evaluating percutaneous techniques for mitral leading to a reduction in the mitral annular diameter and
valve repair for patients with mitral regurgitation. There regurgitation (Figs. 20.19 and 20.20). There have been several

4 1.00
MR jet area/ LA area
MR grade (0–4)

3 0.75

2 0.50
* *
1 0.25

0 0.00
Baseline Post-device Baseline Post-device
Angiographic MR gade MR jet area/ LA area

0.25 20
Regurgitant volume (mL)

0.20
15
ERO (cm2)

0.15
10
0.10 * *
5 FIGURE 20.20. Acute effects of percutaneous
0.05
mitral annuloplasty with the Cardiac Dimen-
0.00 0 sions device in dogs. (A) Grouped data for all
Baseline Post-device Baseline Post-device parameters of mitral regurgitation (MR) sever-
ity at baseline and post-device (p < .05 vs.
A ERO Regurgitant volume baseline).
 va lv u l a r h e a r t d i s e a s e i n t h e c a r d i a c c a t h e t e r i z a t i o n l a b o r a t o r y 483

B Baseline Post-device

C Baseline Post-device

D Baseline Post-device

FIGURE 20.20. Continued. ERO, effective

regurgitant orifice. Representative examples of
contrast ventriculography (B), MR jet area/left
atrial area (C), and proximal isovelocity surface
area measurements (D) before and after device
placement in a single dog are shown. In B,
arrows indicate reflux of contrast into pulmo-
nary veins.

animal studies demonstrating the potential efficacy of this sinus to the left circumflex artery, which may be injured
approach.81–83 The main challenges to this technique will be during device deployment. For either percutaneous approach
reliance on the coronary sinus, which can be mobile and is to mitral valve repair, efficacy as a stand-alone intervention
subject to thrombosis, erosions, and other complications as also will need to be compared to open surgery, which is fre-
has been demonstrated in studies of patients who undergo quently supplemented with other adjunctive measures (e.g.,
biventricular placing; and the proximity of the coronary leaflet resection, chordal surgery).
484 chapter 20

These new technologic advances are potentially a less tion. The clinical utility of the dobutamine challenge in the
invasive therapeutic approach to the patient with valvular catheterization laboratory. Circulation 2002;106:809–813.
heart disease. There has been great enthusiasm generated for 18. Carabello BA, Ballard WL, Gazes PC. Cardiology Pearls. Phila-
this concept of catheter-based therapy for these patients. delphia: Hanley & Belfus, 1994:142.
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However, the ultimate role of this technology will need to
measurement of the transmitral gradient in patients with
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 2 Echocardiographic
1 Assessment of Valvular
Heart Disease
Raymond F. Stainback

Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 Mitral Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

Grading System for Valve Lesions . . . . . . . . . . . . . . . . . . 488 Tricuspid Valve Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Jet Lesion Anatomy by Color Doppler . . . . . . . . . . . . . . . 489 Pulmonary Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . 528
Aortic Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 Prosthetic Valve Dysfunction . . . . . . . . . . . . . . . . . . . . . . 529
Chronic Aortic Regurgitation . . . . . . . . . . . . . . . . . . . . . . 500 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Acute Severe Aortic Regurgitation. . . . . . . . . . . . . . . . . . 507

Key Points Aortic Stenosis

General • The degree of apparent cusp immobility does not always
reflect the degree of hemodynamic severity, and quantita-
• Echocardiography is the primary tool for the noninvasive
tive measures are needed.
detection, quantitation, and follow-up assessment of val-
• The echocardiography imaging window that will yield
vular heart disease.
the highest aortic valve velocity (most coaxial to the jet’s
• No single echocardiography method can be considered a
net vector within the vena contractor) is not predictable
robust “gold standard” for quantification of lesion sever-
from valve morphology or jet appearance by color
ity in all situations.
Doppler.
• Valve lesion severity is often diagnosed by a synthesis of
• Flow velocities and gradients can vary tremendously
several anatomic, qualitative, and quantitative echocar-
beat-to-beat with irregular rhythms.
diography severity indicators.
• Valve area by continuity equation: The left ventricular
• For best practice, laboratories should routinely obtain as
outflow tract (LVOT) diameter measurement is squared,
many severity parameters as possible, so that adequate
so that any significant LVOT diameter (D) measurement
scanning and interpretation skills are maintained for
error will also be squared, producing a potentially unac-
accurate diagnoses in difficult cases.
ceptable error in the aortic valve area calculation.
• Transesophageal echocardiography (TEE) may be needed
• For a given valve area, the measured aortic valve gradient
in conjunction with the transthoracic exam (TTE) for a
is strongly influenced by heart rate, stroke volume, ejec-
definitive diagnosis.
tion duration, left ventricle (LV) contractility and preload
and afterload. Therefore, peak and mean velocity and
Color Doppler pressure gradient measurements in isolation can be
misleading.
• Imaging the full extent of an expanding jet within the
receiving chamber using multiple views is necessary and
helpful for determining lesion severity.
Aortic Regurgitation
• The overall jet size within the receiving chamber viewed
in isolation can be one of the least effective parameters • Determining the severity of chronic aortic regurgitation
for judging lesion severity, unless it is very small or very can be one of the most challenging tasks for a cardiolo-
large. gist. The final diagnosis may be the result of an inte-
• Applying several of the described quantitative methods grated analysis of several parameters.
requires an understanding of all of the component parts • There are many potential pitfalls for using color Doppler
of a jet lesion as depicted by color Doppler. jet size as an indicator for regurgitation severity. With

487
488 chapter 21

good imaging practices are employed, however, a very Prosthetic Valve Assessment
small aortic regurgitation (AR) jet by color Doppler likely
represents mild AR, and a very large AR jet likely repre- • Distinctive imaging artifacts aid in recognition of
sents severe AR. mechanical prosthetic valves.
• In AR, pressure half-time (PHT) values are generally • Shadowing and reverberation artifacts, however, also
useful only in the extremes and when the continuous- hamper detection of either obstructive or insufficiency
wave (CW) Doppler signal’s outer edge is clearly definable lesions and make their mechanisms (thrombus, pannus,
and the interrogating beam is well aligned with the vegetation, paravalvular leak, or leaflet malfunction) dif-
regurgitant jet. ficult to determine.
• Acute severe AR usually represents a surgical emer- • Whenever prosthetic valve dysfunction is suspected,
gency, in which case early TEE for confirmation of comprehensive TTE and TEE are frequently needed in
the diagnosis, its mechanism, and surgical planning is order to address the situation.
indicated.

Overview
Mitral Stenosis
• Severe mitral valve (MV) stenosis is most often rheumatic Echocardiography is the primary tool for the noninvasive
in origin. detection, quantitation, and follow-up assessment of valvular
• Mitral valve areas that cause clinical symptoms can vary heart disease.1–4 In most cases, features of the two-dimen-
markedly among patients depending on body size, cardiac sional (2D) [increasingly three-dimensional (3D)5] and M-
output, and heart rate. mode and Doppler evaluation provide important measurable
• The MV area should be confirmed using two or three parameters and indirect clues regarding lesion severity and
methods, given the number of potential pitfalls of each. etiology.6,7 Because Doppler is used to evaluate a wide range
• The mean MV gradient may be low in severe mitral of non–valve-related cardiovascular pathology, basic Doppler
stenosis (MS) when there is low cardiac output or concepts are presented in Chapter 5. An echocardiogram can
bradycardia. often quickly and accurately define valve lesion as clearly
• In equivocal cases exercise stress Doppler may be useful. mild or clearly severe based upon certain highly specific
features. Frequently, however, valve disease is neither clearly
mild nor clearly severe. No single echocardiography method
Mitral Regurgitation can be considered a robust gold standard for quantification
• Detection of mitral regurgitation (MR) by Doppler is rela- of lesion severity in all situations. In challenging cases,
tively easy. However, accurate grading of MR severity can lesion severity is often diagnosed by a synthesis of several
be technically challenging. No one method is sensitive anatomic, qualitative, and quantitative echocardiography
and specific in all cases. severity indicators that are outlined herein. Valve disease
• When several findings are in agreement regarding lesion can be simple (isolated obstructive or insufficiency lesions)
severity, an accurate “integrated diagnosis” is possible in or complex. Examples of complex valve disease include
most situations. mixed stenosis and regurgitation of the same valve; multiple
valve involvement; associated dynamic obstructive lesions,
congenital malformations, and cardiomyopathies; or pros-
Tricuspid Valve Disease thetic valve dysfunction. Such complications and other vari-
• Tricuspid valve stenosis is an uncommon diagnosis. It ables (imaging artifacts, tachycardia, irregular rhythm, low
should be considered in all symptomatic patients with output states, and high or low afterload or preload) influence
rheumatic heart disease. the extent to which certain Doppler methods are applicable
• Clinically significant tricuspid stenosis (TS) is poorly tol- or valid. Accordingly, the most common pitfalls of each
erated and is associated with modest resting tricuspid method will be addressed. For best practice, laboratories
inflow gradients (mean gradient >5 mm Hg). should routinely obtain as many lesion severity parameters
• Paradoxical septal motion by M-mode and two- as possible, so that adequate skills are maintained for accu-
dimensional (2D) examination and hepatic vein systolic rate diagnoses in difficult cases. Transesophageal echocar-
flow reversal can be important signs of severe TR. diography (TEE) may be needed in conjunction with the
• Torrential “unobstructed” TR may be easily missed by transthoracic exam (TTE) for a definitive diagnosis.
color Doppler alone.

Pulmonary Valve Disease

Grading System for Valve Lesions
• Low-velocity severe PR can be easily missed by color Valve lesions are reported as mild, moderate, or severe.8 The
Doppler. Careful attention to the PV spectral Doppler use of “mild-to-moderate” or “moderate-to-severe” is desir-
signal and recognition of the signs of RV volume overload able, when appropriate, because lesions frequently lie within
are important. these gray zones. Left-sided valve regurgitant lesions (aortic
• PS is relatively uncommon in adult patients, although it and mitral) that are just detectable by color or continuous-
is relatively easily to diagnose in most cases by routine wave (CW) Doppler and are of little or no hemodynamic sig-
PV Doppler examination. nificance may be called “trace” or “trivial.” Trace or trivial
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 489
and even mild right-sided (tricuspid and pulmonary) regurgi- isovelocity surface area (PISA). The PISA and CW Doppler
tant lesions are common in individuals with normal anatomy, signal of a regurgitant jet can be used to calculate the effec-
and reporting these often nonpathologic findings is not tive regurgitant orifice area (EROA)13 and regurgitant volume
always necessary unless there has been a change in compari- (RV). Under ideal circumstances (relatively flat anatomic
son with a prior examination. A numerical classification orifice, relatively discrete opening, and appropriate color
scheme (e.g., 1+, 2+, 3+, 4+) for regurgitation (or stenosis) is Doppler Nyquist limit setting), the outer edge PISA assumes
potentially confusing because the definitions may vary a hemispheric shape with a measurable radius r. The area of
among laboratories (e.g., 3+ may mean “moderate” in one a hemisphere (PISA) is 2πr 2. Blood flow velocity at the site of
laboratory and “moderate-to-severe” in another). this hemisphere is the same as the aliasing velocity, Va,
which is obtained from the color map. Instantaneous flow is
the cross-sectional area (PISA) multiplied by the instanta-
Jet Lesion Anatomy by Color Doppler neous flow velocity (Va):

Applying several of the quantitative methods described Flow = 2πr 2 × Va

below requires an understanding of the component parts of which is simplified as
a jet lesion as depicted by color Doppler. As illustrated in
Figure 21.1, a jet lesion consists of a proximal flow conver- Flow = 6.28r 2 × Va.
gence (PFC) zone, flow within the anatomic orifice, a physi-
The EROA can be calculated by a modification of the conti-
ologic orifice (vena contracta), and the expanding jet within
nuity equation because instantaneous peak PISA flow must
the receiving chamber.9 Many of the following comments
equal instantaneous peak flow across the regurgitant orifice
regarding jet anatomy by color Doppler apply more to regur-
(Vpk). Using the PISA radius (r), Va (from the color Doppler
gitant jets than to stenotic lesions.
map), and peak regurgitation velocity (Vpk) from the mitral
or aortic regurgitation CW Doppler signal, EROA can be
Proximal Flow Convergence and Proximal calculated:
Isovelocity Surface Area10–12
EROA = 6.28r 2 × Va/Vpk
Laminar blood flow exiting a pressurized chamber produces
a localized, uniform PFC pattern by color Doppler just proxi- This method has been validated, when imaging conditions
mal to a narrowed orifice. The PFC size varies directly with permit, for the mitral, aortic, and tricuspid valves.
the flow rate, which is related to the orifice size and driving Regurgitant volume (RV) is the cross-sectional area of
pressure. Discernible color bands are present within the PFC flow (EROA) multiplied by the time-velocity integral (VTI) of
zone due to a velocity gradient and progressive aliasing of flow at the EROA, as measured by CW Doppler (see examples
laminar blood flow proximal to the orifice. The geometric below):
area of the color transition surface is known as a proximal RV = EROA × VTI
Analysis of the PFC for derivation of the PISA radius, com-
bined with CW Doppler, can be used to calculate the area of
a stenotic mitral valve (see example below). Although a PISA
signal may not always be adequate for quantitative measure-
ment, the presence of a prominent PFC is a potentially
PFC important finding that should raise suspicion for a hemody-
VC
namically important lesion.
Jet

Vena Contracta by Color Doppler9,14–16

Immediately downstream from the anatomic orifice, is a
physiologic orifice, where the highest velocity laminar flow
occurs within an area slightly smaller than that of the
upstream anatomic orifice. This region of compressed
laminar flow is known as the vena contracta. The highest
flow velocities measured by CW Doppler occur within
the vena contracta and not within the anatomic orifice. The
cross-sectional area of the vena contracta is known as
the effective regurgitant orifice area (EROA), which too, is
slightly smaller than the anatomic orifice area. With careful
imaging [zooming the proximal jet region and applying color
Doppler at a high frame rate (small color sector)], the vena
contracta width can be measured (see examples below). The
Anatomic orifice Physiologic orifice vena contracta width increases with increasing regurgitation
FIGURE 21.1. Illustration of jet lesion “anatomy” by color flow severity, making this measurable parameter an important
Doppler. PFC, proximal flow convergence; VC, vena contracta. severity indicator.
490 chapter 21

Expanding Jet by Color Doppler Aortic Valve Disease

Imaging the full extent of an expanding jet within the
receiving chamber using multiple views is necessary and Aortic Stenosis
helpful for determining lesion severity.17–20 However, the
overall jet size within the receiving chamber viewed in iso- Two-Dimensional and M-Mode Exam and
lation can be one of the least effective parameters for judging Differential Diagnosis
lesion severity, unless it is very small or very large. This is
because color Doppler represents a velocity map display and The normal, trileaflet aortic valve (AoV) is an almost per-
not a volume map of blood flow. Due to convective forces, fectly symmetrical structure. Leaflet number and symmetry
nonregurgitant “bystander” blood within the receiving are best appreciated in the parasternal short axis view (Fig.
chamber can be entrained by regurgitant blood contained in 21.2). Normal aortic leaflets, also known as cusps, are thin
the jet and labeled by color Doppler. Accordingly, relatively and highly pliable and have a deeply semilunar or “cupped”
small jets under high driving pressure (high velocity) can conformation upon diastolic coaptation. During rapid sys-
entrain significant surrounding blood in the receiving tolic excursion, adjacent aortic cusps come into parallel
chamber, thereby producing a potentially misleadingly large alignment within the bloodstream (Fig. 21.3A) while simul-
expanding jet lesion by color Doppler. By the same token, taneously undergoing partial inversion so that the leaflets,
severe regurgitation may produce a deceptively small color in short axis, assume a circular (cylindrical) conformation
Doppler jet within a receiving chamber if the driving pres- corresponding to the circular aortic annulus (Fig. 21.2A).
sure is low [e.g., severe tricuspid regurgitation (TR) with This overall “tubular” systolic valve shape minimizes blood
normal RV systolic pressure, or severe mitral regurgitation flow resistance and shear forces within the leaflets. Some
(MR) with low systemic pressure and high left atrial (LA) portions of thin and normal aortic valve leaflets may be dif-
pressure]. The extent of receiving chamber enlargement ficult to visualize. On the other hand, certain portions of the
must be taken into account when thinking in terms of normal semilunar-shaped aortic cusps behave as parabolic
regurgitant jet area. “Wall hugging” jets do not entrain as reflectors of the ultrasound beam, producing characteristic
much blood as “free jets,” which may lead to “undercalling” regional areas of increased echogenicity, which should not be
of lesion severity when color Doppler area methods are mistaken for fibrosis or calcification. Diseased or “degenera-
used.21,22 In all such cases, analyses of the PFC zone and vena tive” leaflets become increasingly thickened and well visual-
contracta sizes, along with quantitative flow methods, will ized throughout, except in advanced disease, in which case
help to establish lesion severity more accurately than by jet severe calcification can produce shadowing artifacts and
area size alone. leaflet dropout.

Calcific Aortic Stenosis

Technical Notes on Color Jet Area
Calcific degeneration of a previously normal, trileaflet valve
Jet size is inversely related to the color Doppler Nyquist limit is the most common cause of acquired aortic stenosis (AS)
setting. As a standard, the color Doppler Nyquist limit in adults older than 65, and it is frequently encountered in
should be set in the range of 50 to 60 cm/s. Color gain settings almost all adult echocardiography laboratories. Aortic scle-
also influence jet size. The color gain should be increased rosis is an even more common, possibly related, precursor
until there are a few color pixels overlying areas having no lesion that is differentiated from AS because it produces no
blood flow. Then the gain should be decreased gradually until significant resting gradient (peak velocity <2.5 m/s). Aortic
these color “noise” speckles just disappear. Other factors sclerosis (without significant stenosis) is noteworthy in echo-
may also affect the appearance of the jet size by color Doppler cardiography reporting because it may be a marker for a more
[size and depth of the image sector, pulse repetition fre- generalized atherosclerotic process24 and increased risk,25,26
quency (prf), manufacturer]. Operators should be familiar including possible progression to AS. Aortic valve sclerosis
with these and other variables that may affect the color is recognizable on the 2D exam as leaflet thickening and
Doppler signal.23 increased echogenicity with focal minimal or mildly reduced
The sonographer should evaluate the possibility of sepa- systolic cusp separation (Figs. 21.2B and 21.3B). Focal hyper-
rate (multiple) or geometrically complex proximal flow con- echoic regions indicating fibrosis and calcium deposits may
vergence zones. Using color Doppler in both short axis and occur throughout the leaflets, but they are typically more
multiple long axis and “off-axis” imaging planes along the pronounced in the leaflet bases. Decreased cusp mobility
entire extent of leaflet coaptation zones, the sonographer can also typically occurs first in the leaflet bases (Fig. 21.2B) and
often demonstrate all components of the jet lesion (PFC, gradually works its way into the body of the leaflets
anatomic orifice, vena contracta, expanding jet) within a (Fig. 21.3C,D). The degenerative process can be balanced
single or a few “best” imaging planes. With eccentric jets, among the three cusps or it may involve one or two cusps
the proximal components of a lesion may be best viewed in predominantly.
one imaging plane and the expanding jet lesion in another. Insidiously, over decades, sclerotic aortic valve cusps can
However, all elements should ultimately be included. Three- become increasingly thickened and immobilized, sometimes
dimensional color Doppler imaging offers a potential means with bulky, protruding calcific lesions that can cause promi-
for the more expedient analysis of complex jet geometries nent shadowing and side lobe artifacts within the left ven-
and overall jet size. tricular outflow tract (LVOT) (Fig. 21.3D). Reduced aortic
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 4 91

A B

C D
FIGURE 21.2. (A) Transthoracic echocardiography (TTE), short axis geal echocardiography (TEE), moderate-to-severe aortic stenosis
view of normal aortic valve, with nearly circular opening at the cusp (AS) with larger focal calcifications and planimetered orifice
level. (B) Aortic valve sclerosis. The orifice is triangular shaped with area (0.93 cm2). (D) TEE, heavily calcified aortic cusps with severe
small focal calcifications evident within the cusps. (C) Transesopha- (critical) AS and almost complete cusp immobility.

cusp separation is easily detected by M-mode of the aortic calcific degeneration of a congenitally bicuspid aortic valve
cusps (Fig. 21.4). In severe AS, the aortic cusps can appear is the most common cause of AS in adults younger than 65,
almost “frozen” in a near closed position throughout the and the second most common cause of severe AS overall.
cardiac cycle (Fig. 21.3D). Bicuspid aortic valves can also exhibit predominant aortic
Calcific aortic stenosis is frequently accompanied by regurgitation (AR) or mixed AS and AR. Congenital AS diag-
some lesser degree of aortic regurgitation due to inadequate nosed in childhood, adolescence, or early adulthood is more
closure of the dysmorphic leaflets. Mitral regurgitation also commonly associated with a unicuspid or a commissural
frequently accompanies calcific AS due to commonly associ- valve. The majority of bicuspid aortic valves appear to have
ated degenerative mitral annular and mitral leaflet calcifica- fusion of any two of the three aortic cusps along a single
tion (Fig. 21.3D). “would be” coaptation line. This thickened fusion zone,
between two aortic sinuses of Valsalva, is known as a
“pseudo-raphe,” which can often exhibit prominent focal
Congenitally Bicuspid Aortic Valves
thickening or calcification. The pseudo-raphe’s presence can
Congenitally bicuspid aortic valves are common (1% to 2% sometimes deceptively give the valve a normal trileaflet
of all individuals, predominantly in males27). Although not appearance in the parasternal short axis view upon diastolic
all are destined to develop important hemodynamic lesions, closure, potentially resulting in a missed diagnosis. Upon
492 chapter 21

A B

C D
FIGURE 21.3. Parasternal long axis views of the aortic valve with basal cusp straightening (same patient as in Fig. 21.2B). (C) Moder-
progressive reduction in cusp separation. (A) Normal aortic valve ate-to-severely reduced cusp separation. (D) Severely reduced cusp
with cusps fully straightened. Line indicates aortic annulus diame- separation from severe calcific AS. Arrowhead, associated mitral
ter measured at cusp “hinge” point. (B) Sclerotic valve with reduced annular calcification.

systolic opening, however, the two asymmetrical leaflets suspected. Efforts to clearly image the ascending aorta must
typically form an almond- or football-shaped opening (Fig. always be carefully undertaken because the degree of aortic
21.5). Truly bicuspid valves (two symmetrical sinuses of Val- dilatation may influence surgical timing as much as, or
salva with two symmetrical cusps) are less commonly more than, the presence of aortic valve stenosis (or regurgita-
encountered. Because bicuspid valves cannot undergo normal tion). Bicuspid aortic valves may exhibit relatively preserved
systolic leaflet straightening within the bloodstream, shear mobility in their bases, resulting in systolic doming in the
forces within the leaflet can be great, producing early degen- parasternal long axis view (Fig. 21.5B). M-mode evaluation
eration. In the late stages of bicuspid valve AS, the valve can may show an eccentric closure line, owing to asymmetrical
become heavily calcified and dysmorphic to the point of leaflet size and orientation in the parasternal long axis view
being indistinguishable on echocardiography from trileaflet (Fig. 21.5D). Bicuspid valves may be severely stenotic due to
degenerative calcific AS. small slit-like orifices, even though, by planar imaging, the
overall cusp mobility and separation may appear deceptively
OTHER DIAGNOSTIC CLUES FOR BICUSPID AORTIC VALVES adequate.
Abnormal dilatation of the aortic root, ascending aorta, or
both are commonly associated with bicuspid aortic valves28
Rheumatic Aortic Stenosis
(Fig. 21.5A). When a dilated aortic root or dilated ascending
aorta or both are encountered, without hypertension, par- Rheumatic aortic stenosis is the third most common
ticularly in young adults, a bicuspid aortic valve should be cause of adult valvular AS in Europe and North America.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 493
Rheumatic AS rarely occurs in the absence of associated
rheumatic mitral valve disease. In rheumatic AS, leaflet
thickening due to inflammation occurs primarily in the
leaflet leading edges and not the bases as with calcific AS
(Fig. 21.6). Commissural fusion eventually produces a small,
immobile “fish-mouth” orifice that may also produce signifi-
cant AR. Systolic doming of the leaflets (Fig. 21.7B) may be
present because of relatively preserved mobility of the leaflet
bases. In advanced disease, severe cusp calcification, thick-
ening, and immobility can render rheumatic AS indistin-
guishable from the other forms of advanced valvular AS.

OTHER MORPHOLOGIC FEATURES OF AORTIC STENOSIS

Concentric left ventricular hypertrophy in the presence of a
morphologically abnormal aortic valve that has reduced sys-
tolic opening should always raise suspicion for clinically
important AS or severe LVOT obstruction of any type.
However, because hypertension is a frequent comorbid con-
dition, this is a nonspecific finding. In the late stages of
FIGURE 21.4. M-mode tracing of aortic valve (arrow), showing
moderately reduced systolic cusp separation due to calcific AS.
valvular AS, more often in men, the ventricle can become
RVOT, right ventricular outflow tract; LA, left atrium. dilated.

A B

C D
FIGURE 21.5. Congenitally bicuspid aortic valve by surface echo. orifice area due to cusp systolic doming (see image B). (D) M-mode,
(A) Dilated aortic root (3.8 cm, red line). (B) Systolic doming of the eccentric cusp closure line (arrow), typical of a bicuspid aortic
cusps (arrow). (C) Short axis view shows ovoid or almond-shaped valve.
systolic opening. Note: This view likely represents exaggerated
 494 chapter 21

A B

FIGURE 21.6. Rheumatic AS by surface echo. (A) Parasternal long axis

shows subtle systolic cusp doming (arrow). (B) Parasternal short axis,
systole, shows commissural thickening and fusion (arrows) and a reduced
systolic opening. (C) Diastolic image shows severe thickening localized
C to the cusp margins and commissures.

Nonvalvular Left Ventricular Outflow Valve Area by Planimetry

Tract Obstruction
Although aortic valve planimetry by surface imaging may be
Some patients referred to the lab for possible valvular AS are possible using state-of-the-art surface echocardiography, the
found to have nonvalvular LVOT obstruction. Nonvalvular method has been validated with TEE29,30 (Fig. 21.2D). Aortic
LVOT obstructive lesions identifiable by echocardiography valve area by planimetry is most reliable in calcific AS
include dynamic subaortic stenosis, caused by systolic ante- because the relatively flat stenotic orifice is more likely to
rior motion (SAM) of the mitral leaflets; fixed subaortic ste- lie within a 2D imaging plane. Aortic valve area by TEE is
nosis; and supravalvular aortic stenosis. These entities are most often employed when Doppler data (below) are indeter-
discussed in other chapters. minate (e.g., irregular rhythm) or felt to be unreliable, when
mixed AS and aortic insufficiency (AI) are present, or when
Doppler and catheterization discrepancies are unexplained.
Severity Assessment by Two-Dimensional
Imaging
T ECHNICAL CONSIDERATIONS AND PITFALLS
Planimetry by TEE is frequently not possible when severe
Cusp Mobility
calcification shadows the leaflet’s leading edges. When the
When the aortic valve is abnormal, the echocardiogram cusp margins are clearly defined, a dedicated effort should be
report should generally include a statement regarding the made to obtain the most symmetrical short axis view possi-
degree of leaflet thickening and the extent to which cusp ble, ideally with acquisition of three relatively reproducible
mobility or separation is reduced (mildly, moderately, or area measurements. If gain settings are too low, leaflet
severely). However, the degree of apparent cusp immobility “dropout” can lead to area overestimation of the aortic valve.
does not always reflect the degree of hemodynamic severity, If 2D gain settings are too high, “blooming” of the signal
and quantitative measures are needed. into the orifice can cause an underestimation of valve area.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 495

D1 = 1.8 cm
D2 = 2.1 cm

VTIlvot = 19.8 cm
Vlvot = 0.8 m/s

A B

VTI AoV = 101.8 cm Peak Grad = 58.7 mm Hg

V AoV = 3.8 m/s Mean Grad = 34.8 mm Hg

C
FIGURE 21.7. Aortic valve area (AVA) calculation using the conti- either the velocity-time integral (VTI) data or the velocity (V)
nuity equation. (A) Left ventricular outflow tract (LVOT) diameter, data:
parasternal long axis view. The mid-LVOT diameter is mildly nar-
rowed by “protruding” basal septal hypertrophy (D1, smaller red AVA = (D 2 × 0.785) × (VTILVOT/VTI AoV) or
line). The calcified aortic annulus diameter is larger (D2, larger red AVA = (D 2 × 0.785) × (V LVOT/VAoV).
line). (B) Pulse-wave (PW) Doppler of the LVOT, apical five-chamber
view, for obtaining V LVOT and VTILVOT. (C) Continuous-wave (CW) Result: AVA using D1 (1.8 cm) = 0.5 cm2; AVA using D2 (2.1 cm) =
Doppler of the aortic valve (AoV), apical five-chamber view for 0.7 cm2 (severe AS in both cases, see Table 21.1). Small LVOT diam-
obtaining VAoV and VAoV. Application: The AVA is calculated using eter differences affect calculated AVA.

The method is not reliable in congenital AS (bicuspid valves) (within 20 degrees). Continuous-wave Doppler is needed for
because the stenotic orifice may be curvilinear and not lying measuring pathologic velocities (2.5 to 7 m/s) that exceed the
within a single imaging plane. In this situation, attempted Nyquist limit of pulsed Doppler. Doppler-derived instanta-
imaging planes that cut across a relatively funnel-shaped neous velocity measurements are converted to a pressure
valve will overestimate valve area. The area of the systolic drop or pressure gradient across the valve using the modified
color Doppler flow map in short axis should not be measured Bernoulli equation:
by planimetry due to the low spatial resolution of color
ΔP = 4V 2
Doppler.
Using Doppler, the calculated peak pressure gradient occurs
simultaneously with the maximum transvalvular flow veloc-
ity. The mean pressure gradient is derived by averaging
Doppler Evaluation for Aortic Stenosis
instantaneously sampled gradients throughout the ejection
period:
Continuous-Wave Doppler
ΔPmean = 4V12 + 4V22 + 4V32 + . . . + 4Vn2 /n
The LVOT obstructive gradients are detected and measured
using CW Doppler. Basic Doppler concepts, the pressure- The peak and mean gradients are automatically calculated
velocity relationship, and sites of data acquisition are by the ultrasound system or off-line analysis program when
reviewed in Chapter 5. Spectral Doppler is accurate for clini- the user electronically “traces” the outer edges of the CW
cal purposes when the vectors of the interrogating ultra- spectral Doppler envelope (Figs. 21.7C and 21.8). Both peak
sound beam and the jet lesion are approximately coaxial and mean gradients should be reported.
496 chapter 21

A B

C
FIGURE 21.8. (A,B) Variable AS gradients from different transducer Cycle “a” peak gradient = 81 mm Hg, mean gradient = 56 mm Hg.
types. (A) Suboptimal AS spectral Doppler signal obtained using the Cycle “b” peak gradient = 37 mm Hg, mean gradient = 24 mm Hg.
“steerable” imaging transducer CW Doppler, modified apical view. Because sequential regular beats were not acquired, whether or not
Peak gradient = 46.8 mm Hg. (B) Optimal AS CW Doppler signal in cycle “a” is a postectopic beat cannot be determined. Therefore,
the same patient, using the smaller dedicated CW (Pedoff) trans- neither cycle “a” nor “b” [a PVC (premature ventricular contraction)]
ducer. Peak gradient = 78.3 mm Hg. (C) Variable AS gradients due to is acceptable for valve area calculation.
arrhythmia: CW Doppler of LVOT, apical window, in calcific AS.

COMPARISON WITH CATHETERIZATION recovery can lead to overestimated gradients by Doppler as

Hemodynamic “loading conditions” and heart rate may be compared with catheterization.31 With good technique, AS
vastly different at the time of catheterization versus echocar- velocities and gradients by CW Doppler have been shown to
diography, leading to potentially conflicting results. It is correlate well with simultaneous catheterization data over a
important to bear in mind that the peak instantaneous pres- broad range of pressures.32
sure gradient obtained by Doppler is not comparable to a
reported catheter-derived peak-to-peak gradient. A catheter- K EY T ECHNICAL CONSIDERATIONS
derived peak-to-peak gradient is simply the difference The echocardiography imaging window that will yield the
between the peak pressure recorded in the left ventricle (LV) highest aortic valve velocity (most coaxial to the jet’s net
and in the aorta using either simultaneous fluid-filled trans- vector within the anatomic orifice) is not predictable from
ducer recordings or the “pull-back” method. Because peak valve morphology or jet appearance by color Doppler. There-
left ventricular and aortic pressures do not occur simultane- fore, when AS is suspected, the sonographer must interrogate
ously (left ventricular peak pressure occurs sooner than the the aortic valve with CW Doppler from several acoustic
aortic peak pressure), the peak-to-peak gradient is not, in windows, including apical, right parasternal, subcostal, and
fact, a gradient, but rather a useful clinical parameter that is suprasternal notch. In many patients (hypertensive and older
not comparable to the physiologic Doppler-derived peak patients), the aortic valve plane can be abnormally rotated
instantaneous pressure gradient. A better correlation is anteriorly (Fig. 21.9), which makes Doppler interrogation
observed between Doppler and “cath” data, when the cathe- from the LV apical region inaccurate because of a poorly
ter-derived maximum instantaneous pressure gradient aligned interrogation angle (Ø). In addition, severe aortic
(occurring just before the peak ventricular pressure record- calcification can strongly shadow a jet lesion’s vena con-
ing) and the mean systolic pressure gradient are compared tracta (zone of highest velocity, located on the aortic side of
with the Doppler-derived peak and mean instantaneous pres- the valve) from apical views, making the right parasternal
sure gradients. Additionally, the phenomenon of pressure and sometimes the sternal notch windows more successful.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 497
fused with the aortic valve Doppler signal, because each is a
systolic signal, moving in roughly the same direction (below
the baseline) and occasionally at similar peak velocities. If
an MR CW Doppler signal (high velocity) is mistaken for an
aortic valve CW Doppler signal, severe AS could be errone-
ously diagnosed. Key observation: The aortic valve spectral
Doppler envelope is distinguished from atrioventricular
valve regurgitation lesions (MR or TR) because of its shorter
duration. Both MR and TR occur throughout the isovolumic
contraction and isovolumic relaxation phases, in addition to
the systolic ejection phase. Therefore, MR and TR start
earlier and last longer than aortic outflow. These differences
in signal onset and duration can be easily determined using
the simultaneous ECG and time calibration display.

IRREGULAR R HYTHMS
Flow velocities and gradients can vary tremendously beat to
beat with irregular rhythms as demonstrated in Figure 21.8.
With irregular rhythms, velocity and gradient determina-
tions should be based on an average of five to 10 different
samples. In sinus rhythm, measurement of ectopic beats or
postectopic beats should be excluded by recording three or
FIGURE 21.9. Aortic root angiography, left anterior oblique (LAO) more regularly spaced sequential beats.
projection, in a 62-year-old woman with congenitally bicuspid aortic
valve. The aortic root and ascending aorta are dilated and “angu- Pulsed Doppler
lated.” There is an anteriorly directed negative contrast jet (dark
arrow) of aortic stenosis. The aortic cusps are heavily calcified Techniques for determining flow and stroke volume within
(white arrows). This fluoroscopic image shows the potential vari- the LVOT using pulsed Doppler are discussed in Chapter 5.
ability of an AS jet vector within the chest, and the potential for
aortic valve calcification to shadow the vena contracta zone (aortic In a “best” apical view, the pulsed Doppler sample volume
side of valve) when Doppler interrogation is made from the ventricu- is placed within the LVOT, very close to the aortic valve,
lar side of the valve. without placing it actually within the jet lesion. If the sample
volume is placed too far away from the aortic valve, the
pulsed Doppler signal will be erroneously small. A LVOT
The smaller, nonimaging CW transducer should be employed pulsed Doppler velocity measurement (Fig. 21.7B) is neces-
routinely in AS cases, because this device provides a superior sary for calculating the aortic valve area by the continuity
spectral Doppler envelope, often with higher velocity, than equation.
that achieved with the imaging transducer in part due to its
smaller footprint with easier maneuverability. Although it Valve Area by Continuity Equation33,34
may be argued that the dedicated nonimaging CW trans-
As discussed in Chapter 5, stroke volume (SV) within a
ducer is not needed in every case, its routine use ensures that
conduit having laminar flow is the product of the cross-
a sonographer possesses the necessary skills when confronted
sectional area (CSA) and the VTI of flow measured at a
with a technically challenging case of AS, which is not infre-
defined site. The SV just proximal to the aortic valve (LVOT)
quent in adult echocardiography laboratories.
and the stroke volume within the AoV must be equal. Flow
within a normal (unobstructed) LVOT and flow within the
T ECHNICAL QUALITY OF THE CONTINUOUS-WAVE DOPPLER
aortic stenosis vena contracta (immediately distal to the ana-
SIGNAL AND OTHER CLUES TO AORTIC STENOSIS SEVERITY
tomic orifice) is laminar. Therefore, the following set of
Signs of a technically good CW Doppler signal are uniformed
equations can be applied to derive the simplified continuity
signal density and a clearly defined envelope (Fig. 21.7C). An
equation:
early-peaking signal usually occurs with mild AS, and a mid-
peaking signal is a sign of severe AS (Fig. 21.8). Continuous-
SV = CSA × VTI
wave Doppler signals appearing much denser in the base may
indicate that the interrogating beam is cutting across the jet SV LVOT = SVAoV
lesion rather than being coaxial (Fig. 21.7D). Therefore, one
CSA LVOT × VTILVOT = CSA AoV × VTI AoV
should be highly suspicious of a late-peaking, possibly severe
AS signal that is relatively low in velocity with reduced CSA AoV = CSA LVOT × (VTILVOT/VTI AoV)
signal density, because the interrogating beam may be in
poor alignment, possibly “missing” severe AS. The LVOT is assumed to be circular. The area of a circle =
πr 2. And π ≈ 3.14. Because radius (r) is one half of the
OTHER POTENTIAL PITFALLS diameter (D), the more conveniently measured LVOT diam-
From apical windows, CW spectral Doppler signals from eter can be inserted directly into the formula with the fol-
atrioventricular valve regurgitation (MR and TR) can be con- lowing conversion:
498 chapter 21

LVOT area = πr 2 = π(D/2)2 = D 2 × 0.785

For aortic valve area, either of the following equations may
be used:
AoV Area = π(D/2)2 × (VTILVOT/VTI AoV)
simplified:
AoV Area = (D 2 × 0.785) × (VTILVOT/VTI AoV)
The ratio of LVOT and AoV velocity-time integrals (VTIs) and
the ratio of LVOT and AoV peak velocities should be equal
since the peak velocity at each site occurs simultaneously;
and the instantaneous velocity ratios should be the same at
any point during the ejection phase.
VTILVOT/VTI AoV = VLVOT/VAoV
Therefore, for clinical purposes, the continuity equation can
be further simplified by substituting the VTIs with the peak
velocity measurements:
AoV Area = (D 2 × 0.785) × (VLVOT/VAoV)
FIGURE 21.10. Severe calcific AS with “sigmoid septum” and dis-
See Figure 21.8 for an illustration of aortic valve area calcula- crete basal septal hypertrophy that markedly impinges on the mid-
tion using the continuity equation. LVOT diameter (D1 = 1.3 cm), which is much narrower than the
aortic annulus diameter (D2 = 1.9 cm). LVOT obstruction of this
degree may cause significantly accelerated blood flow within the
POTENTIAL PITFALL LVOT. This situation may cause a significantly overestimated AVA
by the continuity equation because the LVOT Doppler data (acceler-
In all cases, the LVOT diameter measurement is squared, so ated within the LVOT) is placed in the numerator (see equations in
that any significant LVOT diameter (D) measurement error Fig. 21.7).
will also be squared, producing a potentially unacceptable
error in the aortic valve area calculation. Therefore, accurate
LVOT imaging and diameter measurements are critical. The
LVOT diameter can be difficult to measure when excessive
aortic valve area less than one-fourth the reference LVOT
aortic root and annular calcification is present or if paraster-
area. The dimensionless velocity index can be a quick, useful
nal images are poor. The LVOT diameter and the aortic
method for identifying potentially significant obstruction in
annulus diameter are not always interchangeable (Figs. 21.7A
either high- or low-output states when the area calculation
and 21.10). The aortic annulus diameter is measured at the
by continuity equation is not possible or is in doubt (i.e., the
base or “hinge point” of the aortic valve leaflets (Fig. 21.3A).
LVOT diameter cannot be reliably measured). This index can
This annular measurement may be useful for prosthetic
be helpful in the assessment of possible prosthetic aortic
valve selection. Frequently, however, the LVOT, immediately
valve obstruction (Figs. 21.11 and 21.12).
proximal to the aortic annulus (site of pulsed Doppler sample
Calculations of aortic valve resistance 35 and left ventricu-
volume placement) is impinged by an angulated basal septum,
lar stroke work loss36 are other indices of AS severity that
making the LVOT diameter smaller than the aortic valve
may be useful but have not yet emerged as being clinically
annular diameter (Fig. 21.10). When the LVOT is very small
superior to the aortic valve area calculation.
or when there is turbulent or high-velocity LVOT flow proxi-
mal to the aortic annulus due to dynamic LVOT obstruction
Dobutamine Stress Echocardiography
(systolic anterior motion of the mitral valve), the aortic valve
area calculation by simplified continuity equation is not A patient with dilated cardiomyopathy, heart failure, and
reliable, and the aortic valve area by continuity equation will severe AS based on valve area calculation by the continuity
likely be overestimated (Fig. 21.10). equation but with a low-velocity aortic valve gradient (peak
velocity <4 m/s) can present a difficult clinical management
situation. In some such individuals, the cardiomyopathy may
Dimensionless Velocity Index (VLVOT : VAoV)
be secondary to severe AS, with possible benefit to be had
Velocity is proportional to flow across a fixed orifice. In the from aortic valve replacement surgery. Others, however, may
case of a completely normal aortic valve orifice, there should have a primary cardiomyopathy with only mild or moderate
be no significant difference between the peak LVOT velocity AS but reduced calculated valve area (and severely reduced
(VLVOT) by pulsed Doppler and the peak AoV velocity by CW visible cusp separation) due to low cardiac output. Patients in
Doppler (VAoV). Under normal conditions, therefore, the peak the latter group would not benefit from aortic valve replace-
velocities, VLVOT : VAoV, should be close to 1.0 regardless of flow ment surgery. Dobutamine stress echocardiography has been
rate. On the other hand, VLVOT : VAoV will be <1.0 in the pres- used to differentiate these two populations of heart failure
ence of aortic stenosis, because of increased flow velocity patients.37 If the aortic valve area calculation remains in the
across the aortic valve relative to that within the LVOT. severe range with a dobutamine-induced increase in stroke
Severe obstruction is likely if VLVOT : VAoV ≤0.25, indicating an volume, the cardiomyopathy may be secondary to severe AS.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 499

VAoV = 3.6 m/s

Grad pk = 51.8 mm Hg
DVI = 0.44

FIGURE 21.11. Dimensionless velo-

city index (DVI) method used to show
an acceptably increased biologic
aortic valve prosthesis gradient in the
setting of increased stroke volume.
(A) LVOT peak velocity, V LVOT =
1.6 m/s. (B) Aortic valve biologic pros-
thesis peak velocity VAoV = 3.6 m/s;
DVI = 1.6 m/s ÷ 3.6 m/s = 0.44—no
significant obstruction. A B

If ventricular contractile reserve is demonstrated, 38,39 valve would typically be indicated. For a given valve area, the
replacement surgery may be beneficial. measured aortic valve gradient is strongly influenced by
heart rate, stroke volume, ejection duration, LV contractility,
preload, and afterload. Therefore, peak and mean velocity and
Useful Values for Clinical Management
pressure gradient measurements in isolation are not helpful
Asymptomatic patients with isolated AS are managed medi- for clinical management. With normal LV contractility and
cally and followed closely for signs of LV dysfunction or the heart rate, an aortic valve peak velocity ≤2.5 m/s almost
emergence of symptoms. Surgery is the only effective therapy always indicates mild AS, and an area calculation may not
for symptomatic severe AS. With normal ventricular func- be necessary. When peak velocities are between 2.5–4.0 m/s,
tion and normal stroke volume, a peak aortic valve velocity the valve area by continuity equation or by planimetry
of >4 m/s (64 mm Hg) is a clinically important value, because should be calculated with careful consideration given to the
such patients likely have anatomically severe AS and are quality of the obtained data. As a general rule, a mean aortic
likely to reach a surgical end point within 2 years.40 Such valve gradient ≥50 mm Hg almost always indicates severe
patients should be monitored more frequently at this stage aortic valve stenosis, and an area calculation may not be
for the development of symptoms, at which point surgery necessary.

VAoV = 4.8 m/s

Grad pk = 92 mm Hg
DVI = 0.25 (obstructed)
FIGURE 21.12. Dimensionless velo-
city index (DVI) demonstrates an
obstructive gradient in a patient with
a mechanical aortic valve prosthesis.
(A) LVOT peak velocity, V LVOT = 1.1 m/
s. (B) Aortic valve mechanical pros-
thesis peak velocity VAoV = 4.8 m/s;
DVI = 1.1 m/s ÷ 4.8 m/s = 0.25—patho- VLVOT = 1.2 m/s
logic obstruction. Arrow indicates
mechanical prosthesis disk opening
and closure artifacts. A B
500 chapter 21

TABLE 21.1A. Severity of aortic stenosis (AS) by aortic valve TABLE 21.1B. Aortic stenosis severity by valve area
(AoV) area and valve area index
AS severity AoV area (cm 2)
AS severity AoV area (cm 2) AoV index (cm 2/BSA)
Mild 1.5
None >2.0 >1.10 Moderate 1.0–1.5
Mild 1.6–2.0 0.90–1.10 Severe ≤1.0
Mild-to-moderate 1.3–1.6 0.75–0.90
Moderate 1.0–1.3 0.6–0.75
Moderate-to-severe 0.7–1.0 0.4–0.60
Severe <0.70 <0.40
Note: Normal aortic valve area = 3.0–4.0.
BSA, body surface area. can be useful for surgical planning.44 Disease may be acquired
or congenital. Any of the above-mentioned common causes
of aortic stenosis [calcific degeneration, bicuspid valve (Fig.
21.13), rheumatic (Fig. 21.14)] can also be associated with
either mixed disease or a predominant aortic regurgitation
lesion due to cusp prolapse, malcoaptation of the cusp
Aortic Valve Area
margins, or leaflet destruction from superimposed bacterial
Valve area remains the best clinical indicator of AS sever- endocarditis (Fig. 21.15). Chronic AR can be associated with
ity.35, 41 With a valve area of >1.0 cm2, symptoms are probably aortic root enlargement, particularly in the elderly, but also
not due to AS alone. At a valve area of approximately 1.0 cm2, in younger individuals with Marfan syndrome or annuloaor-
flow velocities (and gradients) increase significantly with tic ectasia (Fig. 21.16) or in association with congenitally bi-
physiologic flow. Valve areas in the range of 0.8 to 1.0 cm2 cuspid aortic valves. Congenitally bicuspid aortic valves may
represent a “gray zone” in which symptoms may indeed be exhibit obvious prolapse in the parasternal long axis view
due to AS, yet other clinical factors (concomitant AR, MR, (reverse diastolic doming), which may be obvious (Fig.
coronary artery disease, patient body size, high output state, 21.13A). Frequently, however, the degree of cusp prolapse is
etc.) should be considered. Typical symptoms are almost subtle and involves one cusp, producing a highly eccentric
always due to AS when the valve area is <0.8 cm2 (severe), in AR jet, the severity of which can be difficult to assess and
which case surgery is indicated.42 An aortic valve area index easily underestimated by color Doppler. Subtle congenital
[valve area/body surface area (BSA)] may be of clinical utility prolapse of an otherwise normal trileaflet valve also occa-
in dealing with large or small patients. Table 21.1A, from sionally causes significant AR, as can focal fenestrations
the University of Chicago,43 and Table 21.1B, adapted from along the leaflet margins (tattered flag appearance on sur-
American College of Cardiology (ACC)/American Heart gical inspection), which may be difficult to discern echo-
Association (AHA) practice guidelines,3 each show slightly cardiographically. Associated valve conditions include
different grading systems. The ACC/AHA practice guide- myxomatous degeneration, which can infrequently cause
lines3 recommendations are less precise, and this may be marked prolapse and regurgitation of the otherwise normal
more applicable across different laboratories, given the trileaflet aortic valve, although this condition is usually
underlying margin for potential measurement error and found in association with the more commonly affected
varying patient sizes. mitral and tricuspid valves (see below). Characteristic 2D and
M-mode rheumatic mitral valve abnormalities (MS and MR)
strongly suggest a rheumatic etiology of associated AR.
Chronic Aortic Regurgitation Other congential abnormalities include unicuspid aortic
valves, which may have significant AR, AS, or both, as is the
case with bicuspid valves. Rare quadricuspid aortic valves are
Two-Dimensional and M-Mode Exam and
more often regurgitant than stenotic and frequently become
Differential Diagnosis
“surgical” by the fourth or fifth decade. In congenital “fixed”
The 2D exam is useful for determining the etiology of AR subaortic membrane or tunnel stenosis, the subvalvular jet
to the extent that cusp size, number, coaptation characteris- lesion can traumatize the aortic cusps, leading to aortic
tics, and aortic root size can be evaluated. Native valve AR insufficiency. Supracristal or subarterial ventricular septal
may be secondary to abnormalities of the aortic leaflets, the defects (adjacent to the aortic annulus) can cause severe AR
aortic root, or both. Understanding the mechanism for AR due to inadequate cusp support.

FIGURE 21.13. Chronic severe aortic regurgitation (AR) due to thoracic aorta, shows pan-diastolic flow reversal (downward arrows);
bicuspid aortic valve: various surface echocardiography images in forward flow systolic flow (single arrow). (F) Simpson’s rule: severely
the same patient. (A) Reverse diastolic doming (prolapse) of the increased left ventricle end diastolic volume (LVEDV) = 244 mL. (G)
aortic cusps (arrow). (B) Eccentric AR jet by color Doppler. (C) Left Severely increased LV end systolic volume (LVESV) = 155 mL. Cal-
(L) and right (R) cusp orientation with elliptical orifice (arrows). (D) culation: LVEF = (LVEDV − LVESV)/LVEDV = 36%, moderately
Pathologically large LVOT stroke volume as indicated by pulsed reduced LVEF (see Tables 21.2 and 21.3).
Doppler, VTILVOT = 38.1 cm. (E) Pulsed Doppler, proximal descending
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 5 01

A B

VTI LVOT = 38 cm

C D

E F

G
502 chapter 21

A B

C D
FIGURE 21.14. Rheumatic AR. In this case the mechanism of AR of (A), thickened leaflet margins with central diastolic malcoapta-
could not be determined due to signal attenuation. TEE images in tion (A,B) and a visible central regurgitant orifice (C,D).
the same patient (B–D) demonstrate typical early rheumatic changes

Aortic Root Size Left Ventricular Size and Systolic

Function Assessment
Aortic regurgitation is associated with the presence of aortic
root enlargement,45 particularly if there is expansion (efface- Increased left ventricular dimensions are a hallmark of
ment) of the sinotubular junction (Fig. 21.16). The aortic root chronic significant AR. Recognizing and following abnormal
is measured using the 2D image at the maximum sinus of LV remodeling by echocardiography is important for clinical
Valsalva diameter, perpendicular to the aortic long axis (Fig. decision making. Parasternal long axis measurements of LV
21.5A). Normal values for aortic root size, based on patient end-diastolic and end-systolic diameters (LVEDD and
age ranges, have been published [American Society of Echo- LVESD)47 can be highly reproducible and reflective of overall
cardiography (ASE) guidelines46,47]. An aortic root diameter LV size and contractility in the absence of concomitant
indexed for body surface area of >2.1 mm/m2 is highly spe- regional wall motion abnormalities from coronary artery
cific for aortic root enlargement.46 disease or other cardiomyopathies.
In the past, echocardiography-derived LV volume and
ejection fraction measurements have been thought to be dif-
M-Mode Measurements
ficult to reproduce, if not unreliable, because of variable
M-mode measurements are pertinent for AR assessment imaging quality and technique. Because echocardiography
when used for LV diameter assessment. Diastolic fluttering technology has improved in recent years (improved 2D
of the mitral valve’s anterior leaflet can be a sign of an eccen- imaging and use of left-sided contrast agents), quantitative
tric AR jet striking this leaflet (Fig. 21.17). measures of LV size (volume and mass) and function (ejection
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 503

A B

C D

E F
FIGURE 21.15. TEE: acute, severe AR. This 24-year-old man with descending thoracic aorta shows sinusoidal appearance of forward
a bicuspid aortic valve had mild AR by echocardiography 10 months systolic flow (arrow) and pan-diastolic reverse flow (double arrow).
earlier. (A) Linear whip-like vegetation (arrow) attached to a prolaps- (E) Prominent diastolic mitral regurgitation (MR) by CW Doppler
ing cusp with early aortic root abscess formation (arrowhead); left (upward arrow), a sign of acute severe AR, associated with premature
atrium (LA); left ventricle (LV); aorta (Ao). (B) Severe AR completely mitral valve (MV) closure (downward arrow). (F) TEE gastric window:
fills the LVOT by color Doppler imaging. (C) In a different similar AR deceleration slope (line) by CW Doppler quickly reaches baseline
case, color M-mode helps to display the diastolic timing of the tur- [short pressure half-time (PHT), <200 ms] indicating almost equal
bulent AR jet during tachycardia (brackets). (D) Pulsed Doppler, aortic and ventricular diastolic pressure (severe acute AR).
504 chapter 21

TABLE 21.2. Left ventricular volume and volume index

Normal Mildly Moderately Severely
range dilated dilated dilated

A: Women
Diastolic
LVEDV (mL) 56–104 105–117 118–130 ≥131
Indexed
LVEDV/BSA (mL/m2) 35–75 76–86 87–96 ≥97
Systolic
LVEDV (mL) 19–49 50–59 60–69 ≥70
Indexed
LVEDV/BSA (mL/m2) 12–30 31–36 37–42 ≥43
B: Men
Diastolic
LVEDV (mL) 67–155 156–178 179–201 ≥201
Indexed
LVEDV/BSA (mL/m2) 35–75 76–86 87–96 ≥97
Systolic
LVEDV (mL) 22–58 59–70 71–82 ≥83
Indexed
LVEDV/BSA (mL/m2) 12–30 31–36 37–42 ≥43
Note: The LVEDV and LVESV indexes (mL/m 2) are the most validated
measures.
BSA, body surface area; LVEDV, left ventricular end diastolic volume; LVESV,
FIGURE 21.16. Severely dilated aortic root and ascending thoracic left ventricular end systolic volume (not shown).
aorta (dotted line). Complete effacement (obliteration) of the sinotu-
bular junction (solid line). Prominent proximal flow convergence
zone by color Doppler (arrowhead) and wide vena contracta >0.6 cm
(black arrow) indicate severe AR (see Table 21.4).

LV Ejection Fraction = (LVEDV − LVESV)/LVEDV

fraction) have become increasingly reliable. Accordingly, rec- Reference limits for LV volumes are shown in Table 21.2, and
ommendations for cardiac chamber quantification by echo- reference limits for LV ejection fractions are shown in
cardiography were recently updated.47 Although several Table 21.3.
methods for LV volume assessment exist47 and are applicable
in varying situations, the biplane method of disks (modified
Doppler Evaluation for Aortic Regurgitation
Simpson’s rule48) is recommended when apical foreshorten-
Severity Assessment
ing can be eliminated and the endocardial surfaces are
visible. The method uses summation of elliptical disk
Continuous-Wave Doppler
volumes derived from the apical four- and two-chamber
views (Fig. 21.13F,G). When the LV cavity is relatively sym- In the presence of AR, CW Doppler interrogation of the
metrical and with uniform contractility, the method can also LVOT reveals a characteristic spectral Doppler velocity enve-
be applied to a single plane if either one of the two views is lope produced by diastolic decay of the pressure gradient
technically suboptimal. between the aortic root and aorta (Fig. 21.18). In some techni-

A B
FIGURE 21.17. (A) Eccentric AR jet, striking the mitral anterior leaflet. (B) M-mode of the mitral valve, same patient, shows anterior leaflet
diastolic fluttering from the jet impact (arrows). LA, left atrium; LV, left ventricle.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 505
TABLE 21.3. Left ventricular function by left ventricular ejection PHT T ECHNICAL NOTES AND PITFALLS
fraction (LVEF) The PHT measurements are valid only when the CW inter-
Normal Mildly Moderately Severely rogating beam is coaxial to flow and a clear linear spectral
range reduced reduced reduced velocity envelope “edge” is present. Quality CW signals and
LVEF (%) >55 45–55 30–44 <30 acceptable PHT measurements are simply not possible with
No gender differences.
many eccentric or poorly aligned AR jets. The PHT can be
relatively long (significantly >200 ms) with compensated
chronic severe AR. This is because adaptive remodeling
allows the LV to accept a large regurgitant volume without
cally difficult exams, detection of the characteristic appear- a significant rise in LV diastolic pressure. Another potential
ance of AR by spectral Doppler may be the first or only clue pitfall is that for a given degree of AR, the PHT will appear
to its presence. When the signal is well aligned with the shortened in a patient with high LV filling pressures due to
interrogating beam, the density of the spectral Doppler signal an underlying cardiomyopathy. In this situation, the LV dia-
can be used as a rough qualitative indicator of severity. Mild stolic pressure rises more rapidly for a given regurgitant
degrees of AR produce a faint signal, and moderate or severe volume, quickly reducing the aorta-to-LV diastolic pressure
jets produce a dense signal. This is because signal density difference and shortening the PHT. Systemic vasodilator
correlates with the number of regurgitant red blood cells therapy can also shorten the PHT by decreasing the aortic
within the path of the interrogating beam. In many cases, pressure (low afterload).
the observer is unable to differentiate moderate from severe
AR using jet density. Nonetheless, a dense jet by CW war-
rants further investigation.
Pulsed Doppler-Derived Regurgitant Volume and
PRESSURE H ALF -T IME 49
Regurgitant Fraction50,51
The AR velocity by CW Doppler decays in a linear fashion
according to the rate of pressure equilibration between the Left ventricular outflow tract flow as measured by pulsed
aortic root and left ventricle. The rate of pressure decay can Doppler is increased in AR. This is because LVOT flow
be described by a deceleration time (DT), which is the time includes both the useful forward stroke volume and the
from initial peak velocity to zero velocity when the velocity “wasted” regurgitant volume. When a very high LVOT VTI
slope is extended to the baseline. Pressure half-time (PHT) measurement is encountered (e.g., LVOT VTI >30 cm), severe
is the time for the AR velocity to decline to half of its origi- AR should be suspected (see Fig. 21.13D). The regurgitant
nal peak value. Both the DT and PHT are automatically cal- volume (RV) can be obtained by subtracting a reference
culated when the operator electronically defines the AR forward stroke volume (SV from mitral annulus or RV outflow
velocity deceleration slope (Fig. 21.18). When AR is severe, tract) when there is no important concomitant reference
the aorta-to-LV pressure declines rapidly, producing a short valve regurgitation.52
PHT (Figs. 21.15F and 21.18B). When AR is mild, or mild-to-
moderate (Fig. 21.18A), the PHT is long because the regurgi- RVAR = SV LVOT − SVref valve
tant volume is not sufficient to significantly affect either the
aortic or ventricular diastolic pressures. A PHT <200 almost Details for calculating LVOT, mitral annulus, and RVOT
always indicates severe AR, and a PHT of >500 almost always stroke volume are found in Chapter 5. The regurgitant frac-
indicates mild AR.7 The PHT for moderate AR usually lies tion (RF) is the regurgitant volume divided by the total LVOT
within a wide range (200–500 ms). Mild and severe AR can stroke volume ×100.
also lie within this gray zone, depending on ventricular
loading conditions. RF = RV/SV LVOT × 100

PHT = 561 ms
PHT = 273 ms

ms
A B
FIGURE 21.18. Pressure half time (PHT) measurement in aortic (2.8 m/s, vertical red line). (B) Moderate-to-severe AR with relatively
regurgitation. (A) Mild AR: mildly dense Doppler signal (relative to dense CW signal and short PHT = 273 ms. Deceleration slope (slanted
background noise), long PHT = 561 ms. Early peaking mild AS signal red line). Automatically derived PHT (horizontal green lines).
506 chapter 21

TABLE 21.4. Grading aortic regurgitation: quantitative

parameters
Parameter Mild Severe

Vena contracta (cm) <0.03 ≥0.6

Jet height/LVOT (%) <25 ≥65
Pressure half-time (ms) >500 <200
Regurgitant volume (mL) 30 ≥60
Regurgitant fraction (%) <30 ≥50
Regurgitant orifice area (cm2) <0.1 >0.3
LVOT, left ventricular outflow tract.

The regurgitant fraction is a useful parameter when the total

stroke volume is reduced because of cardiomyopathy. Refer-
ence values appear in Table 21.4. As an additional check (in
the absence of significant MR), the total LV stroke volume FIGURE 21.19. TEE: rheumatic central AR jet by color Doppler.
can also be calculated using the modified Simpson’s rule.51 Anatomic orifice (+); vena contractor width (A) = 0.36 cm; jet height
This type of quantitative analysis can be time-consuming, (B) approximately 50% of LVOT diameter. AR is moderate by these
but it is useful in selected cases. criteria (see Table 21.4).

EFFECTIVE R EGURGITANT ORIFICE A REA (EROA) USING

SPECTRAL DOPPLER mild AR, may be all that is required to make the diagnosis
After calculating the aortic regurgitant volume (see above), in many such cases. As previously mentioned, there are
the EROA (a useful severity indicator) (Table 21.4) can then many potential pitfalls for using color Doppler jet size as an
be calculated. Forward systolic stroke volumes or diastolic indicator for regurgitation severity. With good imaging prac-
RV is the product of the cross-sectional area of the flow tices, however, a very small AR jet by color Doppler likely
(EROA) and the VTI measured at the same site (by CW represents mild AR, and a very large AR jet likely represents
Doppler of the AR jet in this case). severe AR (Table 21.4). For jets that are neither clearly small
nor clearly large, further evaluation is needed. When assess-
RVAR = EROA × VTI AR
ing color Doppler jet size, length and area measurements
EROA = RVAR/VTI AR within the left ventricle can be misleading and unreliable
indicators of severity. The height of jet within the LVOT, just
This method for EROA calculation is reliable only in regular
below the aortic cusps18 and the more proximal vena con-
rhythm and when there is a clear, well-aligned CW Doppler
tracta (VC) size57 (Fig. 21.19), can be a useful and readily
signal.
measurable parameter (Table 21.4). The AR vena contracta
and LVOT jet dimensions should not be based on one “freeze
Aortic Diastolic Flow Reversal by
frame” but on the best assessment of the sustained jet during
Pulsed Doppler53–55
the diastolic period using a zoomed parasternal long axis
As discussed in Chapter 5, the routine pulsed Doppler exam image and a small color sector for high sample rate and
includes interrogation of the proximal descending thoracic improved color Doppler spatial resolution. Central jets are
aorta from the sternal notch window. In normal individuals easier to measure (Fig. 21.19). Eccentric AR jets can be diffi-
(no AR), a normal low-velocity (<40 cm/s) early diastolic flow cult to measure. The area of the AR jet in short axis view at
can be seen. In chronic, compensated severe AR, the early or slightly below the cusp coaptation zone can be very useful
diastolic flow velocity peak is higher (usually >40 cm/s), and for assessing the 3D characteristics of the jet origin and the
flow reversal becomes pan-diastolic (Fig. 21.13G). Unfortu- AR mechanism (e.g., central cusp malcoaptation, valve cusp
nately, the sternal notch window is not available in all sub- perforation, valve extension along a cusp commissural zone,
jects. Pan-diastolic flow reversal in the abdominal aorta, if valve prolapse). Cross-sectional area measurements can be
present, is a more specific sign of severe AR. Pan-diastolic challenging to interpret in rapidly expanding or eccentric
flow reversal is often more evident in acute severe AR (below), jets and because of aortic root motion through the imaging
but it may be less evident in patients with poor aortic plane. Cross-sectional area as a percentage of aortic root size
compliance. may be difficult to interpret if the aortic root size is
abnormal.
Aortic Regurgitation Severity by Color Doppler
Jet Size Proximal Isovelocity Surface Area for
Effective Regurgitant Orifice Area and
Trace and mild AR are frequently detected by color Doppler
Regurgitant Volume58
in many otherwise normal, older individuals.56 Careful
imaging of the entire proximal jet lesion by color Doppler, When a sizable proximal flow convergence zone is visualized
along with a corroborating CW Doppler signal typical of (Figs. 21.16 and 21.20), severe AR should be suspected, and
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 507

A B
FIGURE 21.20. (A) Rheumatic MS. Modified parasternal long axis chordae tendineae, thickened leaflet margins, dilated left atrium
view showing diastolic “doming” of the mitral leaflets; anterior (LA). (B) M-mode of the mitral valve shows anterior diastolic motion
mitral leaflet “hockey-stick” deformity (arrow); thickened, fused of the retracted posterior leaflet (arrows).

this finding alone should prompt a more careful and detailed (particularly with endocarditis), determine ventricular con-
overall assessment using the other methods discussed. tractility, and assist with surgical planning. Patients with
Although often technically challenging, because of calcific baseline poor LV compliance from severe AS or LV hypertro-
shadowing within the aortic root or eccentric jet, calculating phy or other causes will demonstrate signs of hemodynamic
the EROA and RV using PISA has been validated, using the collapse more quickly for a given acute AR volume load. This
formulas presented in the introductory part of this chapter. is because of a steeper LVEDV pressure-volume relationship
curve.
EROA AR = 6.28r 2 × Va/VpkAR
RVAR = EROA × VTI AR Two-Dimensional and M-Mode Signs
In summary, assessment of the severity of chronic aortic The aortic cusps and aortic root should be imaged first in
regurgitation can be one of the most challenging tasks for long axis, short axis, and in oblique imaging planes for signs
the echocardiographer. The final diagnosis may be the result of vegetation, leaflet perforation or prolapse, aortic root
of an integrated analysis of several supportive parameters abscess, aortic root dissection, prosthetic valve rocking
without reliance upon only one or two severity indicators. motion, thrombosis, or prosthetic valve biologic cusp or
When there are indirect signs of possible severe AR, but the mechanical disk opening or closure abnormalities in a
aortic leaflets or the proximal jet cannot be clearly visualized pathology-directed exam. Expedient, systematic evaluation
by TTE, adjunctive TEE can play a valuable role (Figs. 21.14, of the other valves should then be performed. In acute severe
21.15, and 21.19). TEE, cardiac catheterization with aortic AI, the thoracic aorta may exhibit exaggerated pulsatility,
root injection, and, increasingly, cardiac magnetic resonance though this clue may not be present in older patients with
imaging (MRI) can be particularly useful in selected cases. stiffer aortas. Evaluation of LV size and function and the
pericardium is important. In aortic root dissection, pericar-
dial effusion or myocardial ischemia may also be present if
Acute Severe Aortic Regurgitation dissection involves a coronary ostium (more commonly the
right). The LV size may not be dilated as in chronic AR. Left
Acute severe aortic regurgitation can be due to aortic valve ventricle contractility may be hyperdynamic from a hyper-
endocarditis (Fig. 21.15), acute aortic dissection with propaga- adrenergic state and increased preload, unless there is also a
tion into an aortic cusp, an aortic cusp tear from a decelera- complicating preexisting cardiomyopathy.
tion injury (uncommon), or partial sewing ring dehiscence Diastolic (premature) closure of the mitral valve is a sign
or leaflet malfunction in a prosthetic aortic valve. Patients of steep increase in the left ventricular end diastolic pressure
with true acute severe AR represent surgical emergencies that exceeds the left atrial pressure.59 Occasionally, end dia-
and usually present with a relatively narrow pulse pressure stolic (premature) opening of the aortic leaflets can be dem-
and cardiogenic shock (pulmonary edema, tachycardia, low- onstrated by M-mode due to aortic and left ventricular
output state). In hemodynamically unstable or intubated pressure equalization.59 As with chronic AR, the mitral valve
patients, surface echocardiography is frequently suboptimal M-mode image may show reduced valve opening and high-
for a variety of reasons, including tachycardia and signal frequency diastolic fluttering of the mitral anterior leaflet
attenuation. In the presence of cardiogenic shock, a TEE from eccentric AR impact. Because of a fast sample rate,
should be performed as soon as possible after endotracheal color M-mode may be particularly useful in acute severe AR
intubation and establishment of mechanical ventilation. with tachycardia (Fig. 21.15C), in which case routine color
Transesophageal echocardiography is used to firmly estab- Doppler of the LVOT (slower sample rate) may appear confus-
lish the diagnosis, rule out important associated valve disease ing because of turbulent, high-volume systolic and diastolic
508 chapter 21

flow. Color M-mode can quickly confirm the diastolic timing Mitral Valve Disease
of the AR lesion and show an approximate jet height just
below the aortic valve.
Mitral Stenosis
Doppler Signs Two-Dimensional and M-Mode Examination and
With severe AR, color Doppler may almost fill the LVOT (Fig. Differential Diagnosis
21.15B). The color Doppler flow convergence zone and the Mitral valve stenosis can be acquired or congenital. In adult
associated vena contracta should be displayed simultane- echocardiography laboratories, the most common causes of
ously, if possible, and correlated with leaflet abnormalities. acquired mitral stenosis (MS) are rheumatic and degenerative
The aortic valve PHT by CW Doppler obtained in a gastric calcification of the native mitral valve. Mechanical pros-
view is short because of rapid aorta-to-left ventricular dias- thetic mitral valves can become obstructed (stenotic) because
tolic pressure equalization (Fig. 21.15D). Diastolic MR, in the of thrombus or pannus formation. A biologic mitral prosthe-
absence of prolonged PR interval, is another supportive sign sis can undergo calcific degeneration with stenosis due to
of acute severe AR, and it can be demonstrated by CW reduced cusp mobility. Echocardiographic findings of MS
Doppler60 (Fig. 21.15E). Pan-diastolic flow reversal in the from right atrial tumor and congenital MS are discussed in
descending thoracic aorta is usually readily apparent by other chapters.
either surface echo or TEE (Fig. 21.15F).
R HEUMATIC M ITRAL STENOSIS
Quantitative Measures Stenosis is usually the predominant hemodynamic lesion in
rheumatic mitral valve disease. However, varying degrees of
All of the above-mentioned semiquantitative methods can mitral regurgitation are frequently present, with MR some-
confirm the diagnosis of acute severe AR, particularly when times being the predominant lesion. Even in the early disease
the anatomic regurgitant orifice is clearly visualized and the stage, when stenosis may be mild, several echocardiographic
mechanism has been discerned. Calculations of the aortic features of rheumatic mitral valve disease are usually
regurgitant volume and regurgitant fraction are often not present.
feasible or necessary for the diagnosis of acute severe AR.
Rheumatic Leaflet Deformity. Classic rheumatic
changes include leaflet thickening that is more prominent in
Acute AR Superimposed on Chronic
the leaflet leading edges with relatively preserved mobility
Aortic Regurgitation
of the leaflet bases. Relatively preserved basal leaflet mobil-
On some occasions, patients present with many of the fea- ity and a reduced orifice area produce a characteristic dia-
tures of acute severe AR (tachycardia, dyspnea, fever), though stolic “doming” appearance of the valve and a diastolic
cardiogenic shock is not present on initial evaluation. In “hockey-stick deformity” of the anterior mitral leaflet in the
such cases, acute severe AR may have complicated underly- parasternal long axis view (Fig. 21.20A). Leaflet leading-edge
ing chronic AR (likely moderate) for which some degree of inflammation causes commissural fusion, which is the
underlying physiologic adaptation and ventricular remodel- primary mechanism for stenosis. Commissural fusion and
ing had previously occurred. A relatively wide pulse pressure thickened leaflet margins produce an ovoid or circular “fish-
may be present with some degree of LV dilatation. Preexist- mouth” orifice, appreciated in the parasternal short axis
ing valve abnormalities may be linked to the mechanism of view (Fig. 21.21). Degenerative calcification can occur within
acute severe AR (e.g., bicuspid aortic valve as a nidus for the leaflets. In advanced disease, the entire leaflet can even-
endocarditis or acute aortic dissection complicating a previ- tually become severely thickened and calcified with little
ously dilated aortic root with some degree of baseline AR). apparent residual mobility.

A B
FIGURE 21.21. (A) Parasternal short axis view, same patient as in Fig. 21.20), with commissural fusion and “fish-mouth” deformity of the
mitral orifice. (B) Planimetry, “zoomed” mode with planimetry of the mitral orifice (1.2 cm2 = moderate MS, see Table 21.6).
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 509

Submitral Apparatus. Rheumatic inflammation extends TABLE 21.5. Percutaneous balloon mitral valvuloplasty score
into the chordae tendineae and often into the papillary Mobility
muscles. A variable degree of chordal thickening, fusion, and Grade 1 Highly mobile valve; restricted leaflet tips only
shortening occurs. This deformity can be mild, moderate, or Grade 2 Normal mobility; basal and mid-leaflet portions
Grade 3 Mobility limited to the leaflet base
so extreme that the primary region of stenosis is actually
Grade 4 Relatively immobile leaflets throughout
within the fused chords and not at the leaflet level. Chordal
Leaflet thickening
shortening in advanced disease can be so extreme that dis- Grade 1 Leaflets near normal (4–5 mm)
crete chords cannot be differentiated from the brightly echoic Grade 2 Mid-leaflets normal; marked thickening of margins
papillary muscles that seemingly fuse directly into the leaf- (5–8 mm)
lets. Even in mild disease, posterior leaflet tethering and Grade 3 Thickening throughout leaflets (5–8 mm)
Grade 4 Marked thickening throughout the leaflets
immobility relative to the anterior leaflet is a specific feature
(>8–10 mm)
of rheumatic mitral valve disease. On M-mode examination,
Subvalvular thickening
there is a characteristic and highly specific posterior leaflet Grade 1 Minimal thickening just below the leaflets
“anterior diastolic motion” (Fig. 21.20B) because the tethered Grade 2 Thickening up to one third of the chordal length
posterior leaflet must “track” the anterior leaflet instead of Grade 3 Thickening extending to the distal one third of the
exhibiting normal diastolic leaflet separation (see Chapter chords
Grade 4 Extensive thickening and shortening of the papillary
5).
muscles
Rheumatic Left Atrium. The left atrium is often Calcification
severely dilated in rheumatic MS. Swirling left atrial spon- Grade 1 Single area of increased echo brightness
Grade 2 Scattered areas of brightness confined to leaflet
taneous echocardiography contrast (“smoke”) and left atrial margins
or left atrial appendage thrombus are common in rheumatic Grade 3 Brightness extending into the midportion of the
MS. Left atrial thrombus is usually apparent only by TEE. leaflets
In some cases, calcification of the left atrial wall, probably Grade 4 Extensive brightness throughout much of the leaflet
related to pancarditis, results in even suboptimal TEE images tissue
in rheumatic heart disease. Based on surface echocardiography examination.

Percutaneous Balloon Mitral Valvuloplasty Assess-

ment by Echocardiography.61– 63 In properly selected symp- sural calcification (not included in the above-mentioned
tomatic rheumatic MS patients, a durable result, comparable scoring scheme) may also reduce the success rate and predis-
to surgical mitral commissurotomy, can be achieved with pose to MR development. Its presence is usually discernible
percutaneous balloon mitral valvuloplasty (PBMV). Morpho- on the mitral valve (MV) short axis view.62 Percutaneous
logic features, as evaluated by surface echocardiography, have balloon mitral valvuloplasty carries a risk of stroke. A TEE is
been divided into four categories and rated on a scale of 1 to 4 performed in advance of PBMV to ensure that LA or left atrial
for each feature (Table 21.5).61 It has been shown that the best appendage (LAA) thrombus is not present. At some centers,
PBMV results are achieved in young patients having a com- TEE is used to guide the procedure.
bined mitral stenosis or ≤8, mild-to-moderate MR, and no
previous surgery. Other patients with less favorable valve M ITRAL A NNULAR CALCIFICATION
anatomy (score >8) may also benefit from the procedure, but This degenerative change is very commonly seen in the
they may be more likely to have significant residual gradients elderly and in chronic renal failure or hemodialysis patients
or mitral regurgitation. The palliative mechanism of PBMV and possibly in association with coronary artery disease
is separation of the fused mitral commissures. Focal commis- (Figs. 21.3D and 21.22). Some degree of associated MR is also

A B
FIGURE 21.22. Severe mitral annular calcification. (A) Apical bulky annular calcification. The thin chords and “straight” anterior
three-chamber view, TTE, severe annular calcification, involving MV leaflet in diastole (no doming) distinguish this from rheumatic
the leaflet bases (arrow) with associated calcific AS (arrowhead). (B) MV disease. RV, right ventricle.
Apical four-chamber view, same patient shows circumferential
510 chapter 21

TABLE 21.6. Mitral stenosis by valve area (cm2) common mistake that produces an erroneously large valve
Very mild >2.0 area. Ideally, three reproducible measurements are obtained.
Mild >1.5–2.0 Newer 3D echocardiography techniques may be used to
facilitate anatomic orifice location and planimetry.66–68 It
Moderate >1.0–1.5*
should be noted that the planimetered MV area (anatomic
Severe ≤1.0
orifice) may be slightly larger than the Doppler-derived
* Clinically severe MS can occur in this range because of variability of patient mitral valve area (MVA) in the same patient since the latter
size, heart rate, and stroke volume at rest and with exercise.
is a measure of the physiologic orifice (site of vena
contracta).

common. Mitral annular calcification (MAC) is usually dif- PITFALLS

ferentiated from rheumatic mitral disease by echocardiogra- Planimetry, even by 3D imaging, may not be possible when
phy because leaflet thickening, calcification, and immobility there is shadowing artifact from severe calcification or image
begin in the leaflet bases (Fig. 21.22), with relatively pre- dropout from poor imaging windows. In some cases, the
served mobility in the leaflet leading edges. With severe smallest apparent valve orifice area is disproportionately
posterior annular calcification, the posterior leaflet can large relative to the transvalvular gradient by Doppler. This
appear almost completely obscured on surface echocardiog- may be due to stenosis that occurs primarily in the submitral
raphy. Relatively thin chordae tendineae, absence of mitral region because of chordal fusion. In such cases, other methods
leaflet diastolic doming, or hockey-stick deformity (Fig. (below) must be applied. Note: Mitral valve sizes that cause
21.22) can help to distinguish mitral calcific degeneration clinical symptoms (rest or exercise pulmonary congestion)
from rheumatic disease. Even in relatively advanced MAC, can vary markedly among patients depending on body size,
the hemodynamic severity of the associated mitral stenosis cardiac output, and heart rate.69
generally remains in the mild or mild-to-moderate range.
Severe MAC-related mitral stenosis requiring surgery does Doppler Evaluation
occur, in which case the risk for periprosthetic MR is
CONTINUOUS-WAVE DOPPLER: PEAK AND
increased. Because commissural fusion is not the mecha-
M EAN GRADIENTS
nism for stenosis in MAC, percutaneous balloon valvulo-
Transmitral inflow velocity is measured from apical
plasty is not a palliative option.
views using CW Doppler. Color Doppler guidance can help
determine the best beam alignment for “directed” jets.
Echocardiographic Parameters for Mitral
Mitral stenosis is suspected by visual inspection of
Stenosis Severity
the spectral Doppler signal whenever the velocity remains
VALVE A REA BY PLANIMETRY IN R HEUMATIC M ITRAL substantially above the baseline throughout diastole,
STENOSIS 64 (Fig. 21.21 and Table 21.6) because at normal heart rates, the transmitral pressure gra-
With good technique and adequate imaging windows (para- dient normally becomes zero, or very close to zero during
sternal short axis view), direct mitral orifice planimetry can mid-diastole. The valve peak and mean velocities and
be the most accurate method for rheumatic mitral valve area gradients are automatically derived by tracing the spectral
assessment.65 Using fine adjustment of the imaging plane, signal’s outer edge (Fig. 21.23A). Table 21.7 shows
the sonographer should make a concerted effort to image the mean resting gradients that typically accompany mild-,
smallest, most distal anatomic orifice. Because the rheu- moderate-, and severe-range MS. The mean MV gradient is
matic valve can be somewhat funnel shaped, cutting through strongly influenced by heart rate. Tachycardia shortens the
the body of the leaflets and not the leaflet margins is a diastolic time available for transmitral pressure gradient

PHT = .29 (DT)

DT = 760 ms
PHT = 220 ms
MVA = 220÷PHT =1.0 cm2

A B
FIGURE 21.23. Mitral stenosis assessment by CW Doppler, atrial same in both cycles. See image for mitral valve area (MVA) calcula-
fibrillation. Mean gradient varies (A), consistent PHT. Despite dif- tion by PHT method.
ferent RR intervals (B), the PHT measurement (green line) is the
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 511
TABLE 21.7. Mitral stenosis by mean gradient (mm Hg) and VTI. Flow across the mitral valve must equal flow across
Mild <5 a reference valve or conduit, such as the LVOT:
Moderate 5–10 CSA MV × VTI MV = CSA LVOT × VTILVOT
Severe >10
MVA = (D 2 × 0.785) × (VTILVOT/VTI MV)
Note: Rough guidelines for “resting” Doppler assessment of MS. Gradients
are strongly affected by heart rate and cardiac output. VTI MV is derived by electronically outlining the mitral dia-
stolic CW spectral Doppler signal. All variables for the
continuity equation are obtained during a standard Doppler
resolution. Mean gradients that may appear consistent with
examination. Therefore, the method is easily applied. Refer-
mild-to-moderate or moderate MS at rest can quickly
ence flow in the right ventricular outflow tract (RVOT) can
increase into the severe range with increased heart rate (e.
also be used provided that the RVOT diameter can be accu-
g., exercise, tachycardia). The mean gradient can vary mark-
rately measured. The continuity equation method is useful
edly beat-to-beat in irregular rhythms (Fig. 21.23A). Accord-
when there is chordal level stenosis, when valve planimetry
ingly, Table 21.7 is only a rough guide that may be applied
is not possible, or if the PHT measurement is in doubt. The
to patients with normal-range heart rates and stroke
pitfalls of this method are as follows: It cannot be used when
volumes. In irregular rhythm (atrial fibrillation) five to 10
there is also significant MR because this will increase VTI MV
cycles should be averaged for gradient assessment. The peak
relative to the reference valve VTI, resulting in an errone-
gradient may be increased from high LV filling pressures
ously small MV area calculation. The method cannot be
not related to MS or from concomitant MR.
used with significant reference valve regurgitation [i.e., AR
or pulmonary regurgitation (PR)] because the increased
M ITRAL VALVE A REA BY PRESSURE H ALF -T IME M ETHOD 70
VTI ref. relative to VTI MV will result in an erroneously large
During diastole, there is a relatively linear decay of the LA-
MVA calculation. The method may be unreliable in irregu-
to-LV pressure gradient that is inversely proportional to the
lar rhythms because the stoke volume will vary markedly
MV area. The time from MV peak velocity to zero velocity
from beat to beat, and simultaneous mitral and reference
(extending the straight spectral Doppler velocity slope to
valve flows cannot be compared. Averaging multiple
baseline) is known as the deceleration time (DT). The DT
cycles (5 to 10) can be attempted or selecting cycles with a
can be visually estimated using the spectral Doppler image
similar R-R interval, although this is somewhat more
time scale. Mitral stenosis is also described by the PHT—
time-consuming.
time from initial peak pressure difference to half or the peak
pressure difference. The PHT cannot be determined by visual
inspection of the Doppler signal, but it is automatically cal- PROXIMAL ISOVELOCITY SURFACE A REA M ETHOD 75,76
culated by echocardiography systems when the linear decel- A prominent PFC zone is often apparent on the atrial surface
eration slope is electronically defined (Fig. 21.23B). One of of the valve, particularly by TEE. The PISA formula for deriv-
the earliest and most clinically useful applications for the ing valvular EROA was explained in the introduction (see
Doppler exam was validation of the following empirically above). The same formula can be used to calculate the MVA
derived formula: in MS using forward flow. Because the rheumatic MV inflow
surface is frequently funnel-shaped and not flat, the PISA
MVA = 220/PHT may not be hemispheric. Therefore, a correction factor
Because PHT = (0.29) DT, MVA is also easily calculated using (α/180) must be applied. Alpha (α) is the angle formed by
the DT. The advantages are as follows: The mitral inflow DT lines running roughly parallel to the distal valve leaflets
(and PHT) by CW Doppler is easily obtained in many cases. (Fig. 21.25).
Because the PHT is relatively independent of flow, this MVA = (α/180)6.28r 2 × Va/Vpk
method is useful in patients with atrial fibrillation (Fig.
21.23B) or concomitant MR.70,71 The pitfalls are as follows: The MV area by PISA is useful when other methods fail, and
With rapid heart rate (atrial fibrillation) or a large terminal it is a reasonably accurate method in atrial fibrillation. The
A-wave, the deceleration slope may be too short to accurately pitfalls of this method are as follows: The PFC zone may be
define (Fig. 21.24C). The PHT method should be used with difficult to visualize by surface echo. In addition, an “α
caution or not at all in patients with potentially significant measurement” tool is not provided on most analysis systems,
left ventricular diastolic pressure elevation (e.g., advanced though a reasonable estimate can sometimes be made by
cardiomyopathy or significant concomitant AR72). In such visual inspection.
cases, progressive pressure rise in the receiving chamber
hastens the decay of the LA-LV pressure gradient, and the T RICUSPID R EGURGITATION VELOCITY
calculated MV area will be erroneously large. The PHT may Pulmonary hypertension either at rest (in the absence of
appear long secondary to impaired LV relaxation (LV dia- other causes) or during exercise (Fig. 21.24E), is a hallmark
stolic dysfunction) in the absence of significant MS. In addi- of clinically significant MS. An estimate of the systolic pul-
tion, the PHT method is not valid in the first day or two after monary artery pressure (SPAP) using the TR velocity by CW
percutaneous balloon valvuloplasty.73 Doppler (see Chapter 5) is an important element of the
exam.
VALVE A REA BY CONTINUITY EQUATION 74
See aortic stenosis (above) for derivation of the continuity E XERCISE DOPPLER ECHOCARDIOGRAPHY 77,78
equation, which can also be applied to the mitral valve for Exertional dyspnea, the cardinal clinical symptom of MS,
area calculation (MVA). Stroke volume is the product of CSA can also be caused by a number of conditions not related to
512 chapter 21

REST Rest
HR = 54 HR = 54
Grad Mn = 6.1 mm Hg MVA PHT = 1.2 cm2

A B

SPAP = 50 mm Hg
HR = 54
Rest
VTR = 3.5 m/s
Grad. MEAN = 15.5 mm Hg

HR = 90
25 Watts Bike

SPAP = 90 mm Hg
HR = 90
25 Watts Bike
E
FIGURE 21.24. Bicycle stress echocardiography in a large male hypertension at rest, possibly from severe COPD. At low workload
with chronic obstructive pulmonary disease (COPD) and NY Heart (25 W, bicycle ergometry; D,E), increased mean MV gradient =
Assoc. Functional Cass III (NYHAFC III) exertional dyspnea. At rest 15.5 mm Hg and peak systolic positive airway pressure (PAP) =
(A–C) moderate mitral stenosis by valve area from PHT method and 90 mm Hg (HR = 90 bpm), suggesting clinically severe MS. (NYHAFC
mean gradient (see Tables 21.6 and 21.7). Moderate pulmonary I following percutaneous mitral balloon valvuloplasty.)

MS (e.g., primary pulmonary disease). A diagnostic dilemma cant MS (Fig. 21.24), although the valve area calculation
arises when a patient with exertional dyspnea is also found should remain constant. Dobutamine echocardiography in
to have MS with only mild-to-moderate range resting MV rheumatic MS has also been described.79
gradients or valve area. As in the cardiac catheterization
laboratory, repeat hemodynamic measurements during exer-
Conclusion
cise may clarify the situation. With modest exercise (staged
supine bicycle protocol or immediately post treadmill), the The MV area should be confirmed using two or three methods,
mean mitral valve gradient and systolic pulmonary artery given the number of potential pitfalls of each. The valve area
pressure will both increase markedly in clinically signifi- may be mild by planimetry when there is severe chordal level
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 513

Va = 28 cm/s
r = 1.0 cm

A B

Vpk ~
– 200 cm/s
PHT = 266 ms

C
FIGURE 21.25. TEE images illustrate agreement of MVA calcula- 6.28 r 2 × Va/Vpk = 0.8 cm2 (rounded). MVA PHT = 220 ÷ PHT = 0.8 cm2
tion using the proximal isovelocity surface area (PISA) method and (rounded). See images for variables.
PHT method in a patient with atrial fibrillation. MVA PISA = (α/180)

stenosis. The mean MV gradient may be low in severe MS possible in most situations.7 Laboratories should ideally
with low cardiac output or bradycardia. The mean MV gradi- apply as many methods as possible in each case, both for
ent may be high in mild MS with high cardiac output or with confirmation and to maintain the skills needed for difficult
tachycardia. A shortened PHT is possible with severe MS cases.
with concomitant significant AR or cardiomyopathy. In mild
MS, the PHT may appear long if there is impaired LV relax- Two-Dimensional and M-Mode Examination and
ation. The planimetry, PHT, and PISA methods are relatively Differential Diagnosis
reliable in atrial fibrillation. The PHT method should not be
The asymmetrical atrioventricular valves (mitral and tricus-
used early after mitral balloon valvuloplasty. When reporting
pid) are structurally and functionally more complex than the
gradients and when using the continuity equation in atrial
arterial valves (aortic and pulmonic). Normal mitral valve
fibrillation, measurements from five to 10 cycles should be
function depends on both normal structure and function of
averaged. In problematic cases, an exercise Doppler examina-
each component of the so-called mitral apparatus. The mitral
tion may be helpful.
apparatus consists of the mitral annulus and left atrium, the
leaflets, chordae tendineae, the papillary muscles, and the
Mitral Regurgitation left ventricle. Structural abnormalities of any component,
visible by 2D or M-mode evaluation, raises the possibility for
Detection of mitral regurgitation (MR) by Doppler is rela-
valve malfunction and provide clues as to etiology.
tively easy. However, accurate grading of MR severity can be
technically challenging.80 As previously mentioned, no one
method is sensitive and specific in all cases. This section L EFT VENTRICULAR AND L EFT ATRIAL SIZE
reviews the 2D and Doppler supportive signs and semiquan- A dilated left ventricle or left atrium47 should always heighten
titative and quantitative methods for diagnosing the degree the suspicion for the presence of significant MR, because
of MR. When several of these findings are in agreement this condition imposes a volume load on both chambers.
regarding lesion severity, an accurate integrated diagnosis is In patients with known moderate-to-severe or severe MR,
514 chapter 21

measurement of LV size and function are important for sur- is not planar but “saddle-shaped.” Orientation of the valve in
gical timing. In chronic, compensated MR, without cardio- the four-chamber view can sometimes give the appearance
myopathy, the left ventricular end systolic volume should be of mitral valve prolapse (MVP) when there is none. Therefore,
normal and the left ventricular ejection fraction should be the four-chamber view is not used for diagnosing MVP.
≥60% due to low afterload. Left atrial enlargement accom- Mitral valve prolapse can be functional and transient because
panies chronic MR. In acute severe MR, the LA may be of hypovolemia and a hyperdynamic state (reduced LV and
normal in size. Many comorbid conditions can also enlarge mitral annular size leading to leaflet redundancy) or myxo-
the left ventricle (e.g., cardiomyopathy, AR) or the left atrium matous mitral valve degeneration. Mitral valve prolapse can
(e.g., LV diastolic dysfunction, atrial fibrillation, etc.). See be provoked or accentuated by performing a Valsalva maneu-
Tables 21.3 to 21.5 for left ventricular size and function by ver during imaging. In myxomatous MV disease, prolapse
echocardiography. usually results from combined leaflet redundancy and
chordal elongation (Fig. 21.27). The degree of leaflet thicken-
M ITRAL VALVE PROLAPSE AND ing can vary markedly among affected patients. Mitral
MYXOMATOUS DEGENERATION annular dilatation is often present. A characteristic “myxo-
The mitral leaflet systolic coaptation zone normally lies on matous deformity” may include a hypermobile systolic bil-
the ventricular side of an imaginary mitral annular plane, as lowing or parachute-like appearance of the leaflets (Figs.
visualized in the parasternal long axis view or apical three- 21.27 and 21.28). In advanced disease, the leaflets can be
chamber view. The mitral leaflets are said to “prolapse” excessively thickened and calcified, which reduces leaflet
when leaflet closure is followed by a late systolic excursion mobility. Myxomatous changes can be generalized, involv-
of one or both of the mitral leaflets beyond this imaginary ing both leaflets, or be highly localized, sometimes involving
plane, into the left atrial space (Fig. 21.26). The mitral annulus only a single segment of one leaflet. Therefore, careful sys-

A B

C D
FIGURE 21.26. Mitral valve prolapse (MVP), posterior leaflet. (A) in isolation. (D) CW Doppler demonstrates that late systolic MR
Parasternal long axis view. The posterior leaflet (arrow) crosses the (double arrows) is a transient event and unlikely to represent a sig-
annular plane (red line). (B) M-mode shows late systolic hammock nificant regurgitant volume. Single arrow shows onset of systole
sign of MVP. (C) Color Doppler (same patient) suggests significant (MV closure artifact).
MR when a late systolic frame (see arrow, ECG tracing) is viewed
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 515

A B
FIGURE 21.27. Myxomatous degeneration of the mitral and tricus- Gastric long axis view of the LV shows markedly elongated chordae
pid valves and other structures by TEE. (A) MV and tricuspid valve tendineae (arrows) with “parachute” appearance of the two MV
(TV) annular dilatation, “billowing” MV and TV systolic prolapse leaflets.
(albeit in four-chamber view), aneurysmal interatrial septum. (B)

tematic scanning across the entire mitral coaptation line is in MVP and particularly when chordal rupture is present,
required to rule out MVP. Mitral valve prolapse can be a though central MR can occur with balanced prolapse, usually
subtle and rapid event, particularly during tachycardia. without chordal rupture (Fig. 21.28). Eccentric jet lesions
Therefore, the M-mode exam (parasternal long axis views) generally flow away from the dysfunctional leaflet (i.e., pos-
can be helpful in making the diagnosis (Fig. 21.26B). Associ- teriorly directed jet from anterior leaflet prolapse or anterior
ated tricuspid valve prolapse is not uncommon. Aortic valve jet from posterior leaflet prolapse). Chordal rupture is
myxomatous degeneration is occasionally seen. suspected when a leaflet flail segment is seen partially
Mitral valve prolapse can produce any degree of regurgita- underriding the opposing leaflet, usually with an attached
tion (or none at all), depending on whether prolapse is mild, mobile linear echo density (the liberated chord).
moderate, or severe and to what extent the prolapse is bal-
anced between the two leaflets so that systolic coaptation is Surgical Repair of Mitral Valve Prolapse. Use of the
maintained. Myxomatous valve disease predisposes patients standard TTE and TEE views presented in Chapter 5 can
to chordal rupture, which can result in sudden, severe MR. identify all segments of both the posterior and anterior leaf-
Ruptured chords can sometimes be detected by surface echo- lets and the exact site of MR origin (Figs. 21.30 to 21.32).
cardiography (Fig. 21.29) but are more easily identified by Anatomic imaging, combined with color Doppler, will show
TEE (Figs. 21.30 and 21.31). Highly eccentric MR is common the primary site and mechanism of MR (e.g., leaflet

A B
FIGURE 21.28. Bileaflet MV prolapse by TEE, three-chamber view lapse with visible leaflet malcoaptation (no chordal rupture). a, ante-
showing redundant, billowing leaflets with mild central MR due to rior leaflet; p, posterior leaflet; Ao, aortic root; LV, left ventricle.
balanced bileaflet prolapse (A) and severe MR (B) from severe pro-
516 chapter 21

A B

C
FIGURE 21.29. (A) Severe MR due to flail posterior leaflet segment apical three-chamber view. (C) Markedly increased mitral inflow E
(arrow) from chordal rupture, parasternal long axis view. (B) Massive wave by pulsed Doppler = 1.5 cm/s (see Table 21.8) indicating severe
highly eccentric MR jet by color Doppler directed away from the MR. Other quantitative methods are not required. Note: chronic
flail leaflet segment, encircling a severely enlarged left atrium (LA), MR, patient relatively asymptomatic.

tethering, perforation, prolapse, or ruptured chord). Isolated impaired. The degree of MR can be challenging to diagnose
posterior mitral leaflet prolapse or flail segment is generally because of shadowing of the left atrium. At least mild associ-
most amenable to surgical repair (Fig. 21.30). Prolapse or flail ated mitral stenosis is common, and this can affect mitral
segments of the anterior leaflet can be more difficult to inflow gradient peak and mean velocities. As with prosthetic
correct surgically (Fig. 21.32). Many additional factors, valve MR, TEE is frequently required for adequate MR evalu-
including local experience, leaflet calcification, mobility, ation in advanced calcific degeneration of the mitral valve.
annular size, chordal length, and presence of coronary artery
disease, go into the decision-making process. Intraoperative R HEUMATIC M ITRAL R EGURGITATION
TEE is typically performed whenever MV repair is contem- Although mitral stenosis is more commonly associated with
plated in order to confirm the diagnosis, and to assess the rheumatic mitral valve disease, MR can be the predominant
results in the operating room immediately after cardiopul- hemodynamic lesion in some cases. Rheumatic MR can
monary bypass (Fig. 21.30E). result from scarred, restricted leaflets that appear almost
frozen in a semiopen position or from additional leaflet
M ITRAL A NNULAR CALCIFICATION destruction from superimposed endocarditis. Although
Calcific degeneration of the mitral valve is common, particu- rheumatic MS can produce severe left atrial enlargement,
larly in the elderly, and can be present prematurely in chronic particularly with atrial fibrillation, historically it is rheu-
renal failure patients. Calcium deposits most commonly matic MR (usually with mixed MS) that has produced the
infiltrate the posterior aspects of the mitral annulus, though largest of the left atria—“giant left atrium.” The giant left
the process can become circumferential and begin to invade atrium is actually defined by chest x-ray (left atrium touch-
the bases of the leaflets where mobility is most notably ing the right thoracic wall).81
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 517

A B

C D

E F
FIGURE 21.30. Intraoperative TEE, showing the mechanism for wall-hugging left atrial jet (Coanda effect) are seen. This eccentric
severe anteriorly directed eccentric MR due to myxomatous mitral jet lesion is consistent with severe MR although the overall color
valve disease primarily affecting the posterior leaflet with a flail Doppler jet areas is not as large as a comparable central jet lesion
middle scallop (P2) due to chordal rupture. (A) TEE five-chember created by bileaflet prolapse (compare with Fig. 21.28B). The PISA
view. The flail myxomatous-appearing P2 segment and attached method for EROA quantation cannot be used in this case due to the
ruptured chorda tendina (arrow) resembles a duck’s head (a common complex regurgitant orifice shape and a PFC zone that is “con-
appearance). (B) TEE bicommissural view (see Chapter 5 for standard strained” by the LV posterior wall. (E) Surgical specimen (excised P2
views) confirms isolated involvement of the P2 segment. (C) Poste- segment and ruptured chord (black arrow) in the same patient. (F)
rior leaflet, P2 and the ruptured chord (arrow) override the mid Intraoperative TEE immediately after successful quadratic P2
portion of the relatively normal anterior mitral leaflet. (D) Large scallop resection with annular reduction [mitral annuloplastiy ring
color Doppler proximal flow convergence (PFC) zone and a severe, seen in cross exaction (arrows) with no residual MR].
518 chapter 21

A B
FIGURE 21.31. Intraoperative TEE showing the mechanism for severe posteriorly directed MR due to flail anterior leaflet segment A2 from
chordal rupture (arrow).

OTHER INFLAMMATORY CONDITIONS release of collagenase and other destructive enzymes. Chordal
Chordal thickening, shortening, and the resultant systolic rupture can occur, in which case mobile chords or flail leaflet
leaflet tethering causing severe MR can be seen in a number segments may be difficult to distinguish from the vegetation
of other inflammatory conditions (scleroderma; radiation material. Pseudoaneurysms of the mitral valve leaflets can
valvulitis; anorexigenic- and ergotamine-induced valve perforate or impair leaflet function. Perforation may be
disease; and hypereosinophilia). These other etiologies may visible as a segment of leaflet discontinuity or, if punctate,
be difficult, if not impossible, to distinguish echocardio- be apparent by turbulent color Doppler jet lesions arising
graphically (or even on surgical inspection) from rheumatic from areas outside the normal coaptation zones. A perforated
MR. Minimal or no stenosis and the lack of commissural mitral annular abscess can produce an annular echo-free
fusion weigh against rheumatic disease. space and annular MR.

ENDOCARDITIS FUNCTIONAL M ITRAL R EGURGITATION

A variety of anatomic abnormalities may be present on the Functional MR exists when all elements of the mitral appa-
2D or M-mode exam. On M-mode, a mobile echodensity ratus appear morphologically normal, but their function is
adjacent or attached to the leaflets exhibiting independent impaired, usually because of dilated cardiomyopathy (Fig.
motion suggests vegetation. Small vegetations are frequently 21.33). The classic identifiable feature by 2D exam is incom-
visible by TTE, but this is highly dependent on imaging plete closure of the mitral leaflet due to leaflet tethering due
conditions. The presence of possible valve vegetations should to papillary muscle displacement,82 although annular dys-
raise suspicion for significant MR, and a confirmatory TEE function may also play a role. Appreciated more recently is
may be indicated. Microbial pathogens (Staphylococcus the role of LV contractile dyssynergy (detectable and quantifi-
aureus, most notably) can cause leaflet destruction from the able echocardiographically, see other chapters) in patients

A B
FIGURE 21.32. TEE showing severe MR due to unusual cleft defor- view (B) imaging of the mitral valve confirms the regurgitant orifice
mity (confirmed surgically) in the anteromedial commissure region location and lack of associated chordal rupture or prolapse.
(arrowhead). Combined bicommissural (A) and gastric short axis
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 519

A B

C
FIGURE 21.33. Moderate-to-severe functional MR by vena con- applying a smaller but magnified (zoom mode) color sector. (C) Line
tracta (VC) method in a patient with dilated cardiomyopathy. The indicates orthogonal planes A and B, and the presence of a single
leaflets are tethered toward the LV (A). The VC is measured just regurgitant orifice.
distal to the anatomic orifice (VC = 0.6 cm, see Table 21.8) after

with cardiomyopathy and left bundle branch block. In these Doppler Evaluation of Mitral Regurgitation
patients, functional MR can sometimes be improved sub-
PULSED -WAVE DOPPLER
stantially by cardiac resynchronization therapy.83
As described in Chapter 5, the complete exam includes a
CORONARY A RTERY DISEASE 84 pulsed wave (PW) Doppler signal acquired at the mitral
Left ventricular segmental wall motion abnormalities should leaflet tips, the mitral annulus, and the pulmonary vein.
heighten suspicion for MR. Ischemic MR is a common but This simple routine provides important information for MR
not always easily defined entity. Ischemia can transiently assessment by Doppler flow assessment.
affect papillary muscle function, leading to an eccentric MR
jet from leaflet malcoaptation. Myocardial infarction can
cause acute severe MR from a papillary muscle tear (leaflet
prolapse) or complete avulsion (flail leaflets). Dysfunction of
Mitral E Velocity. In severe MR, the mitral
a scarred and retracted papillary muscle can produce severe
forward flow is markedly increased due to the additive
MR from leaflet tethering.85 Extensive ventricular scarring
forward stroke volume and the “wasted” regurgitant
can lead to adverse remodeling and functional MR instead
volume. The increased diastolic flow increases the mitral E
of ischemic MR. A basal myocardial segment scar can distort
velocity. In patients with normal ejection fraction, a
mitral annular geometry and function.
mitral leaflet tip E-wave velocity ≥1.2 cm/s (Fig. 21.29C) is a
OTHER CAUSES OF M ITRAL R EGURGITATION R ECOGNIZABLE sensitive and moderately specific sign of severe MR.86
BY ECHOCARDIOGRAPHY Increased mitral E velocity is not a reliable sign in patients
Systolic anterior motion (SAM) of the mitral valve can cause with cardiomyopathy. However, when the mitral inflow
significant MR. Signs of this abnormality are covered in pattern is A-wave dominant, there is little likelihood of
Chapter 35. severe MR.
520 chapter 21

Pulmonary Vein Systolic Flow Reversal. By TTE and signal can be useful for demonstrating that the MR is not
TEE (Fig. 21.34), the PW Doppler sample volume is placed sustained and is unlikely to be severe, even if dense (Fig.
approximately 1 cm into the right superior pulmonary vein 21.26D). The CW signal can exhibit a V-wave “cut-off” in
(TTE, apical four-chamber view) or in all TEE-visualized severe MR with cardiomyopathy and a high left atrial pres-
pulmonary veins. For a time, based primarily on early TEE sure in acute severe MR (see below). The pitfalls are as
reports, pulmonary vein systolic flow reversal was thought follows: CW density is a helpful supportive sign and not a
to be a highly sensitive and specific sign of severe MR. Later true quantitative measure. The CW Doppler signal can be
reports have shown that pulmonary vein systolic flow rever- shadowed in calcified or prosthetic valves. The CW beam
sal is neither highly sensitive nor highly specific for severe may not be accurately placed within the jet, potentially
MR.87,88 Directed jets that are not severe may enter a pulmo- resulting in a faint jet despite severe MR. In curvilinear,
nary vein. In chronic severe MR, the remodeled LA may eccentric jets, CW Doppler cannot be brought into coaxial
accommodate severe MR without actual pulmonary vein alignment, so that jet CW Doppler density and peak velocity
systolic reversal. Nonetheless, pulmonary vein inflow sys- may be low, even in severe lesions.
tolic blunting or systolic flow reversal should raise the ques-
tion of possibly severe MR, which should be confirmed using
L EFT ATRIAL JET A REA BY COLOR DOPPLER
other methods.
Overall jet size (maximum area) within the left atrium is
Pulsed Doppler of the Left Atrial Appendage. Occa- useful only in extreme circumstances. The area generally
sionally, a highly eccentric severe MR jet travels directly into includes only the zone of sustained “mosaic” color Doppler.
the LAA, where its energy is largely absorbed. Left atrial A mosaic is the appearance of alternating, colored, adjacent
appendage MR jets may be due to paravalvular leaks in the pixels, signifying a zone of high-velocity turbulent flow. A
adjacent prosthetic valves sewing ring or unusual cases of very small left atrial jet usually means mild MR. A very
native valve MVP or endocarditis. This possibility should be large jet that almost fills the left atrium usually means
borne in mind during TEE evaluation. severe MR (Table 21.8). The pitfalls are as follows: A common
pitfall is an inappropriate Nyquist limit setting. The color
CONTINUOUS-WAVE DOPPLER Doppler Nyquist limit setting should be in the range of 50
Continuous-wave CW Doppler density (brightness of the to 60 m/s. Lower or higher settings increase or decrease the
spectral Doppler signal) is proportional to the number of mosaic jet area, respectively. Many other factors (described
regurgitant red blood cells within the path of the interrogat- earlier) affect the size and appearance of the jet. Mild-to-
ing beam. The faint signal of trivial or mild MR can be dis- moderate volume “high-energy” central jets can entrain sur-
tinguished from the dense signal of moderate to severe MR. rounding blood and appear severe by color Doppler. Severe
The bright density of all forward flow in the mitral valve MR can appear mild to moderate by color Doppler if hypo-
(above the baseline) is a useful benchmark for determining tension or high left atrial pressure (unobstructed MR) are
the relative regurgitant density (Fig. 21.35). With MVP or present. Severe eccentric MR with a “wall-hugging” jet may
functional MR, the signal may be dense only in late or in appear only mild to moderate based on area assessment.89
early stole, respectively. In these two situations, the CW The tendency for high-energy jets to “cling” to an adjacent
solid boundaries surface is known as the Coanda effect (Figs.
21.29 to 21.31). In the future, left atrial jet volume assess-
ment using 3D echocardiography may be of incremental
value.

VENA CONTRACTA WIDTH BY COLOR DOPPLER 90,91

When the sonographer confirms that only a single predomi-
nant MR jet is present, the VC height can be a valuable and
relatively easy-to-obtain linear measure of regurgitation
severity that does not vary significantly with hemodynamic
loading conditions. Details of accurate VC imaging tech-
niques have been described9 and are shown in Figures 21.33
and 21.36. Accurate measurement requires optimized
zoomed views of the jet origin (PFC zone, anatomic orifice,
and VC region), without regard to the appearance of the distal
expanding jet lesion. Measurement is made ideally in the
parasternal long axis view to take advantage of the relatively
high axial resolution of color Doppler. The VC width is a
direct linear measurement, and any error is not propagated
due to squaring. The pitfalls are as follows: The VC may not
be visible because of leaflet calcification. The method is not
FIGURE 21.34. TEE, pulmonary vein systolic flow reversal (arrows valid for multiple jets. The VC width may be overestimated
below baseline). Diastolic dominant pulmonary vein forward flow in apical views because of lower color Doppler lateral resolu-
(arrow above baseline) in a patient with significant MR. tion relative to axial resolution.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 5 21

A B

C D
FIGURE 21.35. Mitral regurgitation by CW Doppler, surface echo, dense signal intensity. (D) Severe MR. Mitral inflow (above baseline)
four-chamber view. (A) Trivial or trace MR with faint, incomplete can be used as a reference for signal intensity. Note: Signal profiles
signal. (B) Mild MR with faint but complete spectral Doppler enve- and intensity can be markedly diminished with eccentric jets, shad-
lope. (C) Moderate MR with complete envelope and moderately owing artifacts or with poor interrogating beam alignment.

PROXIMAL ISOVELOCITY SURFACE A REA M ETHOD FOR images are obtained in apical views in zoomed mode (Fig.
EFFECTIVE R EGURGITANT ORIFICE A REA AND 21.36E). In TEE (Fig. 21.37), the best coaxially aligned views
R IGHT VENTRICLE13,92,93 are used. Whether by TTE or TEE, a standard practice is to
This method works best for central jets and may be particu- shift the color Doppler baseline toward the direction of the
larly useful for demonstrating central jets that appear severe regurgitant jet, so that the lower Nyquist limit (Va) is reduced
by color Doppler jet area alone. The concepts of proximal to approximately 40 cm/s or lower. This produces a homoge-
flow convergence and PISA were discussed earlier. In TTE, neous PFC zone color appearance within the PISA border. Va

TABLE 21.8. Mitral regurgitation Doppler and quantitative parameters

Mild Moderate Moderate-to-Severe Severe

Jet area† (color Doppler) Small, central jet(<4 cm or <20%

2
Variable Large, central jet (>10 cm2
LA area) Variable or >40% LA area)
Mitral inflow (PW) A-dominant* E-dominant, >1.2 cm/s*
MR jet density (CW) Faint/incomplete Dense Dense
MR jet contour (CW) Parabolic Parabolic Early-peaking or V-wave
cut-off (triangular)
VC width (cm) <0.3 0.3–0.69 ≥0.7
RV (mL/beat) <30 ≥60
RF (%) <30 ≥50
EROA (cm2) <0.20 0.20–0.29 0.30–0.39 ≥0.40
PW, pulsed-wave Doppler; CW, continuous-wave Doppler; VC, vena contracta; RV, regurgitant volume; RF, regurgitant fraction; EROA, effective regurgitant
orifice area.
* In the absence of other causes of increased LA pressures, individuals >50 yrs.
† Jet area for eccentric jets is not predictable by color Doppler.
522 chapter 21

A B

C D

E F

G H

I
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 523
FIGURE 21.36. MR quantitation using three methods in the same jet by CW Doppler. (I) Pulsed Doppler for VTI of the LVOT. See
patient in a routine exam. (A) LVOT diameter measurement. (B) images for variables.
Zoom mode, for vena contracta (VC) measurement. (C) MV short VC method: VC = 0.5 cm (simple, direct linear measurement).
axis with color Doppler confirms single MR orifice. (D) Moderately PISA method: EROA = 6.28 r 2 × Va/Vpk = 0.22 cm2; RV = EROA ×
large central jet, apical four-chamber view (color Nyquist limit >50 VTI MR = 41.6 mL; SV = 6.28 (r 2) × Va = 118 mL; RF = RV/SV = 0.35
and <60). (E) “Zoomed” view of proximal flow convergence; reduc- (moderate MR, see Table 21.8). Doppler flow method: SV LVOT = 0.785
tion of color Doppler Nyquist limit in direction of the jet lesion; × D LVOT2 × VTI LVOT = 37.7 mL; SVMVann = 0.785 × D MVann2 × VTI MVann =
PISA radius measurement (r). (F) Mid-diastolic mitral annulus diam- 73.2 mL; RV = SVMVann − SV LVOT = 35.5 mL; RF = RV/SVMVann = 0.48.
eter measurement. (G) Pulsed Doppler at the mitral annulus level; All methods are in rough agreement for a diagnosis of moderate MR
MV annulus VTI measurement. (H) VTI and peak velocity of MR (see text for formulas and Table 21.8 for reference values).

can be adjusted to produce a hemispheric shape. The mitral The regurgitant volume (with preserved overall LV systolic
regurgitation peak velocity (Vpk) is obtained from the CW function) is an additional severity indicator (see Table 21.8).
Doppler signal when there is good coaxial alignment of the The mitral valve VTI (VTI MR) is obtained automatically by
beam: outlining the CW Doppler MR signal.
EROA = 6.28r 2 × Va/Vpk
Proximal Isovelocity Surface Area Pitfalls.93,95 The
The EROA can be a useful indicator of severity94 (see Table method is valid only when a single dominant jet is present,
21.8). The regurgitant volume is derived using the following and not if two or more (multiple jets) are identified (Fig. 21.38).
equation: The method may be less reliable when the jet origin is
RV = EROA × VTI MR complex (curvilinear by short axis view) or restrained
by adjacent prolapsing leaflets or ventricular myocar-
or
dium (eccentric jets). In addition, the CW Doppler is diffi-
EROA = RV × VTI MR cult to align in eccentric jets, leading to a low Vpk and an

A B

VMR = 654 cm/s

VTIMR = 224 cm

C
FIGURE 21.37. PISA method for MR quantitation by TEE. A nearly Doppler of the MR jet. Calculations: see images for variables. EROA
perfectly hemispheric PISA is formed by a punctate fenestration = 6.28 r 2 × Va/Vpk = 0.22 cm2 = 0.07 cm2; RV = EROA × VTI MR =
(arrow) in the mitral anterior leaflet base (A, simultaneous 2D and 15.7 mL; SV = 6.28 (r 2) × Va = 114.5 ml; RF = RV/SV = 0.13. All con-
color Doppler image). The radius is easily measured in zoom mode sistent with mild MR (see Table 21.8).
(B). Aliasing velocity (Va) is reduced in direction of jet lesion. (C) CW
524 chapter 21

left atrial blood pool provides an excellent acoustic medium

for imaging, usually with no interposed structures that could
cause signal attenuation. Transesophageal echocardiography
is very useful when surface echocardiography is technically
difficult for any reason, particularly when there is left atrial
shadowing from calcification or a mitral valve prosthesis.
Any of the above-mentioned quantitative measures or indica-
tors can be applied to TEE, potentially with improved accu-
racy in some cases. Many times, surface echocardiography
excels at gathering spectral Doppler data because of an
increased number of potential imaging windows necessary
for obtaining coaxial jet alignment. Transesophageal echo-
cardiography generally excels at providing a higher resolu-
tion detailed look at leaflet anatomy. One must bear in mind
that mild MR to moderate-range jets will appear more
impressive by TEE than by TTE because of improved image
clarity and decreased imaging depths. Therefore, the other
factors regarding jet severity (jet density by CW Doppler, VC,
FIGURE 21.38. TEE shows three separate MR jets (arrows); there-
fore, we cannot use the PISA or vena contracta methods. LV, left PISA analysis, etc.) must be kept in mind to avoid overcalling
ventricle; LA, left atrium. MR severity. Transesophageal echocardiography is ideally
used as a complementary imaging modality when the surface
overestimated EROA. Despite these limitations, the presence exam is inconclusive or when surgery is being considered
of one or more areas of prominent proximal flow convergence (endocarditis with potential abscess, possible mitral valve
(at standard color Doppler Nyquist settings) is a sign of pos- repair, prosthetic valve dysfunction).
sibly significant MR that warrants further investigation.
Therefore, PFC (PISA) imaging attempts are never wasted. Acute Severe Mitral Regurgitation
Acute severe MR should be considered in the differential
M ITRAL A NNULAR FLOW AND R IGHT VENTRICLE BY diagnosis of patients with cardiogenic shock. Acute severe
PULSED DOPPLER 50,51 MR can be inadvertently missed on review of a surface echo-
The standard exam includes pulsed Doppler within the cardiogram without a high index of suspicion. As mentioned
mitral annulus. The mitral annular diameter can be mea- above, the CW and color Doppler signals may be inconspicu-
sured, and mitral annular stroke volume determined (SV = ous in torrential MR (e.g., acute chordal or papillary muscle
CSA × VTI) (see example calculation in Figure 21.36). When rupture) because of systemic hypotension and high left atrial
mitral regurgitation is present, the forward diastolic mitral pressure (low LV-to-LA pressure gradient) due to almost
flow includes the useful forward stroke volume in addition unobstructed (nonturbulent) regurgitant flow. Color Doppler
to the added “wasted” RV. The mitral valve RV can be deter- signs for low-velocity acute severe MR may also be lacking
mined by subtracting the stroke volume obtained at a com- in this situation due to tachycardia with relatively slow color
petent reference valve (LVOT or RVOT) from the increased Doppler sample rate. The MR “V-wave cut-off” sign by CW
mitral annular total SV: Doppler (Fig. 21.39) is usually present, however. Other clues
Total SVMVannulus = SVreference valve − RVMV
See Table 21.8 for clinically useful RV values. When the
overall forward stroke volume is reduced (cardiomyopathy),
the regurgitant volume may be misleadingly low, and the
regurgitant fraction (RF) should be used instead (see Table
21.8 for reference values):
RFMV = RV/SVMV

Pitfalls. The method is difficult to apply in irregular

rhythms (e.g., atrial fibrillation) because of variable stroke
volumes beat to beat. Because annular diameters are squared,
measurement errors are compounded. Significant reference
valve regurgitation invalidates the method. Accurate mitral
annular measurement can be difficult or impossible with
severe mitral annular calcification (Fig. 21.22) or other mor-
phologic deformity.

M ITRAL R EGURGITATION ASSESSMENT BY

FIGURE 21.39. Typical appearance of CW spectral Doppler in acute
T RANSESOPHAGEAL ECHOCARDIOGRAPHY severe MR with cardiogenic shock. Low velocity (3.8 m/s), triangu-
Transesophageal echocardiography can be an ideal modality lar shaped with “v-wave cut-off” (arrows). This patient had papillary
for assessing mitral leaflet morphology and MR severity. The muscle rupture after myocardial infarction.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 525
to the diagnosis include normal or hyperdynamic LV contrac-
tility with a reduced LVOT stroke volume by LVOT PW
Doppler. Acute severe MR is a potential surgical emergency.
Confirmatory TEE for both severity and mechanism assess-
ment should be performed expeditiously when the diagnosis
is suspected.

Tricuspid Valve Disease

Tricuspid Stenosis

Two-Dimensional Imaging and

Differential Diagnosis
Tricuspid stenosis (TS) is an uncommon diagnosis that is
suspected in the clinical setting of systemic venous hyper-
tension with a prolonged y-descent as observed in the jugular
vein, visually; by RA pressure tracing; or by hepatic vein
pulsed Doppler. Rheumatic TS, carcinoid heart disease,
tumor obstruction, and obstructed tricuspid valve (TV) pros-
FIGURE 21.40. Carcinoid heart disease. The patient had torrential
thesis are all important but uncommon conditions that can tricuspid regurgitation (TR) and mild tricuspid stenosis (TS) due to
be recognized by echocardiography. thickened TV leaflets “frozen” in the semiopen position (arrows).

R HEUMATIC T RICUSPID STENOSIS

Rheumatic TV changes that are evident by echocardiography
mirror those seen in rheumatic mitral valve disease: leaflet
leading edge thickening, with reduced mobility; commis-
prosthetic TV (either biologic or mechanical) can develop
sural fusion; and leaflet doming and leaflet tethering from
forward flow obstruction (Fig. 21.41).
chordal shortening and fusion. Rheumatic TS rarely if ever
occurs in the absence of rheumatic MV disease. Associated
Tricuspid Stenosis Assessment by Doppler
TR is common.
Pulse-wave Doppler of the hepatic vein inflow demonstrates
CARCINOID HEART DISEASE a prolonged y-descent due to delayed diastolic RA emptying.
Carcinoid heart disease is suspected by 2D echocardiography Because complicating TS can be easily overlooked in the
when the TV leaflets and submitral apparatus appear mark- setting of dramatic associated TR (rheumatic or carcinoid TV
edly thickened and fully or partially frozen in a semiopen disease), the diastolic tricuspid inflow velocities should
position with marked systolic leaflet malcoaptation (Fig. always be carefully observed by CW Doppler. Values for
21.40). Tricuspid stenosis is usually in the mild to moderate pathologic TV gradients are much lower than for MS, since
range with associated torrential TR. Associated pulmonary systemic venous hypertension is very poorly tolerated. Clini-
stenosis (PS) and PR (due to similar leaflet deformity) are the cally apparent TS (lower extremity edema, ascites, early
rule in carcinoid heart disease, whereas rheumatic PV disease satiety, etc.) can occur whenever the mean resting TV gradi-
is a rare diagnosis, particularly in Western countries. ent is >5 mm Hg. After TV repair, intraoperative TEE is useful
Tricuspid stenosis rarely occurs with obstructive atypical for evaluating successful treatment of TR and also for ensur-
right atrial myxomas or other, usually malignant, tumors. A ing that excessive annular reduction has not created TS.

FIGURE 21.41. (A) Tricuspid valve mechanical prosthesis thrombosis with severe obstruction gradient by CW Doppler. (B) Normalized TV
prosthesis gradient after thrombolytic therapy.
526 chapter 21

Tricuspid Regurgitation POSTTRAUMATIC T RICUSPID R EGURGITATION

Deceleration injuries (e.g., fall from a ladder, car crashes)
Two-Dimensional Examination and can result in chordal rupture or anterior leaflet tear, most
Differential Diagnosis commonly. The anatomic clue for leaflet tear may be the lack
of other valve pathology and an odd appearance to the jet
Hemodynamically significant TR is commonly seen in adult origin (e.g., a basal leaflet jet origin) with the trauma even
echocardiography laboratories. Moderate and even severe- sometimes having occurred years or decades before
range TR is often tolerated without clinical symptoms for diagnosis.
long periods, as long as the pulmonary artery pressure
(forward flow resistance) remains normal (low) and right ven-
tricle systolic function is normal. Echocardiography is impor- R HEUMATIC T RICUSPID R EGURGITATION
tant not only for diagnosis of TR but also for detecting signs The association with rheumatic MV disease is high, with
of eventual right ventricle failure due to volume overload. clinically significant rheumatic TR being much more
common than TR. The degree of rheumatic TR should be
T RICUSPID VALVE PROLAPSE routinely excluded prior to MV surgical repair, since postop-
Tricuspid valve prolapse, often associated with myxomatous erative severe TR is often not well tolerated, particularly in
degeneration of the mitral valve, is recognizable by 2D older patients. Recognizable TV leaflet malcoaptation due to
imaging, though obtaining views that are in true long or leaflet overtethering from chordal thickening, and shorten-
short axis alignment with the TV annulus can be difficult. ing and secondary annular dilatation are usually apparent
In any of a number of views, one or both leaflets may be seen echocardiographically due to increased leaflet and subvalvu-
underriding the opposing leaflet or appearing to cross that lar echogenicity.
annular plane. Flail leaflet segments and severe TR can
result from chordal rupture, related to myxomatous degen- FUNCTIONAL T RICUSPID R EGURGITATION
eration, endocarditis (Fig. 21.42), endomyocardial biopsy,96,97 When the right ventricle is chronically exposed to volume or
or deceleration injury. pressure overload, for whatever reason, annular dilatation

A B

C D
FIGURE 21.42. Signs of severe “unobstructed TR” from TV endo- increased TV inflow velocity (>1 cm/s, single arrow). (C) Large
carditis. (A) Flail leaflets (arrows) with unimpressive color Doppler hepatic vein systolic wave by pulsed Doppler. (D) Paradoxical septal
jet lesion (potentially overlooked laminar flow). (B) Low-velocity TR motion by M-mode, parasternal long axis view with inferolateral
jet by CW Doppler with “v-wave cut-off” (double arrows) with and septal walls moving in unison.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 527

FIGURE 21.43. Paradoxical septal motion as seen by 2D parasternal short axis view. This finding may be seen in right ventricle volume
overload from severe TR, severe pulmonary regurgitation (PR), large atrial septal defect, or any combination of these lesions.

and possibly papillary muscle displacement can cause severe three—in some cases. Paradoxical septal motion occurs
leaflet malcoaptation. Acute pressure overload (acute pulmo- because of equalized right ventricle and LV diastolic pres-
nary embolus) can also cause acute functional TR, as can sure, causing the septum paradoxically to move toward the
acute right ventricle dilatation and right ventricle dysfunc- LV central axis during diastole.
tion from right ventricle infarction. The TV annulus is less
fibromuscular than the MV annulus. The looser TV annulus,
Doppler Evaluation of Tricuspid
therefore, is particularly subject to functional TR that is
Regurgitation Severity
frequently at least partially reversible with medical or other
treatment of the underlying cause of right ventricle pressure COLOR DOPPLER
and or volume overload. However, chronic severe right ven- Severe TR can be missed by color Doppler when there is
tricle volume overload from any cause (PR, atrial septal nearly unobstructed and nonturbulent regurgitant flow (Fig.
defect, and TR itself) begets more functional TR and eventu- 21.42), particularly when associated with low pulmonary
ally leads to right ventricle failure. This process can be accel- artery pressure (low right ventricle to right atrium peak pres-
erated by pulmonary hypertension. Paradoxical septal sure difference). With unobstructed TR, a turbulent color
motion by M-mode (Fig. 21.42A) or 2D inspection (Fig. 21.43) Doppler jet lesion may not be present at all (Fig. 21.42A). On
is a sign of right ventricle volume overload that should the other hand, when the leaflets are reasonably intact, a
prompt a search of significant TR, PR, and ASD—if not all color Doppler jet lesion can be very prominent (Fig. 21.44A),

VTR = 3.5 m/s

A B
FIGURE 21.44. Severe TR with obstructive regurgitant orifice (compare with Fig. 21.42). (A) Larger TR color Doppler area, filling the right
atrium (RA) with a PFC zone. (B) Dense CW Doppler jet with inflow velocity >1 cm/s.
528 chapter 21

and the area of the color Doppler jet as a percentage of the

right atrium (RA) can be a helpful qualitative measure when
the TR. The TR jets under high pressure (pulmonary hyper-
tension or with RVOT obstruction) that are only mild to
moderate may deceptively appear “severe” by color Doppler
jet area because of significant entrained blood flow. A promi-
nent proximal flow convergence zone98 and “wide” vena con-
tracta99 usually signify clinically significant TR. Eccentric
TR jets may be underestimated by color jet area. Because the
TV leaflets are not always clearly visualized by TTE, and
color Doppler alone can be misleading in severe TR, other
Doppler criteria are needed.

SPECTRAL DOPPLER
As with MR, the TR CW Doppler signal density can be
helpful for separating trace or mild TR from moderate- to
severe-range TR. The V-wave cut-off sign indicates rapid
equalization of the right ventricle-RA pressure difference FIGURE 21.45. Severe stenosis of a pulmonary valve homograft
prosthesis (horizontal arrow) with moderate PR (downward arrow)
and is a sign of severe TR (Fig. 21.42C). Because of the larger
with relatively steep deceleration slope.
TV area, the normal TV inflow velocity is lower than that
of the mitral valve. In the absence of TS, a TV inflow velocity
of ≥1 cm/s can be a supportive sign of potentially severe TR
(Figs. 21.42B and 21.44B). The TR velocity by CW Doppler
and residual or very slowly progressive obstruction of previ-
can be used to estimate systolic PA pressure (see Chapter 5),
ously ballooned congenital PS can be seen in adult echocar-
which may influence interpretation of the color Doppler jet
diography laboratories. As previously mentioned, carcinoid
size. Important note: Systolic PA pressure assessment by CW
heart disease (also unusual) is characterized by mixed PS and
Doppler may be unreliable in torrential TR because the
PR, the stenosis component of which is usually mild to
regurgitant flow is relatively unobstructed, in which case the
moderate in severity. An important feature of severe RVOT
modified Bernoulli equation does not apply.
obstruction (PS) is that the right ventricle can produce sys-
temic-level systolic pressures when the pressure rise has
PULSED DOPPLER OF THE HEPATIC VEIN, SUBCOSTAL VIEW
been gradual. A sign of this is a D-shaped ventricular septum
A large hepatic vein systolic wave by pulsed Doppler (Fig.
in the parasternal short axis view of the left ventricle. This
21.42C) can be an important sign of severe TR, particularly
is different from the paradoxical septal motion of right ven-
when the TV is not well visualized either by 2D exam or by
tricle volume overload (see above) in that the septum remains
color Doppler and when correlated with an enlarged right
“flattened” during diastole and systole because the high right
ventricle with paradoxical septal motion. The hepatic vein
ventricle pressure no longer allows the left ventricle systemic
systolic wave, however, may become less prominent with
pressure to determine systolic septal curvature. Interven-
severe right ventricle failure and decreased overall right ven-
tricular septal flattening, however, is a nonspecific finding
tricle stroke volume.
since it will also occur in other conditions leading to right
ventricle pressure overload (pulmonary hypertension from
any cause).
Pulmonary Valve Disease
Doppler Evaluation
Pulmonary Stenosis
Although the pulmonary valve may be difficult to fully visu-
alize by 2D imaging, it is often well aligned for Doppler
Two-Dimensional Evaluation and
evaluation. A routine component of the TTE is CW Doppler
Differential Diagnosis
of the right ventricle outflow tract/pulmonary valve. This
Due to a relatively anterior and immediately retrosternal generally detects either valvular or subvalvular obstruction
position and a posteriorly directed orientation, the pulmo- as in the case of the failed pulmonary homograft prosthesis
nary valve can be difficult to visualize by both surface and in Figure 21.45. Dynamic infundibular RVOT obstructive
transesophageal echocardiography. The normal, thin semilu- gradients are usually late-peaking and can be superimposed
nar cusps are almost identical in morphology to the normal upon the fixed valve lesion. This phenomenon is not uncom-
aortic valve cusps, making them frequently difficult to fully mon in congenital forms of PS.
visualize under normal circumstances. Acquired native
valve PS is distinctly uncommon, with rheumatic heart
Pulmonary Regurgitation
disease only rarely involving this valve. Calcific PS of a
native congenitally normal trileaflet valve is essentially not A trivial to mild degree of PR is present in most normal
a described entity, although calcification and stenosis of a subjects. This is usually detectable by color Doppler on
pulmonary valve biologic prosthesis can occur (Fig. 21.45), routine exam since the valve lies very close to the transducer
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 529

A B

C D
FIGURE 21.46. Mild PR in a normal individual shown by color (A) “laminar” due to unobstructed regurgitant flow. (D) The PR dias-
and CW (B) Doppler. Low velocity with relatively flat deceleration tolic deceleration slope is steep (double arrows) with mild associated
slope. (C,D) Severe “free” PR in a tetralogy of Fallot patient status PS (peak velocity = 3 m/s).
post–pulmonary valvotomy. (C) PR color Doppler jet appears

in the parasternal short axis view, and the PR jet is usually Prosthetic Valve Dysfunction
ideally aligned for detection by Doppler. Even mild PR
lesions, therefore, can appear somewhat prominent by CW Prosthetic valves may be placed in any of the four valve posi-
Doppler, as in Figure 21.46A,B. With small PR regurgitant tions. In addition, the mitral, tricuspid, and pulmonary
volumes, the deceleration time of the PR jet is long, and some valves can be repaired in favorable circumstances. A clinical
degree of persistent PV end-diastolic pressure differential history of prosthetic valve surgery may not be available for
exists, which is even more evident in the setting of pulmo- the sonographer or interpreting physician, although 2D and
nary hypertension (increased PR velocity throughout dias- Doppler signs of prosthetic valves can be recognized.
tole by CW Doppler). Severe PR, on the other hand, produces
a dense but steep deceleration time by CW Doppler with no
significant residual end diastolic pressure difference (Fig.
Mechanical Prostheses: Recognition by
21.46. Unobstructed PR can be due to endocarditis, congeni-
Two-Dimensional Imaging
tal or surgical absence of the valve leaflets, failed prosthesis,
or carcinoid heart disease. Endocarditis is the least likely of Although many old-generation prosthetic valve types remain
these to produce mixed PS and PR. In “free” PR, the brief, in the population, they are now much less commonly encoun-
low-velocity, severe PR jet can be easily missed by color tered in echocardiography laboratories. The most common
Doppler. So careful attention to other signs of right ventricu- type of new-generation mechanical valve prosthesis (in usage
lar volume overload can be important clues for the diagnosis for >20 years) consists of two symmetrical durable pyrolytic
[paradoxical septum, right ventricle enlargement, functional carbon tilting disks, suspended within a rigid ring. The
TR, high forward RVOT VTI by pulsed Doppler and the mechanical valve ring typically produces a small shadowing
typical CW Doppler profile (Fig. 21.46D)]. artifact in the far field. The disks, particularly in the closed
530 chapter 21

A B

C
FIGURE 21.47. Bileaflet mechanical valve prosthesis, mitral posi- prosthetic MR. Jets typically originate from the central margin of
tion. (A) TTE, four-chamber view. Prosthetic valve reverberation the sewing ring as shown. Sewing ring shadowing artifact (absent
artifacts obscure the left atrium (LA). (B) TEE, four-chamber view. far field echos, double arrow, left side); reverberation artifact (addi-
Prosthetic valve reverberation artifacts obscure the left ventricle tional far field echos, double arrows, right side).
(LV). (C) TEE shows normal degree of central bileaflet mechanical

position, produce a prominent and usually easily recogniz- valve, although on detailed inspection annular thickening is
able reverberation artifact. Reverberation consists of addi- seen, and for stentless valves the backing material can often
tional artifactual echo reflections in the far field, be distinguished by careful inspection. The stented biologic
distinguishing it from shadowing, which is the lack of echoes valve, on the other hand, is easily recognized because of the
in the far field. These imaging artifacts aid in recognition of protruding echogenic struts (Fig. 21.48). The biologic leaflets
mechanical prosthetic valves, but they also make obstructive should exhibit opening and closure characteristics typical of
or insufficiency lesions and their mechanisms difficult to any normal aortic valve. Over time, however, reduced leaflet
identify (Fig. 21.47). motion, calcification and even cusp prolapse or flail seg-
ments can sometimes be identified by surface imaging as
shadowing and reverberation artifacts are less problematic.
Biologic Valves: Recognition by
Two-Dimensional Imaging
Doppler Evaluation
Modern biologic valves can be divided into three subtypes
that can be recognized echocardiographically: (1) “Stented” In comparison with normal native valves, normally func-
valves (used in any position) consist of trileaflet semilunar tioning prosthetic valves (and repaired valves) typically
cusps constructed from pericardium or from porcine aortic exhibit mild obstructive gradients at rest. Normal prosthetic
valve zenograft origin, suspended with three rigid supporting valve flow velocities and gradients vary among patients
“struts.” (2) “Stentless” valves (used in the aortic position) according to valve type, patient size, and other hemody-
are porcine aortic valve zenografts supported by a fabric namic variables. Therefore, it is important to conduct a base-
backing instead of struts. (3) Pulmonary autografts or homo- line echocardiography examination, usually within 6 to 8
grafts (used in the aortic or pulmonary positions) consist of weeks after valve implantation surgery for future reference.
the intact pulmonary annular and leaflet structures. Stent- For questionable valves and when baseline data are not avail-
less valves and pulmonary homografts or autografts can be able, reference tables may be consulted for normal valve
difficult to differentiate echocardiographically from a native velocities and gradients.100
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 5 31

A B

C
FIGURE 21.48. Stented biologic prosthesis in the mitral position. strates biologic leaflets in the closed position (arrow) with sewing
(A) Parasternal long axis view and apical two-chamber view. The ring partially shadowing the LV, but with no reverberation
valve “struts” (arrow) protrude into the LV. (C) TEE image demon- artifacts.

Many of the same principles that apply for native valve all aspects of the valve sewing ring with color Doppler, in an
obstructive lesions can be used for evaluating prosthetic attempt to identify sites of abnormal proximal flow conver-
valve forward flow.6 A mechanical valve can become gence in the sewing ring, which can be a sign of a perivalvu-
obstructed due to pannus (organized thrombus) or recent lar leak since the jet lesion (particularly with perivalvular
thrombus formation within the sewing ring. Unfortunately, MR on surface echo) may be hidden by shadowing and rever-
thrombus and pannus formation can be difficult to visualize, beration artifacts. CW Doppler should “explore” the pros-
although TEE may be of significant incremental benefit for thetic ring in case a focal, dense regurgitation jet is
making this diagnosis101 and guiding therapy.102 Perivalvular encountered. Mechanical valves always exhibit a normal
leaks can result from technical failure of a suture or from amount of central regurgitation that originates inside the
inadequacy of the underlying anchoring connective tissue sewing ring and generally extends no more than 1 to 2 cm in
(degenerative changes or destruction from endocarditis). jet length by color Doppler from the valve (Fig. 21.48C). These
Prosthetic valves can become dysfunctional due to obstruc- small jets are normal in the LV outflow tract with a normally
tive lesions or regurgitation. As already alluded to, biologic functioning aortic valve prosthesis. More extensive LVOT
valves undergo degeneration over time, which can produce jets may require further investigation. Although there is no
obstructive, insufficiency, or mixed lesions. normal amount of central leak for a biologic prosthesis, mild
The CW Doppler signal is usually diagnostic for a bileaf- central regurgitation is sometimes seen even immediately
let mechanical valve because of the prominent opening and after implantation. Baseline documentation and routine
closure ultrasound artifacts produced by the disks (Fig. 21.49). follow-up by surface echocardiography are all that is indi-
Prosthetic valve forward flow gradients can increase mark- cated if the forward flow characteristics and leaflet motion
edly from either obstructive or regurgitation lesions. When- are otherwise normal.
ever a prosthetic valve gradient is more than mildly increased, A high peak forward flow gradient across the mitral103 or
a thorough Doppler investigation is warranted. Regardless of tricuspid valve prosthesis and a relatively steep (short) decel-
valve position, the sonographer should systematically image eration time suggest prosthetic valve regurgitation.104 A high
532 chapter 21

A B
FIGURE 21.49. Normal forward flow velocities by CW Doppler of (IC) and isovolumic relaxation (IR) periods are clearly demarcated
a mechanical aortic valve prosthesis (A) and mechanical mitral by the characteristic mechanical leaflet opening and closure arti-
valve prosthesis (B) in the same patient. The isovolumic contraction facts in this patient with “double” mechanical prosthetic valves.

peak and mean gradient and lengthened mitral deceleration comprehensive TTE and TEE are frequently needed in order
time usually suggests prosthetic valve obstruction (Fig. to address the situation.91,102,104 Figures 21.50 and 21.51 show
21.41), although combined obstruction and regurgitation can TEE evaluations of dysfunctional mechanical mitral and
occur. Whenever prosthetic valve dysfunction is suspected, aortic valve prostheses, respectively.

A B

C
FIGURE 21.50. TEE evaluation of severe perivalvular MR in a (upward arrow) is visible. Sewing ring (downward arrow); linear
patient with prosthetic valve bacterial endocarditis. (A) The pros- reverberations, mechanical disks in open position (arrowhead);
thetic leaflets appear in a typical closed position. Mitral annular left atrial appendage (LAA). (C) Dolor Doppler shows severe perival-
abscess with associated vegetation (arrow). (B) In another imaging vular MR (from outside the sewing ring) entering the left atrial
plane, same patient, a localized region of sewing ring dehiscence appendage.
 e c h o c a r d i o g r a p h i c a s s e s s m e n t o f va lv u l a r h e a r t d i s e a s e 533

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 2 Magnetic Resonance
2 Imaging of
Valvular Disease
Scott D. Flamm and Raja Muthupillai

Magnetic Resonance Imaging Methods. . . . . . . . . . . . . . 538 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553

Clinical Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

Key Points methods can visualize the cardiac chambers, valves, and,
when combined with Doppler techniques, can also provide
• Cardiovascular magnetic resonance (CMR) is an accurate
quantitative information about blood and tissue velocity.8,9
and complementary method for evaluating ventricular
Ultrasound based methods are widely available, and are supe-
function and volume analysis.
rior to other methods for visualizing valve leaflets with high
• Cardiovascular magnetic resonance can readily assess
temporal resolution, and for rapidly providing velocity spectra
the morphology of all four cardiac valves and accurately
at a given location. However, ultrasound techniques require
determine the severity of stenosis and regurgitation.
favorable acoustic windows, ultrasound-based volume esti-
The rhythmic contraction of the heart muscle propels blood mates often involve geometric assumptions, and the estima-
carrying nutrients to all organs of the body. The blood flow tion of flow velocity is restricted to the blood moving toward
into and out of the ventricles is well regulated by exquisitely or away from the ultrasound transducer.
designed valves, and any abnormality of the valve structure In this respect, cardiovascular magnetic resonance (CMR)
or function can adversely affect cardiac function. Patient imaging provides a number of tools to assess valvular dys-
management can be significantly improved with accurate function. Conventional spin-echo–based “black-blood” and
knowledge of the type and extent of valve pathology. Clini- gradient-echo “bright-blood” cine magnetic resonance (MR)
cally, a comprehensive diagnostic evaluation of valves imaging can readily provide information about the size and
requires assessment of the following: (1) morphology of the shape of the chambers and parameters that describe global
valve, for example, size, shape, and structure of the valves, LV and right ventricular (RV) function such as stroke volume
and the adjoining supporting structures; (2) hemodynamics and ejection fraction, without the need for geometric assump-
across the valve, for example, direction, speed, and the tions or models. Recent advances in CMR hardware and
amount of blood flow during the cardiac cycle to define the imaging methodology make it possible to obtain cine frame
extent of regurgitation or stenosis; (3) effect of the valvular rates that are comparable to echo ultrasound and acquire
dysfunction on the morphology of the heart, for example, images within a breath-hold. These gradient-echo–based cine
enlargement of the chambers due to volume overload, or imaging methods can be modified to reveal qualitative infor-
hypertrophic adaptation of the pumping chambers due to mation about the presence, extent, and duration of jets caused
pressure overload; and (4) effect of valvular pathology on by regurgitation or stenosis. With respect to estimating the
global left ventricular (LV) function.1 The value of such infor- blood velocities, MR phase-contrast methods can directly
mation has long been recognized, and a number of invasive measure the blood velocity from the phase of the received
and noninvasive methods for evaluating blood flow within MR signal independent of the orientation of the vessel or the
the body have been proposed.2–5 direction of blood flow within the body. As a result, MR can
Conventional catheter x-ray angiographic methods can directly estimate volume flows without geometric assump-
give accurate information about both flow and pressure tions, a characteristic lending technical superiority over
across the valves and is unique in this respect. However, x- Doppler methods. Lastly, CMR techniques provide an array
ray angiography is invasive, imposes a radiation burden, of contrast mechanisms that may be exploited to visualize
requires nephrotoxic contrast media, and carries a small but intracardiac thrombus, postsurgical leaks in and around
not insignificant risk.6,7 Conventional echocardiographic valve structures, and vegetations.10–14

5 37
538 chapter 22

Magnetic Resonance Imaging Methods After 90-degree

pulse
Before 180-degree
pulse
Resulting
image

Magnetic resonance imaging techniques for assessing valvu- Slow flow

lar heart disease in routine clinical practice may be broadly
divided into three broad categories: black-blood imaging
techniques, bright-blood cine imaging techniques, and phase- A
contrast velocity mapping techniques. The physical princi-
ples behind each of the techniques are described in the Mod. flow
following subsections (Table 22.1).

Black-Blood Morphologic Imaging Techniques B

Simple cardiac gated spin-echo (SE) techniques are sensitive Fast flow
to blood flow, and this sensitivity can be exploited to provide
flow-dependent contrast. This is best illustrated by consider-
ing the case of an imaging slice oriented orthogonal to a
flowing vessel (Fig. 22.1). In a simple SE method, the initial C
90-degree radiofrequency (RF) pulse rotates the entire longi- FIGURE 22.1. Spin-echo–based black-blood imaging based on time-
tudinal magnetization (M z) into the transverse plane, creat- of-flight (TOF) phenomenon. Through plane flow through a slice at
different flow rates, slowest on the top panel and the fastest in the
ing transverse magnetization (M xy) that is measurable. The bottom panel. Slow-flowing spins experience both the 90- and the
measurable component of magnetization creates a signal 180-degree pulses, and therefore fully refocus to give a bright signal
that decays rapidly. This signal decay is composed of an (A). On the other hand, if the spin velocity is high enough, none of
irreversible signal loss due to spin–spin interactions (referred the spins experience both the 90- and the 180-degree pulses, and the
resulting image has a signal void (C). If the spin velocity is inter-
to as T2), and a potentially reversible loss of signal due to mediate, then the resulting image has a signal intensity that is
local magnetic field inhomogeneities (referred to as the T2’). proportional to the fraction of the spins that experienced both the
In a simple SE implementation, another RF pulse is applied 90- and the 180-degree radiofrequency (RF) pulses (B). Typically,
after time τ from the 90-degree pulse, such that it rotates M xy the spins near the vessel wall appear brighter as these flow the
by 180 degrees in the transverse plane. This restores the slowest.
signal from the reversible component of signal loss by refo-
cusing the transverse magnetization to form the so-called
spin echo at 2τ, a time often referred to as the echo time
(TE). The nonmoving tissue experiences both the excitation

TABLE 22.1. Magnetic resonance (MR) imaging techniques for assessing valvular heart disease in clinical practice
MR technique Potential information content Clinical applications

Black-blood imaging • Valvular thickening/calcification • Evaluation of stenosis

• Overall shape and geometry of the heart • Effect of valve pathology on heart
• Tissue characterization • Evaluation of vegetations, perivalvular leaks, or
abscesses
Cine bright blood imaging • Volumetric information about RV and LV: • Assess the effect of valve disease on global cardiac
(T1-weighted gradient-echo • End-diastolic volume (EDV) function
and steady-state free • End-systolic volume (ESV) • Assess valve size
precession sequences) • Stroke volume (SV) • Postsurgical evaluation of valves
• Ejection fraction (EF) • Assess shunts with LV and RV stroke volumes
• Cardiac mass (LV mass) in simple single valve disease
• Contraction pattern • Qualitatively assess
• Signal voids due to complex flow regurgitation and stenosis
• Adjust by changing TE (primarily for T1-TFE)
• Valve morphology
• Shape, size, number of leaflets, etc.
Phase-contrast imaging • Quantitative information on: • Evaluation of regurgitant volumes from volume
• Pixel-by-pixel velocity flow curves
• Direction of flow • Assess shunts
• Components of velocity vector • Evaluation of peak velocity in stenosis
• Direct estimation of time gradient from • Estimate the pressure velocity using simplified
peak volume flow Bernoulli equation to grade stenoses
• Direct estimation of peak velocity • Visualization of flow patterns can reveal clinically
• Visualize volume flow patterns, e.g., useful information, e.g., flow reversal in
pulmonary venous flow patterns pulmonary veins due to diastolic dysfunction
• Estimate valve orifice area using velocity time
integral approach
* LV, left ventricle; RV, right ventricle; TFE, turbo field-echo.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 539
(90-degree), and the refocusing (180-degree) pulses, and as a is, with a shorter repetition time (TR) (without having to wait
result the echo formed has full signal due to contributions for the regrowth of M z from zero via spin-lattice or T1 relax-
from the entire magnetization within the slice. On the other ation as is the case for spin-echo techniques).16–18 As a result
hand, for moving tissue (e.g., blood flow) if the velocity is of the rapid application of RF pulses, the steady-state signal
rapid enough, flowing blood experiences the 90-degree pulse, of static spins is diminished compared to flowing spins, and
but can leave the slice before the 180-degree pulse is applied, thus generates an in-flow dependent contrast. With cardiac
resulting in the “black-blood” appearance. For all velocities gating and modern imaging hardware, it is possible to attain
in between the two extremes, the signal intensity in the cine images at high frame rates, obtaining information about
resulting image is proportional to the fraction of the hydro- global and regional function.
gen nuclei that experience both the 90- and the 180-degree
pulses. Such simple spin-echo–based techniques can provide T1-weighted Cine Gradient-Echo Technique
a good anatomic overview of the cardiac chambers, vessels
T1-weighted cine gradient-echo methods are useful in a
leading into and out of the heart, and some limited informa-
number of ways to evaluate valve function. The enhance-
tion about the valves. Recent methodologic advances permit
ment of blood signal caused by the inflow effect can be used
black-blood imaging of the cardiac chambers in any
to visualize valve morphology. For example, an “en-face”
orientation.15
view of the aortic valve can reveal information not only
about the size of the valve, but also about the number of valve
leaflets by highlighting the coherent inflow enhancement
Bright-Blood Imaging Techniques
during systole (Fig. 22.2). The size of the valve orifice can
The bright-blood imaging techniques exploit the presence or also be determined from direct planimetry.
inflow of blood signal within the slice of interest as follows. As blood accelerates through a stenotic valve, a region of
Gradient-echo techniques typically rotate only a fraction of signal loss appears as a jet distal to the stenosis in the gradi-
M z into the transverse plane by applying an RF pulse with a ent-echo images. The size and shape of the jet depend not
limited flip angle (typically around 20 to 30 degrees). The only on the stenosis degree and the hemodynamics across
transverse magnetization that is created is immediately the valve, but also on several MR acquisition parameters,
measured with a gradient reversal. As a result, the gradient- such as in-plane and through-plane voxel size,19 type of gradi-
echo sampling process may be repeated more quickly, that ent-echo sequence used,20 and most importantly, on the TE

A B

FIGURE 22.2. Four frames from a cine gradi-

ent–echo image of the aortic valve demonstrate
the effect of inflow related enhancement char-
acteristic of T1-weighted gradient echo images.
(A) En-face view of the aortic valve at end-dias-
tole shows little signal due to lack of inflow in
contrast to the bright appearance of the infe-
rior vena cava that drains venous blood into the
right atrium. (B,C) Aortic valve opens during
peak and late systole, clearly depicting the
trileaflet configuration, and bright blood signal
across the valve due to inflow enhancement.
(D) Aortic valve closes during early diastole,
and appears dark due to lack of inflow. Such
views readily allow the visualization of the
valve morphology, and direct planimetry can
C D
give information about valve size.
540 chapter 22

used for data collection.21–24 The longer the TE, the greater All spins precess at a characteristic frequency (f) in the
the flow-induced dephasing and the bigger the size of the jet. presence of a homogeneous main magnetic field (B). The
As a result, small flow disturbances can be visualized by frequency of precession is proportional to the strength of the
choosing a longer TE or obscured by a very short TE. field experienced by the spins and is often referred to as the
For the same reasons causing signal loss in stenotic jets resonant or Larmor frequency. The proportionality constant,
described above, regurgitant jets also result in signal loss, γ, is characteristic for each nuclei. The addition of an appro-
and can be readily visualized in cine gradient-echo images priate gradient waveform within the imaging sequence, for
with an appropriate TE. While the extent of signal loss can example, bipolar gradient, allows a spin moving in the direc-
be used as a qualitative measure to determine the severity tion of the magnetic field gradient to accumulate a net phase
of regurgitation, MR provides better methods for accurately shift compared to a static spin. This phase shift can be
quantifying regurgitation volume using phase-contrast directly related to the velocity (ν) of the spin using the fol-
methods (described below).25,26 To visualize the size and lowing relationship25:
duration of the jet, it is necessary to align the imaging slice
f = γ M1 ν,
along the axis of the core of regurgitation. The ability to
freely align the imaging slice parallel to the axis of the regur- where γ is a constant specific to a given nuclei, and for protons
gitant jet is an intrinsic strength of CMR cine imaging the value of γ is 42.57 MHz/tesla (gyromagnetic ratio), and
methods compared to the ultrasound-based methods, partic- M1 is the first temporal moment, an operator controlled
ularly with eccentric regurgitant jets.23 variable that is a function of the strength, shape, duration,
and the temporal position of the gradient waveform within
Steady-State Free Precession Methods the imaging sequence (referred to as the first temporal
TE
With the advent of higher strength gradients, the recently
described steady-state free precession (SSFP) sequences are
moment of the gradient waveform: M1 = ∫ t ⋅ G(t)dt ).
0
gaining wider acceptance [also referred to as balanced fast
In routine clinical imaging, a bipolar gradient waveform
field echo (bFFE), true fast imaging with steady-state preces-
is used to introduce motion sensitivity to an imaging
sion (TrueFISP), or fast imaging employing steady-state
sequence, and the strength of the bipolar gradient is altered
acquisition (FIESTA)] for evaluating LV function.27 The SSFP
to adjust the first temporal moment of the gradient, which
sequence is preferred because of improved temporal resolu-
scales linearly with the induced phase shift, for any given
tion, better blood-to-myocardium contrast, and higher signal
velocity. It is also important to note that the induced phase
over conventional T1-weighted cine gradient-echo sequences,
shift is proportional only to the component of velocity along
making it a sequence of choice for routine LV function
the direction of the magnetic field gradient, and phase is
evaluation.28–30
sensitive to direction of flow along the gradient waveform
However, there is a significant difference between the T1
(Fig. 22.3). Therefore, to measure the true velocity, it is nec-
cine gradient-echo technique and the SSFP cine gradient-
essary to either align the velocity-encoding direction in the
echo technique with respect to visualizing the regurgitant
direction of flow or measure all three components of the
jets. In the case of the T1 cine gradient echo, the sensitivity
velocity vector by superimposing gradients along all three
to regurgitation (or stenosis) can be readily adjusted by
orthogonal directions. In this respect, unlike Doppler
changing the TE. However, SSFP sequences are very sensi-
methods, which can only measure velocity of blood particles
tive to magnetic field inhomogeneities, and, to prevent arti-
moving away or toward the transducer, MR can measure
facts, the shortest possible TEs (<2 ms) are used. In addition,
flow along any direction.
the balanced gradient structure of the SSFP sequences also
makes it relatively insensitive to spin velocity. Because of
these two factors, from a clinical imaging perspective, the Technical Considerations
jet size in the SSFP sequences qualitatively appears less sig-
nificant for the same degree of gradient.31 While MR phase-contrast velocity mapping is a powerful
tool for noninvasively measuring flow velocities within the
human body, the choice of imaging parameters has a pro-
Phase-Contrast Velocity Mapping found influence on the accuracy and precision of velocity
measurements, the practical aspects of which will be dis-
Principle of Phase-Contrast Velocity Mapping cussed in the following subsections.

The measured MR signal, the transverse magnetization

Strength of Velocity Encoding
(M xy), is a vector quantity that has both amplitude and direc-
tion. The amplitude of the signal depends on the interplay As discussed above, the motion-induced phase shift is pro-
among the tissue relaxation parameters (T1, T2, PD [proton portional both to the spin velocity ν, as well as dM1 used in
density], etc.), and the conditions (sequences, TR/TE, etc.) the pulse sequence. By adjusting the strength of velocity
under which the MR data acquisition is conducted. The encoding, that is, dM1, it is possible to induce a very large or
direction of the signal often referred to as the phase, can also a very small phase change in the signal, for a given spin
be manipulated to yield a variety of information such as the velocity. When encoding through plane flow within an
local susceptibility and spin velocity. In MR phase-contrast imaging slice that comprises both the ascending and descend-
velocity mapping (PVM), the phase of the MR signal is ing aorta, for example, the flow toward the head in the
manipulated to yield information about spin velocity. ascending aorta is represented by a positive value, and the
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 5 41

DB DB

G G

–x3 x3 x t0 t1 t2 x0 x1 x2 x t0 t1 t2
t
t

f f

t0 t1 t2 t t0 t1 t2 t

A B
FIGURE 22.3. (A) Effect of bipolar gradient on static spins. On the location x0 at time point t 0 that moves at a constant velocity. Between
left, the field variation imposed by the bipolar gradient is shown time points t 0 and t1, the moving spin traverses through an ever-
schematically. The solid blue line indicates the field gradient between increasing magnetic field strength as shown on the left. Compared
time points to and t1, and the dotted blue line indicates the field gradi- to a static spin at location x0, by virtue of its motion from location x0
ent between time points t1 and t2. The bipolar gradient waveform is to x1 in the presence of the positive lobe of the bipolar gradient ori-
shown on the right, and the corresponding phase evolution diagram ented along the x-axis, the spin accumulates a slightly higher phase
during the course of the gradient is shown below. A spin located at at time point t1. As the gradient polarity is reversed at time point t1,
the isocenter (cyan color) experiences no net additional field and as a the spin starts to accumulate a negative phase shift. As the spin
result accumulates no phase shift. Let us consider the case of a spin continues to move from x1 to x 2 under the influence of the negative
at location xs (red color). This spin experiences a slightly higher mag- lobe of the bipolar gradient, the rate of phase accumulation is even
netic field during the positive lobe of the bipolar gradient between greater, as the spin experiences a much higher negative magnetic
time points t 0 and t1 and during this time accumulates a net positive field strength. At the end of time point t2, unlike a static spin, the
phase shift (with respect to a spin at the isocenter). When the gradi- moving spin accumulates a net negative phase shift. By the same
ent polarity is reversed during time interval t1 and t2, the same spin argument, it is easy to show that spins moving in the opposite direc-
experiences a slightly lower magnetic field strength and starts to tion at the same rate would accumulate a net positive phase shift
accumulate a negative phase shift. At the end of the bipolar gradient under the influence of the same bipolar gradient. Thus, moving spins
lobe, the spin at location xs accumulates no net phase shift. By the accumulate a phase shift that gives information both about the rate
same argument, it is easy to see that static spins do not accumulate of displacement, as well as the direction of motion. This phase accu-
a net phase shift independent of their location along the x-axis. (B) mulation forms the basis of phase contrast measurements in mag-
Effect of bipolar gradient on moving spins. Let us consider a spin at netic resonance imaging.

flow toward the feet in the descending aorta is represented have been developed.32,33 A common approach is to use one
by a negative value or vice versa. The phase-contrast velocity reference acquisition and three velocity-encoded acquisi-
measurements are chosen such that the maximum velocity tions. This requires a total of four acquisitions, and therefore
within the slice of interest induces a phase shift less than the scan time is only twice that of the two-point unidirec-
180 degrees. This limiting value of the strength of the veloc- tional method (Fig. 22.4). However, in this case, the same
ity encoding is often referred to as the Venc value. Any veloci- reference scan is used for all three velocity-encoded images,
ties greater than the Venc value within the slice of interest and therefore the noise in the images is correlated. 32
appear with artificially lower velocities flowing in the other In summary, at least two measurements are required for
direction—a phenomenon referred to as aliasing. Because the encoding velocity in one direction, and four measurements
standard deviation of the measured velocity is proportional are required for measuring velocity in all three directions.
to the Venc value, the Venc value should be chosen just high When clinical conditions warrant the complete resolution of
enough to avoid velocity aliasing in the vessel of interest.32 the velocity vector components, for example, for the estima-
tion of peak velocity of a stenotic jet that does not lie in one
Strategies for Velocity Encoding Directions plane, an appropriate choice of encoding scheme may provide
benefits in reducing velocity noise.
As discussed above, to measure a single component of the vel-
ocity vector using the PC method, two complete sets of mea-
Type of Cardiac Gating
surements are sufficient, yet to measure all three components
of an arbitrary or unknown velocity vector, it is necessary to Most cardiac studies use some form of gating to acquire
have multiple measurements.32,33 The simplest approach to information about temporal variations in velocity (and flow)
completely measure all three components of an arbitrary over the cardiac cycle.34 There are two prominent types of
velocity vector is a direct extension of the simple two-point cardiac gating used in MR quantitative flow imaging: pro-
method, by using three pairs of measurements to measure spective gating and retrospective gating.35,36 In prospective
each component of velocity vector; however, the imaging time gating methods, the MR spectrometer essentially waits for
is tripled compared to the simple two-point method. the electrocardiogram (ECG) trigger (usually identified by
Instead of tripling the acquisition time using the six- the top of the R wave) and then starts to acquire data for
point method to encode for all three components of the most of the cardiac cycle (typically about 80% to 90% of the
velocity vector, more efficient ways for encoding velocities RR interval). The scanner “waits” for the next trigger and
542 chapter 22

FIGURE 22.4. Complete evaluation of the velocity vector compo- scribed Venc value (see text for details). An artificial color scale based
nents by superimposing velocity-encoding gradients along each of on the phase measurements in the velocity-encoded image (RL
the three orthogonal axes. A single frame of the phase contrast direction) is superimposed on the magnitude image for visualization
image obtained with velocity-encoding gradients along the right-left purposes (D). The magnitude image that provides anatomic infor-
(RL) (red), foot-head (FH) (green), and anteroposterior (AP) (brown) mation can be readily reconstructed from the phase contrast mea-
directions is shown in panels A, B, and C, respectively. Note velocity surement data (E). The average velocity (V) across the vessel along
aliasing (B) due to velocities in the FH direction exceeding the pre- the RL, FH, and AP during the cardiac cycle is shown (F).

collects data, and this process continues for all necessary flow,37 and the lesser the undesirable effect of acceleration
views acquired to make an image. As a result of this “dead and other higher order effects.38–40 The effect of convective
time” in the prospective triggering method, data are not acceleration is particularly important in the context of mea-
acquired during a portion of the RR interval (typically end- suring rapid flow through a severe narrowing, for example,
diastole), which has clinical implications for the evaluation valve stenosis. If a peak velocity across the valve of 200 cm/
of valve disease using PVM. For example, much of aortic/pul- sec is measured with an imaging sequence with a TE of 15 ms
monary regurgitation occurs during diastole, and missing a and a slice thickness of 5 mm, then the spins may travel up
portion of diastole can result in substantial underestimation to 30 mm (or six times the slice thickness) between the slice
of the severity of aortic/pulmonary regurgitation. encoding and the measurement, and the resulting velocity
Retrospective gating eliminates this limitation, by con- measurements may be quite erroneous. Recent advances in
tinuously acquiring data without interruption, and the phase- gradient hardware and methodologic improvements make it
encoding step is incremented once during each RR interval, possible to obtain extremely short echo times on the order
while retaining the temporal information of when the data of 1 to 2 ms, which can substantially minimize such errors.
are acquired during the cardiac cycle. After all phase-encod-
ing steps are acquired, the scanner can then retrospectively In-Plane Versus Through-Plane Velocity Encoding
reconstruct images that are spread throughout the cardiac
Estimation of peak velocities (Vm) of stenotic jets is clinically
cycle. For clinical quantitative flow imaging, retrospective
important and can be used to estimate the pressure gradient
gating has been the preferred form of gating, and it is also
(ΔP) using the simplified Bernoulli equation: DP = KVm 2
, where
common clinical practice to average the data to minimize
K is the loss constant usually assumed to be 4. For the pur-
errors introduced by other undesired forms of motion. The
poses of visualizing and quantifying peak velocities in ste-
main disadvantage of the retrospective gating methods is the
notic jets, it is advantageous to encode for velocities in the
prolonged acquisition time, which is on the order of 2 to 3
plane of the jet. However, such in-plane velocity encoding is
minutes per slice per velocity-encoding direction.
fraught with several problems and has to be used carefully in
a clinical setting for the following reasons. First, the dimen-
Choice of TE
sion of the voxel in the slice direction is about two to three
In the context of gradient-echo–based phase-contrast mea- times longer than in the other directions. Therefore, there
surements, shorter echo times (TEs) are desirable for many could be a significant amount of partial volume effect within
reasons. The shorter the TE, the lesser the spurious phase the voxel, if the jet is very small, and can result in an under-
accrual caused by off-resonant effects, the lesser the signal estimation of the peak velocity. Second, the turbulent jet
loss caused by intravoxel dephasing due to fast or irregular may not be in just one plane, and it may be necessary to
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 543
encode for velocities in more than one direction. Lastly, in- Clinical Applications
plane encoding does not permit the measurement of the
cross-sectional area of the vessel and therefore volume flow
rates. In this regard, phase contrast sequences with a spiral Aortic Valve Disease
readout have attractive flow properties, as they result in Cine MR has demonstrated good facility for anatomic evalu-
substantially lower displacement and blurring artifacts for ation of the aortic valve for at least the last decade and a half.
in-plane flow.41 Through-plane velocity encoding allows for Valve morphology can be determined with either spin-echo
simultaneous measurement of velocity as well as the cross- black-blood imaging or gradient-echo bright-blood imaging.
sectional area and therefore volume flow rate. The disadvan- Typically, such imaging is performed using both techniques;
tage of through-plane velocity encoding is that it is important spin-echo imaging helps determine the static morphology of
to position the slice across the location of maximum velocity, the valve, whereas cine imaging provides greater detail
and this may be difficult to determine a priori. However, regarding function.
the peak velocity profile of the jet can extend up to five times Normal aortic valve morphology is trileaflet, although
the diameter of the jet within the imaging plane, allowing bicuspid valves are frequently seen. The typical configura-
some margin for accurate slice placement.42 In general, the tion for a bicuspid valve is fusion of the left and right coro-
location of the phase contrast imaging slice can have a major nary cusps, along with a prominent noncoronary cusp
influence on the accuracy of measurements, not only on resulting in a slit-like or “fish-mouth” opening during ven-
peak velocity estimation but also on the estimation of tricular systole. More severe congenital malformations
regurgitation.43,44 include unicuspid and quadricuspid valves, although these
are infrequently encountered, except in laboratories with a
Partial Volume Effect large volume of congenital studies.
Voxels at the boundary of the vessels contain both static and Static spin-echo imaging can determine the size, shape,
moving spins, and this results in systematic errors that and thickness of the valve cusps, but does a relatively poor
reduce the accuracy of phase contrast measurements.19,45,46 job identifying calcification.56 Alternatively, cine gradient-
Partial volume errors can also occur in through-plane veloc- echo imaging can evaluate the mobility of the valve cusps
ity encoding measurements if the slice intersects the vessel and identify the presence of valvar calcifications, manifested
of interest nonorthogonally. The extent of error is propor- by regions of signal dropout against the background of bright
tional to the ratio of voxel size to vessel size.19,45 Studies have moving blood. Calcium typically has little to no mobile
shown that it is necessary to have roughly four pixels across protons and therefore has little to no signal intensity on cine
the diameter of the vessel of interest (or around 14 voxels imaging.
across the cross section of the lumen) to have errors less than Additional information that may be determined with
10%.47–50 The measurement of peak velocity is a bit more either spin-echo or gradient-echo imaging includes the size
complicated. Estimation of peak velocity from a single pixel of the aortic annulus, the shape and size of the sinus of Val-
may suffer from poor precision, and averaging adjacent voxels salva, the presence of a distinct sinotubular junction (or
would introduce partial volume error. Some studies have effacement thereof), and the caliber of the proximal tubular
suggested that an average of four pixels in the central core of portion of the ascending aorta. These features can be critical
the jet may be used.24 It should also be remembered that MR differentiators of aortic valvular disease etiology, as in
measurements of peak velocities are time-averaged values patients with Marfan syndrome where aneurysmal enlarge-
and in general are lower than instantaneous measurements ment is centered in the aortic root and typically results in
of velocity. complete effacement of the sinotubular junction.

Region of Interest (ROI) Placement Aortic Stenosis

When through-plane velocity encoding is used, MR provides In the evaluation of patients with aortic stenosis, a complete
both the velocity as well as the cross-sectional area of the evaluation should include qualitative and quantitative deter-
vessel of interest, making it simple to compute volume flow. mination of stenosis degree, evaluation of left ventricular
An ROI prescribed smaller than the vessel size would under- function, and quantification of left ventricular volumes and
estimate volume flow, and an ROI that is larger than the mass. These are all parameters for which CMR is now well
vessel size might introduce spurious phase shifts associated positioned to acquire in an accurate and reproducible
with low signal-to-noise ratio (SNR) regions outside the fashion.
vessel of interest.51 From a theoretical point of view, it is Initial evaluation of suspected aortic stenosis begins with
necessary to use an ROI as small as possible but as large as morphologic assessment of the aortic valve, which in normal
necessary to cover the entire vessel.19 From a clinical point adults has a valve orifice of 3 to 4 cm2. An aortic valve orifice
of view, it is common to prescribe the ROI in the high-con- greater than 1.5 cm2 is considered mild stenosis, greater than
trast magnitude images and then transfer them over to the 1.0 to 1.5 cm2 is considered moderate stenosis, and less than
phase difference images, and adjust their size over the cardiac 1.0 cm2 is considered severe stenosis.57 Morphologic assess-
cycle to account for any vessel motion due to vascular com- ment may be performed with spin-echo images, although the
pliance. There have been a number of methods proposed in valve orifice may be overestimated as a result of misposition-
the literature to automatically draw the contours to mini- ing of the acquired imaging slices, or volume averaging from
mize errors due to ROI placement, and such methods have imaging slices that are too thick for accurate determination56
to be clinically validated.52–55 (Fig. 22.5; and Video 22.1 on the DVD).
544 chapter 22

Quantitative Evaluation
While qualitative approaches are sufficient for screening of
valvular disease, the accurate initial determination and
follow-up of patients with aortic valvular disease require
quantification of the degree of stenosis. Similar to echocar-
diography, CMR using flow quantification sequences can
determine the transvalvular gradient by determining the
peak velocity of blood flow through the stenotic orifice.62
Once the peak velocity through the stenotic orifice is deter-
mined, the modified Bernoulli equation allows determina-
tion of both peak and mean transvalvular gradients (Fig. 22.6;
and Video 22.1 on the DVD). Multiple studies have demon-
strated close agreement between gradients determined by
CMR and echocardiography. Similar to echocardiographic
measurements, CMR measurements may underestimate

Area = 0.8 cm2

500 cm/s

333
FIGURE 22.5. A cine gradient-echo sequence was performed across
the face of the aortic valve. This image, acquired during peak systole,
reveals calcific fusion of the commissures between the left and 167
right, and the right and noncoronary cusps. A small, slit-like orifice
remains with a planimetered cross-sectional area of 0.8 cm 2.
0

In the past, cine imaging was performed with slices –167

acquired parallel to the aortic annulus and across the face of
the valve to assess valve orifice size. The relationship was a
reasonable one, although in general less accurate than echo- –333
cardiography as a result of the previously more limited spatial
and temporal resolution afforded by CMR techniques.58
Current techniques using steady-state free-precession –500 cm/s
imaging has both high spatial and temporal resolution and PCA/P
excellent signal to noise and contrast to noise ratios, result- SI 1
ing in high-quality morphologic visualization. This tech-
nique can now determine valve orifice areas with accuracy
comparable to that of echocardiography, although with the 500
same limitations as echocardiography,59,60 namely, that the
imaging plane must be precisely at the valve orifice and not 400
Peak velocity = 4.9 m/sec
slightly proximal or distal to the coaptation zone, which will
Velocity (cm/sec)

Peak gradient = 96 mm Hg
result in overestimation of the orifice. 300

Qualitative Evaluation 200

Qualitative assessment of aortic stenosis severity may be 100

performed with flow-sensitive cine imaging performed paral-
lel to the turbulent jet of stenotic blood. Typically, these flow 0
sensitive sequences have longer TEs (in the range of 6 to 8 ms 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
for clinical use), resulting in sufficient phase dispersion to –100
identify turbulent jets as signal voids within the surrounding
Cardiac phases
bright blood having more laminar flow.61 Mild aortic stenosis
results in a relatively narrow jet of turbulence that extends FIGURE 22.6. The upper half of the image demonstrates a phase-
only to the proximal portion of the ascending aorta. More contrast velocity-encoded image with superimposed color corre-
severe aortic stenosis results in a border jet of signal void that sponding to the velocity of blood flow. The patient has severe aortic
may extend clear to the distal ascending aorta. In addition, stenosis, and a high-velocity jet is seen immediately distal to the
restricted coaptation point of the aortic valve. The graph (lower half)
more severe aortic stenosis may be associated with aneurys- represents the velocity profile of the oval region of interest placed
mal dilation of the ascending aorta, which may be imaged within the velocity jet. A peak velocity of 4.9 m/sec was recorded,
simultaneously. corresponding to a peak gradient of 96 mm Hg.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 545
those found in the catheterization laboratory as a result of face of left ventricular hypertrophy. Despite the presence of
the patient being in a more relaxed state during a CMR a significant gradient (greater than 50 mm Hg mean value),
examination. Lower cardiac outputs, and therefore lower the patient may remain asymptomatic. Nonetheless, once a
stroke volumes, lead to lower transvalvular gradient deter- patient with severe aortic stenosis becomes symptomatic,
minations. For similar reasons, patients with depressed valve replacement surgery is the generally accepted therapeu-
cardiac function may also give artifactually low transvalvu- tic option. Alternatively, patients with severe aortic stenosis
lar gradients despite the presence of more severe degrees of who are symptomatic should have valve surgery considered
stenosis. when there is left ventricular dysfunction or left ventricular
Another approach to quantitative aortic stenosis assess- hypertrophy.
ment is the use of time-velocity integrals (TVIs). This While valvular aortic stenosis has been the focus of this
approach is based on the continuity equation in which all section, concomitant or mimic lesions can also be found
flow through the left ventricular outflow tract is assumed to with CMR. Specifically, subvalvular membranes or masses
move through the stenotic aortic valve. As such, the flow can resulting in LVOT obstruction, turbulence, and gradients can
be based on the simple product of cross-sectional area and be evaluated using a combination of spin-echo and cine
mean velocity, with the valve area easily calculated. Echo- imaging, along with phase-contrast velocity imaging for gra-
cardiography has shown good results compared to the inva- dient evaluation. Similarly, supravalvular stenosis, usually
sively determined Gorlin formula, despite the assumption either congenital or postsurgical in nature, can be evaluated
that the LV outflow tract (LVOT) is round. The TVI approach in comparable fashion.
has not routinely been performed using CMR, yet a recent
report by Caruthers et al.63 has confirmed the excellent Concurrent Valvular Lesions
utility of this approach. These investigators acquired two
When significant aortic insufficiency is also present, the
flow quantification sequences, one in the LVOT, immedi-
qualitative assessment of aortic stenosis may be overesti-
ately subvalvar, and the second in the immediately supraval-
mated as a result of the increase in stroke volume and cardiac
var position. In this study the authors noted a close correlation
output (Fig. 22.7; and Video 22.1 on the DVD). These factors
between CMR and echocardiographically derived values for
also complicate calculations by the Gorlin formula. In these
peak velocities between 1 and 4 m/sec. Velocities greater
cases, the TVI calculation is the preferred approach as it is
than 4 m/sec were slightly underestimated by CMR, although
not dependent on isolated disease and continues to provide
there was no change in the clinical categorization of aortic
an accurate measurement of aortic valve area despite the
stenosis severity.
presence of aortic insufficiency.
Left Ventricular Function and Mass
Aortic Insufficiency
In addition to the qualitative and quantitative approaches to
aortic valve stenosis severity, CMR can also determine left Aortic insufficiency typically has a broader list of etiologies
ventricular function, volumes, and mass, all parameters than aortic stenosis and includes congenital anomalies, such
critical in the global assessment of the patient with aortic as bicuspid valves; rheumatic heart disease; endocarditis; and
stenosis. In the early stages of significant aortic stenosis, the range of cystic medial necrosis, including Marfan syn-
patients may maintain left ventricular function even in the drome. Further, aortic insufficiency may occur secondary to

FIGURE 22.7. Severe calcific aortic stenosis as

seen using a flow-sensitive cine sequence in an
oblique coronal orientation. The left panel
demonstrates a prominent, broad jet of turbu-
lence extending to the mid-ascending aorta
(arrow), and the valve leaflets are nearly immo-
bile. The right panel is from mid-diastole and
demonstrates moderate aortic insufficiency
with a jet of turbulence directed into the basilar
left ventricular cavity (arrowhead). Note the
extensive black areas on the aortic valve cusps
compatible with calcification.
546 chapter 22

aortic dissection, or as a postsurgical consequence. Natu- throughout the cardiac cycle with the change in caliber from
rally, treatment varies depending on the underlying anatomy, systole to diastole. Mean velocities are determined at each
and importantly, on the associated aortic root and proximal phase of the cardiac cycle and then multiplied by the cross-
ascending aortic anatomy. Spin-echo, static images are sectional area of the region of interest to determine instan-
routine in evaluation of aortic valve morphology, and likely taneous flow at each phasic time point.54 These data points
most beneficial for analysis of the aortic root and proximal can be graphed rapidly, and determination of both forward
ascending aorta. and reverse blood flow volumes calculated64 (Fig. 22.8).
The regurgitant fraction is determined by dividing the
Qualitative Evaluation regurgitant volume of blood seen in diastole by the forward
blood flow volume seen during systole (Fig. 22.9; and Video
Cine imaging provides the starting point for evaluation of
22.1 on the DVD). Normal values of aortic regurgitant
aortic sufficiency. Functional imaging across the face of the
fraction range up to 7%, as a result of runoff into the
valve helps determine the valvular morphology, as well as
coronary arteries, as well as compliance of the aortic root
the size of the orifice that fails to coapt during valve closure.
and proximal ascending aorta, and the slight reflux associ-
On cine gradient-echo imaging this lack of coaptation point
ated with aortic valve closure. Variations in measurements
appears as bright white in the center of the valve cusps when
will occur based on the patient’s loading conditions, and
using standard cine gradient-echo imaging with short TEs
for serial studies similar hemodynamic patient states are
that rely on inflow of fresh spins through the valve plane.
necessary.65
Alternatively, flow-sensitive cine imaging (with longer TEs
The phase-contrast velocity encoded MR techniques have
resulting in sufficient phase dispersion and a resultant signal
an additional technical limitation in that the imaging plane
void in areas of turbulence) is used in projections parallel to
within the chest is static. In younger patients or in those
the long axis of the valvular jet. Typically these orientations
with significant aortic insufficiency, there may be a substan-
include a short axis at the base of the left ventricle through
tial degree of excursion of the aortic valve plane through the
the aortic root, as well as a parasternal long axis orientation.
cardiac cycle,66,67 and the valve orifice may alter dynamically
The length and breadth of the signal void related to a turbu-
throughout the cardiac cycle.68 As such, flow measurements
lent jet of insufficiency is used to assess the severity of aortic
may have small variations. Recently, a technique has been
regurgitation. Similar to echocardiography, if the regurgitant
developed to determine and compensate for the valvular
jet is relatively narrow and extends only partially into the
motion during the velocity-encoded acquisition. Taking into
left ventricular cavity, it is considered mild, whereas severe
account the through-plane motion of the aortic valve, correc-
insufficiency is characterized by a broader jet of turbulence
tions are made to the data, which minimizes the underesti-
that extends deep into the left ventricular cavity toward the
mation of aortic regurgitant volume.69
inferolateral wall.
Qualitative determination of eccentric aortic insuffi-
ciency is more complicated and requires placement of mul-
tiple imaging planes parallel to the jet of insufficiency.
Because of the greater complexity in ensuring proper slice
orientation, the degree of severity may be underestimated.
Fortunately, quantitative approaches overcome these
limitations.
Aortic regurgitation
Quantitative Assessment of Aortic Regurgitation 500
Phase-contrast velocity-encoded CMR can assess the sever-
ity of aortic insufficiency in a manner similar to echocar- 400
Forward flow = 223 cc
diography. These techniques include calculation of the
300 Reverse flow = 48 cc
regurgitant volume from the proximal isovelocity surface Regurgitant fraction = 21%
area or evaluation of the spectral profile of the insufficiency
Flux (mL/s)

jet and evaluation of the pressure half-time. However, as in 200

echocardiography, the latter assessment technique is depen-
100
dent on the presence of isolated aortic insufficiency and pre-
served left ventricular function. These approaches are also
0
somewhat more complicated in CMR than in echocardiog-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
raphy, and, as a result, straightforward volumetric approaches
–100
are the most consistently applied in CMR evaluations. To
quantitatively determine the aortic insufficiency volume –200
and regurgitant fraction, a phase-contrast velocity-encoded
Cardiac phases
sequence is applied through the proximal ascending aorta
perpendicular to the directional flow within the aorta. The FIGURE 22.8. This graph denotes blood flow obtained using a
phase-contrast technique measures velocities within each phase-contrast velocity-encoded sequence acquired in the proximal
ascending aorta in a patient with mild aortic insufficiency. The
pixel of the cross-sectional area at each phase throughout the systolic forward flow is color coded red (223 cc/beat), whereas reverse
cardiac cycle. A region of interest is applied circumscribing flow, below the baseline, is color coded blue (48 cc). The resultant
the aortic wall, which is then varied in size iteratively regurgitant fraction is 21%.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 5 47

FIGURE 22.9. A cine phase-contrast

velocity-encoded sequence is shown in a
patient with mild aortic insufficiency.
The left panels are images from peak
systole, and the right panels are images
from mid-diastole. The bottom row cor-
responds to the magnitude image from
the phase-contrast velocity-encoded
sequence. In the middle row are phase
images containing the velocity informa-
tion, as shown in the standard gray-scale
format. The systolic image has white
signal intensity in the ascending aorta
corresponding to forward flow, whereas
the diastolic image has areas of gray
(minimal flow) and black (reverse flow)
corresponding to aortic insufficiency. In
the top row are also phase images, but
they have been colored using a look-up
table, similar to color flow imaging in
echocardiography. The red and yellow
colors in systole correspond to higher
velocity flows in the foot-to-head direc-
tion, whereas in diastole blue denotes
reverse flow in the head-to-foot
direction.

Concurrent Assessment of Left compromised coronary flow reserve, will herald the neces-
Ventricular Function sity for aortic valve replacement, routine monitoring with
noninvasive imaging helps identify those patients at greatest
The comprehensive assessment of aortic regurgitation,
risk. Regrettably, patients with greater left ventricular dila-
similar to aortic stenosis, should include quantification of
tion and worse systolic function are less likely to have symp-
the regurgitant volume and regurgitant fraction, quantitative
tomatic relief or recover left ventricular function following
assessment of global left ventricular function, and quantifi-
valve replacement.
cation of left ventricular volumes and mass. These assess-
ments are essential, as the decision to proceed to surgical
Mitral Valve Disease
replacement of the aortic valve is based on both the sever-
ity of the regurgitant jet and left ventricular size and In the adult population mitral stenosis is almost exclusively
function.57 secondary to rheumatic heart disease, whereas mitral regur-
Patients with significant aortic regurgitation will slowly gitation has a wider range of etiologies including left ven-
dilate their left ventricular end-diastolic and end-systolic tricular ischemic disease resulting in left ventricular and
volumes, though preserving left ventricular ejection fraction mitral annular dilation, endocarditis, rupture of the papil-
and will remain asymptomatic despite increases in preload. lary muscle and/or chordae tendineae, myxomatous changes,
However, as the severity of aortic regurgitation increases and and prolapse, to name the most common.
left ventricular dilation proceeds, left ventricular systolic Spin-echo imaging probably has a role only in mitral ste-
function will eventually decline, and the necessity for aortic nosis, where visualization of thickened leaflets can be identi-
valve replacement will become clearer.70 Unfortunately, up fied. Cine imaging with SSFP techniques is now the state of
to 25% of patients with severe aortic regurgitation remain the art for anatomic leaflet visualization and qualitative
asymptomatic (despite developing severe left ventricular dys- functional analysis.
function) until death. While symptoms of dyspnea, from The mitral valve consists of two leaflets. The anterior
elevated left ventricular pressures, or angina pectoris, from leaflet is relatively flap-shaped, is longer, and has more
548 chapter 22

surface area than the posterior leaflet, whereas the posterior using either spin-echo or cine imaging, though it is typically
leaflet is broader based and crescentic in shape. In addition, performed more consistently and easily with the latter. Mul-
there are multiple chordae tendineae that extend from the tiple short axis cine imaging planes using thin slices are
anterior and posterior papillary muscles providing structural performed from the mitral annulus through the base of the
support for both mitral leaflets. With current SSFP cine left ventricle. The image plane with the smallest valve orifice
imaging techniques, the valve leaflets, mitral annulus, and during ventricular diastole is chosen and the orifice planim-
papillary muscles are well seen. With delayed-enhancement etered by manual tracing of the leaflet tips, with close cor-
techniques, additional tissue characterization (specifically relation of valve areas as compared to Gorlin derived areas.
myocardial necrosis and infarction) can be identified provid- Similar to aortic stenosis, velocity spectra can be deter-
ing additional information, influencing the potential success mined from the mitral valve jet by placing a phase-contrast
of mitral valvular repair. While the chordae tendineae may velocity-encoded sequence parallel to the long axis of the
be seen with SSFP cine imaging, it is not a consistent feature, mitral valve jet. A small region of interest is placed at the
and echocardiography remains the primary tool for their center of greatest turbulence, denoted by signal void on
evaluation. the magnitude images, and the velocity waveforms
recorded. From this, both peak and mean gradients can be
Mitral Stenosis calculated.
While the continuity equation has been employed in
As noted, mitral stenosis occurs almost exclusively as a
echocardiography for mitral stenosis determination, this has
result of rheumatic heart disease. Nonetheless, rarely, adults
not gained routine utility in CMR. However, recent work by
may be seen with congenital mitral stenosis. In addition,
Lin et al.72 has indicated robust determination of mitral valve
other functional equivalents of mitral stenosis, such as left
orifice using the pressure half-time approach.
atrial myxoma, left atrial thrombus, or subvalvular mem-
branes may be identified with CMR.
Mitral Regurgitation
Valvular mitral stenosis is classically identified as fibro-
sis and thickening of the mitral valve leaflets and particu- Mitral regurgitation occurs as a failure of complete coapta-
larly of the mitral valve tips, along with involvement of the tion of the anterior and posterior leaflets of the mitral valve.
chordae tendineae. This thickening results in lack of opening Morphologically, features to be evaluated include vegetation
of the valve leaflets and a reduction in the mitral valve with partial destruction of the valve leaflets, myxomatous
orifice. “Doming” may be seen earlier in the disease process, changes or thickening of the valve leaflets, abnormal motion
whereas calcification is more frequently seen later in the of the leaflets including prolapse and flail, and necrosis and
disease (Fig. 22.10; and Video 22.1 on the DVD). Long-stand- acute infarction of the papillary muscles.
ing mitral stenosis can result in elevation of left atrial pres- Qualitative assessment of mitral regurgitation is per-
sure, dilation of the left atrium, backup of flow through the formed using cine SSFP imaging, as well as more flow-sensi-
pulmonary system, and eventually result in pulmonary tive cine imaging (using longer TEs) to best visualize the jet
hypertension. Complications include thrombus formation of retrogradely directed blood flow. In the four-chamber or
and atrial fibrillation.13,14 parasternal long axis projections, an imaging plane that
The severity of mitral valve stenosis can be determined shows the turbulent jet to best advantage is obtained with
either by direct measurement of the valve orifice or by deter- flow sensitive cine imaging. Signal voids encompassing less
mining the gradient across the valve during maximal flow.71 than 20% of the left atrial cross-sectional area may be con-
Direct assessment of the valve orifice may be performed sidered mild. These jets are typically relatively thin and

FIGURE 22.10. Three static images are represented from a cine from early diastole demonstrates aortic regurgitant flow buffeting
flow-sensitive sequence performed in the parasternal long axis ori- against the anterior leaflet of the mitral valve (arrow). The right
entation. The left image is from peak systole demonstrating a black image from middle to late diastole demonstrates a black jet of tur-
jet of turbulent blood in the proximal ascending aorta (asterisk) from bulent flow emanating from the coaptation point of the stenotic
significant aortic stenosis. The arrowhead denotes focal calcifica- mitral valve (double arrowheads).
tion on the anterior leaflet of the mitral valve. The middle image
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 549
output should be virtually equivalent through the systemic
and pulmonary systems (save for the slight volume of blood
through the bronchial arterial circulation), in the presence
of mitral valve regurgitation the difference between left and
right ventricular stroke volumes is the mitral regurgitant
volume. The mitral regurgitant fraction can be calculated
as the difference between left and right ventricular stroke
volumes divided by left ventricular stroke volume.75,76
The second approach incorporates left ventricular stroke
volume and forward flow through the ascending aorta. Left
ventricular stroke volume is measured by the disk summa-
tion method from a stack of short axis cine images through
the left ventricle. Next, the volume of forward flow through
the aortic valve is calculated using a phase-contrast velocity-
encoded technique placed at the proximal ascending aorta.
The difference between the left ventricular stroke volume
and the forward flow during systole through the ascending
aorta is the mitral regurgitant volume. The mitral regurgi-
tant volume can be divided by the left ventricular stroke
volume to determine mitral regurgitant fraction (Fig. 22.12;
and Video 22.1 on the DVD). The advantage of this approach
is that mitral regurgitation can be determined accurately
FIGURE 22.11. In this patient with severe mitral regurgitation a despite the presence of multivalvular disease, and without
steady-state free precession (SSFP) cine sequence has been acquired regard to the eccentricity or multiplicity of regurgitant jets77,78
in the four-chamber orientation. The mitral regurgitant jet is (Fig. 22.13; and Video 22.1 on the DVD).
denoted by the arrow. The relative lack of flow sensitivity from SSFP
imaging makes the regurgitant jet less conspicuous than if the Finally, it is possible to place a phase-contrast flow quan-
sequence had been acquired using a more flow-sensitive sequence tification sequence across the face of the mitral annulus and
(having a longer TE). Note the enlargement of the left atrium and directly measure forward flow through the valve during dias-
marked thinning of the proximal two thirds of the entire lateral tole and retrograde flow during systole, and therefore directly
wall from prior myocardial infarction.
calculate the regurgitant volume.79 The difficulty with this
approach is the significant through-plane motion of the
mitral annulus and valve throughout the cardiac cycle, and
with respect to the static imaging plane. During both systole
extend only partway back through the left atrium. Alterna-
and diastole, mitral valve and annular motion are opposite
tively, broad jets that extend to the back of the left atrium
the direction of blood flow, and thus measurements in either
and encompass larger percentages of left atrial cross-sec-
portion of the cardiac cycle may be underestimated.80 Kozerke
tional area are consistent with more severe regurgitation
et al.81 have applied a tagging-based motion-adapted flow
(Fig. 22.11; and Video 22.1 on the DVD).
measurement to circumvent this limitation, yet this approach
In addition to measuring mitral regurgitant volumes and
is not yet widely adapted and therefore may not yet be suit-
regurgitant fraction, attention must be paid to left ventricu-
able for routine use.
lar function and size when evaluating patients with mitral
regurgitation. The success of mitral valve repair decreases as
left ventricular size increases and function decreases.73 Accessory Findings
Greater success is obtained in patients who remain asymp-
The severity of mitral regurgitation may be supported by
tomatic or are only mildly symptomatic.
ancillary findings. Specifically, evaluation of pulmonary
blood flow may yield additional, corroborative information.
Quantitative Assessment of Mitral Regurgitation
Normal blood flow pattern in the pulmonary veins demon-
While the qualitative assessments of mitral regurgitation strates dominance of inflow during systole and lesser volume
severity provide a useful guide in valve with central jets of during diastole. Elevations in left atrial pressure are charac-
insufficiency, they are less reliable in the face of eccentric terized by the reversal of these patterns, such that pulmo-
jets or severely prolapsing or flail leaflets. Also, in eccentric nary vein inflow is maximal during diastole. This pattern
jets, particularly those that course along the posterior aspect may be seen with mild to moderate degrees of mitral regur-
of a valve leaflet or along the wall of the left atrium, the gitation. Severe mitral regurgitation, however, can result in
Coanda effect reduces the perceived volume of regurgitant reversal of blood flow within the pulmonary veins during
blood.74 Fortunately, CMR circumvents these limitations by systole (Fig. 22.14). These patterns of blood flow are easily
direct measurements of mitral regurgitant volumes, which seen with CMR phase-contrast velocity-encoded techniques
have shown good correlation with echocardiographic assess- measuring blood flow and velocity through the right upper
ments and invasive angiography.75 lobe pulmonary vein in a manner analogous to that used in
One approach used when there is isolated mitral valve echocardiography.82
insufficiency is to measure the left and right ventricular The papillary muscles are critical structures in mitral
stroke volumes using short axis cine imaging. As cardiac valve function, and rupture or infarction will usually neces-
550 chapter 22

Aortic flow

300

Instantaneous flow (cc/sec)

Left ventricular function: 250
EDV = 390 cc, ESV = 310 cc 200
SV = 80 cc, LVEF = 20% 150
Forward flow = 31 cc/beat
100

Mitral regurgitant volume: 50

LV SV (80 cc) - Ao FF (31 cc) = 49 cc 0
1 2 3 4 5 6 7 8 9 101112131415161718192021 222324252627282930
–50
–100
Mitral regurgitant fr. (49/80) = 61%
Cardiac phases

FIGURE 22.12. This composite set of images details the quantita- axis images from the mid-ventricular level of the same patient. The
tive calculation of mitral regurgitant volume and mitral regurgitant volumetric and functional values are shown in the left lower quad-
fraction (fr.) using the combination of the disk-summation method rant. The patient has a markedly dilated and severely dysfunctional
for left ventricular stroke volume and phase-contrast velocity- left ventricle. The right lower quadrant demonstrates the flow data
encoded sequence to calculate forward flow through the ascending acquired in the mid-ascending aorta demonstrating a calculated
aorta. The left upper quadrant is a flow-sensitive cine sequence forward flow of 31 cc/beat. The mitral regurgitant volume is calcu-
acquired in the four-chamber orientation demonstrating eccentric lated by subtracting the aortic forward flow from the left ventricular
severe mitral regurgitation and mild tricuspid regurgitation. The stroke volume, resulting in a mitral regurgitant volume of 49 cc/
right upper quadrant highlights end-diastolic and end-systolic short beat. Accordingly, the mitral regurgitant fraction is 61%.

Severe mitral regurgitation

500

400
Aorta
Instantaneous flow (cc/sec)

Right superior PV
300

200

100

0
10

13

16

19

22

25

28
1

–100
FIGURE 22.13. A flow-sensitive cine sequence was acquired in the Cardiac phases
four-chamber orientation in a patient with mitral valve prolapse and
severe mitral regurgitation. The arrowhead denotes the prolapse of FIGURE 22.14. Flow curves are depicted from blood flow in the
the posterior leaflet of the mitral valve, and the arrow denotes the ascending aorta and right superior pulmonary vein demonstrating
jet of insufficiency coursing along the posterior aspect of the ante- reversal of blood flow in the right superior pulmonary vein during
rior leaflet of the mitral valve and then to the interatrial septum. ventricular systole (note the portion of the blue curve below the
This form of eccentric mitral insufficiency results in a visual under- baseline denoting reversal of flow). There is prominent flow from
estimation of the severity of mitral regurgitation in what is known the right superior pulmonary vein into the left atrium during
as the Coanda effect. diastole.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 5 51
blood flow. The length and breadth of signal void emanating
from the tricuspid valve leaflets correlates with the severity
of tricuspid stenosis. Quantitative assessment can be per-
formed with phase-contrast velocity-encoded sequences also
performed parallel to the long axis of the turbulent jet. The
spectral velocities are analyzed in similar fashion to those
performed for the mitral valve, and the peak and mean gra-
dients are determined.

Tricuspid Regurgitation
Disease entities such as coronary artery disease and intrinsic
cardiomyopathies, as well as pulmonary hypertension, may
result in right ventricular dilation and progressive stretching
of the tricuspid annulus, resulting in tricuspid regurgitation
(Fig. 22.16; and Video 22.1 on the DVD). Isolated tricuspid
regurgitation is relatively rare, but when present the tricus-
pid regurgitant volume and regurgitant fraction can be cal-
culated directly from the difference in left ventricular and

FIGURE 22.15. This is a short axis image from the same patient in
Figure 22.11. The technique used is the delayed-enhancement
sequence performed after gadolinium administration, which high-
lights infarcted tissue as bright white, and normal myocardium
appears black. Note the marked thinning and bright signal intensity
of the entire lateral wall from prior myocardial infarction involving
the left circumflex coronary artery territory. The arrowheads denote
infarction of both the anterior and posterior papillary muscles,
resulting in the severe mitral regurgitation noted in the cine image
of Figure 22.11.

sitate alteration of mitral repair approach. Delayed-enhance-

ment CMR can now directly determine acutely necrotic or
infarcted papillary muscles necessitating mitral valve
replacement instead of repair (Fig. 22.15). The delayed-
enhancement CMR technique uses a T1-weighted, gradient-
echo sequence prepared with an inversion preparation pulse
following the intravenous administration of a gadolinium
contrast material. After optimizing the inversion delay time,
normal myocardium becomes “nulled” (turns black), whereas
acutely necrotic or infarcted myocardium turns bright
white.83 This technique has been validated extensively in
both animal models and human studies.84–87 Improved knowl-
edge of papillary muscle status may well improve surgical
planning and therefore results, though prospective studies
have yet to be performed.

Tricuspid Valve Disease

The tricuspid valve is normally trileaflet and can be evalu-
ated from a morphologic standpoint with both spin-echo and
cine gradient-echo imaging. Tricuspid stenosis is infrequently
seen, but when present almost invariably occurs as a result
of rheumatic heart disease, although it typically occurs in
concert with mitral and aortic valve involvement.
Qualitative evaluation of tricuspid stenosis severity is
performed similarly to the mitral valve. A flow-sensitive cine FIGURE 22.16. End-diastolic (top) and peak systolic (bottom)
gradient-echo sequence is performed in long axis orienta- images from a flow-sensitive cine sequence demonstrate highly
tions to maximize conspicuity of the stenotic jet of turbulent eccentric, medially directed tricuspid regurgitation (arrows).
552 chapter 22

right ventricular stroke volumes as described previously for Pulmonary Regurgitation

mitral regurgitation. Alternatively, the flow profiles can be
Insufficiency of the pulmonary valve, when mild, usually
determined using a phase-contrast velocity-encoded sequence
has limited consequences for the low-pressure right ventri-
applied parallel to and at the level of the tricuspid annulus
cle. However, as the severity of pulmonic regurgitation
directly measuring forward flow during diastole and regur-
increases, progressive dilation of the right ventricle occurs
gitant flow during systole.88,89 As with the mitral valve plane,
with subsequent involvement of the tricuspid valve and tri-
the tricuspid valve plane too has substantial motion through-
cuspid regurgitation. In severe cases, right ventricular failure
out the cardiac cycle, and flow measurements preferably
ensues.92 Pulmonic regurgitation is easily assessed with a
should be corrected for this motion.
phase-contrast velocity-encoded flow sequence performed
Finally, the magnitude of tricuspid regurgitation can be
perpendicular to the long axis of the main pulmonary artery
measured using right ventricular stroke volume obtained
similar to that used to calculate aortic regurgitation.93,94 Both
using the disk summation method from cine images obtained
forward flow during systole and reverse flow during diastole
through the entire right ventricle and integrating phase-con-
can be directly calculated using the velocity information on
trast velocity-encoded flow measurements from the main
a pixel-by-pixel basis found within the adapted region of
pulmonary artery. The tricuspid regurgitant volume is deter-
interest encompassing the main pulmonary artery. Forward
mined by subtracting pulmonary artery forward flow during
and regurgitant volumes and pulmonary regurgitant frac-
systole from the right ventricular stroke volume, and the
tions are calculated the same as with the aortic valve.95
regurgitant fraction is calculated by dividing tricuspid regur-
gitant volume by right ventricular stroke volume.89–91
Concurrent Disease
Peak systolic right ventricular pressures may also be
determined and are an important component in assessment Central or peripheral pulmonary stenosis may contribute to
of tricuspid valve disease. The tricuspid regurgitant jet peak both pulmonic and tricuspid valve disease. These may be
velocity can be incorporated into the modified Bernoulli difficult to assess with echocardiography, except in younger
equation and the gradient across the tricuspid valve deter- pediatric populations. In adults, contrast-enhanced pulmo-
mined. This value can be incorporated with the estimated nary MR angiography can easily and quickly assess the
right atrial pressure to calculate estimated right ventricular majority of the pulmonary arterial tree. These sequences are
systolic pressure. While this calculation is routinely used in typically performed in a breath-hold providing a luminogram
echocardiography, it has yet to see routine clinical use in of the pulmonary arterial tree and easily identifying the
CMR. presence of stenoses, web-like bands, aneurysms, and arte-
riovenous communications or malformations.
Pulmonary Valve Disease
Diseases of the pulmonary valve, and particularly pulmonic
Endocarditis
stenosis, are more frequently encountered in pediatric and Vegetations of the valves have been the province of trans-
congenital populations (Fig. 22.17; and Video 22.1 on the esophageal echocardiography for many years. Vegetations are
DVD). Nonetheless, with the increasing numbers of adults usually focal, mobile, and located along the lower pressure
with congenital heart disease, discrete examination of the side of the valve leaflet. Identification of such vegetations is
pulmonic valve and surrounding apparatus will likely critical in the treatment of patients with suspected infective
become more frequent. endocarditis. In the past, the spatial and temporal resolution

FIGURE 22.17. Steady-state free pre-

cession (SSFP) cine imaging from a
patient with valvar pulmonic stenosis.
The left panel is a right ventricular
outflow tract projection, and demon-
strates thin, doming pulmonic valve
leaflets and a jet of turbulent flow
extending into the main pulmonary
artery (arrow). The right panel is also a
cine SSFP sequence obtained in the
short axis projection at the mid-ven-
tricular level. This image demonstrates
marked hypertrophy of the right ven-
tricle, as well as a leftward shift of the
interventricular septum during systole
compatible with right-sided pressure
overload.
 m a g n e t i c r e s o n a n c e i m a g i n g o f va lv u l a r d i s e a s e 553
that all prosthetic heart valves are currently MR compatible.
In the past, the Starr-Edwards (St. Jude Medical, St Paul, MN)
Pre-6000 series of prosthetic heart valves were felt to be
incompatible with MR imaging as a result of the metallic
ball-and-cage employed. However, a reassessment of mag-
netic effects on the valve structure was performed and the
valves found to be MR compatible.98
As a result of the susceptibility artifacts, flow measure-
ments, either for stenosis or regurgitation, cannot be made
accurately directly through the valve prosthesis. However,
flow quantification using phase-contrast velocity encoded
techniques may be performed with the imaging slices placed
a few millimeters from the valve, avoiding the susceptibility
artifacts.99
Vegetations or pannus on prosthetic heart valves also
cannot be evaluated directly with CMR as a result of the sus-
ceptibility artifacts. However, processes such as perivalvular
leaks or abscesses are easily evaluated with CMR, as the
abnormalities are typically outside of the localized suscepti-
bility artifacts (Fig. 22.18; and Video 22.1 on the DVD). Further,
the degree of regurgitation of perivalvular leaks is easily quan-
tified using the techniques previously described specific for
each valve. This information can assist in the determination
of proper timing for recurrent valve repair or replacement in
patients who remain hemodynamically stable.

Summary
Cine MR evaluation of valvular disease has now become an
accurate and strongly complementary role to its already cur-
rently accepted gold standard status for ventricular function
and volume analysis. It can readily assess the morphology
and function of all four cardiac valves and accurately deter-
mine degrees of stenosis and regurgitation; more importantly,
it has a distinct advantage in quantifying valvular regurgi-
tant volumes and regurgitant fractions. These advantages
FIGURE 22.18. A perivalvular pseudoaneurysm is identified reflect- may provide further insights into precise timing of repairs
ing partial dehiscence of the suture line of a prosthetic aortic valve. and prediction for valve replacement or repair, as well as
The black blood spin-echo image (upper panel) reveals an ovoid closer monitoring of medical therapies.
signal void between the aortic root and the left atrium (arrowhead).
The lower panel from a cine gradient echo sequence demonstrates
high signal intensity within the same perivalvular pocket (arrow- References
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 2 Balloon Dilatation of the
3 Cardiac Valves
Igor F. Palacios and Pedro L. Sánchez

Percutaneous Pulmonic Valvuloplasty . . . . . . . . . . . . . . 557 Percutaneous Aortic Balloon Valvuloplasty . . . . . . . . . . 569

Percutaneous Mitral Balloon Valvotomy for Patients Percutaneous Tricuspid Balloon Valvuloplasty. . . . . . . . 575
with Rheumatic Mitral Stenosis . . . . . . . . . . . . . . . . 558 Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576

Key Points Percutaneous Pulmonic Valvuloplasty

• Percutaneous balloon pulmonary valvuloplasty (PPV) has
become the treatment of choice for patients with isolated Since its introduction by Kan et al. in 1982, percutaneous
pulmonic valvular stenosis. balloon pulmonary valvuloplasty (PPV) has become the
• Percutaneous mitral balloon commissurotomy (PMV) treatment of choice for patients with isolated pulmonic val-
has been successfully used as an alternative to open or vular stenosis.1–3 In both children and adults with valvular
closed surgical mitral commissurotomy in the treatment pulmonic stenosis balloon valvuloplasty produces excellent
of patients with symptomatic rheumatic mitral immediate and long-term results. Patients with isolated pul-
stenosis. monic stenosis and a transvalvular gradient greater than
• Increase of mitral valve area with PMV is inversely 40 mm Hg are candidates for this technique (Table 23.1).3–9
related to the presence of atrial fibrillation. The technique of PPV is relatively simple. It is performed
• The presence and severity of MR before PMV is an inde- with the patient under sedation and local anesthesia. Before
pendent predictor of unfavorable outcome of PMV. performing PPV, accurate measurement of the pulmonary
• Following PMV, the majority of patients have marked annulus by two-dimensional (2D) echocardiography and
clinical improvement and become New York Heart Asso- angiography is fundamental in the appropriate selection of
ciation (NYHA) class I or II in intermediate- and long- balloon size. Complete right and left catheterization and
term follow-up. right ventricular cineangiography in both the anteroposte-
• Patients with heavily calcified mitral valves under fluo- rior and lateral projections are performed before PPV to docu-
roscopy have a poorer immediate outcome with PMV. ment the severity of the stenosis and the presence of
• The degree of pulmonary artery hypertension before PMV associated lesions.
is inversely related to immediate and long-term outcome The stenotic pulmonic valve is crossed with an end-hole
of PMV. balloon wedge catheter, and the catheter is placed in the left
• The degree of tricuspid regurgitation before PMV is in- pulmonary artery. A 0.035- or 0.038-inch exchange guide-
versely related to the immediate and long-term outcome wire is advanced in the distal left pulmonary artery, and the
of PMV. catheter and venous introducer are removed. When using the
• Aortic valve replacement is the treatment of choice for double-balloon technique, a second guidewire could be placed
symptomatic patients with severe valvular aortic steno- parallel to the first guidewire with the help of a double-
sis, but in nonsurgical candidates, because of associated lumen catheter. In smaller children, double-balloon PPV can
major medical comorbid conditions, percutaneous aortic be performed by introducing a dilating balloon through each
balloon valvuloplasty (PAV) may be considered a short- of the femoral veins. The balloon or balloons dilating the
term palliative intervention. However, clinical restenosis catheters are then advanced and placed straddling the pul-
occurs, frequently, 6 to 12 months after PAV. monic valve. A balloon combination that provides a diameter
20% to 30% greater than the pulmonary annulus is used to
Before 1982, cardiac surgery was the conventional form of provide adequate relief of the stenosis. The valvuloplasty
treatment for symptomatic stenotic valvular heart lesions. balloons are then inflated by hand until the waist produced
Today, percutaneous balloon dilatation of stenotic cardiac by the stenotic pulmonic valve disappears. Two to four brief
valves is being used in many centers for the treatment of inflations are performed to minimize the period of hypoten-
patients with pulmonic, mitral, aortic and tricuspid sion. The inflation/deflation process takes between 15 and
stenosis. 20 seconds. Double-balloon PPV is tolerated better than

557
558 chapter 23

TABLE 23.1. Recommendations for percutaneous pulmonic pulmonary insufficiency occurs frequently, but it does not
valvuloplasty in patients with isolated pulmonic stenosis have significant clinical or hemodynamic consequences.
Level of Follow-up studies have shown that restenosis is uncom-
Current indication Class evidence mon.10,11 Follow-up cardiac catheterization and Doppler
Patients with exertional dyspnea, I Grade B echocardiography studies have demonstrated that significant
angina, syncope, or presyncope restenosis appears to be uncommon. Recurrent stenosis is
Asymptomatic patients with normal much less likely if the final gradient after PPV is less than
cardiac output 30 mm Hg. The residual gradient measured 6 months after
Transvalvular gradient >50 mm Hg I Grade B PPV has been significantly smaller than the one measured
Transvalvular gradient 40 to 49 mm Hg IIa Grade B
Transvalvular gradient 30 to 39 mm Hg IIb Grade C immediately after the procedure. This finding is probably
Transvalvular gradient <30 mm Hg III Grade C related to improvement in the infundibulum stenosis, which
frequently occurs immediately after PPV.

Percutaneous Mitral Balloon Valvotomy for

single-balloon PPV, resulting in less hypotension and brady- Patients with Rheumatic Mitral Stenosis
cardia during balloon inflations. Following completion of the
dilatations, the deflated catheters are removed and repeat Since its introduction in 1984 by Inoue et al.,12 percutaneous
hemodynamics and right ventricular cineangiography are mitral balloon commissurotomy (PMV) has been used suc-
repeated. At the end of the procedure, the catheters are cessfully as an alternative to open or closed surgical mitral
removed and hemostasis is achieved by local pressure. In commissurotomy in the treatment of patients with symp-
most adults, two balloons are required. Patients are observed tomatic rheumatic mitral stenosis.12–34 It produces good
after the procedure in a general medical ward and discharged immediate hemodynamic outcome, has a low complication
the following day. rate, and results in clinical improvement in the majority of
Percutaneous balloon pulmonary valvuloplasty produces patients with mitral stenosis. It is safe and effective, and
a significant decrease in pulmonic gradient. In general, the provides sustained clinical and hemodynamic improvement
pulmonic gradient decreases by 50% to 80%. The results of in patients with rheumatic mitral stenosis. The immediate
PPV from different centers are shown in Table 23.2. Patients and long-term results appear to be similar to those of surgical
with severe pulmonary dysplasia and with hypoplasia of the mitral commissurotomy.12–34 Today, PMV is the preferred
pulmonic annulus are unlikely to have improvement after form of therapy for relief of mitral stenosis for a selected
PPV. In some patients, a significant gradient could develop group of patients with symptomatic mitral stenosis.
across the infundibulum following relief of the valvular
pulmonic stenosis and may be reduced by the use of beta-
blockers or calcium channel blockers. This infundibular Patient Selection
gradient has no clinical importance and disappears or mark- Selection of patients for PMV should be based on symptoms,
edly decreases at follow-up cardiac catheterization or Doppler physical examination, and 2D and Doppler echocardiographic
echocardiography. findings.35 Percutaneous mitral balloon commissurotomy is
Complications of PPV are rare.1–8 They are more frequent usually performed electively. However, emergency PMV can
in neonates. Perforation of the right ventricular outflow tract be performed as a lifesaving procedure in patients with mitral
has been reported to occur in neonates when attempts have stenosis and severe pulmonary edema refractory to medical
been made to cross the pulmonary valve. Similarly, vessel therapy or to cardiogenic shock. Patients considered for PMV
trauma is more frequent in neonates and infants and can be should be symptomatic [New York Heart Association (NYHA)
diminished by using the double-balloon technique. Mild class II or greater], should have no recent thromboembolic
events, have less than two grades of mitral regur-gitation by
contrast ventriculography (using the Sellers classification),36
and have no evidence of left atrial thrombus on 2D and trans-
TABLE 23.2. Immediate results of percutaneous pulmonic esophageal echocardiography (Table 23.3). Transthoracic and
valvuloplasty
transesophageal echocardiography should be performed rou-
Pulmonary pressure (mm Hg) tinely before PMV. Patients in atrial fibrillation and patients
Author No. of patients Pre-PPV Post-PPV with previous embolic episodes should be anticoagulated
with warfarin with a therapeutic prothrombin time for at
Kan et al. 20 68 ± 27 23 ± 5
least 3 months before PMV. Patients with left atrium throm-
Rao et al. 71 91 ± 41 26 ± 19
bus on 2D-echocardiography should be excluded. However,
VACA registry 784 71 ± 33 28 ± 21
PMV could be performed in these patients if the left atrium
Beekman et al. 90 70 ± 24 30 ± 17 thrombus has resolved after warfarin therapy.
Ali Khan et al. 257 97 ± 30 22 ± 20
Schmaltz et al.* 305 72 ± 32 32 ± 25
Massachusetts
Technique
General Hospital** 39 69 ± 26 17 ± 11 The PMV is performed with the patient in the fasting state
* Multicenter study. and under mild sedation. Antibiotics (dicloxacillin 500 mg
** Adults. p.o. q6h for four doses starting before the procedure, or
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 559
TABLE 23.3. Recommendations for percutaneous mitral valvuloplasty
Current indication Class Level of evidence

Symptomatic patients (NYHA functional class II, III, or IV), moderate or severe I Grade A
mitral stenosis (area <1.5 cm2), and valve morphology favorable for percutaneous
balloon valvuloplasty in the absence of left atrial thrombus or moderate to
severe mitral regurgitation
Asymptomatic patients with moderate or severe mitral stenosis (area <1.5 cm2) IIa Grade C
and valve morphology favorable for percutaneous balloon valvuloplasty who
have pulmonary hypertension (pulmonary artery systolic pressure >50 mm Hg
at rest or 60 mm Hg with exercise) in the absence of left atrial thrombus or
moderate to severe mitral regurgitation
Patients with NYHA functional class III to IV, moderate or severe mitral stenosis IIa Grade B
(area <1.5 cm2), and a nonpliable calcified valve who are at high risk for surgery
in the absence of left atrial thrombus or moderate to severe mitral regurgitation.
Asymptomatic patients, moderate or severe mitral stenosis (area <1.5 cm2), and valve IIb Grade B
morphology favorable for percutaneous balloon valvuloplasty who have new onset
of atrial fibrillation in the absence of left atrial thrombus or moderate to severe
mitral regurgitation
Patients in NYHA functional class III to IV, moderate or severe mitral stenosis IIb Grade C
(area <1.5 cm2), and a nonpliable calcified valve who are low-risk candidates for
surgery
Patients with mild mitral stenosis III Grade C

cefazolin 1 g i.v. at the time of the procedure) are used. using a newly designed metallic valvulotome was intro-
Patients allergic to penicillin should receive vancomycin 1 g duced.24 The device consists of a detachable metallic cylinder
i.v. at the time of the procedure. with two articulated bars screwed onto the distal end of a
All patients carefully chosen as candidates for mitral disposable catheter whose proximal end is connected to an
balloon valvuloplasty should undergo diagnostic right and activating pliers. Squeezing the pliers opens the bars up to a
left and transseptal left heart catheterization. Following maximum of 40 mm (Fig. 23.3). The results with this device
transseptal left heart catheterization, systemic anticoagula- are at least comparable to those of the other balloon tech-
tion is achieved by the intravenous administration of niques of PMV,27 and multiple uses after sterilization should
100 units/kg of heparin. In patients older than 40 years, coro- markedly decrease procedural costs.
nary arteriography is recommended and should also be
performed.
The Antegrade Double-Balloon Technique
Hemodynamic measurements, cardiac output, and cine
left ventriculography are performed before and after PMV. In performing PMV using the antegrade double-balloon tech-
Cardiac output is measured by thermodilution and Fick nique (Fig. 23.2), two 0.038-inch, 260 cm long Teflon-coated
method techniques. Mitral valve calcification and angio- exchange wires are placed across the mitral valve into the
graphic severity of mitral regurgitation (the Sellers classifica- left ventricle, through the aortic valve into the ascending and
tion) are graded qualitatively from 0 to 4 as described then the descending aorta.14–16 Care should be taken to main-
elsewhere.36 An oxygen diagnostic run is performed before tain large and smooth loops of the guidewires in the left
and after PMV to determine the presence of left to right ventricular cavity to allow appropriate placement of the
shunt across the atrial septum after PMV. dilating balloons. If a second guidewire cannot be placed into
There is not a unique technique of percutaneous mitral the ascending and descending aorta, a 0.038-inch Amplatzer-
balloon valvuloplasty. Most of the techniques of PMV require type transfer guidewire (AGA Medical Corp., Golden Valley,
transseptal left heart catheterization and use of the antegrade MN) with a preformed curlew at its tip can be placed at the
approach.12–22,24–28 Antegrade PMV can be accomplished using left ventricular apex. In patients with aortic valve prostheses,
a single- (Fig. 23.1) or a double-balloon technique (Fig. 23.2). both guidewires with performed curlew tips should be placed
In this latter approach the two balloons could be placed at the left ventricular apex. When one or both guidewires are
through a single femoral vein and single transseptal punc- placed in the left ventricular apex, the balloons should be
tures, or through two femoral veins and two separate atrial inflated sequentially. Care should be taken to avoid forward
septal punctures. In the retrograde technique of PMV, the movement of the balloons and guidewires to prevent left
balloons dilating the catheters are advanced percutaneously ventricular perforation. Two balloon-dilating catheters,
through the right and left femoral arteries over guidewires chosen according to the patient’s body surface area, are then
that have been snared from the descending aorta. These advanced over each of the guidewires and positioned across
guidewires have been advanced transseptally from the right the mitral valve parallel to the longitudinal axis of the left
femoral vein into the left atrium, the left ventricle, and the ventricle. The balloon valvotomy catheters are then inflated
ascending aorta.37 A retrograde nontransseptal technique of by hand until the indentation produced by the stenotic mitral
PMV has also been described.38 Recently, a technique of PMV valve is no longer seen. Generally one but occasionally two
560 chapter 23

FIGURE 23.1. Double-balloon percuta-

neous technique of percutaneous mitral
valvulotomy (PMV).

or three inflations are performed. After complete deflation atrial septum. A balloon catheter chosen according to the
the balloons are removed sequentially. patient’s height is advanced over the guidewire into the left
atrium. The distal part of the balloon is inflated and advanced
into the left ventricle with the help of the spring wire stylet
The Inoue Technique
that has been inserted through the inner lumen of the cath-
The PMV can also be performed using the Inoue technique eter. Once the catheter is in the left ventricle, the partially
(Fig. 23.2).12 The Inoue balloon is a 12-French (F) shaft, coaxial, inflated balloon is moved back and forth inside the left ven-
double-lumen catheter. The balloon is made of a double layer tricle to ensure that it is free of the chordae tendineae. The
of rubber tubing with a layer of synthetic micromesh in catheter is then gently pulled against the mitral plane until
between. Following transseptal catheterization, a stainless resistance is felt. The balloon is then rapidly inflated to its
steel guidewire is advanced through the transseptal catheter full capacity and then deflated quickly. During inflation of
and placed with its tip coiled into the left atrium and the the balloon, an indentation should be seen in its midportion.
transseptal catheter removed. A 14F dilator is advanced over The catheter is withdrawn into the left atrium and the mitral
the guidewire and used to dilate the femoral vein and the gradient and cardiac output measured. If further dilatations

FIGURE 23.2. Inoue balloon technique of

percutaneous technique of PMV.
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 5 61

FIGURE 23.3. Cribier metallic tech-

nique of PMV.

are required, the stylet is introduced again and the sequence addition, in patients with calcific mitral stenosis, the bal-
of steps described above repeated at a larger balloon volume. loons could increase mitral valve flexibility by the fracture
After each dilatation, its effect should be assessed by pres- of the calcified deposits in the mitral valve leaflets.44
sure measurement, auscultation, and 2D-echocardiography. Although rare, undesirable complications, such as leaflet
If mitral regurgitation occurs, further dilation of the valve tears, left ventricular perforation, tear of the atrial septum
should not be performed. and rupture of chordae, mitral annulus, and papillary muscle
could also occur.
Mechanism
Immediate Outcome
The mechanism of successful PMV is splitting of the fused
commissures toward the mitral annulus, resulting in com- Figure 23.4 shows the hemodynamic changes produced by
missural widening. This mechanism has been demonstrated PMV in one patient. The PMV resulted in a significant
by pathologic, surgical, and echocardiographic studies.39–43 In decrease in mitral gradient, mean left atrium pressure, and

Pre-PMV Post-PMV

FIGURE 23.4. Hemodynamic

changes produced by a success-
ful PMV in one patient with
severe mitral stenosis. At the top
panels simultaneous left atrium
and left ventricular pressures
before (upper left panel) and after
(upper right panel) PMV. LV/LA Pre-PMV LV/LA Post-PMV
562 chapter 23

TABLE 23.4. Immediate changes in mitral valve area after percutaneous mitral valvuloplasty
Author Institution No. of patients Age Pre-PMV Post-PMV

Palacios et al. Massachusetts General Hospital 879 55 ± 15 0.9 ± 0.3 1.9 ± 0.7
Vahanian et al. Tenon 1514 45 ± 15 1.0 ± 0.2 1.9 ± 0.3
Hernández et al. Clínico Madrid 561 53 ± 13 1.0 ± 0.2 1.8 ± 0.4
Stefanadis et al. Athens University 438 44 ± 11 1.0 ± 0.3 2.1 ± 0.5
Chen et al. Guangzhou 4832 37 ± 12 1.1 ± 0.3 2.1 ± 0.2
NHLBI Multicenter 738 54 ± 12 1.0 ± 0.4 2.0 ± 0.2
Inoue et al. Takeda 527 50 ± 10 1.1 ± 0.1 2.0 ± 0.1
Inoue Registry Multicenter 1251 53 ± 15 1.0 ± 0.3 1.8 ± 0.6
Ben Farhat et al. Fattouma 463 33 ± 12 1.0 ± 0.2 2.2 ± 0.4
Arora et al. G.B. Pan 600 27 ±8 0.8 ± 0.2 2.2 ± 0.4
Cribier et al. Ruen 153 36 ± 15 1.0 ± 0.2 2.2 ± 0.4

mean pulmonary artery pressure; and an increase in cardiac A successful hemodynamic outcome [defined as a post-
output and mitral valve area (MVA). Table 23.4 shows the PMV mitral valve area ≥1.5 cm2 and post-PMV mitral regur-
changes in MVA reported by several investigators using dif- gitation (MR) <3 Sellers’ grades] was obtained in 72% of the
ferent techniques of PMV. In most series, PMV is reported to patients. Although a suboptimal result occurred in 28% of
increase MVA from less than 1.0 cm2 to approximately the patients, a post-PMV MVA ≤1.0 cm2 (critical mitral valve
2.0 cm2.18–20,23,25–28,34 area) was present in only 8.7% of these patients.
At the Massachusetts General Hospital, 879 consecutive
patients with mitral stenosis have undergone 939 PMVs
Predictors of Increase in Mitral Valve Area and
between July 1986 and July 2000.28 As shown in Figure 23.5,
Procedural Success
in this group of patients, PMV resulted in a significant
decrease in mitral gradient from 14 ± 6 to 6 ± 3 mm Hg. The Univariate analysis demonstrated that the increase in MVA
mean cardiac output significantly increased from 3.9 ± 1.1 to with PMV is directly related to the balloon size employed as
4.5 ± 1.3 L/min, and the calculated MVA from 0.9 ± 0.3 to it reflects in the effective balloon dilating area (EBDA) and is
1.9 ± 0.7 cm2. In addition, mean pulmonary artery pressure inversely related to the echocardiographic score, the presence
significantly decreased from 36 ± 13 to 29 ± 11 mm Hg and of atrial fibrillation, the presence of fluoroscopic calcium, the
the mean left atrial pressure decreased from 25 ± 7 to presence of previous surgical commissurotomy, older age,
17 ± 7 mm Hg, and consequently, the calculated pulmonary NYHA pre-PMV class, and the presence of MR before PMV.
vascular resistances decreased significantly following PMV. Multiple stepwise regression analysis identified balloon size

Changes in MVA Post-PMV MR ≥3+

1.9 ± 0.6
12
2
p <.001 9.0
1.8
10
1.6
1.4 8
Patients (%)
MVA (cm2)

1.2 0.9 ± 0.3

6
1 6.3
0.8 4
0.6
0.4 2
2.7
0.2
0
0
Pre-PMV Post-PMV MR 3+ FIGURE 23.5. Mean changes in mitral
MR 4+ valve area after PMV (A) and post-PMV
Success: 72%
development of severe (≥3+) mitral regur-
A B gitation (B).
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 563
(p < .02), the echocardiographic score (p < .0001), and the pres- graphic score, valve leaflets thickening and subvalvular
ence of atrial fibrillation (p < .009) and MR before PMV (p < disease correlate best with the increase in MVA produced by
.03) as independent predictors of the increase in MVA with PMV.44 Therefore, suboptimal results with PMV are more
PMV. likely to occur in patients with valves that are more rigid
Univariate predictors of procedural success included age, and more thickened, and those with more subvalvular fibro-
pre-PMV MVA, mean pre-PMV pulmonary artery pressure, sis and calcification.
male sex, echocardiographic score, pre-PMV MR ≥2+, history
of previous surgical commissurotomy, presence of atrial Balloon Size and Effective Balloon Dilating Area
fibrillation, and presence of mitral valve calcification under
The increase in mitral valve area with PMV is directly related
fluoroscopy.
to balloon size. This effect was first demonstrated in a sub-
Multiple stepwise logistic regression analysis identified
group of patients who underwent repeat PMV.45 They ini-
larger pre-PMV MVA [odds ratio (OR) 13.05, 95% confidence
tially underwent PMV with a single balloon, resulting in a
interval (CI) 7.74 to 22.51; p < .001], less degree of pre-PMV
mean mitral valve area of 1.2 ± 0.2 cm2. They underwent
MR (OR 3.85, CI 2.27 to 6.66; p < .001), younger age (OR 3.33,
repeat PMV using the double-balloon technique, which
CI 1.41 to 7.69; p = .006), absence of previous surgical com-
increased the EBDA normalized by body surface area (EBDA/
missurotomy (OR 1.85, CI 1.20 to 2.86; p = .004), male sex
BSA) from 3.41 ± 0.2 to 4.51 ± 0.2 cm2/m2. The mean mitral
(OR 1.92, CI 1.19 to 3.13; p = .008), and echocardiographic
valve area in this group after repeat PMV was 1.8 cm2 ±
score ≤8 (OR 1.69, CI 1.18 to 2.44; p = .004).
0.7 cm2. The increase in MVA in patients who underwent
PMV at the Massachusetts General Hospital using the
double-balloon technique (EBDA of 6.4 ± 0.03 cm2) was sig-
Echocardiographic Score nificantly greater than the increase in MVA achieved in
patients who underwent PMV using the single-balloon tech-
The echocardiographic examination of the mitral valve can
nique (EBDA of 4.3 ± 0.02 cm2). The mean MVAs were 1.9 ±
accurately characterize the severity and extent of the patho-
0.7 and 1.4 ± 0.1 cm2 for patients who underwent PMV with
logic process in patients with mitral stenosis. The most uti-
the double-balloon and the single-balloon techniques, respec-
lized score to identify the anatomic abnormalities of the
tively. However, care should be taken in the selection of
stenotic mitral valve is that described by Wilkins et al.42
dilating balloon catheters so as to obtain an adequate final
(Table 23.5). This echocardiographic score is an important
MVA and no change or a minimal increase in MR.
predictor of the immediate and long-term outcome of PMV.
In this morphologic score, leaflet rigidity, leaflet thickening,
Mitral Valve Calcification
valvular calcification, and subvalvular disease are scored
from 0 to 4. A higher score represents a heavily calcified, The immediate outcome of patients undergoing PMV is
thickened, and immobile valve with extensive thickening inversely related to the severity of valvular calcification seen
and calcification of the subvalvular apparatus. The increase by fluoroscopy. Patients without fluoroscopic calcium have
in MVA with PMV is inversely related to the echocardio- a greater increase in MVA after PMV than patients with cal-
graphic score. The best outcome with PMV occurs in those cified valves. Patients with either no or 1+ fluoroscopic
patients with echocardiographic scores ≤8. The increase in calcium have a greater increase in MVA after PMV (1.1 ± 0.6
MVA is significantly greater in patients with echocardio- and 0.9 ± 0.5 cm2, respectively) than those patients with 2, 3,
graphic scores ≤8 than in those with echocardiographic or 4+ of calcium (0.8 ± 0.6, 0.8 ± 0.5, and 0.6 ± 0.4 cm2,
scores >8. Among the four components of the echocardio- respectively).

TABLE 23.5. The echocardiographic score: echocardiographic grading of the severity and extent of the anatomic abnormalities in
patients with mitral stenosis
Grade Leaflet mobility Valvular thickening Valvular calcification Subvalvular thickening

0 Normal Normal Normal Normal

1 Highly mobile valve Leaflet near normal A single area of Minimal thickening of chordal
with restriction of (4–5 mm) increased echo structures just below the valve
only the leaflet tips brightness
2 Middle portion and Mid-leaflet thickening, Scattered areas of Thickening of chordae
base of leaflets marked at the brightness confined extending up to one third of
reduced mobility margins to thickening of chordal length
leaflet margins
3 Valve leaflets move Thickening Brightness extending Thickening extending to the
forward in diastole extending into the midportion distal third of the chordae
mainly at the base through the of leaflets (5–8 mm)
entire leaflets
4 No or minimal Marked thickening Extensive brightness Extensive thickening and
forward movement of all leaflet tissue throughout most of shortening of all chordae
of the leaflets (>8–10 mm) the leaflet tissue extending down to the
in diastole papillary muscles
* The total score is the sum of each of these echocardiographic features (maximum 16).
564 chapter 23

Previous Surgical Commissurotomy severity of MR determined by angiography before the proce-

dure. This inverse relationship between presence of MR and
Although the increase in MVA with PMV is inversely related
immediate outcome of PMV is in part due to the higher fre-
to the presence of previous surgical mitral commissurotomy,
quency of atrial fibrillation, higher echocardiographic scores,
PMV can produce a good outcome in this group of patients.
calcified mitral valves under fluoroscopy, and older age in
The post-PMV mean MVA in 154 patients with previous
patients with MR before PMV.
surgical commissurotomy was 1.8 ± 0.7 cm2 compared with
a valve area of 1.9 ± 0.6 cm2 in patients without previous
surgical commissurotomy (p < .05). In this group of patients, Complications
an echocardiographic score ≤8 was an important predictor of
Table 23.6 shows the complications reported by several
a successful hemodynamic immediate outcome.
investigators after PMV.18–20,23,25–28,34 Mortality and morbidity
with PMV are low and similar to surgical commissurotomy.
Age
Overall, there is <1% mortality. Severe MR (four grades by
The immediate outcome of PMV is directly related to the age angiography) has been reported in 1% to 5.2% of the patients.
of the patient. The percentage of patients obtaining a good Some of these patients required in-hospital mitral valve
result with this technique decreases as age increases. A suc- replacement. Thromboembolic episodes and stroke have
cessful hemodynamic outcome from PMV was obtained in been reported in 0% to 3.1% and pericardial tamponade in
only <50% of patients ≥65 years old.46 This inverse relation- 0.2% to 4.6% of cases in these series. Pericardial tamponade
ship between age and the immediate outcome from PMV is can occur from transseptal catheterization and more rarely
due to the higher frequency of atrial fibrillation, calcified from ventricular perforation. The PMV is associated with a
valves, and higher echocardiographic scores in elderly 3% to 16% incidence of left to right shunt immediately after
patients. the procedure. However, the pulmonary to systemic flow
ratio is ≥2 : 1 in only a minimum number of patients.
Atrial Fibrillation We have demonstrated that severe MR (four grades by
angiography) occurs in about 3% of patients undergoing
The increase in MVA with PMV is inversely related to the
PMV.28 An undesirable increase in MR (two or more grades
presence of atrial fibrillation; the post-PMV MVA of patients
by angiography) occurred in 10.1% of patients. This undesir-
in normal sinus rhythm was 2.0 ± 0.7 cm2 compared with a
able increase in MR is well tolerated in most patients. Fur-
valve area of 1.7 ± 0.6 cm2 of those patients in atrial fibrilla-
thermore, more than half of them have less MR at follow-up
tion. The inferior immediate outcome of PMV in patients
cardiac catheterization. We have demonstrated that the ratio
with mitral stenosis who are in atrial fibrillation is more
of the effective balloon dilating area to body surface area
likely related to the presence of clinical and morphologic
(EBDA/BSA) is the only predictor of increased MR after
characteristics associated with inferior results after PMV.
PMV.47–49 The EBDA is calculated using standard geometric
Patients in atrial fibrillation are older and present more fre-
formulas. The incidence of MR is lower if balloon sizes are
quently with echocardiographic scores >8, NYHA functional
chosen so that EBDA/BSA is ≤4.0 cm2/m2. The single-balloon
class IV, calcified mitral valves under fluoroscopy, and a
technique results in a lower incidence of MR but provides
previous history of surgical mitral commissurotomy.
less relief of mitral stenosis than the double-balloon tech-
nique. Thus, there is an optimal effective balloon dilating
Mitral Regurgitation Before PMV
area between 3.1 and 4.0 cm2/m2, which achieves a maximal
The presence and severity of mitral regurgitation before PMV MVA with a minimal increase in MR. An echocardiographic
is an independent predictor of unfavorable outcome of PMV. score for the mitral valve that can predict the development
The increase in MVA after PMV is inversely related to the of severe MR following PMV has also been described.43 This

TABLE 23.6. Complications following percutaneous mitral valvuloplasty

Author No. of patients Mortality Tamponade Severe mitral regurgitation Embolism

Palacios et al. 879 0.6% 1.0% 3.4% 1.8%

Vahanian et al. 1514 0.4% 0.3% 3.4% 0.3%
Hernández et al. 561 0.4% 0.6% 4.5%
Stefanadis et al. 438 0.2% 0.0% 3.4% 0.0%
Chen et al. 4832 0.1% 0.8% 1.4% 0.5%
NHLBI 738 3.0% 4.0% 3.0% 3.0%
Inoue et al. 527 0.0% 1.6% 1.9% 0.6%
Inoue registry 1251 0.6% 1.4% 3.8% 0.9%
Ben Farhat et al. 463 0.4% 0.7% 4.6% 2.0%
Arora et al. 600 1.0% 1.3% 1.0% 0.5%
Cribier et al. 153 0.0% 0.7% 1.4% 0.7%
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 565
score takes into account the distribution (even or uneven) of 100
leaflet thickening and calcification, the degree and symme-
90
try of commissural disease, and the severity of subvalvular Echo score ≤8
disease. 80
Left to right shunt through the created atrial communi- 70 Total group
cation occurred in 3% to 16% of the patients undergoing

Survival (%)
PMV. The size of the defect is small as reflected in the pul- 60
monary to systemic flow ratio of <2 : 1 in the majority of 50 Echo score >8
patients. Older age, fluoroscopic evidence of mitral valve
calcification, higher echocardiographic score, pre-PMV lower 40
cardiac output, and higher pre-PMV NYHA functional class 30
are the factors that predispose patients to develop left to right
20
shunt post-PMV.49 Clinical, echocardiographic, surgical, and
hemodynamic follow-up of patients with post-PMV left to 10
p < .0001
right shunt demonstrated that the defect closed in approxi-
0
mately 60%. Persistent left to right shunt at follow-up is
0 20 40 60 80 100 120 140 160 180
small (QP/QS <2 : 1) and clinically well tolerated. In the series
from the Massachusetts General Hospital, there is one patient Time of follow-up (months)
in whom the atrial shunt remained hemodynamically sig- Figure 23.6. Fifteen-year survival for all patients, and for patients
nificant at follow-up. This patient underwent percutaneous with echocardiographic score ≤8 and >8, undergoing percutaneous
mitral balloon valvotomy at the Massachusetts General Hospital.
transcatheter closure of her atrial defect with a clamshell
device. Desideri et al.50 reported atrial shunting determined
by color flow transthoracic echocardiography in 61% of 57
patients immediately after PMV. The shunt persisted in 30% different institutions. We reported an estimated 12-year sur-
of patients at 19 ± 6 (range 9–33) months follow-up. The vival rate of 74% in a cohort of 879 patients undergoing PMV
authors identified the magnitude of the post-PMV atrial at the Massachusetts General Hospital (Fig. 23.6). Death at
shunt (QP/QS >1.5:1), use of a Bifoil balloon (two balloons on follow-up was directly related to age, post-PMV pulmonary
one shaft) and smaller post-PMV MVA as independent pre- artery pressure, and pre-PMV NYHA functional class IV. In
dictors of the persistence of atrial shunt at long-term the same group of patients, the 12-year event-free survival
follow-up. (alive and free of mitral valve replacement or repair and redo
PMV) was 33% (Fig. 23.7). Cox regression analysis identified
age [risk ratio (RR) 1.02; CI 1.01–1.03; p <.0001], pre-PMV
Clinical Follow-Up NYHA functional class IV (RR 1.35; CI 1.00–1.81; p = .05),
Long-term follow-up studies after PMV are encourag- prior commissurotomy (RR .150; CI 1.16–1.92; p = .002), the
ing.21,22,23,25,26,28,34 Following PMV, the majority of patients echocardiographic score (RR 1.31; CI 1.02–1.67; p = .003), pre-
have marked clinical improvement and are assessed as PMV mitral regurgitation ≥2+ (RR 1.56; CI 1.09–2.22; p = .02),
NYHA class I or II. The symptomatic, echocardiographic, post-PMV mitral regurgitation ≥3+ (RR 3.54; CI 2.61–4.72;
and hemodynamic improvement produced by PMV persists p <.0001), and post-PMV mean pulmonary artery pressure
in intermediate- and long-term follow-up. The best long-term (RR 1.02; CI 1.01–1.03; p < .0001) as independent predictors
results are seen in patients with echocardiographic scores ≤8. of combined events at long-term follow-up.
When PMV produces a good immediate outcome in this Actuarial survival and event-free survival rates through-
group of patients, restenosis is unlikely to occur at follow-up. out the follow-up period were significantly better in patients
Although PMV can result in a good outcome in patients with with echocardiographic scores ≤8. Survival rates were 82%
echocardiographic scores >8, hemodynamic and echocardio- for patients with echocardiographic score ≤8 and 57% for
graphic restenosis is frequently demonstrated at follow-up patients with score >8 at a follow-up time of 12 years (p <
despite ongoing clinical improvement. Table 23.7 shows .0001). Event-free survival (38% versus 22%; p < .0001) at 12
long-term follow-up results of patients undergoing PMV at years’ follow-up were also significantly higher for patients

TABLE 23.7. Clinical long-term follow-up after percutaneous mitral valvuloplasty

Author No. of patients Age Follow-up (years) Survival Event-free survival

Palacios et al. 879 55 12 74% 33%#

Iung et al. 1024 49 10 85% 56%#
Hernández et al. 561 53 7 95%* 69%
Orrange et al. 132 44 7 83% 65%#
Ben Farhat et al. 30 29 7 100% 90%
Stefanadis et al. 441 44 9 98% 75%
* Only cardiovascular death considered.
# Survival without intervention and in NYHA class I to II.
566 chapter 23

100 dent predictor of survival and lack of mitral valve calcifica-

90
p <.0001 tion was the strongest predictor of event-free survival.
Recently, data reported in 96 patients ≥75 years of age
80 have shown that these patients present a lower pre-PMV
Event-free survival (%)

70 MVA (0.8 ± 0.3 vs. 0.9 ± 0.3; p = .005), a lower post-PMV MVA
(1.6 ± 0.6 vs. 1.9 ± 0.7; p < .0001), and a lower procedural
60 Echo score ≤8 success (51.0% vs. 71.4%; p < .0001) compared with patients
50 younger than 75 years of age.51 Patients ≥75 years exhibited
a higher in-hospital mortality than patients younger than 75
40
Total group years (3.1% vs. 0.3%) with no significant differences in the
30 other procedure-related complications (cardiac tamponade,
20 Echo score >8 severe MR, significant left to right shunt, and embolism).
Although, in-hospital mortality was higher, in the majority
10
of these patients PMV was considered as a palliative treat-
0 ment. However, technical complications were similar to
0 20 40 60 80 100 120 140 160 180 those more favorable patients aged <75. Survival and event-
free survival rates were 60% and 49% for patients ≥75 years
Time of follow-up (months)
at a follow-up time of 3 years. The echo score is an imperfect
Figure 23.7. Fifteen-year event-free survival for all patients, and for
predictor of hemodynamic improvement in elderly
patients with echocardiographic score ≤8 and >8, undergoing percu-
taneous mitral balloon valvotomy at the Massachusetts General patients.51,52
Hospital. Unfortunately, no randomized study is available for
elderly patients, and a comparison of the results of PMV with
those of the surgical series is difficult because of the differ-
ences in the patients and surgical techniques involved.
with echocardiographic score ≤8. Similar follow-up studies
have been reported in other series with the double-balloon
Follow-Up of Patients with Calcified
technique and with the Inoue technique of PMV.21,23,25,26 Over
Mitral Valves
90% of young patients with pliable valves, in sinus rhythm
and with no evidence of calcium under fluoroscopy remain The presence of fluoroscopically visible calcification on the
free of cardiovascular events at approximately 5 years mitral valve influences the success of PMV. Patients with
follow-up.17,22,34 heavily (≥3 grades) calcified valves under fluoroscopy have a
Functional deterioration at follow-up is late and related poorer immediate outcome as reflected in a smaller post-
primarily to mitral restenosis.26 The incidence of restenosis, PMV MVA and greater post-PMV mitral valve gradient.
as assessed by sequential echocardiography, is approximately Immediate outcome is progressively worse as the calcifica-
40% after 7 years.25 Repeat PMV can be proposed if recurrent tion becomes more severe. The long-term results of percuta-
stenosis leads to symptoms. At the moment, we have only neous mitral balloon valvuloplasty are significantly different
a small number of series available on redo PMV. They show in calcified and uncalcified groups and in subgroups of the
encouraging results in selected patients with favorable char- calcified group.53 The estimated 2-year survival is signifi-
acteristics when restenosis occurs several years after an cantly lower for patients with calcified mitral valves than for
initially successful procedure, and if the predominant those with uncalcified valves (80% vs. 99%). The survival
mechanism of restenosis is commissural refusion.45 curve becomes worse as the severity of valvular calcification
becomes more severe. Freedom from mitral valve replace-
Follow-Up in the Elderly ment at 2 years was significantly lower for patients with
calcified valves than for those with uncalcified valves (67%
Tuzcu et al.46 reported the outcome of PMV in 99 elderly
vs. 93%). Similarly, the estimated event-free survival at 2
patients (≥65 years of age). A successful outcome (valve area
years in the calcified group became significantly poorer as
≥1.5 cm2 without ≥2+ increase in MR and without left to right
the severity of calcification increased. The estimated event-
shunt of ≥1.5 : 1) was achieved in 46 patients. The best multi-
free survival at 2 years was significantly lower for the calci-
variate predictor of success was the combination of echocar-
fied than for the uncalcified group (63% vs. 88%). The
diographic score, NYHA functional class, and inverse of
actuarial survival curves with freedom from combined
MVA. Patients who had an unsuccessful outcome from PMV
events at 2 years in the calcified group became significantly
were in a higher NYHA functional class, had higher echocar-
poorer as the severity of calcification increased. These find-
diographic scores, and smaller MVAs pre-PMV compared to
ings are in agreement with several follow-up studies of surgi-
those patients who had a successful outcome. Actuarial sur-
cal commissurotomy that demonstrate that patients with
vival and combined event-free survival at 3 years were signifi-
calcified mitral valves had a poorer survival compared to
cantly better in the successful group. Mean follow-up was 16
those patients with uncalcified valves.54,55
± 1 months. Actuarial survival (79% ± 7% vs. 62% ± 10%; p =
.04); survival without mitral valve replacement (71% ± 8% vs.
Follow-Up of Patients with Previous
41% ± 8%; p = .002); and event-free survival (54% ± 12% vs.
Surgical Commissurotomy
38% ± 8%; p = .01) at 3 years were significantly better in the
successful group of 46 patients than the unsuccessful group The PMV also has been shown to be a safe procedure in
of 53 patients. Low echocardiographic score was the indepen- patients with previous surgical mitral commissurotomy.56–61
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 5 67
Although a good immediate outcome is frequently achieved Before and after PMV, patients with higher PVR had a smaller
in these patients, follow-up results are not as favorable as MVA, lower cardiac output, and higher mean pulmonary
those obtained in patients without previous surgical com- artery pressure. For groups I, II, and III, the immediate
missurotomy. Although there is no difference in mortality success rates for PMV were 68%, 56%, and 45%, respectively.
between patients with or without a history of previous surgi- Therefore, patients in the group with severely elevated pul-
cal commissurotomy at 4-year follow-up, the number of monary artery resistance before the procedure had lower
patients who required mitral valve replacement (26% vs. 8%) immediate success rates of PMV. At long-term follow-up
or were in NYHA class III or IV (35% vs. 13%) was signifi- patients with severely elevated pulmonary vascular resis-
cantly higher among those patients with previous commis- tance had a significant lower survival and event-free survival
surotomy. However, when the patients are carefully selected (survival with freedom from mitral valve surgery or NYHA
according to the echocardiographic score (≤8), the immediate class III or IV heart failure).
outcome and the 4-year follow-up results are excellent and
similar to those seen in patients without previous surgical Follow-Up of Patients with
commissurotomy. Tricuspid Regurgitation
The degree of tricuspid regurgitation before PMV is inversely
Follow-Up of Patients with Atrial Fibrillation
related to the immediate and long-term outcome of PMV.
We have reported that the presence of atrial fibrillation is Sagie et al.64 divided patients undergoing PMV at the Massa-
associated with inferior immediate and long-term outcome chusetts General Hospital into three groups on the basis of
after PMV as reflected in a smaller post-PMV MVA and a the degree of tricuspid regurgitation determined by 2D and
lower event-free survival (freedom of death, redo-PMV, and color flow Doppler echocardiography before PMV. Patients
mitral valve surgery) at a median follow-up time of 61 months with severe tricuspid regurgitation before PMV were older,
(32% vs. 61%; p < .0001).62 Analysis of preprocedural and had more severe heart failure symptoms measured by NYHA
procedural characteristics revealed that this association is class, and had a higher incidence of echocardiographic scores
most likely explained by the presence of multiple factors in >8, atrial fibrillation, and calcified mitral valves on fluoros-
the atrial fibrillation group that adversely affect the immedi- copy than patients with mild or moderate tricuspid regurgi-
ate and long-term outcome of PMV. Patients in atrial fibril- tation. Patients with severe tricuspid regurgitation had
lation are older and presented more frequently with NYHA smaller MVAs before and after PMV than the patients with
class IV, echocardiographic score >8, calcified valves under mild or moderate tricuspid regurgitation. At long-term
fluoroscopy, and a history of previous surgical commissur- follow-up, patients with severe tricuspid regurgitation had
otomy. In the group of patients in atrial fibrillation, we iden- significantly lower survival and event-free survival (survival
tified severe post-PMV mitral regurgitation (≥3+) (p = .0001), with freedom from mitral valve surgery or NYHA class III
echocardiographic score >8 (p = .004) and pre-PMV NYHA or IV heart failure). The degree of tricuspid regurgitation can
class IV (p = .046) as independent predictors of combined be diminished when the transmitral pressure gradient is suf-
events at follow-up. The presence of atrial fibrillation per se ficiently relieved with PMV.65
should not be the only determinant in the decision process
regarding treatment options in a patient with rheumatic Follow-Up of the Best Patients for PMV
mitral stenosis. The presence of an echocardiographic score
In patients identified as optimal candidates for PMV, this
≤8 primarily identifies a subgroup of patients with atrial
technique results in excellent immediate and long-term
fibrillation in whom percutaneous balloon valvotomy is very
outcome. Optimal candidates for PMV are those patients
likely to be successful and provide good long-term results.
meeting the following characteristics: (1) age ≤45 years old;
Therefore, in this group of patients, PMV should be the pro-
(2) normal sinus rhythm; (3) echocardiographic score ≤8; (4)
cedure of choice.
no history of previous surgical commissurotomy; and (5) pre-
PMV mitral regurgitation ≤1+ Sellers’ grade. From 879 con-
Follow-Up of Patients with Pulmonary
secutive patients undergoing PMV, we identified 136 patients
Artery Hypertension
with optimal preprocedure characteristics. In these patients,
The degree of pulmonary artery hypertension before PMV is PMV results in an 81% success rate and a 3.4% incidence
inversely related to the immediate and long-term outcome of of hospital combined events (death and/or MVR). In these
PMV.28 Chen et al.63 divided 564 patients undergoing PMV at patients, PMV results in a 95% survival and 61% event-free
the Massachusetts General Hospital into three groups on the survival at 12-year follow-up.28
basis of the pulmonary vascular resistance (PVR) obtained at
cardiac catheterization immediately prior to PMV: group I
The Double Balloon vs. the Inoue Techniques
with a PVR ≤250 dynes-sec/cm−5 (normal/mildly elevated
resistance) comprised 332 patients (59%); group II with a PVR Today, the Inoue approach of PMV is the technique more
between 251 and 400 dynes-sec/cm−5 (moderately elevated widely used. There was controversy as to whether the double-
resistance) comprised 110 patients (19.5%) ; group III with a balloon or the Inoue technique provided superior immediate
PVR ≥400 dynes sec/cm−5 comprised of 122 patients (21.5%). and long-term results. We compared the immediate proce-
Patients in groups I and II were younger, had less severe heart dural and the long-term clinical outcomes after PMV using
failure symptoms measured by NYHA class, and had a lower the double-balloon technique (n = 659) and Inoue technique
incidence of echocardiographic scores >8, atrial fibrillation, (n = 233).66 There were no statistically significant differences
and calcium noted on fluoroscopy than patients in group III. in baseline clinical and morphologic characteristics between
568 chapter 23

the double balloon and Inoue patients. Although the post- ≤8 are similar to that reported after surgical mitral
PMV MVA was larger with the double-balloon technique commissurotomy.28,55,69–76
(1.94 ± 0.72 cm2 vs. 1.81 ± 0.58 cm2; p = 0.01), success rate Restenosis after both closed and open surgical mitral
(71.3% vs. 69.1%; p = NS), incidence of ≥3+ MR (9% vs. 9%), commissurotomy has been well documented.69–76 Although
in-hospital complications, and long-term and event-free sur- surgical closed mitral commissurotomy is uncommonly per-
vival were similar with both techniques. In conclusion, both formed in the United States, it is still used frequently in
the Inoue and the double-balloon techniques are equally other countries. Long-term follow-up of 267 patients who
effective techniques of PMV. The procedure of choice should underwent surgical transventricular mitral commissurot-
be performed based on the interventionist's experience in the omy at the Mayo Clinic showed a 79%, 67%, and 55% sur-
technique. vival at 10, 15, and 20 years, respectively. Survival with
freedom from mitral valve replacement was 57%, 36%, and
24%, respectively.77 At the patient ages in this study, atrial
Echocardiographic and Hemodynamic Follow-Up
fibrillation and male gender were independent predictors of
Follow-up studies have shown that the incidence of hemo- death, whereas mitral valve calcification, cardiomegaly, and
dynamic and echocardiographic restenosis is low after MR were independent predictors of repeat mitral valve
PMV.25,26,67 A study of a group of patients undergoing simul- surgery.
taneous clinical evaluation, 2D-Doppler echocardiography, Because of similar patient selection and mechanism of
and transseptal catheterization 2 years after PMV reported a mitral valve dilatation, similar long-term results should be
90% of patients in NYHA classes I and II and 10% of patients expected after PMV. Indeed, prospective, randomized trials
in NYHA class ≥III.67 In this study hemodynamic determi- comparing PMV and surgical closed or open mitral commis-
nation of MVA using the Gorlin equation showed a signifi- surotomy have shown no differences in immediate and 3-
cant decrease in MVA from 2.0 cm2 immediately after PMV year follow-up results between both groups of patients.29–34
to 1.6 cm2 at follow-up. However, there was no significant Furthermore, restenosis at 3-year follow-up occurred in 10%
difference between the echocardiographic MVAs immedi- and 13% of the patients treated with mitral balloon valvulo-
ately after PMV and at follow-up (1.8 cm2 and 1.6 cm2, respec- plasty and surgical commissurotomy, respectively.33
tively; p = NS). Although there was a significant difference Interpretation of long-term clinical follow-up of patients
in the MVA after PMV determined by the Gorlin equation undergoing percutaneous mitral balloon valvuloplasty as
and by 2D echocardiography (2.0 cm2 vs. 1.8 cm2), there was well as their comparison with surgical commissurotomy
no significant difference between the MVA determined by series are confounded by heterogeneity in patient popula-
the Gorlin equation and the echocardiographic calculated tions. Most surgical series have involved a younger popula-
MVA (1.6 cm2 for both) at follow-up. The discrepancy between tion with optimal mitral valve morphology, with a pliable
the 2D-echocardiographic and Gorlin equation determined valve and no calcification and no evidence of subvalvular
post-PMV MVAs is due to the contribution of left to right disease. Comparisons were also made at the beginning of
shunting (undetected by oximetry) across the created inter- PMV. Therefore, surgeons were more experienced than inter-
atrial communication, which results in both an erroneously ventional cardiologists. Differences in age and valve morphol-
high cardiac output and an overestimation of the MVA by ogy may also account for the lower survival and event-free
the Gorlin equation.68 Desideri et al.50 showed no significant survival in PMV series from the United States and Europe.28
differences in MVA (measured by Doppler echocardiography) Several studies have compared the immediate and early
at 19 ± 6 (range 9–33) months’ follow-up between the post- follow-up results of PMV versus closed surgical commissur-
PMV and follow-up MVAs. Mitral valve areas were 2.2 ± otomy in optimal patients for these techniques. The results
0.5 cm2 and 1.9 ± 0.5 cm2, respectively.50 Echocardiographic of these studies have been controversial, showing either supe-
restenosis (MVA ≤ 1.5 cm2 with >50% reduction of the gain) rior outcome from PMV or no significant differences between
was estimated in 39% at 7 years’ follow-up with the Inoue both techniques.29–34 Patel et al.29 randomized 45 patients
technique.25 A mitral area loss ≥0.3 cm2 was seen in 12%, with mitral stenosis and optimal mitral valve morphology to
22%, and 27% of patients at 3, 5, and 7 years, respectively. closed surgical commissurotomy and to PMV. They demon-
Predictors of restenosis included a post-MVA <1.8 cm2 and an strated a larger increase in MVA with PMV (2.1 ± 0.7 vs. 1.3 ±
echo score >8. 0.3 cm2). Shrivastava et al.30 compared the results of single-
balloon PMV, double-balloon PMV, and closed surgical com-
missurotomy in three groups of 20 patients each. The MVA
PMV vs. Surgical Mitral Commissurotomy
postintervention was larger for the double-balloon technique
Results of surgical closed mitral commissurotomy have of PMV. Postintervention valve areas were 1.9 ± 0.8, 1.5 ± 0.4,
demonstrated favorable long-term hemodynamic and symp- and 1.5 ± 0.5 cm2 for the double balloon, the single balloon,
tomatic improvement from this technique. A restenosis rate and the closed surgical commissurotomy techniques, respec-
of 4.2 to 11.4 per 1,000 patients per year was reported by John tively. On the other hand, Arora et al.31 randomized 200
et al.69 in 3724 patients who underwent surgical closed mitral patients with a mean age of 19 ± 7 years and mitral stenosis
commissurotomy. Survival after PMV is similar to that with optimal mitral valve morphology to PMV and to closed
reported after surgical mitral commissurotomy. Although mitral commissurotomy. Both procedures resulted in similar
freedom from mitral valve replacement and freedom from all postintervention MVAs (2.39 ± 0.9 vs. 2.2 ± 0.9 cm2 for the
events after PMV are lower than reported after surgical com- PMV and the mitral commissurotomy groups, respectively)
missurotomy, freedom from both mitral valve replacement and no significant differences in event-free survival at a
and all events in patients with echocardiographic scores mean follow-up period of 22 ± 6 months. Restenosis docu-
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 569
mented by echocardiography was low in both groups, 5% in the 20th week of pregnancy with minimal radiation to the
the PMV group, and 4% in the closed commissurotomy group. fetus.80–82 Because of the definite risk in women with severe
Turi et al.32 randomized 40 patients with severe mitral steno- mitral stenosis of developing symptoms during pregnancy,
sis to PMV and to closed surgical commissurotomy. The pos- PMV should be considered when the patient is considering
tintervention MVA at 1 week (1.6 ± 0.6 vs. 1.6 ± 0.7 cm2) and 8 becoming pregnant.
months (1.6 ± 0.6 vs. 1.8 ± 0.6 cm2) after the procedures were
similar in both groups. Reyes et al. 33 randomized 60 patients
Conclusions
with severe mitral stenosis and favorable valvular anatomy to
PMV and to surgical commissurotomy. They reported no sig- The PMV should be the procedure of choice for the treatment
nificant differences in immediate outcome, complications, of patients with rheumatic mitral stenosis who are, from the
and 3.5 years’ follow-up between both groups of patients. clinical and morphologic points of view, optimal candidates
Improvement was maintained in both groups, but MVAs at for PMV. Patients with echocardiographic scores ≤8 have the
follow-up were larger in the PMV group (2.4 ± 0.6 vs. 1.8 ± best results particularly if they are young, are in sinus
0.4 cm2). rhythm, and have no pulmonary hypertension and no evi-
Ben Farhat et al.34 reported the results of a randomized dence of calcification of the mitral valve under fluoroscopy.
trial designed to compare the immediate and long-term The immediate and long-term results of PMV in this group
results of double-balloon PMV versus those of open and of patients are similar to those reported after surgical mitral
closed surgical mitral commissurotomy in a cohort of commissurotomy. Patients with echocardiographic scores >8
patients with severe rheumatic mitral stenosis. This group have only a 50% chance to obtain a successful hemodynamic
of patients was from the clinical and morphologic point of result with PMV, and long-term follow-up results are less
view optimal candidates for both PMV and surgical commis- good than those from patients with echocardiographic scores
surotomy (closed or open) procedures. They had a mean age ≤8. In patients with echocardiographic scores ≥12, it is
of less than 30 years, absence of mitral valve calcification on unlikely that PMV could produce good immediate or long-
fluoroscopy and 2D echocardiography, and an echocardio- term results. They preferably should undergo open-heart
graphic score ≤8 in all patients. The results demonstrate that surgery. The PMV could be performed in these patients if
the immediate and long-term results of PMV are comparable they are non–high-risk surgical candidates. Finally, much
to those of open mitral commissurotomy and superior to remains to be done in refining indications for patients with
those of closed commissurotomy. The hemodynamic few or no symptoms and those with unfavorable anatomy.
improvement, inhospital complications, and long-term reste- However, surgical therapy for mitral stenosis should actually
nosis rate and need for reintervention were superior for the be reserved for patients who have ≥2 grades of Sellers’ MR
patients treated with either PMV or open commissurotomy by angiography, which can be better treated by mitral valve
than for those treated with closed commissurotomy. The repair, and for those patients with severe mitral valve thick-
postintervention MVAs achieved with PMV were similar to ening and calcification or with significant subvalvular scar-
the one obtained after open surgical commissurotomy (2.5 ± ring who warrant valve replacement.
0.5 vs. 2.2 ± 0.4 cm2) but larger than those obtained after
closed commissurotomy. These initial changes resulted in
an excellent long-term follow-up in the group of patients Percutaneous Aortic Balloon Valvuloplasty
treated with PMV, which was comparable with the open
commissurotomy group and superior to the closed commis- Aortic valve replacement is the treatment of choice for symp-
surotomy group. The inferior results of closed mitral com- tomatic, severe aortic stenosis in the elderly.82–88 However,
missurotomy presented by Ben Farhat et al. are in disagreement associated major medical comorbid conditions increase peri-
with previous studies showing no significant differences in operative complications significantly, and in some cases, the
immediate and follow-up results between PMV and closed risk is so high that surgeons classify these patients as non-
surgical mitral commissurotomy.29–31 However, the increase surgical candidates. Previous bypass surgery, severe conges-
in MVA after closed commissurotomy is not uniform and tive heart failure, low left ventricular ejection fraction, recent
often unsatisfactory. Since open commissurotomy is associ- myocardial infarction, diabetes mellitus, renal failure, and,
ated with a thoracotomy, need for cardiopulmonary bypass, most of all, emergent operation, are independent predictors
higher cost, longer length of hospital stay, and a longer period for operative death in elderly patients undergoing aortic valve
of convalescence, PMV should be the procedure of choice for replacement. Furthermore, 54% of octogenarians require
the treatment of patients with rheumatic mitral stenosis who concomitant surgical procedures, including coronary artery
are from the clinical and morphologic point of view optimal bypass surgery or mitral valve replacement.89,90 Elective peri-
candidates for PMV.35 operative mortality for octogenarians undergoing aortic valve
replacement and coronary artery bypass graft is 24%.89 Emer-
gent perioperative mortality increases to 37% in patients
PMV in Pregnant Women
with severe congestive heart failure requiring pressors, and
Surgical mitral commissurotomy has been performed in can be as high as 50% in patients with cardiogenic shock.91,92
pregnant women with severe mitral stenosis. Since the risk Finally, complicated postoperative course, including enceph-
of anesthesia and surgery for the mother and the fetus are alopathy with discharge to a rehabilitation facility is present
increased, this operation is reserved for those patients with in 38% of the patients.93
incapacitating symptoms refractory to medical therapy.78–80 Since the initial report by Cribier et al.94 in 1986, per-
Under these conditions, PMV can be performed safely after cutaneous aortic balloon valvuloplasty (PAV) has been
570 chapter 23

TABLE 23.8. Recommendations for percutaneous aortic valvuloplasty in adults with aortic stenosis
Current indication Class Level of evidence

A “bridge” to surgery in hemodynamically unstable patients who are at IIa Grade B

high risk for aortic valve replacement
Palliation in patients with serious comorbid conditions IIb Grade B
Patients who require urgent noncardiac surgery IIb Grade B
An alternative to aortic valve replacement III Grade B

considered a palliative form of treatment for elderly patients Retrograde Technique

with calcific aortic stenosis. It is associated with significant
After crossing the aortic valve and determining resting
immediate clinical and hemodynamic improvement.
hemodynamics, a 0.038-inch Amplatz-type heavy exchange
However, the risk of major complications and the high reste-
wire is advanced through the retrograde catheter and placed
nosis rate during the first year are major limitations of this
into the left ventricular cavity. The retrograde catheter is
technique.95–99 In fact, since PAV does not change the natural
then removed leaving the guidewire across the stenotic aortic
history of severe aortic stenosis,100–103 its use in some institu-
valve coiled in the left ventricular apex. A dilating balloon
tions has been abandoned.104 Therefore, elderly patients with
catheter chosen according to the size of the aortic annulus
profound hemodynamic instability due to severe aortic ste-
is then advanced over the guidewire, placed across the aortic
nosis present a challenging dilemma in critical care medi-
valve, and inflated by hand (Fig. 23.8).
cine. If surgery is not an option, PAV can be effectively used
as a lifesaving procedure for immediate relief of the trans-
Antegrade Technique
aortic valve gradient with subsequent hemodynamic stabili-
zation and further consideration for an elective bridge to The left atrium is entered using transseptal catheterization
aortic valve replacement (Table 23.8). with a modified Brockenbrough needle and a Mullins sheath.
In contrast, balloon valvuloplasty is an efficacious treat- A balloon-wedge catheter is advanced through the Mullins
ment option for adolescents and young adults in their early sheath and passed into the left ventricle and then antegrade
20s with aortic stenosis. Balloon valvuloplasty has resulted through the stenotic aortic valve. A soft 0.038-inch exchange
in good long-term palliation with little morbidity and little wire is advanced through the catheter into the ascending and
or no short- or long-term mortality in these patients. Thus, descending aorta, and the catheter and Mullins sheath are
the indications for intervention are considerably more liberal removed. A chosen dilating balloon catheter is then advanced
than those in older adults (Table 23.9). antegrade across the mitral valve, placed across the aortic
valve, and inflated. A variation of the transseptal antegrade
technique using the Inoue balloon has also been reported.
Technique
With this technique, a 26-mm Inoue balloon catheter (at
The technique of percutaneous balloon aortic valvuloplasty maximum balloon volume of 22 to 25 cc) is advanced ante-
is not complex and can be performed using either the retro- grade over a 0.025-inch exchange-length guidewire that has
grade or the antegrade techniques.95 been advanced transseptally from the right atrium into the

TABLE 23.9. Recommendations for percutaneous aortic valvuloplasty in adolescent or young adults
(£21) with aortic stenosis and normal cardiac output
Current indication Class Level of evidence

Symptoms of angina, syncope and dyspnea on exertion, with I Grade B

catheterization peak gradient >50 mm Hg
Catheterization peak gradient >60 mm Hg I Grade B
New-onset ischemic or repolarization changes on ECG at rest or with I Grade B
exercise (ST depression, T-wave inversion over left precordium)
with a gradient >50 mm Hg
Catheterization peak gradient >50 mm Hg if patient wants to play IIa Grade C
competitive sports or desires to become pregnant
Catheterization gradient <50 mm Hg without symptoms or ECG changes III Grade C
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 571

A B

FIGURE 23.8. Cineangiographic

frames of retrograde percutaneous
aortic balloon valvuloplasty. (A)
The guidewire in place across the
aortic valve with a loop into the
left ventricle. (B) The dilating
balloon catheter is placed across
the aortic valve. (C) The dilating
balloon catheter is partially
inflated across the stenotic aortic
valve. Note the indentation in the
balloon caused by the stenotic
aortic valve. (D) Full inflation of
the dilating balloon across the
aortic valves. C D

left atrium and left ventricle and then antegrade across the With both techniques, multiple balloon inflations are
aortic valve into the ascending and descending aorta. Advanc- performed to relieve the stenosis. To monitor systemic blood
ing of the balloon catheter is facilitated by snaring the guide- pressure during and immediately after balloon inflations, a
wire into the descending aorta from either of the femoral radial arterial line should be in place before the inflations.
arteries (Fig. 23.9). In two thirds of the patients, inflations are well tolerated and

Figure 23.9. Transseptal, antegrade aortic balloon valvuloplasty from the descending aorta with the use of a 5-French Microvena
using the Inoue balloon catheter. Following transseptal left heart snare catheter and the balloon catheter removed. Thereafter, a 26-
catheterization a balloon tip catheter is advanced from the right mm Inoue balloon catheter is advanced antegrade across the aortic
atrium into the left atrium and then across the mitral valve into the valve and inflated at a volume between 20 to 24 cc according to the
ascending and descending aorta across the stenotic aortic valve. A aortic annulus until the indentation produced by the stenotic valve
0.025-inch Amplatzer exchange wire is advanced through the balloon is resolved.
catheter into the ascending aorta. The tip of the guidewire is snared
572 chapter 23

longer balloon inflations (>30 seconds) can be performed. In tion, PAV was performed in patients with severe aortic
the other third of the patients only short balloon inflations stenosis discovered at the time of evaluation for major non-
(15 to 30 seconds) can be performed because of significant cardiac surgery, in 65 patients who presented with symptom-
hypotension during balloon inflation. Short balloon infla- atic aortic valve restenosis after a previous successful
tions and a longer period between inflations are used in procedure (redo-PAV), and in 21 patients who presented in
patients with severe depression of left ventricular ejection cardiogenic shock due to critical aortic stenosis. There were
fraction as well as in patients with severe coronary artery 180 women and 130 men with a mean age of 79 ± 1 (range:
disease or carotid disease. The size of the dilating balloon 35–96) years. Mean left ventricular ejection fraction was 48%
catheter (18 to 25 mm in diameter) is chosen according to the ± 15% (range: 10–81%). Ninety percent of the patients were
size of the aortic annulus (not greater than 100% of annulus) in NYHA functional classes III to IV. All patients had more
determined by 2D-echocardiography or angiography. than one major comorbid condition (average 1.3/patient) at
Hemodynamic measurement and cardiac output using the time of presentation, including chronic renal failure
the thermodilution method are determined before and after (21%), severe chronic obstructive pulmonary disease (21%),
completion of the procedure. For patients with significant peripheral vascular disease (17%), previous stroke (15%),
tricuspid regurgitation or left to right shunting, cardiac cancer (15%), and other major comorbidities (38%; liver
output is determined using the Fick method. The aortic valve failure, hip fracture, pulmonary hemorrhage, pulmonary
area (cm2) is calculated using the Gorlin equation.105 Aortic embolism, Alzheimer’s disease, sepsis, diabetes with multi-
valve resistance (dynes-sec/cm−5) proposed as a better indica- ple organ complications, thyroid disease, bleeding disorders,
tor of the hemodynamic significance of aortic stenosis before incapacitating arthritis, multiple myeloma, and AIDS).
and after PAV, can be calculated as previously described.106 Percutaneous aortic balloon valvuloplasty results in a
Left ventricular ejection fraction is calculated by contrast decrease in aortic gradient and a modest increase in aortic
ventriculography or 2D-echocardiography. valve area in the great majority of patients with degenerative
calcific aortic stenosis. The hemodynamic changes produced
by PAV are shown in Table 23.10. Percutaneous aortic balloon
Mechanism
valvuloplasty resulted in a significant decrease in mean sys-
The final aortic valve area obtained with PAV is most likely tolic aortic gradient from 56 ± 1 to 25 ± 1 mm Hg (p = .0001)
related to the underlying valve pathology.107,108 Fresh post- and a significant increase in both cardiac output from 3.7 ±
mortem studies of patients with degenerative calcific aortic 0.06 to 3.9 ± 0.06 L/min (p = 0.0001) and aortic valve area
stenosis in whom commissural fusion, is minimal have from 0.5 ± 0.01 to 0.9 ± 0.02 cm2 (p = .0001). Failure of PAV
shown that the increase in aortic valve area in these patients (no change in aortic valve area) occurred in only 3% of the
occurs as the result of fracture of calcium deposit in the patients. An aortic valve area ≤0.7 cm2 was obtained in about
aortic leaflets.108 In patients with commissural fusion such 38% of the patients. An aortic valve area >0.7 cm2 was
as rheumatic aortic stenosis and some patients with noncal- obtained in 59% of the patients, including 27% of patients
cific bicuspid valve stenosis, PAV produces commissural in whom PAV results in an aortic valve area ≥1.0 cm2. The
splitting with or without cuspal crack. In addition, PAV pro- increase in aortic valve area with PAV is inversely related to
duces stretching of the aortic wall at nonfused commissural the NYHA functional class before PAV and to the severity
sites. Stretching is probably transient and is responsible for of aortic stenosis as reflected in higher aortic gradient and
the cases of early restenosis seen in some patients. Although smaller aortic valve area before PAV.
opening of fused commissures is probably the most effective
mechanism of PAV, commissure fusion seldom occurs in the
Complications
elderly with calcific aortic stenosis.109
Procedural mortality (death in the catheterization labora-
tory) occurred in 12 patients (3%), in-hospital (30-day) mor-
Immediate Results
tality occurred in 34 patients (8.6%); and local vascular
Between February 1986 and February 1993, 394 PAV proce- complications in 49 patients (12%), including the need for
dures were performed at the Massachusetts General Hospital vascular surgery in 38 patients (9.6%), two of whom required
in 310 symptomatic patients with severe, calcific, aortic ste- leg amputation (0.5%). Cerebrovascular accident occurred in
nosis.101 The patients were considered nonsurgical or very five patients (1.2%), severe aortic regurgitation in six patients
high risk surgical candidates at the time of presentation (1.5%), acute renal failure in seven patients (1.7%), significant
because of associated major comorbid conditions. In addi- atrial septal defect in two patients (0.5%) who had antegrade

TABLE 23.10. Immediate results of percutaneous aortic valvuloplasty101

Variable Pre-PAV Post-PAV p value

Mean aortic gradient, mm Hg 56 ± 1 25 ± 1 .0001

Cardiac output, L/min 3.7 ± 0.1 3.9 ± 0.1 .0001
Aortic valve area, cm 2 0.49 ± 0.01 0.87 ± 0.02 .0001
Systolic aortic pressure, mm Hg 129 ± 2 144 ± 2 .0001
Systolic pulmonary artery pressure, mm Hg 49 ± 1 45 ± 1 .003
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 573
PAV, cholesterol emboli in three patients (0.8%), nonfatal
ventricular fibrillation in seven patients (1.7%), myocardial 1.0
infarction in six patients (1.5%), and left ventricular perfora-
tion in one patient (0.2%).101 0.8 AVA ≥ 1.0 cm2
AVA 0.8 - 0.9 cm2
AVA ≤ 0.7 cm2
Long-Term Follow-Up 0.6
%
Although PAV results in immediate hemodynamic and
symptomatic improvement in the great majority of patients, 0.4
the long-term results of PAV show that clinical restenosis
occurs frequently 6 to 12 months after PAV.102,104 Estimated 0.2
actuarial survival at 1-, 3-, and 5-year follow-up of the Mas-
sachusetts General Hospital series were 55% ± 3%, 25% ± 0
3%, and 22% ± 3%, respectively (Fig. 23.10). The correspond- 0 4 8 12 16 20 24 28 32 36 40
ing estimated actuarial event-free survival were 33% ± 2%, Months FIU
13% ± 2%, and 2% ± 1%, respectively (Fig. 23.11). Clinical FIGURE 23.11. Curves for clinical restenosis after PAV for patients
follow-up of the patients who have undergone percutaneous with severe aortic stenosis treated with percutaneous aortic balloon
aortic valvuloplasty have demonstrated that cardiac mortal- valvuloplasty at the Massachusetts General Hospital. Curves for
ity and clinical restenosis (defined as cardiac mortality and three different post-PAV aortic valve areas achieved with the proce-
dure are shown. AVA, aortic valve area post-PAV.
patients returning to the pre-PAV NYHA functional class)
after balloon valvuloplasty is very high. Although mortality
is greater in those patients in whom PAV resulted in an aortic
valve area <0.7 cm2 than in those with post-PAV valve areas
>0.7 cm2 (Fig. 23.10), the survival curve of the natural history of instruments were accompanied by a high rate of resteno-
of patients with severe aortic stenosis treated medically is sis. Healing of the fracture calcium nodules could be expected
unaffected by balloon valvuloplasty. The presence of left to occur early after PAV, resulting in the high incidence of
ventricular dysfunction and the presence of coronary artery restenosis. However, it is possible that if commissure split-
disease adversely affect the prognosis of patients undergoing ting had occurred at the time of PAV, restenosis may not be
PAV. The decrease in aortic valve area at follow-up is inversely as rapid. Although only speculative, this mechanism may
related to the post-PAV aortic valve area (Fig. 23.10). One-year account in part for those patients with a superior long-term
clinical restenosis is greater in patients in whom post-PAV result.
aortic valve area was ≤0.7 cm2 than in those in whom post-
PAV aortic valve area was >0.7 cm2. A high restenosis rate
PAV as a Bridge to Aortic Valve Replacement
(>50%) was also present in patients who have a second or
third PAV with larger balloon sizes. From our cohort of 310 patients who underwent PAV at the
A high incidence of restenosis after PAV in elderly patients Massachusetts General Hospital, there were 40 patients
with calcific aortic stenosis is not unexpected. Previous (13%), 21 men and 19 women, mean age of 75 ± 2 years, who
attempts at surgical aortic valvuloplasty using a wide variety underwent aortic valve replacement 6 ± 1 months after PAV.101
When compared with the group that did not undergo aortic
valve replacement after PAV (n = 270), the group of patients
bridged to surgery were younger (p = .003), had a higher
1.0 cardiac output (p < .003), higher aortic valve area (p = .006),
and higher left ventricular end diastolic pressure (p < .034)
before PAV. Left ventricular ejection fraction was similar in
0.8 AVA ≥ 1.0 cm2
AVA 0.8 - 0.9 cm2 both groups. With PAV, the mean aortic gradient decreased
AVA < 0.7 cm2 from 57 ± 3 to 26 ± 2 mm Hg (p < .001), the cardiac output
0.6 increased from 4.2 ± 1 to 4.5 ± 1 L/min (p = .11), and the aortic
% valve area increased from 0.6 ± 0.04 to 1.0 ± 0.07 cm2 (p <
0.4 .001). Patients who underwent aortic valve replacement had
both higher cardiac output (p < .001) and larger aortic valve
area (p = .03) after PAV than the group of patients that did
0.2 not undergo surgery. In-hospital surgical mortality was 10%.
There were seven deaths occurring at 18 ± 6 months after
0 PAV. There was a significant improvement in symptoms after
0 4 8 12 16 20 24 28 32 36 40
aortic valve replacement. At a mean follow-up of 35 ± 3
Months FIU
months, 87% of the patients bridged to aortic valve replace-
FIGURE 23.10. Actuarial survival curves for patients with severe ment after PAV were in NYHA class I-II and 13% were in
aortic stenosis treated with percutaneous aortic balloon valvulo- class III-IV. As shown in Figure 23.12 estimated actuarial
plasty at the Massachusetts General Hospital. Curves for three dif-
ferent post–percutaneous aortic balloon valvuloplasty (PAV) aortic survival curves at 1, 3, and 5 years were significantly better
valve areas achieved with the procedure are shown. AVA, aortic for the group of patients bridged to aortic valve replacement
valve area post-PAV. after PAV.
5 74 chapter 23

100 Actuarial survival was 38% ± 11% at 27 months’ follow-

up. Cox regression analysis identified post-PAV cardiac index
PAV + AVR as the only predictor for longer survival (p = .02). Although
80
high, the procedure-related mortality after PAV in this group
of patients with cardiogenic shock compares favorably with
Survival (%)

60 the extremely high mortality rate reported in previous surgi-

cal studies in patients with cardiogenic shock and severe
p = .0001 aortic stenosis.91,92 Even though surgical correction with
40
aortic valve replacement is the only therapy that alters the
natural history of severe, symptomatic aortic stenosis in the
20 PAV elderly, there are important guidelines that have to be kept
in mind when managing elderly patients with cardiogenic
shock due to critical aortic stenosis: (1) sustained hypoten-
0
1 4 8
12 16 20 24 28 32 36 sion-associated severe congestive heart failure constitutes a
Time (months) medical emergency, and pharmacologic therapy and bedside
FIGURE 23.12. Comparative actuarial survival for patients under- hemodynamic monitoring should be started immediately; (2)
going percutaneous aortic balloon valvuloplasty at the Massachu- there is no time for procrastination, and emergent interven-
setts General Hospital as a bridge to aortic valve replacement with tional therapy (PAV or aortic valve replacement) should
those who did not undergo AVR.
be done as soon as possible; (3) PAV should be considered
as a bridge to aortic valve replacement, and aortic valve re-
placement with myocardial revascularization, if needed,
PAV for Patients in Cardiogenic Shock
should be performed early after percutaneous balloon
Percutaneous aortic balloon valvuloplasty can be performed valvuloplasty.
successfully in patients with cardiogenic shock due to severe
aortic stenosis.110 In these patients, PAV resulted in a signifi-
cant decrease in aortic gradient and a significant increase in Palliation PAV
aortic valve area and systolic arterial pressure in 90% of Percutaneous aortic balloon valvuloplasty is a palliative
these moribund patients. From our cohort of 310 patients treatment for adult patients with aortic stenosis who are not
who underwent PAV at the Massachusetts General Hospital, candidates for aortic valve replacement.94,104,110 It provides
there were 21 patients, 10 men and 11 women, mean age of immediate hemodynamic and clinical improvement with a
74 ± 3 (range 35–90) years, mean left ventricular ejection low incidence of life-threatening complications. However,
fraction of 29% ± 3% (range 15–61%) who underwent PAV for the major limitation of PAV is the high incidence of resteno-
cardiogenic shock. All patients met the following criteria of sis within 1 year after the procedure. Although PAV results
cardiogenic shock: (1) sustained arterial hypotension with in immediate hemodynamic and symptomatic improvement
systolic blood pressure <90 mm Hg despite maximal inotro- in the great majority of patients, the long-term results of PAV
pic and pressor pharmacologic support; (2) cardiac index show that clinical restenosis occurs frequently 6 to 12
<2.2 L/min/m2; (3) mean pulmonary capillary wedge pressure months after PAV.
or left ventricular end-diastolic pressure (LVEDP) >20 mm Hg;
(4) urinary output <0.5 mL/kg/h; and (5) clinical evidence of
decreased tissue perfusion. PAV for Patients Undergoing Emergency
Before PAV, patients with cardiogenic shock exhibit a Noncardiac Surgery
lower left ventricular ejection fraction (p = .001), and lower
cardiac index (p < .0003) than the group of patients without Some studies have shown that patients with severe aortic
cardiogenic shock. Percutaneous aortic balloon valvuloplasty stenosis undergoing noncardiac surgery could benefit from
resulted in a significant reduction in mean aortic gradient PAV, resulting in a significant improvement in aortic valve
from 49 ± 4 to 21 ± 3 mm Hg (p = .0001), a borderline improve- gradient and aortic valve area with very low complications
ment in cardiac index from 1.8 ± 0.1 to 2.2 ± 0.1 L/min/m2 during noncardiac surgery.111–113 However, O´Keefe et al.,114 in
(p = .06), and a significant improvement in aortic valve area 48 patients with severe aortic stenosis who underwent non-
from 0.5 ± 0.04 to 0.8 ± 0.06 cm2 (p = .0001) in the group of cardiac surgery without preoperative PAV, found no major
patients presenting in cardiogenic shock. Sixteen of these perioperative complications if patients were managed with
patients were successfully weaned from the inotropic support careful monitoring of systemic and pulmonary artery pres-
in the first 24 hours after the valvuloplasty procedure. Com- sure during anesthesia. Therefore, PAV should be limited to
plications in this cohort of patients included procedural mor- those patients with critical aortic stenosis and low ejection
tality in two patients (9.5%), total in-hospital (30-day) fraction, heart failure, or cardiogenic shock, in whom tran-
mortality in nine patients (43%), local vascular complica- sient hemodynamic improvement may decrease the risk of
tions in five patients (24%), local vascular surgery in three perioperative complications.
patients (14%), cerebrovascular accident in one patient (5%),
severe aortic regurgitation in one patient (5%), and choles-
terol embolization in one patient (5%). The major cause of
PAV in Pregnant Women
in-hospital mortality was multiorgan failure despite success- As aortic stenosis in pregnant patients is most commonly
ful PAV. bicuspid with two commissures, PAV should provide effec-
 b a l l o o n d i l a t a t i o n o f t h e c a r d i a c va lv e s 5 75
tive gradient relief in these patients. However, only very aortic stenosis is short lived, it provides a window of oppor-
limited information is available.115,116 tunity, making this technique an attractive alternative for a
select group of patients with symptomatic calcific aortic
stenosis. Today, the PAV indications for patients with severe
PAV for Patients with Congenital Aortic Stenosis degenerative aortic stenosis include the following:
1. Patients who are not surgical candidates or are very
Lababidi et al.119 introduced balloon aortic valvuloplasty
high risk surgical candidates and are incapacitated by symp-
for congenital valvular aortic stenosis in 1984. The aortic
toms of aortic stenosis: Consultation with a cardiac surgeon
valve in patients with congenital aortic stenosis is most
is recommended to identify patients who are truly not can-
commonly bicuspid with two commissures, less frequently
didates for cardiac surgery. Elderly patients with aortic ste-
is unicommissural or noncommissural, and rarely is
nosis should not be denied the opportunity for aortic valve
tricuspid with fusion of one or more of the three commis-
replacement solely on the basis of age.
sures. Balloon valvuloplasty in this patient population
2. As a bridge to aortic valve replacement in patients with
provides effective gradient relief with minimal restenosis
calcific aortic stenosis who require urgent major noncardiac
at follow-up, though progressive aortic insufficiency has
surgical intervention for other organ dysfunction: These
been reported.11,117–122 In this patient cohort, PAV is a
patients may have PAV done to transiently improve their
good alternative to surgical valvuloplasty, and this later
hemodynamics, and therefore, the safety of their urgent
technique should be reserved for those patients with con-
major surgical procedure. After recovery from this surgery,
genital aortic stenosis in whom PAV is unsuccessful or
the decision to replace the aortic valve should be made.
impossible (Table 23.9). Complications are rare and most of
3. As a bridge to aortic valve replacement in patients with
them transient. Arterial access problems due to the large
severe heart failure or cardiogenic shock due to aortic
balloon size are the most common complications. The inci-
stenosis.
dence of a degree of aortic regurgitation post-PAV is compa-
4. In patients with “the Gorlin conundrum” character-
rable to that associated with surgical open valvuloplasty.
ized by poor left ventricular function, low cardiac output,
Appropriate balloon sizing (a balloon diameter equal to or
and small transaortic gradient whose calculated aortic valve
less than the aortic annulus measured by echocardiography
areas by the Gorlin formula are small: In these patients, the
or cineangiography) is essential to decrease the incidence of
low left ventricular ejection fraction could be secondary to a
severe aortic regurgitation and or disruption of the aortic
myopathic left ventricle with an aortic valve that is not ste-
annulus after PAV.
notic, but with a low flow state that results in a falsely low
calculated aortic valve area, or secondary to afterload mis-
match due to severe stenotic aortic valve. In the former,
Patient Selection
surgery will not be of benefit and the surgical risk is very
It is well known that the onset of symptoms in patients high, and in the latter, aortic valve replacement should be
with severe aortic stenosis begins after a latent period of performed. A PAV can be used to solve this dilemma. Improve-
several years, during which increasing left ventricular ment of left ventricular ejection fraction after a successful
obstruction and myocardial overload occurs.123 After the PAV indicates that aortic stenosis was present and the patient
onset of symptoms, the prognosis of patients with aortic should undergo aortic valve replacement. In contrast, the
stenosis without aortic valve replacement is very poor. lack of improvement in the left ventricular ejection fraction
The 5-year survival is less than 50% when congestive after a successful PAV indicates that aortic stenosis was
heart failure, syncope, or angina develops in patients treated never present and the patient was suffering from a cardiomy-
medically. Congestive heart failure carries the worse opathy. Under these later conditions, aortic valve replace-
prognosis; the 50% survival of these patients is 2 years ment should not be performed.
if surgery is not performed. Thus, once symptoms
develop, medical therapy has a limited role in the treatment
of patients with aortic stenosis. Aortic valve replacement
is the treatment of choice for these patients. This technique
has been clearly demonstrated to change the natural Percutaneous Tricuspid Balloon Valvuloplasty
history of patients with severe aortic stenosis. Aortic
valve replacement can be performed with low operative mor- Tricuspid stenosis is rare and is associated with mitral ste-
tality and morbidity. Follow-up studies of these patients dem- nosis. Percutaneous tricuspid balloon valvuloplasty (PTV)
onstrated significant improvement in symptoms and has been performed in few isolated cases with good
excellent long-term survival. Although aortic valve replace- outcome.124–126 Because of the large tricuspid annulus, the
ment in elderly patients, particularly those octogenarians double-balloon technique is preferable. Results from PTV
with severe aortic stenosis, is associated with a greater mor- have been similar to those reported for surgery. The PTV
bidity and mortality, it can be performed safely with low results in a dramatic clinical and hemodynamic improve-
mortality in a selected group of these patients. Furthermore, ment in patients with tricuspid stenosis. With PTV, there is
after surgery, the survival of these patients is not different a decrease in tricuspid gradient and an increase in cardiac
from the survival of other octogenarians with no cardiac output. Significant tricuspid regurgitation rarely occurs, and
diseases.93 restenosis at follow-up is infrequent. Patients with associated
Although the hemodynamic and clinical improvement moderate or severe tricuspid regurgitation are not candidates
produced by PAV in more patients with degenerative calcific for PTV.
5 76 chapter 23

Future Research 12. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N.

Clinical application of transvenous mitral commissurotomy by
a new balloon catheter. J Thorac Cardiovasc Surg 1984;87:
After more than 15 years of extensive clinical evaluation, the
394–402.
technique of percutaneous valvuloplasty, which for practical 13. Lock JE, Kalilullah M, Shrivastava S, Bahl V, Keane JF. Percu-
purposes can be summed up as PMV, has a significant place in taneous catheter commissurotomy in rheumatic mitral steno-
the treatment of mitral stenosis. Pragmatically, a larger use of sis. N Engl J Med 1985;313:1515–1518.
PMV will depend on the solution of economic problems that 14. Al Zaibag M, Ribeiro PA, Al Kassab SA, Al Fagig MR. Percu-
limit the use of the technique in the countries in which rheu- taneous double balloon mitral valvotomy for rheumatic mitral
matic disease is still endemic but in which means are lacking. stenosis. Lancet 1986;1:757–761.
In the industrialized countries, the debate on the use of PMC 15. Palacios I, Block PC, Brandi S, et al. Percutaneous balloon val-
in patients with unfavorable anatomy will require further votomy for patients with severe mitral stenosis. Circulation
1987;75:778–784.
studies, including a large number of patients and a long follow-
16. McKay CR, Kawanishi DT, Rahimtoola SH. Catheter balloon
up. Further proof of the efficacy of PMV in the prevention of
valvuloplasty of the mitral valve in adults using a double
embolism and atrial fibrillation are necessary to further balloon technique. Early hemodynamic results. JAMA
extend the indications to asymptomatic patients. New tools, 1987;257:1753–1761.
such as 3D-echocardiography, may help to refine patient selec- 17. Cohen DJ, Kuntz RE, Gordon SPF, et al. Predictors of long-term
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19. Chen CR, Cheng TO. Percutaneous balloon mitral valvulo-
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still has a place. It would, however, appear important to evalu- surotomy. A report from the National Heart, Lung, and Blood
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Gynecol 1993;169:540–545. 126. Shaw TRD. The Inoue balloon for dilatation of the tricuspid
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 2 Valvular Heart Disease:
4 Surgical Treatment
William E. Cohn, O.H. Frazier, and
Denton A. Cooley

General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586

Mitral Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583 Redo Valve Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Tricuspid Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588

Key Points surotomy, posterior leaflet resection, and annuloplasty.

When deterioration is advanced, valve replacement is
• In adults in the Western world, cardiac valve lesions are
often unavoidable.
usually caused by degenerative heart disease, which pro-
• Recent techniques using artificial chordae tendineae
duces aortic valve stenosis and insufficiency and mitral
have expanded the indications for mitral valve repair.
insufficiency.
• Tricuspid valve disease can be alleviated by an annulo-
• In developing countries, rheumatic heart disease is the
plasty, a valvotomy, both of these procedures, or valve
most frequent cause of valve lesions, including stenosis,
replacement. Functional tricuspid insufficiency accom-
insufficiency, or both. It is the leading cause of mitral
panying mitral stenosis will sometimes resolve after cor-
stenosis.
rection of the mitral condition.
• A common cause of aortic stenosis is a congenitally
• Postoperatively, the main complication of valve replace-
bicuspid aortic valve that calcifies later in life.
ment is thromboembolism, which is associated mostly
• Myocardial ischemia, as well as nonischemic cardiomy-
with mechanical prostheses, especially in the mitral posi-
opathy, can alter mitral valve geometry and result in
tion. Patients with mitral mechanical prostheses should
severe mitral regurgitation.
routinely take an anticoagulant such as sodium warfarin.
• Treatment should be considered for any patient with
In addition, those with aortic mechanical prostheses should
symptoms of heart valve disease.
undergo long-term anticoagulation. Most patients with
• Asymptomatic patients with critical aortic stenosis
chronic atrial fibrillation should also receive warfarin.
should be referred for surgical intervention. In these
• For redo valve procedures, the operative mortality is
cases, the onset of symptoms (chest pain, congestive
increased, particularly in patients with poor cardiac
heart failure, and syncope) is associated with poor sur-
functional status and a need for emergency surgery.
vival without surgery.
• Limited-access heart valve surgery, with the use of a
• Asymptomatic patients with aortic insufficiency should
small incision, is gaining popularity. It may be performed
be referred for surgery on the basis of enlarged left ven-
via the port access approach, which entails peripheral
tricular size on echocardiography.
perfusion and use of a balloon catheter for aortic occlu-
• In adults, symptomatic aortic valve disease almost always
sion; with standard cannulation and a specially designed
necessitates valve replacement.
aortic cross-clamp; or with a combination of these two
• Stenotic mitral valves can often be repaired by interven-
approaches. The results are similar to those obtained in
tional cardiologists, using a double-balloon valvotomy
conventional procedures using a sternotomy, but some
technique.
patients report less musculoskeletal discomfort after the
• Balloon valvotomy has fallen into disfavor for repairing
limited-access procedure.
stenotic aortic valves, because the results are not long
• A number of promising new catheter-based valve-
lasting.
treatment technologies are on the medical horizon but
• When mitral valve surgery is necessary, repair is pre-
are not yet ready for clinical use.
ferred over valve replacement.
• If the anterior leaflet is relatively normal, most mitral Although the first direct attack on valvular heart disease
lesions can be repaired by means of a combined commis- occurred in the 1920s, valve surgery was not taken seriously

5 81
582 chapter 24

by most surgeons until World War II, when Harken1 success-

fully removed foreign bodies from the heart. Once surgeons
realized that the heart could be operated on successfully,
attention turned toward correcting congenital defects,
including valve stenosis and insufficiency, and modern valve
surgery began to evolve. In the late 1940s, Harken et al.,2
Bailey,3 and Brock’s group4 reported the successful repair of
mitral valve disease. Not until the development of cardiopul-
monary bypass and open-heart surgery in the 1950s, however,
were surgeons able to attack acquired valve disease. By the
end of that decade, the caged-ball valve design, pioneered by
Harken, Starr, and Edwards, made valve replacement possi-
ble. The ensuing decades have seen a continual advancement
in valve prostheses and repair techniques. More than 300,000
patients worldwide were expected to undergo heart valve
surgery in 2004.5
Of the 2,500 open-heart operations performed each year
at the Texas Heart Institute in Houston, Texas, about 20%
involve the repair of valve lesions. This chapter describes our
standard surgical approaches for treating acquired valvular FIGURE 24.1. The On-X® Prosthetic Heart Valve, aortic position.
heart disease.6–13

General Considerations made with pyrolytic carbon (Fig. 24.1). When valve replace-
ment is unavoidable, we prefer bileaflet mechanical pros-
Whereas the aortic and mitral valves may be diseased either theses in our younger patients. These valves are reliable
alone or in combination, the tricuspid valve is rarely subject and have a low profile, excellent hemodynamic qualities,
to isolated disease, except when affected by endocarditis, as and an extremely low incidence of complications, including
often seen in intravenous drug abusers. thromboembolism.
Today, diseased stenotic valves can often be repaired non- Bioprostheses are less durable than mechanical valves
surgically by interventional cardiologists, using a double- and are vulnerable to structural deterioration and calcifica-
balloon valvotomy technique. Although highly successful tion, which occurs mainly in adolescent patients. The newer
for repairing the stenotic mitral valve, this approach is less generation of bioprosthetic valves offers longer operative-free
useful for aortic valve repair, because its benefits are not long survival than previous models, especially in the aortic posi-
lasting; after the procedure, many patients have a decreased tion (Fig. 24.2). As a result, the age of patients considered
gradient across the aortic valve, but this effect has been candidates for these valves has been gradually lowered.
reported to last for only a short time.14–17 Complications of Today, to avoid the need for anticoagulants, many younger
balloon mitral valvuloplasty include regurgitation, annular patients opt for a bioprosthesis and accept the risk of requir-
rupture, and an atrial septal defect. ing a reoperation at some later date.
When valve surgery becomes necessary, the indications
should be based on symptoms, as well as physiologic and
pathologic findings, and the risk-benefit ratio should be care-
fully examined in each case. Unfortunately, few evidence-
based guidelines are available to facilitate surgical decision
making in valvular heart disease.
The optimal surgical approach depends on the degree of
physiologic disturbance, the extent and nature of the patho-
logic changes, and the expertise of the surgeon. Whenever
possible, we perform valve repair rather than replacement.
Repair has a number of advantages, eliminating not only the
need for lifelong anticoagulation but also the threat of
mechanical dysfunction and paravalvular leakage. Trans-
esophageal echocardiography is becoming widely used intra-
operatively for assessing the valve anatomy before repair and
for determining the adequacy of repair at the end of the
procedure.
Since the advent of valve replacement surgery, much
experience has been gained with both mechanical and bio-
prosthetic valves. Either type of valve has benefits and draw- FIGURE 24.2. Mosaic UltraTM porcine bioprosthetic valve (Med-
backs. Early mechanical valves were vulnerable to mechanical tronic, Inc., Minneapolis, MN) being maneuvered into position in a
failure, but today’s models are quite durable, especially when patient undergoing aortic valve replacement.
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t 583
After trying various methods of suturing valve prosthe- Mitral Repair Techniques
ses, some surgeons at our institution have reverted to using
The time-honored method for alleviating “pure” mitral ste-
a continuous monofilament polypropylene suture in some
nosis with minimal or no calcification is a commissurotomy
cases.12 This simple technique expedites implantation in any
with subvalvular dissection of fibrosed chordae tendineae
valve position and provides even more security than do indi-
and papillary muscles. Usually, the valve is fused at both
vidual mattress sutures. The continuous-suture technique
commissures and has a slit-like opening. Freeing the fused
also eliminates the need for porous felt pledgets, which can
commissures produces a functional, near-normal valve.
become a source of infection.
Although a closed commissurotomy is possible with the
To prevent infective endocarditis, we routinely adminis-
aid of a transventricular dilator, we always perform an
ter bactericidal antibiotics to all patients undergoing pros-
open procedure with cardiopulmonary bypass support. This
thetic valve replacement. Antibiotics are given before surgery
approach enables us not only to assess the extent of disease
and are continued until all catheters are removed.
and determine the best operative strategy but also to perform
The valve is approached through a standard median ster-
an anatomic repair. Moreover, the open approach facilitates
notomy. After heparin (3 mg/kg) has been administered,
accurate division of the commissure and allows left atrial
access to the systemic arterial system is gained by cannulat-
thrombi to be extracted.
ing the ascending aorta. Cannulation for venous outflow
depends on which valve is involved. For aortic valve proce-
Mitral Valve Replacement
dures, we position the tip of a single right atrial cannula in
the orifice of the inferior vena cava so that some of the per- For patients with extensive calcification or severe fibrotic
forations are in the right atrium. For single or combined distortion, especially in the subvalvular area, valve replace-
procedures involving the mitral valve, the venae cavae are ment is the only option.
often cannulated separately. Recently, it has become clear that, to ensure maximal
In patients undergoing valve replacement, we routinely postoperative ventricular function, the chordal attachments
use moderate systemic hypothermia and cardiac hypother- to papillary muscles should be preserved.18–20 Therefore,
mia as well as a membrane oxygenator. Patients with severe insofar as possible, we remove only the anterior mitral leaflet,
left ventricular hypertrophy may benefit from the addition sparing the posterior leaflet and the chordal attachments.
of propranolol to the cardioplegic solution (approximately In excising the mitral valve, the surgeon must take care
1 mg for a normal adult). In such patients, retrograde coro- not to damage the posterior annulus, which can rupture if
nary sinus blood cardioplegia may also be useful for myocar- an oversized valve is inserted or excessive tissue removed.
dial protection. Our cardiopulmonary bypass time rarely (This uncommon complication is most frequently seen
exceeds 1 hour. in patients with severe annular calcification and is asso-
In combined mitral and aortic procedures, the mitral ciated with a high operative mortality.) Furthermore,
valve is treated first. Traditionally, double valve replacement the nearby circumflex coronary artery may be injured if
necessitates two separate incisions to visualize the valve sutures are placed too deeply during valve replacement or
apparatus. When this approach is impractical, as in patients annuloplasty.
who have undergone a previous median sternotomy, the The valve is usually approached through a standard left
mitral valve can be replaced through the aortic root after the atrial incision. If the case is complex, however, or if the
aortic valve has been excised.7 patient has undergone previous mitral surgery, a transseptal
route may be more appropriate. For combined mitral-aortic
procedures, a single transverse aortotomy can be used, as
Mitral Valve described above.

The mitral valve may be affected by stenosis, insufficiency,

Mitral Insufficiency
or both. The type of surgical treatment depends on the opera-
tive findings. Many mitral lesions can be repaired by means
Indications for Surgery
of a commissurotomy, posterior leaflet resection, and annu-
loplasty. When deterioration is advanced, however, valve Close follow-up observation is essential for patients with
replacement may be unavoidable. mitral insufficiency. If regurgitation is mild (1 to 2+), surgery
may be postponed indefinitely. However, operation should
be considered for patients with moderately severe or severe
Mitral Stenosis
(3 to 4+) regurgitation or for any patient with atrial fibrilla-
tion, increasing pulmonary hypertension, or disabling
Indications for Surgery
symptoms. For those with infective endocarditis, surgery
Surgery should be considered for any patient with symptom- can be performed electively if antibiotic therapy is success-
atic mitral stenosis, including persons in New York Heart ful; otherwise, emergency valve replacement is usually
Association (NYHA) class III or IV who have atrial fibrilla- necessary.
tion, increasing pulmonary hypertension, systemic emboli- According to Haan and colleagues,21 the following vari-
zation, or infective endocarditis. In addition, class II patients ables are associated with a heightened operative risk: age >75
should be considered for surgery if they are older than 40 years, renal failure, and the need for an emergent or a salvage
years, have a significantly reduced valve area, or have valve- procedure. These researchers found that for most patients
related lifestyle limitations. with ventricular dysfunction, mitral valve surgery did not
584 chapter 24

entail a prohibitive operative risk. In fact, mortality rates

remained fairly constant regardless of the ejection fraction
for low-risk to medium-risk patients, increasing only in the
high-risk category (predicted risk >10%). Various recent mitral
valve surgery series involving patients with an ejection frac-
tion of <20% have had an operative mortality of <2%.22,23 In
this respect, clinical experience is at variance with the Amer-
ican College of Cardiology (ACC)/American Heart Associa-
tion (AHA) guidelines,24 which state that valve replacement
for mitral insufficiency should be performed only in patients
who have an ejection fraction of at least 30%.

Mitral Valve Repair

In many series, repair is appropriate for incompetent non-
rheumatic mitral valves in more than 90% of the cases. As
long as the anterior leaflet is functional, there are no absolute
contraindications to reconstruction.25 Compared with valve
replacement, repair is associated with improved left ven-
tricular function and better long-term survival. A variety
of reconstructive techniques have been described.18,26–30
Although we still occasionally perform annuloplasty by
means of commissural plication, we prefer to insert an
annuloplasty ring or a posterior annuloplasty band (Fig. 24.3).
Both of these methods reduce the annular circumference
without necessitating the placement of restrictive sutures
in either the anterior leaflet or the anterior portion of the
annulus.
We also use an annuloplasty ring to treat mitral incom-
petence secondary to valve prolapse. Depending on the
surgeon’s preference, a Carpentier, Cooley, Duran, or Puig-
Massana-Shiley ring11 or a Cosgrove band can be used. The
device reduces the overall circumference of the annulus, FIGURE 24.3. Mitral valve repair involving wedge resection of the
eliminating prolapse of the posterior leaflet. We occasionally posterior leaflet and continuous suturing of an annuloplasty ring in
use a cut section of a 22-mm Dacron graft. This ring is simple place.
and inexpensive to produce.
In patients with ischemic mitral regurgitation, the valve
structure tends to be normal. When these patients have
annular dilatation or ruptured chordae tendineae on the prolapsed anterior leaflet. Later, this technique was applied
posterior leaflet without calcification or leaflet fibrosis, an to other conditions involving mitral insufficiency. When per-
annuloplasty and leaflet repair or resection are usually formed with a septal myectomy, the edge-to-edge technique
satisfactory. To decrease the overall annular circumference, addresses both causes of dynamic obstruction in hyper-
we again insert an annuloplasty ring, thereby making the trophic cardiomyopathy. By sparing the natural valve and
best use of available valve tissue and rendering the valve submitral apparatus, this approach preserves ventricular
competent. Even for combined coronary-valvular procedures, function.
our mean ischemic time is 55 minutes. If chordae tendineae For patients with advanced congestive heart failure, open
are ruptured, they should be removed; the leaflet is then surgery may entail a prohibitive risk. New catheter-based
either excised or imbricated. When chordal or papillary technology has recently been developed to address mitral
rupture affects the anterior leaflet, artificial chordae may regurgitation by means of a percutaneous approach, which
be fashioned from a polytetrafluoroethylene suture. In our may allow these patients to undergo mitral repair without
experience, however, the valve has often needed to be stopping the heart or opening the chest. One such device
replaced. facilitates placement of a clip that attaches the free edges of
For mitral incompetence associated with a ventricular the anterior and posterior leaflets, effecting an edge-to-edge
aneurysm, we perform an endoaneurysmorrhaphy10 by insert- repair (Evalve, Redwood City, CA). In other investigational
ing an oval patch graft inside the left ventricle to restore the approaches (Viacor, Inc., Wilmington, MA), the operator
ventricular anatomy. Once the papillary muscles have works through the coronary sinus to geometrically manipu-
returned to their normal position, mitral regurgitation is late the posterior annulus and thereby improve coaptation
often alleviated. of the leaflet edges (Fig. 24.4). Although these methods are
In 1991, Alfieri introduced the “edge-to-edge” technique 31 still undergoing development, early clinical experience is
for repairing mitral valves that are insufficient because of a promising.
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t 585
In this manner, we are able to spare both the anterior and
posterior chordal and papillary mechanisms.

Aortic Valve
Although congenital aortic valve disease in children is often
amenable to repair, the same cannot be said for acquired
aortic valve disease. Therefore, in adults, operations for
incompetent or stenotic aortic valves almost always entail
valve replacement. Some surgeons believe that the currently
recommended age threshold (≥65 years) for implanting a bio-
prosthesis in the aortic position could be lowered further.32
A good outcome depends on optimal surgical timing, but
this can be hard to judge, especially in asymptomatic patients
with severe disease and symptomatic patients with highly
advanced disease.

Indications for Surgery

The primary indication for aortic valve surgery is the pres-
ence of symptoms (angina, syncope, or dyspnea on exertion).
As long as patients are asymptomatic, their prognosis remains
good, even if the stenosis itself is severe. However, the ACC/
AHA recommends valve replacement for patients with left
ventricular systolic dysfunction, as characterized by a sub-
normal resting ejection fraction (documented by two con-
secutive measurements or independent tests). Even if the
ejection fraction is normal, valve replacement should be con-
sidered for patients with an end-diastolic dimension of
>75 mm or an end-systolic dimension of >55 mm. In small
patients of either sex, these threshold values may need to be
reduced appropriately.
Once symptoms develop, aortic valve replacement should
be undertaken. Patients with congestive heart failure related
to aortic stenosis have a 50% chance of dying within 2 years
FIGURE 24.4. Digital rendering of a regurgitant mitral valve before
(A) and after (B) introduction of a percutaneous transvenous mitral
after the onset of symptoms. Similarly, patients who present
annuloplasty device (Viacor, Inc., Wilmington, MA) into the coro- with syncope or angina have a 50% chance of dying within
nary sinus around the valve. 3 and 5 years, respectively. A fairly objective indicator is the
pressure flow gradient across the left ventricular outflow
tract. When this gradient is >50 mm Hg, operative correction
is generally indicated. According to Carabello,33 however,
patients with a low aortic valve gradient and low ejection
Mitral Valve Replacement fraction without inotropic reserve will probably not benefit
from valve replacement.
In advanced rheumatic heart disease with foreshortening and
thickening of the mitral leaflets and in instances of subacute
bacterial endocarditis, valve replacement (see above) is the Valve-Sparing Aortic Root Surgery
only available option.
When the aortic valve is affected by an aneurysm of the
aortic root, the entire root and valve are traditionally replaced
with a composite valved graft. Recently, however, we began
Intravalvular Implantation
using a new valve-sparing technique whenever possible (Fig.
In patients with sound, flexible mitral leaflets and supple 24.5). Once the entire aneurysmal segment, including the
chordae, we sometimes use a technique known as in situ sinuses of Valsalva, has been removed, the aorta is recon-
intravalvular implantation, particularly if the annular tissue structed with a Dacron graft. The native valve is then incor-
is of poor quality.9 To prevent obstruction of the valve pros- porated into the inner wall of the graft. This technique is
thesis, we divide the anterior leaflet and insert it into the suitable for patients whose aortic valve is structurally normal
annulus. We then implant a low-profile prosthesis, affixing and not calcified, torn, or infected (see also Percutaneous
it to the valve leaflet and annulus with continuous sutures. Valve Replacement, below).
586 chapter 24

mortality are renal insufficiency, prolonged cardiopulmo-

nary bypass, use of a biologic prosthesis, and use of inotropic
drugs; predictors of late mortality are age >60 years, left
ventricular ejection fraction <50%, and NYHA functional
class IV status.

Primary Lesions
Primary tricuspid lesions include rheumatic valvulitis, bac-
terial endocarditis, carcinoid valvulopathy, and traumatic
rupture. Stenosis or regurgitation caused by rheumatic val-
vulitis can be alleviated by an annuloplasty, a valvotomy, or
a combination of these procedures. Alternatively, valve
replacement can be performed.
When bacterial endocarditis results in advanced tricuspid
valve destruction, as it frequently does in drug addicts, the
surgeon is advised to perform a total valvectomy rather than
implant a foreign body or an artificial valve.35 If patients
survive, they may then undergo elective valve replacement
once the infectious process has resolved.
Tricuspid valve disease secondary to chronic placement
of transvalvular pacing leads and defibrillator coils is being
seen with increasing frequency. When surgical correction is
required, the leads must be removed and replaced with
epicardial ones if indicated.
Traumatic disruption of the tricuspid valve can result
from a closed, crushing chest injury. We have treated several
automobile accident victims with papillary muscle dis-
ruption. Such cases always necessitate valve replacement
or repair.36,37

Secondary Lesions
Secondary tricuspid lesions tend to be more common than
primary ones. Secondary lesions arise when rheumatic val-
vulitis in the mitral (and perhaps also the aortic) position
results in pulmonary hypertension and increased pulmonary
vascular resistance, thereby straining the right ventricle and
causing pulmonary and tricuspid valve insufficiency by sec-
ondary annular dilatation. Treatment of secondary lesions
FIGURE 24.5. Valve-sparing aortic root repair: the patient’s native requires sound surgical judgment and expertise. If the leaf-
valve (A) is fixed inside a Dacron tube graft (B), which is used to
replace the aneurysmal aortic segment. lets are relatively normal, repair can be achieved by decreas-
ing the overall circumference of the tricuspid annulus.
However, if the leaflets are calcified or eroded because of
infection or ruptured chordae tendineae, valve replacement
may be necessary.

Tricuspid Valve
Postoperative Care
Acquired lesions of the tricuspid valve may be either primary
or secondary. In managing tricuspid disease, the surgeon Most patients who undergo valve replacement receive tem-
must weigh each case carefully and select the treatment plan porary pacing electrodes to prevent heart block or other
that offers the best chance of long-term success. Surgery is arrhythmias during the early postoperative period. The
generally required for concomitant tricuspid and mitral valve pacing wires are usually removed after 4 or 5 days. A medi-
disease with pulmonary hypertension and right ventricular astinal chest tube is left in place for 48 hours.
failure. However, functional tricuspid insufficiency, which Optimal postoperative care depends on familiarity with
sometimes accompanies mitral stenosis, often resolves after the potential complications of valve surgery. The most feared
correction of the mitral condition. threat is thromboembolism, which is mainly associated with
When tricuspid insufficiency accompanies disease of the mechanical prostheses. Patients with these devices in the
mitral or aortic valve or both, the prognosis is unfavorable. mitral position should routinely take an anticoagulant such
According to Bernal and colleagues,34 predictors of hospital as sodium warfarin (Coumadin). Those with aortic prosthe-
 va lv u l a r h e a r t d i s e a s e : s u r g i c a l t r e a t m e n t 587
ses should also undergo anticoagulation on a long-term basis. approaches reduce the trauma of access and minimize the
However, patients with low-profile bileaflet valves such as need for cardiac dissection for all types of valve repair and
the St. Jude valve (St. Jude Medical, St. Paul, MN), Carbomed- replacement. Because limited-access valve surgery avoids a
ics valve (Sorin Group, Burnaby, British Columbia, Canada), full median sternotomy, it is especially suited for patients at
and ON-X® valve (Medical Carbon Research Institute, LLC, high risk for sternal infection or redo procedures. A number
Austin, TX) can be kept at lower levels of anticoagulation, of incisions and techniques have been described for mitral
particularly if the valve is implanted in the aortic position. and aortic valve surgery. One technique, popularized by
Although anticoagulants are not always prescribed for Gundry40 utilizes a mini-sternotomy that extends from the
patients with bioprostheses, patients with chronic atrial sternal notch to the second or third interspace. A mini-
fibrillation or extensive left atrial dilatation should receive sternotomy can be performed through a 7- or 8-cm skin inci-
sodium warfarin for an indefinite period. sion and avoids division of the lower sternum, the site most
Infection is a relatively rare complication of prosthetic frequently involved in postoperative complications. This
valve implantation. In patients with valve prostheses, we approach is suited for both aortic and mitral valve proce-
routinely continue postoperative bactericidal antibiotic dures. Another option is a right mini-thoracotomy, as popu-
therapy until all invasive catheters have been removed. larized by Cosgrove,41 which is excellent for mitral valve
Subsequently, these patients should receive prophylactic procedures.
antibiotics whenever they undergo dental procedures or Some variations of these and other limited-access inci-
operations on the lower genitourinary or gastrointestinal sions involve a port access approach, which entails peripheral
tract. perfusion and use of a balloon catheter for aortic occlusion.42
When bacterial endocarditis is diagnosed, a second opera- Other approaches use a modified incision but standard
tion may be necessary to replace the prosthetic valve. central cannulation and a modified aortic cross-clamp. One
Although we begin antibiotic therapy to sterilize the blood- of the main challenges of this approach is to keep the car-
stream before surgery, we do not wait when valve replace- diopulmonary bypass time within an acceptable range. In a
ment is needed, because we have found valve replacement few centers, limited-access valve surgery is performed with
to be successful even in the presence of active infection. the aid of endoscopic visualization and robotic surgical
Moreover, delay can be dangerous if it results in irreversible systems. This approach has the potential to reduce further
hemodynamic deterioration or ongoing destruction of peri- the size of the surgical incision.
prosthetic structures. Limited-access aortic valve replacement with the aid of
Valve dehiscence may occasionally result from infection, high thoracic epidural anesthesia in a conscious patient
technical errors, or tissue failure. This complication can be has been reported.43 This approach avoids the potential
alleviated by a repeat open cardiac procedure in which addi- morbidity related to general anesthesia and endotracheal
tional sutures are inserted to secure the valve. intubation.
Today’s mechanical prostheses are extremely durable, Many surgeons are reluctant to adopt limited-access
and valve fracture or failure is quite uncommon. When such valve surgery, but this approach has been so widely publi-
problems do arise, a repeat operation is mandatory. cized that patients often request it. Though a reasonable
approach for most patients with single-valve disease, it is not
well suited for obese patients or those with complex valve
Redo Valve Procedures procedures, multivalve disease, or severe atherosclerosis pro-
hibiting peripheral cannulation.
Redo valve procedures can present technical challenges,
including dissection of adhesions from previous surgery. The
operative mortality may be two or three times higher than
Percutaneous Valve Replacement
for initial valve operations,38 particularly in patients with
poor NYHA functional status and a need for emergency For many elderly or debilitated patients with multiple comor-
surgery. For this reason, reoperation should be undertaken bidities, conventional valve replacement may pose a signifi-
before cardiac functional status deteriorates and other organs cant risk. Percutaneous valve replacement is an attractive
are adversely affected. nonsurgical alternative that is currently being developed and
In patients with tissue valves, the following factors do that offers numerous potential benefits. In 2002, Cribier and
not significantly increase the mortality of redo surgery: age coworkers44 successfully implanted an aortic valve percuta-
at surgery, previous coronary artery bypass grafting (CABG), neously using the antegrade approach, passing the collapsible
position of the valve replaced, type of implant, and the pres- valve up the femoral vein, across the atrial septum and mitral
ence of coronary artery disease.39 Therefore, lowering the age valve to reach the aortic annulus. More recently, Paniagua
range for tissue valve implantation may be justified. and colleagues,45 at our hospital, performed a similar proce-
In selected patients, limited-access valve surgery can dure using a collapsible prosthesis that needs no supportive
achieve results comparable to those of traditional operations struts; these researchers used the retrograde approach, which
while hastening recovery. has several advantages over the antegrade one. This technol-
ogy is associated with numerous challenges, but early clini-
cal work shows promise. If the technical hurdles can be
Limited-Access Valve Surgery
surmounted, percutaneous aortic valve replacement may
A number of techniques have been introduced for perform- prove to be an important advance in the treatment of valve
ing limited-access valve surgery. These nonsternotomy disease.
588 chapter 24

Outcomes common in the patients with mechanical valves, and other

complications were similar with both valve types.
Heart valve surgery can be performed safely and effectively,
restoring countless patients to normal, healthy lives. The Limited-Access Versus Conventional Valve Surgery
Cleveland Clinic,46 which performs the largest number of
valve procedures in the United States, reported a 2.9% overall Mitral Position
mortality for the 2,254 valve operations that it performed in
2003. Valve replacement generally entails a higher morbidity In one of the largest single-center studies to compare the
and mortality than most other routine heart operations,47 outcomes of limited-access versus conventional valve proce-
and its outcome often depends more on patient risk factors dures, Mihaljevic and coworkers52 documented a periopera-
than on valve choice or technical considerations. After aortic tive mortality of 0.2% for limited-access mitral procedures
and mitral valve replacement, respectively, the 10- and 15- and 0.3% for conventional mitral procedures. At 1, 3, and 5
year mortality is as high as 20%.48 years, the actuarial survival rates were 98%, 97%, and 95%
versus 97%, 91%, and 86% after these two types of surgery,
respectively.
Isolated Versus Combined Operations
Aortic Position
Mitral Position
The same study showed a perioperative mortality of 2% for
As of late 2004, the National Cardiac Database maintained limited-access aortic valve surgery versus 2.7% for conven-
by the Society of Thoracic Surgeons49 reported an unadjusted tional aortic valve surgery. At 1, 3, and 5 years, the two
operative mortality of approximately 2% for mitral valve respective approaches yielded actuarial survival rates of 98%,
repair alone, 7.5% for mitral repair plus CABG, 6.4% for 94%, and 82% versus 94%, 90%, and 86%.
mitral replacement alone, and 11% for mitral replacement
plus CABG.

Aortic Position
Summary
In the National Cardiac Database, the unadjusted operative Introduced in the mid-20th century, valve repair and replace-
mortality was approximately 4.6% for aortic valve replace- ment continue to account for a large share of the cardiac
ment alone, 6.2% for aortic valve replacement plus CABG, surgeon’s caseload. Treatment should be considered for any
and 10% for combined aortic and mitral valve replacement patient with symptoms. Stenotic mitral valves can often be
in late 2004. repaired by an interventional cardiologist using a double-
balloon valvotomy technique, but this approach should
be avoided for aortic valve repair, as it does not offer long-
Mechanical Versus Bioprosthetic Valves
lasting results. When surgery is necessary, repair (if possible)
is preferred over valve replacement. If replacement is un-
Mitral Position
avoidable, surgeons can choose from a wide array of pros-
The Department of Veterans Affairs randomized trial50 thetic valves and operative techniques, including
showed that, 15 years after mitral valve replacement, all- limited-access approaches. Postoperatively, the most dreaded
cause mortality was no different with mechanical valves complication is thromboembolism. To prevent this problem,
than with bioprosthetic ones. Although the bioprostheses patients with mitral mechanical prostheses should routinely
had more structural deterioration in all age groups, this com- take an anticoagulant such as sodium warfarin; those with
plication was more prevalent in younger patients (<65 years aortic mechanical prostheses should also undergo long-term
old). Both valve types had similar thromboembolism rates, anticoagulation. When repeat valve surgery is necessary, it
but mechanical valves tended to cause more bleeding com- should be undertaken before cardiac functional status dete-
plications. Similarly, the Edinburgh randomized trial,51 riorates and other organs are adversely affected. Catheter-
which followed patients for 20 years, showed that both types based approaches for valve repair are currently being
of valves yielded similar mortality and thromboembolism developed, but their merit is not yet clear. Nevertheless, the
rates but that mechanical valves resulted in increased currently available options are offering even high-risk surgi-
bleeding. cal patients a chance to overcome their valve disease and
enjoy a normal life.
Aortic Position
At 18 years’ follow-up, Veterans Affairs patients with an References
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SEC TION IV

Coronary Artery
Disease
 2 Coronary Artery Disease:
5 Pathologic Anatomy
and Pathogenesis
L. Maximilian Buja and
Hugh A. McAllister, Jr.

Coronary Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 593 Determinants of Infarct Development and Size and

Coronary Thrombosis and Other Acute Coronary Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 Reperfusion, Preconditioning, Stunning, and
Nonatherosclerotic Coronary Vascular Diseases . . . . . . 596 Hibernation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Pathology of Angina Pectoris and Sudden Cardiac Pathology of Interventionally Treated Coronary
Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596 Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Pathology of Acute Myocardial Infarction . . . . . . . . . . . 598 New Approaches to Myocardial Modulation . . . . . . . . . 606
Pathogenesis of Myocardial Ischemic Injury. . . . . . . . . . 600 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607

Key Points including gene therapy and stem cell therapy, are under
retina investigation.
• Coronary atherosclerosis is the dominant underlying
cause of coronary artery disease (CAD) although non- The clinical manifestations of coronary artery disease (CAD),
atherosclerotic types of coronary (ischemic) heart disease also known as coronary (ischemic) heart disease, are diverse,
do occur. with a spectrum that encompasses various forms of angina
• Vulnerable coronary plaques usually have thin fibrous pectoris, myocardial infarction (MI), sudden cardiac death,
capsules and are prone to erosion, septum and thrombo- and chronic coronary heart disease. These syndromes result
sis leading to acute myocardial ischemia. from complex interactions between the coronary circulation
• The clinical spectrum of CAD includes angina pectoris, and the myocardium, usually with coronary atherosclerosis
myocardial infarction (MI), sudden cardiac death and as the major anatomic substrate for disease.1–3
chronic coronary heart disease. Fallowing coronary occlu-
sion, irreversible myocardial ischemic injury beginner
within 20–30 minutes in the subendocardium, and MI Coronary Atherosclerosis
then progresses over 3 or more hours in a wavefront pattern
through the myocardial bed-at-risk. MI is produced by The blood supply to the heart is provided by the left and right
ischemic myocardial cell death mediated by the distinc- coronary arteries and branches of these major vessels (Fig.
tion pathological processes of oncosis and apoptosis. 25.1).1–3 The anterior wall of the left ventricle (LV) and the
• The myocardium can be preconditioned resist the pro- anterior portion of the interventricular septum are supplied
gression of MI by prior brief periods of reversible myocar- by the left anterior descending (LAD) coronary artery and its
dial ischemic (myocardial preconditioning). diagonal and septal branches. The lateral wall of the LV is
• The consequences to the myocardium of coronary reper- supplied by the left circumflex coronary artery (LCCA). The
fusion include reperfusion injury, salvage of myocardium, posterior wall of the left ventricle and posterior interven-
stumming and hibernation. tricular septum are usually perfused by the right coronary
• Major cleternuinants of the prognosis of CAD are MI size artery (RCA), which also supplies the right ventricle (RV).
and the quality of remodeling of the remaining visable Further details about coronary artery anatomy are presented
myocardium. in the first chapter of this book.
• Distinctive pathobiological features are seen with estab- The major cause of CAD is coronary atherosclerosis (arte-
lished treatments for CAD, including coronary angio- riosclerosis), a process that develops as an inflammatory
plasty and coronary artery surgery, and new approaches, response of the vessel wall to chronic, multifactorial injury

593
594 chapter 25

Post Descending A

RCA

A.V. Node A. L. Circ. A.

S.A. Node A. L. Main A.

L. Circ. Marginal A.

LAD L. Marginal A.
R. Marginal A.

Septal A. L. Diagonal A.

FIGURE 25.1. Diagram of the usual anatomic distribution of the FIGURE 25.2. Left main coronary artery from a 6-year-old girl with
coronary arteries also showing a typical distribution of atheroscle- homozygous familial hypercholesterolemia. The artery is severely
rotic plaques (dark areas). involved by atherosclerotic plaque. The plaque is composed of
fibrous tissue (dark areas) and foam cells and lipid (light areas). Low
magnification photomicrograph.

and leads to the formation of atherosclerotic plaques (fibrous weakening and intimal fibrosis, with lymphocytic inflam-
plaques, atheromas).4–6 These plaques are regions of thick- matory infiltrates.7–9
ened intima and are composed of various mixtures of fibrous Atherosclerotic disease leads to extensive remodeling
tissue, cells, and lipid (Fig. 25.2).7–9 of the vessel wall. Dilatation of the vessel occurs in such a
Initially, atherosclerosis is a focal disease. There is a way that the lumen is maintained despite the presence of
predilection for formation of atherosclerotic plaques adjacent intimal plaque, which may develop in an eccentric or concen-
to branch points in areas of nonlaminal flow and low-shear tric pattern (Fig. 25.3).10–12 Luminal narrowing occurs only
stress adjacent to areas of high-shear stress.10 It is postulated when atherosclerotic disease is advanced. Approximately
that the flow patterns in such regions promote endothelial 50% narrowing of luminal diameter (75% luminal area) is
dysfunction and increased contact of endothelium with needed before blood flow is affected. Areas of severe narrow-
leukocytes and platelets. Areas of predilection for severe ing often develop in the setting of multifocal disease. All of
atherosclerosis in the coronary system include the proximal these changes can lead to underestimation of the extent and
LAD coronary artery and the proximal and distal RCAs severity of coronary atherosclerosis on visual inspection of
(Fig. 25.1). Established atherosclerosis involves all three coronary arteriograms (“luminograms”) (Fig. 25.4).13 Quanti-
layers of the arterial wall such that, in addition to intimal tative coronary arteriography can provide more objective
thickening, diseased areas exhibit medial degeneration and measurements of absolute coronary dimensions and flow.

35

30

25
IEL area, mm2

20

15

10 FIGURE 25.3. Compensatory enlargement of human coronary arter-

ies in relation to plaque formation. In graph, area encompassed by
5 internal elastic lamina (IEL area) is plotted against lesion area for
sections of left main coronary artery from 136 adult hearts obtained
0 postmortem. The IEL area is potential lumen area if no plaque was
0 5 10 15 20 present. The IEL area progressively increases as lesion area increases
Lesion area, mm2 in a linear manner (r = .44; p < .001; standard error of 4.8 mm2 indi-
cated by the dotted lines above and below regression line). Below
graph is diagrammatic representation of sequence of changes in ath-
erosclerotic arteries, which may eventually lead to lumen narrowing.
A Arteries initially enlarge, preserving nearly normal lumen cross
section, but it appears that normal lumen area may not be maintained
once lesion occupies more than 40% of IEL area (A).
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 595

A 0
25% Coronary arteries
Angiographic 50% atherosclerosis of variable severity
100% 50% 25%
view 25%
(diameter) 0
Platelet Spasm
aggregation
Platelet
Spasm aggregation
Histologic
view Plaque erosion-
(area) rupture-hemorrhage
Increased myocardial
oxygen demand
Normal 50% ↓ Diameter 75% ↓ Diameter Occlusive
75% ↓ X-sectional 95% ↓ X-sectional Other predisposing
area area thrombosis factors

Minimal diameter Minimal diameter

B Maximal diameter –75% ↓ from normal 88% ↓ Acute myocardial ischemia
–50% ↓ but only 50% ↓ from from normal but
from normal maximal diameter 75% ↓ from
in adjacent segment maximal diameter
Acute myocardial Angina pectoris
0 infarction
Angiographic 25%
view 50% 75% 88%
50%
(Diameter) 25% Healed infarct Sudden cardiac death
0 altered electrical activity arrhythmia

FIGURE 25.5. Pathogenetic mechanisms of acute ischemic heart

Histologic disease and potential clinical outcomes.
view
(area)

50% ↓ Diameter 75% ↓ Diameter 88% ↓ Diameter

75% ↓ X-sectional 95% ↓ X-sectional area 98% ↓ X-sectional area susceptible to such changes are atheromatous plaques with
area (20% ↓ from maximal (23% ↓ from maximal thin fibrous capsules and large cores of lipid-rich debris, and
(maximal area) X-sectional area) X-sectional area) these lesions are designated as vulnerable plaques (Fig. 25.7).24
FIGURE 25.4. Relationship between reduction in diameter (as seen However, endothelial erosion predisposing to thrombosis
by selective coronary arteriography) and cross-sectional area (as seen
by histologic examination). (Top) A coronary artery with a 50%
can involve fibrocellular plaques without significant lipid
reduction in diameter narrowing has a 75% diminution in cross- content.23
sectional area, and a coronary artery with a 75% reduction in diam- Inflammation adjacent to the plaque surface is important
eter narrowing has a 95% reduction in cross-sectional area. (Bottom) in the pathogenesis of alterations predisposing to thrombosis
In many patients who undergo coronary arteriography, stenosed regardless of the plaque morphology.25,26 Thus, high risk or
segments are not being compared to totally normal segments but
rather to segments of the coronary artery that are somewhat nar- vulnerable plaques are characterized by inflammation asso-
rowed diffusely. Thus, if the least-narrowed segment actually is ciated with a variety of plaque morphologies.25,26 Factors that
itself 50% narrowed, what appears to be a 50% diameter narrowing
in an adjacent segment is in fact a 75% diameter narrowing and,
therefore, a 95% cross-sectional area reduction. Similarly, what
appears to be a 75% diameter narrowing is in fact an 88% diameter
narrowing, which in turn is a 98% cross-sectional diameter narrow-
ing. Because many patients with coronary artery disease have
diffuse luminal narrowings in addition to discrete stenoses, the
bottom panel reflects more accurately the true clinical situation
in such cases.

Coronary Thrombosis and Other Acute

Coronary Lesions
Acute ischemic heart disease is often initiated by acute
changes superimposed on atherosclerotic plaques (Fig.
25.5).3,14 The spectrum of thrombotic lesions includes platelet
aggregates, mural (nonocclusive) thrombi, and occlusive
thrombi (Figs. 25.6 to 25.9).3,14–26 Major thrombi are frequently
FIGURE 25.6. Gross photograph of sections of a coronary artery
associated with significant disruptions of the plaque surface, with an atherosclerotic plaque and occlusive thrombus. A break in
which may appear as fissures, erosion, ulceration, or rupture the plaque capsule has given rise to plaque hemorrhage (arrow) and
(Figs. 25.6 to 25.8). Coronary lesions that are particularly occlusive thrombosis.
596 chapter 25

with occlusive thrombosis often occurs without prior signifi-

cant luminal narrowing by the vulnerable plaque.10–12
Little information is available regarding anatomic corre-
lates of coronary spasm.28 Spasm is usually associated with
atherosclerotic lesions but in some cases occurs without
angiographically evident disease.29–31 Alterations associated
with coronary spasm have included coronary lesions exhibit-
ing neointimal hyperplasia,31 unusual transverse ridges in
the coronary artery,32 and increased numbers of adventitial
mast cells.33 Prominent adventitial inflammation has been
found to be more prevalent in coronary arteries of patients
with a recent history of unstable angina pectoris at rest than
in controls, further suggesting a role for inflammatory medi-
ators in the pathophysiology of coronary spasm.34 Further-
more, increased numbers of mast cells have been found in
the adventitia of ruptured plaques in infarct-related coronary
FIGURE 25.7. Coronary artery shows a ruptured plaque capsule
(arrows) and intraluminal and intraplaque thrombus. Low-power arteries, suggesting a role for histamine release and coronary
photomicrograph. spasm in the development of acute coronary syndromes.35
Mediators released from abnormal myocardium also can
induce coronary spasm in experimental models.36
probably contribute to endothelial injury and disruption of
the plaque surface include hemodynamic trauma, local
attachment and activation of platelets and blood cells, inflam-
Nonatherosclerotic Coronary
matory processes in the plaques, and cytotoxic effects of
Vascular Diseases
plaque contents, including metalloproteinases and other
In a small number of cases of ischemic heart disease, the
enzymes released from macrophages at sites of plaque
coronary arteries are free of atherosclerosis and the clinical
rupture.3,14–26 The likely pathogenetic sequence of plaque
disease is related to some other condition. There is an inter-
rupture is endothelial injury, influx of blood components,
esting spectrum of nonatherosclerotic causes of ischemic
increase in intraplaque pressure, and outward rupture of the
heart disease, including congenital anomalies, dissection
fibrous capsule (Fig. 25.10).17,21 Localized erosion and plaque
(Figs. 25.11 and 25.12), emboli, vasculitis, and other condi-
fissuring also can give rise to platelet aggregation and throm-
tions of the coronary arteries (Table 25.1).37,38 Cocaine use can
bosis.22–25 Disruption of the plaque surface, by any mecha-
precipitate acute myocardial ischemia and infarction as a
nism, predisposes to formation of intraluminal and intramural
result of coronary spasm and/or thrombosis.39,40
(intraplaque) thrombus (Fig. 25.7).
Plaque hemorrhage may occur with or without thrombo-
sis. Two mechanisms of intraplaque hemorrhage are influx Pathology of Angina Pectoris and Sudden
of blood across the damaged endothelial surface of the plaque Cardiac Death
and influx of blood from small intraplaque vessels derived
from the vasa vasorum. Intraplaque hemorrhage can The usual pathologic correlate of angina pectoris is coronary
increase plaque destabilization by contributing to the deposi- atherosclerosis with significant luminal narrowing of one or
tion of lipid, macrophage infiltration, and enlargement of the more of the major coronary arteries.3,14,28 However, there is
necrotic core.27 Due to coronary remodeling, plaque rupture considerable variation in the anatomic extent of large vessel

FIGURE 25.8. Coronary artery shows an erosion of the endothelial FIGURE 25.9. Coronary artery with a small mural thrombus
surface (arrows) leading to superficial hemorrhage in the plaque (H) attached to the surface of an atherosclerotic plaque. High-power
and thrombosis (T) of the lumen. Low-power photomicrograph. photomicrograph.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 597

Thin fibrous capsule

Large lipid-rich core
Accumulation of
macrophages under
capsule
Vascularization
Endothelial damage
Influx of plasma and
erythrocytes
Increased pressure in plaque
Fissure or rupture of capsule
Influx of blood into plaque
Thrombosis
Discharge of foam cells and
FIGURE 25.10. Characteristics of the cholesterol into lumen
Vulnerable plaque Disrupted plaque with thrombus
vulnerable plaque and mechanisms
contributing to disruption of the plaque
capsule and thrombosis. , macrophages; , cholesterol; , vessel; , thrombotic material

CAD associated with the development of symptomatic isch- anatomically demonstrable acute MI, a subset of cases of
emic heart disease. The variability is influenced by a number sudden death are related to acute MI.48–52 There is consider-
of interrelated factors, including the rate of progression of able variability in the reported incidence of acute plaque
large vessel disease and the development of the coronary alterations and thrombotic lesions.48–52 However, evidence of
collateral circulation. Depending on the extent of coronary coronary plaque disruption and thrombosis has been docu-
collateral blood flow, coronary occlusion may lead to a major mented in a significant subset of patients, particularly those
MI or to little or no myocardial damage.41 with a prior history of unstable angina pectoris, an acute MI,
Unstable angina pectoris and related syndromes (prein- or single vessel disease.48–52 Such patients also frequently
farction angina, coronary insufficiency) are associated with show evidence of platelet aggregation in the coronary
a high incidence of acute alterations of plaques (“unstable microcirculation.42,43
plaques”) with superimposed thrombotic lesions, usually Women and men exhibit differences regarding sudden
platelet aggregates or nonocclusive thrombi, as well as plate- cardiac death.52–56 Sudden cardiac death occurs more fre-
let aggregates in the microcirculation of the myocar- quently in men than in women. Differences in coronary
dium.14,22,28,42,43 The accumulation of macrophages at sites of lesions also have been observed, with superficial plaque
unstable, vulnerable plaques indicates an inflammatory erosion rather than plaque rupture occurring more frequently
component to these vascular lesions, as has also been in younger individuals and women.53 There is evidence of a
demonstrated.23–26 higher incidence of plaque rupture in men dying suddenly
Coronary atherosclerosis is the most frequent anatomic during exertion than in men dying suddenly at rest.56 Fur-
substrate of sudden cardiac death.44,45 In large series, ap- thermore, plaque rupture with exertion is characterized by a
proximately 90% of cases exhibit significant atherosclerotic relatively thin fibrous capsule, relatively numerous vasa
narrowing of at least one coronary artery.46,47 Many of the vasorum, and rupture in mid-capsule, whereas plaque rupture
cases also show evidence of previous myocardial injury, at rest tends to occur at the shoulder region of the fibrous
manifest as multifocal myocardial scarring or healed capsule.56 In summary, clinicopathologic studies support the
infarction.45–52 Although most cases do not exhibit an concept of three major mechanisms of sudden cardiac death:

FIGURE 25.11. Gross photograph of a spontaneously dissected

coronary artery with a hematoma in the wall and marked compres- FIGURE 25.12. Coronary artery with spontaneous dissecting
sion of the lumen. hematoma (DH) in the vessel wall. Low-power photomicrograph.
598 chapter 25

TABLE 25.1. Causes of myocardial ischemia and infarction Pathology of Acute Myocardial Infarction
without coronary atherosclerosis
Coronary artery disease other than atherosclerosis Myocardial infarction is defined as the death of heart muscle
Arteritis resulting from severe, prolonged ischemia. It usually involves
Luetic
Granulomatous (Takayasu’s disease) the LV.3,57–61 The relatively unusual RV infarcts occur in asso-
Polyarteritis nodosa ciation with LV infarcts, particularly posterior transmural
Mucocutaneous lymph node (Kawasaki’s) syndrome LV infarcts, or as isolated entities, usually in association
Disseminated lupus erythematosus with pulmonary hypertension. Most MIs are confined to the
Rheumatoid arthritis
Ankylosing spondylitis
distribution of a single coronary artery and are designated as
Trauma to coronary arteries anterior, anteroseptal, lateral, and posteroinferior. Multire-
Laceration gional infarcts also occur. Myocardial infarctions are desig-
Thrombosis nated as subendocardial (non–Q-wave) when the necrosis is
Iatrogenic limited to the inner half of the ventricular wall (Fig. 25.13)
Coronary mural thickening with metabolic diseases or intimal
proliferative disease or transmural (Q-wave) when the necrosis involves not only
Mucopolysaccharidoses (Hurler’s disease) the inner half but significant amounts of the outer half of
Homocystinuria the ventricular wall (Figs. 25.14 and 25.15). The electrocar-
Fabry’s disease diographic (ECG) correlates are the ST segment elevation
Amyloidosis
Juvenile intimal sclerosis
with Q-wave pattern for transmural infarcts and the ST
(idiopathic arterial calcification of infancy) segment depression without Q-wave pattern for subendocar-
Intimal hyperplasia associated with contraceptive steroids or dial infarcts.3,57–61
with the postpartum period The overall incidence of occlusive coronary thrombosis
Pseudoxanthoma elasticum and associated plaque fissure or rupture is high (greater than
Coronary fibrosis caused by radiation therapy
Luminal narrowing by other mechanisms 75%) for acute MI.3,14–28 The thrombus typically involves the
Spasm of coronary arteries major coronary artery in the distribution of the infarcted
(Prinzmetal’s angina with normal coronary arteries) myocardium. However, there is a significant difference
Spasm after nitroglycerin withdrawal in incidence of thrombosis according to the type of infarct.
Dissection of the aorta
Dissection of the coronary artery
In autopsy studies, occlusive coronary thrombi are found in
Emboli to coronary arteries more than 90% of cases of transmural (Q-wave) MI but in
Infective endocarditis only about one third of cases of subendocardial (non-Q-wave)
Prolapse of mitral valve MI.3,14–28 Subendocardial MI without occlusive thrombosis is
Mural thrombus from left atrium, left ventricle related to the influence of other factors, such as more subtle
Prosthetic valve emboli
Cardiac myxoma coronary lesions (platelet aggregation, nonocclusive thrombi)
Associated with cardiopulmonary bypass surgery and and factors that increase myocardial oxygen demand (e.g.,
coronary arteriography aortic stenosis, systemic hypertension, cardiac hypertrophy,
Paradoxical emboli excessive stress, or exertion) (Fig. 25.5). The occurrence of
Papillary fibroelastoma of the aortic valve (“fixed embolus”)
Congenital coronary artery anomalies
subendocardial MI without occlusive thrombosis highlights
Anomalous origin of left coronary from pulmonary artery
Left coronary artery from anterior sinus of Valsalva
Coronary arteriovenous and arteriocameral fistulae
Coronary artery aneurysms
Myocardial oxygen demand–supply disproportion
Aortic stenosis, all forms
Incomplete differentiation of the aortic valve
Aortic insufficiency
Carbon monoxide poisoning
Thyrotoxicosis
Prolonged hypotension
Hematological (in situ thrombosis)
Polycythemia vera
Thrombocytosis
Disseminated intravascular coagulation
Hypercoagulability
Hypercoagulability, thrombosis, thrombocytopenic purpura
Miscellaneous
Myocardial contusion
Myocardial infarction with normal coronary arteries

ischemia-induced ventricular arrhythmia without acute MI;

FIGURE 25.13. Heart section demonstrates an acute subendocar-
acute MI with ventricular arrhythmia; and primary ventric- dial myocardial infarct involving the anterior left ventricle. The
ular arrhythmia associated with old myocardial damage and necrotic subendocardial myocardium is pale yellow and rimmed by
altered electrical conduction (Fig. 25.5).44,45 a red area of congestion.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 599

FIGURE 25.16. Heart shows a rupture of the posterior papillary

FIGURE 25.14. Transverse sections of the heart demonstrate a large muscle (arrows) due to an acute myocardial infarct.
acute transmural anteroseptal myocardial infarct related to an
occlusive thrombus (arrow) of the proximal left anterior descending
coronary artery.

the increased susceptibility of the human subendocardium

to ischemic injury. This susceptibility is caused by a more
tenuous oxygen supply-demand balance in this region versus
the subepicardium. This, in turn, is related to the pattern of
distribution of the collateral circulation and to local meta-
bolic differences in subendocardial versus subepicardial
myocytes.3
The major complications of acute MI are infarct expan-
sion (shape change leading to stretching and thinning of the
ventricular wall), infarct extension (additional necrosis), car-
diogenic shock and recurrent ventricular arrhythmias related
to large infarct size (generally greater than 33% to 40% of
LV mass), papillary muscle dysfunction, papillary muscle
rupture (Fig. 25.16), external cardiac rupture (Fig. 25.17), ven-
tricular aneurysm (Fig. 25.18), ventricular pseudoaneurysm
(due to sealing off of a relatively slowly evolving rupture),
ventricular septal rupture, pericarditis (nonspecific and
FIGURE 25.17. Section of heart shows an acute transmural poste-
rior myocardial infarct with an external rupture site (arrow).

FIGURE 25.15. Acutely infarcted myocardium contains necrotic

myocytes with contraction bands (black arrows) and an infiltrate of FIGURE 25.18. Left ventricular aneurysm with mural thrombus
neutrophils (white arrows). High-magnification micrograph. resulting from healing of a transmural myocardial infarct.
600 chapter 25

autoimmune, e.g., Dressler’s syndrome) systemic emboliza- The metabolic alterations are associated with inhibition
tion from an LV mural thrombus, and pulmonary of contraction (excitation-contraction uncoupling) and asso-
thromboembolism.58 ciated alterations in ionic transport systems located in the
The risk of infarct rupture is significant during the first sarcolemma and organellar membranes.59 The initial altera-
week of MI before significant organization of the necrotic tion is loss of intracellular K + due to increased efflux of the
tissue.57,58 Healing of MI involves neutrophil infiltration fol- ion.66,67 Although the mechanism is unclear, it may involve
lowed by formation of granulation tissue. Granulation tissue activation of ATP-dependent K + channels due to change in
is grossly visible at approximately 10 days and completely the ATP/adenosine diphosphate (ADP) ratio or a mechanism
replaces the necrotic tissue by 2 to 3 weeks. Thereafter, the to reduce osmotic load. Another early change is an increase
granulation tissue is converted to a dense scar; this process in free Mg2+ , followed by a decrease in total Mg 2+ . Once ATP
is completed in 2 to 3 months. decreases substantially, the Na + ,K + –adenosine triphospha-
tase (ATPase) is inhibited, resulting in a further loss of K +
and an increase in Na + . The accompanying influx of extracel-
Pathogenesis of Myocardial Ischemic Injury lular fluid leads to cell swelling. An early increase in cyto-
solic Ca2+ also occurs as the result of multifactorial changes
The pathogenesis of ischemic myocardial cell injury and in transport systems of the sarcolemma and sarcoplasmic
necrosis involves complex metabolic and structural altera- reticulum.63–66 Alterations in myofibrillar proteins leads to
tions induced by severely reduced blood flow (Fig. 25.19).59–67 decreased sensitivity to Ca 2+ , resulting in impaired contrac-
As a result of oxygen deprivation, mitochondrial oxidative tility in spite of the elevated cytosolic Ca2+ .67
phosphorylation rapidly ceases, with resultant loss of the Advanced ischemic myocardial cell injury is mediated by
major source of adenosine triphosphate (ATP) synthesis. Ini- progressive membrane damage involving several contribu-
tially, there is a compensatory increase in anaerobic glycoly- tory factors (Fig. 25.19).61,64,67 Calcium accumulation or other
sis. However, this process leads to accumulation of hydrogen metabolic changes lead to phospholipase activation and
ions and lactate, with a resultant intracellular acidosis and resultant phospholipid degradation and release of lysophos-
inhibition of glycolysis as well as mitochondrial fatty acid pholipids and free fatty acids. Impaired mitochondrial fatty
and energy metabolism.59 acid metabolism leads to accumulation of various lipid

Cardiac myocyte
O2
–
↓ATP ↑H2PO4 ↑Lactate ↑H+ ↓pH

Plasmalemma Endoplasmic Mitochondria

reticulum

↓K+ ↑Na+ ↑Cl– ↑H2O ↓Mg2+ ↑Ca2+ Endothelium

Leukocytes

–
O2, H2O2, ·OH, NO
Protease ↑TG
activation ↑FFA Decreased Phospholipase
and/or other ↑Acyl-CoA phospholipid activation with
mechanisms ↑Acyl-carnitine synthesis FFA & LPL release

Alterations of Disruption of Accumulation Phospholipid Lipid

myofibrillar proteins cytoskeleton of amphipathic depletion peroxidation
↓ Ca2+ sensitivity lipids Impaired membrane
↓ Contraction integrity
↓↓ATP ↑↑Calcium ↑pH
↓↓↓
Irreversible injury

FIGURE 25.19. Postulated sequence of alterations involved in the alterations include increased phospholipid (PL) degradation with
pathogenesis of irreversible myocardial ischemic injury. Oxygen release of free fatty acids (FFA) and lysophospholipids (LPL) and
deficiency induces metabolic changes, including decreased adeno- decreased phospholipid synthesis. Lipid peroxidation occurs as a
sine triphosphate (ATP), decreased pH, and lactate accumulation, in result of attack by free radicals produced at least in part by the gen-
ischemic myocytes. The altered metabolic milieu leads to impaired eration of excess electrons (e-) in oxygen-deprived mitochondria.
membrane transport with resultant derangements in intracellular Free radicals also may be derived from metabolism of arachidonic
electrolytes. An increase in cytosolic Ca 2+ triggers the activation of acid and catecholamines, metabolism of adenine nucleotides by
proteases and phospholipases with resultant cytoskeletal damage xanthine oxidase in endothelium (species dependent), and activation
and impaired membrane phospholipid balance. Alterations of myo- of neutrophils and macrophages. The irreversible phase of injury
fibrillar contractile proteins lead to decreased Ca 2+ sensitivity and appears to be mediated by severe membrane damage produced by
decreased contraction in spite of the increased cytosolic Ca 2+ . Lipid phospholipid loss, lipid peroxidation and cytoskeletal damage.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 6 01
species, including long-chain acyl coenzyme A (CoA) and ogy.67,70,71 Apoptosis is characterized by a series of molecular
acyl carnitine, which, together with products of phospholipid and biochemical events, termed programmed cell death,
degradation, can incorporate into membranes and impair including (1) gene activation (programmed cell death); (2) per-
their function. Free radicals, including toxic oxygen species, turbations of mitochondria, including membrane permeabil-
are generated from ischemic myocytes, ischemic endothe- ity transition and cytochrome c release; (3) activation of a
lium, and activated leukocytes. These toxic chemicals induce cascade of cytosolic aspartate-specific cysteine proteases
peroxidative damage to fatty acids of membrane phospholip- (caspases); (4) endonuclease activation leading to double-
ids. Probably as a result of protease activation, cytoskeletal stranded DNA fragmentation; and (5) altered phospholipid
filaments, which normally anchor the sarcolemma to adja- distribution of cell membranes and other surface properties
cent myofibrils, become damaged, and their anchoring and with preservation of selective membrane permeability (Fig.
stabilizing effect on the sarcolemma is lost. All of these 25.20).68,69 Apoptosis can be triggered by activation of a death
changes lead to a progressive increase in membrane permea- receptor pathway or a mitochondrial pathway.72,73 Apoptosis
bility, further derangements in the intracellular ionic milieu, is also characterized by distinctive morphologic alterations
and ATP exhaustion. The terminal event in initiating irre- featuring cell and nuclear shrinkage and fragmentation, with
versible myocyte injury appears to be physical disruption of subsequent phagocytosis of apoptotic bodies by adjacent
the sarcolemma of the swollen myocyte.61,64,67 viable cells without exudative inflammation.68,69
The sequence of abnormalities described above consti- In contrast, numerous studies have reported ischemic
tute the well-documented pathophysiologic basis of cell myocardial damage to be characterized by cell swelling with
injury leading to cell death in cardiac myocytes subjected to altered cellular ionic composition due to altered membrane
a major ischemic or hypoxic insult. However, recent discov- permeability.61–67 This pattern of cell injury and death with
eries have indicated that other pathophysiologic mechanisms cell swelling has been designated as oncosis.69 Some reports
can contribute to cell injury and death, in particular apopto- have proposed a major role for apoptosis in myocardial isch-
sis or programmed cell death.68,69 Following the recognition emic injury and infarction.71,72 However, such a role for apo-
of apoptosis as a major and distinctive mode of cell death, ptosis may be overstated because of overinterpretation of
reports have been published implicating apoptosis in MI, evidence of DNA fragmentation based on the TUNEL
reperfusion injury, and other forms of cardiovascular pathol- method, which is not specific for apoptosis.74,75 Evidence has

Withdrawal of Glucocorticoids
Positive
Palmitate tropic factors Tumor necrosis factor (TNF)
stimuli
other stimuli Others
Fas/TNFR-1
Death domain activation
FADD TRADD Adaptor
Bcl-2 Bax proteins
Sentrin
Mitochondrion
Cyt c
Kinase
Caspase 8 cascade
Ceramide
O2 radicals/NO
Cyt c
NF-κB/IκB
Apaf-1 Caspase 3 (CPP32)
Caspase 9
dATP Caspase
Apoptosome cascade Cell
PARP cleavage
survival Ionizing radiation
Gene transcription Altered Drugs
↑Ca2+ (c-myc, p53, etc.) chromatin
structure
Toxins
Activation of New cell surface Recognition
Ca2+ - dependent properties including by phagocytes
enzymes ↑ phosphatidyl serine
in outer leaflet Phagocytosis
Endonuclease(s) Protease(s) Transglutaminase
without
DNA fragmentation Disruption of Cross-linking inflammation
and chromatin cyloskeleton of cytoplasmic
condensation proteins and
cell shrinkage

FIGURE 25.20. Mechanisms of cell death by apoptosis. Apoptosis FADD and TRADD, and subsequent activation of a cysteine prote-
may be caused by self-activation of a lethal metabolic pathway (pro- ase (caspase) cascade, with activation of caspase-3 (CPP32) as the
grammed cell death) or can be triggered by exogenous factors. Apo- key event. Mitochondria have an important role through the release
ptosis may be initiated by activation of a death receptor pathway or of cytochrome C, which is regulated by bcl-2 (which itself is regu-
a mitochondrial pathway, with loci of interaction between the two lated by related proteins Bax/Bak), and subsequent activation of
pathways. The death receptor pathway involves activation of the apoptotic protease-activating factor-1 (Apaf-1).
Fas/tumor necrosis factor receptor (TNFR) and its death domains,
602 chapter 25

been presented showing TUNEL labeling of ischemic myo- Determinants of Infarct Development and Size
cytes with classic features of oncosis as well as viable myo- and Remodeling
cytes undergoing DNA repair.76,77 Although certain assays
have been proposed to be more reliable for detection of pat- After coronary artery occlusion, the myocardium can with-
terns of DNA fragmentation characteristic of apoptosis, the stand up to about 20 minutes of severe ischemia without
DNA labeling data need to be interpreted in relation to other developing irreversible injury. However, after about 20 to 30
features of cell injury.78–80 Other studies have found that minutes of severe ischemia, irreversible myocardial injury
ischemic myocytes with the apoptotic markers of annexin V begins.61 The subsequent degradative changes give rise to
membrane labeling also exhibit ultrastructural features of recognizable myocardial necrosis. In the human and dog,
oncotic damage.81 Nevertheless, work using caspase inhibi- myocardial necrosis first appears in the ischemic subendo-
tors does suggest that apoptosis as well as oncosis may con- cardium, because this area usually has a more severe reduc-
tribute to the overall magnitude of ischemic necrosis.82,83 tion in perfusion compared with the subepicardium. Over
The rate and magnitude of ATP reduction may be a criti- the ensuing 3 to 6 hours, irreversible myocardial injury pro-
cal determinant of whether an injured myocyte progresses gresses in a wavefront pattern from the subendocardium into
to death by apoptosis or oncosis, because an ATP analogue, the subepicardium (Fig. 25.21).60 In the experimental animal
d-ATP, is a key component of a molecular complex that medi- and probably in humans as well, most MIs are completed
ates cytochrome c release with activation of the caspase within approximately 6 hours after the onset of coronary
cascade and apoptotic death.67,74,84 The severity of hypoxia occlusion. However, a slower pattern of evolution of MI can
and reperfusion influence whether myocytes die by apoptosis occur when the coronary collateral perfusion is abundant or
or oncosis, as does the severity of metabolic inhibition in when the stimulus for myocardial ischemia is intermittent
experimental studies.85,86 It is possible then that severely (e.g., in the case of episodes of intermittent platelet aggrega-
ischemic myocytes progress rapidly to cell death with swell- tion before occlusive thrombosis).
ing (oncosis), whereas less severely ischemic myocytes may Established myocardial infarcts have distinct central and
develop apoptosis. It is likely, however, that the same injured peripheral regions (Fig. 25.22).61–63 In the central zone of
myocyte may undergo activation of the apoptotic pathway severe ischemia, the necrotic myocytes exhibit clear sarco-
with activation of the caspase cascade followed by activation plasm with separation of organelles (evidence of edema);
of oncotic mechanisms, leading to cell membrane damage clumped nuclear chromatin, stretched myofibrils with
and terminal cell swelling and rupture.67,74–81 Thus, apoptotic widened I-bands, swollen mitochondria containing amor-
and oncotic mechanisms may be operative in the same myo- phous matrix (flocculent) densities composed of denatured
cytes during progression to irreversible ischemic injury and lipid and protein and linear densities representing fused
necrosis. cristae, and defects (holes) in the sarcolemma. In the periph-

Cross-section
of myocardium

0 hrs

Necrosis

40 minutes
FIGURE 25.21. Progression of cell death
versus time as a wavefront of necrosis at
various time intervals after coronary
Coronary occlusion. Necrosis occurs first in the
Necrosis subendocardial myocardium. With
thrombus
longer intervals of occlusion, a wave-
front of cell death moves from the sub-
2 hrs endocardial zone across the wall to
involve progressively more of the trans-
mural thickness of the ischemic zone. In
contrast, the lateral margins in the sub-
endocardial region of the infarct are
Necrosis established as early as 40 minutes after
occlusion and are sharply defined by the
anatomic boundaries of the ischemic
24 hrs bed.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 603

FIGURE 25.22. Patterns of myocardial injury in an

acute transmural myocardial infarct. C.B., myofibrillar
contraction band; L.D., lipid droplet; Mf., myofibril; Mt.,
mitochondrion; Mt.-A.D., mitochondrion with amor-
phous matrix (flocculent) densities; Mt.-A.D. + Ca D.,
mitochondrion with amorphous matrix densities and
calcium phosphate deposits; N., nucleus; N.-Cl. Chr.,
nucleus with clumped chromatin; SI.D., sarcolemmal Mt. N. L.D. Mf. Mt.-A.D. N.-Cl.Chr. Mf. L.D. C.B. N.-Cl.Chr. Sl.D.
defect. Sl.D. Mt.-A.D. + Ca D.

eral region of an infarct, which has some degree of collateral blood flow available shortly after coronary occlusion. Infarct
perfusion, many necrotic myocytes exhibit edematous sar- size also can be influenced by the major determinants of
coplasm; disruption of the myofibrils with the formation of myocardial metabolic demand, which are heart rate, wall
dense transverse (contraction) bands, swollen mitochondria tension (determined by blood pressure), and myocardial
containing calcium phosphate deposits as well as amorphous contractility.
matrix densities, variable amounts of lipid droplets, and Infarct size also influences the overall response of the
clumped nuclear chromatin. A third population of cells at ventricle to an ischemic insult. Myocardial remodeling refers
the outermost periphery of infarcts contains excess numbers to a complex of compensatory changes, including structural
of lipid droplets but does not exhibit the features of irrevers- and functional modifications of the viable myocardium to
ible injury just described. The pattern of injury seen in the ventricular wall stress. The response includes hypertrophy
infarcted periphery is also characteristic of myocardial injury of cardiomyocytes, death of cardiomyocytes by apoptotic
produced by temporary coronary occlusion followed by reper- or oncotic mechanisms, and cardiomyocyte regeneration,
fusion. In general, the most reliable ultrastructural features probably involving activation of endogenous stem cells.67
of irreversible injury are the amorphous matrix densities in Other changes involve connective tissue restructuring and
the mitochondria and the sarcolemmal defects. proliferation and microcirculatory changes. If the initial
The myocardial bed at risk, or risk zone, refers to the damage is relatively limited, remodeling can be effective and
mass of myocardium that receives its blood supply from a lead to normalization of wall stress. If the initial damage is
major coronary artery that develops occlusion (Figs. 25.21 severe, remodeling may be inadequate or ineffective, leading
and 25.22).60 After occlusion, the severity of the ischemia is to fixed structural dilatation of the ventricle and congestive
determined by the amount of preexisting collateral circula- heart failure. The end stage of this process is ischemic
tion into the myocardial bed at risk. The collateral blood flow cardiomyopathy.
is derived from collateral channels connecting the occluded
and nonoccluded coronary systems. With time there is pro-
gressive increase in coronary collateral blood flow. However, Reperfusion, Preconditioning, Stunning,
much of this increase in flow may occur too late to salvage and Hibernation
significant amounts of myocardium.
The size of the MI is determined by the mass of necrotic A number of factors can significantly modulate the myocar-
myocardium within the bed at risk (Figs. 25.21 and 25.22).60,61 dial response and subsequent outcome following an ischemic
The bed at risk will also contain viable but injured myocar- episode.67 The progression of myocardial ischemia can be
dium. The border zone refers to the nonnecrotic but dysfunc- profoundly influenced by reperfusion (Fig. 25.23). However,
tional myocardium within the ischemic bed at risk. The size the effects of reperfusion are complex.89–91 Reperfusion clearly
of the border zone varies inversely with the relative amount can limit the extent of myocardial necrosis if instituted early
of necrotic myocardium, which increases with time as the enough after the onset of coronary occlusion. However,
wavefront of necrosis progresses. The border zone exists pri- reperfusion also changes the pattern of myocardial injury by
marily in the subepicardial half of the bed at risk and has a causing hemorrhage within the severely damaged myocar-
very small lateral dimension, owing to a sharp demarcation dium and by producing a pattern of myocardial injury char-
between vascular beds supplied by the occluded and patent acterized by contraction bands and calcification. Reperfusion
major coronary arteries. also accelerates the release of intracellular enzymes and pro-
The major determinants of ultimate infarct size, there- teins from damaged myocardium. This may lead to a marked
fore, are the duration and severity of ischemia, the size of elevation of serum levels of these infarct markers without
the myocardial bed at risk, and the amount of collateral necessarily implying further myocardial necrosis. The timing
604 chapter 25

A The rate of progression of myocardial necrosis can be

influenced by prior short intervals of coronary occlusion and
reperfusion. Specifically, experimental evidence indicates
that the extent of myocardial necrosis after 60 to 90 minutes
of coronary occlusion is significantly less in animals that
had been pretreated with one or more 5-minute intervals of
coronary occlusion before the induction of permanent occlu-
Patchy areas undergo irreversible myocyte injury sion.67,92,93 However, after 120 minutes of coronary occlusion,
within 30 minutes of severe ischemia the effect on infarct size is lost. This phenomenon is known
as preconditioning (Fig. 25.24).67,92,93 A reduced rate of ATP
Large areas of myocardium undergo reversible injury depletion correlates with the beneficial effects of precondi-
during 30 minutes of coronary occlusion and are tioning.92,93 Further studies have indicated that classic pre-
salvaged by reperfusion but with transient dysfunction
(stunning)
conditioning involves activation of receptors for adenosine
and other agonists, G-protein–coupled protein kinase C, and
B sarcolemmal and mitochondrial ATP-dependent potassium

Inner zone myocardium undergoes irreversible injury

Shortened
during initial 40–60 minutes of severe ischemia action
Adenosine potential -
Mid-zone myocardium becomes severely injured during Adenosine K+ decreased
and related K ATP calcium
coronary occlusion and is subject to irreversible injury receptors channel influx
upon reperfusion (reperfusion-induced cell death)
Protein kinase C(PKC)
Outer zone myocardium becomes less severely injured G proteins
Ca2+
during coronary occlusion and is salvageable upon
reperfusion but with transient dysfunction (stunning)
K ATP K
+
FIGURE 25.23. Influences of duration of coronary occlusion and channel
timing of reperfusion on the response of the ischemic myocardium. Kinase cascade
(A) When reperfusion is achieved within 30 minutes of coronary Mitochondrion
ATP
occlusion, minimal irreversible injury occurs and most of the isch- Mitogen-activated
emic myocardium is salvaged but with transient dysfunction (stun- protein kinases
ning). (B) When reperfusion occurs within 2 hours of coronary ATP (MAP kinases)
reduced
occlusion, a significant amount of subendocardial myocardium rate of Myofibrils
develops irreversible injury, including some myocytes that probably ATP decline NF-ΚB
become irreversibly injured at the time of reperfusion (reperfusion- SOD– O2
–

induced cell death); however, reperfusion also results in significant Cytoskeleton

Gene Activation
salvage of subepicardial myocardium that would have developed Superoxide dismutase
irreversible injury with permanent coronary occlusion. NOS Nitric oxide synthase
Ca2+ Ca2+ Heat shock proteins
Decreased Early gene family
calcium NO
influx Nucleus
HSP27

HSP60
HSP70 HSP90

of reperfusion is critical to the outcome, with the potential FIGURE 25.24. Postulated mechanisms of early ischemic myocar-
dial preconditioning and second window of protection. Brief periods
for myocardial salvage being greater with earlier interven- of coronary occlusion lead to an initially slower rate of ATP decline
tion. Although reperfusion can clearly salvage myocardium, and reduced rate of progression to irreversible injury and necrosis
it may also induce additional injury. The concept of reperfu- during subsequent prolonged coronary occlusion; this phenomenon
sion injury implies the development of further damage, as a is ischemic preconditioning. Significant events in ischemic precon-
ditioning are activation of adenosine and related receptors, activa-
result of the reperfusion, to myocytes that were injured but tion of protein kinase C (PKC), and opening of ATP-dependent K +
that remained viable during a previous ischemic episode. channels in the sarcolemma and mitochondria. Available evidence
Such injury may involve functional impairment, arrhyth- supports opening of the mitochondrial K ATP channels as the critical
mia, and progression to cell death.67,87–89 Major mediators of event, although the downstream mechanisms are still unclear. One
reperfusion injury are oxygen radicals and neutrophils. The effect is decreased Ca 2+ influx, and subsequent blunting of injury
induced by Ca 2+ overload. Brief episodes of coronary occlusion lead
oxygen radicals are generated by injured myocytes and non- to early ischemic preconditioning followed by a refractory period
myocytes in the ischemic zone due to an oxidative burst and the subsequent onset of a second window of protection. The
upon reperfusion as well as neutrophils that gain access to second window of protection is related to gene activation mediated
the ischemic zone and become activated upon reperfu- by a kinase cascade, including mitogen-activated protein (MAP)
kinases, and nuclear factor κB (NF-κB). Gene products implicated in
sion.67,89–91 The neutrophils also contribute to microvascular the second window of protection include superoxide dismutase,
obstruction and the no-reflow phenomenon in the reperfused nitric oxide synthase and its product, nitric oxide, and heat shock
myocardium.67,89–91 proteins, including HSP27, which interacts with the cytoskeleton.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 605
channels, with a key role for the mitochondrial K chan-
nels.94–100 After a refractory period, a second late phase of
myocardial protection during a subsequent ischemic event
develops, a phenomenon known as the second window of
protection (SWOP),96,101,102 which is related to ischemia-
induced gene activation with production of various gene
products, including superoxide dismutase, nitric oxide syn-
thase, and stress (heat shock) proteins.96,102–104 Recently, a
protective effect on the extent of myocardial ischemic
damage has been observed with multiple, brief coronary
occlusions during early reperfusion after coronary occlusion,
a phenomenon termed postconditioning.105
Prolonged functional depression, requiring up to 24 hours
or longer for recovery, develops on reperfusion even after
relatively brief periods of coronary occlusion, on the order of
15 minutes, which are insufficient to cause myocardial
necrosis. This phenomenon has been referred to as myocar- FIGURE 25.25. Coronary artery after percutaneous transluminal
coronary angioplasty shows areas of plaque disruption (arrows)
dial stunning.67 A related condition, termed hibernation, with microthrombus on the surface. Low-magnification
refers to chronic depression of myocardial function owing to photomicrograph.
a chronic moderate reduction of perfusion.67 Preconditioning
and stunning are independent phenomena, since the precon-
ditioning effect is short term, transient, and not mediated
through stunning. Free-radical effects and calcium loading broblasts) and connective tissue matrix without lipid depos-
have been implicated in the pathogenesis of stunning, as well its. A similar lesion is seen in animal models of arterial
as other components of reperfusion injury.67,106,107 After longer injury.114 Experimental evidence supports a role for platelet
intervals of coronary occlusion, on the order of 2 to 4 hours, activation in the pathogenesis of the lesion.114 This process
necrosis of the subendocardium develops and even more of intimal proliferation leads to restenosis of lesions in 30%
severe and persistent functional depression occurs.108 In to 40% of cases within 6 months. The use of vascular stents
experimental studies, after 2 hours of coronary occlusion LV in conjunction with angioplasty has significantly improved
regional sites of moderate dysfunction during ischemia the long-term patency rates, although the stents do invoke a
recovered normal or near-normal regional contractile func- viable amount of intimal reaction.117–119 The potential of drug
tion after 1 to 4 weeks of reperfusion, whereas after 4 hours eluting stents to improve long-term outcomes is under active
of coronary occlusion, contractile dysfunction persisted after investigation.120,121
4 weeks of reperfusion.108 Degenerative changes in cardio- Saphenous vein coronary artery bypass grafts (SVCABGs)
myocytes develop in chronically underperfused, hibernating develop diffuse fibrocellular intimal thickening, medial degen-
myocardium.67 These changes can influence the degree of eration and atrophy, and vascular dilatation within several
functional recovery upon complete restoration of blood months after implantation (Figs. 25.27 and 25.28).122–124 Sub-
flow.67 sequently, the grafts are prone to development of eccentric
Therefore, depending on the interval of coronary occlu- intimal plaques with lipid deposition (atherosclerosis).122–124
sion before reperfusion, various degrees of contractile dys-
function, necrosis, or both are seen with reperfusion. These
observations emphasize the need for early intervention to
salvage myocardium.67,109 On balance, early reperfusion
results in a major net positive effect, making early reperfu-
sion an important goal in the treatment of acute ischemic
heart disease.110,111

Pathology of Interventionally Treated

Coronary Artery Disease
Percutaneous transluminal coronary angioplasty (PTCA)
can produce a variety of acute effects, including dilatation of
the vessel caused by stretching of the intima and media,
damage to the endothelial surface, multiple fissures in the
plaque, and dissection of the media (Figs. 25.25 and 25.26).112,113
The acute injury initiates a reparative response that leads to
intimal proliferation.112–114 Similar effects occur after ather- FIGURE 25.26. Close-up view of microthrombus on surface of a
ectomy and laser angioplasty.115,116 The resultant fibrocellular fissured plaque following percutaneous transluminal coronary
tissue is composed of modified smooth muscle cells (myofi- angioplasty. High-magnification photomicrograph.
606 chapter 25

FIGURE 25.29. Severe atherosclerosis in a saphenous vein graft in

place for 7 years. Multiple cross sections through the saphenous vein
bypass graft (SVBG), distal anastomosis (arrow), and distal coronary
artery (CA). The saphenous vein shows marked atherosclerosis and
acute occlusive thrombosis with plaque hemorrhage. The distal
coronary artery has focal plaque, but a residual lumen is present.
There was a massive acute myocardial infarct in the distribution of
the occluded vein graft.

FIGURE 25.27. Saphenous vein–coronary artery bypass graft

implanted for several months. The vein graft shows diffuse
concentric fibromuscular intimal thickening. Low-power
photomicrograph.
New Approaches to Myocardial Modulation
A new era is developing in the therapeutic application of new
Plaque fissuring and thrombosis also may develop (Figs. insights regarding the pathogenesis of myocardial ischemic
25.29 and 25.30). Therefore, all of the changes seen in natu- disease. Ongoing testing is being conducted to understand
rally occurring atherosclerosis may also develop in the genetic factors influencing outcomes and to successfully
saphenous veins, thereby creating a finite limit to the benefi- achieve genetic manipulation (gene therapy) of the processes
cial effects of these grafts. With improvements in surgical responsible for the response of the arterial wall to injury,
technique, the use of internal mammary arteries for coro- with the goals of retarding or preventing intimal prolifera-
nary bypass has taken on more widespread application. The tion and thrombosis at sites of coronary injury.127–133 Alterna-
internal mammary arteries are more resistant to the intimal tive approaches are being explored for the treatment of
injury and intimal proliferation observed in saphenous veins intractable angina pectoris.134,135 One surgical approach is the
and, therefore, the arterial bypass grafts have prolonged use of transmyocardial laser treatment to create new myo-
potency.125,126 cardial microvasculature.135–138 Another approach is the

FIGURE 25.30. This segment of vein graft is involved by a large

FIGURE 25.28. Further detail of the fibrocellular intimal prolifera- atheroma with lipid-laden core and thin fibrous capsule. Hemor-
tion in a saphenous vein–coronary artery bypass graft. Medium- rhage is present in the plaque core (H). The lumen is occluded
power photomicrograph. by recent thrombus (T). Low-power photomicrograph.
 c oro n a r y a r t e r y d i s e a s e : pat h ol o g ic a n at om y a n d pat h o g e n e s i s 607
intravascular delivery of genetically engineered growth 6. Willerson JT, Ridker PM. Inflammation as a cardiovascular
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25–34.
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 2 Inflammation, C-Reactive
6 Protein, and
Vulnerable Plaques
Paolo Calabró, James T. Willerson, and
Edward T.H. Yeh

C-Reactive Protein as a Clinical Marker. . . . . . . . . . . . . 611 C-Reactive Protein Production . . . . . . . . . . . . . . . . . . . . . 617

Biologic Effects of C-Reactive Protein . . . . . . . . . . . . . . . 615 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
C-Reactive Protein Receptors . . . . . . . . . . . . . . . . . . . . . . 616

Key Points Tillet and Francis working in Oswald Avery’s laboratory

in 1929 during the course of studies of patients with Strepto-
• C-reactive protein, in combination with lipid profile,
coccus pneumoniae infection first discovered CRP, and it was
provides very good cardiovascular risk prediction.
classified as the first “acute phase” protein. C-reactive protein
• C-reactive protein is not only a marker of inflammation,
is a pentamer of 23-kd subunits, and during the acute-phase
but also a mediator of cardiovascular pathology.
response preformed CRP is rapidly secreted and its blood
• C-reactive protein can be produced by vascular smooth
level, usually low in healthy individuals, can rise 100- to
muscle cells and adipocytes, which may contribute to its
200-fold or higher above the reference value within 10 hours,
role in vascular inflammation.
declining to baseline over a period of 7 to 12 days.4
• C-reactive protein levels can be modulated by statins,
C-reactive protein has been heavily studied in part
which may contribute to statin’s antiatherogenic effect.
because of its biologic profile; that is, it is not consumed or
Inflammation appears to play a pivotal role in all phases of produced during the reaction, its blood levels do not show
atherosclerosis, from the fatty streak lesion formation to diurnal or seasonal variation, and it has a 19-hour half-life.
the acute coronary event due to vulnerable plaque rupture.1 Analytical factors also play a role, including relative low cost
There are various inflammatory markers that have been of the available accurate high-sensitivity assays.5
shown to predict cardiovascular events. These include cell
adhesion molecules, cytokines, acute phase reactants, such
as fibrinogen, serum amyloid A, and C-reactive protein (CRP). C-Reactive Protein as a Clinical Marker
This last molecule, selected a simple downstream marker of
inflammation, has recently emerged as a major cardiovascu- C-reactive protein has been consistently shown to be a prog-
lar risk factor. nostic marker of adverse clinical cardiac events, such as
A large body of evidence has shown that atherosclerosis death, acute myocardial infarction (AMI), and urgent revas-
is an inflammatory disease. Indeed, vascular inflammation cularization in patients with acute coronary syndromes
contributes to the pathogenesis of atherosclerosis, and later (ACS). In the early 1990s, Liuzzo et al.6 demonstrated that
in the disease process, it is a major determinant for the acute CRP levels can predict clinical outcome of patients
coronary syndromes.1 Therefore, the identification of specific with acute coronary syndromes. This study specifically
triggers and mechanisms of underlying inflammation and a addressed the short-term predictive value of inflammatory
better understanding of each step involved in this complex markers, and of CRP in particular, in ACS evaluating the in-
process might lead to new ways to manage this important hospital composite rates of death, myocardial infarction (MI),
clinical problem. recurrent ischemia, and urgent revascularization in a selected
Among the inflammatory markers, CRP is the most population of patients with unstable angina (UA), all Braun-
extensively studied in cardiovascular disease.2,3 wald’s class IIIb, and negative troponin T values. The results

611
612 chapter 26

of this study showed that CRP levels, and, to a lesser extent, p Trend <.001
serum amyloid A (SAA) protein levels significantly predicted p <.001
3
adverse events. C-reactive protein serum levels above 3 mg/L p <.001

Relative risk of MI
(90th percentile of distribution in healthy subjects) was asso-
ciated with an approximately fivefold increased risk of recur- 2 p = .03
rent events. More recent large studies have supported the
finding that high serum CRP levels are predictors for short-
term mortality in patients with ACS.7,8 In particular, the 1
study by Morrow et al.7 showed an 18-fold increased risk of
death among patients with UA and non-ST elevation MI
(NSTEMI) (using a CRP determination and a cutoff of 15.5 mg/ 0
L). More recently, Mueller et al.8 have assessed the prognostic ≤0.055 0.056–0.114 0.115–0.210 ≥0.211
role of CRP in 1042 patients with non-ST elevation ACSs
(NSTEACSs) undergoing an early invasive strategy (within 24 Quartile of hs-CRP (range, mg/dL)
hours) and showed significantly higher in-hospital mortality FIGURE 26.1. Risk of future myocardial infarction (MI) in appar-
ently healthy men increases in higher quartiles of hs-CRP.
in patients having serum CRP levels greater than 10 mg/L
than in those with CRP less than 3 mg/L (3.7% vs. 1.2%). In
patients with NSTEACS, CRP significantly predicts the
recurrence of cardiac events even in the long term. Finally,
in the Honolulu Heart Study, the odds of MI rose not only in
the first few years of follow-up, but also for as long as 20 years
in the follow-up period. Thus, it is clear that inflammation Health Study were monitored for more than 8 years for the
plays an early as well as late role in the atherosclerotic process, development of first MI, stroke, or venous thrombosis (Fig.
and the assessment of CRP might provide a method to ascer- 26.1). In that study, baseline serum CRP levels were higher
tain that risk early in life.9 among men who developed MIs or strokes than among those
Interestingly, CRP has also been studied in sera from 302 who remained free of disease. Moreover, the men in the
autopsies from men and women whose only inflammatory quartile with the highest serum CRP values had three times
condition was atherosclerosis.10 The lowest elevation of the risk of MI as the men in the lowest quartile, whereas the
serum CRP was found in those who died of noncardiac risk of stroke was approximately doubled. Risks were stable
causes, whereas stable plaques showed a modest elevation, over long periods of time and were independent of other lipid
erosive plaques a greater elevation, and marked elevations in and nonlipid risk factors.
CRP were seen in ruptured plaques. Data from the Women’s Health Study have also been
In one study, baseline levels of CRP were significantly important in understanding the role of CRP in risk detection.
associated with the risk of sudden cardiac death over a 17- Among 28,263 apparently healthy postmenopausal women
year period (p for trend = .001).11 who were monitored prospectively for future vascular events,
C-reactive protein also has been shown to be a prognostic four inflammatory markers [CRP, SAA, interleukin-6 (IL-6),
marker of adverse clinical cardiac events in stable patients. and intercellular adhesion molecule-1 (sICAM-1)] were all
An important paper that addressed the issue of whether found to be significant predictors of risk; CRP, however, was
markers of inflammation predict risk of recurrent events the most significant predictor in univariate analysis, outper-
among stable patients with a prior history of MI was the one forming homocysteine, lipoprotein(a), and low-density lipo-
by Ridker et al.,12 a nested case-control study done in post-MI protein cholesterol (LDL-C)14,15 (Fig. 26.2).
patients as part of the Cholesterol and Recurrent Events
(CARE) trial. Blood samples from 391 participants who sub-
sequently developed recurrent nonfatal MI or a fatal event
were compared with samples from 391 age- and sex-matched
patients who did not have a recurrent event. Serum CRP and
Lipoprotein(a)
SAA levels in prerandomization samples were compared
with those at follow-up. Levels were higher among cases than Homocysteine
IL-6
controls (p = .05 for CRP; p = .006 for SAA). Those with levels
TC
in the highest quartile had a relative risk of a recurrent event
LDL-C
that was 75% higher than those in the lowest quartile (p =
slCAM-1
.02 for both CRP and SAA).12 Baseline lipid levels were virtu- SAA
ally identical among those with and without evidence of Apo B
inflammation. Thus, low-grade inflammation as assessed by TC: HDL-C
CRP predicts risk of recurrent events after MI. hs-CRP
These data in secondary prevention complement evi- hs-CRP + TC: HDL-C
dence in primary prevention that indicates that CRP levels
1.0 0 2.0 4.0 6.0
are a strong predictor of cardiac events, even after adjustment
Relative risk of future CV events
for traditional risk factors. FIGURE 26.2. Direct comparison of relative risk of future cardio-
This effect was initially described by Ridker et al.13 in vascular events associated with levels of lipid and inflammatory
1997, in which apparently healthy men from the Physicians’ risk factors in the Women’s Health Study.
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s 613
A subgroup analysis was limited to women with LDL-C
<130 mg/dL, the National Cholesterol Education Program
(NCEP) goal for primary prevention.16 In this analysis, women
with elevated baseline serum levels of CRP, SAA, IL-6, or 25
sICAM-1 were at increased risk for cardiovascular (CV) 20

Relative risk
events, but the effect remained strongest for CRP and
15
SAA.16
One of the new features of the NCEP publication was the 10
>3.0
inclusion of the metabolic syndrome in risk stratification.16 1.0–3.0 L
5 g/
This syndrome refers to the presence of at least three of the <1.0 m
,
following: abdominal obesity, elevated triglycerides, reduced 0 RP
10+ 5 to 9 2 to 4 0 to 1 -C
levels of high-density lipoprotein cholesterol (HDL-C), high h s
blood pressure, and high fasting glucose. All of these char- Framingham 10-Year risk (%)
acteristics are also modestly associated with elevated levels FIGURE 26.3. C-reactive protein adds prognostic information at all
of serum CRP. Moreover, serum CRP levels correlate with levels of risk as defined by the Framingham risk score.
other components of the metabolic syndrome that are not
easily measured in clinical practice, including fasting
insulin, microalbuminuria, and impaired fibrinolysis.17 To
address the role of CRP in the setting of the metabolic syn-
drome, a recent study evaluated interrelationships among
serum CRP levels, the metabolic syndrome, and incident CV
events among 14,719 apparently healthy women, 24% of
whom had the metabolic syndrome, who were followed up
for an 8-year period for MI, stroke, coronary revasculariza- mittee also recommended that serum CRP measurements
tion, or CV death. In brief, at all levels of the metabolic syn- could be a useful prognosticator in patients with ACS or
drome, serum levels of CRP improved risk prediction for stable CAD (class IIa, level B). However, the committee
future CV events. Furthermore, serum CRP levels were emphasized that the benefit of therapy based on serum CRP
highly predictive even among those with the metabolic syn- results is uncertain. This is an important first step in incor-
drome at study entry.17 In addition to predicting thrombotic porating CRP into the risk prediction strategy of CV
events, serum CRP levels also predicted type 2 diabetes, diseases.
which shares common inflammatory processes with athero- Recently, Danesh et al.21 reported that elevated serum
sclerosis.18 These findings have implications for therapies levels of CRP are associated with only a moderate increase
targeting insulin resistance and diabetes as well as cardio- in the risk of congestive heart disease (CHD). Although
vascular disease (CVD). these findings are consistent with the literature previously
As mentioned earlier, CRP is highly stable and can be discussed, the independent relative risk associated with
stored for many years without degradation. There are a increased serum CRP levels in the Danesh study is consider-
number of commercially available CRP measurements, and ably less than in previous reports. Using a multivariate
they are reasonably concordant in the CRP value measured. analysis, the authors found that the predictive value of CRP
Furthermore, there is no difference in the CRP distribution measurement adds relatively little to that provided by assess-
curve between men and women. Serum CRP levels are also ments of traditional risk factors. The new findings raised a
independent from age and racial consideration. Finally, there discussion and called into question the clinical value of mea-
is no diurnal variation in the serum CRP level.3 Thus, CRP suring CRP as a predictor of the risk of CHD. The authors
can be measured in a nonfasting individual at any time of concluded that the recent recommendations regarding the
the day. These attributes of CRP probably account for the use of measurement of CRP in the prediction of CHD may
clinical usefulness of serum CRP levels as a marker of need to be reviewed.21 However, several concerns were raised
inflammation.19 by experts in the field pointing out concerns about statistical
The American Heart Association and the Centers for or methodologic issues and how the authors may have under-
Disease Control and Prevention Consensus Report on using estimated the cardiovascular risk associated with serum
inflammatory markers as prognostic predictors in patients CRP values.22–25
with CVDs was published in Circulation in January 2003.20 We believe that CRP and cholesterol measurements
Although this report recommends that the entire adult popu- should be the cornerstones of CV risk stratification (Fig.
lation should not be screened for serum CRP levels for the 26.4). C-reactive protein is particularly useful in the patients
purpose of CV risk assessment (class III, level C), it concludes with LDL-C between 3.4 mmol/L and 4.1 mmol/L because
that measurement of serum CRP is reasonable for assessing that level of LDL demands a more aggressive management
absolute risk for coronary disease risk, particularly in inter- strategy either through lifestyle change or drug therapy (Fig.
mediate-risk individuals. Indeed, in patients with the Fram- 26.4).
ingham score of 10% to 20% risk, the CRP level may help Exercise and weight loss lead to reduction in serum CRP
direct future evaluation and therapy in the primary preven- levels.26 Furthermore, several statins have been shown to
tion of CVD (class IIa, level B) (Fig. 26.3). However, the com- reduce CRP levels by 25% to 50%.27–30 The Air Force/Texas
mittee considered CRP measurements to be less useful in Coronary Atherosclerosis Prevention Study (AFCAPS/
patients without CV risk factors (class IIb, level C). The com- TexCAPS) included men and women without CHD who had
614 chapter 26

insight into mechanisms by which more aggressive statin

regimens augment the reduction in vascular risk (Fig. 26.5
CRP level Interpretation and Table 26.1). In the study, patients assigned to receive
μg/mL 80 mg of atorvastatin daily were significantly more likely
than those assigned to receive 40 mg of pravastatin daily to
have a decrease in the levels of both LDL-C and CRP to the
target values. Nonetheless, once target levels were met, the
Repeat test in one month authors found little evidence of a differential outcome accord-
Exclude other processes ing to the specific statin given, suggesting that achieving the
target levels of LDL-C and CRP was more important in
determining the outcomes than was the specific choice of
10 statin.
Moreover, a large-scale, randomized clinical trial—Justi-
fication for the Use of Statins in Primary Prevention: an
High risk
Intervention Trial Evaluating Rosuvastatin (JUPITER)—will
evaluate the effects of statin therapy in subjects who have
3 both LDL-C levels below those currently used to target
Intermediate risk therapy and CRP levels that indicate heightened risk of a
1 CHD event. This trial is randomizing 15,000 men (>55 years)
Low risk
and women (>65 years) with no history of coronary disease,
LDL-C levels of <130 mg/dL, and hs-CRP levels of >2.0 mg/dL
to placebo or rosuvastatin, a new high-potency statin. 33,34
FIGURE 26.4. C-reactive protein level and cardiovascular risk. The
CRP levels are listed on the left and interpretations are on the Participants will be followed for a composite end point of MI,
right. stroke, unstable angina, cardiovascular death, or coronary
intervention.35 The results of JUPITER should provide impor-
tant information regarding the use of CRP values to guide
initiation of lipid-lowering therapy in a primary prevention
population deemed to be at low cardiovascular risk by current
criteria.

average total and LDL-C plasma levels and below-average

HDL-C plasma levels. Treatment with lovastatin in AFCAPS/
TexCAPS showed a risk reduction of 37% for first acute coro-
nary events over 5 years. An outcomes analysis was per-
formed (high sensitivity) with data from the participants
(aged 35 to 62 years) stratified by high or low total choles- 0.10 LDL cholesterol
terol/HDL-C ratio and hs-CRP (high sensitivity) values. ≥70 mg/dL,
Cumulative rate of recurrent myocardial infarction

Compared with results of the placebo arm, the statin arm CRP ≥2 mg/L
demonstrated marked event reduction in the high ratio/high LDL cholesterol
0.08
CRP, high ratio/low CRP, and low ratio/high CRP groups. In <70 mg/dL,
or death from coronary causes

contrast, statin therapy had little effect on the rate of events CRP ≥2 mg/L
in individuals with low ratio/low CRP values. Similar results LDL cholesterol
occurred in subjects stratified by LDL-C and hs-CRP levels 0.06 ≥70 mg/dL,
above and below baseline median values.31 These findings CRP <2 mg/L
suggest that serum CRP assay can identify individuals at LDL cholesterol
<70 mg/dL,
seemingly low risk who will nonetheless benefit from statin
0.04 CRP <2 mg/L
treatment.
Ridker et al.32 analyzed data from the pravastatin or ator-
vastatin evaluation and infection trial-thrombolysis in
myocardial infarction (PROVE-IT TIMI) 22 in order to inves- 0.02
tigate if statin treatment, lowering LDL and CRP levels,
affects clinical outcomes. The data indicate that among
patients with ACSs who are treated with a statin, achieving 0.00
a target level of CRP of less than 2 mg per liter is associated 0.0 0.5 1.0 1.5 2.0 2.5
with a significant improvement in event-free survival, an Follow-up (years)
effect present at all levels of LDL-C achieved. Furthermore, FIGURE 26.5. Cumulative incidence of recurrent myocardial
data from this study demonstrate the concomitant infarction or death from coronary causes, according to the achieved
importance of both lipid and CRP reduction, providing levels of both LDL cholesterol and CRP.
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s 615
TABLE 26.1. Relative risk of recurrent coronary events after statin therapy according to the quartile of low-density lipoprotein (LDL)
and c-reactive protein (CRP) levels achieved
Quartile

Variable 1† 2 3 4

Achieved LDL cholesterol

Quartile value—mg/dL <54 54–71 72–94 >94
Relative risk adjusted for age 1.0 1.1 1.3 1.8
95% confidence interval (CI) — 0.8–1.6 0.9–1.9 1.2–2.5
p value — 0.60 0.10 0.002
Relative risk adjusted for age and achieved CRP 1.0 1.1 1.3 1.7
95% Cl — 0.7–1.6 0.9–1.8 1.2–2.4
p value — 0.70 0.20 0.006
Relative risk adjusted for age and other risk factors 1.0 1.1 1.3 1.7
95% Cl — 0.7–1.6 0.9–1.9 1.2–2.5
p value — 0.70 0.20 0.003
Relative risk adjusted for age, achieved CRP, and other risk factors 1.0 1.1 1.2 1.7
95% Cl — 0.7–1.6 0.8–1.8 1.2–2.4
p value — 0.80 0.30 0.006
Achieved CRP
Quartile value—mg/L <0.9 0.9–1.9 2.0–4.2 >4.2
Relative risk adjusted for age 1.0 1.5 1.5 1.9
95% Cl — 1.0–2.3 1.0–2.3 1.3–2.8
p value — 0.04 0.04 <0.001
Relative risk adjusted for age and achieved LDL cholesterol 1.0 1.5 1.4 1.8
95% Cl — 1.0–2.2 1.0–2.1 1.2–2.6
p value — 0.06 0.07 0.004
Relative risk adjusted for age and other risk factors 1.0 1.5 1.4 1.8
95% Cl — 1.0–2.3 0.9–2.1 1.2–2.7
p value — 0.04 0.09 0.003
Relative risk adjusted for age, achieved LDL cholesterol, and other risk factors 1.0 1.5 1.3 1.7
95% Cl — 1.0–2.2 0.9–2.0 1.1–2.5
p value — 0.06 0.15 0.01

Biologic Effects of C-Reactive Protein Studies have also shown that CRP interacts with vascular
smooth muscle cells (VSMCs). It has been suggested that CRP
The link between CRP and atherosclerosis was initially sug- induces relaxation of human vessels independent from endo-
gested to be that of a surrogate biomarker versus a mediator thelium.41 C-reactive protein causes in vitro nuclear factor
of atherosclerosis. This view has been recently revisited, (NF)-κB activation, which could lead to the induction of
with a significant literature suggesting that CRP has a direct MCP-1, IL-6, and iNOS gene expression. It also activates the
proatherogenic and proinflammatory effect, thus participat- mitogen-activated protein kinase (MAPK) pathway.42 C-
ing in lesion formation and plaque vulnerability. reactive protein was recently demonstrated to markedly
A growing body of evidence indicates that CRP directly upregulate AT1-R messenger RNA (mRNA) and protein ex-
interacts with different vascular cells. pression and increase AT1-R numbers on VSMCs. Further-
First, several reports have described effects supposed to more, CRP promotes VSM migration and proliferation in vitro
be atherogenic by CRP, at concentrations known to predict and increases reactive oxygen species (ROS) production.43
vascular events, on endothelial cells. We have demonstrated Finally, several reports have shown an interaction of CRP
that a dose-dependent significant expression of ICAM-1, vas- with monocytes and macrophages. C-reactive protein has
cular cell adhesion molecule-1 (VCAM-1), and E-selectin was been demonstrated to induce tissue factor expression and
detected in human umbilical vein endothelial cells (HUVECs) release in monocytes/macrophages.44 Furthermore, CRP acts
following CRP stimulation.36 Furthermore, CRP was demon- as a chemoattractant for monocytes.45 Importantly, soluble
strated to induce expression of monocyte chemoattractant CRP and immobilized CRP have been demonstrated to
protein-1 (MCP-1) in HUVECs.37 An involvement of endothe- mediate the uptake of native LDL into macrophages.46
lin-1 (ET-1) and IL-6 in these CRP-mediated effects was dem- Another important mechanism of CRP action in athero-
onstrated in saphenous vein endothelial cells.38 C-reactive sclerosis is the ability of the protein to activate the comple-
protein was also shown to inhibit nitric oxide (NO) produc- ment system via the classic pathway.47 It has been known
tion and stimulation of NO release via downregulation of for years that complement plays a role in atherosclerosis.48
endothelial NO synthase (eNOS).39 Lastly, CRP was demon- It has been shown that animals lacking components of
strated to increase plasminogen activator inhibitor-1 (PAI-1) the complement system are protected against diet-induced
in human aortic endothelial cells.40 atherogenesis.49 Various complement proteins, including
616 chapter 26

the terminal complement complex C5b-9, have been shown the concentration of 10 mM (10 times higher than present in
to deposit in human and animal atherosclerotic lesions, but our experiments with CRP) does not affect ICAM-1 expres-
not in healthy arterial tissue.50,51 Since there is now evidence sion on endothelial cells.56
that CRP colocalizes with activated complement fragments With the development of a human CRP-transgenic (CRP-
in atherosclerotic lesions and in infarcted myocardium, tg) mouse, an animal model is now available to determine
CRP-mediated complement activation in the arterial the role CRP plays in vivo. It is important to remember that
wall may be an important pathogenic feature in human mice do not produce CRP in measurable quantities, and the
atherogenesis.51–53 primary pentraxin for immunity in the mouse is the serum
However, several questions about CRP’s mechanism of amyloid P. Two studies revealed that expression of human
action remain unanswered. Recently, Khreiss et al.54 pro- CRP in mice actively promoted adverse cardiovascular pro-
vided evidence suggesting that native, pentameric CRP must cesses. First, human CRP created a prothrombotic pheno-
undergo structural modification, forming monomeric- type, as evidenced by higher rates of thrombotic occlusion
modified subunits, before promoting a proinflammatory after arterial injury.60 Second, by crossing CRP-tg mice with
phenotype named mCRP. This molecular finding may serve apolipoprotein E (apoE)–/– mice, CRP was shown to be an
to influence not only basic molecular research examining active player in atherogenesis in vivo.61 These CRP-tg/
CRP’s detrimental effect, but also the clinical use of CRP as apoE–/– mice had accelerated aortic atherosclerosis, which
a prognostic marker. However, diagnostic differentiation was associated with increased complement deposition and
between the different forms of CRP is not available at the elevated expression of angiotensin type 1 receptor, VCAM-1,
present time. Though it is still unclear, the findings by and collagen within the lesions.61 Further studies using these
Khreiss et al. raise the possibility that patients with more CRP-tg mice will no doubt confirm the in vitro results impli-
mCRP or CRP with a tendency to become modified more cating CRP with endothelial dysfunction, as evidenced by
readily may exhibit a greater proinflammatory phenotype impaired NO production and enhanced endothelin-1 release.
and hence be at even greater risk for adverse cardiovascular Furthermore, it will provide a model to assess new therapeu-
events. C-reactive protein must undergo a structural change tic strategies aimed at decreasing CRP levels and to deter-
on cell membrane binding for endothelial activation, and this mine whether this strategy has an effect on plaque initiation,
active component is deposited in the wall of the blood vessel, progression, and rupture.
where it can promote atherogenesis. In this paper, the authors
showed that mCRP was able to induce endothelial activation
within 4 hours, whereas with native CRP, similar results C-Reactive Protein Receptors
were not obtained until 24 hours later, because mCRP actions
were based on a tissue rather than a serum environment. C-reactive protein binding to cellular receptors has been
Because the effects of native CRP are dependent on an intensively investigated with conflicting results. There are
unidentified serum cofactor,36 a cofactor that may not be no clear data as to whether CRP could interact with FC
present at physiologic levels in cell culture, in vitro concen- receptors or with a specific CRP receptor.62,63 In support of
trations of CRP may need to be higher to compensate for this the last theory, it has been reported that binding of native
difference. CRP to monocytic U-937 cells is not prevented by a blocking
In collaboration with the Khreiss group, we have recently anti-CD32 (FcγRII) monoclonal antibody.62
tried to identify this cofactor in in vitro experiments. We did C-reactive protein binding to FcγRs has been suggested
show a clear synergy between both native and mCRP and in monocytes, and direct evidence for binding of native
CD14, a molecule involved in the innate host defense,55 in CRP to COS cells transfected with CD64 (FcγRI) has been
the activation of the endothelial cells evaluated by ICAM-1 reported.64,65 Neutrophils, however, do not normally express
expression.56 In these experiments, CD14 appeared to be a CD64, but do express the low-affinity immunoglobulin G
strong cofactor enhancing proinflammatory activity of the (IgG) receptors CD16 (FcγRIII) and FcγRII.66
two structural distinct isoforms of CRP; moreover, the com- The low-affinity IgG receptor FcγRIIa was proposed to be
bination of mCRP and CD14 produced stronger activation of the major CRP receptor on leukocytes,63,67 and evidence sup-
endothelial cells than combined treatment with mCRP and ports this theory. It has been reported that native CRP binds
lipopolysaccharide (LPS), another suggested serum cofactor. phagocytic cells (neutrophils and monocytes) with a specific
More recently a contamination issue has been raised FcγRIIa allelic phenotype, thereby implicating FcγRIIa R/
about CRP obtained from commercial sources and some of R131 as the receptor for native CRP on human phagocytes.67
its biologic properties. In particular, two reports have demon- Furthermore, CRP was reported to induce FcγRIIa signaling
strated that CRP has no acute vasoactive properties per se, in granulocytes, and experiments in mice that were FcγRII-
but commercially available preparations do because of the and γ-chain–deficient showed deficient CRP-mediated
presence of the preservative NaN3.57,58 It is a well-established biologic responses compared with wild-type mice.68 Certain
fact that sodium azide is a potent vasorelaxant and that the investigators, however, have not been able to reproduce these
most commonly reported health effect from azide exposure findings and recommend caution in interpretation of the data
is hypotension.59 Thus, to address if other CRP biologic about CRP binding to FcγRs. The major criticism of these
effects observed in vitro are due to NaN3 contamination, we studies is the use of anti-CRP antibodies in the detection of
have performed control experiments looking at membrane CRP binding to FcγRIIa, thus possibly causing false-positive
ICAM-1 expression on endothelial cells, detected by flow results due to IgG contamination of the CRP reagent.69 Fur-
cytometry, following exposure to CRP or NaN3 at concentra- thermore, a recent review claims that CRP does not interact
tions found in the commercial preparations. NaN3 even at at all with FcRs.70
 i n f l a m m at ion, c-r e ac t i v e p rot e i n, a n d v u l n e r a bl e p l aqu e s 617
Attempting to resolve this controversy, Manolov et al.71 specifically the cell type involved in the local generation of
used a different technique (ultrasensitive fluorescence micro- CRP within the arterial wall.
scopy) to study the association, dissociation, and equilibrium Attempting to address this important question, we re-
of CRP binding to FcγRIIa. In this report, the authors cently showed that human coronary artery smooth muscle
demonstrated that CRP indeed binds to FcγRIIa with low cells (HCASMCs), but not human umbilical vein endothelial
association and dissociation rates, thus providing the first cells (HUVECs), can synthesize CRP following stimulation
quantitative characterization of CRP binding to FcγRIIa. by inflammatory cytokines.78 The HCASMCs and HUVECs
were stimulated with IL-1β, IL-6, their combination, TNF-α,
or LPS at different concentrations and the cell culture super-
C-Reactive Protein Production natants were analyzed by high-sensitivity enzyme-linked
immunosorbent assay (ELISA) specific for human CRP. C-
One of the outstanding unresolved issues about CRP is reactive protein production was minimal without stimula-
the source of production in humans. It has been assumed tion, and incubation of HCASMCs with 50 ng/mL of IL-1β or
that only the liver in response to microbial infection, tissue 10 ng/mL of IL-6 alone led to a small, but significant induc-
injury, and autoimmune disorders synthesizes CRP, as with tion. Maximal CRP production was observed after the com-
other acute-phase proteins. It had been shown that IL-1β, bination of the two cytokines. Tumor necrosis factor-α or
tumor necrosis factor-α (TNF-α), and IL-6 strongly induced LPS also induced a similar level of CRP production and
the expression of CRP in human hepatocytes and in hepa- showed a dose-response relationship. In contrast, CRP pro-
toma cell lines.72,73 Moreover, two IL-6 responsive elements duction could not be detected in HUVECs following similar
have been identified proximal to the site of initiation of stimulation protocols.
transcription of the protein.74 To confirm the results of CRP protein production in
More recently, however, several studies expanded the HCASMCs, we also assayed the mRNA levels in HCASMCs
variety of cell types that could participate in CRP produc- by RT-PCR using specific primers for the CRP. Interleukin-1β
tion. Two studies have shown that both epithelial cells of the plus IL-6 combination caused a significant increase in CRP
respiratory tract and renal epithelium can produce CRP mRNA level compared to baseline. Treatment with LPS and
under certain circumstances.75,76 Gould and Weiser75 demon- TNF-α also upregulates the CRP mRNA levels.
strated that CRP is present in secretions of the human Our findings, thus, provided a direct demonstration that
respiratory tract, that human respiratory epithelial cells are HCASMCs, but not HUVECs, are a source of locally pro-
capable of CRP expression, and that this protein may con- duced CRP in the arterial wall.78 The locally produced CRP
tribute to bacterial clearance in the human respiratory tract. may directly participate in atherogenesis and the develop-
Jabs et al.76 showed that renal cortical tubular epithelial cells ment of cardiovascular complications.
(TECs) express CRP mRNA and protein after stimulation More recently, we have also shown for the first time
with inflammatory cytokines, concluding that inflamed using an in vitro system that human adipocytes can produce
kidneys represent a novel site of CRP formation in vivo. CRP under similar inflammatory conditions. We have inves-
Moreover, neuronal cells also seem to be capable of synthe- tigated whether CRP is produced by cells in adipose tissue
sizing acute-phase reactants involved in the pathogenesis of in response to inflammatory stimuli in culture, and we have
neurodegenerative disease such as Alzheimer’s disease demonstrated that human adipocytes, but not preadipocytes,
(AD).77 These data shed new light on the acute-phase reaction cultured in vitro produce CRP following exposure to inflam-
not merely representing a systemic inflammatory pathway, matory cytokines, such as IL-1β, IL-6, TNF-α, LPS, and
but probably being part of the local immune response. The resistin. Moreover, the response to the different molecules
relevance of these observations to the pathogenesis of athero- was additive, peaking in adipocytes incubated with all the
sclerosis is uncertain. stimuli. Interestingly, resistin, the most recently identified
Interestingly, CRP has been observed to colocalize adipocytokine and proposed as an inflammatory marker for
with the terminal complement complex in atherosclerotic atherosclerosis, also induced an increase in CRP production
plaques.51 In this report, however, the authors suggested that by adipocytes.79
CRP presence is due to deposition from circulating CRP These data confirm that the adipocyte, largely thought
produced by the liver instead of local synthesis. to be an inert storage cell whose main function was to
In contrast, work by Yasojima et al.53 using different store excess energy in the form of triglycerides, has a
techniques suggested that cells in the arterial wall synthe- more complex role in the organism, thus suggesting a link
size CRP. By reverse-transcriptase polymerase chain reaction between inflammatory status, obesity, and cardiovascular
(RT-PCR), they detected the mRNAs for CRP and the events.79
classic complement components C1 to C9 in both normal
arterial and plaque tissue, establishing that they can be
endogenously generated by arteries, with plaque levels 10.2- Summary
fold higher than normal artery. By Western blotting, they
showed that the protein levels of CRP and complement pro- To better understand the role of CRP as a clinical marker,
teins were also upregulated in plaque tissue and that there we have to wait for more clinical data; in particular, the
was full activation of the classic complement pathway. By results of the Jupiter trial will help regarding the use of
in situ hybridization, they also detected intense signals for serum CRP values to guide initiation of lipid-lowering
CRP and C4 mRNAs in smooth muscle–like cells and mac- therapy in a primary prevention population deemed to be at
rophages in the thickened intima of plaques, thus not showing low cardiovascular risk by means of current criteria.
618 chapter 26

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45. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein U-937. J Immunol 1990;144(1):231–238.
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47. Kaplan MH, Volanakis JE. Interaction of C-reactive protein 65. Marnell LL, Mold C, Volzer MA, Burlingame RW, Du Clos TW.
complexes with the complement system. I. Consumption of C-reactive protein binds to Fc gamma RI in transfected COS
human complement associated with the reaction of C-reactive cells. J Immunol 1995;155(4):2185–2193.
protein with pneumococcal C-polysaccharide and with the 66. Ravetch JV, Perussia B. Alternative membrane forms of Fc
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1974;112(6):2135–2147. phils. Cell type-specific expression of two genes that differ in
48. Torzewski M, Torzewski J, Bowyer DE, et al. Immunohisto- single nucleotide substitutions. J Exp Med 1989;170(2):481–
chemical colocalization of the terminal complex of human 497.
complement and smooth muscle cell alpha-actin in early ath- 67. Stein MP, Edberg JC, Kimberly RP, et al. C-reactive protein
erosclerotic lesions. Arterioscler Thromb Vasc Biol 1997;17(11): binding to FcgammaRIIa on human monocytes and neutro-
2448–2452. phils is allele-specific. J Clin Invest 2000;105(3):369–376.
49. Buono C, Come CE, Witztum JL, et al. Influence of C3 deficiency 68. Stein MP, Mold C, Du Clos TW. C-reactive protein binding to
on atherosclerosis. Circulation 2002;105(25):3025–3031. murine leukocytes requires Fc gamma receptors. J Immunol
50. Seifert PS, Hugo F, Hansson GK, Bhakdi S. Prelesional comple- 2000;164(3):1514–1520.
ment activation in experimental atherosclerosis. Terminal 69. Hundt M, Zielinska-Skowronek M, Schmidt RE. Lack of spe-
C5b-9 complement deposition coincides with cholesterol accu- cific receptors for C-reactive protein on white blood cells. Eur
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Lab Invest 1989;60(6):747–754. 70. Pepys MB, Hirschfield GM. C-reactive protein: a critical update.
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in the intima of early atherosclerotic lesions of human J. Ultrasensitive confocal fluorescence microscopy of C-
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72. Moshage HJ, Roelofs HM, van Pelt JF, et al. The effect of inter- 76. Jabs WJ, Logering BA, Gerke P, et al. The kidney as a second
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2 Atherosclerotic
7 Vulnerable Plaques:
A Pathophysiology,
Detection, and Treatment
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

Pathologic Features of Culprit Lesions Responsible Detection of Vulnerable Plaques: The Need for
for Acute Coronary Syndromes . . . . . . . . . . . . . . . . . 623 New Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . 624
Histopathologic Features of Culprit Lesions. . . . . . . . . . 623 Imaging of Vulnerable Plaques: Invasive Methods . . . . . 625
“Vulnerable Blood” and the Role of the Noninvasive Imaging of Vulnerable Plaques. . . . . . . . . . 628
Coagulation System . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Treatment of Vulnerable Plaques . . . . . . . . . . . . . . . . . . . 630
Use of Inflammatory Biomarkers for Detection Avoiding “Triggers” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
of High-Risk Patients. . . . . . . . . . . . . . . . . . . . . . . . . . 624 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633

myocardial infarction, and sudden cardiac death) often

Key Points develop following superimposition of an arterial thrombus
• Atherosclerotic plaque ulceration and fissuring lead to and dynamic coronary vasoconstriction over an underlying
thrombosis and vasoconstriction. disrupted atherosclerotic plaque. Luminal narrowing by
• Local coagulation factors and blood components, in inward-growing atherosclerotic plaques (sometimes exagger-
addition to plaque fissuring and ulceration, contribute ated by coronary spasm) cause the ischemic manifestations
to determining the development of thrombosis. of coronary heart disease. This process is often complicated
• Several different imaging procedures, including intra- by formation of a mural or occluding thrombus over the
vascular ultrasound, elastography, thermography, optical atherosclerotic lesion. Coronary thrombosis is a key event
coherence tomography (OCT), magnetic resonance in the development of acute myocardial infarction. First
imaging (MRI), and computed tomography (CT) are being suggested in 1912 by James Herrick, the pivotal role of
developed to detect vulnerable atherosclerotic plaques. thrombosis in the development of unstable angina and
• Although it is variable among patient groups, perhaps myocardial infarction was finally confirmed through experi-
20% to 40% of patients with acute coronary artery mental studies in animals, and angiography and angioscopy
syndromes have more than one vulnerable plaque, studies in humans the last two decades of the 20th
suggesting a relatively widespread inflammatory state century.3–6
within the coronary arteries. Atherosclerosis is an inflammatory disease resulting
from acute or multiple repeated injuries inflicted upon
Cardiovascular disease is the leading cause of death for the endothelium and arterial wall, beginning early in
both men and women in the United States and most other life.7–10
developed countries.1 Its rate is rapidly rising in developing High plasma concentrations of low-density lipoprotein
countries, and will become the leading cause of death (LDL) cholesterol, elevated blood pressure, diabetes, smoking,
worldwide by 2010.2 In the majority of cases, atherosclerosis elevated homocyst(e)ine level, oxidant stresses, systemic
is the primary pathologic mechanism responsible for coro- and local inflammation, infections, low high-density lipo-
nary artery disease, ischemic stroke, and peripheral vascular protein (HDL), and other factors (e.g., trauma, radiation, psy-
disease. Acute coronary syndromes (unstable angina, acute chosocial stress, hypercoagulability, and anatomic locations

6 21
622 chapter 27A

that confer abnormally high or low shear stress) play impor- proteinase inhibitors.13,16,17 This sequence of events eventu-
tant roles in atherogenesis and development of plaques. ally results in the weakening and thinning of the fibrous cap,
Together these variables account for the majority of cases. particularly at the shoulder area of the plaque where a larger
The search for the remaining attributable risk is focused number of inflammatory cells are usually present.18 A weak-
on both genetic and lifestyle factors. Polymorphisms that ened fibrous cap, coupled with high mechanical stress (again
have modest associations with coronary atherosclerosis have higher at the plaque shoulder) may eventually lead to disrup-
been described for genes involved in lipoprotein metabolism, tion of the fibrous cap and plaque rupture.19
hypertension, inflammation, oxidation, and regulation of the Disruption of plaque surface or endothelium denu-
cell cycle, as well as in genes not known to be involved in dation exposes the underlying highly thrombogenic tissue-
atherosclerosis, and in genes of unknown function.11,12 Some factor–rich matrix to circulating platelets and white blood
of these associations have been found in one kindred and not cells.20 These changes, usually associated with platelet
in others. adhesion and aggregation, coupled with the release of
A complex set of inflammatory cytokines and different prothrombotic and proinflammatory cytokines, and dy-
cellular components are involved in initiation and progres- namic vasoconstriction initiate the coagulation cascade and
sion of atherosclerosis (Fig. 27A.1). Persistent endothelial chain of events leading to transition of a stable plaque
injury leads to monocyte recruitment, macrophage infiltra- to an unstable plaque, often accompanied by thrombus
tion, activation of T cells, mast cells, and recruitment of formation and resulting clinical syndromes.21 Several differ-
dendritic cells (rarely neutrophils), each contributing to and ent platelet- and non–platelet-derived mediators, including
aggravating the inflammatory state in the plaques.13–15 thromboxane A 2, serotonin, adenosine diphosphate (ADP),
Chronic inflammation in plaques inhibits the production of thrombin, tissue factor, oxygen-derived free radicals, plate-
collagen by the smooth muscle cells and, at the same time, let-activating factor, and endothelin contribute to throm-
enhances collagen breakdown by increasing the release of bosis formation and vasoconstriction in injured arteries
matrix metalloproteinases and decreasing the activity of (Fig. 27A.2).22–28

FIGURE 27A.1. A complex set of inflammatory cytokines derived from different cellular components (macrophages, smooth muscle cells,
platelets, endothelial cells, dendritic cells, T lymphocytes, and mast cells) play roles in initiation and progression of atherosclerosis.
 at h erosclerot ic v u l n er a ble pl aqu es 623
TABLE 27A.1. Pathologic features commonly associated with
vulnerable plaques
Large lipid pool (>40% plaque volume)
Thin fibrous cap (<65 μm)
Macrophage infiltration
Activated T cells and mast cells
Outward remodeling
Decreased collagen content of cap
Necrotic core
Increased neoangiogenesis
Calcium nodule

Histopathologic Features of Culprit Lesions

Most of our current knowledge about atherosclerotic lesion-
induced coronary thrombosis, rapid lesion progression, or
symptomatic disease is derived from retrospective autopsy
studies.31,33,39 The plaques in these studies are often called
“culprit lesions.”
Histologically, the culprit lesions often show one of the
following features:
Plaque rupture: A ruptured plaque is the most common cause
of coronary thrombosis and is responsible for 60% to 70%
of cases of sudden cardiac death (SCD) or acute myocardial
infarction (AMI). Ruptured plaques present with a deep
plaque injury and a significant, real defect or gap in the
fibrous cap. This defect often exposes the thrombogenic
FIGURE 27A.2. Several different platelet- and non–platelet-derived plaque tissue to blood.31,39,40 These lesions often demon-
mediators including thromboxane A 2, serotonin, adenosine diphos- strate a large lipid pool (>40% plaque volume), a necrotic
phate (ADP), thrombin, oxygen-derived free radicals, platelet-
core, a thin fibrous cap (<65 μm), large number of macro-
activating factor, and endothelin contribute to thrombosis for-
mation and vasoconstriction in injured arteries. phages, outward remodeling, decreased collagen content
of cap, and increased neoangiogenesis (Table 27A.1). Ret-
rospective studies suggest that a thin-cap fibroatheroma
(TCFA) closely resembles a ruptured plaque and can be
considered as a prototype rupture-prone lesion (Fig. 27A.3)

Pathologic Features of Culprit Lesions

Responsible for Acute Coronary Syndromes
Retrospective autopsy studies since the 1960s have demon-
strated that a majority of sudden cardiac death and myo-
cardial infarction cases arise from coronary lesions,
demonstrating rupture or erosion and often showing consid-
erable degrees of inflammation, yet causing percent area
stenosis of only 70% to 90%, corresponding to 50% to 70%
diameter stenosis.29–35 First introduced in 1989, the terminol-
ogy and definition of vulnerable plaques have been consis-
tently debated and updated.36,37 The latest consensus by
experts in the field 38 has suggested the following terminol-
ogy: Lesions at an increased risk for thrombosis or rapid
progression are called “vulnerable” or “high-risk” plaques.38
The term thrombosis-prone may also be applied to such
plaques. These terms mainly describe the concept and
function of these lesions and do not present their histologic
characteristics. Patients may be considered “high risk” or
FIGURE 27A.3. Histopathologic features of vulnerable atheroscle-
“vulnerable” based on the presence of high-risk/vulnerable rotic plaques include a thin fibrous cap, a large lipid core, mild to mod-
plaques, or high-risk blood, or an increased conventional risk erate deep calcification, outward remodeling, neovascularization, and
factor profile.38 infiltration of inflammatory cells especially at the shoulder region.
624 chapter 27A

and a culprit for the majority of acute coronary syndromes Use of Inflammatory Biomarkers for Detection
(ACSs). Many of these features have been used as targets of High-Risk Patients
for diagnostic imaging techniques that will be described
later.41,42 For information on this subject, see Chapter 27B.
Plaque erosion: Eroded plaques are more often observed in
younger smoking women.32,39 Plaque erosion features a
loss or dysfunction of endothelium, with no disruption Detection of Vulnerable Plaques: The Need for
of the fibrous cap. These lesions do not show any struc- New Imaging Techniques
tural defect or gap in the plaque, which is often rich in
smooth muscle cells and proteoglycans.35 Almost half of the cases of MI present as SCD with no prior
Calcified nodule: A plaque with a calcified nodule is an diagnosis of coronary artery disease.47,48 This suggests that
uncommon type of plaque and is responsible, at most, for our current clinical evaluation methods (e.g., risk factor
5% of acute coronary events. These lesions are character- charts, electrocardiography, angiography, and stress tests) fail
ized by heavy calcification and the loss or dysfunction of to accurately identify either vulnerable lesions or vulnerable
endothelial cells over the calcified nodule.35 patients.
For decades, coronary arteriography has been the “gold
standard” technique for identifying atherosclerotic coronary
“Vulnerable Blood” and the Role of the lesions and guiding in lesion-specific treatments for isch-
Coagulation System emic heart disease. However, serial angiogram studies in the
mid-1980s showed that up to two thirds of AMIs develop
Vulnerability of individuals to develop a clinical coronary from culprit lesions with a luminal diameter narrowing of
event not only is dictated by the presence of vulnerable often <50% and without hemodynamic significance (Fig.
plaques, but also is affected by the status of their coagulation 27A.4).49–53 In a series of classic studies, Glagov et al.54 showed
system and the vulnerability of their myocardium to isch- that human coronary arteries enlarge in relation to plaque
emic events. Vulnerable plaques and even ruptured plaques area, and therefore plaque mass (at least in lesions with <40%
may be found in people with no symptoms prior to their cross-sectional luminal narrowing) is not correlated with
myocardial infarction (MI). A rupture may occur at a time lumen size in humans. Indeed, a study by Naqvi, Shah, and
when the patient’s blood is less prone to coagulation. In fact, colleagues55 examined the perfusion imaging stress tests of
longitudinal studies of subjects with ruptured plaques in patients who subsequently had nonfatal MI. Only 60% of the
their coronary arteriograms have shown a low incidence of infarcts developed in a territory that was ischemic on the
clinical events when they are vigorously treated with plaque- prior study, which exceeds the 33% random expectation but
stabilizing medications, such as statins and antiplatelet is far below the expected 100%. Techniques are needed to
medications.43 Coagulation may be affected by genetic dif- identify those particular lesions that may not be stenotic, but
ferences, diet, smoking, homocysteine levels, viscosity, and are at increased risk of developing an acute complication in
use of different medications. There is a strong interaction the near future.41
between the coagulation system and the inflammatory This challenge becomes more serious when one considers
processes, and their dual inhibition is an important step in the fact that these less-severely stenotic plaques are 5 to 10
stabilizing vulnerable patients.10 Local factors, such as spasm, times more common than severely stenotic plaques.13 In fact,
stenosis, proximal location of the lesion, and shear stress asymptomatic atherosclerotic lesions may be found in a large
may affect thrombosis development propensity as well.
In fact, individuals vary in their genetic levels of protein
S, protein C, or activated protein C (e.g., factor V Leiden).
Moreover, even in the same individual, susceptibility to
thrombosis may substantially fluctuate over time. In fact, 200
animal studies have shown that individual propensity for 180 27

arterial thrombosis may be more influenced by blood compo- 160

nents than by elements within the arterial wall.44 In addition
Number of MI patients

35

to the proinflammatory and prothrombotic state of athero- 140

sclerotic plaques, the loss of the normal thrombotic–throm- 120
bolytic equilibrium in the circulating blood, and local flow 100
conditions, play major roles in thrombosis formation. Coagu- 12
80
lation is more likely after ingestion of a fatty meal, smoking, 8
132
dehydration, lack of physical activity, many infections, use 60
of estrogens, stress, presence of adenocarcinoma, polycythe- 40 1
10 72
13
mia, thrombocytosis, hyperhomocyst(e)inemia, increased 20 5
6
7
circulating pool of tissue factor (TF), factor V and VII, high 11
27 23

lipoprotein (a) [Lp(a)] levels, and discontinuation of antithrom- 0 Little et al 1988 Nobuyoshi et al 1991 Giroud et al 1992
Ambrose et al 1988 ALL

botic or antiinflammatory medication.45,46 In addition to dif- <50% 50-70% >70%

ferences in the thrombotic diathesis of the patient’s plasma, FIGURE 27A.4. Majority of acute myocardial infarctions develop
coagulation will be favored by low shear stress, slow flow due from culprit lesions with a luminal diameter narrowing of often
to spasm, mural thrombosis, embolism or stenosis. <50% and without hemodynamic significance.53
 at h erosclerot ic v u l n er a ble pl aqu es 625

FIGURE 27A.5. Different diagnostic methods for detection of vul- ultrasound (IVUS), angioscopy, optical coherence tomography
nerable plaques. Counterclockwise: Magnetic resonance imaging (OCT), thermography, virtual histology, near-infrared (NIR).
(MRI), computed tomography (CT) scan, angiography, intravascular

number of people, even in the very early years of life. Ath- Multiple new technologies for in vivo characterization of
erosclerosis develops in early childhood as fatty streaks along vulnerable plaques in patients are under development (Fig.
the arterial tree, and progresses toward more advanced lesions 27A.5).41 These new techniques focus on one or more histo-
over the years. This was first described by William Osler,56 logic or functional features of vulnerable plaques (e.g., struc-
and later described in detail by Enos et al.,57 McNamara et ture, composition, deformability, cellular density, chemical
al.,58 and others59,60 who showed the presence of atheroscle- composition, metabolic state, temperature, etc.).
rotic coronary artery disease in young U.S. soldiers killed
during the Korean and Vietnam Wars. These findings were
later confirmed in the Pathobiological Determinants of Ath- Imaging of Vulnerable Plaques:
erosclerosis in Youth (PDAY) and the Bogalusa studies, which Invasive Methods
showed that atherosclerosis originates in childhood and is
related to the presence of coronary artery disease (CAD) risk
Coronary Arteriography
factors.59,60 This has been observed in other countries as
well.61 More recent studies using in vivo diagnostic tech- First introduced in 1958, coronary arteriography has been the
niques, such as intravascular ultrasonography (IVUS) have method of choice for assessment of luminal stenoses in coro-
also shown a high prevalence of atherosclerotic lesions in nary artery lesions. However, it has limited spatial resolution
asymptomatic subjects.62 Using IVUS in asymptomatic and is unable to detect fine calcification and fine irregulari-
transplant donors, Tuzcu et al.62 found coronary atheromas ties of the luminal surface, including fissuring and superfi-
in 17% of donors younger than 20 years, 37% of those aged cial thrombosis. Most importantly, however, arteriography,
20 to 29 years, and 60% of those aged 30 to 39 years, whereas by virtue of its reliance on luminal contrast, is in fact a
arteriography failed to find lesions in 97% of these individu- “luminography” technique and reveals almost nothing about
als. Despite the high prevalence of atherosclerotic disease the plaque contents and thus, using current equipment and
in adults, only a relatively small fraction of these indivi- techniques, angiographers are not able to assess plaque
duals develop cardiovascular complications. Therefore, new inflammation, cap thickness, or the size of the lipid pool.
imaging techniques need not only to detect the anatomic Nevertheless, several arteriographic features have been
presence of often nonsignificant lesions, but also to deter- shown to be of prognostic importance. These arteriographic
mine the functional characteristics associated with their predictors of lesion progression include the presence of throm-
vulnerability. bosis,63,64 ulcerated lesions,65 irregular surface, and long
626 chapter 27A

lesions.63,66 Coronary spasm could predict progression in a rupture, one had an erosion, and 20 had neither. Arteriogra-
few studies67,68 but not others.69 Lesions in the right coronary phy was not as sensitive as IVUS in detecting rupture.78
artery (RCA) and the left anterior descending (LAD) are also
more prone to progress.66,67 A proximal location and a branch Intravascular Ultrasound Elastography
point position, or being on the inner curve of a vessel (or other
Intravascular ultrasound elastography technology is based on
region of abnormally low shear stress such as a “shelf”)
the differences in hardness and elasticity of tissues with dif-
are also predictors of progression.49 Recently, “blush sign” or
ferent histopathologic composition. This technique assesses
transient retaining of faint contrast in the plaque after passage
the conformational change in coronary plaques resulting
of the dye column (possibly reflecting fissuring or neovascu-
from intracoronary pressure changes during the cardiac
larization) has been described as a strong predictor of progres-
cycle. By measuring the local strain over the plaque, this
sion in hemodynamically insignificant lesions.70
technique can discriminate between soft and hard tissues.
Intravascular ultrasound elastography combines ultrasound
Intravascular Ultrasound images with radiofrequency measurements to detect regions
of increased strain that have been shown to be vulnerable to
Intravascular ultrasound (IVUS) uses miniaturized crystals
rupture. Elastography can assess the mechanical properties
incorporated at catheter tips and provides real-time, cross-
of the arterial wall, and soft, vulnerable plaques have a higher
sectional and longitudinal, high-resolution images of the
strain level than hard plaques. Fibrous caps of vulnerable
arterial wall with three-dimensional (3D) reconstruction
plaques have a high strain level and, by discriminating lipid-
capabilities.71 The safety of this technique is well estab-
rich plaques from fibrous ones, elastography can be used for
lished.72 It is a widely available technology and is increas-
detection of plaques at risk of rupture.79,80 Ex vivo studies
ingly used routinely in clinical practice and for research
have shown that measured strain is positively correlated
purposes. Common two-dimensional (2D) IVUS images use
with the number of macrophages and is inversely correlated
ultrasound frequencies in the range of 20 to 40 MHz and
with the number of smooth muscle cells.81 In vivo pig studies
generate an axial resolution of 100 to 200 μm and a lateral
have demonstrated the accuracy of IVUS elastography in
resolution of 250 μm. Intravascular ultrasound allows precise
identifying lipid-rich plaques and macrophages. Fatty plaques
tomographic measurement of lumen area and plaque size,
show higher strain compared to fibrous lesions, and high-
distribution, and, to some extent, composition.73 It provides
strain plaques have abundant macrophages.82
valuable information on the remodeling state of the artery,
presence of thrombi, and, to some extent, the content of
Integrated Backscatter
plaque. Plaques can be characterized as echoreflective (cor-
Intravascular Ultrasound
responding to calcified plaque), hyperechoic (representing
fibrous plaque), and hypoechoic (indicating a lipid-rich core). Integrated backscatter (IB) IVUS combines IB with conven-
Intravascular ultrasound can detect macrocalcification three tional 2D echo and construction of color-coded maps of arter-
times better than angiography; however, it has lower sensi- ies to provide additional information about plaque composition
tivity for lipid-rich than calcified lesions.73 and aid in detection of vulnerable plaques.83 Intravascular
There are disadvantages to using IVUS. The currently ultrasound, by relying on echo intensity alone, cannot accu-
available systems do not have enough resolution to visualize rately differentiate lipid cores from fibrous tissue. In IB IVUS,
vulnerable plaque caps. Intravascular ultrasound is not able variables of the radiofrequency envelope generated from ex
to accurately image the area behind calcified regions because vivo plaque have been correlated with histologic features of
of their acoustic shadows and does not provide information plaque vulnerability to develop modified algorithms, which
about the activity of the plaque and inflammation.74 Intra- assist in detection of the lipid-rich plaques believed to repre-
vascular ultrasound has a very low sensitivity to detect sent vulnerable plaques. 83 Increasing the transducer frequency
microcalcification areas of <0.05 mm, and only 37% sensitiv- (40 MHz) and high sampling rate (2 GHz) allows detailed anal-
ity to detect plaque rupture. In fact, IVUS cannot distinguish ysis by use of IB measurement. In vivo application of IB IVUS
caps thinner than approximately 0.4 mm, whereas pathologic has been shown to improve the resolution to about 40 μm.84
studies indicate that almost all ruptured plaques are thinner However, the resolution of this technique undergoes a signifi-
than 0.075 mm.75,76 cant reduction as imaging moves off axis.84
In IVUS studies, ruptured plaques are found in most
patients with MI, in about half with unstable angina, and in
Coronary Angioscopy
a minority of patients with stable angina.77 Ge et al.78 used
IVUS to study 42 patients with unstable angina pectoris and Intracoronary angioscopy uses a fiber optic to transmit the
102 patients with stable angina pectoris. Intravascular ultra- visible light and provides a small field of view from the
sound identified 29 ruptures (only a third of which were interior surface of coronary arteries. Angioscopy has been
identified by angiography). No patient had more than one reported by several groups to be more sensitive than angiog-
ruptured plaque. Of the 102 patients with stable angina pec- raphy or intravascular ultrasound in detecting thrombosis
toris, eight had a ruptured plaque. The disrupted plaques and fissuring.42,85,86 Angioscopy permits direct visualization
averaged 56% diameter stenosis versus 68% for the nondis- of the arterial surface, presence of thrombi, plaque color (red,
rupted but symptomatic plaques. The disrupted plaques also white, or yellow), and endothelial disruptions (tears, ulcer-
had a thinner cap (0.47 ± 0.2 mm vs. 0.96 ± 0.94 mm), a larger ations, and fissures).87 Specific color patterns of coronary
echolucent area, and were more likely to be eccentric (94 vs. plaques as detected by angioscopy have been correlated with
64%). Of the patients with unstable angina, 21 exhibited different clinical coronary events. On angioscopy, the normal
 at h erosclerot ic v u l n er a ble pl aqu es 627
artery appears as glistening white. In histologic studies, abundance of macrophages and T cells that are known to be
yellow plaques often show high concentrations of choles- metabolically active with high consumption of glucose and
terol-laden crystals with a thin cap and smooth white plaques O2, and high thermogenesis.96 Thermal heterogeneity of
generally have a thick fibrous cap. Yellow lipid-laden living carotid atherosclerotic plaques, examined ex vivo, was
plaques—undetected by angiography—are more common in first described in 1996 by Casscells et al.95 and Willerson’s
patients with AMI and unstable angina.88 These plaques group97 (Fig. 27A.6). Stefanadis and colleagues98 described 26
often show surface irregularity and an intimal flap because patients with MI in whom thermography revealed marked
of rupture or ulceration. In patients with old MI and stable temperature heterogeneity. Plaque temperature heterogene-
angina, smooth white lesions (presumed to be more fibrotic) ity was present in 20%, 40%, and 67% of the patients with
are frequently observed. Acute coronary syndromes occur stable angina, unstable angina, and AMI, respectively, and
more often in patients with glistening yellow plaques than did not correlate with the degree of stenosis. Temperature
in those with non–glistening yellow plaques.87 heterogeneity was absent in the control group. Among the 30
Angioscopy catheters are too large to use in small-caliber patients with stable angina pectoris, some had uniform tem-
vessels or cross-stenotic lesions. Angioscopy is unable to peratures like the patients without coronary disease, but a
provide the deeper plaque characterization afforded by ultra- few had culprit plaques with lesions as warm as 0.2°, 0.3°, or
sound and furthermore is limited by the need to inflate a proxi- even 0.5°C above the reference temperature elsewhere in the
mal balloon or flush saline solutions to provide a blood-free vessel.98 The temperature heterogeneity correlates not only
visual field. This can create ischemia, limiting viewing time. with symptoms but also with serum levels of C-reactive
More importantly, inflation at the proximal major coronary protein (CRP) and serum amyloid A.99 In a follow-up study
arteries may preclude the evaluation of those critical seg- after patients undergoing angioplasty, temperature was a pre-
ments. Another major drawback is the subjective method of dictor of adverse events.100 In this study, the mean tempera-
color-lesion interpretation for which a number of automated ture of the culprit plaque in patients with stable angina
colorimetric systems are under development. Nevertheless, pectoris who had an adverse event in follow-up was 0.5°C,
angioscopy continues to provide important information versus 0.1°C in patients without an event.100 Stefanadis and
about coronary syndromes and vulnerable plaque.89,90 colleagues101 also showed that coronary temperature hetero-
geneity is decreased by statin therapy.
More recently, lesser degrees of temperature heterogene-
Optical Coherence Tomography
ity have been reported by Verheye et al.,102 Webster et al.,103
Optical coherence tomography (OCT) employs a laser (near- Schmermund et al.,104 Dudek et al.,105 perhaps because a
infrared) beam as the light source that is directed to and larger proportion of their patients were taking antiinflam-
reflected back from the tissue. Optical coherence tomogra- matory medications or statins, and in addition, their
phy measures the intensity of the reflected infrared light and thermography techniques do not obstruct flow, whereas
has a remarkable resolution of 10 to 20 μm.91,92 Current tech- the larger thermistor used earlier by Stefanadis often
niques have a penetration depth of 1 to 2 mm. Studies have “wedges” the lesion and reduces blood flow. It should be
validated the ability of OCT in measuring cap thickness and noted that blood flow can potentially attenuate the measured
differentiating lipid-rich tissue from fibrous and calcified temperature heterogeneity over the atherosclerotic plaque.
tissues.91,92 This technique has often been quoted as “optical That complete obstruction of blood flow may markedly
biopsy.” An autopsy study has shown remarkable ability of increase the degree of detected temperature heterogeneity
OCT to detect and quantify cell density within the fibrous and proximal occlusion of the artery by use of a balloon has
cap, though this ability is mainly limited to the most super-
ficial regions of the plaques.93 Optical coherence tomography
is comparable to high-resolution IVUS in its ability to detect
plaques and discriminating fibrous from calcified plaques. 26.4 27.6
Moreover, OCT has a higher resolution than IVUS, allowing
it to identify intimal hyperplasia, internal and external
elastic laminas, and histologic features of vulnerable plaques
not detected by IVUS.94
The major limitation with OCT imaging is the need for
proximal occlusion as the presence of blood significantly
reduces the OCT image quality. It also has limited tissue
penetration. Optical coherence tomography is currently 26.9
being tested in multiple human clinical trials and its poten- 25.9
tial combination with polarization imaging, spectroscopic
analysis, or elastography may further enhance its ability to
detect vulnerable plaques.42
29.2

Intravascular Thermography
29.6
Heat, as a sign of inflammation, can be used to locate foci of 28.3
inflammation in the arterial wall.95 Inflamed vulnerable FIGURE 27A.6. Endarterectomized carotid plaques show tempera-
plaques may give off more heat as they usually show an ture heterogeneity (all temperatures are °C).
628 chapter 27A

been suggested as a method to improve the temperature tion, water content, physical state, molecular motion, or
reading from arterial wall. diffusion.86 It provides imaging without using ionizing radia-
Toutouzas et al.106 reported a good correlation between tion and can be safely repeated sequentially over time to
remodeling index (defined as the ratio of the external elastic monitor progression or regression of atherosclerotic lesions.86
membrane area at the lesion to that at the proximal site It has been used to detect atherosclerotic plaques (and assess
determined by intracoronary ultrasound) and temperature effect of lipid-lowering drugs on plaques) in animal models.
difference between the atherosclerotic plaque and the healthy Magnetic resonance imaging has been used with success
vessel wall in patients with acute coronary syndromes. They to study atherosclerotic plaques in human carotid, aortic,
also showed that serum matrix metalloproteinase 9 (MMP-9) peripheral, and coronary arterial disease and for in vivo
concentration is correlated with temperature difference in visualization of arterial thrombi.110 Superficial location and
patient’s ACSs.107 Temperature heterogeneity is associated immobility of carotid arteries have made them especially
with vascular remodeling, which is, by itself, associated with suitable targets for MRI studies.111 Magnetic resonance
local inflammation in plaque.108 imaging has been used to assess the effect of lipid-lowering
Verheye et al.102 examined the relation of clinical presen- therapy (statins) in hypercholesterolemic patients. A signifi-
tation to the number of hot lesions. On average, half of the cant regression of atherosclerotic lesions was observed after
patients with stable angina pectoris had a hot lesion, versus 12 months of statin therapy.112 Interestingly, a decrease in the
an average of one lesion per patient with unstable angina and vessel wall area occurred in absence of significant changes
two hot lesions per patients with MI. They also demonstrated in the lumen area.113,114
that temperature heterogeneity is determined by plaque com- Better visualization of the arterial wall may be achieved
position and macrophage mass. They randomized 20 New by use of preparatory pulses that render the signal from the
Zealand rabbits to receive 6 months of either a normal diet blood flow black. This method has been used to study human
(n = 10) or a cholesterol-rich (0.3%) diet (n = 10). At 6 months, carotid artery, aorta, and coronary arterial lumen and wall.115
10 control rabbits and five hypercholesterolemic rabbits were Magnetic resonance spatial resolution can be improved with
euthanized, and the five remaining rabbits were put on a higher field strength magnets (e.g., 3 T), surface coils, intra-
normal diet for 3 months.109 In the hypercholesterolemic coronary antennae, or superconductivity. Recently, several
rabbits, marked temperature heterogeneity (up to 1°C) was groups have reported that plaque macrophages can be imaged
observed at sites of thick plaques with high macrophage by their uptake of iron-containing nanoparticles.116 Tagging
content, but no temperature heterogeneity was seen in gadolinium or iron oxide particles with LDL or plaque-
plaques with low macrophage content. Interestingly, in specific antibodies are other opportunities for molecular
rabbits who received 3 months of a low-cholesterol diet, imaging of atherosclerosis.
plaque thickness remained unchanged, but the macrophage Magnetic resonance imaging is more time-consuming
content decreased significantly.109 and expensive than computed tomography, and some
Thermography is currently under evaluation in human patients are ineligible by virtue of pacemakers or other
clinical trials in New Zealand, Brazil, Europe, Japan, and the embedded metal, but it has extraordinary potential for plaque
U.S. Human clinical trials will determine the safety, repro- characterization.117,118
ducibility, and clinical utility of this method. If approved by
Computed Tomography Imaging
the U.S. Food and Drug Administration, it may be used to
detect vulnerable plaques and to predict the risk of vulnera- Autopsy studies have consistently demonstrated that calci-
ble lesions and vulnerable patients. Its combination with fication is a common complication of advanced atherosclero-
palpography, IB IVUS, OCT, and other techniques is cur- sis. Multiple clinical studies have demonstrated that this
rently being examined. calcification can be detected by fluoroscopy and more accu-
rately and quantitatively by fast-gated spiral computed
tomography (CT), electron-beam CT (EBCT), or multidetec-
Noninvasive Imaging of Vulnerable Plaques tor CT (MDCT).119 The EBCT machines use a focused elec-
tron beam targeted at two detector rings positioned in a
semicircle fashion underneath the patient. This technique
Magnetic Resonance Imaging
produces arterial slice images as thin as 3 mm. Electron-
High-resolution magnetic resonance imaging (MRI) is a beam CT needs about 30 to 40 slices (during one or two sepa-
promising method for noninvasive imaging of vulnerable rate breath-holds) from the aortic root to the apex of the heart
plaques. During MRI studies, the patient is subjected to a to measure coronary calcium.86 Multidetector scanners
high local magnetic field [e.g., 1.5 tesla (T)], which aligns the utilize multiple rows of detectors, which move in a helical
protons. A radiofrequency pulse excites these protons, which motion around the patient and can image multiple simulta-
in turn emit a signal that can be detected by receiver coils. neous sections at higher speeds. The radiation dose of EBCT
Detected signals are influenced by the relaxation times (T1 is less than that of MDCT.
and T2), proton density, motion and flow, molecular diffu- Although EBCT offers a better temporal resolution and
sion, magnetization transfer, changes in susceptibility, etc.86 fewer motion artifacts, MDCT has better spatial resolution,
Magnetic resonance imaging of the atherosclerotic less noise, and higher speed. The first multislice CT scanners
plaques is influenced by the signal intensity, contrast, and were introduced in the early 1990s and were improved over
lack of noise.86 Magnetic resonance imaging can differentiate time. Newer 64-detector CT scanners can perform 64 slices
plaque components based on their biophysical and biochemi- per rotation with a resolution of 0.4 mm in only a few seconds
cal parameters, such as chemical composition and concentra- (5 to 13 seconds), even allowing evaluation of patients with
 at h erosclerot ic v u l n er a ble pl aqu es 629
severe pulmonary disease and congestive heart failure in one conjunction with, but not replacing, stress testing. Thus the
breath-hold. Short duration of scanning also minimizes costs are additive.
motion artifacts. Their high resolution allows visualization In theory, the use of calcium scoring appears to identify
of the entire coronary tree with high accuracy. They can be persons with preclinical coronary disease, some of whom are
used to assess the overall calcium burden, and to detect and not identified by careful review of symptoms and physical
characterize individual atherosclerotic plaques. Moreover, examination, stress testing, and laboratory tests including
when used in conjunction with contrast media, MDCT can CRP. It may help select patients for whom statins may
assess blood flow, evaluate dimensions of the lumen and prevent unheralded MI or SCD. It may also identify patients
arterial wall, and characterize arterial wall with high resolu- in need of more dietary advice, and more frequent follow-up
tion. Coronary calcium assessments by EBCT and MDCT visits. Though these uses of CT are not yet substantiated by
systems show good correlation.120 clinical trials, case series attest to the plausibility of these
Coronary artery calcium (CAC) is a predictor of an uses of CT.
increased risk of coronary heart disease (CHD) events. Computed tomography angiography (CTA) is easily and
Calcium is present in atherosclerotic coronary arteries and rapidly performed by intravenous injection, and the images
can be quantified quickly and noninvasively with EBCT or obtained with the 64-slice machines are nearly as good as tra-
MDCT. Histopathologic studies have shown a close correla- ditional but more invasive and more costly arteriograms. One
tion between whole heart, coronary artery, and segmental caveat is that heavily calcified stenoses appear more severe
coronary atherosclerotic plaque area and EBCT coronary than they are due to the calcium “blooming” artifact. Another
calcium area. However, coronary calcium below a threshold is that stenoses are judged more severe by CTA because it is
value of 130 Hounsfield units may not be detectable by able to identify the true reference diameter, whereas arterio-
EBCT.121 The CAC score may be used to estimate the burden grams can underestimate the severity of a stenosis by compar-
of atherosclerosis in coronary arteries. The role of calcifica- ing it to a region with angiographically inapparent disease
tion in plaque vulnerability is controversial. Although some (e.g., some patients have no normal areas, only diffuse smooth,
authors have found calcified regions in association with concentric disease mistaken for normal). However, the main
adverse clinical events,39 others have suggested that plaque drawback is the inability to perform interventional proce-
calcification may actually represent stabilized plaques, as dures, which means that some patients must have a second
many high-risk plaques often lack calcium. procedure, which entails more time, cost, dye load, and radia-
Nevertheless, a few studies have shown that CAC is an tion. Thus, at present, CTA is most often used in the emer-
independent predictor of future CHD events.122–125 Calcium gency room setting where patients with chest symptoms can
scoring is increasingly being used in primary or secondary be ruled out for coronary occlusion, pulmonary embolus, and
risk assessment, and it may prove to be useful in identifying aortic dissection with a single procedure (albeit one with a
vulnerable plaques and vulnerable patients.126 A high calcium radiation approximately that of 1000 chest x-rays).
score is a sensitive but not a specific marker for coronary As with MR angiography, CT angiography has great
stenosis. A recent meta-analysis of four large studies showed potential as a single comprehensive evaluation of the vulner-
that calcium score is an independent predictor of cardiovas- able patient, as follows: First, MDCT should be able to provide
cular events with a relative risk of about 2.1 in persons with information about the vulnerability of specific plaques;
low amounts of CAC (i.e., CAC score, 1 to 100) and much such plaques are large, remodeled, proximal, located opposite
higher relative risks in persons with high CAC scores (>400) branch points or in areas that flex, and they retain dye (plaque
than in those with no evidence of CAC.127 “blush”). Although even 64-slice CTA cannot distinguish a
Currently, the primary goal of coronary calcium screen- 1-mm-thick cap from a 0.1-mm, it may be able to determine
ing is to aid in risk stratification of subjects who are at which plaques have a large lipid core. Finally, the new
intermediate risk based on Framingham tables. It is also machines, together with advances in image filtering, may
assumed that knowledge of CAC score may further encour- permit the detection of speckled calcium beneath lipid cores,
age patients to adhere to their therapeutic regimen. which is a feature of high-risk plaques. However, the detailed
Low-density lipoprotein lowering with statin drugs can evaluation of multiple plaques would prove time-consuming,
slow (and sometimes halt or even reverse) the progression of and it is not known if such analyses could be automated.
atherosclerosis measured as an increase in mean calcium- Second, CTA may prove useful—and convenient to both
volume score over a 12-month period.128 However, more data patient and doctor—in simultaneously evaluating carotid
are needed before concluding that this decrease in CAC artery stenosis, aortic plaque and aneurysm, renal artery
progression will be translated into a reduction in clinical stenosis, and iliac stenosis. Detecting these (often unsus-
events.129 pected) conditions is useful in its own right and because
Increasing use of calcium scanning has raised some con- some studies suggest that coronary patients with peripheral
cerns. Multidetector CT delivers considerable radiation, and disease merit a more aggressive approach.
although it may be justified in high-risk or symptomatic Third, if the patient has not had a recent echocardiogram,
patients, it should be used in the general population only CTA conveniently provides left and right ventricular size,
after careful assessment of its risk-benefits ratio. In fact, shape, regional wall motion, and ejection fraction, left atrial
false-positive test results may lead to unnecessary anxiety size and presence of thrombus, valve calcification, and peri-
and interventions. The cost of the calcium scan (approxi- cardial effusion. Perfusion imaging should soon be possible
mately $500 to $1000) is another factor that needs to be kept as well.
in mind in clinical decision making; though it is roughly Fourth, MDCT can provide information about pulmo-
half that of radionuclide stress testing, it is usually used in nary edema, effusion, infection, embolus, and malignancy.
630 chapter 27A

Lung cancer shares with atherosclerosis such risk factors as dence is likewise suggestive, but not definitive, for the use
age, smoking, and diet, and thus some patients undergo of B vitamin supplements (particularly folic acid, B6, and B12)
bypass surgery and spend several months recuperating only to lower serum homocysteine levels.146,147 Normalizing
to have to undergo a procedure for a lung nodule. Such situ- homocysteine, like statins and vitamin C, improves endo-
ations may be avoided by CT screening, which has proven thelial function, and endothelial dysfunction is a predictor
useful for identifying lung cancer when it is surgically of clinical events.148
curable. Of particular interest is the Mediterranean diet (or Indo-
Finally, CTA may occasionally detect unexpected disease Mediterranean diet).149–152 These diets, which are rich in olive
in the gallbladder, pancreas, liver, ovary, or kidneys. Careful and canola oil, whole grain cereals, fish, and vegetables, have
clinical trials will be needed to determine whether the fre- been shown in randomized trials to reduce the risk of MI
quency and clinical utility of such findings, even with the and cardiac death by approximately 50% without altering
apparent convenience and rationale of comprehensive assess- LDL and HDL cholesterol levels or body weight. The benefits
ment of patient vulnerability, justify the radiation, and offset begin by 6 months—and by 4 months in the Gruppo Italiano
other costs. per lo Studio della Sopravvivenza (GISSI) trial of fish oils.153
Antioxidative, antiinflammatory, and antithrombotic mech-
anisms have been suggested, but in the Lyon Heart Study,
Treatment of Vulnerable Plaques patients were already well treated with standard medications
and the control group was fed a traditional low-fat diet.150
Thus, it is clear that there are factors other than intake of
Current Therapy
saturated fat and cholesterol that have an important impact
Because there is not yet an accepted way to detect and follow on cardiovascular outcomes.
the course of vulnerable plaques, there is no proven interven- As for supplements, vitamins A, E, and C confer no
tion for reducing the risk of plaque rupture, plaque erosion, benefit, though the combination of E and C may offer some
or plaque thrombosis per se. However, the risk factors for MI protection as may L-arginine and selenium, though data are
and angina pectoris are nearly identical in most studies, and limited. Many patients self-prescribe coenzyme Q10, though
those for SCD are similar; risks of these outcomes have been there is no clinical trial that supports this.154–156
reduced, albeit modestly, in most primary and secondary
prevention studies by reducing blood pressure,130–132 choles-
Lipid-Lowering Medications
terol levels,133–137 cigarette smoking,138 and adding an aspirin
regimen.49 Some of the benefit is due to a slowing of athero- Randomized trials have clearly shown that statins reduce the
genesis and some to a stabilization of vulnerable plaque. risk of MI, cardiac death, and stroke,133–137 and there is evi-
Atherogenesis and vulnerable plaque differ in several respects: dence that niacin, resins, and fibrates can do the same.157,158
vulnerable plaques are characterized by inflammation, a thin Statins also exert antiinflammatory effects independent of
fibrous cap, a tendency to thrombose, coronary vasoconstric- their effects on lipid levels.159 New drugs that block intesti-
tion, calcification, and superficial erosion. These factors are nal fat absorption (e.g., ezetimibe or orlistat) or inhibit other
less closely identified with atherosclerotic progression per se. aspects of lipid metabolism, such as cholesterol esterase
Indeed, there is some evidence that the inflammatory process transfer protein (CETP) inhibitors, are entering clinical
may have a mixed effect in atherogenesis (the beneficial trials.
effect being the removal of cholesterol from the plaque), It is important to note that even as the enormous public-
whereas in vulnerable plaques, inflammation is overwhelm- ity and marketing of the statins has not yet resulted in the
ingly dangerous. Likewise, exercise probably reduces the risk majority of patients reaching their LDL goal, the reductions
of developing vulnerable plaques. in mortality do not reach significance until 6 to 12 months
after the drugs are begun. Higher doses may confer an earlier
benefit, as suggested by the Myocardial Ischemia Reduction
Diet and Dietary Supplements
with Aggressive Cholesterol Lowering (MIRACL) trial, and
Diet remains the cornerstone of treatment of cardiovascular combinations with niacin may yet prove to work faster than
disease because this single approach can reduce hyperten- statins alone.160 As statins do not reduce mortality for at least
sion139,140 (in particular, by reducing intake of salt and increas- 6 months to 1 year, local interventional therapies may be
ing that of magnesium and potassium and by reducing needed to “buy time” until statin therapy confers significant
weight) and also in reducing serum glucose and LDL choles- protection.
terol. Other important dietary opportunities, as reviewed by
Hu et al.,141 include the incorporation of more fish in the diet,
Apo A-I Milano
which appears to lower the risk of sudden cardiac death
independent of any effect on cholesterol. The substitution of Apolipoprotein A-I Milano (apoA-I Milano) is a naturally occurring
monounsaturated and polyunsaturated fats for trans fats also mutant of apoA-I, with a cysteine-to-arginine substitution at
appears to be important.142,143 position 173. It was first described in 1980 in three members
Other epidemiologic studies suggest that a moderate con- of an Italian family who had significant hypertriglyceride-
sumption of alcohol (especially red wine), and of tea rather mia with very markedly decreased levels of HDL cholesterol
than coffee, together with an increased intake of water (pre- (7 to 14 mg/dL).161,162 In its carriers, apoA-I Milano is associated
sumably offsetting the atherothrombotic effects of elevated with longevity and freedom from vascular disease despite
viscosity) may reduce cardiovascular mortality.144,145 Evi- markedly reduced HDL and elevated triglyceride levels.163 In
 at h erosclerot ic v u l n er a ble pl aqu es 6 31
1989, Badimon, Fuster, and colleagues164 showed that admin- Because of the side effects of such broad antiinflamma-
istration of homologous HDL–very high density lipoprotein tory approaches as corticosteroids and nonsteroidal antiin-
(VHDL) fraction to cholesterol-fed rabbits dramatically inhib- flammatory drugs, and because of the 1-year delay until
ited the extent of aortic fatty streaks and lowered lipid depo- statins even begin to reduce mortality, more specific antiin-
sition in the arterial wall and liver without modifying the flammatory approaches are worth investigating. Examples of
plasma lipid levels. candidate drugs include inhibitors of lipoxygenases, tumor
Ameli and coauthors165 showed that repeated administra- necrosis factor-α (TNF-α) and its receptor (and related
tion of recombinant apoA-I Milano reduced intimal thickening members of that family), blockers of monocyte chemoattrac-
and macrophage content after balloon injury in cholesterol- tant peptide-1 (MCP-1), CD40 and its ligand, intercellular
fed rabbits without changing the arterial total cholesterol adhesion molecule-1 (ICAM-1), vascular cell adhesion
content. Soma and associates166 tested the effect of a recom- molecule-1 (VCAM-1), interleukin-1 (IL-1), interleukin-6 (IL-
binant disulfide-linked apoA-I Milano on neointimal formation 6), matrix metalloproteinases 1, 3, 8, 9, and 13, CRP, and, in
induced by periarterial manipulation in cholesterol–fed particular, nuclear factor κB (NF-κB), whose activation is one
rabbits. These researchers observed a marked inhibition of of the most important molecular controls of the inflamma-
neointimal formation and proliferation of smooth muscle tory process.179, 180
cells. Particularly promising are the peroxisome proliferator-
Shah and coworkers167 demonstrated that recombinant activated receptor (PPAR) agonists, such as the fibrates (which
apoA-I Milano reduced atherosclerosis progression, plaque lipid decrease LDL and triglyceride levels) and glitazones (which
content, and inflammation in apoE-deficient mice on a decrease serum glucose), yet each has unique antiinflamma-
high-cholesterol diet. Later, these authors showed that a tory actions.181
single high dose of recombinant apoA-I Milano could rapidly
mobilize tissue cholesterol, reduce plaque lipid by 40% to
Vaccination and Atherosclerosis
50%, and reduce macrophage content by 29% to 36% in
apoE-deficient mice. These findings suggest a strategy for the A desirable alternative might be to avoid the antigens incit-
rapid stabilization of plaques. Navab and associates168 devel- ing the inflammatory response, or remove them, mask them,
oped an oral form of apoA-I mimetic peptides (D-4F) that, or induce tolerance.182,183 However, the science and tech-
when administered orally to LDL receptor-null mice on a niques of antigen masking and of desensitization therapies
Western diet decreased the lesions by 79%; when added to remain poorly understood. Antigens that might be avoided
the drinking water of apoE-null mice, this agent reduced the include oxidized LDL cholesterol, as previously discussed.
lesions by approximately 75%. Other antigens of interest include heat shock proteins (HSP)
These series suggest that apoA-I therapy may be used to 60 and 65 and β2-glycoprotein I.184,185
stabilize atherosclerotic plaques and induce their regression
by promoting reverse cholesterol transport and removal of
Role of Infections
oxidized lipids. Several groups are investigating gene transfer
of apoA-I to induce regression of atherosclerosis.169–172 Nissen Candidates include infections, such as Chlamydia pneu-
et al.173 recently reported significant regression of coronary moniae, herpes simplex viruses, Helicobacter pylori, Porphy-
atherosclerosis as measured by IVUS following intravenous romonas gingivalis, Mycoplasma pneumoniae, other
administration of recombinant ApoA-I Milano/phospholipid infections that induce expression of HSPs (e.g., HSP 65), and
complex (ETC-216) in 123 patients. Studies of novel HDL- influenza.186 C. pneumoniae has been studied more exten-
raising agents such as torcetrapib are also underway.174 sively; however, the results of large human clinical trials
using antibiotics against it have been disappointing.187,188
Because upper respiratory infections precede approxi-
Antiinflammatory Drugs
mately one third of AMIs,189 we examined whether vaccina-
One of the most exciting developments in the past few years tion against influenza was associated with a reduced rate
has been the identification of serum levels of CRP as a marker of MI in persons over 65 years old with chronic coronary
of the risk of MI and death in patients hospitalized for angina disease. In a multivariate analysis, we found a 66% reduction
or MI and as a (somewhat weaker) predictor years before the in the rate of reinfarction but not in mortality.190 A simulta-
onset of angina or MI.175 In most studies of primary and sec- neous study found a similar reduction in the risk of SCD,191
ondary prevention, CRP is a slightly better predictor than and a subsequent study found a similar reduction in the risk
LDL cholesterol or even the LDL/HDL ratio.176 of stroke.192 A small randomized trial yielded similar find-
Angiotensin-converting enzyme (ACE) inhibitors have ings,193 but one case-control trial has described no associa-
been shown not only to reduce blood pressure and prevent tion of vaccination with cardiovascular events.194 To test the
MI, beginning at about 6 months, but also to have significant effect of influenza on atherosclerosis, we inoculated athero-
antiinflammatory effects.177,178 Together with the numerous sclerotic apoE-deficient mice with influenza A; we found a
recent demonstrations that inflammation promotes throm- marked increase in inflammation and thrombosis in plaques,
bosis, and vice versa, an interplay of factors suggests the but not in normal regions of the aorta.195
promise of combination therapies. Thus, the next few years The association is plausible because of influenza’s asso-
will bring results of clinical trials that will help identify the ciation with the winter increase in cardiovascular events,196
specific CRP and cholesterol/HDL goals that may be reached the upsurge in cardiovascular events that followed the 1918
by a combination of dietary, lipid-lowering, and antiinflam- Spanish flu pandemic,197 the known effects of inflammation
matory interventions. on inactivation of HDL,198,199 and the fact that acute respira-
632 chapter 27A

tory infections increase fibrinogen, CRP, and (by hemocon- infarction are not clear, but may simply relate to the reduced
centration) concentrations of clotting factors. Moreover, number of heartbeats and the reduced rate of pressure rise in
influenza can cause tachycardia, hypoxemia, elevations in the coronary arteries.210
norepinephrine, and other plausible triggers for MI or stroke. The recently released Antihypertensive and Lipid Lower-
The fact that influenza vaccine is effective and inexpensive ing Treatment to Prevent Heart Attack Trial (ALLHAT) sug-
(and backup strategies are available, such as the neuramini- gested that the benefits of diuretics are essentially equal to
dase inhibitors and amantadine) suggests that it is important that of ACE inhibitors and beta-blockers, but the caveat is
to confirm or refute the influenza hypothesis.186 that most ALLHAT patients did not have coronary athero-
sclerosis. Thus, the multiple demonstrated benefits of ACE
inhibitors and beta-blockers in patients with known coro-
Prevention of Thrombosis
nary disease should not be ignored.210,211
The fact that aspirin reduces the risk of MI and death by only
20% to 30% (and that in some 30% to 40% of patients, Inhibition of Neovascularization
aspirin produces little or no improvement in bleeding time
or in in vitro platelet aggregation) led to studies combining Inhibition of neovascularization is another potential method
aspirin with ticlopidine or clopidogrel. Adding either drug to for stabilizing plaques and reducing plaque growth. Folk-
aspirin reduced the risk of acute thrombotic occlusion with man’s lab212 used recombinant murine angiogenesis inhibi-
stenting, and clopidogrel reduced the incidence of MI in tors (endostatin and TNP-470) in apolipoprotein E–deficient
patients with unstable angina.200 (apoE−/−) mice and showed that these drugs significantly
In the Aspirin and Coumadin After Acute Coronary Syn- reduce plaque progression (by 85% and 70%, respectively)
dromes Trial (ASPECT 2) in patients with ACSs, warfarin without affecting cholesterol levels.213
titrated to an international normalized ratio (INR) of 3 to 4
and warfarin titrated to 2 to 2.5 plus low-dose aspirin reduced Local and Regional Therapies
by 50% the combined incidence of stroke, MI, and death Stenting, clopidogrel, and GPIIb/IIIa inhibitors reduce the
compared to low-dose aspirin alone.201 Likewise, in the Anti- incidence of acute complications with angioplasty. New
thrombotics in the Prevention of Reocclusion In Coronary drug-eluting stents, in particular, have been shown to mark-
Thrombolysis (APRICOT)-2 trial of 308 patients with AMI edly reduce restenosis rates. Together with the recent recog-
treated with thrombolysis, those randomized to warfarin nition that percutaneous coronary intervention (PCI) serves
(INR 2 to 3) plus aspirin had a 14% rate of MI or revascular- mainly to reduce angina and increase walking distance some
ization over 3 months, versus 36% for aspirin alone.202 20% to 30%, whereas most MIs and coronary deaths are pre-
In a British study of men with cardiovascular risk factors cipitated by thrombosis of a plaque less than 50% diameter
but no MI or angina, warfarin—alone or with aspirin—again stenosis (DS), and that most patients with MI have a second
reduced the event rate compared to aspirin alone.203 Taking or even a third vulnerable lesion, interventional cardiologists
into consideration that not all the patients are protected by are now planning trials of stenting for hot plaques.
the current regimens, new combination regimens (with pos- Despite their cost, drug-eluting stents are particularly
sibly three drugs) and novel antithrombotics, such as inhibi- attractive for treatment of vulnerable plaques because mac-
tors of thrombin, tissue factor, or glycoprotein Ib (GPIb), rophage content has repeatedly been shown to predispose
merit study to confer further protection. to restenosis.214 Moreover, Stefanadis et al.100 found that
warmer lesions post–percutaneous transluminal coronary
Treatment of Hypertension angioplasty (PTCA) had a higher rate of subsequent events.
Interventionalists have also noted that plaque vulnerability
The ability to fi nd vulnerable plaques will make it possible could help decide whether to intervene on a 50% to 70% DS
to test the hypothesis that vulnerable patients require lower lesion, or influence stent selection. For example, if a 20%
blood pressure, e.g., 120/70 mm Hg. As noted earlier, ACE stenosis that is 10 mm downstream of the ischemia-causing
inhibitors not only reduce blood pressure, stroke risk, and culprit is hot or otherwise vulnerable, the interventionalist
mortality in congestive heart failure, but also reduce the may select a stent that is long enough to treat both lesions.
risk of reinfarction and of progressive atherosclerosis.204–206
Several mechanisms may contribute, including the antiin-
Balloon Angioplasty with Drug-Eluting Stents
flammatory action of ACE inhibitors. Related and equally
promising drugs are the angiotensin receptor blockers, which Balloon angioplasty has been used in humans since 1977, and
have the putative benefits of blocking angiotensin-II formed the advent of coronary stenting in 1986 led to a marked
by the action of tissue chymases and of increasing the stimu- reduction in the postangioplasty restenosis rate. Further
lation of the type 2 receptor of angiotensin-II.207,208 However, improvement has been achieved with stents coated with
limited clinical information, to date, suggests that the ben- antiproliferative drugs (such as sirolimus and paclitaxel),
efits are similar to those of ACE inhibitors, albeit with a which can potentially abolish in-stent restenosis. The
lower incidence of angioneurotic edema and cough.209 concept of local drug delivery via coated stents offers both
β-adrenergic blockade reduces blood pressure, cardiac the biologic and the mechanical means of preventing such
contractility, increases diastolic filling time, and decreases restenosis. Several drugs are being used for this purpose.
vulnerability to arrhythmias. It also reduces the risks of Paclitaxel- and sirolimus-eluting stents have been studied
reinfarction and of mortality in congestive heart failure. The extensively with major success in minimizing the risk of
mechanism(s) by which beta-blockers reduce the risk of in-stent restenosis.215–222 Newer stent designs and new molec-
 at h erosclerot ic v u l n er a ble pl aqu es 633
ular and cellular stents including those covered with stem also the adrenergic systems.231–233 Recently, these drugs have
cells are under development and may confer major improve- been associated with an increased risk of SCD.234
ments in the field. In summary, vulnerable plaques represent a wide variety
The potential benefit of stenting hemodynamically of anatomic variations of atherosclerosis, reflecting multiple
nonsignificant but vulnerable (e.g., hot, remodeled) plaques genetic and environmental risk factors. A correspondingly
remains to be investigated in randomized clinical trials. wide variety of medical and surgical treatments—some
Several drugs with different mechanisms of action (antiprolif- current and others in development—are likely to achieve
erative, anticoagulant, antiinflammatory, gene-transferring, major reductions in morbidity and mortality caused by vul-
etc.) are being investigated for use in these stents. Better char- nerable plaques.
acterization and classification of each lesion with new detec-
tion techniques will help investigators decide which coated
stent is best suited for treating a specific lesion. Summary
Use of antiproliferative drugs in oral form after stent
implantation is another promising therapy for preventing During the past two decades, we have witnessed considerable
restenosis. Farb and coworkers223 used oral everolimus (a progress in understanding the pathogenesis of atherosclerosis
macrolide of the same family as sirolimus) to inhibit in-stent and vulnerable plaques. Multiple methods are being investi-
neointimal growth in the iliac arteries of rabbits. This drug gated for detection of vulnerable plaques. A combination of
reduced in-stent neointimal growth significantly (42% to several detection techniques may be used to screen and
46%). The safety and efficacy of such treatment in humans detect lesions invasively or noninvasively. This can lead to
remains to be proven.223 development of more efficient methods to prevent and control
coronary heart disease. A comprehensive preventive and
Photodynamic Therapy therapeutic approach would considerably reduce the risk of
fatal and nonfatal heart attacks.
Photodynamic therapy (PDT) has been used in treatment of A major goal in preventive care and treatment of CHD
cancer lesions and has been evaluated for focal treatment of patients is to identify patients who are vulnerable to acute
atherosclerosis and prevention of restenosis.224,225 Motexafin coronary thrombosis.38 These “vulnerable patients” are
lutetium (MLu, Antrin) has been used most in atherosclero- likely to have a high atherosclerotic burden, high-risk/
sis research because of its tendency to accumulate in plaques. vulnerable plaques, or thrombogenic blood. Traditional and
Pilot studies have used motexafin lutetium and endovascular newly identified risk factors235 and imaging methods, both
illumination and resulted in a reduction of plaque volume in invasive and noninvasive,41 are likely to be of increasing
animal models, presumably due to apoptosis of macrophages utility in identifying such patients and guiding therapy.38
and smooth muscle cells.226 Other new agents are being
developed to be used in photodynamic therapy of vulnerable
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 2 Biomarkers of
7 Inflammation as
B Surrogate Markers
in Detection of
Vulnerable Plaques and
Vulnerable Patients
Mohammad Madjid, Samuel Ward Casscells, and
James T. Willerson

High-Sensitivity C-Reactive Protein . . . . . . . . . . . . . . . . 642 Serum Amyloid A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646

Leukocyte Count . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 CD40 Ligand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Lipoprotein-Associated Phospholipase A 2 . . . . . . . . . . . . 644 Proinflammatory Cytokines . . . . . . . . . . . . . . . . . . . . . . 646
Myeloperoxidase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645 Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
Pregnancy-Associated Plasma Protein-A . . . . . . . . . . . . . 645 Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648

Key Points • Elevated serum amyloid A at hospital admission in patients

with unstable angina predicts a poorer prognosis.
• C-reactive protein (CRP) activates endothelial cells to
• CD40 and CD40 ligand levels predict prognosis in
express adhesion molecules, VCAM and ICAM, and
patients with ACS.
Monocyte Chemotactic Protein, and CRP decreases the
• The primary proinflammatory cytokines are interleukin-
availability of nitric oxide. Thus, it is a proinflammatory
1 and -6 and tumor necrosis factor-α. Increased serum
substance and its serum level is also a predictor of future
levels of the proinflammatory cytokines are associated
vascular events.
with a poorer prognosis, development of congestive
• White blood cell counts are independent predictors of
heart failure (CHF), and of progressive atherosclerosis.
cardiovascular events.
Increased serum levels of interleukin-10 are associated
• Lipoprotein-associated phospholipase A 2 (Lp-PLA 2) may
with a better prognosis in patients with coronary artery
have both proinflammatory and antiinflammatory effects.
disease (CAD).
High Lp-PLA 2 levels predict future cardiovascular
events. Traditional risk factors, such as those included in the Fram-
• Myeloperoxidase is proinflammatory and its serum level ingham risk tables, fail to predict all patients at risk of
is a predictor of prognosis of cardiovascular events in cardiovascular events. Therefore, an extensive search is
patients. under way to find markers that can identify patients at risk
• In troponin-negative acute coronary syndrome (ACS) of adverse cardiovascular events. As a general rule, new risk
patients, elevated pregnancy-associated plasma protein-A predictors need to be biologically plausible, measurable,
is an independent predictor of adverse outcome during 6 repeatable, and show strong and graded relation to the disease.
months of follow-up. Accuracy and precision of the related laboratory tests and

6 41
6 42 chapter 27 B

low or modest variability in the clinical setting are also Women’s Health Study,22 the Honolulu Heart Study,23 and the
necessary.1 In the past decade, several biomarkers have been National Health and Nutrition Examination Survey
identified that can be used for prediction of future risk of (NHANES) study, which have shown similar, consistent
events, prognosis after interventions, monitoring therapy, results in this regard.2 In general, there is a reproducible,
and risk stratification for the purpose of clinical decision dose-dependent relationship between hsCRP levels and the
making.2 risk of incident coronary heart disease (CHD), sudden death,
Atherosclerosis is an inflammatory disease characterized and peripheral arterial disease.2 hsCRP can predict recurrent
by multifocal lesions and systemic elevations of a number of MI in acute coronary syndromes,24,25 estimate the risk of
acute-phase proteins, cytokines, and cell adhesion molecules, restenosis after percutaneous coronary intervention (PCI),26
including but not limited to, high sensitivity C-reactive and predict prognosis and recurrent events in patients with
protein (hsCRP),3 white blood cells,4 lipoprotein-associated stroke27 and peripheral arterial disease.28
phospholipase A 2 (Lp-PLA 2),5 myeloperoxidase (MPO),6 Several meta-analyses of prospective population-based
pregnancy-associated plasma protein-A,7 serum amyloid A studies have shown an increase in relative risk for major
(SAA),8 tumor necrosis factor-α (TNF-α),9 interleukin-6 (IL- coronary events for patients at the upper tertile versus the
6),10,11 soluble intercellular adhesion molecule-1 (sICAM-1),12 lowest tertile of hsCRP (Fig. 27B.1). The initial estimates for
sP-selectin,13 and CD40 and CD40 ligand.14 These markers the odds of major coronary events in subjects with high
have been studied for the prediction of coronary events in hsCRP were approximately 1.9 [95% confidence interval (CI)
apparently healthy men and women, as well as among 1.5 to 2.3].29 However, more recent studies have suggested a
patients with stable angina, acute coronary syndromes (ACS), relative risk of 1.45 (95% CI 1.25 vs. 1.68) after adjusting for
and in secondary prevention.3 The list of inflammatory other risk factors.30,31
markers used for this purpose is growing rapidly. This chapter C-reactive protein has a well-standardized assay that is
discusses several of the markers that have generated enough widely available at this time. It has a long-term stability
evidence to support their clinical use, and briefly discusses during storage and a long half-life, and it lacks diurnal varia-
some of the emerging biomarkers. tion and age- and sex-dependence. These attributes, coupled
with its strong predictive power, have helped it become a part
of routine clinical practice in many settings.32 hsCRP testing
High-Sensitivity C-Reactive Protein is currently used to identify apparently healthy men and
women at risk of developing cardiovascular events (Fig.
C-reactive protein is an acute-phase reactant and its levels 27B.2).15
increase many fold, nonspecifically, after injury, inflamma- hsCRP is widely ordered (at the discretion of the physi-
tion, or infection. It activates the classic complement pathway cian) along with lipid profiles in patients judged by global
and possesses proatherogenic and proinflammatory proper- risk assessment to be at intermediate CHD risk (10% to 20%
ties.15 It activates endothelial cells to express the adhesion risk in 10 years). It is also widely used in subjects free of
molecules intercellular adhesion molecule-1 (ICAM-1), vas- cardiovascular disease (CVD). hsCRP may potentially help
cular cell adhesion molecule-1 (VCAM-1), selectins, and the direct further evaluation and therapy in the primary preven-
chemokine monocyte chemotactic protein-1, and decreases tion of CVD; however, the benefits of such an approach
the expression and bioavailability of endothelial nitric oxide remain to be proven. Knowledge of hsCRP levels may help
synthase in human endothelial cells.15,16 It is produced by the motivate patients to improve their lifestyle behaviors.1
liver in response to a rise in IL-6 levels. Aortic smooth muscle Statins have been shown to reduce CRP levels by 25% to
cells and adipocytes also produce CRP. In the absence of 50%.33–35 Studies are under way to investigate the effect of
inflammation, CRP levels are usually less than 1 μg/mL, statins in reducing risk in patients with high CRP levels and
whereas in the presence of infections, autoimmune diseases,
or malignancy, they can rise to as high as 100 μg/mL or even
more. Most of CRP’s predictive power resides in the range
between 1 to 5 μg/mL. Serum CRP levels higher than 15 μg/
mL suggest the presence of an infection or other systemic Danesh (2000)
inflammatory process and require a repeat measurement Ridker (1997)
Koenig (1999)
weeks to months later.
Kuller (1996)
Multiple prospective cohort studies in different popula-
Lowe (1999)
tions have shown that high-sensitivity C-Reactive Protein
Tracy (1997)
(hsCRP) is a reliable marker of systemic inflammation and a
Tracy (1997)
strong predictor of future myocardial infarction (MI) and Witherell (1999)
stroke. The hsCRP level is a predictor of both short-term (a Ridker (1998)
few years) and long-term risk (up to 20 years).17 Multiple Agewall (1998)
studies have shown that CRP determination can be of value Roivainen (2000)
in primary and secondary prevention in men and women, Overall 2.0 (95% Cl 12.6 to 2.5)
and in the young and the elderly.18,19 The large cohort studies 0.1 1 10
that have demonstrated this predictive role include the
Relative risk for CHD
MONICA (MONItoring trends and determinants in CArdio- FIGURE 27B.1. C-reactive protein (CRP) and coronary heart disease
vascular disease) study of the Augsburg Center in Germany,20 (CHD). Relative risk top vs. bottom tertile. Prospective—persons
the Atherosclerosis Risk in Communities Study,21 the without cardiovascular disease (CVD) at baseline.
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s 643

CRP Level TABLE 27B.1. Patient characteristics and conditions associated

with increased or decreased levels of hsCRP
mg/mL Interpretation Increased levels Decreased levels

Elevated blood pressure

Elevated body mass index Moderate alcohol
Repeat test in 1 month. consumption
Exclude other processes. Cigarette smoking Increased activity/endurance
exercise
Metabolic syndrome/diabetes Weight loss
10 mellitus
Low high-density lipoprotein Medications
(HDL)/high triglycerides
Estrogen/progestogen hormone use Statins
High risk
Chronic infections (gingivitis, Fibrates
bronchitis)
Chronic inflammation Niacin
3 (rheumatoid arthritis) Aspirin
Intermediate risk
1
Low risk
Leukocyte Count
FIGURE 27B.2. Interpretation of CRP level.
Inflammatory cells play a critical role in atherosclerosis.
Therefore, it is not surprising that white blood cell (WBC)
low low-density lipoprotein (LDL) levels.36 In a study by count is an independent risk factor for incident cardiovascu-
Nissen and colleagues,37 using intravascular ultrasound for lar events in apparently healthy individuals without CVD,
assessing plaque burden, after adjustment for the reduction a risk factor for recurrent cardiovascular events in CHD
in blood lipid levels, the decrease in CRP levels was indepen- patients, and a prognostic marker of future events in ACS
dently and significantly correlated with the rate of disease patients.4 White blood cells may exert their deleterious
progression. In fact, patients with greater reductions in both effects through several mechanisms summarized in Table
LDL cholesterol and CRP had significantly slower rates of 27B.2.
progression of their atherosclerotic lesions. Another study Leukocyte count has been correlated with CHD since the
using statins for reducing the risk of recurrent MI or death early 1920s.43 Several large, prospective studies in CHD-free
from coronary causes in patients with acute coronary syn- populations have shown a consistent and positive correlation
dromes showed that patients with lower CRP levels after between leukocyte count and risk of CHD (Fig. 27B.3),44–47
statin therapy had better clinical outcomes than those with even after adjustment for other risk factors.48–50 The predic-
higher CRP levels, regardless of the final level of LDL cho- tive value of high WBC is especially robust in smokers.4 In
lesterol.38 Losing weight and controlling diabetes can also subjects with angiographically documented coronary artery
lower CRP levels (Table 27B.1).2 Serial hsCRP testing is not stenosis, both WBC and neutrophil count correlated with the
recommended for monitoring the effects of treatment.1 number and the extent, severity, and location of coronary
Current guidelines discourage use of hsCRP in application stenosis and patient survival.51,52 Other studies have shown
of secondary prevention measures, but the authors recom-
mend periodic measurements of serum CRP along with
lipids.1
hsCRP is correlated with body weight and is raised in the
TABLE 27B.2. Possible mechanisms of action of leukocytes in
metabolic syndrome. Adipose tissues produce CRP, and coronary heart disease
weight loss reduces the hsCRP levels. These findings have
Endothelial cell injury caused by proteolytic enzymes
led some authors to suggest that hsCRP may be a marker for
obesity and insulin resistance.39,40 Another limitation of CRP Vessel plugging
is its nonspecificity for vascular inflammation and the fact Decreased perfusion
that its predictive power is at least partially affected by the Abnormal leukocyte aggregation
obesity level. hsCRP loses some of its predictive power when Effects on blood flow
adjustments for other risk factors are made in multivariate Increased expression of monocyte tissue factors
analyses. In fact, some recent studies have cast doubt on the Activation of coagulation system
ability of hsCRP to add additional prognostic information in Association with atherosclerotic risk factors
the presence of traditional risk factors.31 Another limitation Electrical instability
of hsCRP is its moderate, within-individual variability.41,42
Increased thrombus formation in coronary heart disease (CHD)
Currently, in a manner similar to cholesterol, two separate
Involvement in hematologic stress syndrome
measurements of hsCRP (i.e., 2 weeks apart and then aver-
Increased leukocyte adhesion in coronary artery disease (CAD)
aged) are recommended to classify a subject’s risk level.
644 chapter 27 B

CHD incidence
Zalokar et al (1981)
BRHS (1992)
MRFIT I (1992)
MRFIT II (1992)
Gillum et al (1993) males
Gillum et al (1993) females
Weijenberg et al (1996)
Folsom et al (1997) males
Folsom et al (1997) females
Lee et al (2001)
Aronow et al (2003)
Manttari et al (1992)

CHD mortality
FIGURE 27B.3. Point estimate and 95%
Grimm et al (1985) confidence intervals for odds of CHD
Gillum et al (1993) events associated with high leukocyte
Brown et al (2001) counts. For more detail, please see Madjid
Lee et al (2001), Afric. Americans
Lee et al (2001), Whites
M. et al. Leukocyte count and coronary
Weijenberg et al (1996) heart disease: implications for risk
Ali et al (2001) assessment. J Am Coll Cardiol. 2004
0 1 2 3 4 5 6 7 8 16;44(10):1945–56.

a strong effect of leukocyte count on prognosis of patients of both markers was associated with an almost sevenfold
with CHD after an MI event. In the first Persantine-Aspirin elevation of risk.64
Reinfarction Study (PARIS-1), after adjustment for other risk
factors, including smoking, baseline leukocyte count was
strongly associated with recurrent coronary events and total Lipoprotein-Associated Phospholipase A2
mortality after an MI event.53 Leukocyte count is also a pre-
dictor of prognosis in MI patients54,55 and an independent Lipoprotein-associated phospholipase A 2 (Lp-PLA 2), also
predictor of in-hospital, 6-week, and 1-year mortality in acute known as platelet-activating factor acetylhydrolase (PAF-
MI (AMI) patients.4,56 AH), is an enzyme that hydrolyzes oxidized phospholipids
In addition, a high leukocyte count is a risk factor resulting in production of proinflammatory lysophosphati-
for increased mortality in patients with unstable angina dylcholine (lysoPC) and oxidized nonesterified fatty acids
pectoris57,58 and unstable angina or non-ST elevation MI (NEFAs).5 On the other hand, hydrolysis of platelet-activating
(NSTEMI).59,60 In the latter patients, high baseline leukocyte factor and other phospholipids has antiinflammatory effects.
counts have been associated with poorer myocardial reperfu- Therefore, Lp-PLA 2 can have both proinflammatory and anti-
sion, more extensive coronary artery disease (CAD), and inflammatory actions.
higher 6-month mortality.60 The same study also found WBC Lp-PLA 2 is produced by inflammatory cells and co-travels
count and CRP to be independent, additive predictors of the primarily (70–80%) with circulating LDL, and its enzyme
6-month mortality.60 activity is higher in small, dense LDL.65 Lp-PLA 2 levels are
The Hiroshima and Nagasaki Adult Health Study in a lower in menopausal women than in men, with levels
large population of asymptomatic subjects showed that total increasing with age.5
leukocyte count could predict the incidence of CHD.61 More- In human atherosclerotic plaques, Lp-PLA 2 is both
over, high eosinophil, neutrophil, and monocyte (but not produced locally by inflammatory cells (macrophages, T
lymphocyte) counts were independent predictors of events.61 cells, mast cells) and is possibly internalized with LDL from
Such an effect was observed for monocyte counts in the Paris circulation. An autopsy study showed that in coronary
Prospective Study II and for neutrophil and eosinophil counts plaques, positive Lp-PLA 2 immunostaining is particularly
in a United Kingdom study.62,63 When combined with the marked in macrophage-rich areas within thin-cap
widely available and inexpensive leukocyte count, CRP may fibroatheromas.5
yield additional information about risk and prognosis for Several studies have shown that high Lp-PLA 2 levels
patients with unstable angina or MI.60 (measured as its mass or activity) predict future cardiovascu-
Leukocyte count is safe, reliable, inexpensive, easy to lar events. In most studies, the attributable risk for develop-
interpret, and routinely ordered in inpatient and outpatient ment of coronary events, stroke, or death remains statistically
settings. In fact, its combination with other inflammatory significant even after full adjustment for traditional risk
markers (such as hsCRP) may act synergistically to predict factors.66–70 The strength of association varies and is generally
cardiovascular events. A recent report from the Women’s modest (hazard ratios < 2), which is typical of common risk
Health Initiative Observational Study in 72,242 postmeno- factors (Fig. 27B.4).5 Because of different sources of produc-
pausal CVD-free women aged 50 to 79 years showed that a tion and metabolic pathways, there is no correlation between
WBC count greater than 6.7 × 109 cells/L was an independent CRP and Lp-PLA 2, though they have additive value in pre-
predictor of CVD events and all-cause mortality. Moreover, dicting cardiovascular risk.68,70
in logistic regression analyses of the CHD risk, high hsCRP In a case–cohort analysis of the West of Scotland Coro-
and high WBC had an additive effect, and having high values nary Prevention Study (WOSCOPS), CRP, WBC, and fibrino-
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s 645

Risk ratios for CHD based on Lp-PLA2 levels inhibitors of Lp-PLA 2 have been able to reduce >95% of the
circulating enzyme activity.5 If proved safe and effective,
these agents may find a place in stabilizing vulnerable
All LDL concentrations 1.0 1.5 2.5
plaques.
310 420
Myeloperoxidase
LDL <130 mg/dL 1.0 2.2 3.5
Polymorphonuclear neutrophils (PMNs) play a critical role in
310 420 myocardial cell injury and undergo degranulation within the
coronary circulation in ACS.26,76 A major product of PMN
LDL ≥130 mg/dL 3.15 3.7 5.1 activation is myeloperoxidase, a hemoprotein with micro-
bicidal activity. Myeloperoxidase (MPO) also has potent
350 460 proatherogenic properties, such as the ability to oxidize LDL
cholesterol, activating metalloproteinases, and catalytically
300 320 340 360 380 400 420 440 460
consuming endothelium-derived nitric oxide, hence impair-
LP-PLA2 ng/mL
ing its vasodilatory and antiinflammatory functions.77 Serum
FIGURE 27B.4. Risk ratios for CHD based on lipoprotein-associ-
ated phospholipase A 2 (Lp-PLA 2) levels. level of MPO is a predictor of prognosis of cardiovascular
events in patients.
In a case-control study of patients with and without angi-
gen levels were strong predictors of the risk of coronary ographically determined CAD, leukocyte and blood MPO,
events, but the association of these variables with risk was both levels were significantly greater in patients with CAD
markedly attenuated in multivariate models. After adjust- than in controls.6 Even after adjusting for traditional risk
ment for traditional risk factors and hsCRP, high baseline factors and WBC counts, MPO levels were significantly and
Lp-PLA 2 levels were still strongly associated with increased strongly associated with the presence of CAD.6
risk for CHD events.71 In a case–control analysis from the In patients with ACS enrolled in the c7E3 Anti-Platelet
Women’s Health Study, baseline Lp-PLA 2 levels were higher Therapy in Unstable Refractory Angina (CAPTURE) trial,
in women who later developed cardiovascular events. patients with elevated MPO levels (>350 μg/L) experienced a
However, this association lost its significance after adjust- markedly increased cardiac risk on 6-month follow-up, par-
ment for traditional risk factors and hsCRP.67 ticularly in patients with troponin T levels below 0.01 μg/L.77
In a prospective, case cohort study in apparently healthy, In a multivariate model, including other biochemical markers,
middle-aged men and women followed for 6 years in the Ath- troponin T, CRP, vascular endothelial growth factor (VEGF),
erosclerosis Risk in Communities (ARIC) study, both Lp- soluble CD40 ligand, and MPO were all independent predic-
PLA 2 and CRP were associated with incident CHD after tors of the patients’ 6-month outcome.77
adjustment for age, sex, and race with a hazard ratio of 1.78 for In a study of 604 sequential patients presenting to the
the highest tertile of Lp-PLA 2 and 2.53 for the highest category emergency department with chest pain, baseline plasma
of CRP versus the lowest categories.68 However, in a multi- myeloperoxidase levels predicted the risk of MI, even in
variate model adjusting for several risk factors, including LDL patients with negative troponin T tests.78 The initial myelo-
cholesterol, the association of Lp-PLA 2 with CHD was attenu- peroxidase levels also predicted the risk of major adverse
ated and not statistically significant. In individuals with LDL cardiac events within 30 days and 6 months after presenta-
measurements <130 mg/dL, Lp-PLA 2 and CRP were still both tion, even in absence of myocardial necrosis.78
significantly and independently associated with CHD even
after full adjustment for other risk factors.68
A more recent report from the MONICA Augsburg study Pregnancy-Associated Plasma Protein-A
showed that, after 14 years of follow-up, elevated levels of
Lp-PLA 2 are predictive of future coronary events in appar- Pregnancy-associated plasma protein-A (PAPP-A) is a zinc-
ently healthy middle-aged men with moderately elevated binding matrix metalloproteinase that is abundantly
total cholesterol, independent of CRP.69 expressed in plaque cells and extracellular matrix of eroded
In the Rotterdam Study, after adjustment for traditional and ruptured plaques.7 It has been suggested to be a marker
risk factors, WBC, and CRP, Lp-PLA 2 activity was a strong of plaque destabilization. Circulating PAPP-A levels have
predictor of both coronary heart disease and ischemic been observed to be significantly higher in patients with
stroke.70 Lp-PLA 2 levels have been correlated with the extent unstable angina or AMI than in patients with stable angina
of angiographic CAD on univariate, but not multivariate, and controls.7
analysis.72 In the same population, higher Lp-PLA 2 levels A later study in patients with chronic stable angina found
were associated with a greater risk of incident cardiovascular that patients with complex coronary stenoses had a signifi-
events, even after adjusting for other risk factors and CRP.72 cantly higher PAPP-A and PAPP-A/proMBP ratio than those
Treatment with statins or fenofibrate decreases Lp-PLA 2 without complex lesions [the proform of eosinophil major
activity by 20% to 30% without an effect on synthesis and basic protein (proMBP) is the endogenous inhibitor of PAPP-
secretion of Lp-PLA 2 by macrophages.73,74 Currently, several A].79 In asymptomatic male subjects whose carotid intima-
potent Lp-PLA 2 inhibitors are being evaluated for lowering media thickness (IMT) and lesion status were evaluated by
Lp-PLA 2 activity in plasma and tissues.75 Oral forms of these noninvasive ultrasonography, the presence of hyperlipidemia
646 chapter 27 B

and hyperechoic or isoechoic and echogenic lesions was asso- percentile distribution (>3.71 ng/mL) has been reported to be
ciated with significantly higher PAPP-A levels.80 more than three times.14
In troponin-negative hospitalized ACS patients, elevated Patients with unstable angina have significantly raised
PAPP-A is an independent predictor of adverse outcome serum levels of sCD40L when compared with patients with
during 6 months of follow-up.81 In a sub-study of the stable angina and controls.92 T cells in patients with unstable
CAPTURE trial, elevated PAPP-A levels (>12.6 mIU/L), in angina had enhanced surface expression of CD40L and
patients with ACS indicated an increased risk of death or MI increased release of sCD40L on anti-CD3/anti-CD28 stimu-
at 30 days and 6 months, even in patients with negative tro- lation in vitro.92 In a large study on patients with acute coro-
ponin T results.82 nary syndromes, sCD40L levels indicated a significantly
increased risk of death or nonfatal MI during 6 months of
follow-up.93 In subjects presenting with chest pain, an ele-
Serum Amyloid A vated sCD40L level identified patients with acute coronary
syndromes who were at high risk for death or nonfatal MI.93
Serum amyloid A (SAA) is a family of proteins that is syn- The increased risk in patients with elevated sCD40L can be
thesized in the liver and plays a significant role in the acute- reduced by treatment with abciximab.93
phase response.76 In response to infections and stresses, SAA In the OPUS-TIMI16 trial, patients who developed death,
is secreted as the predominant apolipoprotein on plasma MI, or congestive heart failure (CHF) within 10 months of
high-density lipoprotein (HDL) particles, replacing apolipo- the study had significantly higher baseline plasma sCD40L
protein A-I. Serum amyloid A maintains the reverse choles- levels than controls, after adjustment for other risk predic-
terol transport system. Moreover, SAA is present in tors and levels of troponin (cTnI) and CRP.94
atherosclerotic lesions, and cells in the artery walls are able In subjects with an acute coronary syndrome enrolled in
to express SAA.83 Several studies have suggested an associa- the Myocardial Ischemia Reduction with Aggressive Choles-
tion between SAA levels and cardiovascular disease.84 Ele- terol Lowering (MIRACL) study, those with high sCD40L
vated SAA on hospital admission in patients with unstable levels (>90th percentile) were at increased risk of a recurrent
angina is a predictor of poor prognosis.85 In the TIMI11A cardiovascular event.95 This risk increase was abolished by
study, high baseline SAA predicted a higher incidence of atorvastatin, though its effect on sCD40L levels was not
early death for hospitalized unstable angina and non-Q MI significant.95 Plasma levels of sCD40L are higher in diabetic
patients, even with a negative rapid assay for cTnT.86 patients and intensive multifactorial risk management can
The National Heart, Lung, and Blood Institute– reduce the elevated levels.96 In patients with successful
sponsored Women’s Ischemia Syndrome Evaluation (WISE) balloon angioplasty, plasma levels of sCD40L can predict
study evaluated women referred for coronary angiography restenosis.97,98
for suspected myocardial ischemia and showed that, after
adjusting for conventional risk factors, SAA levels are
still independently and moderately associated with angio- Proinflammatory Cytokines
graphic CAD and highly predictive of 3-year cardiovascular
events.8 The main proinflammatory cytokines are IL-1 and IL-6 and
Serum amyloid A has also been shown to be associated TNF-α. TNF-α is produced by the endothelial cells, smooth
with a higher rate of recurrent coronary events in stable muscle cells, and macrophages, and plays a major role by
patients who have had an acute MI87,88 and to predict poor inducing the synthesis of the other cytokines. IL-1 and IL-6
outcome in patients with unstable angina.89 High-dose ator- are multifunctional cytokines with extensive humoral and
vastatin has been shown to reduce the elevated levels of SAA cellular immune effects. IL-6 is a major mediator of the
and CRP (but not IL-6).90 acute-phase response and the primary determinant of CRP
production.99
Multiple studies have implied that proinflammatory
CD40 Ligand cytokines play important roles in atherogenesis, and their
circulating levels can predict cardiovascular events. In the
CD40 ligand (CD40L also called CD154) is a trimeric trans- Health, Aging, and Body Composition (Health ABC) Study,
membrane protein of the tumor necrosis factor family and, 2,225 participants 70 to 79 years old, without baseline car-
in conjunction with its receptor CD40, plays a major role diovascular disease, were followed for 3.6 years for incidence
in vascular inflammation. Several types of immune cells of CHD, stroke, and CHF events.100 High IL-6 levels were
express CD40 and CD40 ligand and both are present in significantly associated with all outcomes (CHD events,
human atherosclerotic plaques.91 CD40 signaling in plate- stroke, and CHF events).100 TNF-α showed significant
lets, monocytes, endothelial cells, and smooth muscle cells associations with CHD and CHF events, whereas CRP was
promotes a large number of proatherogenic and prothrom- significantly associated with CHF events.100 In a long-term
botic functions. CD40L is present both in a membrane-bound study in healthy men, baseline levels of IL-6 predicted MI
form and in a soluble form in plasma (sCD40L). More incidence.11
than 95% of the circulating CD40L is derived from platelets. In apparently healthy postmenopausal women studied
In healthy, middle-aged women, baseline sCD40L levels can in the Women’s Health Initiative, median baseline levels of
predict subsequent development of MI, stroke, or cardiovas- CRP and IL-6 were independent predictors of incident CHD.101
cular death.14 The relative risk of developing future cardio- Use of hormone replacement therapy was associated with
vascular events in women with CD40L levels above the 95th significantly elevated median CRP levels, but did not increase
 biom a r k e r s of i n f l a m m at ion a s su r rog at e m a r k e r s 6 47
IL-6 levels.101 In asymptomatic elderly subjects enrolled in expressed on the surface of endothelial cells. These mole-
the Framingham Study, high serum IL-6 and CRP levels and cules, which can be found on different cell types present in
increased production of TNF-α by the peripheral blood mono- the arterial wall, include VCAM-1, ICAM-1, endothelial
nuclear cells were associated with future risk of developing leukocyte adhesion molecule (ELAM-1), P-selectin, and E-
CHF.102 Subjects with elevated levels of all three biomarkers selectin.108 VCAM-1 plays a critical role in monocyte
were at the highest risk of developing CHF.102 In the Choles- adherence to endothelial cells under flow conditions and
terol and Recurrent Events (CARE) trial, high TNF-α levels ICAM-1 ligands include CD11a/CD18 (LFA-1) and CD11b/
were predictive of recurrent nonfatal MI or a fatal cardiovas- CD18 (Mac-1), which are present on monocytes, lympho-
cular event.9 In fact, the excess risk of recurrent coronary cytes, and neutrophils.109 Atherosclerotic plaques demon-
events after MI was predominantly seen among those with strate increased expression of ICAM-1 and VCAM-1.
the highest levels of TNF-α.9 Membrane-bound forms of these adhesion molecules are dif-
The effects of TNF-α are mediated by two receptors (TNF- ficult to measure; however, their soluble forms can be mea-
R1 and TNF-R2), which circulate in soluble forms (sTNF-R1 sured in the serum or plasma, and they indicate the expression
and sTNF-R2, respectively). These can be measured with of membrane-bound adhesion molecules.
greater accuracy and reliability than TNF-α itself.103 The In apparently healthy women participating in the
soluble receptors may promote inflammation in the absence Women’s Health Study, mean levels of soluble P-selectin
of free TNF ligand. In disease-free women participating in were significantly higher at baseline among women who
the Nurses’ Health Study and men participating in the Health subsequently experienced cardiovascular events compared
Professionals Follow-Up Study, high levels of IL-6 and CRP with those who did not.13 In a subset of subjects from the
were significantly associated with an increased risk of CHD Atherosclerosis Risk in Communities (ARIC) study, baseline
in both sexes, whereas high levels of soluble TNF-α receptors levels of VCAM-1 were not significantly different among the
were predictors of CHD only among women. However, after patients with incident CHD, those with carotid artery ath-
adjustment for lipid and nonlipid factors, these associations erosclerosis (CAA), and control subjects.110 Patients with
were all attenuated and only CRP levels remained signifi- CHD or CAA had higher levels of E-selectin and ICAM-1
cantly associated with development of CHD.103 compared with the control subjects. The relationship of
Interleukin-18 plays a central role in the inflammatory ICAM-1 and E-selectin with CHD and CAA was independent
cascade and in the processes of innate and acquired immuni- of other known CHD risk factors.110
ties. IL-18 induces interferon-γ (IFN-γ) production in T In healthy men enrolled in the Physicians’ Health Study,
lymphocytes and natural killer cells and acts in synergy there was a significant association between increasing base-
with IL-12 to promote the development of T helper 1 (Th-1) line concentration of sICAM-1 and risk of future MI, even
responses.104 Increased local expression of IL-18 in human after adjustment for lipid and nonlipid risk factors.111 In
atherosclerotic plaque has been reported.105 Serum IL-18 level apparently healthy postmenopausal women, sICAM-1, along
is a strong independent predictor of cardiovascular death in with CRP, SAA, IL-6, and homocysteine, were predictors of
patients with coronary artery disease (with either stable or cardiovascular events on follow-up. However, in multivariate
unstable angina).104 In the Prospective Epidemiological Study analyses, hsCRP was the only inflammatory plasma markers
of Myocardial Infarction (PRIME) study, baseline level of IL- that could independently predict future events.112 In a pro-
18 was an independent predictor of coronary events in spective study of asymptomatic men who were monitored
healthy, middle-aged European men.106 for 16 years, ICAM-1 was a predictor of CHD. However, its
Interestingly, low levels of the antiinflammatory cyto- association lost significance after adjustments for some
kine IL-10 is an important prognostic determinant in patients classic coronary risk factors and indicators of socioeconomic
with acute coronary syndromes.107 In a sub-study of The status.113 After similar adjustments, VCAM-1, E-selectin, and
CAPTURE trial, patients with high IL-10 levels (>3.5 pg/mL) P-selectin did not add much predictive information to that
had a lower risk of death and nonfatal MI on 6 months after provided by established risk factors.113
admission compared with patients with elevated IL-10 In the Epidemiological Study of Myocardial Infarction in
levels.107 The predictive value of IL-10 was independent of apparently healthy middle-aged men, plasma ICAM-1 was an
myocardial necrosis, but had significant interaction with independent predictor of the risk for MI, coronary death, and
CRP levels. Patients with both high CRP and IL-10 serum also for angina pectoris. Subjects with high CRP had
levels had less risk than patients with high CRP but with increased coronary risk only if ICAM-1 was high. An ele-
low IL-10 levels.107 This suggests that the balance between vated level of VCAM-1 was not associated with any risk of
proinflammatory and antiinflammatory markers may be a future acute coronary event or angina pectoris.114
major determinant of patients’ prognosis. In a prospective, nested case-control study in patients
with CHD enrolled in a secondary prevention trial, baseline
serum concentrations of sICAM-1 could significantly predict
Adhesion Molecules future coronary events even after multivariate adjustment
for traditional risk factors.12 In healthy male participants in
The adhesion molecules permit rolling of monocytes and the Physicians’ Health Study, there was no association
lymphocytes on the endothelium and firm attachment and between sVCAM-1 levels and the risk of future MI.115 In
migration of the blood cells into the arterial wall.108 Adher- contrast, in patients with documented CAD, higher levels of
ence of circulating leukocytes to the endothelial cells and sVCAM-1, sICAM-1, and sE-selectin were associated with
their entry into the arterial wall depend on a cascade of increased risk of future death from cardiovascular causes.116
events mediated by a family of cellular adhesion molecules In a multivariate model, sVCAM-1 was still a predictor of
648 chapter 27 B

fatal events even after simultaneously controlling for sICAM- References

1, sE-selectin, and CRP.12
1. Smith SC Jr, Anderson JL, Cannon RO 3rd, et al. CDC/AHA
In apparently healthy middle-aged men participating in
Workshop on Markers of Inflammation and Cardiovascular
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 2 Global Differences in
8 Atherosclerosis
Philip A. Poole-Wilson

Size of the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 Prevention of Coronary Heart Disease Around

Changing Pattern of Disease Around the World . . . . . . 654 the World. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
Country Differences in Atherosclerosis . . . . . . . . . . . . . 655 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655

Key Points common and dominate patterns of disease in most countries

primarily because of the epidemiologic transition from com-
• Cardiovascular disease causes one third of the deaths in
municable (infectious disease) to noncommunicable disease
the world.
(chronic diseases) as the major cause of death and disability
• Eighty percent of these deaths are in developing
around the world.7,8 With the decline of infectious diseases,
countries.
particularly in the young, life expectancy, the global popula-
• In developed countries death from infectious diseases
tion, and the proportion of elderly persons in most countries
has diminished as death from cardiovascular disease has
has increased. In 1950, the global population was 2.5 billion.
increased.
In 2000, it was 6.0 billion, and it is estimated to reach 9.0
• The proportion of cardiovascular deaths due to coronary
billion by 2050. These demographic changes are the second
heart disease and stroke varies between countries.
major cause of the increase in the impact of cardiovascular
• The risk factors for cardiovascular diseases are known.
disease.
• Deaths can be largely accounted for by nine risk
factors.
• These risk factors are common across the world regard-
less of geography, ethnicity, and gender.
Size of the Problem
• The origins of many risk factors relate to social, eco-
The size of the problem around the world is difficult to esti-
nomic, fiscal, and political circumstances.
mate. Whereas reliable figures may be available in developed
• Global institutions allocate insufficient funds to the pre-
countries, in many parts of the world, there is not sufficient
vention of cardiovascular disease.
organizational capacity to obtain accurate figures. The diag-
• Informing the public and patients will put pressure on
nosis may be used to explain deaths to the satisfaction of
politicians to respond to the increasing global attrition of
grieving relatives with little attention to accuracy. In many
cardiovascular disease.
countries, coronary artery disease is a socially acceptable
The consequences of atherosclerosis are grouped under the cause of death. Without postmortem evidence, the diagnosis
broad phrase “cardiovascular diseases,” which is made up of may be in error. Equally, it may be overlooked particularly
coronary heart disease, cerebrovascular disease, and other in patients dying suddenly where often the diagnosis is in
circulatory disorders. These afflictions include the many fact acute myocardial ischemia. A further difficulty can arise
manifestations of coronary heart disease, such as myocardial in some countries because health authorities have no interest
infarction, acute coronary syndromes, and heart failure, and in coronary artery disease, regarding it as a disease of the
the consequences of peripheral disease, such as stroke, elderly, a pleasant way to die, a personal responsibility, a
peripheral vascular disease, aortic disease, and renal failure. disease of affluence, and a problem limited to the male
Myocardial infarction and stroke have become the major gender. All five of these beliefs and attitudes are serious
global causes of death and disability around the world.1–5 misconceptions and untrue.
Much is now known about the natural history and patho- The consequences of atherosclerosis in causing cardio-
physiology of atherosclerosis. The disorder begins in child- vascular deaths have been estimated by the World Health
hood and the lesions in the arterial vasculature develop over Organization (WHO) (Table 28.1).9 In 2002, the world popula-
many decades.6 The clinical sequelae appear in middle age tion was 6.22 billion. The total number of deaths was 57.0
or later life. Cardiovascular disorders are becoming more million (0.9%). Cardiovascular deaths occurred in 16.7

653
654 chapter 28

TABLE 28.1. Global causes of death Percentage 65 years or older

Population 6,224,000,000 30
Total deaths per year 57,027,000 (0.9%) 2000
Cardiovascular deaths 16,665,000 (31%)
43% coronary heart disease 2050
33% stroke 20
78% not in high-income
countries
52% in women
AIDS 2,821,000
Tuberculosis 1,605,000 10
Malaria 1,222,000 (mostly in Africa)

0
Europe North Oceania Asia Latin Near Sub-
million (29% of the total deaths). The greater number of America America East Saharan
these deaths (52%) occurred in women. Of those, 43% were Caribbean North Africa
due to coronary artery disease and 33% to cerebrovascular Africa
FIGURE 28.2. Persons over the age of 65 years projected to 2050 in
disease, and 78% were not in high income or developed different regions of the world.
countries. Hypertensive heart disease10 caused 0.9 million
(5%) deaths, rheumatic heart disease11,12 0.33 million (2.0%)
deaths, and inflammatory heart disease 0.40 million (2.4%)
deaths. By contrast, AIDS accounted for 2.82 million deaths, medical treatments, but also as a consequence of social and
tuberculosis 1.61 million, and malaria 1.22 million. The hygienic change reducing the impact of infectious diseases.
deaths from malaria were mostly in Africa and many in One consequence is that the proportion of elderly persons in
children. populations is changing rapidly and will do so for the next
The burden of disease can be assessed by calculating dis- several decades (Fig. 28.2). Such an alteration in the demog-
ability-adjusted lost years (DALYs). In 2002, cardiovascular raphy of society has major implications for economic and
disease accounted for 9.9% of lost years, whereas HIV/AIDS social change in many countries. A second consequence is
accounted for 5.8%, tuberculosis 2.4%, and malaria 3.0%. that in developed countries there has been a major switch in
the causes of death. The pattern of disease whereby infections
were the dominant causes of death has been replaced by
Changing Pattern of Disease Around chronic diseases, and notably atherosclerosis, as the primary
the World cause. That epidemiologic transition in health is common
around the world. However, in poorer countries noncommu-
The 20th century saw a most remarkable increase in public nicable diseases continue to be the dominant cause of death
health. Life expectancy measured in years accrued is possibly (Fig. 28.3).14 Those countries can be expected to change their
the crudest but simplest measure of public health. Over the pattern of disease as public health improves.
last century, life expectancy in what are now developed coun- It is a common belief that poverty and economic prosper-
tries increased from about 40 years to almost 80 years (Fig. ity are closely linked to health, but it is not so (Fig. 28.4).15
28.1).13 In general, women have a life expectancy 1 or 2 years Among countries with a high life expectancy, there is con-
greater than men, and that greater longevity has been main- siderable variation in income per capita. Among countries
tained as life expectancy has increased. The large increase in with a low income per capita, there is a large difference in
life expectancy has been brought about partly as a result of life expectancy. The precise reasons are many and complex,

100
% Of total deaths in group
90
90
80
Women 80
Life expectancy (y)

70
70 Communicable
60 60
Men diseases
50 50 Noncommunicable
40 40 diseases
30 30 Injuries
20 20
10 10
0
0
1500 1600 1700 1800 1900 2000 Global World Global
FIGURE 28.1. Expectation of life over centuries in England and poorest 20% average richest 20%
Wales. FIGURE 28.3. The burden of disease among the global poor.14
 globa l differ ences in at h erosclerosis 655
Life expectancy (years) Country Differences in Atherosclerosis
80
The proportion of persons in countries who die from the
1990 consequence of atherosclerosis varies. For example, in the
70
1960 United States and the United Kingdom (Fig. 28.8), coronary
heart disease is the most common manifestation of athero-
60 About 1930 sclerosis, whereas in other countries, such as Japan, stroke is
more common. In China, stroke is more common than coro-
About 1900 nary heart disease, but the pattern is changing and is expected
50
to change even further as the population moves from rural
communities to towns. Urbanization17 leads to alterations of
40 lifestyle with a changed diet, reduction of exercise, and
increase in diabetes and obesity. In the towns and cities of
China, coronary heart disease is becoming more common.
30
0 5000 10000 15000 20000 25000 A common misconception is that atherosclerosis is a disease
of affluent and developing countries; that is simply falla-
Income per capita (normalized to U.S. dollars) cious. Seventy-eight percent of deaths from coronary heart
FIGURE 28.4. Life expectancy by income and historical period.15 disease occur in developing countries. Even in low-income
regions such as sub-Saharan Africa, where AIDS ravages
populations, the probability of dying from a chronic disease
but what is clear is that the relation between low income and (noncommunicable disease) is higher than in established
health is not linear. The macroeconomic impact of HIV/ market economies.4 The reasons for this apparent paradox
AIDS has been investigated extensively; less is known about are unclear, but include all the known risk factors and the
the consequences of chronic disease and cardiovascular possibility that poor nutrition and illness in childhood are
disease.16 In younger persons, death from HIV/AIDS just linked to early atherosclerosis. The attributable causes of
exceeds cardiovascular disease taken as a whole (Fig. 28.5).9 death in developing countries are shown in Figure 28.9 for
Heart disease and cerebrovascular disease together are the low- and high-income countries.9
sources of the greatest proportion of disease burden in men
and women (Fig. 28.6).9 Loss of persons from society or inca-
pacity of contributory and talented individuals in the age
range 35 to 70 years leads to social, economic, and political Risk Factors
instability.16
Predictions have been made with regard to how the The so-called risk factors for coronary heart disease are
causes of death will alter over the next two decades (Fig. well known.18,19 These risk factors appear to be similar
28.7).1 Heart and lung disease remain the leading causes of across all countries regardless of gender, geography or ethnic-
deaths and of disability. The position in 2020 is projected to ity.19 Variation in the prevalence of heart disease among
be little different from that in 1990. A major factor is the countries can be largely explained on the basis of the degree
change in the demography of populations with respect to age to which any particular risk is present. One study19 claims
(Fig. 28.2). In those between the age of 15 and 59 (Fig. 28.5),9 that nine risk factors can account for 90% of cardiovascular
the most common cause of death globally is HIV/AIDS, but events. Furthermore, these risk factors are the same risk
that is equaled by deaths from ischemic heart disease and factors that are related to cancer, diabetes, and respiratory
cerebrovascular disease. In those over the age of 60, the diseases. The consequence for public health policy is that the
sequelae of atherosclerosis are by far the major causes of modification of risk factors may bring greater benefit to a
death. country than the treatment of specific diseases. The attribut-

15−59 years 60 years and over

2279 HIV/AIDS 5823 Ischemic heart disease

1331 Ischemic heart disease 4692 Cerebrovascular disease
1037 Tuberculosis 2399 COPD
811 Road traffic accidents 1398 Lower respiratory infection
783 Cerebrovascular disease 929 Trachea, bronchitis,lung cancer
672 Self-inflicted injuries 754 Diabetes mellitus
475 Violence 735 Hypertensive heart diease
382 Cirrhosis of the liver 606 Stomach cancer
352 Lower respiratory infections 496 Tuberculosis
343 COPD 478 Colon and rectal cancers
FIGURE 28.5. Leading causes of mortality in adults,
2002.9 COPD, chronic obstructive pulmonary disease. (Deaths 000)
656 chapter 28

Males Females

9.2 Heart disease 8.4 Unipolar depressive disorder

6.9 HIV/AIDS 7.3 HIV/AIDS
6.9 Cerebrovascular disease 6.8 Maternal conditions
4.3 Tuberculosis 5.3 Ischemic heart disease
4.2 COPD 5.2 Cerebrovascular disease
3.8 Unipolar depressive disorders 3.2 Cataracts
3.6 Hearing loss, adult onset 2.8 Hearing loss, adult onset
3.1 Motor vehicle accidents 2.8 COPD
2.8 Cataracts 2.6 Tuberculosis
2.5 Alcohol use disorders 2.0 Osteoarthritis
FIGURE 28.6. Leading causes of disease burden [dis-
ability-adjusted lost years (DALYs)]. Persons aged 15 and
(DALYs) over, worldwide, 2002.9

able mortality is shown in Table 28.2.9 In developed coun- Prevention of Coronary Heart Disease Around
tries, the recent fall in events relating to coronary heart the World
disease has been associated with both advances in medical
treatment and reduction of risk factors in almost equal For many years, organizations have sought to prevent the
proportions.20,21 development of coronary heart disease in the many countries
Risk factors such as smoking, poor diet, obesity, and lack of the world. The World Health Organization (WHO) in its
of exercise have been quantitated in many countries of the constitution states that health is a state of complete physical,
world, although the accuracy of some estimates is question- mental, and social well-being and not merely the absence of
able. What is less clear is the issue of what is the underlying disease or infirmity. In the declaration of Alma Ata in 1978,
cause of these risk factors. Many are related to agricultural it is further stated that the existing gross inequality in the
policy and food availability. Social deprivation is closely health status of the people, particularly between developed
linked to coronary heart disease.22–25 Climate change, fiscal and developing countries, is politically, socially, and eco-
policy particularly in relation to tobacco, industrialization, nomically unacceptable, and it is therefore of common
and urbanization are associated with risk factors and an concern to all countries. Others have spoken of the moral
increase in coronary heart disease. Thus, the origins of the principles underlying the care of others.26–28 However, it is
increase in atherosclerosis and differences in prevalence and only recently that this problem has been approached more
incidence among countries may be explained more by social directly. The Framework Convention on Tobacco Control
circumstances within a country than by specific conven- adopted at the 56th World Health Assembly in 2003 has had
tional risk factors. It is for this reason that the idea of car- considerable impact around the world, not only in encourag-
diovascular disease as a personal responsibility is a myth. ing countries to introduce legislation, but also in changing
The understanding of the impact of stress and social depriva- the mood and minds of the public to regard smoking as the
tion and how these are linked to the development of coronary loathsome habit it is. Equally, the Global Strategy on Diet,
artery disease is currently a matter of considerable research. Physical Activity, and Health, which was adopted at the 57th
Certainly major stresses, such as earthquakes and natural World Health Assembly in 2004, may have the same conse-
disasters, are associated with an increase in deaths from quence. Informing the public and politicians of the size and
heart disease. On the other hand, in selected wars, possibly nature of the problem may have greater consequences overall
due to the impact of diet, coronary heart disease has than many other approaches.
decreased. Social deprivation leads to depression and bio- Those responsible for intervening are many, but too often
chemical changes within the body that promote the develop- groups of experts claim this problem to be their own. The
ment of atherosclerosis. greatest need is for more cooperation among experts. Epide-

Ischemic heart disease 1 1 Ischemic heart disease U.S.

Cerebrovascular disease 2 2 Cerebrovascular disease
Lower respiratory infections 3 3 COPD
Diarrheal diseases 4 4 Lower respiratory infections U.K. CHD
Perinatal period 5 5 Trachea, bronchus, and lung Stroke
COPD 6 6 Motor vehicle accidents
Tuberculosis 7 7 Tuberculosis Japan Other CVD
Measles 8 8 Stomach cancer
Motor vehicle accidents 9 9 HIV Other
Trachea, bronchus, and lung 10 10 Self-inflicted injuries China (rural)
Malaria 11 11 Diarrheal diseases
Self-inflicted injuries 12 12 Cirrhosis of the liver
Cirrhosis of the liver 13 13 Liver cancer China (urban)
Stomach cancer 14 14 Violence
Diabetes mellitus 15 15 War 0 500 1000 1500
16 16
20 19 Annual mortality per 100,000 males 35–74 years
21 27
30 29 FIGURE 28.8. Causes of death in China, Japan, U.K., and U.S. WHO
FIGURE 28.7. Rank order of deaths in the world 1990–2020.1 statistics.
 globa l differ ences in at h erosclerosis 657
Cardiovascular diseases
Malignant neoplasms
Injuries
Respiratory infections High mortality
Respiratory diseases Low mortality
HIV/AIDS
Perinatal conditions
Diarrheal diseases
Tuberculosis
Digestive diseases
Childhood diseases
Malaria
Diabetes mellitus
Genitourinary system disease
Neuropsychiatric disorders
Maternal conditions
FIGURE 28.9. Deaths attributable to 16 leading causes: 0 2000 4000 6000 8000 10,000 12,000
developing countries, 2001.9 Deaths (000)

miologists, health economists, the media, and politicians change. Until recently, the media have focused more on
need to demonstrate a more active role. Nurses, health glamorous advances in medical care than on changes that
workers, and primary physicians can influence the public would lead to prevention.
and patients and their families. Hospital physicians, cardiol- The burden of noncommunicable diseases and particu-
ogists, and university scholars must emphasize the impor- larly atherosclerosis in developing countries outweighs com-
tance of the prevention of disease rather than the cure of the municable diseases. That fact is only just being widely
acutely ill. There is a role for medically qualified persons, appreciated and was referred to as the double burden requir-
but a greater role in prevention for those who work in profes- ing a double response by the WHO Health Report in 2003.9
sions closely allied to medicine. Perhaps the greatest respon- It was proposed that a comprehensive health care system was
sibility resides with political leaders who need to consider required that integrated the prevention and control of both
the implications for coronary heart disease when making communicable and noncommunicable diseases. Sadly, that
political decisions on socioeconomic factors in a country and is not yet happening. There is at present insufficient coordi-
on fiscal matters. Reducing multiple risk factors will not nation among health specialists, politicians, health bodies,
bring about total equity around the world in terms of healthy and nongovernmental organizations. The Millennium
life expectancy, but it will reduce substantially the current Project with its development goals,33 the World Bank, the
differences in equality.29 The reduction in the costs of drugs Global Fund,34 the Commission for Africa,35 and the more
as they come off patent will make them more available to recent WHO reports are largely silent with regard to cardio-
the global population. International collective action,30 vascular disease; a change is needed. The World Heart
engagement of developed countries,31 action by civil society,32 Federation36 and other nongovernmental organizations have
and above all, involvement of the public and patients are put forward principles to be adopted so as to promote suc-
essential for a successful program of prevention. cessful policies on prevention.37
The preventive approach to heart disease is undervalued
and underused around the world. This is partly because of a
lack of knowledge and partly because of the desire of physi- Summary
cians to treat the acutely sick. Gains from prevention are not
immediately evident so that the elation associated with Heart disease and stroke are a global challenge. The diseases
bringing about an immediate impact on a patient’s condition are common and becoming more common. The problem
is absent. Some commercial interests may obstruct policy exists regardless of ethnicity, gender, or geography. The

TABLE 28.2. Attributable mortality by risk factor (%) 9

Developing countries

Developed countries Low mortality High mortality

Blood pressure 22 Blood pressure 13.8 Underweight 13

Tobacco 18 Tobacco 7.9 Unsafe sex 10.1
Cholesterol 16 Alcohol 5.3 Blood pressure 7.4
Overweight 10.5 Cholesterol 5.3 Unsafe water 5.8
Few fruit & veg. 7.5 Few fruit & veg. 4.9 Cholesterol 5.3
Physical inactivity 6.3 Overweight 4.8 Tobacco 4.6
Alcohol 4.2 Indoor smoke 3.5 Indoor smoke 3.9
Urban air poll. 1.1 Physical inactivity 3.0 Few fruit & veg. 3.6
Carcinogens 0.5 Urban air poll. 2.7 Zinc deficiency 2.9
Lead exposure 0.6 Underweight 1.8 Vit. A deficiency 2.8
658 chapter 28

causes are known and prevention is possible by applying 17. Godfrey R, Julien M. Urbanisation and health. Clin Med 2005;
existing scientific knowledge. A strong international effort 5:137–141.
will encourage country-led initiatives, but perhaps the key 18. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J III.
to success is to inform better the public and patients so that Factors of risk in the development of coronary heart disease—
six year follow-up experience. The Framingham Study. Ann
political leaders react in a manner the enhances the health
Intern Med 1961;55:33–50.
of the people of the world. 19. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modi-
fiable risk factors associated with myocardial infarction in 52
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disability by cause 1990–2020: Global Burden of Disease Study. coronary heart disease mortality in England and Wales between
Lancet 1997;349:1498–1504. 1981 and 2000. Circulation 2004;109:1101–1107.
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Lancet 1997;349:1436–1442. 874.
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expectancy and disability-adjusted life expectancy: global in male mortality by social class (based on occupation). Popul
Burden of Disease Study. Lancet 1997;349:1347–1352. Trends 1996;86:5–20.
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5. Howson CP, Reddy KS, Ryan TJ, Bale JR. Control of Cardiovas- 24. Rosengren A, Hawken S, Ounpuu S, et al. Association of psy-
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 2 Coronary Artery Disease:
9 Regulation of Coronary
Blood Flow
Robert J. Bache

Determinants of Myocardial Oxygen Consumption . . . 659 Transmural Distribution of Myocardial Blood Flow . . . 663
Epicardial Coronary Arteries . . . . . . . . . . . . . . . . . . . . . . 660 Coronary Collateral Circulation . . . . . . . . . . . . . . . . . . . 663
Coronary Resistance Vessels . . . . . . . . . . . . . . . . . . . . . . 661 Coronary Steal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Endothelium-Dependent Vasodilation . . . . . . . . . . . . . . . 662 Left Ventricular Hypertrophy . . . . . . . . . . . . . . . . . . . . . . 664

Over a wide range of activity, coronary blood flow is closely Determinants of Myocardial
matched to myocardial metabolic requirements to maintain Oxygen Consumption
a consistently high level of oxygen extraction by the heart.
Even during resting conditions 70% to 80% of the oxygen Approximately 85% of the ATP produced in the heart is uti-
perfusing the coronary capillaries is extracted by the myocar- lized to support contractile activity, so that indices of cardiac
dium, so there is little ability to increase oxygen uptake by pump function can be used to estimate myocardial oxygen
means of increasing oxygen extraction.1 For this reason, demands. Furthermore, therapies that decrease the response
increases of oxygen demands during exercise or other stress of contractile work during exercise can prevent the develop-
must be met by proportionate increases in coronary flow. ment of ischemia in myocardial regions in which flow reserve
Close coupling of coronary blood flow to cardiac work is is limited by a coronary stenosis. The hemodynamic vari-
further mandated by the strongly oxidative nature of energy ables that determine myocardial energy consumption (Table
production by the heart. More than 95% of the adenosine tri- 29.1) include the following:
phosphate (ATP) utilized by the myocardium is produced
through oxidative phosphorylation, which requires a continu-
ous supply of oxygen to the mitochondria.2 Since the ATP pool
of the heart turns over four to five times per minute, failure of
Systolic Wall Tension
ATP production to equal ATP consumption results in loss of
contractile function within a few seconds. Reductions of coro- Force produced by the contracting myocardium to generate
nary blood flow by as little as 10% to 20% result in contractile pressure is expressed in terms of wall tension. Systolic wall
dysfunction and depletion of high-energy phosphates.3,4 These tension is directly proportional to left ventricular systolic
considerations imply that the myocardium functions near the pressure. Since wall tension is expressed as force per unit
brink of ischemia, and emphasizes the importance of the cross-sectional area, it is directly proportional to left ven-
mechanisms by which coronary vasomotor tone is adjusted in tricular cavity diameter and inversely proportional to wall
response to beat-to-beat changes of myocardial energy thickness. Since wall tension cannot be directly measured,
demands. Ischemia occurs when diseased coronary vessels systolic arterial pressure is commonly used as a surrogate for
are unable to deliver sufficient arterial inflow to meet myocar- systolic wall tension. Because the effects of left ventricular
dial metabolic demands. When coronary flow is limited by an cavity diameter and wall thickness are neglected, the rela-
arterial stenosis, myocardial oxygen demands play a decisive tionship between systolic arterial pressure and myocardial
role in setting the threshold for ischemia. oxygen consumption is imprecise. However, changes in

659
660 chapter 29

TABLE 29.1. Determinants of myocardial oxygen consumption cause vasodilation. In the normal heart, exercise results in
Systolic wall stress endothelium-dependent vasodilation of the epicardial arter-
Left ventricle (LV) systolic pressure ies, which is mediated by nitric oxide, so that blockade of
LV diameter nitric oxide production prevents normal coronary artery
Wall thickness vasodilation during exercise.6,7 Endothelial dysfunction
Contractility resulting from hyperlipidemia, hypertension, or atheroscle-
Heart rate rosis blunts or abolishes the normal epicardial artery dilation
during exercise.8
Autopsy studies of patients with atherosclerotic disease
have demonstrated that approximately 75% of coronary ath-
eromas are eccentric in location, leaving part of the vessel
systolic wall stress are directly proportional to changes in wall uninvolved. The existence of a relatively uninvolved
systolic blood pressure and are predictive of changes in segment explains the observation that coronary stenoses
oxygen consumption during exercise. often do not behave as fixed narrowings, but have some
degree of compliance and are able to undergo active vasomo-
tion.9,10 The intraarterial distending pressure within a
Contractility
stenosis opposes the vasomotor tone and elasticity of the
Myocardial contractility describes the rate of tension devel- arterial wall, which act to constrict the vessel. Compliant
opment during cardiac contraction. An increase in contrac- stenoses can interact with the distal resistance vessels as the
tility causes an increase in the rate of pressure development result of hydrodynamic changes in the stenotic segment.
and an increase in the velocity of shortening of the contract- Thus, when exercise results in vasodilation of the distal
ing myocardium. The first-time derivative of left ventricular resistance vessels, the increased blood velocity (kinetic
pressure during isovolumic contraction (dP/dtmax) is used to energy) within the stenotic segment causes a proportionate
estimate myocardial contractility. This variable changes in decrease in pressure (potential energy) acting to distend the
parallel with contractility, but is also influenced by both left stenosis. As the distending pressure in the stenosis decreases
ventricular preload (end-diastolic pressure) and afterload (sys- with increasing flow, the arterial wall elasticity and vasocon-
tolic pressure). Direct determination of this index of contrac- strictor tone act to collapse the stenosis and increase stenosis
tility requires high-fidelity measurements of left ventricular severity.11 This effect is augmented by endothelial dysfunc-
systolic pressure in the catheterization laboratory. tion in the atherosclerotic coronary circulation, since the
normal flow-mediated vasodilator response is absent.9,12 When
a stenosis is severe, the effects of increasing blood velocity
Heart Rate
within the stenosis can be sufficient to cause a paradoxical
Heart rate is a summing factor for the energy cost of cardiac decrease in blood flow in response to resistance vessel dila-
contraction. Since systolic wall tension and contractility are tors such as adenosine or dipyridamole. In addition, a compli-
computed on a per beat basis, changes in heart rate bear a ant segment of arterial wall at the site of a stenosis can
strong relationship to changes in myocardial oxygen uptake. undergo active vasoconstriction in response to sympathetic
Furthermore, heart rate directly influences contractility, so nervous system activation or agonists such as ergonovine,
that increases of heart rate during exercise or other stress serotonin, or thromboxane. Sympathetic vasoconstriction is
result in increased contractility. augmented in the atherosclerotic coronary circulation, since
adrenergic stimulation causes endothelial release of nitric
oxide, which opposes vasoconstriction in normal coronary
Rate-Pressure Product
vessels but is lost in atherosclerotic vessels (Table 29.2).13
The product of heart rate and systolic arterial pressure (rate-
pressure product) is a convenient index for estimating changes
in myocardial oxygen demands. Proportional changes in
heart rate or systolic pressure have equal effects on myocar-
dial oxygen consumption.5 The rate-pressure product is espe- TABLE 29.2. Relative potency of vasodilators on epicardial
coronary arteries and coronary arterioles in normal subjects (n)
cially useful for estimating the cardiac workload during and in patients with coronary risk factors or minimal coronary
exercise testing. disease and endothelial dysfunction (Dys)
Epicardial artery Coronary arterioles

n Dys n Dys
Epicardial Coronary Arteries
Acetylcholine ++ Constrict + Constrict
The epicardial arteries form a network of vessels that arbo- Nitrates ++++ ++++ + +
rize over the surface of the heart and give off branches that Adenosine + ↔ ++++ ++++
penetrate into the myocardium. Normal epicardial arteries Dipyridamole + ↔ +++ +++
are true conduit vessels that contribute little to total coro- Serotonin Constrict Constrict +++ +++
nary vascular resistance. The epicardial arteries are richly
Nifedipine + ↔ ++ ++
innervated with sympathetic nerve fibers, and coronary
Verapamil + ↔ + +
artery smooth muscle cells contain both α-adrenoceptors
Exercise + ↔ +++ +++
that mediate vasoconstriction as well as β-receptors that
 corona ry a rt e ry dise a se : r egu l at ion of corona ry bl ood f l ow 6 61
Isometric exercise causes greater activation of the sympa- smooth muscle cell membrane to cause vasodilation.18 Ade-
thetic nervous system than dynamic exercise; consequently, nosine can be taken up by the myocardial myocytes for
the tendency toward constriction of stenotic coronary artery reincorporation into the adenine nucleotide pool or can be
segments is more prominent with isometric exercise than deaminated to inosine, which has little vasodilator activity.
with dynamic exercise.10 These reactions occur very quickly, so that the half-life of
adenosine is only a few seconds. The vasodilator effect of
adenosine can be inhibited by methyl xanthines such as
Coronary Resistance Vessels theophylline, which act as adenosine receptor blockers. Ade-
nosine receptor blockade does not interfere with the normal
The principal resistance to blood flow resides in coronary increase in myocardial blood flow during exercise or other
microvessels smaller than 400 μm in diameter. Coronary increases of oxygen demands, implying that adenosine is not
resistance vessels can be divided functionally into two sepa- a principal mediator of normal metabolic vasoregulation.19
rate segments: arterioles and resistance arteries. Coronary However, adenosine production increases markedly during
arterioles less than 100 μm in diameter mediate metabolic ischemia and does contribute to vasodilation of coronary
vasoregulation and autoregulation, by which blood flow is resistance vessels in ischemic myocardial regions.20 Other
adjusted in response to myocardial demands and is main- metabolic perturbations that occur during ischemia, includ-
tained constant over a range of perfusion pressures. Coronary ing accumulation of hydrogen ion and lactate, can also cause
resistance arteries 100 to 300 μm in diameter account for as coronary vasodilation, but these changes are not likely to
much as 40% of total coronary resistance but do not partici- contribute to regulation of arteriolar tone during physiologic
pate in metabolic flow regulation.14 Because of important conditions. Decreases of arterial oxygen tension and increases
differences in the responses of the coronary arterioles and of carbon dioxide tension exert vasodilator effects on coro-
the resistance arteries, these vascular segments are discussed nary resistance vessels, with evidence for a synergistic inter-
separately. action between them.21 Oxygen diffusion out of the coronary
microvessels occurs so rapidly that oxygen tension in arteri-
oles and even small arteries is lower than in aortic blood,
Coronary Arterioles
suggesting a direct role for oxygen in the local regulation of
Regulation of blood flow in response to changing myocardial blood flow.22
needs occurs at the level of the coronary arterioles. Coupling
of arteriolar vasomotor tone to myocardial metabolic
Myogenic Mechanisms
demands appears to involve ATP-sensitive potassium chan-
nels (K+ATP) in coronary vascular smooth muscle cells.15,16 Myogenic automaticity refers to the intrinsic property of
Opening of K+ATP channels results in outward flux of potas- smooth muscle to respond to stretch with a counteracting
sium, thereby causing an increase of membrane potential in increase in contractile force. Thus, an increase in intralumi-
the smooth muscle cell. This hyperpolarization causes nal distending pressure causes the vascular smooth muscle
voltage-dependent calcium channels to close; the resultant to contract, whereas a decrease in pressure results in vasodi-
decreased influx of calcium produces relaxation of the vas- lation. Myogenic activity is an intrinsic property of coronary
cular smooth muscle (vasodilation).15 Pharmacologic inhibi- arterioles and is not altered by endothelial denudation.23
tion of K+ATP channel opening has been demonstrated to Myogenic responses to changes of intraluminal pressure are
impair coronary autoregulation, metabolic vasoregulation, more prominent in arterioles from the subepicardium than
and ischemic vasodilation.15,16 These channels open in from the subendocardium of the left ventricle, suggesting
response to decreases of intracellular ATP or increases of that intrinsic differences in responsiveness could contribute
ADP. Such alterations of high-energy phosphates occur to the lesser ability to autoregulate in the subendocardium.24
during ischemia, but cannot account for coronary vasodila- Although myogenic activity can be demonstrated in isolated
tion that occurs during physiologic increases of myocardial coronary arterioles, the contribution of myogenic mecha-
oxygen demands during exercise or other stress. Although nisms to regulation of blood flow in the intact heart is likely
the factors that regulate vascular K+ATP channel activity of less importance than metabolic or endothelium-mediated
during physiologic conditions are uncertain, the critical responses.
importance of this channel is demonstrated by the finding
that mice with genetic deletion of coronary K+ATP channels
Resistance Arteries
are vulnerable to myocardial ischemia and sudden death.17
Adenosine has been suggested as a mediator of metabolic Small arteries (100 to 300 μm in diameter) contribute up to
coronary vasodilation.18 When cardiac work is increased, the 40% of total coronary resistance but, unlike the arterioles,
rate of ATP utilization by the contractile apparatus tran- these vessels are not responsive to the metabolic state of the
siently exceeds the rate of resynthesis of ATP, resulting in myocardium.25 However, when increased cardiac activity
an increase of free adenosine diphosphate (ADP). The cyto- results in metabolic vasodilation of the coronary arterioles,
solic enzyme adenylate kinase can then act on two molecules the resultant increase of blood flow causes shear-mediated
of ADP to form one molecule each of ATP and adenosine endothelium-dependent dilation of the resistance arteries.
monophosphate (AMP). The AMP released by this reaction Loss of flow-mediated vasodilatation of the resistance arter-
can be catabolized to adenosine, which can be transported ies in patients in whom hyperlipidemia, atherosclerosis, or
out of the myocyte into the interstitial fluid. In the intersti- hypertension has resulted in endothelial dysfunction can
tial fluid, adenosine engages receptors on the coronary impair vasodilator reserve even in the absence of occlusive
662 chapter 29

coronary artery disease. This is supported by the finding that Agonist

vasodilator reserve measured with positron emission tomog-
raphy is impaired in patients with hyperlipidemia but with Ca2+
angiographically normal coronary arteries, and that this Endothelial
abnormality can be corrected by lipid-lowering therapy.25,26 cell Shear
Ca2+ 2+ stress
Ca
2+ Akt
Penetrating Arteries Ca2+ Ca calmodulin
Cyclooxygenase eNOS P AA P-450
Intramyocardial arteries can be divided into two classes: AA L-arg EDHF
class A arteries arborize soon after entering the myocardium PGI2 NO
and supply principally the outer two thirds of the left ven- ONOO– O2– K+
tricular wall; and class B arteries penetrate deep into the EDHF
PGI2 NO
myocardium before arborizing to supply blood to the suben- Smooth muscle
docardium.27 The class B vessels are also called penetrating cell Adenylyl Guanylyl
arteries. The potential influence of the penetrating arteries cAMP cyclase cyclase
K+
on blood flow is documented by the finding that pressure in
hyperpolarization
arterioles in the subendocardium is less than in subepicar- K+ hyperpolarization cGMP GTP
dial arterioles, indicating that a significant pressure loss 2+
Ca Relaxation Ca2+
occurs across the penetrating arteries.23 Furthermore, vaso-
motor activity of the penetrating arteries can selectively K+
influence blood flow to the subendocardium. Vasodilation of FIGURE 29.1. Endothelium-dependent vasodilator mechanisms.
Agonists such as acetylcholine, bradykinin, or histamine engage
the penetrating arteries appears to be a mechanism by which
specific receptors on endothelial cells that increase cytosolic
nitroglycerin can augment blood flow to the subendocar- calcium. Calmodulin binds the calcium, and the calcium-calmodu-
dium in ischemic myocardial regions.28 lin complex activates eNOS to catalyze the conversion of L-arginine
(L-arg) to produce nitric oxide (NO). The increased cytosolic calcium
also activates cyclooxygenase to augment production of prostacyclin
(PGI 2) from arachidonic acid (AA). Shear stress acts open calcium
Endothelium-Dependent Vasodilation channels but also activates Akt, which phosphorylates eNOS to
cause a sustained increase of enzyme activity. Mechanisms respon-
sible for production of endothelium-dependent hyperpolarizing
Nitric Oxide factor (EDHF) are currently unclear, but may result from P-450
acting on arachidonic acid. NO produced in endothelial cells dif-
The importance of the vascular endothelium in mediating
fuses to the underlying smooth muscle to activate guanylyl cyclase,
vasodilator responses was first demonstrated by Furchgott thereby increasing cytosolic cyclic guanosine monophosphate
and Zawadski,29 who observed that acetylcholine caused (cGMP) levels, which produce relaxation by decreasing cytosolic
relaxation of isolated coronary artery rings when the endo- calcium as well as by decreasing calcium sensitivity of the
thelium was intact, but produced contraction when the endo- contractile proteins. Increased superoxide (O2 –) production in the
atherosclerotic coronary circulation consumes NO to produce per-
thelium was removed. Subsequent studies demonstrated that oxynitrite (ONOO –), thereby decreasing NO bioavailability and
a number of agonists including acetylcholine, bradykinin, causing endothelial dysfunction.
histamine, and thrombin cause coronary vasodilation indi-
rectly by engaging specific receptors on the endothelium that
trigger the release of one or more endothelium-derived relax-
ing factors (EDRFs).30 The principal mediator of this vasodila- by cytokines or inflammatory mediators, and which is not
tion is nitric oxide (NO), which is produced when the regulated by the intracellular calcium content (Fig 29.1).
constitutive endothelial cell enzyme nitric oxide synthase Endothelium-dependent NO-mediated coronary vasodi-
(eNOS) acts on arginine to produce citrulline with liberation lation is impaired in the setting of hyperlipidemia or athero-
of NO. Enzyme nitric oxide synthase is a calcium-calmodu- sclerosis. Impairment of NO-dependent vasodilation appears
lin–dependent P-450 enzyme; agonists that produce endothe- to result in part from increased oxygen free radical produc-
lium-dependent NO-mediated vasodilation generally act by tion in the atherosclerotic vessel, which quenches NO,
causing increases of intracellular calcium to activate the thereby attenuating its biologic actions.33,34 There is some
enzyme.31 Alternatively, eNOS can be activated by serine evidence that arginine administration can improve endothe-
phosphorylation, thereby causing sustained increases of NO lium-dependent vasodilator mechanisms. Since intracellular
production. Nitric oxide produced by eNOS can diffuse to arginine is present in excess, arginine deficiency is unlikely
the vascular smooth muscle and activate guanylate cyclase; to directly limit NO production. However, circulating argi-
the resultant increase in cyclic guanosine monophosphate nine analogues, such as asymmetric dimethylarginine, have
(cGMP) causes relaxation of the vascular smooth muscle. been identified that can act as endogenous competitive
The shear force produced by blood flowing over the endothe- inhibitors of arginine.35 Increased levels of these endogenous
lial cells can also activate eNOS; in this way dilation of the eNOS inhibitors are found in patients with coronary disease,
epicardial arteries is coordinated with the increased flow congestive heart failure, and renal failure, and may con-
produced by metabolic dilation of the coronary resistance tribute to endothelial dysfunction in these conditions.
vessels during exercise.6,31–33 Enzyme nitric oxide synthase is Arginine administration could potentially exert a beneficial
distinct from inducible nitric oxide synthase (iNOS), which effect by competition with these endogenous inhibitors of
is not present in normal coronary vessels but can be induced NO synthase.
 corona ry a rt e ry dise a se : r egu l at ion of corona ry bl ood f l ow 663

Prostacyclin sate for underperfusion of the subendocardium during systole,

during diastole vasomotor tone of the resistance vessels is
Prostacyclin is a coronary vasodilator and potent inhibitor maintained lower in the subendocardium than in the sub-
of platelet aggregation that is produced from arachidonic acid epicardium. As a result, vasodilator reserve is lower in the
by vascular endothelial cells. Prostacyclin is synthesized by subendocardium than in the subepicardium.
the enzyme cyclooxygenase so that nonsteroidal antiinflam- In response to an arterial stenosis, the coronary resis-
matory agents that inhibit cyclooxygenase can decrease pros- tance vessels undergo vasodilation to compensate for the
tacyclin production.36 The rate-limiting step for prostacyclin additional resistance caused by the stenosis. The need for
synthesis appears to be the availability of arachidonic acid this vasodilation during basal conditions compromises the
mobilized from membrane phospholipids by phospholipase ability for further dilation to increase blood flow during
A 2. Basal prostacyclin production in the coronary circulation exercise or other stress.41 A stenosis that is sufficiently severe
is insufficient to be detectable using current technology.36 to elicit near maximal vasodilation of the resistance vessels
Prostacyclin is released in response to agonists that interact is termed a critical stenosis, inasmuch as an increase in
with specific endothelial cell surface receptors including bra- myocardial metabolic demand cannot be met by an increase
dykinin, histamine, and thrombin, as well as by increased in blood flow, so that ischemia results. When a coronary
endothelial shear forces that cause release of calcium from stenosis limits blood flow below the metabolic demands of
intracellular stores, thereby activating phospholipase A 2.37 the myocardium, the limited arterial inflow is preferentially
Production of prostacyclin in response to these stimuli is redistributed to the outer myocardial layers, so that hypoper-
transient even when the agonist is continuously present. fusion and ischemia are most severe in the subendocardium.
Most evidence suggests that prostacyclin functions princi- This redistribution of blood flow away from the subendocar-
pally as an antiplatelet and antithrombotic molecule with dium initially occurs because vasodilator reserve is least in
only a modest influence on coronary vasomotor activity in the subendocardium. In addition, ischemic vasodilation of
the normal heart. the coronary resistance vessels can result in a marked
pressure drop across a stenosis; because of the decreased
Hyperpolarizing Factor distal coronary pressure, the intramural vessels are less
able to resist the compressing effects of the extravascular
Studies in isolated coronary vessels have demonstrated that forces. Since intramyocardial pressure is highest in the sub-
the vasodilator response to acetylcholine and certain other endocardium, impedance to blood flow is greatest in this
endothelium-dependent agonists cannot be fully accounted region. Increases of left ventricular diastolic pressure will
for by NO or prostacyclin. These agents cause hyperpolariza- further augment the extravascular compressive forces and
tion of the vascular smooth muscle cell membrane by opening amplify the redistribution of blood flow away from the
of calcium-activated potassium channels; membrane hyper- subendocardium.
polarization decreases calcium influx, thereby resulting in
vasodilation.38 The mediators of this effect have been termed
endothelium-dependent hyperpolarizing factors (EDHFs); Coronary Collateral Circulation
current evidence suggests that they are cytochrome P-450–
dependent metabolites of arachidonic acid. The extent to Normal human hearts possess a rudimentary network of
which EDHF contributes to regulation of coronary blood intercoronary collateral anastomoses 20 to 300 μm in diam-
flow during physiologic conditions is unknown. eter.42 These intrinsic collateral vessels are generally insuf-
ficient to limit myocardial injury during acute coronary
occlusion, but form a scaffold for the development of an effec-
Transmural Distribution of Myocardial tive collateral circulation in response to occlusive coronary
Blood Flow artery disease.42 If a coronary occlusion occurs gradually,
sufficient time for collateral vessel development can prevent
In the normal heart blood flow to the subendocardium is myocardial infarction, despite total coronary occlusion. Col-
maintained 20% to 40% higher than flow to the subepicar- lateral vessel development is stimulated by hemodynami-
dium, reflecting greater systolic tension development and cally significant coronary artery stenoses. High-grade
greater oxygen utilization in the subendocardium.39 Mainte- coronary stenotic lesions are required to stimulate growth of
nance of this perfusion gradient favoring the subendocar- well-developed collateral vessels. A stenosis causing less
dium requires active vasomotion of the coronary resistance than 80% luminal narrowing is rarely associated with well-
vessels. During systole the contracting myocardium com- developed collaterals, whereas stenoses causing 95% narrow-
presses the thin-walled microvessels within the wall of the ing are almost always associated with good collateral filling.43
left ventricle; the interaction between the extravascular The rate of collateral development has been studied in
forces acting to collapse the vessels and the intravascular patients hospitalized for acute myocardial infarction. Sequen-
distending pressure that resists collapse of the vessels is tial coronary angiograms demonstrated that approximately
termed the vascular waterfall.40 In a vascular waterfall, the 50% of patients developed an effective collateral circulation
outflow pressure that impedes flow is not the venous pres- within 2 weeks and approximately two thirds by 2 months
sure, but rather results from the compressing force acting on after acute coronary occlusion.44 It is unclear whether col-
the intramural vessels. Since extravascular compressive lateral vessel growth proceeds at a similar rate in patients
forces increase from epicardium to endocardium, impedance with high-grade coronary stenotic lesions and recurrent isch-
to blood flow is greatest in the subendocardium. To compen- emia but without tissue necrosis.
664 chapter 29

Collateral vessel development can occur by sprouting of consequently, part of their vasodilator reserve is utilized even
new vessels (angiogenesis) or by growth and remodeling of during basal conditions. In response to an increase of myocar-
the rudimentary intercoronary anastomoses that exist in dial oxygen demands (exercise) or a pharmacologic small-
normal hearts (arteriogenesis).45 Angiogenesis predominates vessel dilator (e.g., adenosine or dipyridamole), the resistance
in regions adjacent to infarcted myocardium, likely as the vessels in both the normally perfused and collateral-
result of growth factors released from necrotic myocytes and dependent regions dilate. Since vasodilator reserve is greater
recruited inflammatory cells. In contrast, collateral vessel in the normal zone than in the collateral zone, flow will
growth in response to a coronary stenosis in the absence of increase preferentially in the normal zone. When a stenosis
infarct occurs principally through arteriogenesis.46 It appears exists in a common artery that supplies both the normal and
that increased flow (endothelial shear) initiates growth of the collateral zones, the increased flow rate will magnify the pres-
collateral vessels. In the normal heart there is little flow in sure drop across the narrowing and cause a decrease in distal
the rudimentary collateral vessels, since blood pressure in coronary pressure. If the fall in distal perfusion pressure
adjacent coronary arteries is equal. However, when a coro- exceeds the ability of the resistance vessels in the collateral
nary stenosis causes a decrease in distal coronary pressure, zone to dilate, then an absolute decrease in flow into the col-
blood from the adjacent arteries flows through the rudimen- lateral zone will occur.53 Drugs that cause dilation of coronary
tary collateral vessels into the lower pressure vessel. The resistance vessels such as adenosine or dipyridamole have the
resultant endothelial shear causes expression of adhesion potential to cause coronary steal, while agents such as nitro-
molecules that attract monocytes46 that release growth glycerin that act to dilate collateral vessels and proximal
factors that exert mitogenic effects on endothelial and smooth coronary arteries (including compliant stenotic segments)
muscle cells. Administration of growth factors (basic fibro- oppose the development of steal.
blast growth factor, vascular endothelial growth factor) have
been shown to accelerate collateral vessel growth in experi-
mental animals subjected to coronary occlusion, but clinical Left Ventricular Hypertrophy
trials of growth factor treatment in patients with ischemic
heart disease have not produced beneficial effects.47,48 Left ventricular hypertrophy (LVH) is associated with struc-
Although marked collateral vessel growth can occur in tural and functional abnormalities of the coronary circula-
response to coronary artery occlusion, vasodilator reserve is tion that can increase the vulnerability to ischemia during
not normal in regions perfused by collateral vessels. Thus, exercise or other stress. In patients with hypertension, LVH
developed collateral vessels can provide adequate arterial confers an increased risk for development of angina pectoris,
inflow to meet myocardial needs during resting conditions, congestive heart failure, and sudden death.54 Furthermore, a
but the ability to augment flow in response to exercise or coronary stenosis that limits arterial inflow during exercise
other stress is less than in normally perfused myocardial causes more severe subendocardial hypoperfusion in animals
regions.49 Furthermore, occlusive disease in the donor arter- with LVH than in animals without hypertrophy.55 Acute
ies from which collateral vessels originate can impair the coronary occlusion results in infarction of a greater fraction
ability to increase blood flow. Well-developed collateral of the myocardial region at risk and a higher incidence of
vessels have a well-organized muscular media and are respon- sudden death in animals with LVH than in normal animals.56
sive to vasodilator and vasoconstrictor stimuli; as a result, Epicardial coronary artery lumen diameter is increased in
collateral vessels can undergo vasomotor activity.50 Vasocon- LVH, but this is less than expected for the increase in myo-
striction of collateral vessels can worsen hypoperfusion of a cardial mass.57 Maximum coronary flow rates per gram of
collateral-dependent region of myocardium and lower the myocardium are impaired in the hypertrophied heart. This
threshold for ischemia during exercise.51 Nitroglycerin is a impairment of coronary vasodilator reserve results from
potent collateral vessel dilator that has been demonstrated both failure of the coronary vessels to grow in proportion to
to improve exercise tolerance in patients with single- the increased myocardial mass, as well as because of increased
vessel coronary occlusion and a region of viable collateral- extravascular forces in the hypertrophied heart that act to
dependent myocardium.51 compress the intramural coronary microvasculature.58 The
effects of the increased extravascular forces in the hypertro-
phied heart are most prominent in the subendocardium, so
Coronary Steal that exercise can result in transmural redistribution of blood
flow away from the subendocardium even in the absence of
Coronary steal occurs when coronary vasodilation causes an atherosclerotic coronary artery disease. In patients with
increase of blood flow in one myocardial region but a paradoxi- severe pressure overload LVH, especially that resulting from
cal decrease in flow in an adjacent region.52 This can occur aortic stenosis, the abnormalities of coronary perfusion can
when adjacent collateral-dependent and normally perfused be sufficient to result in exertional angina pectoris even in
myocardial regions derive their blood supply from a common the absence of occlusive coronary artery disease.
stenotic coronary artery. The stenosis in the common feeding
artery is critical in the development of coronary steal, because
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846–853. perfusion. Pharmacol Ther 2000;86:87–110.
20. Duncker DJ, van Zon NS, Pavek T, Herrlinger SK, Bache RJ. 42. Baroldi G, Scomazzoni G. Coronary circulation in the normal
Endogenous adenosine opposes hypoperfusion and loss of wall and pathologic heart. Washington, DC: Armed Forces Institute
motion during exercise produced by K+ATP channel-blockade. J of Pathology, 1967.
Clin Invest 1995;95:285–295. 43. Cohen M, Sherman W, Rentrop KP, Gorlin R. Determinants of
21. Broten TP, Feigl EO. Role of myocardial oxygen and carbon collateral filling observed during sudden controlled coronary
dioxide in coronary autoregulation. Am J Physiol 1992;262: artery occlusion in human subjects. J Am Coll Cardiol 1989;
H1231–H1237. 13:297–303.
22. Wieringa PA, Stassen HG, Van Kan JJ, Spaan JA. Oxygen diffu- 44. Schwartz H, Leiboff RH, Bren GB, et al. Temporal evolution of
sion in a network model of the myocardial microcirculation. the human coronary collateral circulation after myocardial
Int J Microcirc Clin Exp 1993;13:137–169. infarction. J Am Coll Cardiol 1984;4:1088–1093.
666 chapter 29

45. Helisch A, Schaper W. Arteriogenesis: the development 53. Kaufmann PA, Mandinov L, Seiler C, Hess OM. Impact of
and growth of collateral arteries. Microcirculation 2003;10: exercise-induced coronary vasomotion on anti-ischemic
83–97. therapy. Coron Artery Dis 2000;11:363–369.
46. Schaper W, Ito WD. Molecular mechanisms of coronary col- 54. Koren MJ, Devereaux RB, Casale PN, Savage DD, Laragh JH.
lateral vessel growth. Circ Res 1996;79:911–919. Relation of left ventricular mass of geometry to morbidity and
47. Rosinberg A, Khan TA, Sellke FW, Laham RJ. Therapeutic mortality in uncomplicated essential hypertension. Ann Intern
angiogenesis for myocardial ischemia. Expert Rev Cardiovasc Med 1991;114:345–352.
Ther 2004;2:271–283. 55. Bache RJ, Wright L, Laxson DL, Dai X. Effect of a coronary
48. Scheinowitz M. therapeutic myocardial angiogenesis: past, stenosis on myocardial blood flow during exercise in the chron-
present and future. Mol Cell Biochem 2004;264:75–83. ically pressure overloaded hypertrophied left ventricle. Circula-
49. Bache RJ, Schwartz JS. Myocardial blood flow during exercise tion 1990;81:1967–1973.
after gradual coronary occlusion in the dog. Am J Physiol 1983; 56. Dellsperger KC, Clothier JL, Koyanagi S, Inou T, Marcus ML.
245(Heart Circ Physiol 14):131–138. Effects of coronary artery occlusion in animals with hyperten-
50. Foreman BW, Dai XZ, Bache RJ. Vasoconstriction of canine sion and left ventricular hypertrophy. J Cardiovasc Pharmacol
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3:9–12. Circ Physiol 38):H271–H281.
 3 Coronary Heart
0 Disease Syndromes:
Pathophysiology and
Clinical Recognition
James T. Willerson, Attilio Maseri,
and Paul W. Armstrong

Stable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 Vulnerable or Unstable Atherosclerotic Plaque . . . . . . . 672

Variant Angina (“Prinzmetal’s Angina”). . . . . . . . . . . . . 670 Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . 677
Unstable Angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691

Key Points or permanent coronary artery occlusion (ST segment

elevation MI, STEMI).
• Atherosclerotic plaque fissuring or ulceration generally • The functional absence or diminished effect of nitric
cause the development of the acute coronary artery oxide (NO), tissue-type plasminogen activator (t-PA),
disease syndromes. and prostacyclin at sites of vascular injury contributes
• Vulnerable or “unstable” atherosclerotic plaques have to dynamic thrombosis, vasoconstriction, fibroprolifera-
temperature and pH heterogeneity, thin fibrous caps, tion, and inflammation at sites of coronary artery athero-
inflammatory cells primarily macrophages, and activated sclerosis and plaque fissuring and ulceration.
T cells on their surface, and an adjacent lipid pool. Some • Unstable angina, NSTEMI, and STEMI represent a con-
patients have multiple unstable atherosclerotic plaques tinuum of thrombosis and vasoconstriction in that
simultaneously. unstable angina is often caused by transient and
• Several serum markers when elevated help identify recurrent coronary artery thrombosis and vasoconstric-
patients at increased risk for future vascular events, tion, NSTEMI by slightly more prolonged but still
including C-reactive protein (CRP), CD40SL, pregnancy- usually transient thrombosis and vasoconstriction or
associated protein, serum amyloid protein (SAP), brain subtotal coronary artery occlusion, and STEMI by
natriuretic peptide (BNP), vascular cell adhesion mole- prolonged and usually permanent coronary artery
cule (VCAM), intracellular adhesion molecule (ICAM), occlusion.
and interleukin-6. • Power failure complications of MIs occur in patients
• Unstable angina and non-ST segment elevation myocar- with ≥40% irreversible damage to the left ventricle (LV)
dial infarction (NSTEMI) are associated with atheroscle- and include cardiogenic shock, medically refractory con-
rotic plaque fissuring or ulceration, adherence of platelets gestive heart failure (CHF), and medically refractory
at the same sites, the accumulation of thromboxane arrhythmias.
A 2, serotonin, adenosine diphosphate (ADP), thrombin, • Even with relatively small MIs, mechanical problems,
tissue factor, oxygen-derived free radicals, and endothelin such as acute mitral regurgitation (MR), ventricular
promoting growth of the thrombus and dynamic vaso- septal defects (VSDs), and ventricular aneurysms may
constriction with transient (unstable angina or NSTEMI) lead to shock and CHF.

6 67
668 chapter 30

TABLE 30.1. Coronary heart disease syndromes

Stable angina pectoris
Unstable angina pectoris
Variant angina (“Prinzmetal’s angina”)
Acute myocardial infarction
Non-Q wave or non-ST elevation (usually nontransmural infarcts)
Q wave or ST elevation (usually transmural myocardial infarcts)

Stable Angina

Pathophysiology
The coronary heart disease syndromes are listed in
Table 30.1.
Angina pectoris is the clinical term used to describe
chest discomfort resulting from a relative oxygen deficiency FIGURE 30.2. Typical narrowing and occlusion of the coronary
in heart muscle. Heberden1 named this entity when he artery by atherosclerosis in patients with unstable angina and MI.
In many other patients, the severity of the left anterior descending
identified a “disorder of the breast marked with strong and
coronary artery stenosis is less than that demonstrated in this right
peculiar symptoms and considerable for the kind of danger anterior oblique projection of the left coronary artery by coronary
belonging to it” associated with a “strangling and anxiety,” arteriography.
which he suggested should be called “angina pectoris.” This
description was enlarged on by Herrick2 in 1912. Angina is
usually described by the patient as a left precordial tightness
or ache provoked by exercise or emotion and relieved by rest. tion, severe aortic valvular regurgitation or stenosis, cardio-
Many patients deny they have pain, but when questioned myopathy, or dilated ventricle(s) in whom severe coronary
closely, they identify chest tightness, chest pressure, or ache artery stenoses are not present. The explanation for angina
associated with effort, emotion, and/or cold exposure. Angina when CAD is not present is that even normal coronary arter-
occurs when oxygen demand exceeds supply.3–7 Most indi- ies may not adequately supply hypertrophied, dilated, or
viduals with angina have underlying atherosclerotic coro- failing heart muscle with oxygen. On occasion, limited coro-
nary artery disease (CAD) (Figs. 30.1 and 30.2). nary vasodilator reserve may explain angina, especially in
However, angina may also develop in some patients with some patients with severe ventricular hypertrophy associ-
ventricular hypertrophy, left ventricular (LV) outflow obstruc- ated with LV outflow obstruction, including valvular aortic

A
FIGURE 30.1. (A) A typical atherosclerotic plaque in which plaque leading to coronary artery luminal diameter narrowing and the
has ruptured, leading to the development of coronary artery throm- need for some additional revascularization procedure is shown.
bosis. Such a patient may or may not have had angina at effort before Patients who develop coronary heart disease after cardiac transplan-
the plaque rupture and thrombosis, and may have abruptly devel- tation also demonstrate this same alteration in their coronary arter-
oped severe chest pain and a myocardial infarction (MI) with plaque ies (i.e., neointimal proliferation). Native atheromas have substantial
rupture and coronary artery thrombosis. (B) The neointimal prolif- fibroproliferative alterations as well.
eration occurring with restenosis after coronary artery angioplasty,
 corona ry h e a rt dise a se sy n drom e s 669
stenosis and hypertrophic obstructive cardiomyopathy, and
in patients with poorly controlled systemic arterial hyper- t-PA
PGI2 –
tension.8,9 Coronary artery vasoconstriction occurring with PGI2 +
EDRF
exercise or stress may also be a contributing factor.10,11 Most EDRF
humans without coronary heart disease or ventricular hyper-
trophy do not develop angina with effort or stress, probably Platelet aggregation
because the heart is protected from an important imbalance
between oxygen supply and demand by other factors that Platelet
Mechanical attachment at site
limit physical activity, such as dyspnea and fatigue. obstruction of endothelial
The predisposing pathologic alteration in coronary arter- cell injury
ies responsible for angina is atherosclerosis, atherothrombo- Vasoconstriction
sclerosis, and neointimal fibrous proliferation (Fig. 30.3; see
also Figs. 30.1 and 30.2). The term atherothrombosclerosis Transient platelet
describes the relative importance of each of its components, aggregation
including atherosclerosis, thrombosis, and fibrosclerosis, in
the development of the process that has long been called
atherosclerosis, but in fact often includes evidence of throm-
bosis in the progressive atherosclerotic plaque. Embolic ath- Release of mediators
erosclerotic debris and platelet aggregates may contribute to Thromboxane A2
distal coronary artery occlusion and limitation of coronary Serotonin
flow reserve (Fig. 30.3). Severe narrowing of the lumen of Mechanical
Adenosine diphosphate
the coronary artery results in a decreased ability to deliver obstruction
Thrombin
oxygen, especially when oxygen demand in the heart is Platelet-activating factor
increased, as with increases in heart rate, contractile state, Vasoconstriction
Oxygen-derived
or myocardial wall tension, or a combination of these.3–7 free radicals
Therefore, stable and relatively predictable angina may Tissue factor
develop during exercise, cold exposure, or emotional stress Endothelin

or after eating a large meal. Angina may also occur because FIGURE 30.3. Schematic diagram suggests probable mechanisms
of extracardiac influences. In particular, severe anemia or responsible for the conversion from chronic coronary heart disease
carbon monoxide exposure reduces the amount of oxygen to acute coronary artery disease syndromes. In this scheme, endo-
delivered to the heart and may result in angina under condi- thelial injury, generally at sites of atherosclerotic plaques and usually
plaque ulceration or fissuring, is associated with platelet adhesion
tions that would otherwise be well tolerated. Increases in
and aggregation and the release and activation of selected mediators,
systemic arterial pressure and consequent dilatation of the including thromboxane A 2, serotonin, adenosine diphosphate, plate-
heart may result in angina. Increases in heart rate or con- let-activating factor, thrombin, oxygen-derived free radicals, and
tractile state, as with hyperthyroidism, pheochromocytoma, endothelin. Local accumulation of thromboxane A 2, serotonin,
and exogenous administration or release of catecholamines, platelet-activating factor, thrombin, adenosine diphosphate, and
tissue factor promotes platelet aggregation. Thromboxane A 2, sero-
may also lead to angina. Cold exposure decreases oxygen tonin, thrombin, and platelet activating factor are vasoconstrictors
delivery by causing coronary artery vasoconstriction and at sites of endothelial injury. Therefore, the conversion from chronic
increases systemic blood pressure, ventricular wall tension, stable to acute unstable coronary heart disease syndromes is usually
and oxygen demand. associated with endothelial injury, platelet aggregation, accumula-
tion of platelet and other cell-derived mediators, further platelet
aggregation, and vasoconstriction, with consequent dynamic nar-
Physical Examination/Bedside Findings rowing of the coronary artery lumen. In addition to atherosclerotic
plaque fissuring or ulceration, other reasons for endothelial injury
The findings on physical examination in the patient with include flow shear stress, hypertension, immune complex deposition
stable angina pectoris are highly variable. Sometimes, there and complement activation, infection, and mechanical injury to the
endothelium as it occurs with coronary artery angioplasty, stents,
are no localizing or suggestive physical findings. Alterna- and after heart transplantation. Injured endothelial cells have
tively, associated risk factors, such as systemic arterial reduced amounts of the normally present vasoprotective substances
hypertension, hyperlipidemia, valvular heart disease, heart that when present prevent thrombosis, vasoconstriction, and inflam-
failure, or peripheral atherosclerosis may result in a specific mation, nitric oxide (NO), tissue-type plasminogen activator (t-PA),
and prostacyclin (PGI 2).
physical finding, such as elevated blood pressure, a promi-
nent fourth heart sound (S4), an accentuated aortic closure
sound, a paradoxically split second heart sound (S2) [systemic
arterial hypertension, during an episode of angina or with
left bundle branch block (LBBB)], reduced peripheral pulse
(i.e., carotid, femoral, or lower extremity pulse with or or complex ventricular premature beats, S4, murmur of
without bruit over the artery), murmur of aortic stenosis or mitral insufficiency, S3 moist rales, and peripheral vascular
mitral insufficiency (the most commonly associated valvular disease.
heart diseases with CAD), or a third heart sound (S3) with The electrocardiogram (ECG) may be normal, but it often
heart failure or rapid filling of the ventricle, such as occurs shows ST-T-wave changes, usually ST depression and T-wave
with moderately severe and severe aortic or mitral insuffi- flattening or inversion during angina. On occasion, ST-T-
ciency. The patient with coronary heart disease and stable wave depression or inverted T waves persist for weeks or
angina may or may not have an enlarged heart, frequent longer, presumably reflecting chronic ischemia. The ECG
67 0 chapter 30

may also show ventricular ectopic beats or evidence of a prior

12 100%
Q wave myocardial infarction (MI). An echocardiogram may
be normal at rest or may show regional or global wall motion Ca prevalence/event risk 90%

Ca prevalence/event risk ratio

10

Ca prevalence; event risk

abnormalities, including reduced left ventricular ejection 80%
fraction or increased LV dimensions (“ischemic cardiomyopa- 8
70%
thy”), consistent with myocardial ischemia or infarction, or Ca prevalence 60%
mitral insufficiency. Chest x-ray may show a normal-sized or 6 50%
enlarged heart with or without heart failure. On occasion, the 40%
patient has coronary artery calcification on the chest x-ray. 4 30%
Rapid-speed computed tomography (CT) [or electron 10-Year
event risk 20%
beam CT (EBCT)] often identifies coronary artery calcifica- 2
tion. Several studies12–16 have shown that coronary calcium 10%
assessment using fluoroscopy or EBCT imaging has a sensi- 0 0%
tivity for significant angiographic stenoses comparable with 25 35 45 55 65 75
that of exercise tests when used in symptomatic patients, but Age (years)
the specificity is lower. Symptomatic patients with coronary FIGURE 30.4. Coronary artery calcium (Ca) prevalence, 10-year
calcium have at least a fourfold increased risk of death or event risk, and prevalence/risk ratio in asymptomatic men. Event
infarction compared with those with no calcification. The risk and calcium prevalence are plotted against the right axis, and
fluoroscopic finding of at least one calcified coronary artery prevalence/risk ratio is plotted against the left axis. Prevalence/risk
or the EBCT identification of a coronary calcium score curve decreases with age, demonstrating serious overprediction in
the young and moderate overprediction in the elderly.
exceeding 100 has been shown to be predictive of the pres-
ence of advanced coronary plaque and stenosis. In general,
greater degrees of calcification in coronary arteries are con-
sistent with greater amounts of atherosclerotic plaque and Hemodynamic monitoring typically shows increases in
more advanced coronary luminal diameter narrowing. An mean pulmonary capillary wedge pressure during angina
advantage of an assessment of coronary artery calcium is pectoris. With the onset of myocardial ischemia, the initial
that it can be done irrespective of the patient’s ability to hemodynamic change in the left ventricle is a decrease in
exercise and regardless of the presence or absence of resting myocardial compliance and an increase in stiffness. This
electrocardiographic abnormalities. However, a valuable results in a sharp increase in mean pulmonary capillary
finding in the symptomatic patient is a negative EBCT study wedge pressure during angina, with a return to baseline as the
for coronary calcium. The negative predictive value of such angina resolves. The change in compliance is followed by ST-
a calcium scan for significant stenosis of a major coronary T wave changes on the ECG, a decline in regional systolic
artery is greater than 90%. Thus, EBCT scanning might be wall thickening, and finally, the development of chest pain,
an appropriate first test in individuals with atypical cardiac with this entire sequence occurring within a few seconds.
symptoms in whom the likelihood for ischemic disease is
considered to be small by the responsible physician. Patients
with a zero or very low calcium score (i.e., <10) may generally Variant Angina (“Prinzmetal’s Angina”)
be reassured and further testing directed at noncardiac eti-
ologies of chest pain. On the other hand, if the calcium score Patients with variant angina pectoris (“Prinzmetal’s angina”)
is consistent with moderate or severe atherosclerotic plaque have angina at rest, often in the early morning hours, associ-
development, additional cardiac evaluation, including stress ated with ST-segment elevation on the ECG and the presence
testing ideally with perfusion or functional evaluation, may of coronary artery spasm that causes focal obliteration of a
be indicated. We must keep in mind individual variation, coronary artery lumen (Fig. 30.5).17,18
however, and even in the absence of coronary artery calcifi- In the early descriptions of typical angina, Latham19 and
cation, one may have coronary heart disease as the cause of Osler20 suggested that this entity was due to periodic spasm
one’s chest pain. We do not recommend routine screening of of a large coronary artery. Subsequently, however, clinical
patients for coronary calcification. studies with anatomic correlations suggested that fixed ath-
Asymptomatic individuals differ from symptomatic erosclerotic CAD was responsible for typical angina and MI.
patients in that the risk of subsequent morbid events is rela- In 1959, Prinzmetal and coworkers21 revived interest in
tively small. Data are not conclusive regarding the ability of coronary arterial spasm when they described a group of indi-
coronary calcification in asymptomatic individuals to predict viduals with “variant angina.” The clinical features of this
short-term coronary artery risks.12 Figure 30.4 demonstrates, syndrome are distinctly different from those of typical
however, that prevalence/risk relationships decrease with angina.17,21–48 First, the patients described by Prinzmetal and
age. Although serious overprediction may occur in the young, coworkers usually had chest pain at rest rather than with
overprediction is only moderate in the elderly. It should be physical exertion or emotional stimulation. Second, the epi-
stressed, however, that extensive coronary artery calcifica- sodes of pain tended to recur at roughly the same time(s) each
tion does not necessarily indicate the presence of a signifi- day, often during the early morning hours, awakening the
cant coronary artery stenosis, and some patients with very patient from sleep. Third, the patient with variant angina
advanced coronary calcium scores have no significant coro- usually had ST-segment elevation on the ECG recorded during
nary artery stenosis or functional abnormality on stress chest pain (Fig. 30.5). Fourth, the episodes of chest pain were
perfusion or LV functional analysis. sometimes accompanied by atrioventricular block or ven-
 corona ry h e a rt dise a se sy n drom e s 671
firmed the existence of this syndrome and have shown the
presence of coronary artery spasm at sites of fixed coronary
A Arterial spasm
artery stenosis and in regions of the coronary vasculature
where no obvious stenosis exists. In patients with clinically
active coronary artery spasm, variant angina can often be
induced by ergonovine maleate.33–43 Other maneuvers that
ST segment have been used to produce coronary artery spasm in suscep-
elevation
tible patients include hyperventilation with the administra-
tion of an alkaline buffer, cold pressor testing, and the
administration of methacholine, a parasympathomimetic
agent, acetylcholine, or serotonin.38,41–48 We have speculated
that endothelial or adventitial injury, often in association
with coronary artery stenosis, leads to the accumulation of
platelets and white blood cells, mononuclear cells, including
Normalization mast cells, and T cells, and the release of humoral mediators,
of ECG including serotonin, thromboxane A 2, prostaglandin D2,
thrombin, leukotrienes, platelet-activating factor, endothe-
B After nitroglycerin lin, or histamine, which singly or in combination may cause
coronary artery spasm (see Figs. 30.3 and 30.5).49–58 Exposure
of tissue factor59 and accumulation of local inhibitors of
A B thrombolysis, such as the endogenous inhibitor of tissue
Channel 1 plasminogen activator (PAI-1),60 and activation of procoagu-
lant factors, such as factors X and Xa (Fig. 30.6),61 may also

Channel 2

Baseline recording Just before chest pain

XII
C D TF
VII VIIa PK
Channel 1 XI HK
HK
XIIa
IX
Ca2+
VIIa/TF XIa
Channel 2

IXa
During chest pain With pain relidf Ca2+
PL
VIIIa VIII
FIGURE 30.5. Top: (Inset A) Focal obliteration of the coronary
artery lumen caused by coronary artery spasm at a spot marked by X Xa
the arrows. (Inset B) The associated ST-segment elevation that
occurs with coronary artery spasm (A–D) Continuous 24–hour
Holter recording in a patient with coronary artery spasm before
chest pain (A,B), as chest pain begins (B), during chest pain (C), and Ca2+ Va V
with pain relief (D). The T wave prominence and ST-segment eleva- PL
tion that occur with coronary artery spasm are demonstrated.
Bottom: (D) Resolution of the coronary artery spasm after adminis- PL Th
tration of nitroglycerin. (Inset) Normalization of the electrocardio-
gram (ECG).
Fibrinogen Fibrin
monomer

tricular ectopic activity, and occasionally, the patients had Fibrin

transient ventricular tachycardia. Finally, the chest polymer
discomfort of variant angina was quickly relieved by nitro- XIIIa XIII
glycerin, after which the ST-segment elevation resolved. Cross-linked
Prinzmetal’s patients did not undergo selective coronary arte- fibrin
riography, but Prinzmetal and coworkers hypothesized that polymer
patients with variant angina had severe proximal stenoses of FIGURE 30.6. Schematic representation of the role of tissue factor
(TF), factors IX, X, XI, XII, and VIII in the formation of thrombin
one or more large coronary arteries in which spasm occurred (Th) and the subsequent role of thrombin in the formation of fibrin.
periodically. Since the original description of variant angina HK, high-molecular-weight; PK, prekallikrein; PL, phospholipids;
by Prinzmetal and coworkers, many observers21–32 have con- PT, prothrombin.
67 2 chapter 30

contribute to the development of thrombosis. This is espe-

cially likely to be true when endothelial injury decreases Subendocardium
vascular concentrations of the endogenous inhibitors of
inflammation, thrombosis, and vasoconstriction, nitric
oxide, tissue plasminogen activator, and/or prostacyclin (see
Fig. 30.3).53–55 It also seems highly likely that the endothe- Subepicardium
lium-derived vasoconstrictor, endothelin, is responsible for
coronary artery constriction or spasm in some patients (Fig.
30.3).53–55 Local plaque and systemic increases in catechol-
amine concentrations also contribute to the development of Left ventricle
plaque thrombosis and vasoconstriction.

Unstable Angina

Pathophysiology
Angina occurring in a crescendo pattern, with limited physi-
cal activity or at rest, is known as unstable angina. The chest
discomfort is typically milder than that occurring with
acute MI, being described as recurrent chest or epigastric Subendocardial
A (non-Q-wave) myocardial infarction
“tightness” or “pressure” and as usually “not severe” in
character. Typically, the episodes of angina last less than 30
minutes; they may or may not be associated with nausea. On
occasion, however, unstable angina is associated with more
severe and prolonged chest pain or nausea, making its clini- R
P P
cal differentiation from acute MI at the bedside difficult. In
these situations, serial ECGs and measurement of serum R
T
creatine kinase (CK) and its relatively specific cardiac isoen- T
Electrocardiographic changes
zyme, CK-MB, and of troponin I or T are needed to distin-
of (non-Q-wave) myocardial infarction
guish unstable angina from acute MI. While unstable angina
and non-ST segment elevation myocardial infarction B
(NSTEMI) both lead to ST segment flattening or depression FIGURE 30.7. (A) Schematic diagram shows the location of
and T-wave flattening or inversion (Fig. 30.7), increases in myocardial necrosis with non-ST segment elevation myocardial
troponin I or T or of CK-MB identify the presence of myo- infarction (NSTEMI) and a representation of the typical electrocar-
cardial necrosis. diographic changes. (B) Typical electrocardiogram (ECG) in a patient
with acute NSTEMI. With these infarcts, the ECG is unable to
Unstable angina is usually caused by a primary decrease provide specific evidence of the presence of the infarct but ST-
in coronary blood flow and myocardial oxygen delivery segment depression of varying magnitude and T-wave abnormali-
occurring as a consequence of atherosclerotic plaque fissur- ties, usually T-wave flattening or inversion, often develop. The only
ing or ulceration.59–70 The atherosclerotic plaque fissuring or evolution of the electrocardiographic abnormalities is a return to
ulceration is followed by platelet adhesion and aggregation the normal pattern.
at the site of plaque disruption and transient thrombosis or
subtotal coronary artery occlusion with dynamic vasocon-
striction. Platelet adhesion occurs by platelet attachment to
exposed collagen and to von Willebrand binding sites largely by intense emotion, tachycardia, or systemic hypertension.
through platelet glycoprotein Ib receptors. Thrombosis and Alternatively, unstable angina may occur as a result of a
vasoconstriction are promoted by the local accumulation of reduction in myocardial blood flow associated with severe
powerful promoters of platelet aggregation and vasoconstric- and progressive coronary artery atherosclerosis or dynamic
tion at these same sites, including thromboxane A 2, sero- coronary artery constriction associated with coronary artery
tonin, adenosine diphosphate, platelet-activating factor (PAF), spasm.17,18
thrombin, oxygen-derived free radicals, tissue factor, and
endothelin (see Fig. 30.3).49–58 All but endothelin promote
thrombosis. Thromboxane A 2, serotonin, PAF, and thrombin Vulnerable or Unstable Atherosclerotic Plaque
are also vasoconstrictors. Endothelin is a powerful vasocon-
strictor. There is also a loss of the endogenous inhibitors of
Pathophysiology
thrombosis and vasoconstriction, nitric oxide (NO), tissue-
type plasminogen activator (t-PA), and prostacyclin at sites Figure 30.8 demonstrates the characteristics of the “vulner-
of vascular injury (Fig. 30.3).65–70 able” unstable atherosclerotic plaque herein defined as one
Unstable angina may also occur in the individual with a likely to ulcerate or fissure or otherwise promote platelet
severe coronary artery stenosis or partially occluded coro- adherence and aggregation and vasoactive mediator accumu-
nary artery when myocardial oxygen demand is increased lation leading to the development of thrombosis, dynamic
 corona ry h e a rt dise a se sy n drom e s 67 3

Relative cell density

12 vs delta T (Celsius)

10

Relative cell density

Macrophages Degradation 8
of collagen
in fibrous 6
cap
Protease 4
release
VCAM
Integrin 2
receptors

Oxidized LDL 0
0 1 2 3 4 5
Delta T (C)
A
FIGURE 30.9. Relationship between temperature heterogeneity and
Anatomy of 30% of fatal myocardial infarctions: Erosion inflammatory cell presence in human carotid plaques removed at
carotid endarterectomy.

vasoconstriction, and fibroproliferation. The morphologic

characteristics of the unstable plaque include a thin fibrous
cap, the presence of inflammatory cells on or beneath the
atherosclerotic plaque surface, and an adjacent lipid core.
Casscells et al.71 have shown that such plaques in the human
carotid artery have temperature heterogeneity with tempera-
tures varying by 0.2° to 2°C in that part of the plaque where
the inflammation exists (Fig. 30.9). More recently, others
have confirmed these observations and shown the same tem-
perature heterogeneity in vivo in human coronary arteries in
patients with unstable angina and acute MI (Fig. 30.10).72 In
B
vivo studies have shown that the temperature heterogeneity
Anatomy of 60% of fatal myocardial infarctions: Rupture is more commonly in the 0.15° to 1°C range in the vulnerable
atherosclerotic plaque. Maseri, Borst, and others73–75
have suggested that unstable atherosclerotic plaques may
develop as part of widespread inflammation and that a sub-
stantial number of patients have multiple unstable plaques
simultaneously.
Endothelium
Thrombus
Macrophages
Thin fibrous cap
Difference from background temperature (°C)

Cholesterol,
Diffuse intimal thickening old hemorrhage,
(dense collagen, sparse cell debris, 3
smooth muscle cells) calcium
2.5

C 1.5
FIGURE 30.8. (A) Potential mechanisms responsible for athero-
1
sclerotic plaque fissuring and ulceration. Oxidized low-density lipo-
protein (LDL) within the atherosclerotic plaque promotes the
upregulation of vascular cell adhesion molecule (VCAM) and other 0.5
integrins, resulting in the recruitment of inflammatory cells, pri-
marily monocytes-derived macrophages but including activated T 0
cells and mast cells; subsequent protease release from the mononu- Controls Stable angina Unstable Acute
clear cells; and degradation of collagen in the fibrous cap, leading to angina myocardial
its fissuring and ulceration. (B) Atherosclerotic plaque fissuring, infarction
leading to platelet adhesion and aggregation and thrombosis. (C)
Atherosclerotic plaque ulceration and thrombosis. FIGURE 30.10. Increased temperature of infarct-related plaques in
patients with unstable angina and with acute MI compared with
controls and with patients with stable angina.
674 chapter 30

12.0 Group 1 Group 2A Group 2B 39.4 mg/dL

11.0 Group 1 Group 2A Group 2B

Serum amyloid a protein (mg/dL)

30.0
C-Reactive protein (mg/dL) 10.0 27.5
9.0 25.0
8.0 22.5
7.0 20.0
6.0 17.5
5.0 15.0
4.0 12.5
10.0
3.0
7.5
2.0
5.0
1.0 2.5
0.3 0.3
Adm. Peak Adm. Peak Adm. Peak Adm. Peak
A value value B value value
FIGURE 30.11. Plasma levels of C-reactive protein (A) and serum value for serum amyloid A protein, which exceeded the values on
amyloid A protein (B) in patients with stable angina (group 1), in the scale, is shown numerically and joined by a dashed line to the
patients with unstable angina and levels of C-reactive protein corresponding value on admission. The level of C-reactive protein
<0.3 mg/dL on admission (Adm.) (group 2A), and in patients with is <0.3 mg/dL horizontal line in A) in 90% of normal subjects. The
unstable angina and levels of C-reactive protein ≥0.3 mg/dL on median normal level of serum amyloid A protein is 0.3 mg/dL
admission (group 2B). Circles, urgent coronary artery bypass or (dashed horizontal line in B); 96% of normal subjects have levels of
angioplasty; squares, cardiac death or MI. In one patient, the peak serum amyloid A protein <1.0 mg/dL.

Several studies have shown that patients with unstable A 6

6
angina, NSTEMI, and ST segment elevation MI (STEMI) with
elevated serum C-reactive protein (CRP) levels at hospital dis- p = .014
30-day mortality relative risk

5
charge, elevations in serum troponin I or T at hospital admis-
sion, or increases in serum interleukin-6 concentrations or of 4 3.5
multiple biomarkers during their hospital admission have an
increased risk of future coronary events, presumably reflecting 3
the importance of inflammation in the instability of their
unstable atherosclerotic plaques (Figs. 30.11 to 30.16).76–86,96 2 1.8
Increases in troponin I and T identify myocardial necrosis 1
and possibly more extensive plaque instability, longer duration 1
of platelet-derived thrombosis and vasoconstriction, and n = 67 n = 150 n = 155 n = 78
0
0 1 2 3

No. of elevated cardiac biomarkers

B
0.25
Probability of death wihin 30 days

14 13
p = .0001
30-day mortality relative risk

0.20 12

10
0.15
8
0.10 5.7
6

0.05 4
2.1
2 1
0.00
0 0.1 0.5 1 2 5 10 15 n = 504 n = 717 n = 324 n = 90
0
Troponin T (ng/mL) 0 1 2 3

FIGURE 30.12. Probability of death within 30 days according to No. of elevated cardiac biomarkers
the serum troponin T level at hospital admission. Dots represent FIGURE 30.13. Relative 30-day mortality risks in OPUS-TIMI 16
simple estimates of mortality derived from ranges of the troponin (A) and TACTICS-TIMI 18 (B) in patients stratified by the number
T level that contained at least 70 patients. of elevated cardiac biomarkers.
 corona ry h e a rt dise a se sy n drom e s 675

Relative risk of future cardiovascular events

Mortality at 42 days (% of patients)
8 7.5 8
7
6.0 7
6
6
5
4 3.4 3.7 5
3 4
2 1.7 3
1.0
1 2
831 174 148 134 50 67
0
0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 ≥9.0 1
Cardiac troponin I (ng/mL) 0
Risk ratio 95% <0.5 0.5−1.0 1.0−2.0 2.0−3.0 3.0−4.0 4.0−5.0 5.0−10.0 10.0−20.0 >20
1.0 1.8 3.5 3.9 6.2 7.8
confidence _ 0.5−6.7 1.2−10.6 1.3−11.7 1.7−22.3 2.6−23.0
interval
“Low risk” “Moderate risk” “High risk”
FIGURE 30.14. The mortality incidence at 42 days in patients
HsCRP (mg/l)
admitted to the hospital with unstable angina or NSTEMI (non-Q-
wave MI) based on their initial cardiac troponin serum levels (nano- FIGURE 30.15. Relative risks of future cardiovascular events across
grams per milligram). The number of patients in each category is a full clinical range of high-sensitivity C-reactive protein (hsCRP)
shown within each black bar. values. Black bars represent crude relative risks; gray bars, risk
adjusted for FRS.

sometimes platelet emboli and occlusive disease of distal arter- predict the development of future coronary events, even in
ies (Figs. 30.12 and 30.13).78–86 Table 30.2 lists other biomarkers otherwise apparently healthy individuals. Figure 30.11 dem-
that have been shown to be predictive of future cardiovascular onstrates that for patients with unstable angina and NSTEMIs
events (Figs. 30.14 and 30.15).87–95 with CRP values of 0.3 mg/dL or higher, there is an increased
It has also been shown by Sabatine et al.96 that elevations risk of future coronary events, including urgent coronary
in serum troponin, CRP, and brain natriuretic peptide (BNP) artery bypass surgery or angioplasty, cardiac death, or MI.
each provide unique prognostic information in patients with Similar data have been provided for patients who have ele-
acute coronary syndrome (ACS). A relatively simple multi- vated serum fibrinogen values at hospital discharge.83
marker strategy that categorizes patients with ACS based on Several groups have shown the importance of increases
the number of elevated biomarkers at admission allows risk in serum levels of troponin I as prognostic factors indicative
stratification over a range of short- and long-term major of increased future risk for patients with ACS. Antman and
cardiac events (Fig. 30.13).96 colleagues,78 in a multicenter study of 1404 symptomatic
Berk and coworkers81 were among the first to demon- patients, found a relation between mortality at 42 days and
strate an increase in CRP in patients with acute coronary the serum cardiac troponin I levels at patient admission to
heart disease syndromes. Subsequently, several studies, the hospital (Fig. 30.14). The mortality rate at 42 days was
including those by Maseri and colleagues, demonstrated a significantly higher in the 573 patients with cardiac troponin
poorer prognosis in patients with unstable angina who had I levels of 0.4 ng/mL and greater than in the 831 patients
increased serum CRP and serum amyloid-A protein values.82 with cardiac troponin I levels less than 0.4 ng/mL. For each
Ridker and associates85 (Fig. 30.16) and Koenig and increase of 1 ng/mL in the cardiac troponin I level, there was
coworkers80 demonstrated that increases in serum CRP an associated significant increase in the risk ratio for death,

Framingham 10-year risk <10% Framingham 10-year risk 10% to 20%

5 5

4 4
Relative risk

Relative risk

3 3

2 2

1 1

FIGURE 30.16. Relative risks of future cardio- 0 0

vascular events among those with calculated <0.5 0.5-<1.0 1.0-<3.0 3.0-<10.0 ≥10.0 <0.5 0.5-<1.0 1.0-<3.0 3.0-<10.0 ≥10.0
10-year Framingham risks <10% (left) and
between 10% and 20% (right). hsCRP (mg/L) hsCRP (mg/L)
676 chapter 30

TABLE 30.2. Biomarkers to predict prognosis in patients with active form; and (3) inactivation by a family of endogenous
unstable angina and non-ST segment elevation myocardial inhibitors known as tissue inhibitors of metalloproteinases
infarction (NSTEMI)
(TIMPs).
C-reactive protein Human peripheral blood monocytes produce little MMP,
Brain natriuretic peptide (BNP) but differentiation into macrophages yields higher levels of
CD40L and CD40 MMP-9.97–103 Secretion of MMP-9 from macrophages can be
Myeloperoxidase induced by tumor necrosis factor-α, interleukin-1β, and
Pregnancy-associated protein CD40. Expression of collagenase (MMP-1) and stromelysin
Serum amyloid protein
(MMP-3) in macrophages is regulated by certain bacterial
products, including lipopolysaccharide (endotoxin) and yeast
Vascular cell adhesion molecule (VCAM)
zymosan. Activated T lymphocytes may cause collagenase
Intercellular adhesion molecule (ICAM)
and stromelysin expression in the human monocytes-derived
Interleukin-6 macrophages.
Asymmetric dimethylarginine The MMPs are secreted from cells as inactive zymogens
Troponins and require activation in the extracellular milieu before they
Phospholipase A 2 are capable of degrading extracellular matrix molecules.
Macrophage-derived reactive oxygen species activate MMP-2
and MMP-9 and thrombin activates MMP-2. The MMPs
themselves, once processed from the zymogen to active form,
after adjustment for baseline characteristics that were inde- can trigger activation of other members of the MMP family.
pendently predictive of mortality, including ST-segment Mast cells within atheroma may release serine proteinases
depression and age 65 years or older. Similar data have been that activate MMPs.
provided for serum values of troponin T in patients with The endogenous inhibitors known as TIMPs help regu-
unstable coronary heart disease. Lindahl and associates77 late MMP activity under normal circumstances. Four TIMPs
found that the risk of cardiac events in these patients have been described thus far. They exhibit sequence homol-
increased with increasing maximal levels of troponin T ogy and share domains of identical protein structures that
obtained in the initial 24 hours after admission. The lowest consist of highly conserved N-terminal regions believed to
quartile (<0.06 μg/L) constituted a low-risk group, the second be critical for inhibition of the enzyme.
quartile (0.06 to 0.18 μg/L) an intermediate group, and the The balance between MMP activities and their inhibi-
third highest quartile (≥0.18 μg/L) a relatively high-risk group tion by TIMPs is important in the maintenance of homeo-
with 4.3%, 10.5%, and 16% risk of either MI or cardiac death, stasis for the extracellular matrix. Excessive MMP activity
or both, respectively. Biasucci and coworkers86 demonstrated occurs in a number of disease states, including metastatic
an increased risk for future coronary events in patients whose cancer, rheumatoid arthritis, and glomerulosclerosis. There
serum interleukin-6 increased during hospital admission. is evidence that MMPs play a role in accelerated connective
Other serum markers that when elevated are associated with tissue turnover associated with degenerative diseases of
future vascular and myocardial events include CD40L, vessels, including aortic aneurysms and vein graft stenoses,
CD40, serum amyloid protein (SAP), pregnancy-associated as well as migration of smooth muscle cells from the media
protein, vascular cell adhesion molecule (VCAM), intercel- to the intima after arterial injury.
lular adhesion molecule (ICAM), and BNP (Table 30.2).96a Several of the MMPs and TIMPs have been found in
Stability of an atherosclerotic plaque depends largely on atherosclerotic plaques,97–103 including MMP-1 (collagenase),
the structural integrity of its fibrous cap, which is composed MMP-9 (gelatinase B), and stromelysin-1 (MMP-3). Each of
primarily of extracellular matrix components rich in colla- these has been found in the fibrous cap, the atherosclerotic
gen. Available evidence supports a role for the release of lesions’ shoulders, and the base of the lipid core. MMP-7
matrix-degrading enzymes, that is, matrix metalloprotein- (matrilysin) is found primarily in macrophages overlying
ases (MMPs) in the catabolism of the structural macromole- the lipid core. A high expression of MMPs has also been
cules causing a dissolution of the fibrous cap of the plaque.97–103 detected in lipid-laden macrophages in experimental animal
The MMP family includes at least 19 structurally related, lesions.
zincdependent enzymes that function at physiologic pH in Similarly, constitutive expression of TIMP-1 and -2 has
the extracellular space. In addition, membrane-type (MT) been described in both normal and diseased arteries and
metalloproteinases have been identified that have the desig- TIMP-3 has been found in atheromas. Thus, the spatial dis-
nations MT1-MMP through MT4-MMP. tribution of selected TIMPs within atheromas correlates
The MMPs have been broadly classified into three main with that described for MMP expression. Most of the MMPs
groups on the basis of substrate specificity. They include the and TIMPs in atheromas are in macrophages, thereby iden-
collagenases (MMP-1, -8, and -13) that degrade intact fibrillar tifying the macrophage as most likely a key participant in
collagens. The gelatinases (MMP-2 and -9) hydrolyze the the regulation of the balance between synthesis and degrada-
denatured collagen fibril and basement membrane collagen tion of extracellular matrix macromolecules in the athero-
type IV. The stromelysins (MMP-3, -7, -10, and -11) have broad sclerotic plaque.
substrate specificity. For some of the remaining MMPs, Available evidence suggests a probable role for metallo-
substrate specificity has not yet been identified. proteinase release in excess of TIMP presence leading to
Regulation of MMPs occurs at three levels: (1) control of degradation of collagen in the fibrous cap and the subsequent
the rate of gene transcription; (2) conversion of the inactive fissuring and ulceration that predisposes to unstable angina
translational product, and inactive zymogen precursor, to the and acute MI (see Fig. 30.8). The proposed scheme includes
 corona ry h e a rt dise a se sy n drom e s 67 7
the oxidation of low-density lipoprotein (LDL) within the increases in oxygen demand occur in some patients with
plaque and the chemoattractant influence of oxidized LDL CAD who have severe systemic arterial hypertension, sus-
and other oxidation products to promote the expression of tained tachycardia, or both. Alternatively, sustained reduc-
selected adhesion molecules, including VCAM and ICAM tions in myocardial oxygen delivery associated with severe
and the subsequent recruitment of monocyte-derived systemic arterial hypotension may lead to MI, again usually
macrophages, activated T lymphocytes, and mast cells NSTEMI. Approximately 30% of patients with NSTEMI
within the plaque. The release of selected MMPs in excess have an occlusive thrombus in the infarct-related
of their TIMP concentrations locally degrades plaque colla- artery.106,108,109 Nevertheless, in most patients with NSTEMI,
gen within the fibrous cap and leads to fissuring and ulcer- transient coronary artery occlusion, initiated by platelet
ation of the atherosclerotic plaque. One anticipates future aggregation and with associated vasoconstriction most prob-
clinical trials with inhibitors of selected MMPs, but the ably lasting more than 30 minutes and up to 2 hours, is
redundancy within the system, that is, the number of MMPs present (see Figs. 30.3 and 30.7).
and other proteases within plaques that are nonmetalloen- Local accumulation of endothelin causes marked
zymes, may make effective inhibition of these plaque- vasoconstriction; serotonin, adenosine diphosphate, throm-
degrading enzymes difficult. Other approaches to inhibiting bin, and endothelin are mitogens, and they likely contribute
inflammation and the recruitment of monocytes-derived to subsequent local fibroproliferation with increases in
macrophages that may be protective of atherosclerotic the neointima, further narrowing the lumen of the endo-
plaques include inhibiting macrophage homing to unstable thelium-injured coronary artery.110 In 30% (or more) of
atherosclerotic plaques using inhibitors of VCAM and patients with unstable angina and NSTEMIs, there is a
ICAM104 or of antioxidants; inhibitors of selected cytokines, rapid anatomic progression in the severity of the coronary
especially tumor necrosis factor-α; nitric oxide donors; luminal diameter narrowing, most likely associated
inhibitors of nuclear factor κB (NF-κB); and marked lipid with the inclusion of organized thrombus within the
lowering with the use of medications capable of providing plaque and the fibroproliferation that follows plaque fissur-
marked reductions in serum cholesterol and LDL, most espe- ing and ulceration.110 Reductions in fibrinolytic capability
cially statins. at sites of vascular endothelial injury associated with
decreases in vascular tissue concentrations of prostacyclin,
tissue plasminogen activating factor, and nitric oxide
undoubtedly contribute to coronary artery thrombosis,
Acute Myocardial Infarction vasoconstriction, and fibroproliferation at these same sites
(see Fig. 30.3).33–35
Acute MI occurs when there are severe reductions in coro- We have suggested that unstable angina, NSTEMI, and
nary blood flow and myocardial oxygen delivery for more STEMI represent a continuum pathophysiologically.53–55 The
than 20 minutes. The infarct begins on the inner wall or process begins with coronary endothelial injury, usually
subendocardium of the heart and is confined there in the atherosclerotic plaque ulceration or fissuring. The degree of
first 30 minutes to 2 hours (Fig. 30.7; non-Q wave or NSTEMI); coronary artery stenosis where plaque ulceration or fissuring
these are generally subendocardial infarcts. If the coronary occurs may be mild or severe. Approximately half of the
artery thrombosis is transient or does not cause complete coronary stenoses where plaque fissuring or ulceration
coronary artery occlusion, the infarct usually remains largely occurs are sites of less than 50% luminal diameter nar-
confined to the subendocardium (or mid-wall of the heart) rowing.111 We have suggested that when the platelet-fibrin
and a non-Q wave or NSTEMI develops. However, if the coro- thrombus and associated severe vasoconstriction persist for
nary artery occlusion is sustained for longer periods, the periods of less than 20 minutes and often recur, the clinical
myocardial necrosis progresses vertically outward toward syndrome of unstable angina develops.53–55 However,
the epicardium in the next 2 to 3 hours [“Q wave” or ST when the reduction in coronary blood flow and oxygen
elevation infarct (STEMI)] (Fig. 30.17). delivery to the heart is more prolonged, lasting 30 minutes
Herrick2 described acute MI caused by coronary artery to 1 to 2 hours, a NSTEMI occurs. When the period of
thrombosis in 1912. Subsequently, the role of coronary artery inadequate myocardial oxygen delivery persists for more
thrombosis in causing MI was debated77 until studies by than 2 hours, STEMI results (see Fig. 30.3).53–55 When unsta-
DeWood and colleagues105 demonstrated by coronary arteri- ble angina and acute MI are viewed in this manner, it is
ography that coronary artery thrombosis is virtually always easy to appreciate that patients with unstable angina and
the cause of acute Q wave or STEMIs. Buja and Willerson106 NSTEMI have “aborted” Q wave MIs, and therefore, they
confirmed the association between thrombosis of the infarct- remain at risk for new infarction and its consequences
related coronary artery and the development of acute Q wave in the ensuing 6 weeks.106,108,112–115 The risk for renewed
or STEMI by detailed clinicopathologic correlations. Ninety unstable angina and MI persists until the endothelial injury
percent or more of STEMIs have prolonged occlusive coro- is repaired. Other causes of endothelial injury may also lead
nary artery thrombosis in the infarct-related coronary to this same sequence of events, including endothelial injury
artery.105–107 associated with systemic arterial hypertension, flow shear
As noted above, STEMIs are usually caused by persistent stress, smoking, diabetes, infection, aging, immune complex
thrombotic occlusion of a coronary artery resulting in sus- deposition, substance abuse (e.g., cocaine), and the placement
tained reductions in coronary blood flow and myocardial of a coronary artery catheter into a coronary artery, espe-
oxygen availability. Occasionally, increases in myocardial cially with the interventional procedures of percutaneous
oxygen demand above the ability of a stenotic coronary transluminal coronary angioplasty (PTCA) and stent
artery to delivery oxygen cause MI, often NSTEMI. Such placement.53–55
67 8 chapter 30

A Subendocardium B

Subepicardium P R T P R T

Left ventricle

P R T P R T

R R
P Q T P Q T
Electrocardiographic stages identify
Transmural (Q-wave) transmural (Q-wave) myocardial infarction
myocardial infarction

C 02002

I V1 V2

V2 V1
II

V3 V3r
III

aVR V4 V4r

aVL V5 V5r

aVF V6 V6r
400 msec
FIGURE 30.17. (A) Schematic diagram of the topographic location V6 indicating conduction delay in the inferolateral wall, ST eleva-
of myocardial necrosis with STEMI and the associated electrocar- tion in leads II, III, aVF and 4–6, consistent with inferolateral infarc-
diographic changes. (B) The sequential electrocardiographic altera- tion infarction and right ventricular involvement. As shown by the
tions that document the development of a STEMI or Q-wave infarct, right precordial leads, showing prominent ST segment elevation
beginning with T-wave prominence (top), followed by hyperacute (V4r–V6r). ST depression in lead I suggests right coronary artery
ST-segment elevation (middle), T-wave inversion, and the develop- occlusion. Note also ST depression in leads aVR and aVL typical of
ment of a significant Q wave (0.04 seconds in duration) (bottom). (C) acute inferior wall infarction.
Atrial rhythm, rate 50 beats/min, Q waves in leads II, III, aVF and

Fissuring and ulceration of the plaque often (but not Physical Examination/Bedside Findings
always) occur in the asymmetric portion or “shoulder region”
with a thin fibrous cap that is lipid laden. Inflammation at The patient with unstable angina and NSTEMI and STEMI
sites of thin fibrous plaques with adjacent lipid cores best typically appears concerned. There may be no localizing
predicts the vulnerable atherosclerotic plaque and one likely finding or the patient may have an audible S4, cardiac enlarge-
to fissure or ulcerate.59–69 Inflammation is characterized in ment, congestive heart failure (CHF), acute mitral insuf-
the unstable plaque by the accumulation of monocyte-derived ficiency, acute ventricular septal defect, or evidence of
macrophages, activated T cells, and mast cells. Most likely, peripheral vascular disease.
proteases released from the infiltrating mononuclear cells The rest ECG between episodes of unstable angina may
contribute to thinning of the fibrous cap through their deg- be normal or may show the same ST-T wave changes or prior
radation of collagen and subsequent atherosclerotic plaque MI found in patients with stable angina. However, often the
fissuring and ulceration (Fig. 30.8).53,55,68,97–103,110–122 ECG demonstrates ST-T wave changes during angina, usually
 corona ry h e a rt dise a se sy n drom e s 67 9
ST depression or T-wave flattening or inversion in patients back, jaw, left arm, or neck. The pain is usually described as
with unstable angina and NSTEMI, reflecting alterations in the most severe the individual has ever experienced. It gradu-
myocardial perfusion of the “culprit” artery. Similar ECG ally builds in severity, reaches a peak, and then recedes.
changes occur in patients with unstable angina and NSTEMI, Some patients with acute MIs have unstable angina for hours
making it impossible to distinguish them electrocardio- to days before their infarcts. It should be emphasized,
graphically. On occasion, episodes of unstable angina and the however, that 10% to 20% of patients with diabetes
development of NSTEMI are not associated with ST-T wave mellitus who have MIs have “silent” (i.e., painless) ones.127–129
changes on the ECG, but this is unusual. Silent MIs also occur in patients who develop CAD (trans-
Echocardiographic findings are highly variable, but they plant vasculopathy) after cardiac transplantation, occasion-
may include reversible or fixed reductions in regional wall ally in individuals with neuromyopathic abnormalities, and
motion or global LV function abnormalities depending on in some seemingly otherwise normal subjects. One should
the reversibility of ischemia, the presence of MI, and its size. have a high index of suspicion in the patient who presents
In some patients, reductions in regional wall motion occur with new CHF, ventricular arrhythmias, hypotension, heart
with episodes of rest angina and resolve as the angina murmur of mitral insufficiency, systemic embolic events, or
resolves. is resuscitated from sudden death, especially in the diabetic
The chest x-ray also shows great variability in findings patient. Serial serum measurements of CK, CK-MB, and tro-
from a normal-sized heart to cardiomegaly with CHF. Hemo- ponin I or T and serial ECGs should be obtained in such
dynamic findings are similar to those during angina in the patients.
patient with stable angina, that is, one expects to see an
increase in mean pulmonary capillary wedge and left ven- Physical Examination
tricular end-diastolic pressures that are dynamic and resolve
Patients with small MIs, particularly NSTEMIs, often have
as the angina disappears. Patients with angina may also
no detectable abnormality on physical examination. At the
develop transient mitral insufficiency secondary to mitral
other extreme, patients with extensive damage to the left
valve papillary muscle dysfunction.
ventricle, usually those with anterior STEMIs with ≥40%
Coronary artery spasm leads to abrupt and dynamic
irreversible injury of the LV mass, often develop “power-
decreases in myocardial oxygen delivery (Fig. 30.5).17,18 With
failure” complications of their infarcts, including cardio-
a primary decrease in coronary blood flow, there is no asso-
genic shock, severe LV failure, or medically refractory
ciation between the development of angina and exertion, and
arrhythmias (Fig. 30.18).130–134
the majority of anginal episodes occur at limited activity and
rest. These patients usually have little or no change in heart
Inspection and Palpation
rate or blood pressure before the onset of pain. The pain
occurs first and may be followed later by increased blood The findings on physical examination in patients with acute
pressure or heart rate. MI depend primarily on the extent of the myocardial damage.
In the patient with unstable angina, continuous electro- Most patients are in obvious discomfort and diaphoretic.
cardiographic monitoring often documents transient ST- Those with extensive myocardial damage develop a reduc-
segment change immediately before the onset of chest pain, tion in systemic arterial blood pressure, ranging from mild
either ST-segment elevation indicating transmural ischemia to severe, including the development of cardiogenic shock.
as a consequence of spasm in a major epicardial coronary Cardiogenic shock is defined as hypotension resulting from
artery or platelet-initiated transient coronary artery throm- extensive myocardial damage coexisting with evidence that
bosis (see Figs. 30.3 and 30.5) or ST-segment depression.123–125 the reduced blood pressure is inadequate for normal systemic
Most commonly, however, the patient with unstable angina perfusion, so that cool skin, mental confusion, and oliguria
has ST-segment depression when subendocardial ischemia are usually present. Patients with extensive LV myocardial
develops. In some individuals, ST-segment alterations occur necrosis may also have an alternating pulse force (pulsus
in the absence of chest pain; this is referred to as silent isch- alternans) (Fig. 30.19) and frequent premature ventricular
emia.125 Silent ischemia has the same prognosis as painful beats.
episodes of ischemia (see Chapter 31).123–125 If second- or third-degree (complete) atrioventricular
block with sinus rhythm is present, the patient will have
intermittent “cannon” A waves in the jugular venous pulse
(Fig. 30.20). Patients with atrial fibrillation do not have an
Clinical Recognition
A wave in the jugular venous pulse but instead have an
irregularly irregular pulse. Those with important tricuspid
History
insufficiency have prominent V waves in their jugular venous
The history is of utmost importance in the recognition of pulse (Fig. 30.21). Patients with right ventricular (RV) failure
acute MI.1,2,126 Typically, the patient complains of severe have an increased jugular venous pressure, and they may
chest or epigastric pain that lasts until analgesic medication have hepatomegaly, right upper quadrant tenderness when
is administered, usually 30 minutes or longer. The pain is acute hepatic congestion develops, ascites if the RV failure is
often described as being retrosternal or left precordial, as a severe, and peripheral or sacral edema.
“heaviness,” “tightness,” or “like a weight on my chest,” and With acute STEMI, a precordial “ectopic impulse” may
is often associated with nausea and diaphoresis. It may sometimes be palpated over the left precordium, typically
radiate to the back, neck, jaw, or left arm, particularly down along the lower left sternal border or between the left sternal
its ulnar aspect. Occasionally, the pain exists only in the border and the apex. This impulse is caused by an increase
680 chapter 30

Group B Group A
90
PCG-AA
80
Recent
Old 1 2 1 2
70 PCG-MA
Myocardial Loss (%)

60
50 Carotid
40
30
ECG
20
10
FIGURE 30.19. Heart sounds (top), carotid pulse tracing (middle),
0 and electrocardiogram (ECG) (bottom). Pulsus alternans is shown
Without Cardiogenic Shock During Life Cardiogenic Shock During Life as the alternating height in the pulse wave tracing in a woman with
a dilated cardiomyopathy. AA, aortic area; MA, mitral area; PCG,
FIGURE 30.18. Development of “power failure” complications of phonocardiogram.
MI, including cardiogenic shock, occurs in patients with the most
extensive myocardial necrosis from their infarcts.

1 A2 P2

A V H
JUG. C
PULSE

Y
X

VPB
Second LSB
(400 cps)

Fourth LSB
(400 cps)

A FIGURE 30.20. (A) Normal jugular (jug.) venous pulse

Jugular “Cannon” configutation. Note the prominence of the A wave and that
A the X trough is deeper than the Y trough. Heart sounds and
venous pulse the ECG are shown (top). (B) A “cannon” A wave in the
jugular venous pulse. Heart sounds are shown along with
the ECG (top). LSB, left sternal border; VPB, ventricular
premature beat.
 corona ry h e a rt dise a se sy n drom e s 6 81

A v
in regional LV compliance within the area of injury, with a
v
resultant systolic distention or bulging (dyskinesia) of the
injured heart segment. Over hours to a few days after MI, the
compliance of this region decreases (stiffness increases) and
the systolic bulging is replaced by reduced (hypokinetic) or
SEVERE absent (akinetic) regional wall motion. If the systolic bulging
a
a persists, a ventricular aneurysm may be present.
v v
Auscultation
MODERATE
a a S4’s are heard in most patients with acute and chronic CAD
(Fig. 30.22), and they are usually soft and best heard with
Y Y light application of the bell of the stethoscope over the middle
and lower left precordium. S4 is caused by a more forceful
Y atrial contraction against a ventricle whose compliance is
Y
reduced as a consequence of increased ventricular stiffness
a NORMAL caused by the physiologic effects of CAD.
c v c v
When the mitral valve apparatus is damaged, a murmur
of mitral insufficiency may be audible. These murmurs have
X Y
variable auscultatory characteristics; they may be ejection in
X Y
quality, peaking in intensity in mid- to late systole, or they
may be holosystolic (Fig. 30.23). Intermittent myocardial
ischemia with transient dysfunction of the posterior papil-
lary muscle of the mitral valve leads to a murmur of papillary
LR LR
muscle dysfunction typically associated with mild to moder-
1 2 3 1 2 3 ate mitral insufficiency. The murmur of papillary muscle
dysfunction usually begins after the first heart sound (S1),
B peaks in mid- to late systole, and extends up to S2. It is heard
at the cardiac apex and may radiate toward the left sternal
border or into the axilla. If caused by intermittent myocar-
dial ischemia, the murmur is transient. If caused by infarc-
tion of the papillary muscle, the murmur is usually
permanent. Rupture of a papillary muscle with acute MI
causes severe mitral insufficiency and often a soft apical
holosystolic murmur. However, sometimes no audible
murmur occurs with a ruptured papillary muscle, even
though severe mitral insufficiency develops. Acute mitral

FIGURE 30.21. (A) The jugular venous pulse normally (bottom) and Fifth lsb
with moderate (middle) and severe tricuspid insufficiency (top). Note (25 cps)
the marked prominence of the V wave with moderate and severe
tricuspid insufficiency. The V wave correlates with the second heart
S4 S1 SM S3
sound (bottom, 2). The holosystolic murmur of tricuspid insuffi-
ciency is also shown (bottom). Typically, it becomes louder along S2
the lower left sternal border with inspiration. L and R, timing of left
and right ventricular third heart sounds (3). Third heart sounds Apex
occur with moderately severe and severe valvular regurgitation, and (25 cps)
those emanating from the right heart become louder with inspira-
tion. (B) A preferred way to evaluate the jugular venous pulse wave-
form is to examine the right external jugular vein as shown and
simultaneously listen to the heart sounds, timing the A wave with
the first heart sound and the V wave with the second heart sound.
Carotid

FIGURE 30.22. Fourth heart sound (S4), third heart sound (S 3), and
a systolic ejection murmur (SM), representing mitral insufficiency.
LSB, left sternal border; S1, first heart sound; S2, second heart
sound.
682 chapter 30

insufficiency occurs most commonly in patients with infe-

M1 A2 P2 S3 M1 A2 P2 S3 rior or lateral STEMIs and in those with NSTEMIs.135–141
Similarly, those with inferior infarcts and structural damage
PCG-PA to the tricuspid valve may develop tricuspid insufficiency.
Rupture of the interventricular septum occurs most com-
monly in patients with acute anterior infarction, although
it may also occur in the patient with an inferior MI (Fig.
M1 A2 S3 M1 S3 30.24).142–151 The murmur caused by a ventricular septal
SM SM A2
MDM OS MDM defect (VSD) is located along the lower left sternal border, is
PCG-MA holosystolic, and is often associated with a left sternal border
systolic thrill. As pulmonary artery pressure and vascular
resistance increase, the systolic murmur of a VSD becomes
shorter, ultimately disappearing altogether with the develop-
ment of severe pulmonary hypertension (Fig. 30.24). Func-
tionally large acute VSDs (pulmonary to systolic blood flow
of 1.5 to 1 or greater) should be closed usually by surgical
CAROTID intervention when CHF develops in the patient with MI;
otherwise, rapidly progressive CHF and death may ensue. We
recommend prompt coronary arteriography and repair of an
acute VSD with the development of CHF.
ECG A murmur of relative mitral or tricuspid insufficiency
occurs in patients with LV or RV failure, respectively; it is
the result of a spatial abnormality in the orientation of the
FIGURE 30.23. Use of two simultaneous phonocardiograms (PCGs)
to identify heart sounds in the patient with mitral regurgitation. A papillary muscles of the mitral and tricuspid valves caused
loud holosystolic murmur (SM) is noted at both the pulmonary by marked dilatation of the left or right ventricle. The mitral
artery (PCG-PA) and the mitral area (PCG-MA). The aortic compo- and tricuspid insufficiency with these entities is usually
nent of the second heart sound (A 2) is masked by the latter part of mild or moderate and diminishes in severity with diuresis
the murmur, but it can be identified as the widely transmitted sound
immediately preceding the incisura of the carotid pulse tracing and unloading therapy.
(arrow). In this patient, mixed mitral regurgitation and stenosis Third heart sounds occur in patients with acute MIs who
coexist and a mitral valve opening snap (OS) can be seen occurring have ventricular filling pressures (LV end-diastolic pressures)
slightly later than the second pulmonic heart sound (P2) in the of 15 mm Hg or greater and in those with moderately severe
cardiac cycle. A prominent third sound (S3) is seen in both PCG
or severe mitral, aortic, or tricuspid valvular insufficiency
channels, and a mid-diastolic murmur (MDM) is present at the
mitral area. (Fig. 30.22). S3’s are heard in patients with CHF and in those
with rapid filling of the ventricles as a consequence of moder-
ate or severe mitral, tricuspid, or aortic valve incompetence.
S3’s may be rarely heard in some young individuals (i.e., those

A B
LSE

S1 S1
S2 S2
PA 22/ 11
C D E
LSE 2 LICS

S1 S1 S2 S1 E
S2
S2
FIGURE 30.24. The typical holosystolic murmur of a ventricular monary hypertension, the murmur becomes shorter and ejection in
septal defect (VSD) and the influence of increasing pulmonary artery timing. With severe pulmonary hypertension, the systolic murmur
(PA) pressure on the murmur. (A) Murmur of a VSD with normal PA of a VSD disappears. E, ejection click; 2 LICS, second left intercostal
pressure. (B–E) The influence of increasing PA pressure on the spaces; LSE, lower sternal edge.
murmur of a VSD shows that, with the development of severe pul-
 corona ry h e a rt dise a se sy n drom e s 683
opment of CHF when the area of ischemia or infarction is
Expiration Inspiration
1 22 1 22 large. Alternatively, persistent ischemia can lead to chronic
depression of segmental ventricular function, known as
Normal myocardial hibernation, which may also contribute to
CHF and can be reversed, thereby correcting severe CHF,
A2 P2 A2 P2 in selected patients who undergo coronary artery
revascularization.

L BBB Electrocardiographic Diagnosis

As indicated earlier, unstable angina and NSTEMIs have
P2 A2 P2 A2 transient ST-T wave changes that are similar and include ST
FIGURE 30.25. Normal and paradoxical splitting of the second segment depression and T-wave flattening or inversion in
heart sound are shown at top and bottom, respectively. The influ- ECG leads reflecting the myocardium perfused by the culprit
ence of the left bundle branch block (LBBB) to produce paradoxical coronary artery. With LBBB, acute anterior MI is not recog-
splitting of the second heart sound is shown (bottom). nizable from the ECG, since the LBBB pattern simulates that
of an anterior MI in the left precordial leads. However, if the
LBBB pattern is otherwise altered by the presence of diminu-
tive R-wave voltage, S waves, or initial Q waves in leads I,
aVL, or V5 and V6, the patient may have had prior anterior
under 30 years of age) as a result of rapid filling of the and lateral MI. Inferior STEMIs can be recognized in the
ventricle. patient with LBBB because the evolution of Q waves in the
S2 normally splits into two components with inspiration, inferior ECG leads is not altered by LBBB. Abnormal T-wave
the earlier aortic and the later pulmonary valve closure vectors reversed from the normal pattern in patients with
sound, because inspiration increases venous return to the LBBB, that is, inverted T waves in V1 to V3 or upright T waves
right heart and delays pulmonary valve closure (Fig. 30.25). in leads V4 to V6, may indicate anterior or lateral ischemia or
However, the second sound may be paradoxically split (i.e., infarction. In patients with prior STEMI, recognition of new
wider splitting of the second sound during expiration) in the injury in the same general regions of the left ventricle is dif-
patient during angina pectoris, and in the patient with severe ficult. Finally, with rapid electrocardiographic evolution of
LV failure, systemic arterial hypertension, LBBB, or pacing the MI, it may not be possible to differentiate old from new
from the right ventricle, and with the various forms of LV MI from the ECG alone. ST-segment elevation may also
outflow obstruction, including valvular, supravalvular, and occur under other circumstances: (1) with normal early repo-
subvalvular aortic stenosis (see Fig. 30.24). The pulmonary larization; (2) with transient myocardial ischemia, as in
closure sound is increased in intensity in the patient with Prinzmetal’s angina, or with ischemia in an area of previous
moderately severe to severe pulmonary hypertension of any MI; (3) in some individuals with chronic ventricular aneu-
etiology. rysms (Fig. 30.26); (4) transiently after electrical cardiover-
A pericardial friction rub is detected in some patients sion; (5) in the anterior precordial electrocardiographic leads
with STEMIs and almost never in those with acute NSTEMIs. in patients with LBBB; (6) in the anterior precordial leads in
Patients with audible pericardial friction rubs are usually some patients with LV hypertrophy; and (7) in an occasional
those with the largest MIs. If a large pericardial effusion patient with hyperkalemia.
develops, the heart sounds may be distant and the jugular Although the ECG is useful in the recognition of STEMI,
venous pressure elevated. Cardiac tamponade results in the it does not enable one to recognize acute NSTEMI with cer-
development of hypotension, pulsus paradoxus (reduction in tainty. In these patients, the ECG usually demonstrates ST
systolic blood pressure during inspiration of more than depression and T-wave inversion, and the only evolution is a
10 mm Hg), distant heart sounds, and an elevated jugular return to baseline (Fig. 30.27; see also Fig. 30.7). Unfortu-
venous pressure. This is a life-threatening occurrence and nately, unstable angina, subendocardial ischemia, ventric-
requires the removal of the large pericardial effusion and ular hypertrophy, tachycardia, severe emotion, electrolyte
emergent pericardiocentesis. alterations (especially hypokalemia, hypomagnesemia, hypo-
Bibasilar or more extensive moist rales develop in patients calcemia), and the use of certain medications (including
with LV failure. Pulmonary edema occurs with extensive cardiac glycosides) are often associated with similar electro-
MI, in those with myocardial ischemia superimposed on cardiographic changes. Indeed, bizarre and deeply inverted
extensive previous MI, and in some who develop mechanical T-wave alterations occur in some patients with acute intra-
complications (acute VSDs, acute mitral insufficiency, or cerebral hemorrhage. The only useful rule in the electrocar-
large ventricular aneurysms) as a complication of acute MI. diographic recognition of NSTEMI is that the deeper the
ST-segment depression and the longer it lasts, the more likely
Myocardial Stunning and Hibernation is MI.
Transient myocardial ischemia followed by reperfusion may
Serum Enzyme and Cardiac Intracellular
lead to protracted recovery of segmental ventricular func-
Substance Changes
tion, known as myocardial stunning. This is probably caused
by cellular calcium overload and free radical generation.152–159 The relationship of changes in cardiac enzyme concentra-
Stunned myocardial segments may contribute to the devel- tions and other intracellular myocardial substances to the
684 chapter 30

1 2 3

aVR aVL aVF

V1 V2 V3

V4 V5 V6

FIGURE 30.26. Chest radiography (A) and corresponding ECG (B) reflect a ventricular aneurysm. Note the high lateral bulge in the left
ventricular silhouette in the chest x-ray and the persistent ST-segment elevation across the precordium (leads V1 through V6).

I II III aVR aVL aVF

V1 V2 V3 V4 V5 V6

03061

I V1

II V2

V3
III

FIGURE 30.27. (A) Electrocardiographic

aVR V4 patterns seen with an acute NSTEMI. The
T-wave inversion in leads II, III, and aVF and
the ST-segment depression and T-wave inver-
sion in the lateral precordial leads (leads V2
through V6) suggest the presence of NSTEMI.
aVL V5
Lower: Sinus rhythm, combination of
marked generalized, downloping ST depres-
sion and ST elevation more in lead aVR (B)
Provided by Hein J.J. Wellens and Anton
aVF V6 Gorgels. aVR that in lead V1, indicating isch-
emia or NSTEMI due to the left main stem
B 400 msec stenosis or 3 vessel disease.
 corona ry h e a rt dise a se sy n drom e s 685
development of acute MI is shown in Figure 30.28. A previ- of lactic dehydrogenase (LDH) and LDH isoenzymes have
ously preferred enzymatic technique was the measurement also been used to recognize acute MI. There are five LDH
of CK and, in particular, the myocardium-specific CK-MB isoenzymes, and increases in LDH isoenzymes 1 and 2 are
isoenzyme, measured by spectrophotometry, fluorometry, consistent with MI, such that when LDH-1 or -2 elevations
or radioimmunoassay.160–175 CK-MB usually increases in the represent more than 50% of the total, they are often indica-
sera of patients 2 to 3 hours after the onset of acute MI, tive of an acute MI. Increases in LDH occur 18 to 30 hours
reaches a peak at 10 to 12 hours, and returns to normal after MI and usually return to normal within 48 to 72 hours.
within 24 hours after the event in patients with small infarcts Therefore, LDH measurements allow the detection of some
and in those who have reperfusion after endogenous throm- patients with MI who delay their hospital admission in
bolysis. In patients with large infarcts, and those who fail to whom it is not possible to rely on changes in CK and CK-MB
experience reperfusion, CK and CK-MB often peak later (e.g., for infarct detection. However, these are almost never used
18 to 24 hours after infarction) and return to normal 30 to in contemporary practice.
40 hours after the event. Stuttering infarcts, defined as Measurements of CK isoforms, as well as myoglobin,
repeated episodes of infarction with recurrent chest pain have proved useful in detecting reperfusion after thrombo-
over hours to days, result in repeated elevations of serum CK lytic therapy or release of an experimental coronary artery
and CK-MB. occlusion.169–173 The conversion of CK isoform from CKMM-1
Radioimmunoassay measurement of alterations in serum to CKMM-2 in the peripheral circulation appears to correlate
myoglobin concentration allows a slightly earlier recognition with successful reperfusion therapy. Staccato increases in
of acute MI, but there is no means to distinguish myoglobin serum myoglobin in the first 4 to 6 hours after MI are indica-
release from the heart and skeletal muscle when both cardiac tive of reperfusion; rapid peaking of increases in serum CK
and skeletal muscle injury occur. Therefore, in the patient and CK-MB (within 10 to 12 hours from symptom onset) are
with skeletal muscle damage from trauma, intramuscular also often indicative of reperfusion of the MI.
injection, recent surgery, cardioversion, heat exposure, con- Presently, the preferred marker of myocardial necrosis for
sumption of alcohol in excess, or primary skeletal muscle detecting MI is a troponin. Three troponin subunits regulate
disorders, determining the presence of MI is not possible by muscle contraction by modulating the calcium-dependent
measurement of serum myoglobin levels. However, in the interaction of actin and myosin: the tropomyosin-binding
patient without skeletal muscle injury, measurement of serum subunit T, the calcium-binding subunit C, and the actomyo-
myoglobin by radioimmunoassay provides a sensitive and rel- sin–adenosine triphosphatase (ATPase)-inhibiting subunit I.
atively rapid means to detect MI within 1 to 2 hours of the Troponin I exists in three isoforms: slow-twitch, fast-twitch,
event. Myoglobin is released from injured myocardial cells and cardiac. Cardiac troponin I (cTn-I) is the 26.5-kd isoform
within 30 minutes to 2 hours of the event, peaks within 4 to of the muscle subunit and is genetically and structurally
6 hours, and returns to normal values within 10 to 12 hours. distinct from that produced in extracardiac muscle.
Radioimmunoassay measurement of alterations in the Previous studies have shown that increases in cTn-I and
serum concentration of the light chain of myosin may also cardiac troponin T (cTn-T) correlate with acute myocardial
allow a relatively early and precise recognition of acute necrosis in the general population.168,174,175 Both substances
MI.166,167 Measurements of serum transaminase values were are increased in the systemic circulation within 6 to 8 hours
made in the past, but these are nonspecific and they are not after acute MI or other forms of myocardial necrosis, and
relied on now for MI detection. Serial serum measurements they may remain elevated for at least 2 to 3 days. However,
in patients with renal failure, spurious cTn-T elevations and
increases in CK-MB have been found.79 Studies have shown
that cTn-I accurately predicts myocardial injury in patients
with renal failure. Martin and coworkers79 evaluated 56
WBC patients with acute or chronic renal failure or end-stage renal
2X Myoglobin disease, assessing the sensitivity and specificity of cTn-I for
CK and CK-MB detecting myocardial injury in these patients. During a 6-
Elevation of value

ESR
LDH month period, patients admitted with suspected MI were
Troponin I and evaluated. These patients had end-stage renal disease, chronic
Troponin T or acute renal failure, and a mean age of 62 years. There were
an equal number of males and females. Further cardiac
testing, including echocardiography, stress testing, or arteri-
ography, was performed at the discretion of the primary phy-
Normal
sician. Increased cTn-I levels were associated with increased
0 2 4 6 8 10 12 24 48 72 96 120
in-hospital mortality. The sensitivity and specificity for CK-
Time (hrs)
MB were 44% and 56%, respectively, whereas they were 94%
FIGURE 30.28. Typical changes in several substances measured in and 100% for cTn-I. In this study, elevated cTn-I levels were
a patient with an evolving acute MI. Increases in serum myoglobin associated with increased short-term mortality and an ability
concentration are the earliest change indicative of MI. Note that the to risk-stratify patients with severe renal failure and myo-
white blood cell count (WBC) rises early after infarction and that cardial injury. Troponin T values were slightly elevated in
the serum creatine kinase (CK) and MB isoenzyme of CK (CK-MB)
rise before the serum troponin I and T. The erythrocyte sedimenta- patients with renal disease, although not necessarily outside
tion rate (ESR) and lactic dehydrogenase (LDH) rise relatively late of the normal range. Troponin I values appeared to be more
after acute MI. reliable in infarct detection in these patients.79
686 chapter 30

In patients with unstable angina and NSTEMI, elevations

in CRP and troponin I or T identify patients who usually
benefit from interventional therapy, including PTCA and
stent placement when the coronary anatomy allows or coro-
nary artery revascularization when the coronary stenoses are
very diffuse and severe.176

Myocardial Scintigraphy
Radionuclide myocardial scintigraphy techniques for identi- Ant
fication of acute MI can be useful.177–189 These techniques
enable one to visualize the region(s) of acute MI (infarct-avid
imaging technique) or to identify areas of nonreversibly
decreased myocardial perfusion (myocardial perfusion
imaging technique). The prototype infarct-avid imaging
agent, technetium 99m (99mTc) stannous pyrophosphate,
accumulates in irreversibly damaged myocardium 1 to 5
RV
days after MI; its sensitivity in the detection of acute MIs of
3 g or larger is greater than 90% (Fig. 30.29).179,180,189
With successful reperfusion, MI may be detected within
2 to 3 hours of the event.184,185 An alternative to pyrophos-
phate imaging is the use of an antimyosin antibody labeled LAO

a 1b 1c

LL
a 2b 2c

FIGURE 30.30. A thallium 201 myocardial scintigram from a

patient with an acute MI in the anterior (Ant), left anterior oblique
(LAO), and left lateral (LL) views. Only a portion of the interior and
posterior wall of the heart are normally perfused. The anteroseptal
and anterolateral aspects of the heart have marked decrease in
thallium 201 perfusion, as shown by the straight arrows. RV, right
ventricle (curved arrow).
a 3b 3c
with technetium or iodine, which binds to myosin with
myocyte membrane injury and MI.186–188 It has the same sen-
sitivity in MI detection as pyrophosphate, but it does not
accumulate in bone. However, neither of these approaches is
used frequently now.
Thallium 201 (201Tl) and Tc-sestamibi are myocardial per-
fusion imaging agents that accumulate in the myocardium
in direct proportion to blood flow (Fig. 30.30).182,183
a 4b 4c
When used within 24 hours after acute MI, their sensi-
tivities for infarct detection are approximately 90%. The size
of the initial 201Tl or 99mTc-sestamibi defect after acute MI
appears to have prognostic significance, as do persistently
abnormal pyrophosphate scintigrams,189 that is, ones that
remain abnormal for 3 months or longer after MI. Large MIs,
as detected by extensive perfusion defect or by pyrophosphate
FIGURE 30.29. Various transmural MIs as evidenced by techne- or antimyosin antibody uptake, and persistently abnormal
tium 99m stannous pyrophosphate myocardial scintigraphy in the
anterior, left anterior oblique, and left lateral imaging views. (1a–1c)
pyrophosphate scintigrams, are associated with an increased
Large “doughnut” anterolateral MI. (2a–2c) Inferior MI. (3a–3c) risk for future coronary events and heart failure. 99mTc-
Inferolateral MI. (4a–4c) True posterior MI. sestamibi provides information similar to that of 201Tl, but
 corona ry h e a rt dise a se sy n drom e s 687
also allows an evaluation of global and regional systolic func- bypass and evacuate the pericardial fluid/thrombosis while
tion, including systolic wall thickening. they are on bypass rather than attempting to treat the peri-
In addition to these imaging techniques, the cardiovas- cardial tamponade by pericardiocentesis before placing the
cular blood pool can be identified with technetium-labeled patient on bypass. The classic finding in the patient with
erythrocytes to characterize the impact of acute MI on sudden myocardial rupture is the development of electrome-
regional and global ventricular function by dynamic myocar- chanical dissociation (EMD), in which the patient loses
dial scintigraphy.190–193 This latter technique allows measure- blood pressure and becomes unresponsive but has continuing
ment of ventricular ejection fraction, ventricular volumes, electrical activity on the ECG for the subsequent seconds to
regional wall motion, left-to-right shunts (i.e., VSDs), and minutes. Electromechanical dissociation is not specific for
valvular insufficiency, including mitral or tricuspid regurgi- myocardial rupture because it may also occur with a large
tation and the identification of ventricular aneurysms. anteroseptal infarct, pericardial tamponade of any etiology,
Two-dimensional (or three-dimensional) echocardio- and severe systemic hypoxemia or acidosis.
graphic measurements can also be used to detect intramyo-
cardial masses and to evaluate global and segmental ventric-
Differential Diagnosis
ular functional alterations in patients with acute MI.194–198
Transthoracic and transesophageal two-dimensional echo- In theory, the differential diagnosis of acute NSTEMI and
cardiography can also be used for detection of LV thrombi STEMI includes any cause of chest pain, cardiac arrhyth-
complicating acute MIs.196–198 Patients with acute anterior mias, new systolic murmur of mitral insufficiency or VSD,
STEMIS more frequently develop LV mural thrombi acutely heart failure, and sudden death. Important diagnostic
(10% to 40% of such individuals prior to development of considerations include (1) unstable angina, (2) Prinzmetal’s
reperfusion therapies), but probably less often with early angina, (3) pericarditis, and (4) dissecting aortic aneurysm.
reperfusion. This occurs more commonly in patients with Other diagnostic considerations, although less commonly
acute STEMI than in those with NSTEMI. These patients presenting with pain classical for MI, include (1) peptic ulcer
have an increased risk for systemic embolic events, requiring disease, (2) pancreatitis, (3) cholecystitis, (4) pulmonary
that they receive anticoagulants unless there is some contra- embolic disease, (5) spontaneous pneumothorax, and (6)
indication. Echocardiography with Doppler, transthoracic pneumonitis. Careful attention to history, physical examina-
and transesophageal, enables one to detect and estimate the tion, relevant blood tests, ECGs, and noninvasive or invasive
severity of mitral insufficiency and VSDs, to identify ven- imaging test results usually enables one to make the correct
tricular aneurysms and pseudoaneurysms, and to assess the diagnosis.
extent of wall motion abnormalities in patients with infarc-
tion.199–206 Detection of these abnormalities is important,
Estimation of Infarct Size
especially in patients with a low-output state, hypotension,
or heart failure, since proper medical management or surgi- Accurate measurements of the extent of reversible and irre-
cal repair may save the patient’s life. versible cell damage can be useful in predicting prognosis
Pseudoaneurysms (false aneurysms) developing after MI and selecting optimal future therapy for patients. Ideally,
(most commonly acute STEMIs) represent partial tears in the such measurements should be relatively noninvasive, appli-
left ventricle and an immediate risk for complete rupture. cable early in the patient’s clinical course, capable of being
They are distinguished from true aneurysms by demonstra- repeated with reasonable frequency, able to provide quantita-
tion—on two-dimensional echocardiogram, angiography, tion of the extent of damage with various types of infarcts,
radionuclide ventriculography, or magnetic resonance and generally available. No perfect measurement of infarct
imaging (MRI)—of their communication with the true left size or of the extent of ischemic damage exists at present,
ventricle by a narrow channel or neck. True LV aneurysms although several methods have been used: (1) enzymatic
communicate with the LV cavity by an imperceptible indices of infarct size, most importantly, measurement of
pathway. False LV aneurysms rupture spontaneously and CK-MB enzyme release from the heart207; (2) scintigraphic
should be surgically corrected as soon as they are identified. measurements of infarct size, including infarct-avid scinti-
Patients at greatest risk for heart rupture after MI are those graphic techniques (with 99mTc stannous pyrophosphate or
with systemic arterial hypertension who are experiencing antimyosin antibody)208–210 and myocardial perfusion tech-
their first MIs and elderly patients. Blood pressure elevations niques (201Tl or 99mTc-sestamibi and other technetium-based
should be prevented in patients with MIs to minimize this perfusion markers); (3) two-dimensional transthoracic or
risk. When myocardial rupture occurs after MI, most patients transesophageal echocardiography; and (4) dynamic myocar-
die suddenly of exsanguinations or cardiac tamponade. A few dial scintigraphy to estimate abnormalities of global and
develop tamponade with a sealing of the tear by a blood clot segmental ventricular function, using either first-pass or
in the pericardial space. Although blood does not usually clot equilibrium techniques. Evaluation of global LV function
in the pericardial space, in the patient with extensive MI, it with MRI and utilizing Gadolinium allows estimation of
may clot as a consequence of the loss of segmental wall infarct size. Each of these techniques has its limitations, but
motion in the infarcted segment. Thus, continued bleeding each also provides important information concerning the
is prevented, providing the observant physician an opportu- location and relative size of an infarct.
nity to recognize the development of an enlarging pericardial Three-dimensional estimates of the extent of myocardial
effusion with early tamponade and to intervene surgically to damage are needed for accurate scintigraphic measurements
correct the tamponade and repair the myocardial rupture. It (single photon emission computed tomography) and with
appears best to place these patients on cardiopulmonary other imaging techniques, including three-dimensional
688 chapter 30

echocardiography and MRI. Distinction of reversibly (“viable”

myocardium) and irreversibly injured myocardium can be
made in patients by positron emission tomography (PET)
imaging evaluation that combines estimates of myocardial
perfusion (rubidium or other PET perfusion marker) and fluo- PA
Thermistor and
rodeoxyglucose studies to identify reversibly injured myocar-
SVC distal lumen
dium as regions with reduced perfusion but persistent
metabolic activity. Persistent metabolic activity is indicated
by uptake and utilization of fluorodeoxyglucose (indicative
of reversible injury to the myocardium) even when perfusion Balloon
is markedly reduced or absent. One may also demonstrate RA inflated
reversible wall motion abnormalities by echocardiography,
radionuclide ventriculography, or MRI when potent inotropic Proximal
stimuli, such as dobutamine, dopamine, or paired electrical lumen
stimulations, are used, or during low-level exercise 5 to 7
days after MI.211–220 Finally, the extent of myocardial scar
may be identified by MRI and estimated by a QRS scoring RA
system.221,221a

Evaluation of Ventricular Function mm Hg

LA
Invasive and noninvasive techniques can be used to allow 30
25 A a PAW
more precise characterization of ventricular function in
patients with reduced systemic arterial blood pressure and 20
c V v
uncertain LV functional status. Flow-directed catheters, such 15 C
as the Swan-Ganz catheter, allow measurement of LV filling 10
pressure without entering a systemic artery or the LV (Fig. 5
30.31).222
This balloon-tipped, flow-directed catheter can be placed
in the pulmonary artery from a systemic vein (Fig. 30.31).
The Swan-Ganz catheter is positioned in the pulmonary
artery either with the aid of fluoroscopy or with continuous I second
pressure monitoring to identify the characteristic right atrial,
RV, and pulmonary artery pressures. Once the catheter is in FIGURE 30.31. (A) Path taken by a Swan-Ganz catheter. The cath-
eter is inserted into a systemic vein, threaded into the right heart,
the pulmonary artery, the balloon is inflated, facilitating the and positioned in the pulmonary artery (PA). In this location, pul-
measurement of pulmonary capillary wedge pressure. In monary artery and pulmonary capillary wedge pressures and cardiac
the absence of mitral valve disease, the mean pulmonary output may be measured. RA, right atrium; RV, right ventricle; SVC,
capillary wedge pressure is the same as the LV end-diastolic superior vena cava. (B) The pulmonary artery wedge (PAW) pressure,
and the A, C, and V waves in both the LA and PAW pressure wave
pressure (Fig. 30.31). forms.
Measurement of LV filling pressure with the Swan-Ganz
catheter enables one to differentiate hypotension caused by
hypovolemia from cardiogenic shock and LV failure. Mean
pulmonary capillary wedge pressures less than 12 mm Hg diography with Doppler assessment facilitate the detection
with hypotension occur with hypovolemia and those 15 mm Hg of LV thrombi, VSDs, and mitral insufficiency, as well as an
or higher are usually associated with cardiogenic shock and estimation of their severity. Transesophageal echocardiogra-
LV failure. In addition, cardiac output may be measured with phy facilitates a more precise detection of small intracardiac
the same catheter. The patient with an acute MI and shock thrombi than does transthoracic echocardiography. Three-
should also have an indwelling arterial cannula placed to dimensional echocardiography has been developed, and it
allow accurate measurement of and to detect moment-to- may facilitate even more accurate characterization of sys-
moment changes in systemic arterial pressure. The flow- tolic function and detection of thrombi in the future.
directed pulmonary arterial catheter may also be utilized to
help idealize mean pulmonary capillary wedge pressure either
Prognosis
with volume infusion with normal saline when the patient is
hypovolemic or by diuresis when the patient is hypervolemic Most patients with acute MIs who survive to reach the hos-
to values of 15 to 18 mm Hg in the hypotensive patient. pital and subsequently receive appropriate therapy for their
Both LV and RV function after acute MI can be assessed MIs have a relatively uncomplicated course. However, some
noninvasively with either dynamic myocardial scintigraphy, patients develop life-threatening complications during the
echocardiography, or MRI. These methodologies facilitate first 1 to 2 weeks, and others die (Table 30.3). During the
measurement of ventricular ejection fraction, ventricular early 1970s, more than 50% of patients died before reaching
dimensions or volumes, and segmental wall motion. Two- the hospital, primarily due to ventricular arrhythmias during
dimensional echocardiography and transesophageal echocar- the seconds or minutes after onset of chest pain. Since the
 corona ry h e a rt dise a se sy n drom e s 689
TABLE 30.3. Life-threatening complications of acute myocardial Papillary muscle dysfunction, mediated by ischemia
infarction with a transient apical systolic murmur or by infarction with
Ventricular arrhythmias (ventricular tachycardia, ventricular a permanent apical systolic murmur, usually causes less
fibrillation or asystole) severe mitral regurgitation, and the patient can generally
Extremely rapid atrial arrhythmias in association with extensive be stabilized by unloading therapy with a diuretic and
MI (atrial flutter or atrial fibrillation) nitroprusside or, if needed, temporary intraaortic balloon
Heart block [second-degree (Mobitz II) or third-degree] support.
Marked bradycardia Chordae tendineae rupture is not usually caused by MI,
Infarction ≥40% of left ventricle but instead may lead to acute mitral regurgitation as a con-
Extensive RV infarction sequence of spontaneous rupture, in the Marfan syndrome
Acute ventricular septal defects patient, in some women with mitral valve prolapse, in
Acute and severe mitral regurgitation
patients with chest wall trauma, or secondary to trauma on
the mitral valve apparatus of significant valvular aortic
Severe pulmonary edema
insufficiency, with endocarditis, or as a consequence of acute
Rupture of the heart
rheumatic fever.
Systemic and/or pulmonary emboli Acute VSDs occur primarily in the muscular septum and
Extension of the MI develop within 1 day to 2 weeks after MI, resulting in a new
Markedly increased LV end-systolic volume after MI holosystolic murmur along the lower left sternal border,
Occluded proximal LAD after anterior MI often associated with a systolic thrill in the same location
and a significant oxygen step-up between the right atrium
* LAD, left anterior descending coronary artery; LV, left ventricular; MI,
myocardial infarction; RV, right ventricular. and the right ventricle. The VSD places a pressure and volume
load on the left and right ventricles and may result in sudden,
or gradual, hemodynamic decompensation, with severe CHF,
hypotension, and relentless hemodynamic deterioration. We
believe that immediate surgical correction of a large VSD is
late 1980s, emergency ambulance systems have achieved a indicated with the development of the earliest signs of hemo-
25% to 30% reduction in the incidence of death before hos- dynamic deterioration (e.g., increased respiratory rate, tachy-
pitalization of patients with acute MIs and sudden cardiac cardia, hypotension). In the future, it may be possible to do
arrest syndromes.223–225 this in the cardiac catheterization laboratory with a device,
Overall mortality in patients with acute MIs who reach such as a “clam shell” occluder. Such patients are often
the hospital ranges from 3% to 30%, depending on the popu- placed on an intraaortic balloon and other unloading therapy
lation studied and the promptness and success of the therapy and are usually taken to the cardiac catheterization suite
given in opening the infarct-related artery. In general, patients for coronary arteriography and then to surgery to repair the
with anterior MIs have a higher mortality than those with VSD and bypass significantly narrowed coronary arteries. In
inferior MIs, probably because of a greater loss of LV patients with large left-to-right shunts, 1.5 to 2.0 or greater,
muscle. surgical closure of the VSD becomes mandatory to prevent
Patients can be categorized into groups with differing the subsequent development of severe pulmonary artery
prognoses on the basis of their initial hemodynamic mea- hypertension. However, in the hemodynamically stable
surements. Patients without LV failure and with a mean patient, VSD closure can be delayed for 4 to 6 weeks
systolic arterial pressure of greater than 110 mm Hg, an with resultant lowering of operative risk. Antibiotic
average cardiac index greater than 2.5 L/min/m2, and a prophylaxis against infective endocarditis with dental or sur-
normal pulmonary capillary wedge pressure (or pulmonary gical work is necessary in these patients, even after VSD
artery diastolic pressure) have low mortality rates. Death in closure.
these patients is usually caused by a ventricular arrhythmia, Patients with cardiogenic shock and systolic arterial
later infarct extension, or a mechanical complication (e.g., pressures of 80 mm Hg or less, decreased peripheral perfu-
myocardial, septal, or papillary muscle rupture). sion without a reversible cause, reduced mean cardiac index
A ruptured papillary muscle of the mitral valve leads to (<2 L/min/m2), and an increased pulmonary capillary wedge
fulminant left heart failure with pulmonary edema and or pulmonary artery diastolic pressure (>25 mm Hg) have an
often hypotension, and the patient is typically unresponsive increased mortality, unless the infarct-related artery can be
to diuretics and unloading interventions. This catastrophic opened by percutaneous coronary intervention (PCI) or
event should be suspected when a patient with an inferior, emergent surgery within the first 1 to 2 hours after the
lateral or NSTEMI abruptly develops fulminant left heart event.226 Percutaneous coronary intervention is capable of
failure with a new apical murmur, often soft, of mitral insuf- more rapid reperfusion than thrombolysis in desperately
ficiency. On occasion, however, the severity of the LV failure ill patients with MI and cardiogenic shock and, if the
is such that no murmur is generated. Prominent V waves are cardiac catheterization facility is available and an experi-
usually found in the pulmonary capillary wedge tracing by enced team on site or close by, is the preferred means for
flow-directed catheter. An echocardiogram and Doppler eval- providing rapid and potentially lifesaving reperfusion in
uation demonstrate severe mitral regurgitation and some- these patients.227 Very early reperfusion, that is, within 2
times a flail mitral leaflet. Ordinarily, the only chance for hours, in patients with cardiogenic shock or severe heart
survival is immediate surgical repair or replacement of the failure by PCI may save the lives of more than half of these
mitral valve. patients.227
690 chapter 30

Longer-term mortality after recovery from an initial MI

25
is related to the presence of ventricular arrhythmias, the Open
extent of myocardial damage, the age of the patient, and the Closed
LV end-systolic volume (Fig. 30.32). Persistent occlusion of 20
the infarct-related artery, most especially the proximal left

Mortality (%)
anterior descending coronary artery, is also associated with 15
a reduced long-term survival (Fig. 30.33).
In general, if the patient is less than 50 years of age at the
10
time of the initial MI, the annual mortality rate is approxi-
mately 5% or less. If the patient is 50 years of age or older,
the mortality rate is approximately doubled. If a patient sur- 5
vives for 1 year after MI, there is a 75% chance of 5-year
survival. If a patient survives for 5 years after MI, there is an 0
approximately 50% or greater chance of 15-year survival. Save Tami Welty Kander Eur Anderson
These numbers will improve in the coming years with exten- et ai et ai coop meta-
sive efforts at prevention of future coronary events, utilizing analysis
potent lipid-lowering, antioxidant, and antithrombotic thera- FIGURE 30.33. Mortality in patients with an open versus a closed
pies and with earlier reperfusion in patients with STEMI. infarct-related artery after MI. The presence of an open artery at
discharge confers a significant survival benefit in the first year after
In-hospital and immediate posthospital complications acute MI.
are related directly to infarct size. When more than 40% of
the LV muscle mass is irreversibly damaged and reperfusion
is not accomplished by PCI or surgical revascularization
within the first 1 to 2 hours, one can expect power-failure cally refractory ventricular arrhythmias. Patients with small
complications, including cardiogenic shock, CHF, and medi- MIs (irrespective of the location) are less likely to experience
such complications. However, a strategically located small
MI may cause heart block, acute development of a VSD, or
papillary muscle dysfunction or rupture resulting in acute
mitral insufficiency. In addition, patients with multiple
small MIs may ultimately develop cardiogenic shock, medi-
cally refractory CHF, or medically refractory arrhythmias as
a consequence of the cumulative muscle loss. Even a small
100 MI may be associated with ventricular arrhythmias; there-
90 EF ≥50% fore, continuous electrocardiographic monitoring is neces-
sary for at least 2 to 3 days after MI, irrespective of infarct
80
21ESV ≥55 mL (n = 1931) size or clinical complications.
70 12 ESV ≥55 mL (n = 186)
Accurate predictors of longer-term prognosis in patients
100 with acute MI are needed. Serial CK measurements can be
90 EF 40 − 49% important prognostically, as patients with the largest MIs are
23 ESV >95 mL (n = 60) most likely to experience cardiogenic shock, refractory CHF,
Survival (%)

80
or refractory ventricular arrhythmias; however, several hours
70 to a few days are required to complete such measurements.
60 Myocardial perfusion imaging, 201Tl, or 99mTc-sestamibi
myocardial scintigraphy may be used at hospital admission
50 ESV ≥95 mL (n = 60)
13 to estimate the extent of the myocardial perfusion defect.
100 Patients with the largest perfusion defects have a poorer
90 EF <40% prognosis during hospitalization and a higher mortality in
80
the short-term follow-up. Similarly, patients with the most
extensive ventricular functional abnormalities (as detected
70 by radionuclide ventriculography, echocardiography, mag-
60 16 ESV >130 mL (n = 53) netic resonance imaging, or angiography) and those with
50
large anterior MIs may develop “pump failure” and impor-
tant ventricular arrhythmias. Patients with anterior STEMIs
40 16 ESV ≥130 mL (n = 53) who extend their infarction in hospital have increased mor-
0 1 2 3 4 5 6 7 8 9 10 bidity and mortality.227–229
Years Patients with ventricular ejection fractions below 40%
and those with similar ventricular dysfunction and complex
ventricular ectopy (frequent ventricular premature beats,
FIGURE 30.32. Actuarial survival curves for patients with low coupled ventricular premature beats, or short bursts of ven-
end-systolic volume (ESV) versus high ESV at various ejection frac-
tions (EFs) after MI. In patients with left ventricular EF <50%, tricular tachycardia) at the time of hospital discharge, and
ESV plays a greater role in predicting survival than does left ven- those with severe global and segmental ventricular dysfunc-
tricular EF. tion or a reversible perfusion or function defect on low-level
 corona ry h e a rt dise a se sy n drom e s 6 91
exercise or stress testing at the time of hospital discharge, thrombotic therapy for at least several weeks after the event.
have a relatively poor prognosis unless the infarct-related and Reclosure of the infarct-related artery is associated with a
other critically narrowed arteries can be better perfused by poor prognosis.
PCI or surgical therapy.
Remodeling of the Left Ventricle
Summary
(“Infarct Expansion”)
The acute coronary artery disease syndromes are usually
Infarct expansion or remodeling of the infarct and peri-infarct caused by atherosclerotic plaque fissuring or ulceration.
regions refers to shape alterations in the infarct and peri- Patients with unstable angina and NSTEMI should be hospi-
infarct areas that result from stress and strain alterations in talized as an emergency in a coronary care unit. There, they
the infarct and adjacent areas. Most likely, metalloproteinase should receive medications directed at preventing the stabi-
release and alterations in myocardial wall stress related to the lization and persistence of a thrombus and the associated
local influence of angiotensin and endothelin play a role in the vasoconstriction at the sites of fissured or ulcerated athero-
remodeling process. The remodeling phenomenon causes sclerotic plaque(s) (see Chapter 27A). Patients with STEMI are
changes in contractile patterns in the infarct and peri-infarct treated by PCI or thrombolytic therapy acutely (see Chapters
regions and dilatation of the heart over time.230–233a Infarct 40 and 44). There is a continuum from unstable angina to
expansion or remodeling occurs primarily in patients with NSTEMI and STEMI that usually depends on the duration
anterior STEMIs, in those with large MIs, in those with sys- of severe coronary artery narrowing by dynamic thrombosis
temic arterial hypertension, in those with permanently and vasoconstriction. When the thrombosis and associated
occluded infarct-related arteries, and in older individuals. vasoconstriction are transient and repetitive but developing
Infarct remodeling leads to increases in LV end-diastolic and and resolving within 5 to 15 to 20 minutes, one has unstable
end-systolic volumes and dimensions and decline in LV func- angina. When the thrombosis and associated vasoconstric-
tion with a fall in LV ejection fraction in the several weeks to tion are more durable but persist for 30 minutes up to 2 hours
years after the infarct. Previous studies have demonstrated before resolving, one has a NSTEMI. In some patients, a
that angiotensin-converting enzyme inhibitors reduce the partially but not completely occlusive coronary thrombus,
magnitude of the remodeling phenomenon and preserve LV also causes unstable angina and NSTEMI. When the throm-
function when administered hours to a few days after MI, bosis and associated vasoconstriction are more permanent,
especially in patients with anterior STEMIs.233–241 The same is one has a STEMI.
likely to be true for the angiotensin receptor antagonists and Acute and longer term prognosis and best therapies, that
the combination of angiotensin-converting enzyme inhibi- is, medical versus interventional (PCI or coronary artery
tors and angiotensin receptor antagonists. Revascularization bypass graft) for patients with unstable angina and NSTEMI
with subsequent patency of the infarct-related artery also may be selected by measuring several biomarkers, including
reduces the magnitude of post-MI remodeling. Inhibutors of serum CRP, BNP, and troponin. Increases in CD40L, and
matrix metalloproteinases are also being evaluated.233a CD40, serum amyloid protein, interleukin-6, myeloperoxi-
dase, asymmetric dimethylarginine, VCAM, and ICAM also
Infarct Extension
appear to identify patients at risk for adverse events in the
Infarct extension is the result of new MI hours to days after future.
the original event, often associated with reocclusion of
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 3 Silent Ischemia
1 Matthew B. O’Steen and Neal S. Kleiman

Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Detection and Documentation of Silent

Mechanisms of Altered Pain Perception During Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Myocardial Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Prognosis in Patients with Silent Ischemia . . . . . . . . . . 705
Size of the Ischemic Area (“Ischemic Burden”) . . . . . . . 701 Treatment of Silent Myocardial Ischemia . . . . . . . . . . . 707
Hemodynamics and Left Ventricular Function . . . . . . . 702 Results of Suppressing Ischemia . . . . . . . . . . . . . . . . . . . 708
Silent Ischemia in Patients with Diabetes Mellitus . . . 702 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708

Key Points that, as is seen in many other disease processes, not only MI
and sudden death but also myocardial ischemia could occur
• Multiple mechanisms of silent ischemia have been
in the absence of symptoms.
proposed.
The results of an early study by Twiss and Sokolow,7 in
• The incidence and clinical significance of silent ischemia
which 21 of 66 patients with exertional angina pectoris
and the need for screening and therapy vary depending
underwent two-step exercise testing without developing
on the population being studied.
chest discomfort, led the authors to state, “The electrocar-
• Multiple methods for evaluating silent ischemia are
diographic changes after exercise are not dependent on the
available; each has utility in different clinical settings.
reproduction of pain while allowing that the percentage of
positive results is much greater if pain is induced.” Eventu-
ally, the use of more mechanistically based and hence more
Historical Perspective sensitive and specific nuclear and echocardiographic imaging
adjuncts to stress testing reinforced the prognostic signifi-
Since Heberden’s original description in 17721 of an exer-
cance of decreased blood flow to viable areas of myocardium
tional “disorder of the breast” and the subsequent recogni-
both in the presence and in the absence of symptoms. Simi-
tion that angina pectoris was associated with obstructive
larly, the development of drugs that could delay the develop-
narrowing of the coronary arteries, clinicians caring for
ment of ischemia and of successful revascularization
patients with coronary artery disease (CAD) have regarded
techniques that could prevent the development of previously
angina as the benchmark by which to measure the prognosis
demonstrable ischemia led to increased interest in studying
and gauge the treatment of patients with coronary arterial
and characterizing asymptomatic or “silent” ischemia. This
atherosclerosis. However, reports of coronary atherosclero-
effort was followed by attempts to determine whether treat-
sis, occasionally severe, in asymptomatic young soldiers
ment of silent or asymptomatic ischemia would improve the
killed in the First World War and the Korean War1,2 and in
outcome of patients in whom it was present. Therefore, it
pilots,3 coupled with the increasing recognition that the elec-
was no longer clear that adequate control of symptoms con-
trocardiographic changes of infarction were often present in
stituted optimal treatment for all patients with ischemic
individuals with no history of chest pain,4–6 led to the uneasy
heart disease.
acceptance that interruption of blood supply to the myocar-
dium was not necessarily heralded by angina pectoris. As the
ability to recognize myocardial ischemia increased, so did Mechanisms of Altered Pain Perception
the awareness that objective measures of detection were nec- During Myocardial Ischemia
essary in patients who were either asymptomatic or whose
symptoms did not fulfill typical descriptions. It is now well It is likely that a multitude of mechanisms are responsible
accepted that a large proportion of patients has evidence of for the variability of individuals’ ability (or willingness) to
remote myocardial infarction (MI) but give no clinical history sense pain as a result of myocardial ischemia. Experimental
suggesting such an event. The development and acceptance studies have demonstrated that activation of the baroreceptor
of Masters’ two-step test from the 1920s through the 1950s, reflex arc by pressor agents can induce hypoanalgesia in rats.
and later of the exercise treadmill test, led to the recognition Accordingly, stimulation of the efferent loop of this arc

699
70 0 chapter 31

(cardiopulmonary vagal pathways) may be responsible for the It remains fair to state that the role of endorphins in mediat-
absence of pain in humans.8 Because increases in the blood ing the perception of cardiac ischemia remains unresolved.
pressure repeatedly stimulates this pathway, it has been pos-
tulated that hypertensive patients have a higher pain thresh-
Silent Ischemia and Inflammation
old than nonhypertensives. Patients with angiographically
documented CAD and hypertension, for example, tend to Recent speculation has focused on the role of inflammatory
have a higher mean dental pain threshold than normotensive processes in the perception of cardiac ischemia. Many
patients, and experience fewer episodes of angina during inflammatory mediators have nociceptive properties; vascu-
daily life.9 Patients with infiltrative autonomic neuropathies, lar and perivascular inflammatory processes may stimulate
such as that associated with diabetes, may also have dimin- or sensitize local afferent fibers. Patients with silent isch-
ished afferent loop sensitivity. This group is discussed sepa- emia have been noted to have an antiinflammatory pattern
rately in a later section. of cytokine production (increased levels of IL-4 and IL-10, and
decreased monocytes expression of CD11b/CD18), which
may increase the threshold for nerve activation and block the
Altered Central Nervous System pain transmission pathway.16 Mazzone and colleagues16 eval-
Processing Mechanisms uated the expression of the peripheral benzodiazepine recep-
For a noxious stimulus to be perceived as pain, frontal tor on circulating leukocytes in 24 patients with and 33
cortical activation must occur. Cortical activation can be patients without angina during exercise-induced myocardial
traced physiologically by detecting increased blood flow ischemia. Flow cytometric determinations showed increased
using positron emission tomography (PET). Comparison of expression of peripheral benzodiazepine receptors on all
changes in regional cerebral flow reveal equivalent degrees classes of leukocytes in patients whose ischemia was silent
of thalamic activation in both angina as well as in silent compared with patients who developed symptoms during
ischemia, but a lesser extent of cortical activation in patients ischemia. It is unknown whether the presence of these recep-
with painless ischemia.10 This finding suggests differential tors on leukocytes plays a causal role in the lack of symp-
gating of afferent stimuli at the thalamic level with only toms during myocardial ischemia or whether leukocytes
some impulses being allowed to pass through to the frontal merely represent one cell class in which peripheral benzodi-
cortex. azepine receptor expression is upregulated.17

Endorphins and Angina Central Nervous System Processing:

Evaluation of Pain Threshold
β-endorphins are recognized as modulators of pain; elevated
plasma endorphins raise an individual’s threshold for expe- Silent ischemia is induced daily in many patients undergoing
riencing pain. Since these endogenous compounds antago- coronary angioplasty of a vessel supplying viable myocar-
nize the same central receptors that are blocked by opiates, dium. However, it has been estimated that 16% to 47% of
which have been used successfully for a century to treat patients do not experience pain during the procedure. Con-
angina, it is tempting to consider that endorphin production sequently, this procedure may provide a model for evaluating
or sensitivity may play a role in moderating the perception silent ischemia. Falcone et al.18 evaluated pain threshold
of angina. In patients with established coronary artery using dental stimulation in patients with and without angina
disease, β-endorphin levels in patients with silent ischemia during daily life undergoing PTCA. During pulpal stimula-
have been reported to be almost twice as high as in asymp- tion, 66.2% of patients reported pain whereas 33.7% remained
tomatic individuals.11 The same finding has been noted in asymptomatic, even at maximal stimulation, recognizing
patients undergoing percutaneous transluminal coronary that sedation and analgesia may also modify the sensation
angioplasty: Plasma levels of β-endorphins are lower in and reporting of pain. The study cohort was then divided into
symptomatic patients and decrease significantly during two groups according to the presence or absence of angina
balloon inflation. In patients with silent ischemia, plasma during myocardial ischemia. Although the two groups
levels of β-endorphins have been reported to be higher before appeared demographically similar, dental pain could be pro-
and to remain stable during balloon angioplasty when com- voked in 81% of patients with and 36% of patients without
pared with patients who develop angina during ischemic symptoms during PTCA. The authors concluded that indi-
symptoms, suggesting that endogenous opiate levels and vidual profiles of generalized pain perception were likely to
their variation during ischemia are associated with individ- influence their perception of angina during episodes of myo-
ual experience.12 Investigation of percutaneous trans- cardial ischemia. Duration or intensity of ischemia and left
luminal coronary angioplasty (PTCA)-induced ischemia, has ventricular dysfunction were not absolute factors in deter-
suggested that there may be a threshold beyond which mining the occurrence of angina. However, it is worth noting
β-endorphins must increase in order to suppress anginal that the same may not apply to angina during exercise or
symptoms in response to ischemic stimuli.13 However, when during daily living, possibly due to different pathophysio-
the induction of angina is compared to perception of other logic mechanisms involved (Table 31.1).
noxious stimuli, the same elevations in β-endorphin levels
(as high as fivefold) that decrease perception of electrical pain
Psychological Aspects of Silent Ischemia
stimuli14 or of exogenous radiant heat15 do not appear to
affect the sensation of exercise-induced angina. It is possible In CAD as in most other disease states, psychological factors
that higher endorphin levels may affect the angina threshold. may influence the perception of discomfort as pain. These
 silent ischemia 7 01
TABLE 31.1. Proposed mechanisms of silent ischemia the differences between patients with silent ischemia and
Differences in somatic pain thresholds those with symptomatic ischemia during exercise testing 1
Increased endorphin levels
to 6 months after recovery from a coronary event. Compared
with patients with symptomatic ischemia during testing,
Alterations in immunoinflammatory response to pain
those with silent ischemia had less extensive reversible
Autonomic neuropathy
defects on stress thallium scintigraphy (Table 31.2), less func-
Abnormal central nervous system processing/gating of pain tional impairment during treadmill testing (longer exercise
duration and longer time to ST depression), and less frequent
ST depression during ambulatory electrocardiographic moni-
factors may affect the response to therapy as well. The psy- toring. In a similar study, Zellweger and colleagues23 reported
chological comfort associated with increased medical sur- that when stress scintigraphy was performed on 356 patients
veillance as well as the perception that a medical strategy is 6 months after successful percutaneous coronary interven-
being pursued may result in a significant “placebo effect.” tion (PCI), 62% of patients in whom ischemia was docu-
For example, Amsterdam et al.19 reported that in patients mented were asymptomatic and the summed stress score
with silent ischemia, placebo therapy led to a 44% reduction (i.e., the degree of stress-induced ischemia) was substantially
of ischemic episodes and 50% reduction in total duration of lower among asymptomatic compared with symptomatic
ST depression. patients.
In an elegant study, Friedman et al.20 showed a strong In another study of 300 consecutive patients with docu-
relation between silent ischemia and “type A” personality. mented CAD and reversible hypoperfusion on exercise ses-
When 10 patients with this behavioral trait underwent psy- tamibi tomography, Marcassa and colleagues24 compared the
chological counseling, which resulted in marked decreases extent of hypoperfusion and the presence of symptoms
in the feeling of “time urgency” and hostility (markers of during exercise stress testing. Patients with painful ischemia
type A personality), the mean frequency of ischemic episodes had lower values for workload, exercise time, and peak-rate
declined from an initial 6.6 to 3.1 ischemic episodes per 24 pressure product. These patients more frequently had signifi-
hours. Whether this decrease resulted from a truly altered cant ST segment depression during exercise than did patients
perception threshold or reduction in endorphin secretion and with silent ischemia. Patients with symptoms during isch-
in rate-pressure product is not known. Similarly, data from emia had more evidence of reversible hypoperfusion than did
the Canadian Amlodipine/Atenolol in Silent Ischemia Study patients with silent ischemia (16% ± 10% vs. 11% ± 7%)
(CASIS) suggest that quantitatively determined high levels despite comparable extent of stress hypoperfusion (22% ±
of daily psychological stress may reduce the threshold at 12% vs. 22% ± 13%).
which angina is reported in patients with clinically stable In contrast, Elhendy and associates25 studied 224 con-
coronary artery disease.21 secutive patients with limited exercise capacity and com-
pletely or partially reversible perfusion abnormalities during
dobutamine stress sestamibi single photon emission com-
Size of the Ischemic Area (“Ischemic Burden”) puted tomography (SPECT) and found no difference in the
extent or severity of perfusion defects between symptomatic
The relation between the amount of ischemic myocardium and asymptomatic patients.
and the presence and severity of symptoms is hotly debated. Discordant results have been reported in at least 10
In a study of 963 patients, Narins and coworkers22 examined studies that used myocardial perfusion scintigraphy to

TABLE 31.2. Thallium-201 myocardial perfusion scintigraphic studies comparing the amount of ischemic myocardium in patients with
or without chest pain during exercise testing
First author Year No. of patients Method Selection criteria Reversible defects (% of patients)

Amount of ischemia equal in patients with or without chest pain

Hecht27 1989 112 SPECT CAD; reversible defects 100%
Gasperetti 28 1990 103 Planar Reversible defects 100%
Heller29 1990 234 Planar Reversible defects 100%
Mahmarian30 1990 356 SPECT Unselected 54%
Bandu131 1994 294 SPECT Unselected 94%
Amount of ischemia greater in patients with than without chest pain
Kurata31 1990 471 SPECT Unselected 37%
Galli32 1990 200 Planar Old MI; reversible defects 100%
Travin33 1991 268 Planar Reversible defects 100%
Hendler34 1992 152 SPECT Ex ECG+ 83%
Klein 26 1994 117 SPECT Ex ECG+ 80%
Ex ECG+, positive exercise electrocardiogram; MI, myocardial infarction; Pts, patients; SPECT, single-photon emission computed tomography.
702 chapter 31

compare the amount of ischemic myocardium in patients ity.41–46 The Detection of Ischemia in Asymptomatic Diabe-
with and without chest pain during exercise testing.26–34 tes (DIAD) investigators evaluated patients with type II
Several potential explanations exist for these discrepant diabetes mellitus and no symptoms suggesting CAD; 522
findings. The earlier studies were conducted using widely patients underwent adenosine sestamibi SPECT. Sixteen
different patient populations, ranging from clinically asymp- percent of patients had evidence of abnormal myocardial
tomatic patients to only those with evidence of a marked perfusion; 6% had perfusion defects ≥5% of the left ventricu-
ischemic response to exercise. Multivariable analysis was lar mass. Predictors of these moderate to large defects
seldom performed in these studies, and varying definitions included male sex, diminished heart rate response to the
of silent ischemia were used. Valsalva maneuver, and symptoms of autonomic dysfunc-
tion.47 The cohort is currently being followed for clinical
outcomes. Some authors have suggested that the occurrence
Hemodynamics and Left Ventricular Function of silent ischemic responses in patients with diabetes appears
to be related to the severity of microvascular disease, partic-
In general, acute left ventricular dysfunction is a conse- ularly as manifested by microalbuminuria. The combination
quence of the extent of ischemia. Hence, findings relating of microvascular disease and silent myocardial ischemia in
the presence of ischemic symptoms to left ventricular func- patients with diabetes appears to be associated with a con-
tion might be expected to follow those related to the level of siderably greater likelihood of subsequent events.47–50
ischemic burden. Similar discrepancies exist in the literature Although it is commonly accepted that asymptomatic
concerning left ventricular performance during exercise ischemia is more common among people with than among
testing in patients with silent and symptomatic ischemia. In people without diabetes, there are conflicting data regarding
a study that included 131 patients with angiographically the frequency of silent ischemia in individuals with diabetes
documented coronary artery disease, Bonow and associates35 mellitus. The Framingham Study investigators initially
found that patients with silent ischemia were less likely to reported that in subjects with diabetes, the incidence of pain-
develop a decrease in left ventricular ejection fraction during less myocardial infarction was higher than in those without
exercise radionuclide ventriculography than were patients diabetes.51 Several studies suggested that diabetic patients
who developed angina during testing. A similar observation may have a high incidence of transient silent ST changes
was made by Matsubara et al.12: pulmonary artery wedge during ambulatory Holter monitoring.52,53 In a well-
pressure at peak exercise was significantly lower and the controlled patient population, Nesto et al.54 demonstrated
cardiac index was significantly higher in patients with silent that only 28% of patients with diabetes who had thallium
ischemia compared with patients who experienced angina. scintigraphic indications of ischemia experienced angina
On the other hand, Cohn and associates36 and Vassiliadis and pectoris during a treadmill test compared with 68% of
colleagues37,38 found no differences in global ejection fraction patients without a diagnosis of diabetes. An analysis of
or regional wall motion abnormalities during exercise testing patients with diabetes enrolled in the Asymptomatic Cardiac
in symptomatic and asymptomatic patients. The inclusion Ischemia Pilot (ACIP) database study revealed different
of patients with prior myocardial infarction in the latter two results when patients with and without diabetes were com-
studies may explain the differences from the former study. pared. As expected, multivessel disease was more common
in the group with diabetes (87% vs. 74%). However, the per-
centage of patients without angina during the exercise test
Silent Ischemia in Patients with was similar in both groups (36% and 39%, respectively). The
Diabetes Mellitus percentage of patients with only asymptomatic ST-segment
depression during the 48-hour ambulatory electrocardiogra-
Patients with diabetes represent a classic example of patients phy (AECG) were also comparable (94% vs. 88%, respec-
in whom the afferent loop of the cardiac sensory mechanism tively). An even more surprising finding was that despite
is altered. The afferent fibers that accompany the cardiac more extensive and diffuse CAD, patients with diabetes
sympathetic nerves are felt to be responsible for transmission tended to have less measurable ischemia during the 48-hour
of cardiac pain. Using the synthetic radiolabeled norepineph- AECG monitoring period, perhaps related to lower achieved
rine analog metaiodobenzylguanidine (MIBG), Langer and workloads. Among patients with diabetes, total ischemic
colleagues39 demonstrated a decrease in cardiac catechol- time per 24 hours, ischemic time per episode, and maximum
amine uptake, indicative of cardiac sympathetic denerva- depth of ST-segment depression were also lower compared
tion, in patients with versus those without diabetes. This with nondiabetic individuals.55 A study of 1737 people with
abnormality was more severe in patients with clinically type II diabetes and known CAD referred for nuclear stress
documented autonomic dysfunction and in patients in whom testing found the frequency of scintigraphic evidence of CAD
ischemia was asymptomatic. These findings suggest a direct was no different in patients without angina (39%) from those
link between worsening of cardiac sympathetic denervation with angina (44%). However, among patients presenting with
in diabetics and silent ischemia. the complaint of shortness of breath, the prevalence of CAD
It is well established that CAD is a major complication was 51%.56 These disparate findings suggest that such factors
of diabetes mellitus, representing the ultimate cause of death as selection bias (particularly with regard to comorbidities),
in more than half of all the patients with this disease.40 the degree of stress to which patients with diabetes are sub-
Furthermore, myocardial infarction in people with diabetes jected during diagnostic testing, and the manner in which
is usually more extensive and more severe than in patients clinical histories are obtained may affect the frequency with
who have diabetes, and is associated with higher mortal- which ischemia is reported.
 silent ischemia 703

Detection and Documentation of with a low likelihood of CAD and without cardiac symptoms
Silent Ischemia have revealed episodes of ST-segment depression exceeding
30 seconds in fewer than 5% of subjects.61
In patients with CAD, it is considerably more common
Exercise Stress Testing to detect ST-segment deviation on Holter monitoring. Other
Exercise testing has been the hallmark of the detection of corroborating evidence of ischemia during daily life can be
myocardial ischemia since the development of the two-step found during such episodes of asymptomatic ST-segment
exercise test by Masters and Geller.57 Although ST-segment depression. Experience with a lightweight nonimaging
deviation in individuals with previously undetected coro- radionuclide gamma camera that can be worn strapped to a
nary artery disease is the sine qua non of a positive test when patient’s chest has demonstrated frequent episodic asymp-
used for screening purposes in a large and generally asymp- tomatic reductions in left ventricular ejection fraction during
tomatic population, much interest in silent ischemia has daily activity,62 especially during periods of mental stress.63
been focused on events in patients who are known to have These episodes are often, but not always, accompanied by
CAD. This interest in patients with documented CAD who ST-segment depression.64 It is therefore likely that many epi-
are already at higher risk than the general population is sodes of ST-segment depression that occur in patients with
perhaps in part a necessary part of the enterprise of establish- obstructive CAD represent actual ischemic events in the
ing that silent ischemia is a bona fide physiologic phenome- myocardium. Conversely, ST-segment depression without
non rather than an artifact of the testing methods. In a reduction in the left ventricular ejection fraction may repre-
retrospective analysis of 1698 patients with CAD who under- sent ischemia that does not involve an amount of myocar-
went exercise treadmill testing, Mark and associates58 dium sufficient to cause left ventricular dysfunction or may
reported that ST-segment deviation occurred in 842 (50%). be nonischemic in origin.
These electrocardiographic (ECG) changes were painless in Painless depression of the ST segment on AECG has been
242 (14%) and were accompanied by angina in 600 (35%). In reported in 40% to 85% of patients with CAD.57,65–74 In
this study, as in a report from the Coronary Artery Surgery patients with unstable rest angina or recent MI, reports from
Study (CASS) registry, prior angina and more frequent epi- some centers have indicated that as many as 50% have
sodes of angina during daily activity were more common evidence of ambulatory ischemia,70–74 although considerable
among patients who developed symptoms during ischemia. controversy exists concerning the frequency with which
Patients with exercise-induced angina were more likely to ambulant ischemia can be detected. For example, in the
have three-vessel CAD, a shorter peak exercise time, and a National Heart, Lung, and Blood Institute sponsored
lower peak heart rate, although the median degree of ST- Thrombolysis in Myocardial Ischemia study (TIMI-3) of 1473
segment deviation observed with electrocardiography was patients with unstable angina or non–Q-wave MI, ischemia
not different.59 These findings confirmed that the presence exceeding 20 minutes in duration, observed during 24 hours
of angina during exercise testing was likely to reproduce of Holter monitoring with results interpreted in an experi-
symptoms that occurred during everyday life, and by exten- enced core laboratory, was present in fewer than 4% of
sion, suggested that patients in whom ischemia could be patients.75 In most cases when ischemia is detected, multiple
provoked without producing angina (or its equivalent) were daily episodes are present with considerable variation in each
likely to experience asymptomatic ischemia during daily individual patient from day to day and week to week.66 In
activity. most such studies, between two thirds and three quarters of
such episodes in any given patient are not accompanied by
angina.
Ambulatory Electrocardiographic Monitoring
Proof that silent ischemia is a common occurrence among
Limitations of Ambulatory
patients at risk for coronary heart disease has relied largely
Electrocardiographic Monitoring
on the use of AECG (Holter) monitoring, because it has
extended the ability to detect ischemia from the clinic to the Several important limitations of AECG should be kept in
daily activities of life and because it has demonstrated that mind. Studies have repeatedly shown that ischemic ST-T
“ambulant” ischemia commonly occurs during daily activi- changes, even though strictly defined by the Minnesota code,
ties even in the absence of angina. Golding and coworkers60 are not specific for CAD and can be seen in healthy individu-
initially reported that transient elevation of the ST segment als or in patients with documented coronary artery disease
occurred in seven of 174 patients undergoing Holter monitor- but without provocable ischemia. On the other hand, studies
ing for detection of arrhythmias. It is unlikely that all epi- performed in patients hospitalized with acute coronary syn-
sodes of ST-segment depression (particularly in a population dromes or MI have shown relatively high frequencies of
in which the presence of disease is not established) represent silent ST-segment shifts, and have indicated that patients in
myocardial ischemia. However, even in patients in whom whom such shifts occur are at significantly higher risk than
exercise-induced ischemia can be demonstrated, it is rare to are those in whom they are absent.76 However it is important
detect prolonged ST-segment depression in normal subjects to recognize that such studies have been performed in
if proper data acquisition techniques are used. Since tran- patients with extremely high a priori risk (i.e., high pretest
sient changes in position can produce brief periods of devia- probability) of ischemia and the results may differ in ambula-
tion in the ST segment, changes are usually required to last tory patients in whom the risk is lower. As during PCI, the
for at least 30 seconds before they are interpreted as repre- influence of sedation on the sensation of angina should also
sentative of possible ischemic events. Studies of individuals be considered. In addition, changes in left ventricular loading
70 4 chapter 31

conditions may also produce alterations in the surface elec- nied by angina. Most patients exhibit a combination of both
trocardiogram and in left ventricular function, particularly symptomatic and symptomless ST-segment changes,
in patients with depressed ejection fractions, which may be although the difference between ECG characteristics of
interpreted mistakenly as representing ischemia.11 Among silent and symptomatic episodes in a given patient is not well
the many causes are T-wave inversions recorded in young documented. Both the degree of ST-segment deviation and
adults, electrolyte disturbances, valvular heart disease, car- the duration of the episodes appear to be similar. When
diomyopathy, drugs, intracranial lesions, and recent food patients with CAD are subjected to differing exercise proto-
ingestion.77 Boon and associates78 demonstrated that the dis- cols, ischemic ST-segment depression usually occurs at
crepancy in reported ischemia greatly depends on the spe- similar rate-pressure products. However, the ischemic thresh-
cific criteria used to define ischemia. In an analysis of Holter old on ambulatory ECG monitoring is considerably more
monitors of 194 asymptomatic hypertensive patients, 11.3% variable88,90 and usually occurs at a lower rate-pressure
were reported to have silent ischemia as defined using the product than during treadmill exercise,66,67,90–94 even in cir-
commonly used criterion of >0.1 mV of ST segment devia- cumstances when an increase in rate-pressure product pre-
tion. When baseline ECG abnormalities were accounted for cedes the onset of ischemia.95
and more stringent criteria were used to define ischemia, Deanfield et al.66 reported that among patients with
such as eliminating sudden ST segment deviation likely to ST-segment depression on exercise testing, the ST-segment
be caused by body movement requiring down-sloping of the changes noted during ambulatory monitoring occurred, on
ST segment and duration of the shifts >1 minute, as well as average, at heart rates of 20 beats per minute (bpm) less than
requiring >0.2 mV ST segment shifts in the presence of the ischemic threshold detected on exercise testing. These
resting ST deviation, the incidence of ischemia was reduced episodes also occurred more frequently in the morning hours
to 5.2%. after rising,91,95,96 following established circadian patterns for
In comparison with the standard ECG, the standard two- physiologic increases in plasma catecholamines97 and plate-
lead AECG is relatively insensitive for detecting ischemia, let aggregability,98 as well as in blood pressure,99 heart rate,92
even when attempts are made to reproduce the leads used and for such clinical events as MI100–102 and sudden cardiac
during standard 12-lead electrocardiography. When patients death.103
with CAD hospitalized for USA or surgery were monitored Assessment of asymptomatic ischemia is often used to
simultaneously using both a two-lead Holter monitoring evaluate the adequacy of medical therapy. However, despite
system and a 12-lead microprocessor-driven real-time ECG the (very) roughly concordant information they provide con-
monitor, the 12-lead microprocessor system detected signifi- cerning whether symptoms occur during ischemia, exercise
cantly more ischemic events than did the two-lead monitor testing and the AECG may detect different effects of anti-
and produced no false-positive results in the normal control anginal treatments. For example, the CASIS investigators
group.79 The utility of AECG as a quantitative technique is evaluated the influence of amlodipine and atenolol on myo-
also unclear. Neither the total duration of ischemic ST cardial ischemia during exercise stress testing and AECG
depression nor the total number of ischemic episodes corre- monitoring. Ischemia during treadmill testing was more
sponds well with the size of scintigraphic perfusion defects80 effectively suppressed by amlodipine, whereas ischemia
or with the anatomic extent of angiographic coronary artery during AECG monitoring was more effectively suppressed
disease.81 However, in patients hospitalized with MI and by atenolol. The combination of both drugs was more effec-
non-ST elevation acute coronary syndromes, use of con- tive than either drug alone in either setting.104
tinuous 12-lead electrocardiogram and continuous vector-
cardiography recording devices does allow quantitative
Nuclear Scintigraphy
measurement of ischemia, which appears to carry prognostic
significance.82–84 The same issues of sensitivity and specificity that led to the
introduction of nuclear imaging for detection of CAD also
apply to detection of ischemia. Tomographic imaging is
Relation Between Ambulatory Electrocardiographic
highly reproducible and has also allowed quantification of
Monitoring and Exercise Stress Testing
the amount of ischemic myocardium. When these studies are
The presence of painless ST-segment shifts on ambulatory interpreted by competent readers, the variation in measuring
ECG and symptomatic status during exercise testing should the size of an ischemia defect is less than 10% in 95% of
be viewed as providing complementary rather than redun- patients.105 As a consequence, exercise SPECT has become
dant or even competing information. Differences between accepted as a very accurate technique for the evaluation of
ischemic responses noted on treadmill testing and on ambu- ischemia suppression.106–108 Adenosine-induced stress during
latory monitoring ischemia may be related in part to dis- SPECT can also be used to track changes in myocardial
similarities in the provoking stimuli. Episodes of ambulatory ischemia after medical therapy as well as after mechanical
ischemia often occur during sedentary activity and can be revascularization.109
provoked by stressors as diverse as mental stress,68,85 cold
exposure,69 or cigarette smoking.86 Psychological stressors,
Relation Between Ambulatory
especially situations that trigger emotional distress, cause
Electrocardiographic Monitoring and
increases in heart rate and blood pressure and may also
Myocardial Perfusion Imaging
trigger coronary vasoconstriction.87–89 In addition, in patients
who have painless ischemic responses on ambulatory ECG, As mentioned above, ambulatory electrocardiographic
ischemia induced during exercise testing may be accompa- changes in a patient with CAD may not necessarily represent
 silent ischemia 705
active ischemia. In the Asymptomatic Cardiac Ischemia previously unidentified group of patients. The frequency
Pilot (ACIP) study, 106 patients with recent coronary angi- with which ischemia is detected and the outcomes of patients
ography underwent both AECG monitoring and stress SPECT with silent ischemia are likely to depend on the extent of
within 3 days. Seventy-four percent of patients with signifi- ischemic myocardium as well as other characteristics such
cant CAD had SPECT abnormalities, whereas 61% had isch- as age, ventricular function, and the clinical setting in which
emia detected by AECG monitoring. The most important the effort to detect ischemia is undertaken. In addition, the
predictors of SPECT abnormalities were the severity of diagnostic techniques used to detect ischemia are likely to
coronary stenosis, followed by total exercise duration, and differ depending on the clinical setting. For these reasons,
patient age. The only predictor of AECG abnormalities was conclusions concerning silent ischemia are likely to differ
the presence of ST depression on the initial treadmill test. among ambulatory patients in whom the presence of CAD
The concordance observed between the SPECT and AECG is uncertain, and patients who are hospitalized with acute
results was only 50%, and no relation was observed between coronary syndromes. Consequently, the subsequent sections
the frequency or duration of AECG ischemia and the quanti- of this chapter will consider patients with known CAD sepa-
fied myocardial perfusion defect size as assessed by SPECT. rately from those in whom the presence of coronary athero-
Thus, these techniques may detect different pathophysio- sclerosis has not been determined.
logic manifestations of ischemia and may be complementary
in more fully defining the functional significance of
Prognosis in the Patient with Known Coronary
CAD.80
Artery Disease
The Bypass Angioplasty Revascularization Investigation
Exercise and Dobutamine Stress Echocardiography
(BARI) trial offered a unique opportunity to follow patients
Exercise and pharmacologic stimulation with catecholamine with multivessel CAD systematically and serially following
derivatives increase cardiac contractility in normal subjects. revascularization. Protocol-mandated symptom-limited
Consequently, when normal segments of myocardium are exercise treadmill testing (ETT) was performed at 1, 3, and 5
visualized using echocardiography, hyperkinetic wall motion years after revascularization with either angioplasty or coro-
is observed. In patients with obstructive CAD and normal nary artery bypass surgery. At the time of the 1-year exercise
wall motion at baseline, ischemia becomes manifest as an test, 26% of patients had ST segment depression during exer-
abnormality of local wall contractility. Stress echocardiogra- cise; 82% of these patients did not report angina during
phy has been validated as a sensitive method of ischemia exercise testing; 69% (18% of the total) had angina neither
detection; however, the method of evaluating wall motion before nor during the test. Only 1% of patients who did not
during stress test depends on a semiquantitative visual eval- experience angina between the time of revascularization and
uation with a limited scoring scale of different grades of exercise testing required a further revascularization; more
dyssynergy.110,111 Despite this limitation, several studies have than half of these patients had a negative exercise test. Exer-
shown that stress echocardiography and SPECT have similar cise time at the 5-year test was associated with decreased
sensitivity in detecting ischemia, ranging from 58% and 61% survival 2 years after the test, but exercise parameters deter-
(with echocardiography and SPECT, respectively) for one- mined on the 1- and 3-year tests were poor predictors. This
vessel disease to 94% for three-vessel disease.112,113 The infu- study pointed out a selection bias that plagues all attempts
sion of dobutamine during stress echocardiography increases to relate stress-induced ischemia to clinical outcome: the
the degree of left ventricular dysfunction in patients with strongest predictor of survival was not the result of exercise
functionally significant coronary artery disease and thus testing, but whether patients were able to undergo exercise
may be a more sensitive indicator of ischemia.114 On the other testing at all. Mortality at 5 years was 25.9% in patients who
hand, as stressors are compounded, the degree to which this did not exercise compared with 8.1% in the group that did
intense combination of tachycardia and increased activity take the test. These results do not support routine stress
reproduces the stresses experienced by an individual during testing after revascularization for multivessel disease;
everyday life becomes questionable. Anginal chest pain is however, they do not exclude the use of other diagnostic
frequently induced in patients with stable coronary artery modalities in patients who are unable to undergo ETT due
disease during stress testing. However, following MI, pain to comorbid illnesses.116
during stress testing may not be associated as clearly with Details from the ROSETTA Registry provide further
an increased risk of adverse event compared with patients insight in relation to the risk of recurrent disease after a
who did not experience angina despite a similar extent of revascularization procedure. In this registry, 791 patients
CAD.115 who had undergone PCI were followed to determine the
difference in cardiac events between patients who received
“routine” (i.e., in the absence of angina) versus “selective”
Prognosis in Patients with Silent Ischemia (clinically determined) functional testing after revascular-
ization. After adjustment for baseline risk characteristics,
That asymptomatic episodes of ischemia occur in patients routine functional testing allowed prediction of a composite
with CAD is now established. Subsequently most attention of cardiac events at 6 months in patients who had undergone
has become directed toward determining the prognostic balloon angioplasty but not among patients who had under-
implications of silent ischemia, its utility at expanding the gone coronary stenting.117 The implication of these two
number of patients who can be identified as being at risk for studies is that in the initial period after revascularization,
catastrophic events, and the ability to extend therapy to a routine surveillance for ischemia in the asymptomatic
70 6 chapter 31

patient is likely to be fruitful only if the perceived risk of events and of cardiac death, 1.7- and 3.5-fold, respectively.
either graft failure or restenosis is high (e.g., after balloon Using men without ischemia as a reference group, there was
angioplasty without stenting or after placement of bare metal a clear relationship between the presence of risk factors and
stents over a long segment of coronary artery). However, the the likelihood of cardiac death during follow-up. Viewed in
longer-term implications are less clear, particularly in light of the preceding studies, it appears that the prognostic
patients with more severe disease or in patients who have information contained in the detection of silent ischemia
received saphenous vein grafts at the time of bypass surgery. increases as patients’ baseline risk increases.
When 356 patients recruited in a Dutch study underwent In one of the largest epidemiologic reports of silent
routine follow-up angiography and scintigraphic stress testing ischemia published to date (Reykjavik study), 9139 randomly
6 months after PCI, 62% of patients with target vessel reste- selected men were screened with a standard resting 12-lead
nosis were asymptomatic. Follow-up for 4 years revealed a ECG and followed for 4 to 24 years. Patients were categorized
risk gradient with the lowest risk for patients without isch- by the presence of ischemic symptoms and indications of
emia, greater risk of recurrent events in patients with silent ischemic heart disease on the resting ECG. The prevalence
ischemia, and the greatest risk in patients with symptomatic of ST-T changes (classified as ischemic by the Minnesota
ischemia.23 code) in the absence of angina among men without overt
coronary artery disease was strongly influenced by age,
increasing from 2% at age 40 years to 30% at age 80 years.
Prognosis in Asymptomatic Patients Without
Men with ST-T changes, but no symptoms were older and
Known Coronary Artery Disease
had higher serum triglyceride levels, more frequently were
Elhendy and associates118 evaluated the utility of exercise hypertensive, had left ventricular hypertrophy, and took
echocardiography in 1618 middle-aged patients (average age antihypertensive medications, digitalis, or diuretics. The
55 years with low risk for CAD based on a prespecified serum cholesterol level did not differ between the two groups.
algorithm). In this very low risk cohort, the rates of cardiac After adjustment for other risk factors, the risk ratio among
mortality and nonfatal MI were 0.1 and 0.25 per 100 person- men with silent ST segment shifts was 2.0 for death from
years, respectively. In models used to predict cardiac events CAD and 1.6 for subsequent MI in men with these ST changes
using clinical variables, exercise stress variables, and echo- when compared with asymptomatic men with no evidence
cardiography variables in a sequential fashion, none of the of exercise-induced alterations in the ST segment.121 Although
exercise ECG features predicted future cardiac events. the prognostic value of stress testing in women has also been
Changes in the wall motion score index predicted outcome; assessed,122,123 there are currently no data to indicate whether
however, over half of the patients with subsequent cardiac the frequency or prognosis of silent ischemia differs accord-
events did not have abnormal stress echocardiographic ing to sex.
results. Taken in aggregate, these findings call into question
the routine use of exercise testing to screen low-risk asymp-
Ambulatory Electrocardiographic Monitoring,
tomatic patients.
Exercise Stress Test, and Prognosis
Marwick and associates119 evaluated the utility of exer-
cise stress echocardiography for predicting mortality in a The prognosis associated with asymptomatic myocardial
cohort of 1859 patients without angina or other evidence of ischemia detected using electrocardiographic means also
CAD. Only four (0.2%) patients developed angina during appears to be related to the overall clinical risk group
exercise and 215 (12%) patients developed ST-segment depres- from which patients are selected. Ambulatory electrocardio-
sion during exercise, indicating that the vast majority of graphic findings in patients hospitalized in a coronary care
ischemic episodes in this cohort were silent. Overall annual- unit with unstable rest angina are associated with a high
ized mortality was 0.9%, with annualized cardiac mortality likelihood of impending MI. On the other hand, studies in
of 0.2%. Although ischemia detected by stress echocardiog- patients with stable manifestations of CAD tend to indicate
raphy was a predictor of mortality at an average of 4.7 years, that the risk associated with silent myocardial ischemia
multivariate analysis revealed that only resting ejection frac- is more questionable. Quyyumi and colleagues81 studied
tion and Duke treadmill score (annualized mortality 2% for patients with CAD categorized as low risk (i.e., excluding
an intermediate- or high-risk score and 0.4% for patients patients with left main disease, three-vessel disease with left
with a low-risk score) were predictive of outcomes. These ventricular dysfunction at rest, three-vessel disease with
findings suggested that in a group with a low a priori risk of inducible ischemia, two-vessel disease with impaired left
cardiac events, the detection of silent ischemia provides little ventricular function, and inducible ischemia). Among these
prognostic information. “low-risk” patients, 39% had ST depression during AECG
A clearer perspective on the relation of basal risk to the monitoring; 82% of those episodes were asymptomatic,
prognostic value of silent exercise-induced ischemia comes which, however, did not predict higher risk for cardiac events
from the Kuopio Ischemic Heart Disease (KIHD) risk factor in the future.
study. Laukkanen and associates120 performed bicycle ergome- In a retrospective analysis of 1402 patients with ECG
try on 1769 asymptomatic middle-aged men with a broad evidence of ischemia during treadmill testing, Cole and Elle-
spectrum of known risk factors for CAD. Eleven percent of stad124 reported that coronary events (cardiac death, MI, or
participants had silent ischemia during exercise and an addi- progression of angina) were twice as frequent in patients
tional 3.1% had silent ischemia after exercise. After adjust- with symptomatic ischemia than those with silent ischemia.
ing for conventional risk factors, men with silent ischemia In reviewing the 5-year outcome of 842 consecutive patients
during exercise had an increased risk of acute coronary in the Duke Cardiovascular Database who had angiographi-
 silent ischemia 707
cally documented coronary disease and abnormal exercise noting that several investigators have established that the
test results, Mark et al.58 found that patients with silent size of an ischemic defect is a critical determinant of outcome,
ischemia during exercise testing had significantly better independent of symptoms.129
overall survival and infarct-free survival rates than did
patients with angina. Similarly, among 1773 veteran patients
referred for treadmill testing, a difference in mortality at Treatment of Silent Myocardial Ischemia
2 years was observed based on the development of angina
during exercise.125 While the treatment of ischemia for the purpose of relieving
The importance of asymptomatic ischemia on exercise angina or dyspnea has been established for several decades,
testing after MI is often debated. Villella et al.126 studied 6296 the management of asymptomatic ischemia has been a
patients undergoing an exercise test an average of 28 days matter of greater controversy. Only recently as revasculariza-
after intravenous thrombolytic therapy for a myocardial tion techniques, particularly percutaneous coronary inter-
infarction. Residual ischemia was detected in 26% of patients, ventions with the use of drug-eluting stents, have been
of whom 67% were asymptomatic. The 6-month mortality refined, and the results become more robust, has consensus
was 1.7% for those with a positive test, 0.9% for those who been reached about the use of revascularization strategies to
had a negative test, and 1.3% for patients whose test was not treat ischemia in the asymptomatic patient.
diagnostic. After adjustment for myocardial ischemia accom- The ACIP trial was designed as a pilot study to determine
panied by symptoms of angina, only symptomatic induced precisely whether suppression of silent ischemia was possible
ischemia and low-work capacity were associated with an using one of three strategies: angina-guided medical therapy,
increased risk of death at 6 months, although asymptomatic ischemia-guided medical therapy, or revascularization using
ischemia was not. Even after analysis of silent ischemia by balloon angioplasty or bypass surgery. Patients selected for
the occurrence of ST-segment depression at maximal or sub- this study had evidence of myocardial ischemia on both
maximal levels of exercise or on the degree of ST-segment ambulatory and exercise treadmill testing. Ischemia sup-
depression, exercise-induced asymptomatic myocardial isch- pression after a period of 12 weeks using medical therapy
emia was not significantly associated with a higher risk of was performed using one of two regimens: (1) atenolol and
death compared with exercise stress testing with negative nifedipine, or (2) diltiazem and isosorbide dinitrate. With a
results. The ability to exercise for more than 6 minutes was regimen of atenolol and nifedipine, ischemic changes on the
a predictor of good prognosis regardless of the associated AECG could be suppressed in 47% of patients. In the group
ECG changes. treated with diltiazem and isosorbide dinitrate, ischemia
The Asymptomatic Cardiac Ischemia Pilot (ACIP) trial was suppressed in 31% of patients. In the medical therapy
contributed significantly to our understanding the impor- group, the average doses (combined ischemia- and angina-
tance of silent ischemia.127 Conti et al.127 compared the guided therapy) of each medication at 12 weeks were as
outcome of patients who had angina either within the 6 follows: atenolol 84 mg, nifedipine 34 mg, diltiazem 91 mg,
weeks prior to enrollment or during the period of the study. and isosorbide dinitrate 36 mg. Thus, the degree of medical
These investigators reported that symptomatic patients in therapy can be described as moderately intense. The degree
ACIP had a higher incidence of death, MI, or hospitalization of ischemia suppression was similar in the ischemia- and in
for ischemic events (15.3% symptomatic vs. 7.8% asymptom- the angina-guided groups. The revascularization strategy led
atic per 12 months). Interestingly, this difference was present to suppression of ischemia in 70% of patients having bypass
mainly in patients who had angina within the 6 weeks pre- surgery versus 46% of patients undergoing angioplasty. It is
ceding the study period. Unlike patients who were symptom- likely that the prevalent use of drug-eluting stents would
atic during the period of recruitment, patients with angina increase the latter figure significantly.
occurring only during AECG or stress testing were not found The findings of other trials have been similar. In CASIS,
to have a higher incidence of adverse cardiac events than patients were selected according to the presence of ischemia
asymptomatic patients.128 during treadmill testing and ambulatory monitoring and
subsequently were assigned to receive either atenolol or
amlodipine. Each group underwent a counterbalanced, cross-
Nuclear Imaging and Prognosis
over evaluation of single drug and placebo, followed by evalu-
In recent years, tomographic myocardial scintigraphy has ation of the combination. Suppression of ischemia during
gained acceptance as the most widely used and reliable exercise testing and ambulatory monitoring was similar in
measure of the quantity of myocardium that is ischemic. patients with and without exercise-induced angina. Exercise
Consequently, the relationship between ischemic defect size time to angina improved by 29% with amlodipine, 16% with
and prognosis has recently garnered much attention. There atenolol, and 39% with combination therapy. Similarly in
is consensus that, viewed on the background of other risk the ASIST trial, after 4 weeks of treatment with atenolol of
factors for mortality, the size of the ischemic defect is related patients with Canadian Cardiovascular class I or II angina,
to the likelihood of suffering a cardiac event. Reports from the number and duration of ischemic episodes on ambulatory
several large nuclear laboratories indicate a largely dichoto- ECG decreased significantly compared with placebo.104 In a
mous relationship. Defects exceeding 15% to 20% of the similar study, Frishman and colleagues130 were able to sup-
myocardium are associated with a significantly higher likeli- press ambulatory ischemia as well as exercise-induced isch-
hood of catastrophic events at 1 to 2 years than are smaller emia using a long-acting preparation of verapamil, atenolol,
defects. While the concept that the quantity of myocardium or amlodipine. In a smaller study, Dakik et al.109 compared
at risk determines a patient’s outcome is not new, it is worth intensive medical therapy to percutaneous revascularization
70 8 chapter 31

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undergoing serial exercise thallium-201 tomography. Am J 121. Sigurdsson E, Sigfusson N, Sigvaldason H, Thorgeirsson G.
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R. Exercise-induced silent ischemia: age, diabetes mellitus, pre- 130. Frishman WH, Glasser S, Stone P, Deedwania PC, Johnson M,
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 3 Coronary Disease
2 in Women
Allen P. Burke, Frank D. Kolodgie, and
Renu Virmani

Epidemiology of Coronary Disease in Women . . . . . . . . 713 Physiology of Coronary Disease in Women . . . . . . . . . . 718
Risk Factors for Coronary Artery Disease Postmenopausal Hormone Replacement Therapy
in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 and Risk of Coronary Disease . . . . . . . . . . . . . . . . . . 719
Clinical Features of Coronary Heart Disease Pathology of Coronary Disease in Women . . . . . . . . . . . 720
in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724

Key Points trends in the traditional coronary risk factors, with a decrease
in cigarette smoking and improvement in diet and lipids. In
• There are pathologic and physiologic differences in coro-
this study, an increase in postmenopausal hormone replace-
nary artery disease in women as compared to men.
ment therapy was considered beneficial. However, the preva-
• Hormone replacement therapy: failure of a promise?
lence of overweight, defined as a body mass index (BMI) of
• Risk factors: do they have the same impact in women as
25 or more, increased by 38%. Therefore, obesity-related mor-
in men with coronary disease?
bidity, including metabolic syndrome and type 2 diabetes,
• Small vessel coronary disease plays a role in women.
appears to be increasingly important as a coronary risk factor
• Plaque erosion is important in premenopausal women.
in women.2
In approximately 50% of patients, the first manifestation
Epidemiology of Coronary Disease in Women of coronary heart disease (CHD) is sudden death. Sudden
cardiac death occurs in more than 300,000 persons per year
Cardiovascular disease remains the number one cause of in the United States and is the most frequent cause of death
mortality for women in the United States, and coronary in the industrialized world. The most frequent cause of
artery disease accounts for more than half of cardiovascular sudden death is coronary artery disease, which is thought to
deaths. Coronary artery disease results in the deaths of more be a male-predominant disease.3 Data from the Framingham
than 250,000 women each year and is therefore the single study show that sudden death in women lags behind men by
largest killer of American women. For several decades, the almost 20 years, somewhat longer than the lag period of
underrepresentation of women in clinical trials led to a acute coronary syndromes. The annual sudden death rate in
general misconception that coronary artery disease was women is approximately half that in men for all ages com-
mostly a disease of men. Epidemiologic studies focusing on bined. Only 94 of 2873 women died suddenly compared with
women have demonstrated that they are indeed vulnerable 230 of 2336 men of comparable age.4 The incidence of sudden
to coronary atherosclerosis, but that it typically develops 10 death in men and women increases with age, approximately
to 15 years later than in their male counterparts. Although doubling with each decade of age in women. In both sexes
controversial, many studies suggest that sex differences exist 26% of deaths occur in persons without overt CHD. In
in the mortality rates of ischemic heart disease, with women women, 63% of death occurred in the absence of prior CHD
having a worse prognosis, possibly due to delayed diagnosis. compared with 44% in men. Of the CHD deaths in men and
Consequently, early and accurate diagnosis of coronary women, 76% were sudden deaths. In men with prior CHD,
artery disease is crucial for reducing mortality rates in 34% of deaths were sudden as compared with 16% in women.4
women.1 Thus it appears that coronary sudden death is less frequent
The Nurses’ Health Study has tracked cardiovascular in women than in men, but it is more likely to occur in
disease in women with data available through 1994. From women without prior coronary disease.
1980 to 1992, there was a 31% decrease in the incidence of While similar mechanisms operate to induce coronary
coronary disease. During this period, there were positive artery disease in women and men, gender-related differences

713
714 chapter 32

exist in the anatomy and physiology of the myocardium, and CHD in women with type 2 DM.14 Cigarette smoking is
sex hormones modify the course of disease in women. The strongly associated with an increased risk of CHD among
morphologic basis for the clinical differences between men women with type 2 DM, and quitting smoking seems to
and women with acute coronary syndromes remain unclear, decrease this excess risk substantially.15
but ongoing studies are providing valuable data that will Dietary factors may mitigate the risk of coronary disease
refine in the future gender-based treatment strategies for a in diabetic women. A higher consumption of fish and long-
highly prevalent disease. chain omega-3 fatty acids was associated with a lower CHD
incidence and total mortality among diabetic women.16 Mod-
erate alcohol consumption was associated with reduced CHD
Risk Factors for Coronary Artery Disease risk in women with diabetes.17
in Women
Dietary Factors
The usual risk factor for coronary artery disease, cigarette
smoking, diabetes mellitus, hypertension, dyslipidemia, In the Nurses’ Health Study, frequent nut consumption was
obesity, sedentary lifestyle, and poor nutrition, are similar associated with a reduced risk of both fatal CHD and nonfa-
in women and men. In general, women with unstable angina tal myocardial infarction in women.18 Consumption of fish
and non–Q-wave myocardial infarction are, in comparison is associated with a significantly reduced progression of coro-
to men, older, less frequently white, and have a higher inci- nary artery atherosclerosis in women with coronary artery
dence of diabetes and hypertension.5 disease.19 In a different study, no protective effect of dietary
phytoestrogens (isoflavonoids and lignans) was demonstrated
in women against cardiovascular disease risk, although a
Diabetes
small risk reduction with higher lignan intake was suggested
Obesity and sedentary lifestyle in the United States have for smokers.20
been linked to increased risk of coronary artery disease in
men and women. The prevalence of obesity has increased in
Body Mass Index/Metabolic Syndrome
the last decade and it is estimated that currently 30% to 40%
of adult women are obese.2 In the Nurses’ Health Study, the Obesity and metabolic syndrome are interrelated risk factors
multivariate relative risks of fatal CHD across categories of for coronary disease in women. The influence of BMI on
diabetes duration (up to 25 years) ranged from 2.75 to 11.9, cardiovascular disease in women may be greater than previ-
compared with nondiabetic women.6 ously thought, with increased adverse outcomes even at
Diabetes mellitus is a more significant risk factor for the moderately increased body weight.21 In a recent prospective
presence and severity of CHD in women than in men. Women study, however, the metabolic syndrome, but not BMI, pre-
appear to be at particularly high risk as the gender advantage dicted future cardiovascular risk in women.22
for CHD is counterbalanced by an increased incidence of In women with suspected myocardial ischemia, the met-
obesity and diabetes.7 Diabetes is linked to both hyperlipid- abolic syndrome modifies the cardiovascular risk associated
emia and obesity in men and women but especially in with angiographic coronary disease. In one study, the meta-
women.8,9 In a recent meta-analysis, the relative risk of coro- bolic syndrome was found to be a predictor of 4-year car-
nary death from diabetes was 2.58 [95% confidence interval diovascular risk only when associated with significant
(CI) 2.05–3.26] for women and 1.85 (1.47–2.33) for men; the angiographic coronary artery disease.23 Although weight loss
difference was statistically significant (p = .045).10 should be advised in overweight and obese women, control
There is evidence that the role of diabetes as a risk factor of all modifiable risk factors in both normal and overweight
for coronary artery disease in women is influenced by race. persons to prevent transition to the metabolic syndrome
The population-attributable risk of CHD incidence associ- should be considered the ultimate goal.
ated with a medical history of diabetes has been calculated There are measures of obesity other than simple BMI that
at 8.7% in African-American women, compared to 6.1% in have been espoused in assessing coronary risk in women.
American women of European background. A history of dia- The waist/hip ratio and waist circumference have been inde-
betes was a significant predictor of CHD incidence and mor- pendently associated with risk of coronary disease in
tality in African-American women and explained some of women.24 Also known as the hypertriglyceride waist,
the excess coronary incidence in younger African-American increased waist/hip ratio is associated with increased coro-
compared to American women of European background.11 In nary risk factors among women.25 In a forensic autopsy study
Australia, aboriginal women with diabetes experience a sig- in women with preclinical atherosclerosis, the coronary
nificantly higher risk of CHD than women without diabetes, intima–media thicknesses were highest with increased
and women with diabetes had a higher CHD risk than men amounts of intraperitoneal fat, a reflection of the waist/hip
with diabetes.12 ratio.26
There is a complex interaction between diabetes and As with diabetes, there is an interplay between measures
other risk factors for coronary disease in women. Obesity of obesity and metabolic syndrome and other traditional risk
enhances the risk of CHD among women with type 2 diabe- factors. Smoking adversely affects insulin secretion (β-cell
tes mellitus (DM), especially when it precedes the diagnosis function) and whole blood viscosity in postmenopausal
of overt diabetes.13 Increased insulin resistance in associa- women with established coronary artery disease, which
tion with elevated plasminogen activator inhibitor-1 (PAI-1) could be of importance as a mechanism for the increased risk
and dyslipidemia appears to underpin the increased risk of in female smokers.27
 corona ry dise a se i n wom en 715
TABLE 32.1. Mechanism of death and risk factors in 51 women who died suddenly from severe coronary artery disease
Mechanism of death (n) Age >50 years, % Total cholesterol, mg/dL Body mass index Glycohemoglobin, mean % Cigarette smokers, n (%)

Plaque erosion (18) 3 (17%) 191 ± 68 27 ± 4.3 6.7 ± 0.7 14 (78%)

Plaque rupture (8) 7 (87%)* 272 ± 61* 31 ± 4.4* 8.8 ± 4.4 4 (50%)
Stable plaque, no 2 (29%) 178 ± 57 30 ± 10.6 8.0 ± 4.5 2 (29%)
infarct (7)
Stable plaque, 9 (50%) 198 ± 61 28 ± 9.0 10.2 ± 5.0* 9 (50%)
healed infarct (18)
p value *.001 vs. plaque *.01 vs. stable plaque; *.02 vs. eroded *.001 vs. eroded plaque
erosion; .03 vs. .01 vs. stable plaque, plaque
stable plaque, no healed infarct; .02 vs.
infarct plaque erosion

Hypertension elevated levels of lipoprotein (a) [Lp(a)] (>500 mg/L) was found
to be an important risk factor for CHD in both black and
Epidemiologic studies have documented a strong association white women.32 However, the importance of smoking as a
between high blood pressure (systolic and diastolic) and risk risk factor, overrides the effect of Lp(a), which is lower in
of CHD in men and women. In women >45 years of age, 60% smokers compared with nonsmokers.27
of whites and 79% of blacks have hypertension. After adjust- In contrast to prior data among hyperlipidemic men, the
ing for other risk factors, 29% of CHD events in women (>30 current data suggest that lipoprotein associated phospholi-
years) were attributable to blood pressure levels that exceed phase A2 [Lp-PLA(2)] is not a strong predictor of future car-
high normal (>130/85 mm Hg).28 diovascular risk among unselected women.33

Smoking
Dyslipidemia
More than 50% of myocardial infarctions among middle-
In contrast to men, women show only a weak association of aged women are attributable to cigarette smoking.34 It has
total cholesterol and low-density lipoprotein (LDL) levels been reported that the excess risk for CHD in women from
with CHD.29 However, high-density lipoprotein (HDL) cho- smoking was two- to fourfold and was similar to that in
lesterol is closely and inversely associated with CHD risk in men.35 The evidence associating cigarette smoking, elevated
women. Triglycerides are an independent predictor of coro- serum cholesterol, and high blood pressure and coronary
nary artery disease in older women but not in men.15,29 disease in women is strong.36
However, more current data support recommendations for
aggressive lipid lowering in women with existing CHD, or
Plaque Morphology and Classic Risk Factors
who are at risk for developing CHD.30
Other serum lipid components have been demonstrated Clinical studies relating risk factors and coronary disease in
as potential risk factors for atherosclerotic heart disease in women cannot take into account plaque morphology and the
women. In a cross-sectional study, women with CHD had morphologic heterogeneity of coronary atherosclerosis. In an
higher plasma concentrations of apolipoprotein B100 (apoB), autopsy study of sudden coronary death, coronary plaque
as well as total cholesterol, LDL cholesterol, triglycerides, morphology was related to risk factors in 51 sudden coronary
and lower levels of HDL cholesterol. In this study, apoB was deaths in women (mean age 50 ± 12 years) and compared to
superior to other lipids in discriminating between women 15 women (mean age 50 ± 19 years) who died a traumatic
with and women without coronary disease.31 Because of this death (Tables 32.1 and 32.2).37 The risk factor analysis was
association, measurement of apoB has been recommended as performed in all cases at autopsy. The postmortem serum
a screening risk factor especially in women. In another study, was evaluated for total cholesterol (TC), HDL cholesterol,

TABLE 32.2. Multivariate association between risk factors and morphology of culprit plaque in 51
women, compared to 47 noncoronary deaths (trauma and cardiac noncoronary)
Multivariate

Risk factor Plaque morphology p (univariate) Z p Odds ratio

Total cholesterol, mg/dL Rupture <.0001 3.0 .002 31

Cigarette smoking Erosion .003 2.5 .01 16
Glycosylated hemoglobin >8 Stable plaque .001 2.8 .006 7.1
Hypertension Stable plaque .006 2.3 .02 4.0
716 chapter 32

and thiocyanate levels. Smokers were identified as those levels, by univariate analysis, was associated with risk in
with a thiocyanate level of >90 mg/dL. Glucose intolerance women nurses.45 An independent relationship between serum
(diabetic screen) was determined by red blood cell glycosyl- A amyloid and angiographic coronary artery disease was
ated hemoglobin, and hypertension was assessed by renal established in women, greater than that for CRP.49 There is
vascular morphometric analysis. Compared with control evidence that plasma fibrinogen is associated with an excess
subjects, women with plaque ruptures had elevated TC (270 risk of heart disease in women.50 Confounding the relation-
± 55 vs. 194 ± 44 mg/dL, p = .002), and those with erosions ship between inflammatory markers and risk of heart disease
were more likely to be smokers (78% vs. 33%, p = .01). in women is the finding that there are independent relation-
Women with stable plaque and healed infarct had elevated ships between levels of interleukin-6 (IL-6) and age, BMI,
glycosylated hemoglobin (10.2% ± 5.0% vs. 6.4% ± 0.4% in smoking, systolic blood pressure, alcohol use, presence of
control subjects, p = .001) and were more likely to be hyper- diabetes, and frequency of exercise.51
tensive (50% vs. 15% in control subjects, p = .03). By multi- A study evaluating women for suspected ischemia in the
variate analysis, cigarette smoking was associated with absence of acute myocardial infarction or congestive heart
plaque erosion [p = .03, odds ratio (OR) 21], glycosylated failure has found that lower hemoglobin levels are associated
hemoglobin with stable plaque and healed infarct (p = .03, with higher risk for adverse cardiovascular outcomes.52
OR 41), total cholesterol with plaque rupture (p = .02, OR 7),
and hypertension with stable plaque with healed infarct (p =
.02, OR 15). Effective risk factor modification is therefore Clinical Features of Coronary Heart Disease
essential in women, as in men, in reducing the risk of sud- in Women
den coronary death, due to a variety of morphologic
substrates.37
Symptoms and Diagnosis
Genetic Risk Factors Women, especially those who are premenopausal, may expe-
rience symptoms of myocardial ischemia differently from
Hereditary factors as well as multiple risk factors are essen-
men, leading to underdiagnosis or misdiagnosis. Atypical
tial when coronary artery disease is expressed in women.38
chest symptoms occur more frequently in premenopausal
The genetics of coronary artery disease has been studied in
women than in postmenopausal women with or without
the context of single nucleotide polymorphisms in both men
hormone replacement therapy.53
and women, in cross-sectional studies. In one study from
Women, more than men, have their initial manifesta-
Japan, diabetes and smoking were the two classic risk factors
tion of CHD as stable or unstable angina, as opposed to
most strongly associated with heart disease in women; in
sudden death or acute myocardial infarction. In addition,
addition, two polymorphisms (the replacement of four gua-
they are likely to be referred for diagnostic tests at a more
nines with five guanines at position –668 in the PAI-1 gene
advanced stage of disease.54 In a large study from Sweden,
and the replacement of five adenines with six adenines at
comprising men and women transported by ambulance to
position –1171 in the stromelysin-1 gene) were associated
an acute care center with symptoms that raised the suspi-
with a significant risk of myocardial infarction.39 In another
cion of coronary artery disease, women were older than
Japanese study, the –11751/5A→6A SNP (6-SNP-single nucle-
men, and had a lower incidence of previous acute myocar-
otide polymorphism) of the stromelysin-1 gene [matrix metal-
dial infarction, angina pectoris, and current smoking.
loproteinase-3(MMP-3)] was significantly associated with
Among those patients with an acute coronary syndrome,
CHD in low-risk women, and the 3932T→C SNP of APOE
women more frequently complained of dyspnea than men,
gene was associated with CHD in high-risk women.40
and were less frequently described as clammy. Even though
Observational cross-sectional studies have shown that
women were less frequently diagnosed with an acute coro-
short legs in women, in relation to body height, are associ-
nary syndrome (22% vs. 37%) or acute myocardial infarc-
ated with coronary artery disease.41 The reason for this obser-
tion (10% vs. 18%), and less frequently showed signs of
vation, which presumably has a genetic basis, is unknown.
myocardial ischemia on the electrocardiogram (ECG) upon
admission to the emergency department, the mortality rate
Inflammatory Markers
at 1 year was the same in women (17.2%) and men (18.7%).55
Serum levels of high-sensitivity C-reactive protein (hsCRP) These results raise the suspicion that women may be under-
have been found to be a better predictor of coronary artery diagnosed with coronary disease, or that other factors such
disease than LDL in young women.42,43 These observations as microvascular disease may be the basis for coronary
have been expanded to older women as well.44 More recent symptoms in women.
studies, however, have emphasized the importance of plasma The diagnostic information from an ECG taken while the
lipids in assessing coronary risk in women, beyond that of patient is at rest and after exercise is considered less reliable
inflammatory markers.45,46 in women than in men. However, this lack of reliability is
Serum CRP levels have been used in conjunction with mostly due to a high percentage of false-positive tests
other risk factor markers in women. Serum hsCRP adds explained by a lower prevalence of CHD. In postmenopausal
clinically important prognostic information to the metabolic women with signs of unstable angina and ischemia on an
syndrome.47 Lp-PLA(2) and CRP may be complementary in ECG taken while at rest, the prevalence of coronary athero-
identifying middle-age men and women at high risk.48 sclerosis is high—85%. Although there is controversy regard-
Other inflammatory markers have been used as risk ing the sensitivity of ECG changes in postmenopausal
factors for CHD in women. Tumor necrosis factor-α receptor women, ST-T changes at the early exercise test has been
 corona ry dise a se i n wom en 717
shown to have a high positive predictive value, especially in differences between coronary atherosclerotic plaques in
combination with a low maximum workload.56 pre- and postmenopausal women, and between men and
The sensitivity of stress myocardial perfusion studies is women in general, have been only incompletely studied
similar in men and women with angiographically docu- (see below).59
mented coronary artery disease.57 In addition, adenosine
stress testing with single photon emission computed tomog-
Prognosis and Treatment
raphy has comparable incremental value for prediction of
cardiac death in women and men and is equally informative The prognosis in women with coronary artery disease is
for subsequent invasive management decisions in both generally considered poorer than that of men. The overall
genders.58 morbidity and mortality following the initial ischemic heart
event is worse in women, and the case fatality rate is greater
in women than in men.54 At 1-year following initial catheter-
Syndrome X
ization, men report significantly better health-related quality
Cardiac syndrome X, a condition defined by the presence of of life than women undergoing treatment for coronary artery
angina-like chest pain, a positive response to stress testing, disease.60
and normal coronary arteriograms, has been shown to occur It is unclear whether the relatively bad prognosis in
in approximately 20% to 30% of angina patients undergoing women is the result of late diagnosis, less aggressive treat-
coronary arteriography. The prevalence of syndrome X is ment, or inherent differences in pathophysiology. In a large
significantly higher in women than in men. Syndrome X is multicenter trial in the mid-1990s, women hospitalized with
likely a heterogeneous process, and the morphologic basis for acute myocardial infarction were older than men (66 vs. 58
the syndrome is largely unknown. In the majority of patients years, p < .0001), more likely diabetic (19% vs. 10%, p = .03),
with chest pain and normal coronary arteriograms, symp- more frequently hypertensive (54% vs. 39%, p = .005), more
toms may be noncardiac in origin, or result from small vessel likely to have a history of prior congestive heart failure (5%
disease. The proportion of women with angina, normal coro- vs, 0%, p = .002), and presented later after symptom onset
nary angiograms, and undiagnosed epicardial disease (false- (229 vs. 174 minutes, p = .0004). The in-hospital mortality
negative angiograms) is not clear (Fig. 32.1). The morphologic in women was 3.3-fold higher than in men (9.3% vs. 2.8%,

A B

C D

FIGURE 32.1. Cross sections of epicardial coronary arteries from a in the left anterior descending). There are multifocal areas of sig-
56-year-old woman who died 1 day after coronary angiography with nificant stenoses at autopsy. (A) Proximal left anterior descending.
severe necrotizing bronchopneumonia. Coronary angiography dem- (B) Left diagonal. (C) Proximal right coronary. (D) Proximal left cir-
onstrated no significant stenosis (focal narrowing of less than 25% cumflex artery.
718 chapter 32

p = .005), but after adjustment for comorbid baseline charac- There is no doubt that women fare worse than men after
teristics, only advanced age independently correlated with coronary artery bypass graft surgery. The reasons for women’s
mortality. Such data suggest that the gender difference in bad prognosis stem from anatomic differences (smaller native
prognosis is related to lack of timely care and control of risk coronary arteries), a lower number of anastomoses, and a
factors. lower internal thoracic (mammary) artery availability.
There is less consensus on gender differences in prognosis Women have a higher 12-month mortality (14% in women
after coronary interventions. Concerns about possible sex- vs. 6% in men), and higher morbidity in terms of readmis-
related complications should not dissuade physicians from sions, angina symptoms, antianginal drug use, and effort
performing percutaneous interventions when clinically indi- tolerance.72 The higher hospital mortality and morbidity in
cated in women. After angioplasty performed for unstable women undergoing coronary surgery are partially related to
angina and rest pain, survival rates in two separate studies the severity of coronary atherosclerosis and comorbid condi-
were shown to be excellent in both women and men, without tions.73 Diabetes is an especially bad prognostic factor in
gender bias in subsequent myocardial infarction rates. During women undergoing coronary artery bypass grafting, and is
follow-up, however, women were more likely to have severe more prevalent in women.74 Although there is no doubt that
angina and were less likely to have had coronary artery early mortality is significantly higher for women after coro-
bypass grafting.61,62 In a recent study of primary percutaneous nary artery bypass graft surgery, long-term relative mortality
intervention, women had a higher 30-day mortality, but this risk for women is similar to that of men.75 Both men and
was based on increased age, a higher incidences of comorbidi- women improve in physical, social, and emotional function-
ties, and longer times of reperfusion.63 Other data suggest, ing after surgery, and recovery over time is similar in men
however, that women have more adverse in-hospital out- and women. However, women’s health-related quality-of-life
comes after percutaneous transluminal coronary angioplasty scale scores remained less favorable than men’s through 1
and stenting compared with men. Data from the Nationwide year after surgery.76
Inpatient Sample demonstrated that in 1997, women had a Information on the relative benefit of coronary artery
roughly twofold higher mortality than men in every compari- bypass grafting versus stent-assisted percutaneous coronary
son group, including conventional angioplasty alone and intervention for improvement of cardiac-related health status
stents, and significantly higher coronary artery bypass graft in women and how it compares with men is limited. In the
rates than men whether or not there was acute myocardial Stent or Surgery Trial, 206 women and 782 men with multi-
infarction at the time of presentation.64 In the fragmin during vessel disease were randomized to surgery and percutaneous
instability in coronary artery disease (FRISC) study, an early coronary intervention (PCI). At 1 year after intervention,
invasive strategy in women with unstable coronary syn- both procedures appeared equally effective in women,
dromes did not reduce the risk of future events, unlike that although surgery was clearly superior in men.77 The type of
in men.65 The benefit of an early invasive strategy incorporat- bypass surgery may play a role in women’s prognosis. Evi-
ing intracoronary stents in women with unstable coronary dence suggests that off-pump coronary artery bypass graft
artery disease has been more recently espoused, however.66 (CABG) surgery may be better for women than on-pump
Among patients with acute myocardial infarction ran- CABG surgery because it appears to reduce mortality and
domized to thrombolytic therapy, mortality and intracranial respiratory complications, shorten the time of hospitaliza-
bleeding was significantly higher in women than in men. In tion, and increase discharges directly home.78
contrast, women and men had similar in-hospital mortality In patients requiring emergent surgery after percutane-
after randomization to primary angioplasty.67 More recently, ous angioplasty, a Kaplan-Meier model with follow-up aver-
women and men presenting with an acute ST-segment eleva- aging 5.3 years, showed a markedly increased in-hospital
tion myocardial infarction were randomized to receive either mortality in women compared to men (p = .003), but a com-
direct angioplasty or accelerated tissue plasminogen activa- parable long-term survival.79 In this study, women had an
tor. Although the relative benefit of direct angioplasty to increased initial risk for failure of angioplasty, although
thrombolytic treatment appeared to be similar in women gender was not found to be an independent predictor of post-
and men, women derived a larger absolute benefit from direct operative death.79
percutaneous intervention with stenting.68
In a more recent study of women receiving coronary
stents, they are over twice as likely as men to have proce- Physiology of Coronary Disease in Women
dural failure or complications and suffer hospital mortality.
However, the increase in female morbidity may largely be
Sex Hormones and Vascular Disease
due to more adverse baseline characteristics, and long-term
event-free survival and restenosis rate are similar in men and Much of the research in the pathophysiology of coronary
women.69 An Israeli study showed that coronary stenting has disease in women stems from observations noting differ-
similar success rates among women and men, with similar ences in pre- and postmenopausal disease. Although these
restenosis rates as well as early and late major adverse cardiac differences likely have a hormonal basis, it has been demon-
events.70 In another study, in which women were older and strated that a large part of the increased risk for coronary
with a higher incidence of comorbidities and more unstable artery disease in postmenopausal women versus perimeno-
presentation, women treated with coronary stenting showed pausal women stems from a great increase in traditional risk
acute and midterm clinical results similar to those observed factors as age progresses.80 However, qualitative differences
in men, but were significantly more likely to develop angio- in the clinical and pathologic expression of coronary disease
graphic restenosis.71 in premenopausal women cannot be ignored.
 corona ry dise a se i n wom en 719
Estrogens have in vitro vasodilatory effects, and have pain but without obstructive coronary artery disease (consti-
been shown to improve dilator responses of atherosclerotic tuting syndrome X patients) have stress-induced reduction in
coronary arteries in monkeys.81 Estrogen’s effects on vas- myocardial phosphocreatine-adenosine triphosphate ratio by
cular reactivity have been used to explain the symptoms phosphorus 31 nuclear magnetic resonance spectroscopy
of syndrome X in postmenopausal women, and justify the (MRS), consistent with myocardial ischemia.89
use of hormone replacement therapy, especially in such Women with angina and normal epicardial coronary
women. Estrogen vasoactive properties involve endothelium- arteries (as assessed angiographically) have higher rates of
dependent effects and, in postmenopausal women, forearm anginal hospitalization, repeat catheterization, and greater
vasodilatation induced by acetylcholine is potentiated by the treatment costs, suggesting that some patients with syn-
acute local administration of intravenous estradiol. Estro- drome X may progress to overt coronary artery disease.89
gen’s potentiation of endothelium-dependent vascular relax- These patients were found to have stress-induced reduc-
ation and its inhibition of vascular smooth muscle contraction tion in myocardial phosphocreatine-adenosine triphosphate
may contribute to some of the clinical findings of CHD in ratio by phosphorus 31 nuclear MRS (abnormal MRS), con-
women.82 The relationship, however, between vasomotor sistent with myocardial ischemia.89 In a follow-up study of
abnormalities, coronary symptoms, and estrogen remains women with syndrome X, endothelial function testing with
speculative.59 intracoronary acetylcholine identified a group of patients
In vitro studies have shown other effects of steroid hor- with diffuse vasoconstriction (in the absence of epicardial
mones of vascular function. A possible mechanism by which spasm) who ultimately developed epicardial coronary
estradiol exerts one of its cardioprotective effects is by limit- disease.90 Furthermore, the Women and Ischemia Syndrome
ing the inflammatory response to injury by modulating the Evaluation (WISE), sponsored by the National Heart, Lung,
expression of cellular adhesion molecules from the endothe- and Blood Institute, studied 163 women referred for clini-
lium.83 Furthermore, β-estradiol inhibits proliferation of cally indicated coronary angiography who underwent coro-
coronary smooth muscle cells.84 nary reactivity assessment with a median follow-up of 48
Hormonal variations have been observed in women with months. In this study, impaired coronary vasomotor response
clinically documented coronary artery disease. Among pre- to acetylcholine was independently linked to adverse car-
menopausal women undergoing coronary angiography for diovascular outcomes regardless of coronary artery disease
suspected myocardial ischemia, disruption of ovulatory severity.91
cycling characterized by hypoestrogenemia of hypothalamic Reduced coronary vasodilator function and impaired
origin appears to be associated with angiographic disease.85 response of resistance vessels to increased sympathetic stim-
Hyperandrogenemia and low levels of sex hormone ulation, as seen in postmenopausal women with syndrome
binding globulin are frequently found in women with meta- X, has also been demonstrated in premenopausal women
bolic syndrome in postmenopausal women. Low plasma with diabetes.92 Diabetes has well-documented effects on
levels of sex hormone binding globulin are associated with microvessels in the kidney, including hyalinization and
CHD in women independently of insulin, obesity markers, intimal thickening, but pathologic studies of coronary micro-
and dyslipidemia.86 In addition, in postmenopausal women vasculature in diabetics are few.
decreased serum testosterone levels are associated with coro-
nary artery disease independently of the other metabolic risk
factors.87 Postmenopausal Hormone Replacement
Therapy and Risk of Coronary Disease
Coronary Microvascular Disease in Women
Healthy Women
A decrease in vasodilator capacity of small vessels has been
documented especially in postmenopausal women and forms It was long assumed that hormone replacement therapy
the theoretical basis for syndrome X. Even in asymptomatic would reduce the risk of coronary artery disease in post-
women, assessment of coronary endothelium-independent menopausal women, because of estrogen’s apparent protec-
and -dependent function with intracoronary administration tive effect on atherosclerosis. However, the Women’s Health
of adenosine and acetylcholine has found that the postmeno- Initiative, the first randomized prospective trial of the effect
pausal state is associated with a greater abnormality in of hormone replacement therapy on heart disease in healthy
coronary endothelial function at the level of the micro- women, demonstrated that conjugated equine estrogen plus
circulation.88 The abnormal vasodilatory coronary blood progestin does not confer cardiac protection and may increase
flow responses and an increased sensitivity of the coronary the risk of CHD, especially during the first year after the
microcirculation to vasoconstrictor stimuli in syndrome X initiation of hormone use.93 In healthy women with prior
patients has been termed microvascular angina.59 The pro- hysterectomy, the use of conjugated equine estrogen increases
portion of women with syndrome X who suffer from myo- the risk of stroke, decreases the risk of hip fracture, and does
cardial ischemia is unclear, however. Nevertheless, ischemic not affect the incidence of CHD incidence in postmeno-
electrocardiographic findings, the presence of myocardial pausal women.94 In a case-control study of British women,
perfusion defects during stress testing, coronary sinus oxygen hormone replacement therapy was associated with a small
saturation abnormalities and pH changes, as well as myocar- increase in risk of acute myocardial infarction in the first
dial lactate production and alterations of cardiac high-energy year of use (adjusted OR being 1.14), with subsequent reduc-
phosphate, are seen during stress testing in a proportion of tions in the risk (OR 0.85 at 13 to 60 months, and OR 0.42
patients with syndrome X.59 One in five women with chest after 5 years).95
720 chapter 32

Women with Prior Heart Disease Pathology of Coronary Disease in Women

Hormone replacement therapy has not been shown to be of
significant benefit in women with established coronary The characteristics of coronary artery plaques in women
artery disease. In the Heart and Estrogen/Progestin Replace- have been studied by angiography, intravascular ultrasound,
ment Study (HERS), during an average follow-up of 4.1 years, and histopathologic means. In patients with unstable angina
treatment with oral conjugated equine estrogen plus and non–Q-wave infarction, angiography has revealed less
medroxyprogesterone acetate did not reduce the overall rate severe coronary artery disease in women than in men, with
of coronary events in postmenopausal women with estab- fewer critical stenoses.5 Intravascular ultrasound of coronary
lished coronary disease.96 In the same cohort, estrogen plus lesions has shown smaller coronary arteries in women than
progestin use had no effect on all-cause mortality (hazard in men,108,109 which was independent of body size in the
ratio 1.0).97 In older postmenopausal women with established left anterior descending artery.109 Women and men had
coronary artery atherosclerosis, 17β-estradiol (the endoge- similar reference and lesion plaque burden, eccentricity,
nous hormone, as opposed to conjugated equine estrogen) and calcium.108 In this study, reference plaque referred to
with or without medroxyprogesterone acetate had no signifi- angiographically normal 5 mm segments maximal and distal
cant effect on the progression of atherosclerosis as assessed to lesions, and plaque burden calculated as plaque + media
by quantitative coronary angiography in a double-blinded divided by external elastic lamina area.
placebo study.98 In a 2-year follow-up study, estradiol valerate Few autopsy studies have analyzed plaque morphology in
did not reduce the overall risk of further cardiac events in women dying with severe coronary disease. Few histopatho-
postmenopausal women who had survived a myocardial logic studies have compared coronary plaques in women and
infarction.99 In women with abnormal glucose tolerances, men. The plaque composition of the native coronary arteries
postmenopausal hormone therapy was associated with a and saphenous venous conduits in women contain more cel-
worsening of coronary atherosclerosis and exacerbation of lular fibrous tissue than dense fibrous tissue, interpreted as
the profile of inflammatory markers in women.100 representing plaques at a younger stage than in men.110 In an
In a nonrandomized observational study, postmenopausal autopsy study of eight women <40 years of age dying a coro-
women undergoing coronary artery bypass had a signifi- nary death, the large amount of lipid-containing foam cells
cantly improved in-hospital survival if they had been receiv- and the relative lack of acellular scar tissue in coronary
ing hormone replacement therapy.101 plaques suggest a greater potential for reversibility of these
plaques.111 A different autopsy study comparing men and
women dying with acute myocardial infarction demonstrated
Effect of Hormone Replacement on Coronary Risk that there are more deaths in women during the acute phase
of myocardial infarction, in the first infarction, and from
Current data do not support hormone replacement therapy rupture of the left ventricle, with less severe narrowing of
for the purpose of coronary risk reduction, in contrast to the left main coronary artery.112
earlier meta-analyses that suggested the opposite.102 The
reasons for the lack of estrogen’s protective effect are unclear. Definition of Plaque Rupture and Erosion
The apparent protective effect of combination menopausal
hormone therapy with estrogen and progesterone is due to More recent autopsy studies have addressed the mechanisms
differences in other patient characteristics and bias of healthy of coronary thrombosis, plaque rupture and erosion, and
women taking postmenopausal hormones.103 It has been pro- their prevalence in women and men. Coronary artery thrombi
posed that differences in hormone regimen (estrogen alone, have been separated into two types based on the morphology
synthetic vs. endogenous) do not affect the outcome of the of the underlying plaque. Coronary plaque rupture is defined
Women’s Health Initiative data.104 However, others have as a luminal thrombus overlying a disrupted fibrous cap; the
speculated that estrogen alone may have a beneficial lipid core is in direct contact with the thrombus. In contrast,
effect.103 plaque erosion is identified when serial sectioning of a
The multiplicity of effects of exogenous hormones likely thrombosed arterial segment fails to reveal fibrous cap
play a role in their effects on coronary disease in women. rupture.113 Typically, the endothelium is absent at the plaque–
Hormone replacement treatment has both prothrombotic thrombus interface, with the exposed intima consisting pre-
and antiatherogenic effects, and its failure in reducing the dominantly of smooth muscle cells and proteoglycans, with
risk of cardiovascular events in postmenopausal women minimal inflammation (Fig. 32.2). It is important to note
might be because of the stage of their atherosclerosis at the that this form of thrombotic occlusion does not require a
time of initiation of treatment.105 Furthermore, the early necrotic core as lipid pools are commonly seen in the deep
increased risk of CHD and stroke with estrogen and proges- intima.114
tin therapy may be attributable to a rise in very low density
Clinical and Morphologic Differences of Plaque
lipoprotein (VLDL) triglycerides in addition to thrombosis.106
Rupture Versus Superficial Erosion
Although oral estrogen replacement therapy in postmeno-
pausal women improves endothelial function, it also The mean age in cases of coronary thrombosis due to
increases plasma CRP and IL-6 concentration. It has been plaque rupture is significantly less than that of plaque
suggested that lower doses of conjugated equine estrogen rupture, and the mean percent cross-sectional area stenosis
may eliminate the increase in vascular inflammatory (excluding the thrombus itself) is likewise less. Plaque calci-
markers while preserving the favorable effects of estrogen on fication is significantly less in erosions, possibly reflecting
endothelial function.107 the younger age at presentation. The thrombus resulting
 corona ry dise a se i n wom en 7 21

A Movat B α-actin C CD61

D F-II E CD68 F CD45Ro

FIGURE 32.2. Acute plaque erosion. (A) Cross section of epicardial Immunohistochemical localization of luminal platelets (antiplate-
coronary artery with nonocclusive thrombus caused by acute plaque let glycoprotein, CD61). (D) Immunohistochemical localization of
erosion. Movat pentachrome stain. (B) Immunohistochemical local- fibrin (anti–fibrin II). (E,F). Paucity of macrophages (anti-CD68, E),
ization of smooth muscle cells (anti–α-actin) at site of thrombus. (C) and T lymphocytes (anti-CD45RO, F) at site of erosive thrombus.

from erosion is less likely occlusive than the thrombus study from our laboratory explored the possibility of whether
caused by rupture.113 the accumulation of specific types of proteoglycans discrimi-
Identification of cell type by immunohistochemical nates among lesions types associated with sudden coronary
staining demonstrates several differences between ruptures events. Plaque erosions demonstrated a selective increase in
and erosions. In plaque ruptures, macrophages are typically hyaluronan and versican content at the plaque–thrombus
seen infiltrating the thin fibrous cap at the margins of the interface compared with the fibrous caps of ruptures or stable
rupture site. Foci of KP-1–positive macrophages, universally plaques.117 These differences occurred despite similarities in
present in ruptures, are seen in only half of erosions. Con- SMC phenotype between erosion and stable plaques. In fact,
versely, clusters of α-actin–positive smooth muscle cells are plaque rupture sites contain very little proteoglycan content
seen at the luminal surface adjacent to the thrombus in relative to stable or eroded lesions.
almost all erosions, compared to a minority of ruptures, The appearance of increased hyaluronan at the plaque–
likely those with ongoing healing. Cell activation, indicated thrombus interface is unique, and therefore we postulated that
by anti–human leukocyte antigen DR (HLA-DR) staining, is hyaluronan might provide a high-risk substrate for the devel-
seen in both macrophages and T cells in almost all ruptures, opment of thrombosis in erosion. Indirect support for this
but in fewer than half of erosions.113 notion comes from culture models demonstrating a decreased
potential for endothelial cell adherence, growth, and survival
on hyaluronan substrates.118 Further, the major cell surface
Erosions Present a Plaque Substrate Rich in
receptor for hyaluronan (CD44) was found highly localized to
Proteoglycan and Hyaluronan
a subset of SMCs at the plaque–thrombus interface as well as
Proteoglycans (versican, biglycan, and decorin) and hyaluro- in some platelets and inflammatory cells within the throm-
nan are extracellular matrix molecules that have been shown bus.117 Hyaluronan binds to the specific receptors, such as
to accumulate in topographically distinct patterns within CD44 and the receptor for hyaluronan-mediated motility
the developing atherosclerotic plaque.115 The mechanically (RHAMM), as well as other proteins, such as TSG-6, collagen,
active environment of the artery can sense mechanical and proteoglycans. CD44 has been shown to mediate the adhe-
stimuli that result in the regulation of extracellular matrix sion of platelets to hyaluronan.119 The de-endothelialized
synthesis by the smooth muscle cells (SMCs). Lee et al.116 surface of erosion exposes hyaluronan to the flowing blood,
have shown that versican-hyaluronan aggregation is thereby promoting platelet attachment via a CD44-dependent
enhanced, but the hydrodynamic size of proteoglycans is not mechanism.120 Moreover, the expression of CD44 in erosion
altered by mechanical SMC deformation. In addition, a four- may also promote vascular cell activation and migration of
fold increase in steady-state messenger RNA (mRNA) for the SMCs to the wounded edge represented by the loss of endothe-
hyaluronan-binding protein TSG6 expression was observed lium. Consistent with a wounding hypothesis, acute erosions
following deformation. Although early observations demon- are often superimposed on what appears to be repeated epi-
strated that plaque erosions were rich in proteoglycans, the sodes of thrombosis and healing such that layers of platelets
extensive nature of the extracellular matrix in culprit plaques and fibrin are commonly found deep within the plaque.114
with or without coronary thrombi was unknown. A recent The increase in hyaluronan/versican may be secondary to
722 chapter 32

mechanical deformation of SMCs in vivo because vessel vaso- 1.4

spasm has previously been reported to be more common in Men
women presenting with acute coronary syndromes.121
1.2
Unlike plaque rupture in which a precursor plaque can

Mean # healed plaque ruptures

be identified (i.e., vulnerable plaque) no such “pre-erosion
lesion” has been described for plaque erosion. Indeed, the 1
formation of thrombi in plaque erosion most likely involves Women
multiple factors including fibrinolytic dysfunction, or abnor- .8
malities to surface endothelium, SMCs, or both. Fibrinolytic
dysfunction, in particular, elevated plasma and tissue levels
.6
of tissue factor and PAI-1 may represent a risk factor for coro-
nary thrombosis. Previous studies have shown alterations in
the plasminogen activator system in human coronary .4
plaque.122 Further studies of eroded coronary plaques have
shown tissue factor expression in both SMCs and macro- .2
phages in plaque erosions.123 Intimal expression of PAI-1 was
75% in eroded vessels as compared with 20% in control
nonthrombosed arteries.123 0

Male >50
Male ≤50
Fem >50
Fem ≤50
Differences Between Coronary Lesions in Pre- and
Postmenopausal Women
In a series of 51 cases of sudden coronary death and 47 control
deaths in women who died from noncoronary causes, and a
FIGURE 32.4. Frequency of healed plaque ruptures, men and
larger group of men, the number of acute plaque ruptures, women dying suddenly with severe coronary disease, by age group-
healed plaque ruptures, vulnerable plaques, and acute plaque ing. An autopsy study of 51 women and 135 men dying with severe
erosions were compared among groups (men, premenopausal coronary artery disease. Numbers of healed plaque ruptures quan-
women, and postmenopausal women).124 Women older than titated per heart. p < .0001, females <50 years old vs. males; p = .01,
females ≤50 years old vs. females >50 years old.
50 years of age were much more likely to have a ruptured
plaque than were younger, premenopausal women, and had
comparable numbers to the men (Fig. 32.3). Healed plaque
ruptures were infrequent in women, especially premeno- pausal women (Fig. 32.4). Plaque erosions were far more
common as a cause of coronary thrombosis in premeno-
pausal women (Table 32.1). These results suggest that plaque
instability in the form of plaque rupture is uncommon in
women with physiologic estrogen levels, and that plaque
.6 progression by this mechanism, which has been detailed in
Women
autopsy studies,125 begins at a later age than in men. In the
.5 51 women who died of coronary disease, the mean number
of thin cap atheromas, the presumed precursor lesion of acute
Mean # acute ruptures

Men plaque rupture, and numbers of plaque with a lipid core

.4
increased significantly as women advanced into the post-
menopausal years, supporting this concept (Figs. 32.5 and
.3 32.6).124 The mean thickness of the fibrous cap decreased in
postmenopausal women (Fig. 32.7). Because plaque progres-
.2 sion may result both from repeated rupture and repeated
erosion, a better understanding of the effect of estrogen on
atherosclerosis may yield insights into the nature of coro-
.1
nary artery disease.37,124,126
0
Coronary Artery Remodeling in Women
Male >50
Male ≤50
Fem >50
Fem ≤50

Data obtained from intravascular ultrasound have suggested

that arterial diameter in women may be smaller than
that in men with coronary disease, even adjusted for body
size.109 The role of coronary artery remodeling in response to
FIGURE 32.3. Frequency of acute plaque ruptures, men and women plaque enlargement is well known, but the gender effect on
dying suddenly with severe coronary disease, by age grouping. An remodeling has not been studied in detail. In one autopsy
autopsy study of 51 women and 135 men dying with severe coronary
artery disease. Numbers of healed plaque ruptures quantitated per
study, the degree of positive remodeling in women was less
heart. p = .006, females ≤50 years old vs. females >50 years old; p = than that in men, especially in proximal arterial segments127
.02, females >50 years old vs. males ≤50 years old. (Fig. 32.8). Further morphologic studies investigating the dif-
 corona ry dise a se i n wom en 723
1.4

Mean numbers of vulnerable plaques

1.2

.8

.6

.4
FIGURE 32.5. Mean number of thin cap fibroatheromas in 51 women
.2
who died suddenly from severe coronary disease. The left bar shows the
mean numbers in younger women, and the right bar, the mean number
in older women. The difference was significant (p < .0001, Student’s 0
t-test). <50 years >50 years

30 400

Mean thickness of fibrous cap, μm

350
25
300
Mean % lipid core

20 250
200
15
150
10
100

5 50
0
0 <50 years >50 years
<50 years >50 years FIGURE 32.7. Mean fibrous cap thickness (μm) in 51 women who
FIGURE 32.6. Mean proportion (%) of plaques with a lipid core in died suddenly from severe coronary disease. The left bar shows the
51 women who died suddenly from severe coronary disease. The left mean thickness in younger women, and the right bar, mean thick-
bar shows the mean proportion of such lesions in younger women, ness in older women. The difference was significant (p = .02, Stu-
and the right bar, the proportion in older women. The difference was dent’s t-test).
significant (p = .02, Student’s t-test).

.14

.12
lel - expected iel, mm2/plaque area

Proximal
.1 Distal

.08

.06

.04
FIGURE 32.8. Remodeling, as assessed by internal elastic lamina (IEL) expansion
adjusted for plaque size, was greater in proximal (left main, left anterior descend-
ing before diagonal, first 3 cm of right coronary, left circumflex prior to obtuse .02
marginal) as compared to more distal segments in both men and women. Remod-
eling was greater in men than women (p = .01, means table with Fisher’s post-hoc .0
test), and greater in proximal than distal segments (p < .0001, means table with
Fisher’s post-hoc test). Males Females
724 chapter 32

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 3 Exercise Testing
3 Bernard R. Chaitman, Masarrath J. Moinuddin,
and Junko Sano

Introduction and Safety of Exercise Testing . . . . . . . . . . 729 Prognostic Use of Exercise Testing . . . . . . . . . . . . . . . . . 736
Indications and Contraindications . . . . . . . . . . . . . . . . . . 729 Exercise Testing After Acute Coronary Syndrome or
Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731 to Risk Stratify in the Emergency Department . . . . 738
Exercise Testing in the Diagnosis of Coronary Other Uses of Exercise Testing. . . . . . . . . . . . . . . . . . . . . 739
Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

Introduction and Safety of Exercise Testing Indications and Contraindications

Stress testing is a technique used primarily for the diagnos- Good clinical judgment is the most important factor in
tic, prognostic, and functional assessment of patients with determining the indications and contraindications for exer-
known or suspected coronary artery disease (CAD).1 Exer- cise testing. The patient should not eat or smoke for at least
cise, or the ability to do work, when used as the stressor can 2 hours before the test and should dress appropriately for
reproduce symptoms and provide an objective estimate of exercise. A brief history and physical examination should be
functional capacity that is a general measure of cardiopul- performed by appropriate trained medical personnel to rule
monary and musculoskeletal reserve. Vagal tone is progres- out contraindications to testing. Patients with a history of
sively withdrawn as dynamic exercise progresses and intermediate- or high-risk unstable angina or increasing
sympathetic discharge is increased. Cardiac output increases chest pain at rest should not undergo exercise testing until
coincident with the increase in heart rate, stroke volume, and the condition stabilizes. Patients with poorly controlled or
venous return. An estimate of an individual’s maximum unexplained low blood pressure or heart failure and those
heart rate can be calculated from the formula 220 minus age with severe valvular or congenital heart disease, particularly
(years), assuming a standard deviation of 10 to 12 beats/min. severe aortic stenosis, should be identified and usually not
Systolic blood pressure increases with progressive levels of undergo testing. Table 33.1 summarizes absolute and relative
work, and peak rate pressure product achieved (heart rate × contraindications to exercise testing. Standard indications
systolic blood pressure) provides an estimate of myocardial for exercise testing are found in Appendix 33.1.1 The indica-
oxygen demand at specific workloads. tions should always be known before the test is performed
Exercise testing is often used in conjunction with an to maximize the informational content derived from the
imaging procedure, such as myocardial perfusion imaging test. The procedure, attendant risks, including the extremely
or echocardiography, to enhance its diagnostic accuracy, low risk of death and myocardial infarction, and benefits of
particularly in patients with an intermediate pretest risk of the test should be explained to the patient, and a written
disease. In general exercise testing is a safe procedure; informed consent form obtained.
however, in one report, four myocardial infarctions, deaths The Mason-Likar modification of the standard 12-lead
or both, occurred per 10,000 tests performed.1,2 The risk is electrocardiogram (ECG) is the most frequent lead system
greater in patients after myocardial infarction and in patients used for exercise testing. This modification involves moving
undergoing evaluation for malignant ventricular arrhyth- the limb electrodes to the torso to minimize motion artifact.
mias, and the risk is least in asymptomatic patients being It should be noted that the Mason-Likar lead placement
evaluated for an adverse risk profile. Because of the risks, results in increased voltage in the inferior leads and a right-
albeit small, exercise testing should be performed only by ward axis shift. In some patients with a prior inferior Q-wave
well-trained technicians and physicians. In addition, the infarction, the Mason-Likar configuration can cause inferior
staff must be advanced cardiac life support (ACLS) certified Q waves to disappear and a Q wave in lead aVL to appear.
and have immediate access to appropriate equipment and Therefore, a standard resting 12-lead ECG with the elec-
medications to perform cardiopulmonary resuscitation if trodes placed at the extremities is usually obtained before
required. performance of the exercise test. After the limb leads have

729
730 chapter 33

TABLE 33.1. Contraindications to exercise testing (1.7 mph at 5% incline). The main disadvantages of this pro-
Absolute tocol are the large increments in work that occur between
Acute myocardial infarction (within 2 d) stages and the additional energy requirements in patients
High-risk unstable angina who are required to run rather than walk in the fourth or
Uncontrolled cardiac arrhythmias causing symptoms or subsequent stages of the protocol. Other treadmill protocols
hemodynamic compromise
such as ramp protocols, 3 the modified Balke, Naughton, or
Symptomatic severe aortic stenosis
Uncontrolled symptomatic heart failure standard or modified Asymptomatic Cardiac Ischemia Pilot
Acute pulmonary embolus or pulmonary infarction (ACIP) protocols were developed to provide a more linear
Acute myocarditis or pericarditis increase in heart rate and oxygen consumption at progres-
Acute aortic dissection sively increasing workloads. In patients with severe limita-
Relative* tion of exercise capacity, the 6-minute walk test can be used
Left main coronary stenosis
to provide a more objective assessment of functional capacity
Moderate stenotic valvular heart disease
Electrolyte abnormalities than a subjective description of symptoms. Although the 6-
Severe arterial hypertension† minute walk test is popular to test patients with more severe
Tachyarrhythmias or bradyarrhythmias heart failure, it is not as objective as cardiopulmonary testing
Hypertrophic cardiomyopathy and other forms of outflow tract in establishing peak aerobic capacity.
obstruction
Mental or physical impairment leading to inability to exercise
adequately Postexercise Period
High-degree atrioventricular block
It is important to be aware that some abnormal responses
* Relative contraindications can be superseded if the benefits of exercise only occur in the postexercise recovery phase. To achieve
outweigh the risks.
maximal sensitivity to detect ST-segment shifts, patients
† In the absence of definitive evidence, the committee suggests systolic blood
pressure of >200 mm Hg and/or diastolic blood pressure of >10 mm Hg. should be in the supine position during the postexercise
period; however, this is not always desirable. In patients who
experience severe angina, dyspnea, or ventricular arrhyth-
mias during the exercise test, the lower preload associated
with the sitting or erect position may be preferable. In other
been moved to the torso, tracings should be recorded with
the patient in the supine and upright positions. The tracing
in the upright position is usually selected as the baseline
tracing from which exercise tracings are compared. Table
33.2 summarizes the main indications for termination of TABLE 33.2. Indications for terminating exercise testing
an exercise test.1
Absolute indications
Drop in systolic blood pressure of >10 mm Hg from baseline
Bicycle Ergometer Protocols blood pressure despite an increase in workload, when
accompanied by other evidence of ischemia
Bicycle ergometers have mechanical or electrical brakes to Moderate to severe angina
vary workloads that are calibrated in kiloponds (kpm) or Increasing nervous system symptoms (e.g., ataxia, dizziness, or
watts (W). The initial power output is usually 25 or 50 W near-syncope)
depending on the ability of the particular patient, followed Signs of poor perfusion (cyanosis or pallor)
by increases of 25 to 50 W every 3 minutes until the end Technical difficulties in monitoring ECG or systolic blood
pressure
point of the test is reached. Bicycle ergometers are usually Subject’s desire to stop
less expensive, occupy less space, and make less noise than Sustained ventricular tachycardia
a treadmill. In addition, upper body motion is usually less ST elevation (≥1.0 mm) in leads without diagnostic Q-waves
than that with a treadmill, making it easier to measure (other than V1 or aVR)
blood pressure, auscultate the chest, and record the ECG. Relative indications
However, a significant proportion of patients experience dif- Drop in systolic blood pressure of (≥10 mm Hg from baseline
blood pressure despite an increase in workload, in the
ficulty in performing optimally on a bicycle compared with absence of other evidence of ischemia
a treadmill. In addition, maximal oxygen uptake tends to be ST or QRS changes such as excessive ST depression (>2 mm of
5% to 10% lower than with treadmill exercise, and maximal horizontal or down-sloping ST-segment depression) or marked
cardiac output and stroke volume are correspondingly axis shift
Arrhythmias other than sustained ventricular tachycardia,
reduced. including multifocal PVCs, triplets of PVCs, supraventricular
tachycardia, heart block, or bradyarrhythmias
Treadmill Protocols Fatigue, shortness of breath, wheezing, leg cramps, or
claudication
There are numerous treadmill exercise protocols; it is impor- Development of bundle branch block or IVCD that cannot be
tant to select a protocol that is suited to the patient’s physical distinguished from ventricular tachycardia
ability. An optimal protocol should last at least 6 to 12 Increasing chest pain
Hypertensive response*
minutes. The most popular is the Bruce protocol because of
the extensive published data on the diagnostic and prognos- * In the absence of definitive evidence, the committee suggests systolic blood
pressure of >250 mm Hg and/or a diastolic blood pressure of >115 mm Hg.
tic use of this protocol. In patients with limited exercise
ECG, electrocardiogram; PVCs, premature ventricular contractions; ICD,
capacity, the Bruce protocol can be modified by adding an implantable cardioverter-defibrillator discharge; IVCD, intraventricular con-
initial zero stage (1.7 mph at 0% incline) and one-half stage duction delay.
 e x ercise t est i ng 7 31
patients, particularly those patients who attain a high work- Maximum predicted heart rate
load, it is preferable to have a cool-down period to avoid
postexercise hypotension, which occasionally occurs. Moni-
toring should continue for approximately 5 minutes after Peak heart
Abnormal heart-rate
rate
exercise or until hemodynamic changes stabilize and the Chronotropic
recovery is present
heart rate and ECG have returned close to baseline. If exer- when the heart rate
Chronotropic incompetence if
in the first minute
cise-induced ST-segment changes have improved but not reserve <85% age
postexercise does
completely returned to normal, the patient may be discon- predicted in the
not decrease by
absence of beta-
nected from the electrocardiograph, sit in a location proxi- ≥12 bpm from peak
blocker therapy
mate to the laboratory, and 20 to 30 minutes later have a heart rate (see text)
Resst heart rate
repeat ECG done to confirm that the ECG has returned to
baseline. Exercise 1-min post

FIGURE 33.1. Example of chronotropic incompetence and abnor-

mal heart-rate recovery (see text).
Interpretation
the rapid changes in cardiac output and autonomic tone that
Symptoms
occur in the immediate postexercise phase.
The quality, character, intensity, and duration of chest pain An inappropriate increase in the heart rate with exercise
induced by exercise may be helpful in establishing a diagno- may be observed in patients with impaired left ventricular
sis even in the absence of ST-segment depression. It is impor- dysfunction. Alternatively, this response may be observed in
tant to obtain an accurate account of symptoms, in particular, patients who are physically deconditioned, hypovolemic,
chest pain that occurs during or after exercise testing. anemic, or in atrial fibrillation. A blunted heart rate response
may be a sign of chronotropic incompetence, a variable asso-
ciated with an increased risk of cardiac events in higher
Physical Signs
clinical risk patients (Fig. 33.1). Chronotropic incompetence
Cardiac examination immediately after exercise may reveal is usually defined by inability to achieve 85% of age-
a precordial bulge or third heart sound resulting from left predicted maximum in the absence of beta-blocker therapy.
ventricular dysfunction. Papillary muscle dysfunction due to Alternatively, chronotropic incompetence can be defined by
transitory ischemia may result in a mitral regurgitation the percent of heart rate reserve achieved (peak heart rate—
murmur. rest heart rate)/220—age—rest heart rate). Values <80% are
considered abnormal.4 Occasionally, the heart-rate response
in the early postexercise phase, when vagal tone is usually
Heart Rate and Blood Pressure Response
high, takes longer to decelerate. This form of abnormal heart-
Blood pressure is dependent on cardiac output and peripheral rate recovery is defined by a heart rate that fails to decrease
resistance. Systolic blood pressure rises to 160 to 220 mm Hg by at least 12 beats per minute (bpm) in the first minute
at peak exercise, whereas diastolic blood pressure does not postexertion using a 2-minute cool-down or by 18 bpm if the
usually change by more than ± 10 mm Hg from the resting exercise test is stopped abruptly. Abnormal heart-rate recov-
value in normal subjects. An inadequate rise (<120 mm Hg) ery is associated with increased long-term mortality even
or a progressive fall in systolic blood pressure (>10 mm Hg) after adjustment for exercise-induced ST-segment depression,
during exercise may be associated with severe CAD and angina, coronary disease extent, left ventricular dysfunction,
ischemic dysfunction (Table 33.3). However, some normal and Duke treadmill score (Fig. 33.2).5
subjects may have a transient drop in systolic blood pressure
shortly after maximal exercise due to a mismatch between
Electrocardiographic Changes
During exercise, there are changes in virtually all compo-
nents of the ECG in normal subjects, including progressive
TABLE 33.3. Exercise parameters associated with an adverse shortening of the PR and QT intervals. The amplitude of the
prognosis and multivessel coronary artery disease
P wave increases and the amplitude of the T wave decreases
Duration of symptom-limiting exercise <5 METs during exercise. There is also a progressive rightward shift
Failure to increase systolic blood pressure ≥120 mm Hg, or a in the QRS axis. R-wave amplitude changes have also been
sustained decrease ≥10 mm Hg, or below rest levels, during noted to occur during exercise. J-point depression may occur,
progressive exercise particularly in older subjects, but the ST segment is rapidly
ST segment depression ≥2 mm, down-sloping ST segment, starting up-sloping (Fig. 33.3). Myocardial ischemia most often mani-
at <5 METs, involving ≥5 leads, persisting ≥5 minutes into
fests itself as ST-segment shifts. To determine the magnitude
recovery
of ST-segment shift, the ST level should be measured relative
Exercise-induced ST segment elevation (aV excluded)
to the PR segment. The PQ junction is often chosen as the
Angina pectoris at low exercise workloads
point of reference (Fig. 33.4). The J point is then identified
Reproducible sustained (>30 sec) or symptomatic ventricular and the ST segment level is measured 60 to 80 ms after the
tachycardia
J point, depending on heart rate (ST 60 is usually measured
Acute systemic illness (pulmonary embolism, aortic dissection)
at heart rates >130 to 140/min). When the baseline ST segment
732 chapter 33

1 Both normal Exercise

Rest
0.9
Severe CAD
0.8
Survival

Abnormal HR recovery
0.7
0.6 Both abnormal II II

0.5
0 1 2 3 4 5 6 7 8
Years after stress test
No. at risk
Both normal 18171802 1784 1666 1415 1170 868 706 475
Severe CAD 280 273 264 251 210 161 127 90 79
Abnl HR Rec 697 678 665 614 508 395 299 243 143 PQ junction
Both abnormal 141 129 125 117 84 51 49 40 29
FIGURE 33.2. Kaplan-Meier plot showing heart rate (HR) recovery
with severity of coronary artery disease (CAD) and the risk of death.
The abnormal HR was independent of gender, age, left ventricular
systolic function (LVSF), functional capacity, exercise-induced
angina, beta-blocker usage, and severity of CAD in determining J ST80
prognosis.
FIGURE 33.4. A 74-year-old man referred for evaluation of stable
angina. The rest ECG exhibits 0.9 mm ST-segment elevation (early
repolarization) (arrow). The exercise tracing shows J-point depres-
is depressed, an additional 0.1 mV (1 mm) of flat or down- sion of 3.2-mm ST depression and 2.5-mm ST-segment depression
(STD) at 80 ms after the J point (ST80). The PQ junction represents
sloping ST-segment depression is required to call the test
baseline. The test was stopped for angina at a heart rate of 135/min.
abnormal. The standard criteria for abnormal ST-segment This type of slow up-sloping STD (bottom panel) represents an
depression is horizontal or down-sloping ST-segment depres- ischemic response in symptomatic patients or individuals with
sion of 0.10 mV (1 mm) ≥60 to 80 ms after the J point in three an intermediate to high-risk pre-test risk.
consecutive beats (Fig. 33.5). A slow, upward sloping (>0.7 to

1 mV/s) ST segment depressed 0.15 or more at 80 ms after the

J point in three consecutive beats is also considered by some
Patient A Patient B to be a manifestation of exercise-induced myocardial isch-
emia (Fig. 33.4).
In most laboratories, the exercise ECG is printed out in
V4
a 3 × 4 format or 2.5 sec/3-lead group. To maximize the
V4 opportunity of meeting the above criteria, some laboratories
have adopted a strategy of recording a full 10 seconds of ECG
data with leads II, aVF, and V5 when the tracing starts to show
abnormal beats close to the ischemic threshold. A 10- as
opposed to a 2.5-second tracing increases the likelihood of
capturing consecutive abnormal beats with a stable baseline
(Fig. 33.6). It will require future study to determine if two
consecutive abnormal beats for the majority of beats in a
10-second study has the same diagnostic accuracy as three
V5 V5 consecutive beats in a 3 × 4 format. Coronary artery disease
severity is usually greatest in the presence of down-sloping
ST-segment depression, followed by horizontal ST-segment
depression and finally slow up-sloping ST-segment depres-
sion (Figs. 33.4 and 33.7). The magnitude of the ischemic
response is related to coronary disease severity and extent.
Patients with early onset of myocardial ischemia manifest
as typical angina or an ST-segment shift at low exercise
workloads with an “ischemic” pattern that persists late into
V6 the recovery phase, and they have an increased risk of multi-
V6
vessel disease and future cardiac events.
FIGURE 33.3. Examples of two different patients with normal exer- ST-segment elevation may also indicate myocardial isch-
cise electrocardiograms at peak exercise heart rates of 175 to emia. Exercise-induced ST-segment elevation ≥1 mm occur-
180 bpm. Patient A has no J-point or ST-segment shift. Patient B has ring in a noninfarct territory usually indicates transmural
J-point depression of 1.6, 1.4, and 0.7 mm in leads V4, V5, and V6; the
ST segment is rapidly up-sloping in patient B, depressed <0.5 mm at
ischemia and is associated with severe proximal coronary
60 ms after the J-point. Both tracings are normal responses to exer- disease or coronary vasospasm. In this situation, the local-
cise. J-point depression is more common in older individuals. ization of the ST-segment elevation is relatively specific for
 e x ercise t est i ng 733

Lead V5

Rest

2:30 exercise

Peak exercise

FIGURE 33.5. A 58-year-old man with typical angina. The rest ECG is
normal. At 2 : 30 seconds of exercise at a heart rate of 125/min, the patient
manifests abnormal beats (star). At peak exercise, the ST segment is
down-sloping, depressed 1.5 mm 80 ms after the J-point. The ischemic
response persists at least 6 minutes in the postexercise phase. This type
of ischemic pattern in a symptomatic patient with ST segment depression 6-min post
appearing early during exercise, worsening as exercise progresses, associ-
ated with down-sloping ST segments that persist late into the recovery
phase is a high-risk study that normally warrants a cardiac catheteriza-
tion if there are no clinical contraindications.

the distribution of the coronary artery involved in contrast motion abnormalities than patients without this finding; in
to ST-segment depression, which does not help localize the most patients, this type of pattern does not represent an
affected coronary arteries. ST-segment elevation ≥1 mm ischemic response (Fig. 33.8).
during exercise in Q-wave leads from a prior myocardial T-wave inversion, usually noted in the postexercise phase,
infarction (MI) is often associated with more extensive wall is not diagnostic of myocardial ischemia in the absence of

FIGURE 33.6. Example of a continuous ST80 0.4 1.7 1.8 0.8 1.0 0.8
lead V5 recording during exercise. Of the
six beats recorded with a relatively stable
baseline, three are abnormal (star) with
at least two consecutive beats that meet
criteria for abnormality (J-point and
ST80 ≥1 mm depressed). The remaining
beats show lesser degrees of ST segment
depression (0.4 and 0.8 mm ST80 depres-
sion) that do not meet criteria for abnor-
mality. This type of ECG pattern with at PR junction
least two consecutive abnormal beats
and at least 50% of all beats recorded
abnormal should be considered an abnor-
mal test in a patient that is at intermedi-
ate to high pretest clinical risk.
 Rest 3:00 Peak 4:00 Post
V1

V2

FIGURE 33.7. A 64-year-old man with

V3
chronic angina for 2 years is referred for
testing because of decreased exercise
tolerance over the past several months.
The rest ECG is normal. The exercise
V4 ECG is abnormal in leads V3 to V6 after
3 : 00 with slight worsening of the ST-
segment changes at peak. The ischemic
abnormality persists 4 : 00 postexercise
V5 with down-sloping ST-segment depres-
sion. This classic ischemic response to
exercise represents a high-risk study
manifest by early onset of ischemic
ECG changes involving five or more
V6
leads, persisting late into the recovery
phase associated with ST segment
depression ≥2 mm.

Rest Exercise

V1 V1

V2 V2

V3 V3

J J

FIGURE 33.8. A 46-year-old woman status post–anteroseptal myocar-

dial infarction and percutaneous coronary intervention (PCI) 4 days prior
to testing. The rest ECG exhibits QS complexes in V1 to V3 with J-point
elevation of 1.4 mm that becomes 2.5 mm at 80 ms after the J-point. The
postexercise tracing (magnified) shows J-point elevation of 2.5 mm that
becomes 3.5 mm at 80 ms after the J-point. Exercise-induced ST segment
elevation in an infarct territory with QS complexes indicates a more
extensive wall motion abnormality and decreased ejection fraction com-
pared to postinfarct patients without this finding. This type of abnormal-
ity does not generally indicate an ischemic response.
 e x ercise t est i ng 735
ST-segment depression criteria. The same is true for pseudo- Rest Exercise
normalization of T waves (i.e., inverted T waves that become
upright with exercise).

Exercise Testing in the Diagnosis of Coronary

Artery Disease
II
Figure 33.9 illustrates how the sensitivity, specificity, and
predictive accuracy of a noninvasive test can be determined. FIGURE 33.10. A 63-year-old woman with left ventricular hyper-
Sensitivity is decreased by false-negative results and specific- trophy (LVH) and QRS duration of 98 ms (rest) developed a rate-
ity is decreased by false-positive results. In general, the sen- related left bundle branch block (LBBB) at a heart rate of 88/min that
sitivity and specificity of a test are not influenced by the persisted throughout the exercise test. The ST depression observed
(arrow) during the LBBB is nondiagnostic in the presence of the
pretest likelihood of disease. However, the predictive accu- conduction disturbance.
racy of a test is highly dependent on the pretest estimate of
disease according to bayesian theory.1
In a meta-analysis of published trials of patients undergo- sensitivity and decreases specificity since patients with a
ing exercise testing and coronary arteriography, the mean negative test tend not to be referred for catheterization,
sensitivity and specificity for the diagnosis of obstructive whereas patients with an abnormal test are referred for
CAD ≥70% were 68% and 77%, respectively, and for three- catheterization. When studies that avoid workup bias are
vessel or left main coronary disease ≥70% were 86% and examined, the sensitivity and specificity of horizontal or
53%.6 The sensitivity to detect obstructive CAD with exer- down-sloping ST-segment depression ≥0.1 mV for obstructive
cise testing is increased when the coronary artery narrowing CAD ≥70% is 50% and 90%, respectively.7,8
is more severe (e.g., stenosis ≥70% vs. 50%) and when CAD There are several situations in which the specificity of
is more extensive (three-vessel vs. one-vessel disease). The the exercise test to exclude CAD is reduced. Patients with
sensitivity for obstructive single-vessel right or left circum- left bundle branch block (Fig. 33.10), rest ST-segment depres-
flex is approximately 50% even when the heart rate achieved sion ≥1 mm, Wolff-Parkinson-White syndrome (Fig. 33.11), or
is ≥85% of age-predicted maximum. Thus, a patient should left ventricular hypertrophy, or patients on digitalis therapy
never be told he or she does not have obstructive coronary may have changes with exercise that are nondiagnostic for
disease on the basis of a normal exercise electrocardiogram CAD; in this clinical setting it is best to perform the test in
and normal exercise capacity. The sensitivity of the test is conjunction with an imaging procedure (i.e., nuclear or echo-
decreased when the level of exercise performed is submaxi- cardiographic). During exercise, patients with right bundle
mal, a limited lead set is used, or the ECG is abnormal with branch block may manifest exercise-induced ST-segment
findings that reduce the potential to detect ST-segment depression in leads V1 to V4, a nonspecific finding for CAD
depression (i.e., extensive anterior Q-wave MI). Most pub- (Fig. 33.12). Other causes of a false-positive test include severe
lished studies comparing noninvasive testing to coronary
angiography suffer from posttest referral bias that increases

Rest Exercise

I
Test Coronary disease
result
+ –

+ TP FP All + tests

– FN TN All – tests
V3
CAD No CAD All tests

FIGURE 33.11. This 42-year-old man was referred for atypical chest
pain. The rest ECG shows a preexcitation pattern with a short PR
interval and delta wave (arrow). The exercise tracing shows persis-
FIGURE 33.9. Sensitivity = TP/CAD; specificity = TN/no CAD; tence of the delta wave and exercise-induced down-sloping ST
predictive accuracy of a positive test = −TP/all + tests; predictive segment depression of 0.9 mm in lead I (arrow) and horizontal ST
accuracy of a negative test = TN/all − tests; efficiency = (TP + TN)/all segment depression of 1.9 mm in lead V3 (arrow). Exercise-induced
tests. FN, false negative; FP, false positive; TN, true negative; TP, ST segment depression is a nondiagnostic finding for coronary
true positive. artery disease in patients with preexcitation syndrome.
736 chapter 33

Rest Exercise
Prognostic Use of Exercise Testing

Electrocardiography
A major indication for exercise testing is to estimate the
V1
V1 prognosis and determine the need for subsequent workup
that may include cardiac catheterization and coronary revas-
cularization. If the posttest likelihood of a cardiac event,
estimated using clinical and exercise test variables, cannot
be reduced by a coronary revascularization procedure (e.g.,
estimated 5-year risk of a cardiac event after exercise testing
<0.8%/year), then there is little need to proceed further. Exer-
cise test variables associated with an increased likelihood of
multivessel disease and future cardiac events include early
V2 V2 onset of ischemia (Figs. 33.5 and 33.7), angina, or complex
ventricular arrhythmias at low exercise workloads, inability
to complete low levels of work [i.e., functional capacity <5
metabolic equivalents (METs)], extensive and profound exer-
cise-induced ST-segment abnormalities, hemodynamic insta-
bility such as a drop in systolic blood pressure during exercise,
abnormal heart rate response (Fig. 33.1), and persistence of
ischemic changes late into the recovery phase (Fig. 33.7;
Table 33.3).
Functional capacity is one of the most important prog-
V3 V3
nostic exercise test variables since it provides a global esti-
mate of cardiac and pulmonary reserve. Patients who have
FIGURE 33.12. A 62-year-old man referred for atypical chest pain
3 years after a coronary bypass procedure. The rest ECG exhibits onset of ST-segment depression at high exercise workloads
right bundle branch block (RBBB). In lead V2 at rest, the J point and (e.g., >10 METs) have a favorable prognosis regardless of
ST80 are depressed 0.8 mm and 1.3 mm. The postexercise tracing in whether or not abnormal ST segment depression is present.2
lead V2 shows 2.3- and 3.1-mm depression, respectively. Leads V1 Myers et al.9 reported a 12% increase in survival for every 1-
and V3 are also more depressed than at rest. Exercise-induced ST
segment depression in leads V1 to V4 is a nonspecific finding in
MET increment in exercise capacity in a 6213-patient cohort
patients with RBBB. followed for a mean of 6 years (Fig. 33.13).9 The risk gradient
for future cardiac events is greatest in individuals who
cannot perform exercise, followed by those who are unable
to complete the exercise protocol. The lower the exercise
anemia, hypoxia, and hypokalemia. Mitral valve prolapse is capacity, estimated in METS, the greater the risk. Patients
associated with an increased incidence of false positives, with exercise-induced ischemia or hemodynamic compro-
particularly when the prolapse is moderate-severe. Women mise (e.g., hypotension) at low workloads (i.e., <5 METS)
have a higher incidence of exercise-induced ST-segment should be referred for cardiac catheterization and revascular-
changes than men, and in low-risk women the presence of ization if there are no clinical contraindications. The likeli-
exercise-induced ST-segment depression is often a false- hood of angiographic high-risk anatomy is high, and if
positive finding for CAD. When the diagnosis of CAD is in present, would be an indication for coronary revasculariza-
doubt, imaging studies should be considered. A negative ECG tion regardless of symptomatic status.
test in a woman with excellent exercise capacity carries Exercise testing should never be categorized as positive
similar diagnostic information as in men. or negative based solely on the ST-segment response. The
The posttest likelihood of CAD in a patient should be entire variable set that includes final exercise capacity,
estimated from the data obtained from the exercise test and hemodynamic and heart rate responses, symptoms, and
the pretest likelihood of CAD. Since the sensitivity and workload at which symptoms or the ischemic response
specificity of exercise electrocardiography are less than become manifest are critical in order to provide the best
100%, false-positive tests are more likely in patients with a prognostic estimates possible. Mark and colleagues10 devised
low pretest likelihood of CAD such as young asymptomatic a treadmill score and applied it to 2842 symptomatic inpa-
women without atherosclerotic risk factors than in older tients who were being evaluated by treadmill exercise testing
men with typical angina. The posttest likelihood of CAD is and cardiac catheterization. The treadmill score was calcu-
increased in subjects with more abnormal exercise test lated on the basis of the duration of exercise, the amount of
results (≥0.2 mV ST-segment depression at low exercise work- maximal electrocardiographic depression, and the presence
loads vs. a borderline abnormal ECG at high exercise work- or absence of angina occurring during exercise. The authors
loads). Similarly, false-negative results are more common found that the treadmill score was a better discriminator
when the pretest likelihood of CAD is high. These bayesian than clinical assessment alone and appeared to better distin-
principles should be used to estimate posttest likelihood of guish patients who subsequently died from those who lived.
CAD and should also be applied when risk-stratifying patients Approximately one third of patients had scores indicating
for future cardiac event rates using the exercise test. low risk (≥+7) with a 93% 5-year survival rate (i.e., annual
 e x ercise t est i ng 7 37

A Normal Subjects C Subjects with Cardiovascular Disease

100 100
>8 MET
75

Percentage Surviving

Percentage Surviving
75
5–8 MET >8 MET
50
<5 MET 50 5–8 MET
<5 MET
25
25
0
0 3.5 7.0 10.5 14.0 0
0 3.5 7.0 10.5 14.0
B Normal Subjects
100 D Subjects with Cardiovascular Disease
100
>100%
75

Percentage Surviving
75–100% 75

Percentage Surviving
50–74%
>100%
FIGURE 33.13. Survival curves for normal subjects 50 75–100%
stratified according to peak exercise capacity (A) and <50% 50 <50% 50–74%
according to the percentage of age-predicted exercise
capacity achieved (B) and survival curves for subjects 25
25
with cardiovascular disease stratified according to peak
exercise capacity (C) and according to the percentage of 0
age predicted exercise capacity achieved (D). These figures 0
0 3.5 7.0 10.5 14.0 0 3.5 7.0 10.5 14.0
show that the survival rate was lower for patients with Years of Follow-up
decreased exercise capacity. Years of Follow-up

mortality rate of 1.4%). High-risk scores (≤–11) occurred in event rates for low-, intermediate-, and high-risk women are
13% of patients; the mortality rate in this group was three less than those observed in men.13 Similarly, women tend
times greater, with a 67% 5-year survival rate (i.e., annual to have a lower exercise capacity than men, and middle-aged
mortality rate of approximately 7%). women in general tend to have less extensive coronary
The Duke treadmill score (DTS) has been extensively disease than men. Thus, it is apparent that the use of clini-
validated and was tested in 613 outpatients by the Duke cal and exercise multivariate risk scores to estimate prog-
group.11 It does not perform as well in elderly individuals nosis is highly dependent on the population from which the
(≥75 years) as compared to patients <75 years.12 The DTS data are derived. Other scoring techniques developed in
was compiled in a younger patient population and the populations different from those in which the original DTS
elderly are known to have decreased exercise capacity com- was derived, such as the score developed by Morise and col-
pared to younger individuals. The DTS-predicted cardiac leagues,14,15 perform better than the DTS (Fig. 33.14). Pretest

Pretest score
1.00
Low
Survival

Intermediate-High
0.95

Log-Rand 46.12 p <.00001

0.90
0.0 1.0 2.0 3.0
Years

Exercise score Duke score

1.00 1.00
Low Low
Survival
Survival

0.95 Intermediate-High
0.95
Intermediate-High

Log-Rand 81.50 p <.00001 Log-Rank 20.62 p <.00001

0.90 0.90
FIGURE 33.14. Three Kaplan-Meier survival plots for
0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0
low- and intermediate-high risk groups using pretest,
exercise, and Duke treadmill scores. Years Years
738 chapter 33

and exercise test scores performed better than the Duke

treadmill score in stratifying women with a low prevalence

Hazards Ratio of Death

for coronary artery disease.14,15 However, in the final analy-
2.1
sis, exercise scores just like the ST-segment response are 4 (2.1-4.8)

imperfect, and clinicians should use all the clinical and 1.9
exercise test variables to estimate prognostic risk and base 3 (1.3-2.9)
1.0
their future management strategies on the totality of evi- 2.0
2 1.6
dence. It is clear that exercise scores do provide significantly (1.3-3.2)
(1.1-2.4)
1.0
more information that just a single variable such as an ST- 1
segment shift.16
0
In patients with compensated heart failure, cardiopulmo- <5 MET 5–8 MET >8 MET
Adjusted for Age
nary exercise testing is effective in estimating mortality
Exercise Capacity Categories
Adjusted for
risk. In eligible patients that reach anaerobic threshold and
Framingham Risk Score
have a peak volume of oxygen consumption (VO2) >14 mL
FIGURE 33.15. Hazards ratios of all-cause death when adjusted for
O2/min/kg, the survival rate may not be improved with age (white bars) and Framingham risk score (FRS) (gray bars) for each
cardiac transplantation, whereas survival rates in patients of the exercise capacity categories (in MET) <5, 5 to 8, and >8. The
with a peak VO2 <14 mL/min/kg, or <50% of predicted VO2 highest exercise capacity category (>8 MET) was the reference cate-
are sufficiently low that cardiac transplantation should be gory. Hazards ratios are listed within the bars; 95% confidence
intervals (CIs) are shown.
considered.17,18 Heart failure patients who improve over time
and have improved cardiopulmonary performance are often
removed from the transplant list. In one series of 508 patients
with heart failure, the predictive value of exercise gas
exchange parameters was attenuated with carvedilol
clinical risk scores for future cardiac events such as death,
therapy.19 Exercise testing is not very useful after cardiac
MI, or stroke (e.g., 1% to 3%/year), exercise testing may be a
transplantation to evaluate patients for rejection or coronary
useful procedure to further stratify prognostic risk.
vasculopathy.20 Dobutamine echocardiography is a more sen-
sitive test for this purpose.21
Exercise Testing After Acute Coronary
Asymptomatic Subjects
Syndrome or to Risk Stratify in the
Emergency Department
Exercise testing is not recommended as a diagnostic test to
screen the general population for CAD. However, in certain Exercise testing after MI is widely practiced to risk-stratify
circumstances, exercise testing may provide useful prognos- patients, assess therapy, evaluate functional capacity, and
tic information in asymptomatic subjects with a relatively determine home and work activity recommendations. In
high pretest risk of coronary disease.22 In 25,927 apparently many patients, reperfusion therapy is established early with
healthy men evaluated at the Cooper clinic, 10-year survival angioplasty to the infarct-related vessel, and uncomplicated
was 94% in subjects with atherosclerotic risk factors and an patients may be discharged 3 to 4 days after the index
abnormal exercise test compared to 99% in subjects without event.28–31 In this setting, exercise testing is usually per-
risk factors and a normal test.23 Balady et al.24 evaluated 3043 formed 2 to 3 weeks or 3 to 6 weeks after discharge to estab-
offspring from the Framingham Heart Study (average age 43 lish recommendations for leisure or work physical activities.
years), and reported that in the highest Framingham risk In patients who are ineligible for the former strategy or
group of men (10-year predicted cardiovascular event risk receive thrombolytic therapy only, submaximal exercise
≥20%), failure to reach target heart rate and exercise-induced testing before hospital discharge is useful to assess func-
ST depression both doubled the risk of an event; each MET tional capacity, determine residual ischemia, and assess exer-
increment in exercise capacity reduced risk by 13% during cise-induced arrhythmias that might warrant a predischarge
an 18-year follow-up. The use of the Framingham risk score cardiac catheterization and revascularization.1
to establish a pretest likelihood of future cardiac events and In low- to intermediate-risk patients with unstable
subsequent selection of intermediate- or higher risk individ- angina, exercise testing can help determine if a patient needs
uals for noninvasive testing using the exercise electrocardio- hospital admission and triage to the cardiac care unit (CCU)
gram or in some cases coronary artery calcification to provide or a step-down monitored bed, or can be discharged from the
incremental prognostic information is well established.25 In emergency room after appropriate workup (e.g., asymptom-
5721 asymptomatic women followed an average of 8.4 years atic, negative biomarkers, normal exercise test).32
(mean age 52 years), mortality increased 9% for each unit In the emergency department, exercise testing with or
increase in Framingham risk score and decreased 17% for without imaging procedures is used to risk stratify individu-
each 1-MET increase in exercise capacity (Fig. 33.15).26 In a als with a low-intermediate pretest likelihood of coronary
different series of 2994 asymptomatic women with lower disease, such as a younger individual with atypical chest
Framingham risk scores, exercise capacity, abnormal heart- pain without significant risk factors and a normal rest ECG
rate recovery, and chronotropic incompetence were indepen- who presents to the emergency department because of an
dent predictors of cardiovascular mortality; exercise-induced episode of chest pain that occurred the prior day. A normal
ST-segment depression did not predict mortality.27 Thus, in exercise test in this setting is associated with a very low risk
asymptomatic men and women with moderate to high pretest of cardiac events over the next few years.33
 e x ercise t est i ng 739

Other Uses of Exercise Testing Elderly Patients

Exercise protocols should be tailored for the elderly popula-
Cardiac Arrhythmias tion. Abrupt changes in walking speed or grade are not as well
tolerated as in younger individuals and may not allow as
The prognostic significance of ventricular arrhythmias accurate an estimate of aerobic capacity as a more gradual
during or after exercise testing is well established.34–36 In protocol. Older patients are more likely to have cardiac events
general, the mortality is greatest in patients who have and an increased risk for all-cause mortality. Jeger et al.41
complex ventricular ectopy at low exercise workloads, par- studied 292 patients >75 years of age with chronic angina
ticularly postexercise, or who have ventricular tachycardia. receiving two or more antianginal drugs who underwent
In a study of 2885 Framingham Offspring Heart participants, exercise testing and were followed for 1 year. The 1-year mor-
exercise-induced premature ventricular beats were associ- tality rate was 1.4% versus 5.3% and the death/MI rate was
ated with a significant increased total mortality risk during 2.8% versus 15.8% in patients with a normal versus abnormal
a mean follow-up of 15 years, although the risk for hard exercise test. Lai et al.42 studied 1872 men ≥65 years of age
cardiac events (i.e., cardiac death or MI) was not significant. and reported that the peak METs achieved was an important
The all-cause mortality risk persisted after adjustment for predictor of all-cause mortality, and exercise-induced ST-
left ventricular function, ischemic ST-segment response, and segment depression predicted cardiovascular mortality. In an
presence of recovery premature ventricular beats.37 Frolkis angiographic substudy from the same population, a treadmill
et al.38 studied 29,244 patients (mean age 56 years) over a risk score was developed that provided more diagnostic infor-
mean 5.3 years and reported that frequent ventricular ectopy mation than ST-segment depression alone.42 In a 7354 study,
during the recovery phase of exercise was a better predictor patients >65 years reported by Messinger-Rapport et al.,43
of total mortality than ventricular ectopy occurring during impaired functional capacity and abnormal heart-rate recov-
exercise. O’Neill et al.39 reported complex ventricular ectopy ery were independent predictors of all-cause mortality.
appearing in the postexercise phase predicted increased mor-
tality (hazard ratio of 1.76) in 2123 patients with an ejection
fraction <35% (Fig. 33.16).39 Revascularization
Exercise-induced atrial arrhythmias do not predict
cardiac mortality or the need for coronary revascularization, An exercise ECG is often performed before revascularization
although there is an increased future risk of spontaneous in stable patients with coronary disease to provide an objec-
supraventricular tachyarrhythmias.40 Exercise testing is tive evidence of functional capacity and to document
indicated to adjust settings in rate-adaptive pacemakers and myocardial ischemia. The exercise ECG may be normal in
can be helpful in evaluating the ability to increase ventricu- patients with single-vessel coronary disease, particularly
lar rate in subjects with congenital heart block. when the right or left circumflex coronary artery is the
culprit vessel. Exercise electrocardiography is of little value
in localizing the territory of myocardial ischemia unless ST-
segment elevation occurs. Therefore, stress testing is usually
performed in combination with a nuclear imaging procedure
to determine the location and severity of myocardial isch-
1 emia. The value of early exercise testing after coronary revas-
cularization was evaluated in 1678 patients enrolled in the
Nonsevere VEA in recovery
bypass angioplasty revascularization investigation (BARI)
0.8 trial, a National Institutes of Health (NIH)-funded study that
Survival

tested coronary artery bypass graft (CABG) versus percutane-

No VEA in recovery ous transluminal coronary angioplasty (PTCA).44 The sub-
0.6 jects had serial symptom limited treadmill tests performed
Severe VEA in recovery at 1, 3, and 5 years after revascularization. Routine exercise
Log-rank χ2 = 15, df = 2, p = .0005 electrocardiography performed early after the procedure was
0.4 not predictive of subsequent cardiac events. Nevertheless,
0 1 2 3 4 5 the exercise ECG after coronary revascularization can be
Years after stress test useful in evaluating selected patients with symptoms due to
Number at risk incomplete revascularization, graft closure, or restenosis, as
No. VEA 1833 1425 1108 813 569 366 well as to assess functional capacity in selected patients
Nonsevere referred for cardiac rehabilitation.45 In this setting, knowl-
150 120 89 64 54 37
edge of the pre-revascularization exercise ECG findings can
Severe 140 99 79 50 39 21
facilitate interpretation of the post-revascularization exer-
FIGURE 33.16. Of 2123 patients with left ventricular systolic ejec-
tion fraction ≤35% who underwent treadmill exercise, 140 (7%) had cise findings by allowing comparison of ischemic thresholds
severe ventricular ectopy during recovery. Severe ventricular and change in functional capacity (Fig. 33.17). There is a
ectopy was defined as the presence of ventricular triplets, sustained small but finite risk of stent thrombosis when exercise
or nonsustained ventricular tachycardia, ventricular flutter, testing is done post–percutaneous coronary intervention
polymorphic ventricular tachycardia, or ventricular fibrillation.
Severe ventricular ectopy during recovery was associated with an
(PCI). Clinical stent thrombosis or access site complications
increased risk of death (3-year death rates 37% vs. 22%, Hazard ratio were not increased in a 1000-patient series randomized to an
1.76). exercise test versus no test 1 day after PCI.46
74 0 chapter 33

Exercise capacity Duke score between 35% and 80%. Values <40% are pathologically
reduced and indicate circulatory insufficiency. The breathing
100% 100%
Stage 3 reserve capacity of the ventilatory system is calculated as 1
–5 to 2
Percent survival

minus the ratio of peak exercise minute ventilation (VE) to

90% 90% maximal voluntary ventilation with normal values >30%.
≥3
≤–6 Lower values indicate ventilatory impairment, especially
<Stage 3
80% 80% when accompanied by oxygen desaturation. The respiratory
≥3
exchange ratio (Vco2/Vo2) is generally >1.2. Values <1.1,
Stage 3
70%
<Stage 3
70%
–5 to 2 particularly <1.0 in the absence of other metabolic abnor-
≤–6 malities, suggest poor effort, anxiety, or mild disease. Car-
A B
60% 60% diopulmonary exercise testing of cardiac and pulmonary
0 1 2 3 4 5 6 0 1 2 3 4 5 6 response to exercise can be useful in clarifying the etiology
Years from exercise test Years from exercise test of a patient’s symptoms (Fig. 33.18).
FIGURE 33.17. Survival curves 6 years after exercise test based on
ability to exercise to Bruce stage 3 (A) and the Duke scores (B).
Though both were used as prognostic indicators, exercise capacity Exercise Test Reporting
to Bruce stage 3 was an independent predictor of improved survival
for patients after revascularization. The exercise test report should include the indications that
prompted the test, a list of cardioactive medications that may
influence functional capacity or ECG response, and the exer-
cise protocol used. The report should list the reasons for
stopping exercise, the peak exercise capacity in minutes and
METs, the rest and peak heart rate and blood pressure, the
Valvular Heart Disease
percent maximum heart rate achieved, and a description of
As a general rule, exercise testing should not be performed any abnormalities seen on the exercise ECG tracing. When
in patients with severe aortic stenosis. However, in certain myocardial ischemia or angina occurs, the time of onset and
circumstances, it may be of value combined with echocar- offset should be reported. Cardiac arrhythmias (simple or
diographic imaging to assess rest-exercise gradients and complex) that occur during or after exercise should be noted.
provide an objective assessment of functional capacity in It is often useful to standardize the report output to referring
patients with relatively high peak Doppler aortic valve gra- physicians by designing a statement databank that remains
dients. Exercise testing is contraindicated in patients with uniform over time. Statements such as “submaximal test, no
severe aortic stenosis when the indication for surgical repair significant abnormalities noted at the workload performed”
is obvious. Testing should be carried out only by a physician to indicate that cardiac reserve may not have been fully
familiar with the patient, and the test should be terminated tested, or “high risk study, with exercise-induced angina and
if there is an inappropriate increase or decrease in blood pres- ST-segment changes at low exercise workloads” to prompt
sure, heart rate, or the development of cardiac arrhythmias additional workup, or “excellent exercise capacity with
or symptoms such as angina or excessive dyspnea. Exercise minor exercise-induced ST-segment changes that do not
testing is also helpful to determine functional capacity in meet diagnostic criteria for myocardial ischemia” to indicate
patients with other forms of valvular heart disease such as a lower risk study can facilitate patient management.
mitral stenosis or insufficiency (see Appendix).

Cardiopulmonary Exercise Testing

Gas exchange data can provide important information to Peak VO2
evaluate functional capacity and distinguish cardiovascular
from pulmonary limitations during exercise.47 Testing Normal Low
involves measurements of respiratory oxygen uptake (Vo2), ≥85% predicted <85% predicted
carbon dioxide production (Vco2), and ventilatory parameters
during a symptom-limited exercise test. The relationship Mild Anaerobic threshold
Anxiety Obesity
between work output, oxygen consumption, heart rate, and disease
cardiac output during exercise is linear. Peak exercise capac- Normal Low
≥40% predicted <40% predicted
ity is decreased when the ratio of measured to predicted PkVO2 PkVO2
Vo2max is <85% to 90% for age and gender. Measured Vo2 in
mL/min/kg divided by 3.5 mL O2·kg−1·min−1 determines the Breathing Breathing
number of METs associated with activity. Work and leisure reserve reserve
activities can be calculated in multiples of METs; the in- Normal Low Normal Low
formation obtained can then be used to prescribe physical ≥30% <30% ≥30% <30%
activities or estimate disability.
The gas exchange anaerobic threshold is the point at Poor Deconditioning Coronary Ventilatory Circulatory Mixed
which Ve increases disproportionately relative to Vo2 and effort disease impairment impairment lesions
work; it usually occurs at 40% to 60% of Vo2max in normal, FIGURE 33.18. Gas exchange parameters can be used to help
untrained individuals with a wide range of normal values resolve cardiac vs. pulmonary causes of dyspnea (see text).
 e x ercise t est i ng 741

Summary 6. Gianrossi R, Detrano R, Mulvihill D, et al. Exercise-induced

ST depression in the diagnosis of coronary artery disease. A
meta-analysis. Circulation 1989;80:87–98.
Exercise testing is a procedure associated with a very low
7. Froelicher VF, Fearon WF, Ferguson C, et al. Lessons learned
risk of complications that provides important diagnostic, from studies of the standard exercise ECG test. Chest
prognostic, and functional information for the evaluation of 1999;116:1442–1451.
patients with suspect or proven cardiac disease. When exer- 8. Morise AP, Diamond GA. Comparison of the sensitivity and
cise testing is used to establish a diagnosis of coronary specificity of exercise electrocardiography in biased and unbi-
disease, the clinician should be aware that the diagnostic ased populations of men and women. Am Heart J 1995;130:741–
accuracy of the test is imperfect and dependent on the pretest 747.
risk of disease. Patients with excellent exercise capacity and 9. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood
a normal electrocardiogram can be reassured that their prog- JE. Exercise capacity and mortality among men referred for
exercise testing. N Engl J Med 2002;346:793–801.
nosis is favorable, but they should never be told they do not
10. Mark DB, Hlatky MA, Harrell FE, et al. Exercise treadmill
have coronary disease on the basis of a normal test. Exercise
score for predicting prognosis in coronary artery disease. Ann
test variables associated with an adverse long-term prognosis Intern Med 1987;106:793–800.
include typical angina or ischemic ECG changes, complex 11. Mark DB, Shaw L, Harrell FE, et al. Prognostic value of a tread-
ventricular arrhythmias at low exercise workloads (e.g., <5 mill exercise score in outpatients with suspected coronary
METs), inability to increase heart rate or systolic blood pres- artery disease. N Engl J Med 1991;325:849–853.
sure with progressive workloads, a fall in blood pressure 12. Kwok JMF, Miller TD, Hodge DO, Gibbons RJ. Prognostic value
during exercise, and abnormal heart-rate recovery. Exercise- of the Duke treadmill score in the elderly. J Am Coll Cardiol
induced ischemic responses at a low workload are usually 2002;39:1475–1481.
considered an indication for cardiac catheterization and 13. Alexander KP, Shaw LJ, DeLong ER, Mark DB, Peterson ED.
Value of exercise treadmill testing in women. J Am Coll Cardiol
coronary revascularization in the absence of a clinical con-
1998;32:1657–1664.
traindication. Functional capacity is one of the most impor-
14. Morise AP, Jalisi F. Evaluation of pretest and exercise test
tant variables used to estimate prognosis and provides an scores to assess all-cause mortality in unselected patients
objective measure of cardiopulmonary and musculoskeletal presenting for exercise testing with symptoms of suspected
reserve. Peak aerobic capacity is used for disability evalua- coronary artery disease. J Am Coll Cardiol 2003;42:842–850.
tion, activity recommendations after a cardiac event, and 15. Morise AP, Olson MB, Merz CNB, et al. Validation of the accu-
calibration of rate-related cardiac pacemakers. Cardiopulmo- racy of pretest and exercise test scores in women with a low
nary testing with gas exchange measurements should be prevalence of coronary disease: the NHLBI-sponsored Women’s
considered in patients with dyspnea where the etiology of Ischemia Syndrome Evaluation (WISE) study. Am Heart J
the symptoms (i.e., cardiac or pulmonary) is in doubt. Exer- 2004;147:1085–1092.
16. Aktas MK, Ozduran V, Pothier CE, Lang R, Lauer MS. Global
cise testing should be combined with an imaging procedure
risk scores and exercise testing for predicting all-cause mortality
if the rest ECG contains abnormalities that preclude assess-
in a preventive medicine program. JAMA 2004;292:1462–1468.
ment of the exercise tracing, or if there are clinical indica- 17. Corra U, Mezzani A, Bosimini E, Giannuzzi P. Cardiopulmo-
tions that require the location(s) of the ischemic territory be nary exercise testing and prognosis in chronic heart failure: a
defined. prognosticating algorithm for the individual patient. Chest
2004;126:942–950.
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1. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guide- and severely impaired exercise capacity considered for heart
line update for exercise testing: a report of the American transplantation. J Am Coll Cardiol 1998;31:577–582.
College of Cardiology/American Heart Association Task Force 19. Corra U, Mezzani A, Bosimini E, et al. Limited predicted value
on Practice Guidelines (Committee on Exercise Testing), 2002. of cardiopulmonary exercise indices in patients with moderate
American College of Cardiology Web site. Available at: www. chronic heart failure treated with carvedilol. Am Heart J
acc.org/clinical/guidelines/exercise/dirIndex.htm. 2004;147:553–560.
2. Chaitman BR. Exercise stress testing. In: Libby P, Zipes D, 20. Myers J, Geiran O, Simonsen S, Ghuyoumi A, Gullestad L.
Bonow R, Braunwald E, eds. Braunwald’s Heart Disease: A Text- Clinical and exercise test determinants of survival after cardiac
book of Cardiovascular Medicine, 7th ed. Philadelphia: WB transplantation. Chest 2003;124:2000–2005.
Saunders, 2005:153–177. 21. Fang JC, Rocco T, Jarcho J, Ganz P, Mudge GH. Noninvasive
3. Porszasz J Casaburi R, Somfay A, Woodhouse LJ, Whipp B. A assessment of transplant-associated arteriosclerosis. Am Heart
treadmill protocol using simultaneous changes in speed and J 1998;135:980–987.
grade. Med Sci Sports Exerc 2003;35:1596–1603. 22. Erikssen G, Bodegard J, Bjornholt JV, Liestol K, Thelle DS,
4. Azarbal B, Hayes SW, Lewin HC, Hachamovitch R, Cohen I, Erikssen J. Exercise testing of healthy men in a new perspec-
Berman DS. The incremental prognostic value of percentage of tive: from diagnosis to prognosis. Eur Heart J 2004;25:978–
heart rate reserve achieved over myocardial perfusion single- 986.
photon emission computed tomography in the prediction of 23. Gibbons LW, Mitchell TL, Wei M, Blair SN, Cooper KH.
cardiac death and all-cause mortality: superiority over 85% of Maximal exercise test as a predictor of risk for mortality from
maximal age-predicted heart rate. J Am Coll Cardiol 2004; coronary heart disease in asymptomatic men. Am J Cardiol
44:423–430. 2000;86:53–58.
5. Vivekananthan DP, Blackstone EH, Potheir CE, Lauer MS. 24. Balady GJ, Larson MG, Vasan RS, Leip EP, O’Donnell CJ, Levy
Heart rate recovery after exercise is a predictor of mortality, D. Usefulness of exercise testing in the prediction of coronary
independent of the angiographic severity of coronary disease. J disease risk among asymptomatic persons as a function of the
Am Coll Cardiol 2003;42:831–838. Framingham Risk Score. Circulation 2004;110:1920–1925.
74 2 chapter 33

25. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. 44. Krone RJ, Hardison RM, Chaitman BR, et al. Risk stratification
Coronary artery calcium score combined with Framingham after successful coronary revascularization: the lack of a role
Score for risk prediction in asymptomatic individuals. JAMA for routine exercise testing. J Am Coll Cardiol 2001;38:136–
2004;291:210–215. 142.
26. Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and 45. Sellier P, Chatellier G, D’Agrosa-Boiteux MC, et al. Use of non-
the risk of death in women. The St. James Women Take Heart invasive cardiac investigations to predict clinical endpoints
Project. Circulation 2003;108:1554–1559. after coronary bypass graft surgery in coronary artery disease
27. Mora S, Redberg RF, Cui Y, et al. Ability of exercise testing to patients: results from the prognosis and evaluation of risk in
predict cardiovascular and all-cause death in asymptomatic the coronary operated patient (PERISCOP) study. Eur Heart J
women. A 20-year follow-up of the Lipid Research Clinics 2003;24:916–926.
Prevalence Study. JAMA 2003;290:1600–1607. 46. Roffi M, Wenaweser P, Windecker S, et al. Early exercise after
28. Topol EJ, Burek K, O’Neill WW, et al. A randomized controlled coronary stenting is safe. J Am Coll Cardiol 2003;42:1569–
trial of hospital discharge three days after myocardial infarc- 1573.
tion in the era of reperfusion. N Engl J Med 1988;138:1083– 47. Weisman IM, Marciniuk D, Martinez FJ, et al. ATS/ACCP
1088. statement on cardiopulmonary exercise testing. Am J Respir
29. Grines CL, Marsalese DL, Brodie B, et al. Safety and cost-effec- Crit Care Med 2003;167:211–277.
tiveness of early discharge after primary angioplasty in low risk
patients with acute myocardial infarction. J Am Coll Cardiol
1998;31:967–972.
30. De Luca G, Suryapranata H, van’t Hof AWJ, et al. Prognostic Appendix 33.1
assessment of patients with acute myocardial infarction treated
with primary angioplasty: implications for early discharge.
I. The American College of Cardiology/American Heart
Circulation 2004;109:2737–2743.
31. Newby LK, Eisenstein EL, Califf RM, et al. Cost effectiveness Association (ACC/AHA) classifications I, II, and III are
of early discharge after uncomplicated acute myocardial infarc- used to summarize indications as follows:
tion. N Engl J Med 2000;342:749–755. Class I: Conditions for which there is evidence and/or
32. Amsterdam EZ, Kirk JD, Diercks DB, Lewis WR, Turnipseed general agreement that a given procedure or
SD. Immediate exercise testing to evaluate low-risk patients treatment is useful and effective.
presenting to the emergency department with chest pain. J Am Class II: Conditions for which there is conflicting
Coll Cardiol 2002;40:251–256. evidence and/or a divergence of opinion about
33. Gibbons RJ, Hodge DO, Berman DS, et al. Long-term outcome the usefulness/efficacy of a procedure or
of patients with intermediate-risk exercise electrocardiograms
treatment.
who do not have myocardial perfusion defects on radionuclide
Class IIa: Weight of evidence/opinion is in favor of
imaging. Circulation 1999;100:2140–2145.
34. Jouven X, Zureik M, Desnos M, Courbon D, Ducimetiere P. usefulness/efficacy.
Long-term outcome in asymptomatic men and exercise-induced Class IIb: Usefulness/efficacy is less well established by
premature ventricular depolarizations. N Engl J Med 2000;343: evidence/opinion.
826–833. Class III: Conditions for which there is evidence and/or
35. Engel G, Beckerman JG, Froelicher VF, et al. Electrocardio- general agreement that the procedure/treat-
graphic arrhythmia risk testing. Curr Probl Cardiol 2004;29: ment is not useful/effective and in some cases
365–432. may be harmful.
36. Partington S, Myers J, Cho S, Froelicher V, Chun S. Prevalence
and prognostic value of exercise-induced ventricular arrhyth- II. Exercise testing to diagnose obstructive coronary artery
mias. Am Heart J 2003;145:139–146. disease
37. Morshedi-Meibodi A, Evans JC, Levy D, Larson MG, Vasan RS. Class I: Adult patients (including those with complete
Clinical correlates and prognostic significance of exercise- right bundle-branch block or less than 1 mm or
induced ventricular premature beats in the community: resting ST depression) with an intermediate
the Framingham Heart Study. Circulation 2004;109:2417– pretest probability of CAD on the basis of
2422.
gender, age, and symptoms (specific exceptions
38. Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent
ventricular ectopy after exercise as a predictor of death. N Engl
are noted under classes II and III below).
J Med 2003;348:781–790. Class IIa: Patients with vasospastic angina.
39. O’Neill JO, Young JB, Pothier CE, Lauer MS. Severe frequent Class IIb: 1. Patients with a high pretest probability of
ventricular ectopy after exercise as a predictor of death in CAD by age, symptoms, and gender.
patients with heart failure. J Am Coll Cardiol 2004;44:820– 2. Patients with a low pretest probability of
826. CAD by age, symptoms, and gender.
40. Bunch TJ, Chadrasekaran K, Gersh BJ, et al. The prognostic 3. Patients with <1 mm of baseline ST depres-
significance of exercise-induced atrial arrhythmias. J Am Coll sion and taking digoxin.
Cardiol 2004;43:1236–1240. 4. Patients with electrocardiographic criteria
41. Jeger RV, Zellweger MJ, Kaiser C. Prognostic value of stress
for left ventricular hypertrophy (LVH) and
testing in patients over 75 years of age with chronic angina.
Chest 2004;125:1124–1131.
<1 mm of baseline ST depression.
42. Lai S, Kaykha A, Yamazaki T, et al. Treadmill scores in elderly Class III: 1. Patients with the following baseline ECG
men. J Am Coll Cardiol 2004;43:606–615. abnormalities:
43. Messinger-Rapport B, Pothier Snader CE, Blackstone EH, Yu D, • Preexcitation (Wolff-Parkinson-White)
Lauer MS. Value of exercise capacity and heart rate recovery in syndrome
older people. J Am Geriatr Soc 2003;51:63–68. • Electronically paced ventricular rhythm
 e x ercise t est i ng 74 3
• >1 mm of resting ST depression not done (symptoms limited; about 14 to
• Complete left bundle branch block 21 days).*
2. Patients with a documented myocardial 3. Late after discharge for prognostic assess-
infarction or prior coronary angiography ment, activity prescription, evaluation of
demonstrating significant disease have an medical therapy, and cardiac rehabilita-
established diagnosis of CAD; however, tion if the early exercise test was submaxi-
ischemia and risk can be determined by mal (symptom limited; about 3 to 6
testing (see sections III and IV). weeks).*
Class IIa: After discharge for activity counseling and/or
III. Risk assessment and prognosis in patients with symp-
exercise training as part of cardiac rehabilita-
toms or a prior history of CAD
tion in patients who have undergone coronary
Class I: 1. Patients undergoing initial evaluation
revascularization.
with suspected or known CAD, including
Class IIb: 1. Patients with the following ECG
those with complete right bundle-branch
abnormalities:
block or <1 mm of resting ST depression.
• Complete left bundle-branch block
Specific exceptions are noted below in
• Pre-excitation syndrome
class IIb.
• LVH
2. Patients with suspected or known CAD,
• Digoxin therapy
previously evaluated, now presenting with
• >1 mm of resting ST-segment depression
significant change in clinical status.
• Electronically paced ventricular rhythm
3. Low-risk unstable angina patients 8 to 12
2. Periodic monitoring in patients who con-
hours after presentation who have been
tinue to participate in exercise training or
free of active ischemic or heart failure
cardiac rehabilitation.
symptoms (level of evidence: B).
Class III: 1. Severe comorbidity likely to limit life
4. Intermediate-risk unstable angina patients
expectancy and/or candidacy for
203 days after presentation who have been
revascularization.
free of active ischemic or heart failure
2. At any time to evaluate patients with
symptoms (level of evidence: B).
acute myocardial infarction who have
Class IIa: Intermediate-risk unstable angina patients
uncompensated congestive heart failure,
who have initial cardiac markers that are
cardiac arrhythmia, or noncardiac condi-
normal, a repeat ECG without significant
tions that severely limit their ability to
change, and cardiac markers 6 to 12 hours
exercise (level of evidence: C).
after the onset of symptoms that are normal
3. Before discharge to evaluate patients
and no other evidence of ischemia during
who have already been selected for, or
observation (level of evidence: B).
have undergone, cardiac catheterization.
Class IIb: 1. Patients with the following resting ECG
Although a stress test may be useful before
abnormalities:
or after catheterization to evaluate or
• Preexcitation (Wolff-Parkinson-White)
identify ischemia in the distribution of a
syndrome
coronary lesion of borderline severity,
• Electronically paced ventricular rhythm
stress imaging tests are recommended
• 1 mm or more of resting ST depression
(level of evidence: C).
• Complete left bundle-branch block or
any interventricular conduction defect V. Exercise testing with ventilatory gas analysis
with a QRS duration >120 ms Class I: 1. Evaluation of exercise capacity and
2. Patients with a stable clinical course who response to therapy in patients with heart
undergo periodic monitoring to guide failure who are being considered for heart
treatment. transplantation.
Class III: 1. Patients with severe comorbidity likely to 2. Assistance in the differentiation of cardiac
limit life expectancy and/or candidacy for versus pulmonary limitations as a cause of
revascularization. exercise-induced dyspnea or impaired exer-
2. High-risk unstable angina patients (level cise capacity when the cause is uncertain.
of evidence: C). Class IIa: Evaluation of exercise capacity when indi-
cated for medical reasons in patients in whom
IV. After myocardial infarction
the estimates of exercise capacity from exer-
Class I: 1. Before discharge for prognostic assess-
cise test time or work rate are unreliable.
ment, activity prescription, evaluation of
Class IIb: 1. Evaluation of the patient’s response to spe-
medical therapy (submaximal at about 4
cific therapeutic interventions in which
to 6 days).*
improvement of exercise tolerance is an
2. Early after discharge for prognostic assess-
important goal or end point.
ment, activity prescription, evaluation of
medical therapy, and cardiac rehabilita-
tion if the predischarge exercise test was * Exceptions are noted under classes IIb and III.
74 4 chapter 33

2. Determination of the intensity for exer- • Preexcitation

cise training as part of comprehensive • Electronically paced ventricular rhythm
cardiac rehabilitation. • >1-mm ST depression
• Complete left bundle branch block
Class III: Routine use to evaluate exercise capacity.
VI. Special groups: women, asymptomatic individuals, and Exercise Testing Before and After Revascularization
postrevascularization patients Class I: 1. Demonstration of ischemia before
revascularization.
Exercise testing in asymptomatic persons without known 2. Evaluation of patients with recurrent
CAD: symptoms that suggest ischemia after
Class I: None revascularization.
Class IIa: Evaluation of asymptomatic persons with Class IIa: After discharge for activity counseling and/or
diabetes mellitus who plan to start vigorous exercise training as part of cardiac rehabilita-
exercise (level of evidence: C). tion in patients who have undergone coronary
Class IIb: 1. Evaluation of persons with multiple revascularization.
risk factors as a guide to risk-reduction Class IIb: 1. Detection of restenosis in selected, high-
therapy.** risk asymptomatic patients within the
2. Evaluation of asymptomatic men older first 12 months after percutaneous coro-
than 45 years and women older than 55 nary intervention (PCI).
years: 2. Periodic monitoring of selected, high-risk
• Who plan to start vigorous exercise asymptomatic patients for restenosis, graft
(especially if sedentary) or occlusion, incomplete coronary revascu-
• Who are involved in occupations in larization, or disease progression.
which impairment might affect public Class III: 1. Localization of ischemia for determining
safety or who are at high risk for CAD the site of intervention.
due to other diseases (e.g., peripheral 2. Routine, periodic monitoring of asymp-
vascular disease and chronic renal tomatic patients after percutaneous
failure). coronary intervention (PCI) or coronary
Class III: Routine screening of asymptomatic men or artery bypass grafting without specific
women. indications.

Valvular Heart Disease Investigation of Heart Rhythm Disorders

Class I: In chronic aortic regurgitation, assessment Class I: 1. Identification of appropriate settings in

of functional capacity and symptomatic patients with rate-adaptive pacemakers.
responses in patients with a history of equivo- 2. Evaluation of congenital complete heart
cal symptoms. block in patients considering increased
Class IIa: 1. In chronic aortic regurgitation, evaluation physical activity or participation in com-
of symptoms and functional capacity petitive sports (level of evidence: C).
before participation in athletic activities. Class IIa: 1. Evaluation of patients with known or
2. In chronic aortic regurgitation, prognostic suspected exercise-induced arrhythmias.
assessment before aortic valve replace- 2. Evaluation of medical, surgical, or
ment in asymptomatic or minimally ablative therapy in patients with exercise-
symptomatic patients with left ventricu- induced arrhythmias (including atrial
lar dysfunction. fibrillation).
Class IIb: Evaluation of exercise capacity in patients Class IIb: 1. Investigation of isolated ventricular
with valvular heart disease. Comprehensive ectopic beats in middle-aged patients
discussion is found in the ACC/AHA valvular without other evidence of CAD.
heart disease guidelines. 2. Investigation of prolonged first-degree
Class III: Diagnosis of CAD in patients with moderate atrioventricular block or type I second-
to severe valvular disease or with the follow- degree Wenckebach, left bundle branch
ing baseline ECG abnormalities: block, right bundle branch block, or iso-
lated ectopic beats in young patients con-
sidering participation in competitive
sports (level of evidence: C).
** Multiple risk factors are defined as hypercholesterolemia Class III: Routine investigation of isolated ectopic beats
(>240 mg/dL), hypertension (systolic blood pressure >140 mm Hg or in young patients.
diastolic blood pressure >90 mm Hg), smoking, diabetes, and family
history of heart attack or sudden cardiac death in a first-degree rela-
tive younger than 60 years. An alternative approach might be to
select patients with a Framingham risk score consistent with at
least a moderate risk of serious cardiac events within 5 years.
 3 Coronary Angiography
4 Robert F. Wilson and Carl W. White

Technical Aspects of Coronary Angiography . . . . . . . . . 745 Coronary Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 776

Complications of Coronary Angiography . . . . . . . . . . . . 758 Nonatherosclerotic Coronary Artery Disease. . . . . . . . . 788
Coronary Anatomy and Radiographic Evaluation . . . . . 762

Key Points Technical Aspects of Coronary Angiography

• Nonionic, low osmolar, and iso-osmolar contrast media
have substantially less deleterious effect on ventricular Facility Requirements
function and should be used in patients with acute isch-
emic syndromes, heart failure, severe aortic stenosis, and Radiographic Imaging
left main coronary artery disease.
• High-grade stenoses are often associated with a total Radiographic imaging of coronary arteries is demanding
failure of vascular remodeling. Calculating percent ste- because they are small and move quickly with contraction
noses is flawed, and on average, overestimates diameter of the heart. A radiographic imaging system can be divided
stenosis by 30% when compared to an angiographic into an x-ray generator consisting of a high-voltage trans-
equivalent. former and x-ray tube, and an imaging chain that is com-
• In patients with multivessel coronary atherosclerosis and posed of an image detector and a display (video). The general
isolated discrete stenoses varying in severity between schematic is shown in Figure 34.1.3–5
10% and 95% stenosis, measurements of the anatomic
X-R AY GENERATION
stenosis severity were not correlated significantly with
The x-ray photons are generated by a vacuum tube that has
the reactive hyperemic response.
a stationary cathode and a rotating anode. A focal spot on
• In patients, a fractional flow reserve (FFR) of >0.75 is
the anode is bombarded by electrons from the cathode,
highly correlated with noninvasive tests of myocardial
exciting the anode to produce high-energy photons with X
ischemia.
radiation wavelengths (less than 1 Å). The energy of the elec-
• Deferral of an interventional procedure based on a
trons, and hence the energy (or wavelength) of the generated
normal coronary flow reserve or an FFR greater than or
photons, is determined by the voltage potential between the
equal to 0.75 is associated with a lower clinical event rate
cathode and anode. A high tension, three-phase transformer
than if the procedure had been done as originally
is used to generate the voltage potential, which normally
planned.
ranges between 50 and 100 kV. The number of available elec-
The advent of selective coronary angiography almost five trons accelerated into the anode, and hence number of
decades ago revolutionized the clinical practice of cardiology photons produced, is controlled by the amount of current
and since then has added immeasurably to our understand- (measured in mA) passed through a filament in the cathode.
ing of coronary artery disease and its sequelae. Since its In practice, about 350 to 1000 mA of current through the
inception in the 1950s, it has become one of the most cathode is needed to generate an x-ray beam adequate for
common invasive medical procedures. In 2004, coronary cineangiography.
angiography was performed in over 2 million patients Less than 1% of the electron energy delivered to the
in more than 1500 catheterization laboratories in the anode results in x-ray photons that become part of the x-ray
United States and in an estimated 4.5 million patients beam leaving the tube. A large fraction of the delivered
worldwide.1,2 energy is converted into photons, which are reabsorbed

74 5
74 6 chapter 34

H G
Video camera
Cine camera F
E
C-arm gantry
D
Image intensifier
C

B
A

Collimator

Cathode

Aluminum
screen X-ray tube

Anode

Collimator
FIGURE 34.1. Schematic of radiographic imaging system for cine- crystal cause electron emission from the photocathode (B). The
angiography. The x-ray beam is generated by an x-ray tube (lower electrons are accelerated (C) and focused on a phosphor screen (D).
right box). The beam passes through a collimator (lower left box), The image on the screen is split optically (F) and imaged with a
where lead apertures form and limit the beam. On intersection with video pickup device (G) or 35mm cine film (H). A photo detector (E)
the patient, most of the beam is reflected or absorbed. The remain- measures the photon output from the central zone of the phosphor
ing photons pass through to the image intensifier (upper right box), image and provides feedback to adjust the x-ray dose and iris
where they impact on a cesium iodide crystal (A). Photons from the settings.

within the anode and heat. Rotation of the anode effectively photons, or quantum, to create the image. An insufficient
increases the surface area over which the heat generation can number of photons reaching the imaging device leads to a
be dispersed. The capacity of the x-ray tube to dissipate heat grainy image appearance (termed quantum mottling).
is of considerable practical importance to angiographic labo-
ratories because tubes with a low heat capacity limit the rate IMAGE DETECTION
at which angiographic pictures can be taken during the After photon emission from the x-ray tube, the beam passes
procedure. through a filter to eliminate low-energy photons and through
The sharpness of the image cast onto the imaging device a collimator, a series of lead apertures that form and limit
is affected by the size of the focal spot on the anode (the area the beam directed at the patient. On interfacing with the
of the anode bombarded with electrons). The smaller the patient, some photons are absorbed, some are reflected (scatter
focal spot, the crisper the shadow the x-ray beam can cast. radiation), and some pass through entirely, reaching the
Conversely, however, fewer photons can be generated from image detector. A grid over the image intensifier helps screen
small focal spots. For thinner adults and shallow radiographic out scatter radiation by passing only photons that are
angles, a focal spot of 0.6 to 0.7 mm provides good resolution relatively perpendicular to the image detector face and by
with an adequate number of photons to create a good image, screening out low-energy x-rays.
but focal spots of 1.0 to 1.2 mm may be needed for larger On impact with the cesium iodide crystal on the face of
patients and extreme angulation. the image intensifier, the x-ray photons are absorbed and
All x-ray tube anodes are beveled (Fig. 34.1). Less acute cause the emission of lower energy photons. In older systems,
bevels on the rotating anode reduce the focal spot and beam these photons are absorbed by a photocathode coating the
angle and refine the x-ray beam because more lower energy inner surface of the crystal and cause electron emission from
photons are absorbed within the anode. As the anode angle the photocathode. The electrons are accelerated and focused
is reduced, however, the amount of heat generated increases. onto a phosphor screen, where they liberate photons in the
In practice, modern x-ray tubes for coronary angiography visible light range. The light from the phosphor screen of the
have an anode angle of 8 to 10 degrees. image intensifier is picked up on a television camera and
Within the emitted x-ray beam, the photons vary from displayed as a fluoroscopic video image, or recorded onto
lower energy “soft” radiation to higher energy “hard” radia- cineangiographic film (usually 35 mm). In modern “flat
tion. By increasing the voltage potential (kilovolt, kV) panel” detectors, charge couple devices (CCDs) absorb the
between the cathode and anode, a “harder,” higher energy electron and create a digital image.
spectra is produced. This leads to increased radiographic pen- The dimension of the image intensifier determines the
etration and contrast. Good imaging also requires enough size of the field that can be imaged. Most image intensifiers
 corona ry a ngiogr a ph y 747
are bi- or trimodal, such that several field sizes can be imaged CINEANGIOGRAPHY
from one large detector, allowing image magnification. In For cineangiography, an x-ray beam must be pulsed to provide
the older image intensifiers, the entire cesium iodide crystal for adequate “stop motion” imaging and to limit x-ray expo-
face can be focused onto the phosphor screen or a smaller sure. Thirty to 60 exposures/sec are needed to give the
portion can be imaged, ignoring photons from the periphery appearance of a “live” continuous image, although 15 frames/
of the crystal. Focusing on a smaller part of the input crystal sec can produce a relatively smooth image if the software
face increases the magnification of the image on the phos- eliminates flicker. Frame rates greater than 30/sec are needed
phor screen but decreases the signal intensity (fewer elec- only in patients with rapid heart rates. The exposure duration
trons are focused onto the same size phosphor screen). This per frame should not exceed 5 to 8 ms to prevent motion
is compensated for by increasing the x-ray dose, which blurring.6 Exposure time control is achieved by pulsing the
increases the number of x-ray photons and hence the number current to the x-ray tube. Initially, this was accomplished by
of electrons emitted per area of the central crystal. The pulsing the power to the high-energy transformer (“the gen-
increase in x-ray dose to the patient is mitigated by the erator”) leading to the x-ray tube. Modern switching systems
smaller field of radiation. Larger field sizes (9 to 11 inches) pulse the high-voltage side of the transformer output, yield-
are needed for ventriculography, and smaller sizes (4 to 5 ing relatively square pulse waves. Pulsing at 7.5 to 15 frames/
inches) may be required for pediatric angiography. For coro- sec has now been applied to fluoroscopy with some reduction
nary angiography, the optimum size of image intensifier is 5 in radiation exposure.7
to 7 inches (13 to 18 cm).
In flat-panel detectors, magnification of the image is DIGITAL PROCESSING, DISPLAY, AND STORAGE
accomplished digitally by restricting image acquisition to a Originally, a 35 mm film camera was used to record the
smaller portion of the CCD pickup. Since pixel density phosphor screen image as cineangiography. Nearly all newer
(pixels per square centimeter on the CCD chip), the number radiographic systems incorporate digital image processing of
of pixels is smaller in a magnified image. Unlike the older the video pickup signal or obtain the image directly from
image intensifier design, image acquisition resolution is the CCD chips. For coronary angiography, a pixel matrix of at
same for unmagnified and magnified images obtained on a least 512 × 512 density and 256 gray levels (8 bits) per frame
digital flat panel detector. Radiation exposure, however, is are needed to give acceptable resolution and a 1024 × 1024
reduced because the field of radiation is limited to the portion matrix is needed for diagnostic quality angiography. A variety
of the detector used for the imaging. of pixel-processing algorithms are employed to enhance
Modern imaging equipment optimizes x-ray generation image clarity.
by way of a feedback loop with the imaging chain. By mea- Display monitors should be able to show all of the image
suring the brightness of the center of the phosphor image of detail presented by the image chain. Monitors display at 525
the intensifier, the amount and energy of photons emitted or 1023 to 1049 lines per screen. The higher line rate provides
from the x-ray tube can be varied to obtain optimal image more resolution, but also decreases the signal-to-noise ratio.
brightness. Automatic brightness control systems adjust for Flat-panel liquid-crystal displays (LCDs) have been used
the radiodensity of the patient by varying kV and mA deliv- recently, but their reaction time and contrast ratio are still
ered to the x-ray tube, and by adjusting an iris between inferior to cathode ray tube (CRT) displays.
the phosphor output screen and the imaging system (video Digitized cineangiograms contain an enormous amount
or film). of information (typically 150 to 800 MB per study), making
storage and computer network transfer a challenge. Nearly
FLUOROSCOPIC DISPLAY all digital images are stored using a DICOM (Digital Imaging
Images obtained from the imaging device are displayed on a and COmmunication in Medicine) format that permits inter-
video system. The video image is composed of horizontal change of information between different manufacturers’
lines. Modern displays show 1024 lines per image. Older systems. In many labs, storage is done on compact discs or
systems used an interlaced display mode that was used in DVDs. The discs are then filed similarly to the older 35 mm
commercial television (NTSC standard). Using the interlaced film studies or placed into an automated jukebox, which is
display, every other line on the video output is scanned every attached to a computer network. These automated mass
1/60th of a second. By alternating the scans, a complete storage devices, called picture archiving communication
image is displayed every 1/30th of a second. This interlacing systems (PACSs), can store huge numbers of angiograms that
process eliminates the apparent image flicker that the eye can be retrieved over a computer network anywhere in the
perceives when images are scanned at 30 frames/second. hospital or over the Internet. Transmission speed of Intranet
Images of a rapidly moving heart, however, can be blurred and Internet connections remains a problem, so many of the
because motion has occurred between the first and second images are downgraded to a lower resolution to permit more
interlacing scans that paint the entire image. rapid transmission and to reduce storage costs.
More recent systems use a progressive scan method where
the entire image is displayed line by line every 1/60th of a IMAGE R ESOLUTION
second. This process permits better resolution of moving The image quality can be defined by several methods. Overall
objects. It also, however, leads to additional electronic noise resolution of the digital image is limited by pixel density.
and some quantum mottle (see above). Most manufacturers Although initial acquisition of 1024 × 1024 pixel matrix is
also employ systems that pulse the x-ray exposure. This the rule, saved images are typically downgraded to 512 × 512
“pulse fluoro” approach can further improve image sharp- density to save storage space. Image resolution is measured
ness. Radiation exposure is modestly reduced. as the ability of the eventual image display (film or video) to
74 8 chapter 34

distinguish closely spaced lead wires and pixel density. To laboratory personnel results from scatter radiation from the
provide adequate resolution of fine coronary detail, the cine- patient (primarily internal reflection). Scatter radiation
angiographic film resolution should exceed 3.5 to 4.0 line increases directly with the size of the patient and the number
pairs per millimeter for a 6- to 7-inch image intensifier field.6 of photons in the x-ray beam and inversely with the energy
Image intensifier veiling glare is tested by filming a circular of the photons (higher kV energy photons are less likely to
lead disk. The contrast ratio of the disk to the surrounding be reflected).
area should be at least 20 : 1. The radiation exposure for personnel can be reduced by
Regardless of the display mode, image distortion occurs attention to the patient exposure factors described above, by
for the following reasons: (1) Magnification of the image is having the personnel stay as far away as possible from the x-
dependent on the distance between the x-ray tube, the patient, ray source (the dose falls inversely with distance), and by
and the image intensifier. Objects closer to the tube are more having the personnel wear radiation shielding.17,18 Most of the
magnified. (2) Images close to the x-ray tube and far from the reflected radiation is directed away from the beam direction
image intensifier are more blurred. (3) Photon scatter within (i.e., away from the image intensifier). Physician exposure is
the image intensifier and subsequent phosphor display pickup greatest when the image intensifier is pointed away from the
(veiling glare) can lead to a loss of contrast. In addition, in physician (Fig. 34.2).13,17 The brachial and radial artery
older units the image intensifier is not entirely flat; it is approaches to catheter insertion increases physician radia-
slightly curved like a pin cushion and increases the apparent tion exposure by nearly 40% compared to the femoral
size of objects at the periphery. approach.9–11
All personnel should wear lead aprons with 0.5-mm lead
Radiation Protection lining, a thyroid shield, and eye protection.9 Aprons with
0.5-mm lead shielding absorb 90% of the x-ray dose (70% for
Radiation protection is an important responsibility for all
0.25-mm lead lining) and leaded glasses reduce lens exposure
catheterization laboratory personnel.8–19 To achieve adequate
by approximately 40%. Leaded surgical gloves, however,
imaging, the newer image detectors need to receive 10 to
absorb only 10% of the radiation dose and have minimal
40 μR/frame (varying inversely with image intensifier field
efficacy. A table shield is also effective in reducing scatter
size in older units).19 For routine fluoroscopy using a 6- to 7-
radiation and should be used in all laboratories.
inch field, this amounts to a skin entrance dose of approxi-
All personnel should also wear radiation detection badges
mately 3 to 10 R/min (increasing with angulation and patient
to quantitate their own exposure and identify faulty equip-
density) because most of the x-ray beam is absorbed or
ment. The annual environmental radiation exposure (e.g.,
reflected by the patient. Cineangiography increases the skin
from radon and cosmic rays) is about 360 rem/year in most
entrance dose to approximately 20 to 70 mR/frame (0.6–2.1 R/
parts of the United States. Current accepted limits (U.S.) for
sec at 30 frames/sec, increasing with angulation and patient
radiation exposure for personnel are 30 to 50 rem/year super-
density). The deep midline tissue dose is approximately one
ficial skin dose, 50 to 75 rem/year for the hands and forearms,
tenth of the skin dose and it should be kept in mind that the
5 to 15 rem/year for the lens, 5 rem/year (and <3 rem for any
field of radiation is small, so that the average total body dose
3-month period) deep dose (under the lead apron), and a
is substantially smaller than the chest dose. Patient radiation
cumulative dose of <1 rem/years of age.15,16
exposure can be minimized primarily by keeping the foot off
the x-ray on-off switch, by proper collimation of the x-ray
Physical Layout and Physiologic
beam to prevent needless exposure of peripheral structures,
Recording Equipment
and by maintaining the radiographic equipment such that a
minimum x-ray dose is needed for adequate imaging. A catheterization laboratory should provide at least 600
Unless laboratory staff members place their hands in the square feet of laboratory and control room space, and ade-
radiation path, they should receive very little direct radiation quate facilities for x-ray equipment (generator, etc.) and
exposure because by U.S. law all of the direct radiation emit- storage.3,6 A physiologic monitor for recording the electrocar-
ting from the collimator must land on the image intensifier. diogram (in multiple leads) and intravascular pressures
However, only about 2% of the x-ray photons emitted from should be located outside the radiation field. It is important
the x-ray tube ever reach the image detector, the rest being that the pressure recording system be calibrated daily and
absorbed or reflected. Most of the radiation exposure to the that optimal transducer damping is adjusted. Physiologic

Eye exposure = 35 mR/hr Eye exposure = 110 mR/hr

4 4
3 3
2 25–50 mR/hr 2 25–50 mR/hr
50–100 50–100
1 100–200 1 100–200
200–300 200–300
0 >300 0 >300
Scale (ft) Scale (ft)
FIGURE 34.2. Radiation exposure to personnel during fluorography. Angulation of the x-ray tube toward personnel increases the
exposure.
 corona ry a ngiogr a ph y 74 9
recorders digitize the pressure waveforms and computer- placed in the aorta, some of the side holes opposed the coro-
analyze a variety of hemodynamic parameters (e.g., end-dia- nary ostia and contrast injection opacified these arteries.
stolic pressures, systolic or diastolic pressure gradients Selective injection of contrast media into the coronary arter-
between two transducers, and waveform differentiation). It ies was limited by fear that the available radiographic con-
is important to be familiar with the algorithms used to trast agents would cause ventricular fibrillation. This was
derive these parameters before relying on the computer- quite justified because in an era before direct current cardio-
derived parameters for clinical decision making. version, fibrillation was a lethal complication.
All catheterization laboratories should be equipped to The advent of selective coronary opacification was intro-
manage the complications of catheterization. This includes duced by Mason Sones, who inadvertently selectively injected
a full stock of catheters and emergency drugs, the capability a right coronary artery during an attempted left ventricular
for rapid defibrillation and right heart pacing, and the imme- angiogram. The patient did not develop ventricular fibrilla-
diate availability of an intraaortic balloon pump. tion and Sones went on to develop a selective coronary cath-
eter that could be deflected off the aortic valve into either
Personnel coronary ostium, whereupon contrast could be injected.24
Changes in contrast media and improvements in radiographic
In addition to the cardiologist performing the procedure, a imaging have led to better resolution of the coronary tree
physiologic recording technician should be monitoring and with less toxicity and radiation exposure. Improvements in
recording the electrocardiogram and pressure measure- radiographic positioning equipment enabled steep angulated
ments.6 A circulating nurse should be present during angiog- views of the coronary circulation that are needed to image
raphy to administer drugs and fluids and to retrieve catheters. effectively the proximal left coronary vessels.
A radiologic technician (or equivalent) should be available to With the prior introduction of the Seldinger method of
assist in operating the radiographic equipment and moving peripheral vascular cannulation, Judkins, Amplatz, Abrams,
the x-ray table. In many laboratories, a scrub nurse or techni- Schoonmaker and others invented preformed catheters that
cian is also available to assist in catheter preparation. Should could be passed with great ease from the femoral artery to
a complication develop, additional personnel should be the coronary ostium.24–30 Since then an explosion of catheter
immediately available. material and shapes has made possible nearly effortless can-
For percutaneous procedures that do not involve a nulation of most coronary arteries and bypass grafts. As
cutdown or prolonged catheter placement, the personnel in Melvin Judkins is quoted as saying, “The catheter will find
the room should observe good principles of hygiene. The the coronary ostium unless impeded by the operator.” The
same intensity of sterile practices performed in an operating technique of coronary cannulation and opacification is
room is not supported for percutaneous catheterizations, pri- important, however, because both the safety and quality of
marily because the rate of infection for these procedures is coronary arteriography can be improved by rigorous atten-
extraordinarily low.20 Personnel at the site of catheter inser- tion to certain principles.
tion should wash their hands thoroughly and wear gloves. A
gown, mask, and protective eyewear should be worn to
protect the operator against blood-borne pathogens (e.g., HIV, Patient Preparation
hepatitis). If vascular access is accomplished by cutdown, The evaluation of patients about to undergo coronary angi-
sterile apparel (gown, glove, and mask) and limited room ography should emphasize a detailed history concerning
access should be undertaken because the rate of infection is factors that affect the approach and risks of angiography, a
approximately 10-fold that of percutaneous procedures.20 physical examination concentrating on the cardiovascular
system, and a frank discussion of the procedure and its antic-
ipated risks and benefits.
Techniques of Coronary Angiography
The history should include questions about prior experi-
ence with angiography, and prior or current vascular diseases
Technical History of Coronary Angiography
(e.g., stroke, transient ischemic attack, claudication) and pre-
Nonselective angiography of the coronary arteries was vious vascular procedures (particularly aortic or iliofemoral
accomplished first in the 1920s and 1930s using an aortic revascularization). Additionally, the presence of factors
injection of radiographic contrast media and cut film increasing sensitivity to drugs used during catheterization
imaging.21 Coronary imaging was limited by the toxicity and should be noted so that appropriate precautions can be taken.
limited opacity of the di-iodinated contrast media, the This includes radiographic contrast materials (e.g., diabetes,
restricted rate of contrast injection through the needle or preexisting nephropathy, prior reaction to contrast), prot-
small-lumen catheters used for intravascular access, and amine sulfate (e.g., α1-antitrypsin deficiency), narcotics, ben-
poor radiographic imaging resolution. A variety of methods zodiazepines, and heparin or other anticoagulants (e.g.,
were used subsequently to enhance coronary filling, includ- gastrointestinal disease).
ing acetylcholine-induced cardiac arrest and occlusion of the The physical examination should concentrate on the vas-
distal aorta to limit peripheral arterial runoff.22 Although cular system and elements that might change the approach
normal proximal coronary anatomy could be discerned by for the procedure. The quality of the pulses in both upper
these methods, the structure of distal vessels and diseased (brachial, radial, and ulnar) and lower extremities (femoral,
arteries was poorly defined. dorsalis pedis, popliteal, and posterior tibia) should be
Semi-selective coronary angiography was performed later recorded because problems in obtaining vascular access
using a circular catheter with numerous side holes.23 When may necessitate a change in cannulation site and embolic
75 0 chapter 34

complications can occur in any vascular territory. In patients insulin (such as Lantus) should be administered in the usual
where radial access is anticipated, an Allen test should be dose. If insulin is given, a 5% glucose solution should be
performed to ensure patency of the ulnar artery. Particular infused until catheterization and supplemental oral glucose
attention also should be paid to the quality of carotid artery can be given as needed. Metformin, an oral hypoglycemic
upstroke and the presence of carotid, abdominal (renal), or agent, should be held before and after angiography in patients
femoral bruits. Although not always possible, it is better to with increased risk of renal failure. The drug can lead to
obtain arterial access in arteries without diminished pulse lactic acidosis in the presence of renal failure.32
or bruit. The presence of an abdominal aneurysm should be In all patients, a reliable intravenous access line should
assessed because aneurysms frequently contain thrombus or be established prior to angiography. The infusion port should
other friable material that can be embolized during vascular be large enough to permit a rapid infusion of fluid, should
cannulation. the patient develop reduced intravascular pressure (e.g., as a
The physical examination should also concentrate on result of increased vagal tone or nitrate induced veno-relax-
the cardiovascular illness necessitating angiography. The ation). Patients with renal dysfunction, particularly those
jugular venous pressure and waveform should be noted to with diabetes, should be adequately hydrated before angiog-
assess right heart filling pressure and possible tricuspid raphy. Dehydration increases the risk of contrast induced
regurgitation. The presence of left heart failure should be renal failure.32 There is little evidence to support the use of
assessed and the ability of the patient to lie flat for prolonged mannitol or Lasix prior to angiography to reduce renal dys-
periods should be ascertained (usually by observing the function. Maintenance of continuous urine flow during and
patient supine for 15 to 30 minutes). If possible, patients with after angiography, preferably with alkalinized saline, is the
severe left heart failure should undergo diuresis prior to best deterrent to renal failure.33 In patients with preexisting
angiography. renal dysfunction (creatinine clearance less than 60 mL/min)
After interviewing and examining the patient, the antic- additional measures to reduce the incidence of contrast-
ipated procedure should be explained in sufficient detail to induced nephropathy should be taken (see below).
give the patient an understanding of what will be done, Proper sedation is also an important preparation of the
when it will be done, what will occur after the procedure, patient. Patients awaiting angiography are anxious. Treat-
and what the likely expected findings might be. The main ment with anxiolytic drugs can improve their perception of
goal of this discussion is to ensure informed consent and to the procedure, although elderly patients may have paradoxi-
allay anxiety on the day of the procedure. The procedural cal excitation with benzodiazepines and other sedatives.
description can be supplemented with written or video Before coming to the catheterization laboratory, the patient
format materials. It also can be quite useful to discuss the should void urine and take a nonsoporific sedative (e.g., ben-
implications of certain findings in order to lay the ground- zodiazepine). Careful monitoring of respiration is important
work for future recommendations for treatment. We find it during conscious sedation. If a long procedure is anticipated,
quite useful to involve a responsible family member in the insertion of a urinary catheter may be useful in men with
preangiography preparation. prostatism or other patients who have trouble voiding.
After a discussion of the procedure itself, the potential
risks should be frankly discussed, and informed consent
Vascular Access
should be obtained. A description of potential complications
should be tailored to the patient’s risk factors to provide Access to the arterial vasculature can be accomplished by
an estimate that is as accurate as possible (see below). It is cutdown and direct catheter insertion, or by the percutane-
to no one’s advantage to minimize or exaggerate the risks of ous Seldinger technique.34 For many years, the brachial
angiography. artery was exposed directly and incised with a blade to insert
Before angiography, an electrocardiogram should be Sones catheters into the central circulation. After arteriog-
obtained. The serum potassium and creatinine concentra- raphy, the catheter was withdrawn and the artery was sutured
tions and hemoglobin concentration should be measured to closed. The advantages of cutdown cannulation are control
ensure that special precautions need not be taken. Generally, of the artery and minimal bleeding after the completion of
measurement of blood clotting time (prothrombin time or the repair. The disadvantage is a higher risk of arterial throm-
partial thromboplastin time) is not required unless there is bosis or injury (see below), infection, a scar on the arm, and
a clinical suspicion that they might be abnormal (e.g., anti- limited reuse of the same access site.
coagulant use, liver disease, severe right heart failure, bleed- Introduction of a direct percutaneous needle puncture
ing history).31 If the patient has had prior coronary bypass or method for angiography made possible the development of
other heart surgery, the operative report should be read and femoral-approach angiography, the method used overwhelm-
the position of bypass grafts noted. The patient’s report of ingly at present.34 The skin and subcutaneous tissues about
the operation or the brief notes of other physicians frequently the artery are infiltrated with a local anesthetic (e.g., lido-
can be incomplete or inaccurate. caine or the longer acting bupivacaine). The common femoral
The day of the procedure, the patient should be instructed artery is punctured with a thin walled needle. The site of
to withhold oral intake for 6 hours before the procedure. entry is important because an inferior puncture may enter
Medications should generally be continued, except for hypo- the smaller superficial femoral artery and a superior punc-
glycemic agents. Oral hypoglycemic agents should be held ture may pass through the peritoneal cavity or increase the
the day of the procedure. Doses of long-acting insulin [such risk of retroperitoneal bleeding. The common femoral artery
as neutral protamine Hagedorn (NPH) insulin] should be can be located by finding the superior-anterior iliac crest and
halved and regular insulin should be held. Ultra–long-acting the symphysis pubis (landmarks of the inguinale ligament).
 corona ry a ngiogr a ph y 751
The puncture site should be approximately 5 cm inferior to the artery and may lead to bleeding, total vessel occlusion,
the line at the site of the pulse. Particularly in obese patients, venous thrombosis, or pressure injury of the femoral nerve
the puncture site may be above the groin crease. Where land- or soft tissue. The Femostop is meant to save the hands,
marks are difficult to ascertain, fluoroscopy can be used. In not time.
97% of patients, a portion of the common femoral artery Several vascular closure devices have been developed
overlies the medial femoral head.35 recently. They are divided into percutaneous suture devices
Once the artery is punctured, a 0.035- to 0.038-inch (0.88- (e.g., Perclose) and devices that apply a hemostatic material
to 095-m) flexible guidewire with a “J” tip is passed through (collagen or thrombin) to the puncture site (e.g., Angioseal).
the needle into the arterial lumen.36 Heparin coating on the These devices allow patients to ambulate quickly, usually
wire reduces platelet adhesion.37 Once the guidewire is in within an hour or less. They do not, however, reduce the
place, a dilator is employed to enlarge the tract into the bleeding complications of arteriotomy. The incidences of
artery, after which a catheter (with a tip tapered down to the bleeding, femoral pseudoaneurysm, retroperitoneal hema-
wire) or hemostatic sheath (a short tube with a one-way valve) toma, and surgical repair are similar in patients treated with
is advanced into the vessel. The angiographic catheters are manual compression and those in whom a closure device
advanced through hemostatic valve in the sheath and up to is used.42
the ascending aorta with the aid of the J-tip guidewire. If a Regardless of the method used for hemostasis, the distal
hemostatic sheath is used, the outer diameter of arteriotomy pulse should be monitored frequently until pressure is with-
will be about 0.3 mm larger than the inner diameter of the drawn and for at least several hours thereafter (e.g., every 15
sheath, enlarging the puncture site by one French (F) size. minutes for 1 hour after hemostasis, then every 30 to 60
Although not preferred to a native femoral artery, vascu- minutes). The patient should avoid actions that increase arte-
lar access can be obtained through prosthetic femoral artery rial pressure (e.g., coughing, straining to urinate, sitting up)
grafts (e.g., Dacron), provided that the grafts have been in for 2 to 6 hours. The precise duration of bed rest needed after
place long enough to develop extraluminal fibrosis (i.e., 2 to arterial puncture is not clear but probably decreases with
4 months). Fears of uncontrollable bleeding, infection, and smaller diameter catheters.43
disruption of the pseudointima within the graft, in general,
have not been realized 38,39 and catheter insertion into grafts
Coronary Catheters
is usually safe. In our experience, however, it may take
slightly longer to achieve hemostasis after catheter with- The essential features of a coronary angiographic catheter
drawal, and dislodgment of the pseudointima within the are an adequate lumen area, shape retention, torque control,
graft can occur very infrequently. It has been suggested that radiographic opacity, and safety. Catheters used to cannu-
catheters in vascular grafts be removed after straightening late the coronary arteries were initially constructed of a
with a guidewire.40 woven Dacron or hydrocarbon polymers. Polymers, pre-
More recently, radial artery access has been used, partic- dominantly polyurethanes and polyethylenes, are advanta-
ularly in patients with severe femoral or aortoiliac disease.41,42 geous because they can be extruded and easily shaped. Their
After performing an Allen test to ensure that the ulnar drawbacks are that they also can soften when inserted into
artery is patent, a small needle and guidewire is passed into the body and frequently do not transmit torque to the cath-
the radial artery. An intravascular sheath with a hydrophilic eter tip. To improve shape retention and torque transmis-
coating is then passed into the artery. Vasospasm is common; sion, most manufacturers use wire braiding within the
administration of intraarterial nitroglycerin, calcium catheter wall. Improved polymers have allowed a reduction
channel antagonist (e.g., nicardipine 200 μg), and heparin is in the thickness of the catheter wall, preserving the caliber
critical. of the inner lumen, without a significant loss in handling
The advantage of radial access is that hemostasis after characteristics.
the procedure can be obtained with simple wrist pressure After Sones developed catheters for brachial approach an-
(several devices to apply pressure have been developed). This giography, Judkins and Amplatz designed a series of coronary
allows the patient to ambulate quickly and avoids some of catheters for cannulation from the femoral approach.24–30
the bleeding complications of femoral access, such as retro- Each design has a primary and secondary curve, and tapers
peritoneal hematoma. The disadvantage is that about 2% of at the tip to hug the guidewire (Figs. 34.3 and 34.4).24–30
radial arteries are permanently occluded after the procedure Catheter caliber is measured in French (F) size (French
and catheters are usually limited to size 4F to 6F.42 size = circumference in millimeters). In the 1990s, catheter
After angiography, the extremity with the arteriotomy construction improved remarkably, allowing the manufac-
site should be extended and held straight. The catheters ture of sizes 4F to 6F. The smaller arteriotomy required by
should be withdrawn from the artery, aspirating during with- size 4F to 6F catheters has reduced the time needed for hemo-
drawal to help avoid extrusion of thrombus. Immediately stasis and bed rest after catheter withdrawal, and may prevent
after decannulation, the arterial puncture site should be peripheral vascular complications.40,43 However, smaller
compressed by hand or, in the case of femoral puncture, with catheters (particularly less than 5F) can have insufficient
the use of a device (e.g., a Femostop) to apply local pressure. lumen area to inject contrast adequately into the coronary
Some authors suggest that compression devices lead to a artery (leading to contrast streaming), poor torquing charac-
higher complication rate, but there is little evidence to teristics, and instability within the coronary lumen.44 Rapid
support this view. An unwatched Femostop or other hemo- injection through a small catheter end-hole orifice can lead
static device, however, can be dangerous because changes in to damage of the coronary wall.45 The likelihood of coronary
patient position or muscle tone alter the pressure applied to injury is related directly to the energy content of the contrast
75 2 chapter 34

After cannulation, the pressure at the catheter tip should

be observed. Pressure damping implies that the catheter has
burrowed into the wall of the artery, that there is catheter-
induced vasospasm, or that there is an organic ostial steno-
sis. If present, injection of contrast should be avoided because
it could cause a coronary dissection. The catheter should be
withdrawn slowly. If the pressure normalizes with the cath-
A B C eter in the orifice, a test injection should be done. Free-
flowing contrast without staining of the arterial wall should
be observed before angiography. Since contrast emerges from
the catheter as a jet, it is important that the catheter tip is
coaxial with the proximal artery to avoid contrast-jet–
induced injury to the ostial wall.
Pressure damping from an improper catheter position or
vasospasm is common in the right coronary artery, but in
the left coronary it should alert the angiographer to the pos-
sibility of stenosis in the left main coronary, a particularly
small normal enlarged
aorta aorta aorta dangerous problem. A test injection below the artery or use
FIGURE 34.3. Cannulation of the left coronary artery using a of a “cusp” catheter can define the coronary ostium and
Judkins curve catheter. The catheter is passed to the proximal aorta permit selection of the best catheter shape. Administration
(A) using a guidewire (not shown). It is then advanced to the coro- of nitroglycerin can reduce the tendency for catheter-induced
nary ostium while pressure is monitored from the catheter tip (B ostial vasospasm, although it is not always effective.
and C). The tip should be coaxial with the artery. The length of the
catheter between the primary and secondary curves should increase
with the diameter of the aorta (lower panel). BYPASS GRAFT A NGIOGRAPHY
Coronary artery bypass graft angiography is usually straight-
forward if the grafts are in their usual position. The common
aortic anastomosis sites of bypass grafts are shown in Figure
jet. A single report also describes an increase in catheter-
34.5. Left coronary vein grafts are usually located on the
induced coronary artery dissections associated with 6F cath-
anterolateral portion of the aorta and can be cannulated with
eter use by less experienced operators.46 Newer small
a left vein bypass curve catheter or with a variety of other
catheters have a remarkably large lumen area and may be
coronary catheters (e.g., Judkins right 4 curve, Amplatz right
safer than earlier versions. In general, however, newer cath-
1 or left 1 curves). A small number of surgeons pass the
eters of size 4F to 6F produce acceptable angiography, par-
ticularly when used with a mechanical injector.

Cannulation of the Coronary Ostia

Cannulation of the coronary ostium is the most important
step in angiography. Catheters should be advanced to the
ascending aortic root with the use of a guidewire. Inserting
catheters without a guidewire can lead to retrograde periph-
eral arterial dissection. After aspirating the catheter to
ensure that any debris or air has been removed, the catheter
should be filled with contrast and connected to the pressure
transducer. Left Amplatz and Judkins catheters can be A B C
advanced to the coronary ostium directly and usually require
little manipulation (Figs. 34.3 and 34.4).25,27 Right coronary
Amplatz and Judkins catheters should be advanced to the
aortic valve, withdrawn 1 to 1½ cm and rotated clockwise
until the ostium is engaged (Fig. 34.4).
When cannulating a coronary ostium, fluoroscopy in the
40- to 45-degree left anterior oblique (LAO) projection can be
useful because the coronary ostia are nearly perpendicular
to the view. Alternatively, when the coronary origin is rotated
small normal enlarged
posteriorly (e.g., with left ventricular hypertrophy) or anteri- aorta aorta aorta
orly (e.g., with lung disease), a right anterior oblique (RAO) FIGURE 34.4. Cannulation of the right coronary artery using a
45-degree projection can help significantly. If the coronary Judkins curve catheter. The catheter is passed to the proximal aorta
cannot be cannulated, a different catheter shape should be (A) using a guidewire (not shown). It is then advanced to the level
used, keeping in mind the shape of the aorta, the angle of the of the coronary ostium and rotated clockwise while pressure is
monitored from the catheter tip (B and C). The tip should be coaxial
coronary origin, and the rotation of the heart. If a coronary with the artery. The length of the catheter between the primary and
ostium cannot be found, the possibility of an aberrant origin secondary curves and the angle of the primary curve should increase
should be considered (see below). with the size of the aorta (lower panel).
 corona ry a ngiogr a ph y 75 3
The most common problems in bypass graft angiography
are failure to determine graft patency, failure to fully opacify
the graft and distal coronary, and failure to define a stenosis
at the coronary anastomotic site. It is of paramount impor-
tance that the angiographer know the origin and destination
of each bypass graft. The only reliable source for such infor-
mation is the operative report. If a convincing aortic vein
graft stump is not found and the recipient coronary dose not
fill via collaterals, the vein graft is probably patent. An aortic
root injection with dense aortic opacification should be done
to find the graft or its stump.
Vein bypass grafts are often much larger in caliber
than the native coronary arteries they perfuse, leading to
slow velocity within portions of the graft lumen. Large-
caliber grafts can be difficult to fully opacify, and layering
of contrast within the graft can be confused with a stenotic
lesion or intraluminal thrombus. Better injection (often
using an angioplasty guiding catheter) will minimize the
effects of streaming. The coronary anastomosis may also be
difficult to define because of overlapping bypass graft or
native arteries. It is important that at least one view be
obtained in a radiographic angle that is nearly normal to the
anastomosis.

Radiographic Contrast Material

PREPARATIONS
Iodine, an element that absorbs x-ray photons, is the essential
constituent of angiographic contrast material. In all biologi-
cally compatible angiographic contrast agents, the iodine is
organically bound to a benzene carbon ring (Fig. 34.6). The
compounds are highly water soluble, stay within the extra-
cellular space, and are excreted primarily by renal glomeru-
FIGURE 34.5. Typical locations of coronary artery vein bypass
grafts. The vein graft to the circumflex marginal branch is usually lar filtration (with minimal biliary, salivary, and small bowel
the most superior and leftward vein aortic anastomosis. The vein excretion). An iodine concentration of at least 320 mg/mL
graft to the left anterior descending artery typically arises inferior is required for adequate definition of the coronary arterial
and anterior to the circumflex graft. The right coronary graft arises tree and higher concentrations (i.e., 350 to 370 mg/mL) are
lowest on the aorta and in an anterior-rightward position.
desirable.
In all modern contrast media, three iodine atoms are
bound to a benzene ring (Fig. 34.6). In so-called ionic contrast
circumflex vein graft through the transverse sinus and anas- media the ring is a benzoic acid derivative and in solution it
tomose it to the right-posterior aorta (to minimize graft dissociates into two charged particles.47 Each cationic iodin-
kinking). If the circumflex graft cannot be found, the poste- ated benzene ring has a corresponding anion (usually meglu-
rior aorta should be searched with a left vein bypass graft or mine and sodium in a ratio of 6.6 : 1). The ionic nature of
Amplatz left catheter. contrast increases its osmolality (osmolality = number of
The right coronary vein grafts usually arise at a very particles/volume), which can have profound physiologic
shallow angle from the aorta and can be cannulated easily effects.
with a right vein graft curve catheter. Other catheters (e.g., Many other constituents of contrast solution are impor-
Judkins right 4 curve, Amplatz right 1 or left 1 curves) may tant. In the past, a high or low concentration of sodium
also be successful, particularly when the aortic root is cations led to increased ventricular arrhythmias, but now
enlarged or if the aortic anastomosis is more horizontal. almost all contrast media used for coronary angiography has
Internal mammary artery grafts are best cannulated with a sodium concentration between 150 and 190 mmol/L.48 Eth-
an internal mammary curve catheter, although a Judkins ylenediaminetetraacetic acid (EDTA) is added to nearly all
right 3.5 or 4 curve may suffice. If the internal mammary preparations to remove heavy metal contaminants. Addi-
cannot be engaged selectively, patency can be established tionally, the acidic pH of diatrizoate is neutralized with a
with a subclavian artery angiogram performed after inflation variety of bases (e.g., NaOH, sodium citrate). Citrate and
of a blood pressure cuff to reduce peripheral runoff into the EDTA can bind calcium, reducing the ionized calcium con-
ipsilateral arm. Injection of contrast material into the inter- centration in the blood and interstitial space, which pro-
nal mammary artery can be painful if the artery still per- motes ventricular fibrillation.49–52 Agents with added calcium
fuses the chest wall. Low osmolality contrast media is better (e.g., calcium edetate) and those without citrate cause fewer
tolerated. ventricular arrhythmias and are preferred.49,50,52
75 4 chapter 34

Contrast Media

Ionic Nonionic Iso-osmolar

monomer dimer monomer
O O– (+cation) O O– (+cation) R
C R C R R
I I I II I I I I II I
R R R R R R R R R R
I I I I I I
Preparations Diatrizoate salt Ioxaglate Iopamidol Iodixanol
lohexo
lopromide
loversol
Cation Meglumine and None None None
sodium
Osmolality (mOsm/kg) 1570–2020 600 790–840 290
Viscosity (cp@37°C) 4.2–8.5 7.5 9.0–10.4 11.8
Density (g/mL) 1.34 1.32 1.33–1.41 1.36
FIGURE 34.6. Structure and characteristics of radio-
LD50 (g I/Kg) 7.5 15–17 10–24 15–20 graphic contrast agents. LD50, median lethal dose.

Many of the unwanted effects of contrast material are Ventricular dP/dt falls within seconds after contrast
related to the high osmolality of the contrast solution needed injection followed by a reduction in systemic blood pres-
to obtain an adequate iodine concentration. To reduce the sure.63,64 A reflex-mediated rebound increase in blood pres-
osmolality, an ionic dimer (ioxaglate, Hexabrix) was devel- sure often occurs 8 to 10 seconds later. Ventricular compliance
oped (Fig. 34.6). This compound has only one cation for every decreases, causing end-diastolic pressure to rise.65–67 The
two benzene rings (six iodine atoms/three particles), reduc- negative inotropic response is more pronounced and lasts
ing osmolality by 30% over the diatrizoate salts. Ioxaglate is longer in the presence of coexistent left ventricular dysfunc-
better tolerated than the ionic monomer preparations.53 tion or myocardial ischemia (up to 20 minutes).68,69 Nonionic,
“Nonionic,” lower osmolality solutions have been devel- low osmolar and iso-osmolar contrast media have substan-
oped by creating an iodinated benzene ring that does not tially less deleterious effect on ventricular function and
dissociate, resulting in yet lower osmolality and the absence should be used in patients with acute ischemic syndromes,
of toxic effects associated with the cations. Even these solu- heart failure, severe aortic stenosis, and left main coronary
tions, however, still have an osmolality much greater than artery disease.54,56,63,64,70 In these patients, the additional cost
blood and are quite viscous. Although the nonionic, lower of nonionic media may be offset by the lower incidence of
osmolar solutions are more expensive, they confer signifi- costs related to complications.71
cant advantages, particularly in patients with severe coro- Contrast significantly reduces the rate of sinoatrial node
nary artery disease, reduced ventricular function, or a history depolarization, and prolongs the action potential and repo-
of sensitivity to ionic contrast media.54–57 larization. Intracoronary contrast injection causes an increase
Recently, a nearly iso-osmotic, nonionic contrast medium in QRS voltage and a lengthening of the QRS and QT inter-
(iodixanol) has been developed. This agent appears to further
reduce the risk of angiography, particularly due to its minimal
effects of ventricular compliance, resulting in little effect on 4
Renografin
hemodynamics and little reflex bradycardia. Preliminary
Iohexol
studies suggest it may also reduce the risk of renal failure.
Δ CBF (× resting)

3 Saline
PHYSIOLOGIC EFFECTS OF CONTRAST M ATERIAL 8 mL i.c.
Injection of contrast material initially causes a brief (<5-
second) fall in coronary blood flow caused by passage of the 2
viscous solution through the microcirculation (following
Poiseuille’s law, Fig. 34.7). Immediately thereafter, blood
flow increases by 2.5- to 4.0-fold basal blood flow and returns 1
to normal within about 15 to 20 seconds.58,59 The cause of
the hyperemic response appears to be related in part to the
high osmolality of contrast media since a similar response
is seen after injection of hyperosmolar dextrose solution.60,61 10 20 30 40 50 60 70 80
Stimulation of chemoreceptors in the myocardium may con- Time (sec)
tribute to coronary (and peripheral) vasodilation through the FIGURE 34.7. Changes in coronary blood flow velocity (ΔCBFV)
Bezold-Jarisch reflex60 and a direct effect on the microcircula- after intracoronary (i.c.) injection of ionic contrast media (Renogra-
fin), nonionic contrast media (Iohexol), and saline. An initial fall in
tion cannot be excluded. The hyperemic response after non- coronary blood flow velocity after contrast injection (but not saline)
ionic contrast media is less than that seen after ionic contrast is followed by a hyperemic response that is more marked after ionic
injection (Fig. 34.7).62 contrast injection.
 corona ry a ngiogr a ph y 75 5
vals, in addition to ST-segment shifts.63 The effects on the the coronary catheter via a manifold of stopcocks (Fig. 34.8).
QT interval may be exacerbated by local hypothermia The setup varies widely among laboratories but the essential
induced by use of room temperature contrast material. These elements are a clear syringe (to ensure that bubbles can be
effects are short lasting (<2 minutes). seen prior to injection) connected to a stopcock manifold.
The bradycardia and reduced atrioventricular node con- Using clear tubing, the manifold is connected to a contrast
duction is caused by a direct effect of contrast material on media container, a pressure transducer (for monitoring pres-
conduction tissue and indirectly by stimulation of afferent sure at the catheter tip), and a pressurized bag of saline to
chemoreceptors in the ventricle. Chemoreceptor discharge facilitate connecting the coronary catheter to the injection
causes a reflex-mediated increase in vagal tone and peripheral manifold without the introduction of air. The paramount
sympathetic withdrawal (the Bezold-Jarisch reflex).60,61,72 The importance of keeping the entire injection system free of air
vagally mediated bradycardia can be blocked by atropine, cannot be overemphasized. This can be accomplished by a
although in most patients its brief duration does not merit thorough purging of the manifold and tubing system with
treatment. Prophylactic pacemaker placement to avoid bra- contrast or saline during the setup and vigilance during the
dycardia is not recommended because its routine use procedure. It should be kept in mind, however, that all liquids
increases the frequency of ventricular arrhythmias, includ- contain microbubbles that can cause transient microcircula-
ing fibrillation, without significant benefit.73,74 tory obstruction.80
Contrast media also alters blood coagulation by multiple Motorized injectors permit the injection of specified
mechanisms.75–78 High concentrations of diatrizoate salts amount of contrast material at a specified constant injection
reduce activation of platelets and increase the thrombin rate. Typically, the left coronary is injected with 5 to 12 mL
time, which may prevent clotting within the coronary cath- of contrast material at 3 to 5 mL/sec and the right coronary
eter and thromboembolic complications. Nonionic contrast with 2 to 5 mL at 1 to 4 mL/sec. The rate should be adjusted
media has less effect on coagulation. Iopamidol (a nonionic for the size of the perfusion field and the rate of blood flow
agent) decreases platelet surface charge, which may facilitate in the recipient artery or bypass graft. For each contrast injec-
platelet aggregation, but it also prevents fibrin monomer tion, most angiographers prefer to progressively increase the
assembly and prolongs the thrombin time (although less than initial injection rate by using a ramp (a specified rate of rise
ionic salts).76,77 The high osmolarity of contrast media also in injection speed) to prevent the injection jet from causing
causes transient shrinkage of red blood cells and endothelial the angiographic catheter to “kick” out of the artery. It is
cells, increasing vascular permeability.76 It has been sug- important that the ramp not be too slow, because a good
gested that ionic contrast media (diatrizoate salts) be used in initial injection of contrast media reduces coronary blood
patients with thrombotic coronary syndromes (e.g., infarc- flow transiently and enhances the angiographic image (Fig.
tion or unstable angina), but in clinical studies the overall 34.7). A slow injection results only in contrast hyperemia,
incidence of thrombotic complications is very low when non- which further dilutes the injected contrast. The advantage of
ionic agents are employed.79 motorized injectors is consistency, the ability to deliver large
contrast volumes at high flow rates (e.g., to hypertrophied
INJECTION OF CONTRAST M EDIA hearts), and the ease of injection. The disadvantage is an
Contrast media can be injected into the coronary arteries inability to adjust the flow rate during injection. Recently, a
with the use of a motorized injector or by a handheld syringe. semiautomated injector with variable injection rate control
Hand injection is accomplished with a syringe attached to has been developed for coronary angiography.81

Hand syringe and manifold Automated injector

Pressure transducer
ush
in eb
sal
and
Catheter to patient d u cer
s ge
tran pur
s s ure g for ttle
pre ba t bo
To a ste n t ras
w yc o
To x-ra
To

Hand syringe

FIGURE 34.8. Left panel: One variation of the manifold and syringe system used to inject the coronary arteries by hand. Right panel: A
variable injection speed semiautomated injector for coronary and ventricular angiography.
75 6 chapter 34

Anticoagulation sclerotic and normal coronary arteries dilate after nitroglyc-

erin, but proximal vessels exhibit less dilation than distal
Catheterization itself is associated with platelet activation
epicardial vessels (9% vs. 34% diameter increase).94 Stenotic
and a rise in thromboxane A 2 metabolite excretion.82 The
lesions also relax after nitroglycerin, although severely nar-
presence of catheters within the vascular lumen causes endo-
rowed segments usually dilate little.95 Removal of tone by
thelial denudation and combined with the foreign body of
nitroglycerin permits an assessment of maximal coronary
the catheter is a stimulus for intravascular thrombosis.
caliber, effectively eliminates vasospastic coronary lesions,
Several, but not all, studies suggest that systemic anticoagu-
and facilitates assessments of stenosis severity.
lation with heparin reduces the incidence of thrombotic
Nitroglycerin primarily affects the large-diameter epicar-
complications of angiography (primarily thrombosis at the
dial portion of the coronary artery, and dilation in these
site of catheter insertion),83–85 although heparin has also been
vessels lasts for 10 to 20 minutes. When administered by the
reported to cause additional activation of platelets.86 Antico-
intracoronary route, only small doses of nitroglycerin (100 μg
agulation is not necessary for patients undergoing routine
in the right coronary, 150 μg in the left coronary artery) are
diagnostic angiography from the femoral approach. There is
needed to effect maximal epicardial coronary dilation, and
uniform agreement, however, that heparin (e.g., 2000 U into
these doses have a minimal impact on systemic hemody-
the artery and 3000 U intravenously) should be given to all
namics.94 A 400-μg sublingual dose of nitroglycerin also
patients in whom the brachial or radial approach is used,
causes maximal dilation of the conduit coronary arteries.
because of the higher incidence of thrombosis at the catheter
Nitroglycerin administered into the coronary ostium also
insertion site. In patients undergoing femoral approach angi-
has very brief effects on the microcirculation (usually causing
ography, the risk of thrombotic complications probably
a 1.5- to 2.5-fold increase in coronary blood flow lasting less
increases with the duration of the procedure, a smaller
than 2 minutes), but causes negligible changes in blood flow
femoral artery, or larger catheter, and the presence of periph-
when given by intravenous infusion or by mouth.96,97
eral vascular disease. Patients at higher risk of thrombosis
It should be remembered that the nitrate response in the
should be anticoagulated (3000 to 5000 U intravenously)
large coronary arteries is not complete for 2 minutes after
unless a contraindication exists.
intracoronary administration and 4 minutes after a sublin-
The optimal dose of heparin may vary among patients
gual dose. Additionally, patients undergoing angiography are
because plasma antithrombin III and platelet factor four
often intravascular volume depleted because oral intake has
(which binds heparin) concentrations affect heparin efficacy
been withheld for some time. This can lead to an increased
and availability, respectively.87 Heparin pharmacokinetics
sensitivity to nitrate-induced venodilation and transient
are not affected by the type of contrast media selected.88
hypotension. Since coronary caliber is dependent on distend-
Aspirin decreases platelet activation caused by angiography,
ing pressure, the reproducibility of coronary angiographi-
but its efficacy in reducing complications has not been
cally defined measurements of coronary diameter over time
evaluated.82
is dependent on maintenance of arterial pressure. In patients
At the end of the procedure, the anticoagulant effects of
without heart failure, saline is often given prior to nitroglyc-
heparin can be reversed by administering protamine.89 Prot-
erin administration to blunt the fall in arterial pressure.
amine is a polycationic compound derived from fish sperm
In some patients and particularly in radial artery bypass
(primarily from salmon and herring) that binds to heparin.
graft conduit, nitroglycerin may not entirely reduce arterial
One milligram of protamine binds approximately 100 U
tone. Intracoronary or graft calcium channel blocking agents
(1 mg) of heparin.12 Since heparin is essentially eliminated by
(e.g., nicardipine 100 to 400 μg) may be effective.
first-order kinetics, the amount of protamine needed is a
function of the initial heparin dose and the time since
administration. For a 5000-U heparin dose, the initial prot- Special Situations
amine dose should be 50 mg if less than 20 minutes have
OSTIAL CORONARY STENOSIS
passed and progressively less thereafter (e.g., 30 mg if 60
Coronary angiography in patients with ostial stenosis, par-
minutes has elapsed).9 If insufficient protamine is given, a
ticularly stenosis of the left main coronary artery, is associ-
phenomenon known as “heparin rebound” can occur.13 After
ated with significantly higher incidence of complications.98,99
initial normalization of clotting times from the first
Left main stenosis occurs in 2% to 11% of patients undergo-
protamine dose, protamine degradation by proteinases
ing angiography, but accounts for a significantly greater frac-
leads to release of free heparin and a rebound increase in
tion of mortality associated with the procedure.99 A procedural
clotting time.90,91
mortality rate of 0.75% was found in patients with left main
Protamine should be administered cautiously to patients
coronary stenosis in the Coronary Artery Surgery Study.100
with a prior exposure to the drug (such as NPH insulin, or
Myocardial infarction, persistent angina, profound hypoten-
protamine sulfate or chloride) or patients with a fish allergy,
sion, and ventricular fibrillation also can occur during or
and should not be given to patients with α1-antitrypsin defi-
immediately following angiography in patients with left
ciency (see below).92,93 Very large protamine doses (>4.0 : 1
main coronary stenosis. The likelihood of complications is
protamine/heparin concentration) can have an anticoagulant
greater in patients with angina within 24 hours of catheter-
effect, although it is rarely observed in a clinical setting.12
ization and if the stenosis is in the proximal left main coro-
nary (within 6 mm of the angiographic catheter tip).98
Management of Epicardial Coronary Artery Tone
Complications can be minimized by rapidly identifying
The lumen caliber of epicardial coronary arteries measured the presence of left main stenosis, which occurs more often
at angiography reflects a variable degree of tone. Both athero- in patients with widespread, severe atherosclerosis and may
 corona ry a ngiogr a ph y 75 7
be associated with pressure damping on left coronary can- results.101 Whatever the monitoring methods, assiduous
nulation. When left main stenosis is suspected, a “cusp” attention to heart failure can avoid pulmonary edema and
injection about the ostium may identify its presence and emergency intubation.
morphology. When a significant left main stenosis is present,
nonionic contrast should be used and the number of angio- SHOCK
grams should be limited to only those views required to Coronary angiography in patients with cardiogenic shock is
identify the vessels needing bypass grafts. A catheter tip challenging. In most patients, placement of an intraaortic
shape that will not deeply cannulate the ostium should be balloon pump before angiography is important for stabiliza-
used. If the pressure at the catheter tip always damps on left tion and to prevent hemodynamic collapse during angiogra-
main cannulation, the catheter may need to be withdrawn phy. The balloon pump increases diastolic coronary blood
between injections, although repeated cannulation of a ste- flow in addition to improving systemic blood flow.102 Iso-
notic left main may increase the possibility of catheter- osmotic contrast media should be used routinely and the
induced injury. If adequate filling can be obtained, a minimal number of contrast injections necessary to plan
nonselective “cusp” injection should be used. The pulmo- treatment should be obtained. Special care should be taken
nary capillary wedge pressure monitoring during angiogra- in cannulation of the left main coronary artery because of
phy can be important in patients with severe stenosis or the increased frequency of left main stenosis in patients with
reduced left ventricular function because contrast material cardiogenic shock.
may precipitously reduce left ventricular function. If the
wedge pressure rises significantly, angiography should be AORTIC DILATION
stopped until hemodynamics are controlled. Aortic root dilation, common in patients with aortic valve
Coronary cannulation causes endothelial denudation, disease, prolonged hypertension, and Marfan’s syndrome,
which may be responsible in part for the ischemic complica- presents a particular challenge for coronary cannulation
tions of angiography in this patient group. After angiography, (Amplatz, Judkins). Large curve left coronary catheters
patients with a significant (>50%) left main stenosis should are required (e.g., Judkins left 5 to 7 curve, Amplatz left 3
be monitored because of the higher frequency of ischemia curve).
and hemodynamic deterioration over the following 24 hours. Right coronary cannulation can be especially problem-
Semi-urgent revascularization should be considered after atic because the root is enlarged, elongated, and horizontal.
angiography in patients with severe left main stenosis (>90%), Catheter manipulation can be difficult because of associated
particularly if the lesion is in the proximal left main. tortuosity of the descending aorta and peripheral vessels.
Occasionally, an Amplatz left curve or a specially steamed
HEART FAILURE AND A BNORMAL L EFT catheter may be needed to cannulate the right coronary. The
VENTRICULAR FUNCTION rapid coronary blood flow associated with hypertrophy from
Coronary angiography always causes a transient increase in aortic valve disease or hypertension makes it essential to use
ventricular filling pressure, due mostly to contrast-mediated a catheter of adequate caliber to deliver a rapid injection of
transient increases in diastolic ventricular stiffness. Dia- contrast material (which should be warmed to 37˚C to reduce
stolic stiffness increases for up to 20 minutes after contrast viscosity and the effects of cold contrast–induced hypother-
injection. In contrast, any reduction in systolic contraction mia on the myocardium).
is usually brief (<60 seconds). Patients with preexisting ele-
vated filling pressures may develop frank pulmonary edema T RANSPLANTATION
during or shortly after angiography because of the reduction After transplantation, the majority of patients undergo
in compliance and the concomitant volume load from hyper- annual surveillance angiography to detect transplant-related
tonic contrast material and other fluids given during angiog- vasculopathy. Several factors are unique to transplanted
raphy. In patients with marked left heart failure or an inability hearts.103 The aortic anastomosis causes a ridge in the ascend-
to lie flat because of high left atrial pressure, diuresis should ing aorta, making it important to pass the Judkins left coro-
be accomplished prior to angiography if possible. nary nearly to the sinus of Valsalva to avoid the catheter
Nonionic, low-osmolar contrast agents have a less pro- being hung up on the ridge as it is advanced to the left coro-
nounced effect on myocardial function and intravascular nary ostium. The transplanted heart is usually clockwise
volume than ionic agents and should be used in patients with rotated (from the diaphragmatic perspective) and the left
significantly elevated left heart filling pressures. Iodixanol, coronary ostium is more posterior and the right ostium more
an iso-osmolar contrast agent, has minimal effects on left anterior than usual. Additionally, the ascending aorta is
ventricular diastolic stiffness and may be safer in patients often longer and more horizontal in its more proximal
with severe LV dysfunction. Additionally, in patients with segment. Frequently, the right coronary is better cannulated
poor compensation, some angiographers monitor pulmonary from a right anterior oblique projection and may require a
artery wedge pressure during angiography. If the mean wedge catheter that can reach more anteriorly, such as a Judkins
pressure rises above 20 mm Hg, angiography should be right 5 curve or Amplatz right 2 or left 1 curve.
stopped and appropriate steps should be taken to reduce the
filling pressures (e.g., nitrates, afterload reduction, diuretics,
Outpatient Angiography
intraaortic balloon pump). A recent study suggest that mea-
suring pulmonary artery pressures in patients with acute Although once performed exclusively as an inpatient proce-
coronary syndromes is associated with increased mortality, dure, the majority of angiography is now be performed in the
but patient selection might have significantly biased the outpatient setting.104–108 Outpatient angiography generally
75 8 chapter 34

has a 25% lower hospital cost, but it places some strains on Complications of Coronary Angiography
preangiography patient preparation.104,108 It also imposes more
responsibility on the patient for precatheterization medica- Coronary arteriography is generally a safe procedure, but
tion and site preparation, and postangiography catheter inser- serious complications can occur. The overall incidence of
tion site observation. complications and mortality (Table 34.1) increases directly
Outpatient angiography requires selection of patients with the extent of coronary artery disease (particularly left
who are expected to have a low risk of late complications. main coronary stenosis), the presence of coexistent sig-
Patients with acute ischemic syndromes (unstable angina, nificant valvular disease, a reduced ventricular ejection
infarction) should not go home immediately after angiogra- fraction, reduced functional state, and advancing age.100,111–114
phy because of the risk of recurrent ischemic episodes.107 The complications fall into several groups: those resulting
Patients with left main or severe three-vessel coronary from arterial cannulation, embolization from the aorta, cath-
disease, severe heart failure, bleeding diathesis, and severe eter-induced coronary arterial spasm or dissection, arrhyth-
aortic valve stenosis generally should be observed longer mias, allergic-type reactions from drugs and radiographic
after contrast angiography.107 Many patients undergoing out- contrast material, and angiography-induced deterioration in
patient angiography are admitted to the hospital after the hemodynamics.
procedure, 1% to 2% for observation after a complication,
and the remainder for a surgical procedure (e.g., angioplasty
or bypass surgery).104,105,108
Complications of Arterial Cannulation
More recently, coronary angiography has been performed
in mobile truck trailers stationed at smaller hospitals.109,110
Peripheral Vascular Complications
With the exclusion of higher risk patients through proper
patient selection, the complications of “mobile angiography” Arterial cannulation performed by the Seldinger method
appear not to be increased and patient satisfaction may be usually causes endothelial denudation at the site of catheter
improved.110 Several logistical problems remain. Since a sig- or sheath insertion. During arterial puncture the needle also
nificant fraction of patients undergo a revascularization pro- may pass into or through the posterior wall of the artery, and
cedure based on the information gained from the angiogram, advancement of a guidewire into the posterior wall can result
many patients (if not the majority) will need to travel to a in arterial dissection. Fortunately, the arterial flap proceeds
larger hospital anyway, obviating the advantages of mobile against the flow of blood and usually is sealed rather than
angiography. Additionally, patients who subsequently have propelled down the vessel by the arterial pulse. Dissection,
angioplasty may need to have two procedures (at two hospi- along with endothelial injury, however, may promote local
tals) instead of proceeding with angioplasty in the same thrombosis and arterial occlusion. Perforation of peripheral
procedure as the angiogram. More information will be needed arteries by a guidewire or catheter is uncommon, but proba-
to know if catheterization in mobile structures is cost bly occurs more frequently in patients with tortuous vessels
effective. and when stiff wires or catheters are used.

TABLE 34.1. Incidence of complications following elective coronary angiography

Bourassa et al.111 Davis et al.100 Kennedy et al.112 Noto et al.113
Year 1970–74 1975–76 1979–80 1990

Route Femoral Femoral Brachial F or B F or B

Number of patients 5,250 6,328 1,187 53,581 59,972
Death (%) 0.23 0.15 0.50 0.14 0.11
Myocardial infarction (%) 0.09 0.22 0.42 0.07 0.05
Vascular complication (%) 0.85 0.36 2.8 0.57* 0.43*
Thrombosis (%) 0.68 0.2 1.9 0.23 ns
Dissection/perforation (%) 0.17 0.1 0.9 0.04 ns
Stoke/TIA (%) 0.13 0.02 ns 0.07 0.07
Embolic complication (%) 0.07 0.08 0.17 ns ns
Arrhythmia (%) 1.23 0.63† ns 0.56 0.38
Ventricular fibrillation/ 0.40 ns ns 0.44 ns
tachycardia
Asystole/severe bradycardia 0.25 ns ns 0.09 ns
Contrast reaction (%) ns ns ns ns 0.37
Hemodynamic deterioration 0.1 ns ns ns 0.26
* True incidence probably underestimated because only “in laboratory” complications reported.
† All patients.
F, femoral artery approach.
B, brachial artery approach.
ns, not specified.
 corona ry a ngiogr a ph y 75 9
The development of a hematoma, arterial pseudoaneu- or vascular thrombus (e.g., clot in an abdominal aneurysm),
rysm, or arteriovenous fistula formation after arterial cathe- dislodgment of left ventricular thrombus (e.g., in a ventricu-
ter removal remains an important and probably underreported lar aneurysm or recently infarcted ventricle), and debris or
complication. The importance of immediately obtaining clot extruded from an improperly aspirated angiographic
adequate hemostasis cannot be overemphasized. Once a catheter. Catheter-induced embolization can lead to a variety
small perivascular hematoma has formed it becomes more of complications, depending on the target organ and makeup
difficult to apply effective pressure to the puncture site of the embolus.124–133
because applied force is spread equally throughout the hema- Systemic embolization is more likely when the aorta has
toma. Conversely, prolonged overcompression of the site can severe atherosclerosis or mural thrombus, when a large
occlude the vessel, leading to vascular stasis and thrombosis. abdominal aortic aneurysm is present (typically containing
The affected extremity should be immobilized for at least 4 thrombus), and in elderly patients. In patients undergoing
hours and a catheter of size ≥6F is used. Sandbags applied cardiopulmonary bypass, transesophageal echocardiographic
over the arteriotomy site are ineffective in preventing com- identification of atheroma protruding into the aorta may
plications. A collagen plug device, implanted into the punc- identify patients at risk for embolic complications, and
ture site above the artery, has been developed and appears to pedunculated, mobile aortic masses may be a source of cath-
markedly reduce the time needed for hemostasis.115 eterization-related embolism.134,135 The brachial approach is
The incidence of arterial cannulation site complications preferred in patients predisposed to peripheral embolization
is higher in women, the elderly, in the presence of peripheral unless significant disease in the aortic arch or upper extrem-
vascular disease, when blood flow is reduced (e.g., low cardiac ity vessels is present.
output state or catheter occlusion of the vessel) and with The sequelae of systemic emboli vary widely, from no
brachial access or a low femoral puncture site, probably symptoms to severe tissue necrosis. Thrombotic embolism
related to the smaller size of these vessels.112,116–119 Although frequently results in a loss of the peripheral pulse and occlu-
common sense suggests that arterial complications would be sion of larger branch arteries that can be treated by embolec-
less frequent if smaller catheters were used and arterial tomy, anticoagulation, and in some cases thrombolytic drugs.
access time was minimized, an increase in vascular compli- Cholesterol emboli affect vessels 58 to 800 μm in diameter,
cations has been shown only for catheters >8F (>2.5 mm and the syndrome is characterized by skin changes of livido
outer diameter) in size.117 Patients with synthetic (e.g., reticularis, tissue ischemia with intact peripheral pulses,
Dacron) femoral artery grafts may also have a higher inci- renal dysfunction, eosinophilia, and an elevated erythrocyte
dence for cannulation-related complications, although the sedimentation rate.124–131 The renal insufficiency associated
reported experience suggests that cannulation of grafts that with cholesterol embolization can cause immediate anuria,
have been in place for at least several months is safe. 38,39 but more frequently leads to delayed oliguria. It can be dif-
Heparin anticoagulation during the catheterization reduces ferentiated from contrast-induced renal failure by its minimal
the incidence of arterial thrombosis and the need for surgical reversibility (contrast nephropathy usually is reversible),
embolectomy, but may increase the incidence of hematoma associated skin findings of embolization, and eosinophilia.
formation.84,85,117 Embolization of the splanchnic bed can cause abdominal
Septic complications (access site infection and bactere- pain, ileus, or bowel or spleen infarction, usually with onset
mia) are very uncommon and associated almost exclusively of symptoms within hours of catheterization. Treatment for
with prolonged cannulation or repeated instrumentation of cholesterol embolization consists of supportive care. Antico-
the same site within a short time period.20,120 The most agulation is ineffective.
common organism is Staphylococcus aureus, although other Large peripheral air embolization can occur after acci-
staphylococcal species, streptococci, gram-negative organ- dental injection of air or, more commonly, from inspissation
isms, and anaerobic species can occur.120 The mortality asso- of air through a central venous access catheter in the jugular
ciated with bacteremic episodes can be significant. or subclavian venous systems. Venous air embolisms over 50
The development of Doppler echocardiographic methods to 100 mL can cause acute pulmonary hypertension and
for imaging these complications has revealed that small hypoxemia.136 Arterial air embolism can lead to profound
femoral artery pseudoaneurysms are more common after transient tissue ischemia, including stroke, myocardial isch-
femoral angiography than clinically suspected. Additionally, emia and cardiac arrest.137 The immediate treatment is to tilt
incidence of pseudoaneurysms and arteriovenous fistulas the patient head-down (Trendelenburg position) and on the
may have increased with the more frequent use of aspirin, left side to prevent air from rising to the head or passage from
anticoagulants, and thrombolytic drugs. Many close sponta- the venous system to the left atrium via a patent foramen
neously within 1 to 2 months.121 Until recently, all persistent ovale. Venous air can pass to the arterial circulation without
femoral artery pseudoaneurysms were repaired surgically a clear defect connecting the two circulations, presumably
because late enlargement and rupture can occur. It has been though the pulmonary arteriovenous shunts.137 Aspiration of
shown more recently that prolonged (average 30 minutes) air with a catheter in the right atrium or ventricle may be
compression during ultrasound imaging can be used to close partially effective.138 Breathing 100% oxygen may help treat
over 90% of pseudoaneurysms and small arteriovenous hypoxemia associated with pulmonary artery flow obstruc-
fistulas.122,123 tion. For large emboli, a hyperbaric chamber may be useful
if employed promptly.139
EMBOLIZATION Selective coronary injection of air can occur when the
Embolization of arterial circulation can occur from injection catheter or injection tubing is not completely flushed with
of air, catheter-induced dislodgment of atherosclerotic plaque fluid. Tuohy-Borst Y connectors are a notorious source of air,
76 0 chapter 34

as are tubing connectors. Small bubbles may result in tran- shoveling into the vessel wall). Ostial coronary stenosis is a
sient ischemia without consequence. Larger selective air rare complication of coronary cannulation.152
injections (>1 to 2 mL), however, often result in ventricular Coronary artery embolization usually results from injec-
fibrillation and cardiovascular collapse. tion of air or debris from within the catheter. Small air
emboli typically cause ischemia for 5 to 10 minutes. On
Neurologic Complications angiography, blood flow to the embolized segment is slow,
but the epicardial arteries appear to be intact and no filling
Neurologic complications of coronary angiography include
defect is seen. Thrombotic emboli, however, almost always
local brachial nerve injury from brachial artery cannulation,
lead to occlusion of an artery visible on angiography. Infarc-
ulnar nerve compression during prolonged procedures, tran-
tion is common, and rapid reperfusion with angioplasty can
sient central ischemic attacks, and stroke. Significant neuro-
be effective in limiting injury. Coronary cholesterol embo-
logic events are uncommon, although they probably are
lism can cause a picture similar to either thrombotic or air
underreported (Table 34.1) because the vast majority resolve
embolism, but the effects are usually not reversible. In one
within 24 to 72 hours after the procedure.140–142 Most isch-
series, cholesterol emboli were seen at autopsy in 26% of
emic central neurologic events occur in the posterior distri-
patients undergoing coronary angiography, but most emboli
bution, although any territory can be affected.140–143 In one
were in the myocardium.130,132,133 This underscores the impor-
careful series, transient visual disturbance occurred in 1%
tance of aspirating the coronary catheter and discarding the
of patients.142 Women and patients with an anginal syndrome
aspirate prior to intracoronary injection. Aspiration of shim-
and normal coronary angiograms were more commonly
mering cholesterol crystals is not rare.
affected.142 The most likely mechanism of central neurologic
events is embolism of clot or atheromatous debris from the
aorta or cardiac chambers, although vasospasm and transient Drug Reactions and Toxicity
hypotension during angiography may also be operative in
some patients. Radiographic Contrast Material
Transient cortical blindness can result from contrast
Although usually well tolerated, iodinated contrast material
administration. This syndrome lasts for 1 to 2 days and
can have deleterious consequences related to its normal
resolves spontaneously. Brain imaging (computed tomogra-
physiologic effects and from allergic-type reactions. The
phy or magnetic resonance imaging) is normal.144
negative inotropic effects on ventricular function and intra-
vascular volume expansion can lead to hemodynamic decom-
Coronary Artery Complications and
pensation, primarily in patients with reduced ventricular
Myocardial Infarction
reserve (either diastolic or systolic) and ischemic syn-
Catheter-induced spasm is common in the right coronary but dromes.54,56,69,153 The effects on the conduction system can
very uncommon in the left.145–148 For the most part, the spasm cause transient severe sinus bradycardia or heart block, and
occurs at the catheter tip and may be related to mechanical the effects on ventricular repolarization can cause ventricu-
traction on the artery. Rarely, catheter-induced spasm distal lar fibrillation (see below).
to the catheter tip has been observed. There is no proven
significance of catheter-induced spasm, although some R ENAL DYSFUNCTION
authors have postulated that patients with catheter-induced Contrast agents can also cause renal dysfunction, which is
spasm may be more prone to spontaneous spasm.145,148 Cath- usually transient but can be severe. A transient increase in
eter-induced spasm usually can be prevented by administra- glomerular filtration, an osmotic diuresis, and proteinuria
tion of nitrates and by using an angiographic catheter that all occur soon after contrast administration.154 Clinically
does not tent the artery. evident renal dysfunction with increased serum creatinine
Myocardial infarction is usually caused by catheter- concentration and reduced urine output, however, occurs 48
induced coronary injury, or embolization from the catheter to 72 hours later. The etiology of contrast-induced renal
or left ventricular thrombus. Catheter-induced arterial injury failure is unclear, but transient renal ischemia, physical
is usually caused by the tip of the catheter burrowing into obstruction of the renal tubules, superoxide radical release,
the arterial plaque or media, raising an arterial flap that can and endothelial injury have been proposed.
be extended further by blood flow or by contrast injection Patients with diabetic nephropathy, preexisting renal dys-
through the catheter into the arterial wall.149,150 The most function, dehydration, low cardiac output, and possibly mul-
common and important sites of catheter-induced injury are tiple myeloma are predisposed to develop contrast-induced
the coronary arterial ostia or the internal mammary artery, renal failure, which ranges from an asymptomatic increase
where dissection can lead to thrombosis, spasm, or an exten- in serum creatinine concentration to frank anuria.155–158
sive spiral dissection down the vessel.151 The likelihood probably rises with the amount of contrast
Normal coronary arteries and arteries with ostial lesions media administered, although renal dysfunction is very
or acute angle origins are more likely to suffer catheter- uncommon in patients with a serum creatinine concentra-
induced injury. The occurrence of catheter injury can be tion <150 μmol/L (<1.7 mg/dL).156 In diabetics with preexist-
reduced by careful ostial cannulation with “soft tip” cathe- ing renal insufficiency (serum creatinine concentration
ters, monitoring the pressure at the catheter tip (pressure at >150 mmol/L), Parfrey et al.156 found the risk of a 25% increase
the catheter tip will be damped if the catheter has burrowed in creatinine concentration was 7.2%. In nondiabetic patients
into the wall), and advancing the catheter to the ascending with mild renal insufficiency (creatinine 150 to 250 mmol/L),
aorta using a flexible guidewire (to prevent the tip from there was no significant reduction in renal function after
 corona ry a ngiogr a ph y 761
angiography using small to moderate contrast volumes Treatment of a reaction is tailored to the symptom. Urti-
(<200 mL). The reported incidence of renal failure after con- caria is treated with intravenous antihistamines. Nausea,
trast exposure varies widely, but nearly all investigators find possibly related to intestinal mast cell release, can be less-
that the likelihood of a transient increase in creatinine and ened with antiemetic compounds. Hypotension is treated
oliguria rises sharply in patients with a creatinine concentra- with vasopressor drugs, large doses of corticosteroid drugs
tion >250 mmol/L.155–159 (e.g., 1 g methylprednisolone), and antihistamines. Broncho-
The primary prevention of contrast-induced renal failure spasm is treated with theophylline, inhaled β2-adrenorecep-
is to limit the amount of contrast used to the minimum that tor agonists, and corticosteroids.
is required to obtain an adequate study and to avoid admin-
istering contrast media to dehydrated patients. Patients Anticoagulants
should be well hydrated with 0.9% saline prior to and after
Heparin can result in thrombocytopenia, which can be
angiography (except for patients with heart failure and ele-
dependent on the type of heparin used (bovine, porcine,
vated left atrial pressure at rest). Nonionic media probably
etc.).171 Arterial aggregation and thrombosis can also be
reduces the risk of contrast nephropathy, but the degree of
caused by heparin, although reactions from brief exposure
protection offered is relatively modest.54,56,159 Iso-osmolar
are rare.172
media (iodixanol) may confer greater protection.160
The second most frequent important source of allergic
Recently, two additional methods have been reported to
reactions occurs in association with the anticoagulation
offer some degree of protection from contrast nephropathy.
used during angiography. Protamine sulfate, given to bind
N-acetylcysteine (600 mg every 12 hours for four doses, two
heparin and reverse its effects prior to decannulation, can be
before and two after angiography) and hydration with bicar-
associated with several adverse reactions, including urti-
bonate buffered saline both result in slightly higher glomeru-
caria, severe hypotension, bradycardia, bronchospasm, and
lar filtration rate (GFR) after angiography and may reduce the
noncardiogenic pulmonary edema.173 Severe reactions can
incidence of dialysis.161–163
require vasopressor drug support for several days. The etiol-
Several prior studies suggested that a number of other
ogy of protamine reactions may vary among patients. Immu-
agents might confer protection from contrast nephropathy,
noglobulin E and IgG antibodies, complement activation,
including mannitol (e.g., 25 g in 250 mL of 155 mM saline) to
direct myocardial depression, increases in endothelial per-
increase urine flow prior to and during angiography,164,165
meability due to interaction with membrane-bound heparan
simultaneous administration of the loop diuretic furose-
sulfates, and protamine-stimulated nitric oxide release from
mide,166 dopamine receptor stimulation with fenoldopam,167
the endothelium have been postulated.92,174,175 Immunoglobu-
and theophylline. In general, however, there is no convincing
lin G antibodies are the predominant mechanism in patients
evidence that any of these agents reduce the incidence of
without prior protamine exposure.92 In one series, protamine
renal failure after contrast administration.
given after catheterization reduced white blood cell count by
an average of 23% ± 4%.176
A LLERGIC-T YPE R EACTIONS
Patients with recent protamine exposure or a fish allergy,
Contrast material can also give rise to allergic-type reac-
diabetic patients exposed to neutral protamine zinc (NPH)
tions, but the mechanisms are poorly understood. Nonspe-
insulin, and patients with α1-antitrypsin deficiency are par-
cific mast cell degranulation and activation of complement
ticularly sensitive to protamine.173 Additionally, protamine,
have been implicated, but true immunoglobulin E (IgE)-
when given rapidly to any patient, transiently reduces vascu-
related allergy is rare. Contrast reactions vary from simple
lar resistance and can cause hypotension (possibly related to
urticaria to nausea to an anaphylactoid reaction character-
protamine stimulated nitric oxide release from the endothe-
ized by hypotension and bronchospasm. Patients with a prior
lium).175 To minimize complications, a small test dose of
history of contrast reaction or multiple allergies (including
protamine can be given into the arterial cannula. If the
seafood) and patients who receive ionic contrast media (espe-
patient has local erythema or hypotension, the drug should
cially with a high sodium content) are more likely to have a
be avoided.
contrast reaction.55,168,169
Patients with a history of allergic-type reactions should
Anesthetics
be treated with corticosteroid drugs the day before the pro-
cedure.168 We typically give prednisone (60 mg orally) the True allergies to local “-caine”-type anesthetics are very rare.
night before the procedure, and before the angiography give Patients sometimes claim to be allergic to “novocaine” as a
another dose (30 mg prednisone orally or 250 mg hydrocorti- result of a syncopal episode during a prior procedure (usually
sone intravenously) and an antihistamine (e.g., hydroxyzine, neurally mediated syncope) or a complication related to rapid
50 mg intravenously). In patients predisposed to a contrast or excessive lidocaine administration (seizure, dysarthria,
reaction, administration of prednisone at least 12 hours prior etc.). These “reactions” are not allergic in nature and, based
to angiography reduces the incidence of mild to moderate on the exceptionally low incidence of true lidocaine allergy,
reactions by half. Treatment only on the day of angiography we usually continue to administer lidocaine local anesthesia
has no effect.168 An additional reduction in risk of less severe unless the patient gives a clear history consistent with an
reactions (e.g., bradycardia, mild hypotension, brief angina) IgE-mediated reaction. To date, no patient with a “lidocaine
will occur if nonionic contrast media is utilized.169 Although allergy” has had an adverse reaction. The maximal subcuta-
H 2 histamine receptor antagonists (e.g., cimetidine) have also neous dose should not exceed 5 mg/kg, and solutions con-
been used to prevent reactions, their efficacy is unclear and taining epinephrine should not be used. In patients with a
probably minimal.170 bona fide allergic reaction or local sensitivity to lidocaine,
76 2 chapter 34

the offending agent is usually the preservative methylpara- must be approached with caution, for these are the patients
bate. In these patients lidocaine without the preservative who develop pulmonary edema after contrast injection.54,56,69
(intravenous use lidocaine) or bupivacaine (0.25 to 0.5 mg/ We often ascertain the left ventricular end diastolic or pul-
mL) can be substituted. monary artery wedge pressure prior to angiography in
patients with a prior history of congestive left heart failure,
pulmonary edema, or severe left ventricular dysfunction,
Arrhythmias
particularly if they are decompensated. If the pulmonary
Arrhythmias during angiography can occur from abrasion of wedge pressure is more than 20 mm Hg, it should be reduced
the conduction system by catheters, contrast media–induced prior to contrast injection and the pulmonary wedge or
changes in repolarization, reflex-mediated changes in neural mean pressure should be monitored during the angiogram.
traffic to the heart, and transient myocardial ischemia from Iso-osmolar contrast should be used. If the pressure rises
hemodynamic deterioration. The left bundle branch of the significantly, contrast injections should be withheld. Intra-
conduction system courses near the surface of the left ven- venous nitroglycerin or nitroprusside infusion during angi-
tricular septum and can be injured transiently during can- ography can be used to rapidly reduce filling pressures and
nulation of the left ventricle.177,178 The right bundle branch is facilitate angiography. It is important to remember that con-
located near the tricuspid annulus and can be rendered dys- trast can affect ventricular diastolic function for up to 20
functional by a right heart catheter (particularly if the cath- minutes.
eter is rubbed against the superior annulus repeatedly). In a
patient with a preexisting contralateral bundle branch block,
complete heart block can occur.177,178 In these patients, the Coronary Anatomy and
immediate availability of cardiac pacing (external or by cath- Radiographic Evaluation
eter) should be ascertained prior to catheterization.
Contrast media can induce sinus bradycardia, sinus node Angiographic visualization of the heart, great vessels, and
block, and atrioventricular node block by two mechanisms. coronary arteries is fundamental to the accurate diagnosis
The hyperosmolar and chemical properties of contrast cause of the wide spectrum of cardiovascular diseases that are
activation of ventricular afferent chemoreceptors, which characterized by morphologic abnormalities. Whereas the
reflexively trigger a parasympathetic surge, reducing sinus angiographic evaluation of the past several decades was based
and atrioventricular (AV) node repolarization.60,61,72 The reflex solely on a visual assessment of the anatomy, today this
is blocked partially by muscarinic receptor blockade with visual assessment is frequently aided by computer-assisted
atropine. Iso-osmolar contrast media significantly reduce or quantitation of vessel dimensions and physiologic informa-
eliminate vagally mediated bradycardia. tion, allowing assessment of the functional effects of the
Neurally mediated syncope can also complicate angiog- anatomic abnormalities.
raphy, particularly when the patient is dehydrated and experi-
ences pain. Contrast material may also directly depress
Coronary Anatomy
conduction tissue repolarization and transiently slow heart
rate. Vigorous coughing can maintain blood pressure but
Coronary Ostia
does not hasten clearance of contrast material from the coro-
nary circulation.179 In humans as well as all birds, reptiles, and mammals, the
Prolongation of the ventricular refractory period by con- arterial supply to the heart arises from two ascending aortic
trast media can initiate ventricular fibrillation. Fibrillation branches. The position of these branches that transverse the
occurs more commonly after right compared to left coronary atrioventricular and interventricular sulci in the shape of a
injection. The incidence is less with nonionic or iso-osmolar crown led early anatomists to designate the vessels as coro-
contrast material and with ionic contrast with a physiologic nary (or “crown”) arteries.181–183
calcium ion content.49–52,57 The probability of ventricular The coronary ostia normally are located in the right and
fibrillation also is higher if an excessive volume of contrast left aortic sinuses of Valsalva. The ostia originate at the
material is injected in a single dose. center of each sinus, close to the free edge of the aortic cusp
and just below or no more than 1 cm above the superior edge
of the aortic cusp. Ostia located more than 1 cm above the
Hemodynamic Deterioration
cusp edge are abnormal, occurring in less than 3% of
Although catheterization of the coronary arteries does not patients.184 Although two coronary ostia (one in each sinus)
by itself change ventricular function, injection of contrast are the rule, three or four separate ostia are considered
media causes a reduction in diastolic ventricular compliance normal variants. In up to 30% of cases, the artery to the
and a brief reduction in systolic function. These effects pulmonary conus (conal artery) originates from a separate
appear to be mediated by the osmolarity of the contrast agent ostium rather than its usual position as a branch from the
because iso-osmolar contrast has only minimal effects of proximal right coronary. Absence of a left main coronary
ventricular function.180 trunk resulting in separate aortic origins for the left anterior
In patients with normal or near-normal ventricular descending and circumflex arteries occurs in 0.5% to 1% of
function, the ventricular effects of contrast are not impor- patients.184 Most commonly these two ostia are closely jux-
tant clinically. Patients with markedly reduced systolic taposed with the dual ostia existing as a “double barrel.”
function (ejection fraction <35%) or elevated ventricular Widely separated left anterior descending and circumflex
filling pressure (regardless of systolic function), however, ostia are uncommon.
 corona ry a ngiogr a ph y 76 3

Orientation of Coronary Trunks nence of diagonal branches are variable. The diagonal branch
in its proximal portion may give rise to septal perforating
The anatomic configuration of the aortic-coronary junctions
branches. This is especially likely in cases of chronic isch-
has made careful quantitative measurements of the normal
emic disease with anterior descending occlusion. Hence, the
coronary-aortic branching angles difficult. Using corrosion
angiographic recognition of a septal branch thus does not
casts obtained by injecting casting material through the
conclusively identify the left anterior descending artery. The
aorta under physiologic perfusion pressure, Zamir and Sin-
cardiac apex is usually perfused by the anterior descending
clair185 measured coronary-aortic branching angles in both
artery but may be supplied by an unusually long diagonal
horizontal and vertical planes in normal hearts obtained at
branch or right posterior descending artery.
autopsy. The mean horizontal branching angle was 25 degrees
(range 0–55 degrees) for the left main coronary and 35 degrees
(range 0–88 degrees) for the right main coronary. The mean Left Circumflex Artery
vertical branching angle was 102 degrees (range 77–145 The circumflex artery is also a continuation of the left main
degrees) for the left main and 69 degrees (range 34–110 artery. Its initial course is in the left posterior atrioventricu-
degrees) for the right main coronary. These measured branch- lar groove, circumscribing the mitral valve. The extent and
ing angles correlate poorly with what would be considered distribution of the circumflex artery and right coronary
optimal on theoretical grounds. Such data suggest that this artery are generally reciprocal. If the circumflex artery is
geometry reflects more the anatomy of the aortic root rather extensive in its supply to the posterior and inferior walls of
than the fluid dynamic principles that usually govern arte- the heart, the right coronary will usually be small with fewer
rial branching. branches to these regions. The variability of this reciprocal
arrangement is great, with some hearts exhibiting a dual
Left Main Coronary Artery vascular supply to the same anatomic regions (e.g., the infe-
rior septum) from both the right and circumflex arteries.
The left coronary artery has a single initial trunk in 92% to
96% of autopsy cases.181,182,186 The length of the left coronary,
as derived from pathologic examinations, is 1.0 ± 0.3 cm.187
Ramus Intermedius Branch
Pre- and postmortem angiographic studies have reported that In some hearts, the left main coronary exhibits a trifurcation
patients with bicuspid aortic valves have a higher incidence at its origin instead of the usual bifurcation. This third
of short left main arteries188 and left coronary dominance,189,190 artery, termed ramus intermedius (or diagonalis), acts func-
although the findings have been refuted by some187,191 and tionally as a circumflex branch, supplying a portion of the
affirmed by others.192 Although angiographic measurements obtuse margin of the heart. In a pathologic study of 150
of coronary diameter are probably more accurate than post- hearts, Baptista and coworkers192 found that the left coronary
mortem pathologic studies (due to changes inherent in the artery exhibited a bifurcation configuration in 55%, trifurca-
postmortem state), angiographic measurements of coronary tion (with the ramus branch) in 39%, and a quadrifurcation
length are probably less accurate due to underestimation of (ramus intermedius and a separate diagonal branch) in 7%.
the effects of rotation, angulation, and foreshortening. A trifurcation pattern was most commonly found (60%) in
Virmani et al.187 found no correlation of left main coronary the hearts of female non-Caucasians. The length of the ramus
length with age, sex, heart weight, extent of coronary disease, varied from 20 to 50 mm, and its relative length varied from
or left ventricular wall thickness. 21% to 50% of the length of the left ventricle.
The left main coronary consists of three portions: the
ostium or origin from the aorta; the midportion; and the Right Coronary Artery
distal portion, which includes the bifurcating segments. His-
tologically the left main ostium lacks adventitia and has a The right coronary runs in the anterior atrioventricular
larger proportion of elastic tissue than any other area in the groove and circumscribes the tricuspid valve. The first branch
coronary tree. These anatomic and histologic features may of the right coronary artery is usually to the right ventricular
account for some of the differences in the response of the left outflow tract (the conal branch), although this artery often
main coronary to interventional procedures. Since the arises separately or from a common aortic ostium with the
left main ostium lies within the wall of the aorta it is vulner- right coronary. In midcourse, the right coronary normally
able to diseases primarily affecting the aorta: syphilitic supplies branches to the right ventricle, which usually reach
aortitis, rheumatoid arthritis, radiation-induced aortitis, and the acute margin of the heart (so-called acute marginal
Takayashi’s aortitis.193 branches). In a small number of cases the right coronary may
have an anomalous intraatrial subendocardial course.194 This
unusual condition has no known adverse clinical outcomes
Left Anterior Descending Artery
and is usually recognized only at autopsy. The anatomy of
The left anterior descending artery is a direct continuation the distal right coronary artery, particularly its size and
of the left main coronary with its course along the anterior course over the left ventricle, is quite variable. In 50% to
interventricular sulcus. Several normal variations of the 60% of patients, the right coronary bifurcates at the crux of
length and distribution of this vessel have been recognized. the atrioventricular groove and the interventricular septum,
It is not essential for the anterior descending artery to reach giving rise to the posterior descending branch (which runs
the cardiac apex or to have well-defined septal or diagonal in the posterior interventricular sulcus to meet the anterior
branches to qualify as the anterior descending artery, descending artery coming from the anterior sulcus) and pos-
although both are usually true.184 The number and promi- terior lateral branches (which perfuses the posterior lateral
76 4 chapter 34

left ventricle). In other cases, however, the posterior descend- can result in an inferior wall ischemic pattern on the
ing branch may arise before the crux, either at the acute electrocardiogram.
margin (13%) or at an intermediate position (19%).195 In 10%
to 20% of patients, none of the left ventricular branches arise Coronary Dominance
from the right coronary artery, coming instead from the ter-
The term coronary dominance was introduced by
minal portion of the circumflex artery (see Coronary Domi-
Schlesinger201 in 1940. The “dominant” coronary artery is
nance, below).186,196
the one that gives rise to the posterior descending artery,
traversing the posterior interventricular sulcus and supply-
Sinus Node Artery ing the posterior part of the ventricular septum and often the
In 51% to 70% of humans, the sinus node artery arises from posterolateral wall of the left ventricle as well.202 The right
the right coronary artery.195,196 In contrast, the sinus node coronary artery is dominant in approximately 70% of
artery of swine and dogs almost always (90–100%) arises humans.203 If the circumflex artery terminates in the poste-
from the right coronary.186,197 The sinus node artery arises rior descending artery, left dominance is present. This is seen
from the circumflex artery in the remainder of patients. The in 15%. In the remaining 15%, the posterior septum is sup-
sinus node artery is usually the second branch of the right plied by branches arising from both the right coronary and
coronary artery (excluding the conal branch) and is generally left circumflex artery. In this situation the circulation is said
the first and largest atrial branch. When the sinus node does to be “balanced” (or codominant) and the posterior descend-
not originate from the right coronary artery, it usually is a ing is either dual or absent,202 being supplied by a network of
branch of the circumflex artery. In an anatomic study of 300 small branches. It should be noted that anatomic dominance
human hearts, Nerantzis and Avgoustakis198 found that the does not imply physiologic dominance. Although the right
sinus node artery arose from the circumflex in 37% of cases. coronary artery is usually dominant, the left coronary almost
Although this circumflex sinus node artery usually arises always supplies a greater myocardial mass.204
near the origin of the circumflex, in 21% of patients with a
circumflex origin the artery is an S-shaped vessel that origi- Standard Nomenclature
nates from the posterior-lateral branch of the circumflex. To facilitate clinical studies and communication between
This S-shaped sinus node artery can function as a bridge clinicians, several systems of coronary nomenclature have
between the right and left coronary trunks in the case of been developed. These clinical systems often apply slightly
proximal coronary occlusions. different names to arterial segments than are used in the
anatomy literature. The most commonly used system was
Atrioventricular Nodal Artery developed for the Bypass Angioplasty Revascularization
The atrioventricular nodal artery in nearly 90% of humans Intervention (BARI) trial.205
arises from the right coronary artery in the area of the crux.
In the remainder this artery is a branch of the circumflex Angiographic Views
artery. This pattern of vascular supply is similar to that seen
in swine, but differs greatly from the dog.197 In canines, The importance of obtaining adequate angiographic views of
because of a small nondominant right coronary, the AV nodal the coronary arteries cannot be overemphasized. Since the
artery arises from the left circumflex artery in almost orientation between the planes of the major cardiac grooves
100%.186,197 and septum are different from the standard anteroposterior
(AP) and lateral projections utilized for chest roentgenology,
oblique views must be used to obtain optimal angiographic
Vascular Supply to the Interventricular Septum
visualization of the coronary arteries. An understanding of
In over 99% of patients the blood supply to the anterior the orientation of these structures and the coronary vessels
interventricular septum is from the left anterior descending in the oblique positions can be difficult for the novice, but
coronary.199 In the majority of patients, there is no dominant several teaching models have been developed to facilitate
septal artery; rather, the proximal septal vessels are of equal understanding.206–208
caliber. In 38%, a large dominant septal perforator occurs, We have utilized the schematic diagram shown in Figure
and this is usually but not always the first septal. Septal 34.9, in which the eyes represent the line of sight of the
perforators may exhibit bifurcation or trifurcation. The viewer. In the LAO projection the viewer is sighting down the
branching pattern is unordered (i.e., tertiary branches may interventricular and interatrial septum. All left-sided cardiac
arise from the primary vessel).200 chambers appear to the viewer’s right. In the LAO projection,
Septal branches from the posterior descending artery, the anterior and posterior descending coronary arteries are
arising from either the right coronary or left circumflex seen coursing vertically in the middle of the cardiac silhou-
artery, are the usual vascular supply to the posterior septum. ette, following the path of the interventricular septum. In the
In rare instances, the posterior descending may originate RAO projection, the viewer’s line of sight is the atrioventricu-
from the first septal branch of the anterior descending or lar groove plane. In this projection the two atria and the two
from an obtuse marginal branch of the circumflex artery. ventricles are superimposed. The proximal circumflex and
A more common variant that occurs to differing degrees proximal right coronary arteries are well visualized as they
is the “wrap-around” left anterior descending. In such follow their course in the atrioventricular groove.
cases, the posterior septum is supplied by the anterior The angiographer must evaluate the entire vessel in
descending artery. Distal left anterior descending occlusion several different views to avoid the effects of vessel foreshort-
 corona ry a ngiogr a ph y 76 5

Transverse Plane minimized the problem of foreshortening of the coronary

Posterior arteries.
The use of a standard set of optimal projections for coro-
nary angiography is at best only a guide, since variations in
LA normal coronary anatomy are the rule rather than the
Right Left exception. The following suggestions may be of some help.
The left main coronary artery, which under most circum-
RA LV stances should be visualized first and with great care, can
be seen best in the posteroanterior (PA) (Fig. 34.10) or in a
Lateral View very shallow oblique projection (either RAO or LAO) so that
RV
the left main coronary is just off the spine. The circumflex
artery and its marginal branches can be defined in the RAO
Anterior projection (20- or 30-degree angulation) with 20 to 30
degrees of caudal angulation (Fig. 34.10). A second less steep
RAO or PA view coupled with marked cranial angulation
(30 degrees) (Fig. 34.10) may be helpful in delineating the
course of the anterior descending artery, avoiding overlap
RAO View LAO View by other branches. A steep LAO view (40 degrees) with
severe cranial angulation (40 degrees) (Fig. 34.10) is essential
in viewing the left anterior descending and diagonal branch
Frontal (PA) View bifurcation. An additional LAO caudal view (LAO 40
FIGURE 34.9. Schematic depicting cardiac chamber locations as degrees, caudal 30 degrees, the so-called spider view) (Fig.
viewed in the four standard radiographic projections: Frontal (pos- 34.10) may be of use in visualizing the bifurcation of the
teroanterior, PA), lateral, right anterior oblique (RAO), and left ante-
rior oblique (LAO). The eyes represent the viewer’s line of sight. left main, the proximal circumflex, and left anterior
descending and at times the distal left anterior descending.
The proximal and mid-right coronary arteries are usually
seen well in a 30- to 45-degree LAO projection. A moderate
LAO view with cranial angulation (LAO 20 degrees, cranial
ening that can hide a stenotic lesion and because coronary 20 degrees) (Fig. 34.11A) may be ideal for viewing the bifur-
lesions are frequently eccentric. Although the severity of a cation of the distal right coronary into the posterior descend-
coronary stenosis is often reported as the most severe appear- ing and posterior lateral branches. One view of the right
ance measured in any of the views, physiologic studies show coronary in the RAO view is necessary. At times visualiza-
that an integration of lumen stenosis from many views more tion of the distal right coronary is helped by adding cranial
accurately predicts the degree of blood flow impairment angulation (sometimes up to 60 degrees) to the RAO view
imparted by the lesion.209 In truth, if the lesion can be well (Fig. 34.11B).
visualized, all views are contributory toward assessing ste- A common series of initial projections are as follows:
nosis severity. Additionally, when quantitative angiographic
Left coronary
methods are employed, coronary lesions are best evaluated
in at least two orthogonal projections (e.g., LAO 60 degrees 1. LAO 5
and RAO 30 degrees) in which the lesion can be seen well in 2. RAO 30, caudal 20
both projections without foreshortening or overlap.210 3. PA, cranial 40
In 1981 Paulin211 proposed that radiographic projections 4. LAO 40–45, cranial 30–40
be named by following the course of the x-ray beam as it 5. LAO 40, caudal 30
passes through the heart. The x-ray gantry can be angled in
Right coronary
the horizontal and coronal planes. The position of the imaging
device defines the projection. In the LAO projection, the x- 1. LAO 40, cranial 20
ray beam is angled in the horizontal plane such that it is 2. RAO 45
projected from under and to the right of the patient (right 3. PA, cranial 35 if bifurcation not seen
posterior) to the image intensifier, which is anterior and to
the patient’s left. Similarly, the x-ray beam of the RAO view
Rotational Angiography
originates in the left posterior aspect and passes to the image
tube, which is anterior and rotated to the patient’s right. In The development of rapidly rotating x-ray gantries and digital
caudocranial views the x-ray beam is angled in the coronal imaging makes it possible to image the coronaries from a
(frontal) plane. In the “cranial” view, the x-ray beam origi- 180-degree arc during one coronary contrast injection, reduc-
nates caudally and passes through the heart to the image ing the number of angiographic runs needed to image the
intensifier, which is angled cranially. Conversely, in a caudal coronaries from multiple projections. In one study, the con-
projection the x-ray tube is angled cranially and projects the trast dose using this rotational method was reduced by 27%
x-ray beam caudally to the image tube. The use of multiple and the x-ray dose by 40%, although there was a learning
oblique views in the anterolateral projection in conjunction curve for adopting the method.212 The accuracy of coronary
with angulation in the caudocranial plane has greatly lesion interpretation appeared to be similar to planar imaging,
facilitated optimal visualization of coronary lesions and but the method is still in its infancy.
76 6 chapter 34

FIGURE 34.10. Angiographic projections of a normal left coronary

artery. (A) Selective left coronary angiogram viewed with 30-degree RAO
and 20-degree caudal angulation. (B) Same vessel viewed with 30-degree
RAO and 30-degree cranial angulation. (C) Same vessel viewed in the PA
projection with 35-degree cranial angulation. (D) Same vessel viewed
with 40-degree LAO and 30-degree cranial angulation. (E) Same vessel
viewed with 30-degree LAO and 30-degree caudal angulation. LAD, left
anterior descending; Cx, circumflex; RI, ramus intermedius; LM, left
main.
 corona ry a ngiogr a ph y 767

FIGURE 34.11. Angiographic projections of a normal right coro- right coronary artery; PDA, posterior descending artery; PLA, pos-
nary artery. (A) Selective right coronary angiogram viewed with terolateral artery.
30-degree LAO. (B) Same vessel viewed with 45-degree RAO. RCA,

Coronary Artery Dimensions cross section was assumed, and the cross-sectional area was
estimated to be: (Coronary diameter)2 ÷ (π · 4).
Normal Dimensions in Humans The summed cross-sectional areas of the main right
coronary, the proximal left anterior descending, and proxi-
It has become recognized increasingly that measurements of mal circumflex arteries were called the total coronary area.
coronary artery dimensions at autopsy do not correlate well A summary of these results is given in Table 34.2 and
with in vivo angiographic measurements of coronary diam- Figure 34.13. In men with a large dominant right coronary
eter.213–217 The importance of accurate measurements of distribution, the total coronary area was 32.1 ± 7.3 mm2
normal coronary caliber is underscored by the understanding with the right coronary contributing 38% of the total area,
that coronary atherosclerosis is primarily a diffuse disease the circumflex 29%, and the left anterior descending 33%.
process that may be difficult to recognize angiographically.218 The total coronary area was not statistically different
Thus, without knowing the “true” caliber of an artery it is between patients with small right coronary, balanced, and
often difficult to conclude whether a given coronary segment dominant left coronary distributions (33.5 ± 9.3, 26.8 ± 5.2,
that appears normal angiographically is normal anatomi- and 30.7 ± 5.5 mm2, respectively.223 Using these measure-
cally.219 The importance of recognizing diffuse coronary nar- ments and those of others224,225 it is usually possible to esti-
rowing is underscored by studies in patients with advanced mate “normal” coronary segment diameter in men and
atherosclerosis showing that angiographic measurements women to within ±25% (coefficient of variation). Unfortu-
based on lesion percent stenosis (as a fraction of the diameter nately, nitroglycerin was not given in these studies so that
of the adjacent normal segment) correlate poorly with physi- the effects of differences in coronary vasomotor tone were
ologic measurements of the effect of a given focal stenosis not standardized.
on coronary blood flow.220,221 The rationale for expressing
lesion severity as percent stenosis has recently been rendered
even more tenuous by the findings that in atherosclerosis,
compensatory coronary enlargement precedes the process of
luminal narrowing, and often compensates for any narrow-
ing until this narrowing reaches 40% of the intimal lumen222 Muscularis
(Fig. 34.12). Diameter Plaque
Lumen
Dodge and coworkers223 used computer-based quantita-
tion of angiograms to measure coronary lumen diameter at
96 points in 32 defined coronary segments or major branches Time
in normal arteriograms carefully selected from over 9000 FIGURE 34.12. Concept of compensatory coronary dilation as ini-
tially proposed by Glagov et al.222 The early atherosclerotic plaque
consecutive studies. In these angiograms, absolutely smooth development is associated with a compensatory increase in lumen
lumen borders were used to indicate likely freedom from area. No decrease in lumen caliber is seen until the stenosis reaches
atherosclerotic disease. For these normal arteries, a round nearly 40%.
76 8 chapter 34

TABLE 34.2. Diameter of the main coronary arteries in normal Coronary dilation and increased coronary tone is also seen
men, normal women, and men with left ventricular hypertrophy in long-distance runners.234 Coronary dilation can also result
or dilated cardiomyopathy
from fistulous connections between the artery and a cardiac
Men Women, chamber or vein.
RCA dominant Men with Men with
Location dominant RCA DCM LVH
Effects of Gender, Weight, Age, and Tortuosity on
LM mid 4.5 ± 0.5 3.9 ± 0.4 4.8 ± 0.3 4.9 ± 0.4 Coronary Caliber
Proximal 3.6 ± 0.5 3.2 ± 0.5 3.8 ± 0.5 3.9 ± 0.5
The evidence suggests that females have higher morbidity
LAD
and mortality resulting from attempts at coronary revascu-
Distal LAD 1.7 ± 0.5 1.6 ± 0.4 2.0 ± 0.4 2.1 ± 0.5
larization either with angioplasty235 or bypass surgery.236,237
Proximal Cx 3.4 ± 0.5 2.9 ± 0.6 3.3 ± 0.7 3.6 ± 0.6 Speculation as to reasons for apparent differences in results
Distal Cx 1.6 ± 0.6 1.4 ± 0.4 2.1 ± 1.0 1.7 ± 0.6 has focused on differences in coronary size between men and
Proximal RCA 3.9 ± 0.6 3.3 ± 0.6 4.5 ± 0.5 4.6 ± 0.7 women. In one report, the proximal coronary lumen diame-
Distal RCA 3.1 ± 0.5 3.0 ± 0.5 3.7 ± 0.3 4.1 ± 0.5 ter of women with normal arteries and a right dominant
RCA, right coronary artery; LCA, left coronary artery; R, right coronary coronary circulation was 9% ± 8% less than in similar men.
artery; LM, left main; L, left anterior descending; C, circumflex. Values are In the same study, women had 15.3% smaller main coronary
mean ± SD.
branch areas when normalized for body surface area. In a
collaborative study involving multiple institutions in north-
ern New England, O’Connor et al.237 recorded prospectively
body weight and the luminal diameter of the mid-left ante-
rior descending (LAD) branch in 1325 patients undergoing
Influence of Coronary Artery Length and
coronary artery bypass surgery. Vessel size was strongly
Dominance on Coronary Caliber
The normal diameter of a coronary artery is proportionately
related to the length of the vessel. Although the diameters
of the left main and the left anterior descending segments
are unaffected by anatomic perfusion field size, the left cir-
cumflex artery or right coronary artery is usually signifi-
cantly larger when dominant.223 The diameter of the posterior
descending artery, however, is similar regardless of whether
it arises from the right or circumflex arteries.223
The epicardial distribution, characterized by the arterial
length relative to the distance from its origin to the left
ventricular apex is the principal determinant of branch
diameter. There is a close correlation between the lumen
area of a coronary artery at each point along its length and
the corresponding summed distal branch lengths and regional Lm
myocardial mass, in patients with and without coronary
artery disease.226
C1
R1
Effects of Other Physiologic and Pathologic
Variables on Coronary Caliber
Multiple other physiologic and pathologic processes affect L1
coronary caliber. Acute changes in perfusion pressure mark-
edly alter coronary diameter by changing the distending
force.226 Increased blood flow from heightened myocardial
C3
oxygen demand (e.g., increased heart rate) or drug adminis-
tration lead to coronary relaxation 227–229 by an endothelial- L3
dependent mechanism that affects coronary smooth muscle
vasomotor tone.230 The effects of intraluminal pressure and
endothelial-mediated dilation on coronary caliber can be
altered significantly by vascular pathology.
Other conditions lead to anatomic coronary dilation via
a chronic increase in coronary blood flow. Hypertension and R3
the wide range of conditions resulting in left ventricular
hypertrophy231–233 result in marked increases in epicardial
vessel size.231 When body surface area is used to normalize FIGURE 34.13. Diagram of coronary artery segment nomenclature
for a right coronary dominant circulation. LM, left main; R1, proxi-
for differences in body size, men with left ventricular hyper- mal right coronary; R3, distal right coronary; L1, proximal left
trophy or dilated cardiomyopathy have 37% or 31% larger anterior descending; L3, distal left anterior descending; C1, proxi-
coronary segment areas, respectively, than normal men.223 mal circumflex; C3, distal circumflex (see Table 34.2).
 corona ry a ngiogr a ph y 76 9
related to both gender and body size (body surface area, mass Relationship Between Angiographic Coronary
index, height, and weight). Within each quartile of body size Anatomy and Myocardial Perfusion Field
measurements, the mid-LAD diameter in men was greater (Risk Region)
than that in women with a mean difference range of 0.14 to
There is considerable experimental data relating myocardial
0.23 mm. The smaller LAD diameter in women was also
infarct size and consequent clinical outcomes to the mass of
associated with increased risk of mortality from coronary
myocardium perfused by an infarct-related coronary
bypass surgery. Differing results were found when Kornowski
artery.204,246,247 Calculation of the infarct/risk area ratio is
et al.238 compared coronary cross-sectional area luminal nar-
critical to the assessment of interventions aimed at limiting
rowing, plaque quality, plaque calcium, and lumen location
infarct size. Relating coronary anatomy as viewed from the
in 549 men and 169 women with chronic stable angina using
coronary arteriogram to the myocardial perfusion volume or
intravascular ultrasound. These investigators found that
risk area, however, has proven difficult to accomplish in the
when corrected for body surface area, no differences in these
clinical setting. Quantitating these relationships in patients
parameters of atherosclerosis between men and women could
with atherosclerosis is difficult because of complexities
be identified.
introduced by the presence of diffuse luminal narrowing and
Age, if considered separately from an increased possibil-
vessel occlusion.
ity of the presence of diffuse atherosclerosis, is thought gen-
Experimental studies in normal animals have shown
erally to increase coronary caliber.239 Dodge et al.,223 however,
that geometric characteristics of the arterial tree relate
found no age-related trend toward increased total coronary
directly to regional myocardial perfusion volume. Koiwa’s
area in normal men when the coronary diameter was nor-
group248 has shown in dogs that the maximally dilated
malized for body surface area. Total coronary area in men
coronary artery luminal cross-sectional area is related lin-
with apparently normal coronary arteries was virtually con-
early to the volume it perfuses. The cumulative length of
stant at 15.2 ± 3.6 mm2/m2. Of note, however, in the LAD
arterial branches is also related to the myocardial perfusion
artery a positive correlation was found between age and
volume.249
vessel tortuosity, but not between tortuosity and lumen
In humans, radioisotopic techniques have been used to
diameter. In contrast, Leung et al.240 found a progressive age-
measure the region at risk. Using a method initially vali-
related decrease in the cross-sectioned area of each proximal
dated in the pig,250 technetium-99m–radiolabeled albumin
coronary and reduced total coronary cross-sectional area.
microspheres were injected directly into both coronary arter-
These authors speculate that such changes may be due to
ies of patients presenting with acute infarction during the
decreased coronary flow requirements, attenuated endothe-
period of total coronary occlusion and again following
lial vasodilatory responses, or age-related changes in myo-
achievement of lumen patency after intracoronary throm-
cardial composition.
bolysis.204 Delayed scanning revealed perfusion deficits that
could be quantitated as the area at risk and correlated with
Effects of Normal Variations in Coronary the exact site of coronary occlusion determined with acute
Vasomotor Tone on Coronary Caliber coronary angiography (Fig. 34.14). Data from a limited number
of patients studied with these techniques revealed that infe-
The importance of coronary vasomotor tone on measure-
rior infarcts secondary to right or circumflex coronary artery
ments of coronary caliber, though widely acknowledged, is
occlusions were associated with areas of risk ranging from
often ignored. Normal proximal epicardial coronary caliber
10% to 26% (mean 18%) of left ventricular mass. In contrast,
can increase up to 30% after administration of nitroglycerin,
anterior infarctions resulting from left anterior descending
if coronary perfusion pressure is maintained.241 Angiographic
artery occlusions had risk areas of 14% to 49% (mean 39%).
studies show striking variations in coronary tone depending
Two patients who subsequently expired had risk regions of
on time of day242 and psychological stress.243 In atheroscle-
over 40% of the left ventricular mass. Importantly, the area
rotic monkeys, coronary vasomotor responses can be modu-
lated by estrogen treatment.244 Despite the acknowledgment
of the importance of coronary vasomotor tone, quantitative
studies of atherosclerosis progression or regression too
frequently are performed with this important variable 70
Successful reperfusion (16) N = 29
uncontrolled. 60 Unsuccessful reperfusion (11)
Although vasodilation in response to nitroglycerin is Patient died
seen in normal coronary segments of all sizes, the response 50
% Area at risk

varies in magnitude.95 Those epicardial coronary segments

40
with the smallest basal diameter show the greatest relative
change in dimension.95 Since most coronary stenoses have a 30
portion of the vascular circumference that is relatively
normal, even severe stenoses may dilate in response to nitro- 20
glycerin. However, if stenosis severity is calculated as percent 10
stenosis (comparing lesion diameter to the diameter of the
adjacent normal segment), the stenosis may artifactually 0
RCA LAD CX
RCA
appear to worsen after nitroglycerin administration because + CX
of a comparatively greater dilatory effect on the adjacent FIGURE 34.14. Relationship between site of coronary occlusion
normal segment.245 and the size of the risk area.
770 chapter 34

of the region at risk could not be predicted by careful visual TABLE 34.3. Incidence of coronary artery anomalies, detected by
assessment of the coronary angiogram. angiography
Intravenous technetium-99 m sestamibi has also been Author (ref.) Total no. of patients Anomalies Incidence (%)
used to measure the area at risk in patients with acute infarc- Liberthson 289 Not stated 21 0.6
tion.251,252 The lack of redistribution with this radiopharma-
Engel 257 4,250 51 1.2
ceutical permits imaging to be done with single photon
Chaitman 285 3,750 31 0.83
emission computed tomography up to 6 hours after injection.
Baltaxe258 1,000 9 0.9
Using this technique, quantitative measurements of the
infarct risk area in patients with an initial acute infarction Kimbiris 7,000 45 0.64
correlated poorly with the “best estimate” of two experi- Hobbs297 9,153 601 1.55
enced angiographers.252 These data emphasize again the vari- Wilkins256 10,661 83 0.78
ability of risk areas that are not predictable by the anatomic Yamanaka 254 126,595 1,686 1.3
site of coronary occlusion, and the inability of angiographers
to predict the risk area in individual patients.
Leung et al.240 and others253 developed a semiquantitative
method for determining the myocardial territory supplied by
(myocardial jelly). The in-situ vascular endothelial network
a nutrient vessel based on the relative size of the vessel as
develops separately in the subepicardium 31 days after ovula-
judged by the summed length of the terminal vessel segment.
tion. The coronary anlage (buds) sprout from the wall of the
Although this method is easy to use and has acceptable
aorta-pulmonary trunk as septation is proceeding. After
interobserver variability, it has not been validated in an
completion of aortopulmonary septation these latter two
animal model.
components fuse and a normal coronary circulation begins.
Although the coronary ostia are formed quite early, the distal
Congenital Coronary Anomalies coronary branching pattern remains as a variable inter-
branching network until the cardiac chambers develop.
Embryology The size and distribution of the coronary arteries are
related to and dependent on subsequent myocardial chamber
Although a thorough description of the genesis of the coro-
development. According to Angelini,184 a true mismatch
nary circulation is beyond the scope of this chapter, a few
between the dependent myocardium and its related coronary
important considerations are appropriate. There are at least
arteries is embryologically improbable. Therefore, on physi-
three major anatomic components important in the develop-
ologic grounds, the finding of coronary atresia or hypoplasia
ment of the coronary arterial bed: the myocardial sinusoids,
is unlikely. Instead, either the dependent myocardium is also
the in-situ vascular network, and the coronary anlage184 (Fig.
hypoplastic or, more commonly, the opposite coronary is
34.15). The myocardial sinusoids are an elongation of the
relatively oversized. Thus, at birth the coronary circulation
trabeculae into the developing myocardium. The sinusoids
is usually effectively normal in global physiologic terms and
are the earliest sites of metabolic exchange between the
the angiographic finding of a coronary artery that appears
blood contained in the cavities and the cardiac mesenchyma
hypoplastic is usually only an infrequently occurring coro-
nary arterial pattern. Some coronary anomalies still occur,
however, and are well recognized to be associated with major
adverse clinical consequences.

Incidence and Classification

Tabulations of coronary angiograms suggest that coronary
anomalies occur in the adult population with an incidence
ranging from 0.6% to 1.3%254–258 Yamanaka and Hobbs254
reported the Cleveland Clinic experience from 1960 to 1988
reviewing data from 126,595 angiograms. Coronary artery
anomalies were found in 1686 patients, an incidence of 1.3%.
Of the coronary anomalies, 87% involved the origin and
distribution of the vessel, and 13% were coronary artery fis-
tulas. Table 34.3 shows the incidence for various coronary
anomalies from the Cleveland Clinic study. Since the angio-
grams were obtained primarily to assess coronary atheroscle-
rosis in adults, congenital coronary anomalies resulting in
early or sudden death are not represented.
A variety of classification schema for congenital coro-
nary anomalies has been proposed.259 Although each has its
attributes, the most clinically useful classification divides
congenital coronary anomalies into those that are usually
FIGURE 34.15. Schematic illustration of three major components associated with a benign outcome, and those whose natural
responsible for development of the coronary arterial bed: myocardial history is associated with adverse events. Most adverse out-
sinusoids, in-situ vascular network, and coronary anlage (buds). comes appear to result from decreased myocardial perfusion,
 corona ry a ngiogr a ph y 7 71
although the mechanism of such an ischemia is speculative.
Coronary atherosclerosis does not seem to occur with
increased incidence in anomalous vessels nor is the presence
of coronary anomalies protective against coronary artery
disease.254

Congenital Coronary Anomalies, Often Benign

MYOCARDIAL BRIDGES
That portions of the conduit coronary arteries may take a
short intramural course and be covered by a muscle “bridge”
has been part of the anatomic literature since 1737.260 However,
the clinical significance of such anatomy is more recent in
origin. Muscular myocardial bridges are recognized angio-
graphically by the characteristic narrowing of the coronary
lumen that is seen during systole and that is absent during
diastole. Although most cases of angiographic systolic nar-
rowing correspond with anatomic myocardial bridges, this
finding occasionally may be caused by other mechanisms
A
such as pericardial fibrosis, tumors, or foreign bodies.261
Coronary arterial location in mammalian hearts has
been classified into three main types: type A (hamster, squir-
rel, rat, guinea pig, and rabbit), in which the coronary arteries
are entirely intramyocardial; type B (goat, sheep, dog, cat,
macaque, and humans), in which the coronary arteries are
predominantly epicardial but myocardial bridging is fre-
quent; and type C (horse, cow, pig), in which the coronary
arteries are entirely epicardial and bridging is rarely if ever
seen.262 In humans and other type B mammals, myocardial
bridges are found most frequently in the left anterior descend-
ing artery. Table 34.4 details the incidence of muscular
bridges in the experience of four groups of investigators.
When the results of eight separate autopsy studies were
pooled, myocardial bridges were found in 449 of 1652 cases
(27%).263 This high frequency coupled with the comparative
anatomic data suggest that myocardial bridging is often a
“normal” finding.
The most frequent site of bridging is the mid-segment of B
the left anterior descending artery (Fig. 34.16). A typical mus- FIGURE 34.16. Selective coronary angiogram showing a distinct
cular bridge in this artery is 10 to 20 mm long and 2 to 4 mm muscular bridge in the left anterior descending artery. (A) Selective
thick.261 Portions of other arteries that are located in the coronary angiogram showing a muscular bridge in the left anterior
atrioventricular groove (such as the proximal–middle right descending artery. In diastole, the artery (arrows) is normally dis-
tended. (B) In systole, the artery is compressed by a muscle bridge
and circumflex arteries) are frequently surrounded by scat- (arrows).

TABLE 34.4. Anatomic incidence of muscular bridges (MBs)* tered muscular fibers continuous with the atrial myocar-
262 278
dium and may also exhibit systolic narrowing. These are
Source Polacek Edwards
referred to as myocardial loops. As another variant, arteries
No. of cases 70 270 such as the obtuse marginal branch and ramus intermedius,
Male/female NS NS which are located over the free wall of the left ventricle, may
Incidence of MB (%): plunge into the myocardium at some point in their course.
LCA + RCA 85.7 5.4 These arteries frequently do not resurface. Anatomic studies
LCA 77.7 5.1 suggest that the prevalence of myocardial bridging involving
LAD 60.0 4.7 major coronary veins is less than 5%.262
DIAG 18.5 NS Angiographic studies of myocardial bridging in humans
have shown a much lower prevalence than seen in autopsy
CX 40.0 NS
studies, usually ranging from 0.5% to 7.5%.261,264,265 In one
OM 14.2 0.4
series, however, the occurrence was 16%.266 For systolic nar-
RCA 41.4 0.4
rowing to occur, the external muscular compressive force
* Incidence of muscular bridges. Percentage of patients with muscular bridges must exceed the arterial pressure and the intrinsic arterial
in different locations.
wall stiffness. During angiography, the increased intralumi-
LCA, left coronary artery; RCA, right coronary artery; LAD, left anterior
descending; DIAG, diagonal; CX, circumflex; OM, obtuse marginal; NS, not nal pressure resulting from the pressure of contrast injection
stated. may act to diminish recognition of lesser intramyocardial
772 chapter 34

bridges than might be detected in anatomic studies. In one normal population.281 Administration of nitroglycerin accen-
study, the mean maximum corrected length of artery involved tuated the degree of systolic narrowing.282
in the muscle bridge was 15 mm (range 9 to 44 mm) and the There is a well-described association between left ven-
maximum percent reduction in diameter during systole was tricular hypertrophy (as seen in aortic stenosis, hypertrophic
56% (range 30–100%).264 Long myocardial bridges, often cardiomyopathy and hypertension) and an increased inci-
referred to as tunnels, have been described. dence of myocardial bridges.274,283 This may relate to a greater
Although scattered reports have attributed chest pain in contractile force generated by the myocardium. Although
patients with normal coronary arteries to the finding of a angiographically detected systolic compression occurs rarely
myocardial bridge, these two conditions are not frequently in normal intramural septal arteries, septal “twinkling” or
related causally. Patients with equal degrees of systolic nar- “squeeze” resulting from prominent widespread systolic
rowing do not exhibit a similar clinical or pathophysiologic septal compression is commonly seen in patients with aortic
response. Since coronary flow is predominantly diastolic and stenosis (71%) and hypertrophic cardiomyopathy (74%).283
some animals have wholly intramyocardial arteries, luminal
compression during systole is unlikely to play a frequent role ORIGIN OF THE L EFT CIRCUMFLEX FROM THE R IGHT
in causing myocardial ischemia. Experimental studies in CORONARY SINUS
dogs have shown that systolic myocardial contraction does In the United States the origin of the left circumflex artery
not limit coronary flow at heart rates less than 160 beats/min from the right aortic sinus or from the right coronary
or unless coronary compression extends into early diastole.267 artery is the most common anomaly of coronary arterial
Doppler flow studies in one patient with myocardial bridging origin.284–286 Most patients have no other associated anoma-
and normal arteries have confirmed these findings.117 The lies and no deleterious effects resulting from this congenital
use of intracoronary Doppler measurements of coronary flow anomaly. The anomalous circumflex courses posterior to the
and intravascular ultrasonography (IVUS) may help in defin- aortic root and the noncoronary sinus to enter the left atrio-
ing the clinical significance of coronary bridging.268 ventricular groove and ultimately perfuse its usual territory
Delayed diastolic relaxation in the bridged segment in (Fig. 34.17). The size and variation of the perfusion field is
humans has been reported 269,270 using intravascular ultra- similar to that of the normal circumflex artery.
sound. Rapid atrial pacing with marked shortening of the An anomalous origin of the circumflex artery should be
coronary diastolic perfusion time, especially if combined suspected when contrast injection into the left coronary
with left ventricular hypertrophy, may rarely result in myo- artery reveals what appears to be an unusually long left main
cardial ischemia in patients with bridging.271 Thus it is pos- coronary or flush occlusion of the circumflex (Fig. 34.18).284
sible that certain myocardial bridges, especially those of long The anomalous circumflex origin is often missed during
length that course deeply within the myocardium,272 may be right coronary angiography since deep seating of the right
responsible for sudden unexpected cardiac death following coronary catheter may prevent sufficient reflux of contrast
tachycardia-related ischemia. These occurrences are likely to opacify the aberrant origin (Fig. 34.19). If suspected, the
quite rare, although this anomaly has been reported as the catheter should be withdrawn slowly and repositioned poste-
sole cardiac anomaly in young patients with sudden unex- riorly in the right sinus of Valsalva and the injection repeated
pected death.273 (Fig. 34.20). A right vein bypass curve catheter can be useful
Several anatomic studies have reported a protective effect in cannulating the circumflex ostium, which often is directed
of myocardial bridging.261,274–276 In rabbits whose proximal inferiorly.287
coronary arteries are exclusively intramural, cholesterol- In this anomaly, the proximal circumflex invariably runs
induced atherosclerosis spares these arteries even when a retroaortic course and does not cross between the great
severe lesions develop in the subendocardial arteries.261 The vessels. It has no clinical significance unless the angiogra-
mechanism of such a protective effect is unknown but may pher assumes the vessel is occluded or a significant stenosis
involve protection from systolic wall stress. In humans, myo- in the artery is not identified.
cardial bridges may slightly increase the chances of proximal
coronary atherosclerosis, while protecting the bridged SEPARATE ORIGINS OF THE L EFT A NTERIOR DESCENDING
segment and the distal artery. Postmortem human morpho- AND L EFT CIRCUMFLEX FROM THE SINUS OF VALSALVA
metric studies have shown that when proximal myocardial In this common anomaly the left anterior descending and
bridging is present, intimal thickening and macroscopic circumflex arteries arise from separate but adjacent ostia and
raised atherosclerotic lesions are increased just before the
bridge. Under the bridge, eccentric plaques and raised lesions
are absent, although there is often concentric intimal thick-
ening.277,278 There are isolated case reports of acute myocar-
dial infarction associated with muscle bridges.279,280 However,
when carefully examined, the overall frequency of myocar-
dial infarction is the same in patients with and without
myocardial bridges.
Myocardial bridges have been recognized with increased
frequency following cardiac transplantation. Review of the
FIGURE 34.17. Views of the aortic (left) and pulmonary (right)
angiograms of 64 cardiac transplant patients revealed a 33% valves showing normal origin of the coronary arteries (left) and
incidence of myocardial bridging, a much higher angiograph- anomalous origin of the circumflex artery from the right coronary
ically detected incidence than would be expected in the artery and its usual course posterior to the aorta.
 corona ry a ngiogr a ph y 773

FIGURE 34.18. Selective left coronary artery angiogram in a patient

with anomalous origin of the left circumflex from the right coro- FIGURE 34.20. Repeat selective right coronary angiogram from the
nary artery. Note the apparent very long left main coronary caused same patient as in Figure 34.19. The catheter has been pulled back
by the absence of a circumflex branch. and the anomalous circumflex is now apparent.

a common left main trunk is absent (Fig. 34.21).288 The dis- coronary branches may be misinterpreted as being totally
tribution pattern of both arteries is otherwise normal. The occluded.
anomaly is associated with aortic valve disease and left coro-
nary dominance.289 At angiography it can be difficult to A NOMALOUS CORONARY A RTERY ORIGIN A BOVE THE
determine whether the left main is truly absent or very short, SINOTUBULAR R IDGE
or if a common ostium is present. Occasionally, different In this anomaly either the right (most frequent) or occasion-
catheter curves are needed to inject contrast into the separate ally the left coronary ostium is located 1 to 2 cm above the
left anterior descending and circumflex branches (Fig. 34.22). sinotubular ridge. The distribution of the affected coronary
If unrecognized at catheterization, one of the major left is otherwise normal. This common anomaly should be

FIGURE 34.19. Selective right coronary angiogram from the same

patient as in Figure 34.18. Note that the catheter is positioned deeply
into the ostium of the vessel so that no contrast reflux into the sinus FIGURE 34.21. Separate ostia for the left anterior descending and
is seen. No anomalous circumflex artery is demonstrated. left circumflex arteries from the left sinus of Valsalva.
 7 74 chapter 34

Coronary Arterial Anomalies Associated with

Adverse Outcomes
A NOMALOUS ORIGIN OF EITHER M AJOR CORONARY A RTERY
WITH A PROXIMAL INTERARTERIAL OR SEPTAL COURSE
It is the course of an anomalous coronary artery, rather than
the location of the coronary ostium that is the major deter-
minant of whether the anomaly is benign or has associated
clinical consequences (e.g., angina, ventricular arrhythmias,
syncope, or sudden death).254,291–293 These adverse outcomes
usually occur when the anomalous coronary artery passes
between the aorta and the pulmonary artery, or less com-
monly via a septal pathway. Clinical events, particularly
sudden death, are usually seen during exertion in young
individuals in the absence of coronary atherosclerosis. It is
A postulated that exercise results in kinking or in some way
causes transient limitation in coronary flow because of the
orientation of the vessel at its origin or because it is com-
pressed during its anomalous course.294
It is often difficult to delineate angiographically the prox-
imal course of an anomalous vessel. Although some angiog-
raphers have suggested that performing coronary angiography
in a lateral projection after passing a pulmonary artery cath-
eter localizes the course of the vessel, this technique is of
limited value since in the lateral view both a septal and
interarterial course (between the aorta and pulmonary artery)
will appear posterior to the pulmonary artery and anterior
to the aorta if the septum is caudal to both great vessels. A
ventriculogram or aortic angiogram performed in the RAO
projection is needed.295 Serrota and colleagues295 have devel-
oped a clever “dot and eye” recognition pattern technique for
localization of the initial pathway, which may be helpful.
B Although coronary angiography, if carefully done, can often
FIGURE 34.22. Selective left coronary angiogram in a patient with define the cause of the anomalous vessel, the concomitant
separate ostia for the left anterior descending and left circumflex use of computed tomography (CT) [or, to a lesser extent,
arteries. (A) Selective injection reveals only the left anterior descend- magnetic resonance imaging (MRI)] coronary angiography
ing artery. (B) Catheter reposition now reveals a large dominant cir-
has recently been shown to be especially helpful.296
cumflex vessel; the left anterior descending artery is now not seen.
Several coronary variants sharing a common physiology
appear at greatest risk:
1. Origin of the right coronary artery from the left sinus
suspected when the angiographer is unable to visualize either of Valsalva. When the right coronary artery arises from the
coronary ostium using standard angiographic catheters and left coronary cusp or proximal left main coronary artery, it
usual techniques. An aortic root angiogram may be neces- almost invariably (>99%) follows one path.254 This course
sary to identify the anomalous origin and facilitate selective runs between the aorta and pulmonary artery, placing the
catheterization. patient at risk for adverse events (Fig. 34.23).297 This variant
should be suspected when the right coronary ostium is
A NOMALOUS CORONARY A RTERY ORIGIN FROM POSTERIOR unable to be cannulated in the right coronary sinus or above
SINUS OF VALSALVA the sinotubular ridge, yet collateral vessels are absent. This
Either the right coronary artery or the left main coronary is the most common variant associated with adverse clinical
can take its origin from the posterior sinus of Valsalva (the events.
usual noncoronary sinus). Both of these variants are rare, 2. Origin of the left anterior descending coronary artery
although an ectopic right coronary origin is more common. from the right sinus of Valsalva. If the right aortic cusp or
Except for the anomalous origin, the anatomic course is right sinus gives rise to the left anterior descending artery,
normal and no significant clinical complications have been the artery may initially follow a septal or an anterior free
reported.290 wall course. The anterior free wall path is associated with
tetralogy of Fallot. If unrecognized, it can lead to catastrophic
A BSENT L EFT CIRCUMFLEX complications at the time of surgical repair. Although the
In this rare anomaly, a large “superdominant” right coronary septal pathway occurs less commonly, only patients with a
artery crosses the crux of the heart, ascending the atrioven- septal course are at risk for sudden cardiac death.295
tricular groove to perfuse the posterior and lateral wall of the 3. Origin of the entire left coronary artery from the right
heart. The left anterior descending artery is normal. sinus of Valsalva, arising separately or sharing a common
 corona ry a ngiogr a ph y 7 75
years and despite the lack of surgical treatments, there were
no deaths directly related to the anomalous coronary origins.
Syncope (14%) and aortic regurgitation (21%) were the most
common adverse events.

ORIGIN OF A CORONARY A RTERY FROM THE

PULMONARY A RTERY
Origin of the left coronary artery from the pulmonary artery,
sometimes referred to as the Bland-White-Garland syn-
drome,299 results in perfusion of the left ventricle via collater-
als from the right coronary and a shunt into the pulmonary
artery (Fig. 34.25).300 It generally results in myocardial isch-
emia and is characterized clinically by wheezing, tachypnea,
failure to thrive, and angina. Ninety percent of these patients
die in infancy and very few survive to adult life.301
Survival is occasionally permitted by the development of
intercoronary collaterals, although collateral blood flow
from the contralateral artery is drained partially into the
low-pressure pulmonary artery via the aberrant coronary.
FIGURE 34.23. Schematic diagram illustrating origin of the right This steal phenomenon can permit identification of the aber-
coronary from the left sinus of Valsalva. The usual course of this rant artery when the contralateral vessel is injected with
vessel is between the aorta and pulmonary artery (see text).
contrast media. Undiagnosed adults may present with angina,
mitral regurgitation, a continuous murmur, heart failure, or
ostium with the right coronary artery. In this anomaly the
sudden death. If such patients receive a premortem diagnosis,
left main coronary artery may follow one of the four path-
surgical treatment (coronary reimplantation into the aorta)
ways shown in Figure 34.24; the septal pathway is the most
is advised.302
frequent. The low incidence of this anomaly makes assess-
ment of the risk difficult. If unrecognized, any of these
L EFT M AIN CORONARY ATRESIA
anomalous courses may be associated with complications at
Left main coronary atresia is a very rare coronary anomaly
the time of cardiac surgery.297
in which there is no left coronary atrium. The proximal left
4. Single coronary artery. There are multiple patterns of
main trunk ends blindly and blood flows via small collater-
the single coronary artery, although this anomaly is rare in
als into at least one of the left-sided arteries.303 Pediatric
the absence of other abnormalities of the heart and great
patients are overtly symptomatic early in life. This condition
vessels. The Lipton classification schema as modified by
can occur in the adult population secondary to gradual ath-
Yamanaka and Hobbs,254 designates the anomalous coronary
erosclerotic obstruction and is occasionally compatible with
by the ostium of origin, its anatomic course, and the relation-
normal resting global left ventricular function.304,305 Origin
ship to the great arteries. In the type I pattern, a single coro-
of the right coronary artery from the pulmonary artery is
nary artery from a single ostium perfuses the entire heart.
extremely rare.
This extremely rare anomaly generally has a benign clinical
course. In the type II single coronary pattern, the anomalous
coronary arises from the proximal part of the normal coro- A B
nary. The greatest adverse risk would be expected to occur
in those cases in which the anomalous vessel passes between
the great vessels.
Although the association between the abnormal inter–
great vessel or septal course of the coronary artery and
adverse clinical events is well documented in the Western
medical literature, a recent investigation from Japan raises
interesting questions. Kaku et al.298 report the clinical fea- D
tures of 56 patients (0.33%) with anomalous origins of the C
coronary arteries after review of 17,000 patients with angio-
grams taken between 1968 and 1994, mean age 56 years.
Despite a similar overall incidence of anomalous origin of
the coronary artery in Japan and the United States, the most
frequent anomalous coronary course in the Japanese popula-
tion was the right coronary originating from the left sinus
of Valsalva and coursing between the great vessels (79%). An
anomalous posterior course of the left circumflex, which FIGURE 34.24. Variations in the course of the left coronary artery
(LCA) when it arises from the right sinus of Valsalva. (A) Interarte-
occurs most frequently in the U.S., was seen in only 11%. rial course of the LCA. (B) Transseptal course of the LCA. (C) Course
The left main coronary arising from the posterior sinus of the LCA posterior to the aorta. (D) Course of the LCA anterior to
occurred in 7%. During a mean follow-up period of 5 ± 4 the aorta.
7 76 chapter 34

Coronary Artery Fistula

Although fistulas are relatively common congenital anoma-
lies that have the potential to alter myocardial perfusion,
more than half of patients with a fistula are entirely asymp-
tomatic. Small coronary fistulas are quite common and are
seen in 0.1% to 0.2% of all patients undergoing coronary
angiography.306 Most arise from a small coronary branch and
drain into a single cardiac chamber. The majority of small
fistulas originate from the left anterior descending artery
and drain into the pulmonary artery.307 These are angio-
graphically identifiable by contrast swirling as “smoke” in
the otherwise unopacified pulmonary artery. Most are not
associated with detectable intracardiac shunting, or with
auscultatory abnormalities (e.g., a continuous murmur). The
clinical course is usually benign. Patients with small asymp-
tomatic fistulas should be managed medically.
Although the majority of coronary artery fistulas are
congenital,308,309 many are acquired and have been reported
FIGURE 34.26. A large fusiform aneurysm (arrow) of the left ante-
secondary to deceleration accidents, coronary angioplasty, rior descending artery in a patient with coronary atherosclerosis.
repeated endomyocardial biopsies in heart transplant
patients, permanent ventricular pacing leads, and cardiac
surgery. These acquired forms of coronary fistulas have been
Large congenital fistulas may occasionally persist unde-
increasing in frequency over the past several decades.308
tected into adult life. These abnormalities may be asymp-
tomatic, detected only by a continuous murmur, or may
present with complications such as endocarditis, heart
failure, ischemia, or infarction.310 Large fistulas are associ-
ated with the development of very tortuous ectatic coronary
arteries proximal to the origin of the fistula (Fig. 34.26) and
may empty into any cardiac chamber. About 50% of fistulas
arise from the right coronary, 42% from the left coronary,
and 5% from both.307 The right atrium, pulmonary artery,
and coronary sinus are the most common sites for emptying.
The decision as to which fistulas should necessitate therapy
is at present difficult.311 If therapy is undertaken, the treat-
ment should obliterate the fistula yet maintain antegrade
coronary flow.312 In the past this usually entailed coronary
artery bypass grafting with coronary reimplantation. More
recently, percutaneous transcatheter embolization tech-
niques have been used. Although these techniques are
usually successful and have a low morbidity and mortality,
the obliteration of arterial perfusion to the distal bed makes
these techniques unsuitable for large congenital fistulas.
Another variant is the occurrence of diffuse coronary to
ventricular chamber fistula, which resembles an unusually
prominent Thebesian drainage system.313–315 In these patients,
coronary injection results in diffuse endocardial opacifica-
tion and filling of the ventricular cavity. Either or both coro-
nary artery branches can be affected. Symptoms consistent
with ischemia and abnormal thallium scintigraphy can
occur, but are uncommon.316,317 Acquired fistulas to the ven-
tricular cavity can also occur at myocardial biopsy sites.318

Coronary Atherosclerosis
For over a quarter-century, selective coronary angiography
has remained the ultimate diagnostic test for assessing the
FIGURE 34.25. Origin of the left coronary artery from the pulmo- significance of atherosclerotic lesions in the coronary circu-
nary artery resulting in a steal phenomenon (aorta left, pulmonary lation of humans. Despite criticism regarding interpretation
artery right). Arrows represent direction of coronary flow. and the development of many noninvasive techniques
 corona ry a ngiogr a ph y 777
designed to detect myocardial ischemia, the coronary angio- less of gender, the prevalence and extent of coronary
gram has maintained a preeminent position for the evalua- calcification increases with age with an epidemiologic
tion of coronary atherosclerosis. pattern similar to that known for coronary atherosclerosis.
The total area of coronary calcification detected by EBCT
correlates linearly with histologically determined coronary
Angiographic Assessment of Stable plaque.323 However, the total area of coronary plaque calcifi-
Coronary Atherosclerosis cation significantly underestimates the total associated coro-
Atherosclerosis is a disease of the arterial wall that can nary plaque area. Calcium may be absent or undetectable in
encroach on the vessel lumen and limit blood supply to the small plaques, and the location of coronary calcification may
myocardium. In interpreting coronary angiograms, it is not correlate with the most significant atherosclerotic nar-
important to understand the nature of the atherosclerotic rowing. Studies using intravascular ultrasound have con-
process as it relates to coronary dimensions and the angio- firmed this general premise showing that coronary
graphic appearance of atherosclerosis. calcification correlates with total plaque burden, but not
with the degree of luminal compromise.324
Coronary Changes of Atherosclerosis Absence of detectable coronary artery calcification on
EBCT is highly unlikely in the presence of a severe luminal
COMPENSATORY CORONARY DILATION coronary obstruction, and has been proposed as a screening
Glagov et al.,222 in a seminal observation, using pressure- tool to identify patients at low risk (80% chance of having
perfused postmortem hearts, demonstrated that early in the angiographically normal arteries). Schmermund et al.,325
atherosclerotic process coronary arteries undergo a compen- using EBCT in patients who had recently diagnosed coronary
satory increase in outer diameter of the artery. Although disease and had undergone angiography, found that quantita-
different segments of the same artery may respond differ- tion of coronary artery calcification was comparable to coro-
ently, this compensatory dilation acts to maintain lumen nary angiography in measuring the effect of established
caliber despite thickening of the wall. These investigators cardiovascular risk factor on coronary atherosclerosis.
found that coronary arterial lumen encroachment does not
begin until the atherosclerotic plaque occupies about 40% of A NGIOGRAPHICALLY INAPPARENT
the original lumen area, as determined by the internal elastic DIFFUSE ATHEROSCLEROSIS
lamina (Fig. 34.12). Only at this point is angiography able to Pathology studies demonstrate consistently that atheroscle-
detect the presence of disease. This is an extremely impor- rosis is more widespread than angiograms depict.213,326
tant observation that may explain the frequent discrepancy Although early pathology studies were flawed because they
between pathologic and angiographic assessments of experi- measured the size of coronary vessels in an undistended state
mental atherosclerosis. (leading to overestimation of stenosis), two independent
Clarkson et al.319 studied the pathology of coronary arter- techniques have recently reconfirmed the essential findings.
ies in monkeys with diet-induced atherosclerosis and in Using high-frequency epicardial echocardiography, the coro-
humans (men and women). These investigations found that nary vessels of living human hearts have been evaluated at
as plaque intimal area enlarged, so did the artery size as the time of cardiac surgery.219 The ratio of coronary artery
judged in the internal elastic laminar area. However, there lumen diameter to the thickness of the coronary wall was
was large individual variability. Although the intimal area used to quantify the severity of coronary lesions. In patients
was significantly associated with lumen area, it was a poor without atherosclerosis, the mean coronary lumen to wall
predictor, explaining only 7.5% of the variability. In humans thickness ratio was 5.9 ± 0.3 (± standard error of the mean,
a lack of compensation (decreased lumen size as plaques SEM). In patients with atherosclerotic disease at the site of
enlarged) and a history of coronary heart disease were sig- examination the mean ratio was markedly reduced (2.3 ±
nificantly correlated. Mohiaddin et al.,320 using cardiomag- 0.2), consistent with the marked wall thickening at the site
netic resonance in the aorta of asymptomatic human subjects of obstruction. In angiographically normal arterial segments
with fibrous plaque, showed that after 2 years, total plaque of patients with atherosclerosis elsewhere, however, the
volume increased significantly, although there was no change mean ratio (4.1 ± 0.3) was also reduced, suggesting diffuse
in total lumen volume. wall thickening. Thus, in patients with atherosclerosis else-
where, even normally appearing epicardial segments showed
CORONARY CALCIFICATION significant unrecognized thickening of the arterial wall.326
It has been known for decades that calcification of the ath- Davies,327 in a series of autopsy studies on both men and
erosclerotic plaque is a common occurrence, is associated women, showed a positive relationship between percent cor-
with an advanced disease state and is easily detectable in the onary stenosis, percent plaque burden, percent remodeling,
coronary arteries by fluoroscopy or angiography. Recent evi- and an inverse relationship between percent plaque burden
dence derived from electron beam computed tomography and percent remodeling. The increase in lumen size in an
(EBCT) has challenged the old dogma that coronary plaque atherosclerotic coronary artery may vary widely between
calcification is mainly a marker of end-stage plaque degen- different plaques, even in the same artery. High-grade steno-
eration, but instead has demonstrated that intramural ses are often associated with a total failure of remodeling,
calcium can be observed in all degrees of a atherosclerotic thus the use of the calculation of percent stenosis (comparing
involvement.321 Recent investigations have proposed using the lumen size to the apparently normal cross-sectional area)
EBCT as a noninvasive screening test for coronary athero- is greatly flawed. This calculation, on average, overestimates
sclerosis. Janowitz and colleagues322 have shown that regard- the diameter of stenoses by 30% when compared to an
778 chapter 34

“angiographic equivalvent” calculation of an adjacent arte- Studies in the Dog Studies in Man
rial segment without plaque.328 Maximal Coronary Peak Velocity/
Intravascular ultrasound techniques have demonstrated Dilator Response Resting velocity ratio
similar findings and have confirmed the insensitivity of coro- 5 10
nary angiograms to detect early atheromatous changes.329,330 4
Using intravascular ultrasound, abnormally high intimal/ 3 6
medial thickness measurements have been found in the coro- 2 4
naries of majority of young donor hearts prior to cardiac 1 2
transplantation—all of which appeared angiographically 0 0
0 20 40 60 80 100 0 25 50 75 100
normal.331 The lack of angiographic sensitivity to early, Percent Stenosis Normal Percent Stenosis
diffuse vascular disease is also demonstrated compellingly FIGURE 34.27. Relationship between maximal coronary blood
in cardiac transplant recipients.332 flow or blood flow velocity and percent stenosis in an experimental
In one study of 60 patients studied 1 year or more after study337 and a clinical study. Left: In the animal experiment, a short
transplantation, all had at least minimal intimal thickening concentric stenosis was placed on a normal coronary artery in an
awake, chronically instrumented dog. Resting coronary blood flow
and 63% had moderate or severe intimal thickening even
(dashed line) was not significantly decreased until the percent diam-
though 70% of the patients had arteries that appeared eter stenosis was >85%. In contrast, maximal hyperemic coronary
normal angiographically. Postmortem examination of one blood flow (solid line) was limited when percent diameter stenosis
cardiac transplant patient who died of severe left ventricular was in the 50% to 60% range. Right: In the clinical study, maximal
dysfunction 2 weeks after normal coronary angiography coronary blood flow (expressed as a ratio of peak velocity to resting
velocity) was measured after transient ischemia. The range of
showed severe, diffuse accelerated coronary vasculopathy.333 normal responses in humans is shown by the black bar on the right.
Several IVUS examinations showed that early after trans- Each open circle represents a study in one patient. In contrast to the
plantation, a large proportion of coronary segments show close relationship between percent diameter stenosis and maximal
compensatory dilation of the vessel wall. However, a sub- coronary blood flow in dogs, angiographically determined percent
diameter stenosis was unrelated to hyperemic blood flow impair-
stantial number (22%) show no compensatory dilation, but
ment in humans with widespread atherosclerosis.
rather luminal shrinkage. These findings of inapparent
diffuse disease in angiographically normal coronary arterial
segments are an additional reason why conclusions of ste-
nosis severity based on relative measurements of percent comes. The effect of a given stenosis in limiting coronary
luminal narrowing, either area or diameter, are often in blood flow and thus effecting myocardial ischemia is gener-
error. ally assumed and rarely assessed directly.
The clinical maxim that a coronary stenosis does not
DIABETES AND CORONARY ATHEROSCLEROSIS become functionally significant until it causes a >50% diam-
The problem of coronary atherosclerosis in diabetes mellitus, eter narrowing is an outgrowth of studies in animals by
both types 1 and 2, are especially vexing. Not only is diabetes Gould,337 showing that maximally augmented coronary flow
a highly potent risk factor in the pathogenesis of atheroscle- is not limited until the stenosis is >50% (Fig. 34.27). Although
rosis and the major cause of death in this population, the these studies were performed in animals using externally
typical symptoms of this condition are atypical and often applied constrictors, it was assumed that similar findings
absent. Angiographically the frequent widespread presence would apply to human atherosclerotic lesions.
of diffuse disease makes calcification of percent stenosis as
a marker of disease severity in this patient population most SOURCES OF ERROR IN VISUAL ASSESSMENTS OF
unreliable. “Normal” lumen diameters necessary for a refer- L ESION SEVERITY
ence segment value in this calculation are often impossible Although visual assessment of the severity of luminal nar-
to determine. Diabetics have accelerated progression of rowing remains the standard for patient care today, many
disease after diagnosis, a condition also worsened by renal investigators over the past decade have realized increasingly
failure and need for dialysis, which may accompany diabetic the inadequacy of this approach.222,338–341 Marked intra- and
renal disease.334 A decreased ability to exhibit compensatory interobserver variability in interpretation of lesion severity
luminal enlargement has been found in patients with diabe- has been documented repeatedly. Visual intraobserver vari-
tes, which may contribute to the diffuse nature and acceler- ability (±1 standard deviation) ranges from 7% to 18%,
ated course of this condition.335 Diabetics also have a lesser depending on technique.342–345 The lower value was obtained
degree of coronary collateral circulation associated with from analyses of individual cine frames rather than
severe stenotic lesions. 336 unselected cine runs. Disagreements of 30% to 35% have
been reported when maximal stenosis severity has been
assessed using either a 50% or 70% diameter criterion.345
Visual Assessment of Coronary Arterial Stenosis
Factors increasing observer variability include lesion loca-
Data obtained from analysis of the coronary arteriogram are tion (left main346 or distal lesion345), recent angioplasty,347
traditionally expressed in anatomic terms, describing the and poor quality angiograms.345 Variability is lessened by the
vessel narrowing as a percentage reduction of the adjacent use of manual or electronic calipers or a calibrated magnify-
apparently normal lumen caliber. Reams of studies obtained ing eyepiece.348,349
from over 20 years of investigations relate the number, sever- It is widely known that visual interpretation usually
ity, and distribution of coronary obstructive lesions, assessed overestimates the severity of relatively high-grade lesions350
by visual analysis of the angiogram to a host of clinical out- and underestimates or totally overlooks low-grade lesions.
 corona ry a ngiogr a ph y 779
Although visual interpretation has been reported to under- segments are traced manually. The angiographic catheter is
estimate lesions >50% based on necropsy data, such conclu- used as a scaling device to correct for magnification. The
sions may be somewhat inaccurate because pathologic drawn arterial outlines from two orthogonal angiographic
assessment of the coronary stenosis was carried out in views are manually digitized. The outlines are corrected for
“deflated,” non–pressure-fixed specimens, exaggerating the magnification and distortion using a previously entered
degree of luminal compromise.351 Ex-vivo autopsy studies record of each angiographic laboratory’s x-ray beam diver-
have also shown a high incidence of severely eccentric or gence and pin-cushion distortion and using the actual
slit-like coronary lumina; however, such lumen shapes are diameter of the angiographic catheter. The outlines are com-
rarely seen angiographically. puter-matched at the minimum diameter or another stan-
Although it has been suggested that observer variability dard point of reference visible in both views. Two orthogonal
improves with angiographic experience, frequency of reading, views are then combined to form a three-dimensional repre-
and the use of consensus panels, the superiority of using a sentation, assuming an elliptical lumen contour.
group of experienced angiographers to quantitatively grade From this composite image, lesion minimum diameter
angiograms does not withstand careful scrutiny.342 There is and cross-sectional area are determined in absolute (mm2)
very high (95%) agreement regarding lesion severity when and relative (lesion percent diameter and percent area steno-
determined by panel consensus352; however, the standard sis) terms. This method has been used for many research
deviation of these interpretations of percent stenosis was ± applications and is highly accurate and reproducible. The
14%. No improvement in correlation between three individ- standard deviation of repeated measurements of arterial
ual observers and a three-member consensus panel has been diameter (±0.12 mm) and percent diameter stenosis (±3%) are
found.353 Fortunately, quantitative methods for determining small.208 However, the method is time-consuming and labor-
stenosis severity (see Quantitative Coronary Angiography, intensive. For these reasons it has not seen widespread clini-
below) have today gained ascendancy in research investiga- cal utilization.
tions, and digital methodologies are frequently used in clini-
cal angiographic evaluations. AUTOMATED EDGE DETECTION SYSTEMS
Reiber and colleagues361–363 developed a semiautomated
Quantitative Coronary Angiography method for detecting the edges of coronary artery segment
of interest and of the calibrating catheter (coronary artery
Since the visual interpretation of coronary angiograms is analysis system, CAAS). Similar methods have been devel-
inherently flawed, numerous computer-assisted systems to oped by others, but all use a digitized image obtained from
aid in the geometric assessment of epicardial coronary lesions a cineangiographic film frame or video signal. Nearly all
have been developed.354–357 Although quantitation of coro- techniques detect the arterial edge by videodensitometric
nary stenoses is a giant step forward (compared with visual methods, usually employing a weighted average of the first
assessment), it must be remembered that quantitative angi- and second derivatives of the density change across the artery
ography is an anatomic but not a physiologic measurement to identify the edge.364
tool. The coronary angiogram is a two-dimensional represen- Unlike the early Brown-Dodge system, these methods do
tation of the lumen of the artery under investigation. Changes not match orthogonal images and thus give only lumen
in the size or configuration from an assumed normal vessel diameter rather than cross-sectional area measurements.
may not be sufficient to understand either the physiology Manual matching of the data obtained from orthogonal
involved or to recognize the anatomic extent of the athero- views using the Reiber-CAAS system, however, correlates
sclerotic process (see Physiologic Assessment of Coronary highly with cross-sectional area measured using the Brown-
Arterial Stenosis). Despite these limitations, the develop- Dodge system.365
ment and implementation of quantitative methods for analy-
sis of stenosis severity has improved evaluation of coronary OTHER M ETHODS —VIDEODENSITOMETRY
artery lesions. A number of other investigators have developed other systems
for computer-assisted quantitative coronary angiography366,367
CALIPER M ETHOD or have made important contributions to the field.368–375
In 1971 Gensini et al.358 described an electronic caliper Although most of these methods assess stenosis severity
system in which the borders of the arterial lesion could be using geometric methods, considerable research has been
manually defined using moving cursors. Errors related to directed toward nongeometric methods. Videodensitometry
visual parallax, systematic underestimation of severe has been most commonly used. This technique is based on
obstructions (>75% diameter stenosis) and overestimation of the Lambert-Beer law, which states that the logarithmic
less severe obstructions make this method an imprecise sub- attenuation of the x-ray beam is proportional to the thickness
stitute for computer-based methods. 354,359,360 of the column of contrast within the vessel. This approach
is fundamentally different from others previously described
BROWN-DODGE M ETHOD because it requires minimal assumptions regarding the
Development of quantitative coronary angiography by Brown geometry of the lesion being examined. With this approach,
and colleagues208 at the University of Washington, provided the operator performs an analysis at the site of the narrowest
the seminal advance in the assessment of coronary angio- portion of the vessel as well as at a smooth proximal “normal”
grams. Images obtained from standard 35mm cine film are reference segment. The diameter of the adjacent normal
projected at 5× magnification onto a grid. The vessel edges segment is determined geometrically using the catheter as a
of the lesion and the adjacent proximal and distal “normal” scaling device. The normal lumen is assumed to be circular.
780 chapter 34

Using a previously determined density calibration curve, the held view.381 Reference tables for the true size of a variety of
gray scale level along the arterial segment is converted to an angiographic catheters, together with a comparison of their
optical density profile that is corrected for the optical density angiographic measurements as calculated by two different
of a corresponding background point. An integrated optical algorithms, are available.378
density across the diameter of each arterial segment is cal-
culated. The minimum integrated optical density of the Variations in Lesion Geometry. Most quantitative
coronary lesion is divided by the density of the normal angiographic systems calculate only one lumen diameter
segment and the quotient is multiplied by the normal segment measurement and assume a cylindrical shape if a lesion area
area. The resulting value is the minimum cross-sectional measurement is calculated. The true geometry of a coronary
area of the artery. lesion may vary widely. The Brown-Dodge system assumes
Under very carefully controlled circumstances and in a an elliptical lesion shape and uses integration of two orthogo-
small number of patients, one videodensitometric approach nal views to obtain lumen area. Although major deviations
appeared to correlate well with minimal luminal area mea- from an elliptical shape occur rarely, the use of orthogonal
sured using Brown-Dodge quantitative coronary angiography views and the assumption of an elliptical geometry do not
as well as measurements of coronary flow reserve.375 However, solve all geometric problems. Two acceptable truly orthogo-
there are many theoretical and practical limitations to the nal views are obtainable in only about 50% of lesions exam-
use of videodensitometric techniques. Theoretically, densi- ined.356 The maximal error for two arbitrary orthogonal
tometric techniques are less sensitive to variations in imaging views is small (<25%) only for mild degrees of ellipticity
system resolution, quantum noise, and stenosis cross-sec- (major/minor axis <2).377,382 The error increases as the angle
tional shape than are edge detection techniques.376 However, between views becomes less orthogonal and as lesion ellip-
densitometry is also much more sensitive than edge detec- ticity increases.
tion to densitometric nonlinearities, overlapping structures For angioplasty patient populations, quantitative mea-
(e.g., bone, diaphragm), and a nonperpendicular relationship surements of vessel diameters taken from only one view in
between the vessel and the x-ray beam. The frequent occur- which the lesion appears worst, compare quite closely with
rence of vessel foreshortening in many of the radiographic the average of two diameter measurements from nearly
views results in artifactual increases in density and greatly orthogonal views (minimum diameters of the two views
limits the clinical utility of this technique. At present, the within ±5% in 90% and within ±10% in all but 2.7%).383
usual error with densitometric angiography appears between From these data one could conclude that quantitative mea-
5% and 20%, but can approach 50%.376 For these reasons and surement of one view is adequate for routine clinical pur-
despite initially promising results, videodensitometric poses. However, for research purposes, orthogonal views may
approaches to lesion quantitation have not yet seen wide- sometimes be required. Our experience comparing angiogra-
spread application. phy to Doppler flow reserve measurements has led to the
conclusion that integration of lesion diameters as seen in all
views appears to relate best to physiologic measures of lesion
PROBLEMS IN QUANTITATIVE A NGIOGRAPHY severity.
Technical Problems. Although under ideal circum- Variations in Vasomotor Tone. Day-to-day changes in
stances quantitative angiography can be a reliable and highly coronary smooth muscle motor tone increase the interstudy
accurate measurement technique, many potential pitfalls variability of angiographic measurements and reduce the
exist. Blurring of the vessel edges, the penumbra effect, and power of angiographic methods to detect small changes in
cardiac motion can lead to a widened vessel edge, making coronary caliber in sequential studies. Removal of tone by
edge detection less accurate.354 Compared to visual assess- nitroglycerin permits an assessment of maximal coronary
ment, quantitative angiography requires greater attention to caliber during similar conditions between studies.
optimal angiographic technique. Vessel overlap and unrecog-
nized lesion foreshortening may produce major errors because
Physiologic Assessment of Coronary
single film frames are examined.
Arterial Stenoses
Inaccurate calibration from the angiographic catheter can
be a major problem for quantitative angiography.377–379 The The inaccuracies inherent in even the most sophisticated
use of small catheters (5F or 6F) as the calibration source can methods of anatomic assessment have led to the develop-
lead to significantly less accuracy in the calculation of abso- ment of physiologically based methods to assess coronary
lute diameter measurements.380 Nylon catheters are also stenosis severity. In 1939 Katz and Lindner384 described the
poorly suited for quantitation because they are less radi- coronary reactive hyperemia response that has subsequently
opaque (some newer nylon catheters are impregnated with become the gold standard for the physiologic assessment of
radiopaque material). Even catheters of the same size from stenosis severity. In normal coronary arteries, myocardial
various manufacturers can vary by as much as 25% in diam- blood flow is primarily regulated by the resistance of the
eter. Inaccuracies in angiographic measurement of the true arteriolar vessels (≤400 μm diameter); the epicardial coro-
catheter size of up to 35% also can occur due to inaccurate nary arteries provide little resistance to coronary blood flow
determination of the outer catheter edge (i.e., tracing of the under physiologic circumstances. As a stenosis progresses in
contrast-filled inner lumen rather than the outer contour of an epicardial vessel, a transstenotic pressure gradient devel-
the catheter).361 Some authorities suggest catheter calibration ops. The microvessels dilate to compensate for the reduced
should be based on a catheter empty of contrast, before begin- distal perfusion pressure, thus maintaining normal resting
ning the coronary injection, although this is not a widely blood flow to the myocardium.
 corona ry a ngiogr a ph y 7 81

Anatomy Physiology occlusion or drugs) to resting blood flow is termed coronary

vasodilator reserve (or coronary flow reserve).
Normal 4x The ratio of the intracoronary pressure distal to a stenosis
Flow to the proximal coronary or aortic pressure during condi-
tions of maximal hyperemia is termed the fractional flow
x
Epicardial Artery
Time reserve. These two physiologic measurements (coronary flow
Arteriolar Vasodilation (Papaverine) reserve and the fractional flow reserve) have provided impor-
4x tant clinical techniques to assess limitations in hyperemic
blood flow imparted by a stenosis.
Flow

Epicardial Stenosis x CORONARY FLOW R ESERVE

Time
Arteriolar Vasodilation (Papaverine) Utilization of Doppler methods for measuring blood flow
velocity has provided the major principles for clinical inves-
4x tigation of coronary flow reserve. Initial studies in humans
Flow
were performed using a Doppler crystal applied at surgery to
x the epicardial surface of a coronary vessel.386 These experi-
Microvascular Disease Time ments showed that the reactive hyperemic response in
Arteriolar Vasodilation (Papaverine)
normal human coronary arteries was similar to that obtained
FIGURE 34.28. The effects of an epicardial stenosis on coronary
flow reserve. Top panel: Dilation of a normal microvasculature with in anesthetized animals. However, they failed to confirm in
papaverine causes blood flow to increase fourfold. Middle panel: An humans the relationship between luminal stenosis and flow
epicardial stenosis causes partial microvascular dilation, and papav- impairment previously observed in normal animals (Fig.
erine has little additional effect. Flow reserve is reduced. Bottom 34.27). In patients with multivessel coronary atherosclerosis
panel: Microvascular disease prevents normal arteriolar dilation,
and isolated discrete coronary lesions varying in severity
reducing flow reserve.
between 10% and 95% stenosis, measurements of the ana-
tomic stenosis severity were not correlated significantly
Studies in animals have shown that resting coronary with the reactive hyperemic response (r = −.25).386 Underes-
blood flow can be maintained at normal levels until more timation of lesion severity occurred in 95% of vessels with
than 75% of the arterial cross-sectional area (50% of the >60% diameter stenosis by angiography. Both overestimation
diameter if the obstruction is concentric) is obstructed. At and underestimation of lesions with <60% stenoses were
this point the vasodilator reserve of the arterioles is common.
exhausted, and further vasodilation is impossible. 337 Resting The development and validation of small Doppler cathe-
blood flow does not decrease until 90% of the lumen is ters387 and subsequently Doppler guidewires388 made possible
obstructed. Coronary stenoses that limit myocardial blood the subselective measurement of coronary blood flow veloc-
flow during maximal arteriolar vasodilation are termed ity in individual coronary vessels at the time of angiography
physiologically significant (Fig. 34.28).385 The ratio of (Fig. 34.29). Subselective techniques for measuring flow
maximal hyperemic blood flow (e.g., induced by coronary velocity were necessary for clinical usefulness of this

Percent area stenosis = 95 Translesional gradient = 52mmHg Percent area stenosis = 68 Translesional gradient = 12ml

Phasic
CBFV
(kHz shift) 0–v
peak velocity 1.5 5.0
Mean resting velocity
CBFV
(kHz shift) 0
200
Arterial
Pressure
(mm Hg)
0

ECG

1sec 30 sec
6 mg papaverine 6 mg papaverine
FIGURE 34.29. A record obtained from patient undergoing right only a 1.5–fold increase in blood flow velocity. After angioplasty
coronary artery angioplasty. The top tracing shows phasic coronary (right) the percent area stenosis was decreased to 68% and the trans-
blood flow velocity (CBFV), the second tracing mean coronary blood lesional pressure gradient was reduced to 12 mm Hg. Six milligrams
flow velocity, and the bottom two panels the arterial pressure and of intracoronary papaverine resulted in a 5.0–fold increase in
electrocardiogram. Before angioplasty (left), the lesion produced blood flow velocity, demonstrating that physiologically significant
95% area stenosis with an associated translesional pressure gradient obstruction to coronary blood flow had been removed.
of 52 mm Hg. Six milligrams of intracoronary papaverine produced
782 chapter 34

methodology since coronary atherosclerosis had a heteroge- Normal Obstructive Diseased Superimposed
neous distribution throughout the coronary tree. Since coro- vessel lesion vessel obstruction
nary occlusion is not practical during angiography,
pharmacologic vasodilators were given to create a maximal
2.5 mm 1.25 mm
hyperemic response. The original studies utilized intracoro-
nary papaverine, which results in maximal increases in coro-
nary flow comparable to those achieved with intravenous Diameter stenosis = 50% Diameter stenosis = 50%
transient coronary occlusion or dipyridamole.389 Although CSA = 4.9 mm2 CSA = 1.43 mm2
the short half-life coupled with little effect on systemic FIGURE 34.31. The effects of a 50% diameter stenosis in a normal
hemodynamics made papaverine a useful drug for this vessel (left) and a diffusely diseased vessel (right). A 50% stenosis
in a “normal” artery leaves significantly greater residual cross-
purpose, occasional QT prolongation and rare but potentially sectional area than does a 50% stenosis in an artery that is already
serious transient arrhythmias can occur.390 For this reason, diffusely narrowed. Since the amount of diffuse coronary narrowing
intracoronary adenosine, which has an even shorter half-life cannot be assessed well from a visual analysis of a coronary angio-
than papaverine, has now generally replaced papaverine as gram, a focal 50% stenosis on the angiogram may have vastly dif-
the drug of choice for physiologic studies of the coronary ferent effects on coronary blood flow.
circulation under hyperemic conditions.391
In contrast to measurements obtained in patients with
severe coronary atherosclerosis studied at cardiac surgery,386 limiting flow depending on the true area of the normal
flow reserve measurements obtained in the catheterization segment.
laboratory in patients with only single-vessel disease show a Absolute measurements of the coronary caliber can
curvilinear relationship between percent stenosis and flow provide important information that is independent of diffuse
reserve, similar to that found in animals with normal coro- luminal narrowing. A minimum lesion cross-sectional
nary vessels (Fig. 34.30).209 area ≥2.5 mm2 (≥3.5 mm2 in the proximal left anterior descend-
Lesions causing <70% area stenosis did not cause a sig- ing artery) almost always indicates the absence of flow
nificant reduction of hyperemic blood flow. The disparate impairment by the lesion, regardless of the adjacent arterial
results seen in patients with limited versus those with more diameter.
widespread coronary atherosclerosis probably relates to the One should not conclude from these studies that moder-
unrecognized presence of diffuse luminal encroachment. ate inapparent diffuse coronary atherosclerosis alone impairs
Percent stenosis measurements of a focal lesion in an artery the vasodilator reserve.351 In a study from our laboratory,
with diffuse luminal narrowing leads to underestimation of hyperemic blood flow was normal in atherosclerotic vessels
lesion severity based on an inaccurate determination of the perfused by bypass grafts as long as the graft perfused a non-
“normal” adjacent lumen reference segment. Since the coro- stenotic coronary vessel subserving normal myocardium.392
nary angiogram is a “lumenogram,” it is impossible to know This occurred despite the fact that cross-sectional area of the
whether a segment of a vessel appearing angiographically bypassed artery is diffusely narrowed (40% smaller than a
“normal” has inapparent diffuse disease. As the degree of similar site in matched normal vessels).
diffuse narrowing increases, lesser focal stenoses are required
to impair maximal hyperemic blood flow.392 As shown in FRACTIONAL FLOW R ESERVE
Figure 34.31, a 50% stenosis has greatly different effects on Intracoronary pressure measurements can also provide
important physiologic information regarding the functional
significance of coronary stenoses.393 Commonly termed the
8 fractional flow reserve (FFR), this technique in reality com-
7
pares the intracoronary pressure measured proximal and
distal to a stenosis under conditions of maximal hyperemic
6 flow.394 A ratio of proximal to distal intracoronary pressure
Δ CBFV (× resting)

measured with a fiberoptic pressure-monitoring guidewire

5
during adenosine infusion has been used to assess the physi-
4 ologic significances of coronary stenoses of moderate sever-
ity (40–50%). In 45 patients an FFR of >0.75 has been shown
3 to correlate highly with noninvasive tests of myocardial
2
ischemia. The overall sensitivity, specificity, positive and
negative predictive values, and accuracy were 88%, 100%,
± 1SD
1 r = 0.82 100%, 88%, and 93%, respectively.395
Such FFR measurements can be used to assess the results
0
of balloon angioplasty.396 Using a pressure monitoring wire
0 20 40 60 80 100
to replace a standard angioplasty guidewire, Bech and col-
Diameter stenosis (%) leagues396 showed that an FFR >0.90 stratified patients into
FIGURE 34.30. Relationship between the most severe diameter an optimal post–percutaneous transluminal coronary angio-
stenosis measure in the left or right anterior oblique projection and plasty (PTCA) result. A small amount of additional stratifica-
coronary flow reserve. The open bar represents the range of coronary
flow reserve measured in 13 patients with normal coronary vessels. tion value was obtained when a quantitatively determined
The shaded area along the regression line represents l standard residual percent on diameter stenosis of <35% was combined
deviation (SD) above and below the mean. with the FFR.
 corona ry a ngiogr a ph y 783
In addition to assessing the efficiency of angioplasty, of plaque rupture and progression to acute myocardial infarc-
physiologic measurements assessing the functional signifi- tion. This is perhaps not surprising when one considers the
cance of intermediate coronary lesions has been used to usual frequency of occurrence of mild versus severe athero-
make a decision not to dilate non–flow-limiting lesions.397,398 sclerosis lesions in the coronary tree. For these reasons one
These data indicate that deferral of a coronary intervention cannot predict the site of the coronary lesion that will likely
based on a normal coronary flow reserve or an FFR ≥0.75 is progress to subtotal occlusion from a retrospective review of
associated with a lower clinical event rate than would be angiograms taken shortly before development of the acute
expected if the procedure had been performed as originally event.408 Thus it is unlikely that current coronary interven-
planned.399 tional approaches will play a dominant role in preventing
acute infarction.
L IMITATIONS IN THE USE OF PHYSIOLOGIC FLOW AND Angiography can also be very important in yielding clues
PRESSURE M EASUREMENTS: DUAL ROLES OF THE CORONARY to aid in clarification of clinical syndromes. Unimpressive
EPICARDIAL AND M ICROCIRCULATIONS intraluminal coronary lucencies, both de novo and after
Although attractive in concept there are many limitations angioplasty, may forecast impending total coronary occlu-
in utilizing coronary flow or pressure reserve measurements sion. Specific morphologic characteristics such as the rup-
to define the physiologic significance of a given atheroscle- tured plaque or the lucency of a spontaneous coronary
rotic lesion. Inherent in understanding these limitations is dissection may serve as important clues in the diagnosis of
the fact that the coronary circulation can be regulated by the cause of chest pain in the absence of alterations in coro-
two distinct vascular components connected in series: the nary flow reserve. Similarly, physiologic abnormalities in
epicardial vessels and the microcirculation. Coronary ath- coronary blood flow regulation induced by atherosclerosis
erosclerosis affects primarily the epicardial vessels, and the (e.g., endothelial dysfunction as assessed by infusions of ace-
microcirculation subserved by any given epicardial artery tylcholine or substance P) or other abnormalities may poten-
may be normal or abnormal. A variety of pathophysiologic tiate the effects of a focal coronary lesion or lead to ischemia
conditions (e.g., anemia and polycythemia, diabetes, hyper- in the absence of a hemodynamically significant stenosis
trophy, infarction, vasculitis, wall motion abnormalities, and in the epicardial arteries.409,410 Hence, the absence of a
other conditions involving the coronary microcirculation) flow-limiting stenosis at the time of angiography should not
can reduce flow reserve in myocardium supplied by anatomi- imply the absence of myocardial ischemia or risk of vessel
cally normal epicardial vessel, or by one containing athero- closure.
sclerotic lesions.400–404 Hence, a reduction in the coronary The inaccuracies inherent in even the most sophisticated
flow reserve (CFR) of a coronary artery with a stenosed vessel methods of anatomic assessment have led to the develop-
cannot be taken as prima fasciae evidence that blood flow is ment of physiologically based methods to assess coronary
limited by the stenosis. stenosis severity. In 1939 Katz and Lindner described the
The coronary flow reserve is altered by the hemodynamic coronary reactive hyperemia response that has subsequently
conditions existing at the time of study.405 Increases in heart become the gold standard for the physiologic assessment of
rate or preload reduce flow reserve because these conditions stenosis severity.384
increase resting blood flow without changing hyperemic
flow. In contrast, acute changes in mean arterial pressure
Angiographic Findings in Myocardial Infarction
within the autoregulatory range do not alter the flow reserve
and Acute Coronary Syndromes
ratio because resting and hyperemic blood flow are increas-
ing proportionately as arterial pressure rises. It has been It has been commonly believed that a severe coronary lesion
suggested that flow reserve measurements be obtained during was the forerunner of acute myocardial infarction, and that
atrial pacing to eliminate the confounding effects of heart coronary arteries with less than 50% obstructions were rela-
rate. Despite these limitations, serial measurements of flow tively free of thrombotic risk.411 Recent studies have convinc-
reserve are highly reproducible over time in the absence of ingly refuted this dogma and give evidence that coronary
conditions known to alter resting or hyperemic coronary angiography cannot be used to predict accurately the site
blood flow.406 Repeated measurements of flow reserve sepa- of a subsequent occlusion that will result in myocardial
rated by 1 year, performed on patients under these conditions infarction.412
showed a very high degree of correlation (r = 0.95). Although retrospective reviews of angiograms performed
Unlike CFR, FFR has been shown to be independent of shortly before the development of acute infarction have iden-
loading conditions.407 Although the clinical outcome can tified high-grade coronary stenoses as a risk factor for subse-
suggest that deferral of revascularization in stenotic vessels quent total coronary occlusion, studies in patients having
with FFR >0.75 is a better approach, these studies were per- angiograms both months to years before and shortly after
formed prior to drug-eluting stents. infarction showed that the infarction-related occlusion fre-
quently occurred in a coronary segment without a severe
L IMITATIONS OF AN OPTIMAL HEMODYNAMIC EVALUATION stenosis on the early angiogram. In only 38% of patients was
OF A CORONARY L ESION the most severe angiographic stenosis found to be responsible
Despite the importance of determining the hemodynamic for the subsequent infarction.413 In 60% of patients, the
impact of individual coronary lesions, the pathophysiologic most severe luminal diameter stenosis present in the
consequences of non–flow-limiting lesions must not be over- infarct-related artery prior to the infarction was less than
looked. Little and Applegate408 have shown that lesions of 50%. Similar studies by a number of investigators414–416 have
only mild to moderate severity are most frequently the source confirmed these results.
784 chapter 34

In patients with unstable angina, quantitative angio-

graphic studies show a strikingly different picture. In such
patients angiograms have a high predictive value in deter-
mining the culprit lesion. Lesions associated with unstable
angina usually have a percent diameter stenosis of >85%, a
lesion cross-sectional area of <0.9 mm2, and a morphology
consistent with an irregular eccentric lesion, occasionally
with thrombotic intraluminal filling defects (see below).417
Hence such obstructions are usually visually obvious.
Patients presenting with symptoms of rest angina without
coronary lesions of this severity, should be carefully evalu-
ated for the possibility of coronary spasm.

Pathologic-Angiographic Correlates
Coronary angiography performed very soon after the onset
of clinical symptoms of myocardial infarction usually dem-
FIGURE 34.33. Longitudinal section of a coronary artery at site of
onstrates total occlusion of the coronary artery perusing the total thrombotic occlusion resulting from atherosclerotic plaque
infarct zone. The incidence of total occlusion is nearly 90% rupture. Proximal obstruction (right) is stasis (red blood cell) clot.
if angiography is performed as early as 1 hour after symp- Distal obstruction (left) is atheromatous debris and primarily plate-
toms, but drops to about 70% if angiography is delayed to 12 let clot.
to 24 hours.418 Total occlusion is found less frequently (26%)
in patients having angiography within 24 hours of symptom
serial histologic sections, and is thus often missed on routine
onset of a non–Q-wave infarction.419 This reduction in fre-
autopsy examination.
quency of total coronary occlusion is probably the result of
Pathologic and clinical evidence suggests that coronary
spontaneously occurring thrombolysis.
thrombosis after plaque rupture is a dynamic process.420,421
To understand the angiographic findings of acute coro-
The occlusive thrombus typically has a multilayered struc-
nary syndromes, it is important to consider the underlying
ture, suggesting that it is often formed successively over an
events occurring in the artery during acute infarction. Fis-
extended period of time (days to weeks), rather than occur-
suring or rupture of the atherosclerotic plaque appears to be
ring as a single abrupt event.422 This finding fits with the
the inciting event in both unstable angina and acute myo-
often stuttering course of ischemic symptoms. In addition,
cardial infarction420,421 (Figs. 34.32 and 34.33). Rupture of the
clot fragmentation with distal microembolization has been
fibrous cap also allows blood from the vessel lumen to dissect
identified in 73% of cases carefully studied and can be seen
into the intima and media, thus causing the plaque to expand.
on the angiogram in a smaller fraction of patients.422 Although
Plaque rupture as the nidus for subsequent thrombus forma-
aggregated platelets are the major early component of the
tion can be seen only if the entire thrombus is examined by
thrombus, within in 1 or 2 days this platelet thrombus is
infiltrated and consolidated, leading to a more distinct angio-
graphic edge.422
If the coronary lumen is totally occluded, the blood
between the occlusion site and the nearest proximal side
branch will stagnate with the production of a stasis throm-
bus. The volume of stasis clot is usually (but not always)
relatively small. A recent total coronary occlusion is charac-
terized angiographically by a small remaining vessel stump
that can accumulate contrast. Injection into this stump
usually reveals an often “feathered” hang-up of contrast with
indistinct margins and slow washout. The angiographic cut-
off of an occluded bypass graft usually occurs at the aortic
anastomosis because occlusion within the graft body or at
the coronary insertion leads to total graft thrombosis.
Plaque fissuring, a multilayered thrombus, and distal
microembolization are also seen at postmortem examination
in patients with unstable angina and in humans dying
suddenly with coronary atherosclerosis without evidence
for myocardial infarction.421 Clinically and angiographically,
despite evidence of plaque rupture, patients with unstable
angina have a much smaller burden of clot within the affected
arterial segment than do patients with Q- or non–Q-wave
FIGURE 34.32. Section of a coronary arterial cast (lumen area was
filled with barium gel) from a patient with unstable angina. Note infarction. Coronary angioscopy performed in vivo in patients
the plaque rupture with extension of the lumen into the arterial with unstable angina has shown complex plaques and
wall (plaque ulcer). small intraluminal clots, which are sometimes not visible
 corona ry a ngiogr a ph y 785
angiographically.423 Although patients with unstable angina CONCENTRIC LESIONS
following thrombolytic therapy show small increases in
luminal areas assessed using quantitative angiography, such
improvements are often not visually apparent or usually
clinically sufficient.411,424 A small fraction of patients may
have a more dramatic response.

Angiographic Findings ECCENTRIC LESIONS

Angiographic features of atherosclerotic plaque disruption Type I
have been described qualitatively. Postmortem angiograms
in the setting of plaque rupture have a “complicated” appear- or
ance characterized by irregular arterial borders and intralu-
minal filling defects.425 In vivo angiographic studies of
coronary lesions in patients with unstable angina also show
eccentric lesion shapes, characterized by a narrow neck and Type II
overhanging edges or scalloped borders, a high incidence of
stenosis irregularity, and intraluminal filling defects, which
or
presumably are clot. Following thrombolytic therapy for
acute infarction, similar findings are seen with marked ste-
nosis irregularities and an increased incidence of intralumi-
nal filling defects.426 Additionally, an ulcer crater that was MULTIPLE IRREGULARITIES
obscured by overlying thrombus may become evident as well
as thrombolysis (Fig. 34.34).
Ambrose et al.427,428 developed a system for classifying
coronary stenosis morphology based on its angiographic
appearance (Fig. 34.35). Lesions associated with acute throm-
botic syndromes (unstable angina and infarction) were
usually of type II eccentric morphology, and in most throm- FIGURE 34.35. Angiographic morphology of coronary arterial
stenoses. Type A stenoses (Top) are concentric and have smooth
botic lesions the edges of the lesion were irregular and borders. Type B lesions (middle) are eccentric and are divided into
scalloped.427 two groups: Type I (B1) lesions have a smooth border without over-
Visual interpretation of stenosis morphology is fraught hang while Type II (B2) lesions have irregular borders and/or over-
with marked intraobserver and interobserver variability. For hang. Type C lesions (below) have multiple irregularities.
these reasons, quantitative indices of lesion irregularity
applicable for use with computer-assisted quantitative
is independent of stenosis severity (in terms of lumen obstruc-
angiography have been developed.417 One such quantitative
tion). In one study of patients with stable angina, unstable
measure, the ulceration index, is defined as the diameter of
angina, or recent myocardial infarction, the severity of the
the least severe narrowing within the lesion (the downward
coronary lesion measured either as percent stenosis, or in
lip of the ulcer) divided by the maximum intralesional diam-
absolute terms as minimal cross-sectional area was similar
eter. This index decreases as the irregularity increases and
in all groups, although lesions causing unstable angina
tended to be more severe (Fig. 34.36). The ulceration index
Acute MI Ten days later (Fig. 34.37), however, was significantly lower in lesions
causing unstable angina (0.62 ± 0.05) or infarction (0.61 ±
45° RAO 45° LAO 45° LAO 45° RAO
0.03) than lesions causing stable angina (0.90 ± 0.01).417 A
modified index has also been found useful, but is not inde-
pendent of the stenosis severity.429
The angiographic appearance of blood flow in the artery
distal to a thrombotic lesion also carries some significance.
A system for grading blood flow was developed for the Throm-
bolysis in Myocardial Ischemia (TIMI) trial and has been
used generally since then (Fig. 34.38).430 The TIMI flow clas-
sification is as follows:
0 No antegrade blood flow
1 Faint antegrade blood flow that does not fill the distal
Initial Discharge
vessel
FIGURE 34.34. An angiogram obtained from a patient with acute
2 Reduced antegrade blood flow that fills the distal vessel
myocardial infarction demonstrating clot lysis over time. Angiog- 3 Normal antegrade blood flow
raphy soon after presentation revealed a large clot adherent to the
arterial wall and protruding into vessel lumen (leftmost panel, black Although visual interpretation of the rapidity and com-
arrow). Ten days later, angiography showed an “ulcer” at the site of pleteness of angiographic coronary flow following myocar-
clot attachment (rightmost panel, white arrow). dial infarction has proven helpful in assessing the efficacy
786 chapter 34

100 TIMI flow grade

75
Percent area stenosis

50
TIMI 0 TIMI 1
Occlusion Penetration

25

* p <.05 vs. Unstable angina

** p <.05 vs. Stable angina
0
MI SA UA MI
noninvolved involved
vessel vessel
FIGURE 34.36. Percent area stenosis of lesions causing stable TIMI 2 TIMI 3
angina, myocardial infarction (MI), and unstable angina, and non– Slow flow Normal flow
infarct-related lesions in patients with acute infarction. Although FIGURE 34.38. The TIMI coronary blood flow index, a qualitative
lesions associated with unstable angina tended to be more severe measurement of coronary blood flow.434
than those associated with infarction or unstable angina, there was
significant overlap between groups.
Although coronary flow in the infarct subserving vessel
has been the subject of the greatest study, flow in the angio-
and subsequent clinical outcomes of various therapies, this graphically normal noninvolved vessel in acute infarction
methodology (TIMI flow assessment) has recently been may not be normal. Using Doppler catheter techniques and
shown to exhibit considerable variability. This variability acetylcholine infusions, endothelial dysfunction of the non-
can be diminished by counting the angiographic frames from involved epicardial resistance vessels was found in 75% of
initial vessel opacification until filling of the distal bed.431 patients with acute myocardial infarction.
Recently, an angiographically defined index of microvas-
cular perfusion has been developed, the “TIMI myocardial
perfusion grade.” Also called a myocardial blush score, it is
1.00 measured by observing the myocardial washout of contrast
media after coronary injection. A normal response (grade 3)
is a brisk wash-in–washout. Persistence of contrast after
coronary injection (grade 2) and contrast staining of the myo-
0.75 cardium (grade 1) suggests increased microvascular permea-
bility and obstruction. The absence of myocardial opacification
indicates extensive microcirculatory obstruction, usually
associated with dense infarction. Mortality after acute infarc-
0.50 tion is inversely related to the myocardial blush score, inde-
pendent of TIMI coronary blood flow.
UI

Coronary Reocclusion and Lesion Remodeling

Following Myocardial Infarction
0.25
Coronary angiography has been helpful in identifying
patients at increased risk of recurrent ischemic events after
* p <.01 vs. SA and MI (noninvolved vessel) thrombolysis. Typical plaque rupture morphology is often
not visible immediately after thrombolysis, presumably
0
MI SA UA MI because of unlysed but inapparent thrombus laminated along
noninvolved involved the vessel wall (Fig. 34.34).432 The characteristic morphology
vessel vessel of the infarct-related lesion after thrombolysis was found in
FIGURE 34.37. Calculated ulceration index (UI) of lesions causing one study to be a marker of subsequent reocclusion,433 but
stable angina, myocardial infarction (MI), and unstable angina, and not in another.434
non–infarct-related lesions in patients with acute infarction. The
ulceration index of lesions involved in MI or unstable angina (UA)
Quantitative angiographic studies show that clot lysis
was significantly less than that of lesions uninvolved in infarction continues following thrombolytic therapy for acute infarc-
or associated with stable angina (SA). tion and restoration of vessel patency. In our initial studies,
 corona ry a ngiogr a ph y 787
the minimum lesion cross-sectional area increased 116% ± Human Coronary Collateral Pathways
34% during the 7 to 10 days following intracoronary throm-
The preferred anatomic pathways taken by collateral chan-
bolysis and initial lumen patency.432 In seven of 17 patients,
nels have been described in detail elsewhere.444,445 Some of
minimum luminal cross-sectional area more than doubled.
the more common anatomic connections are as follows:
Similar data have been obtained by other investigators.435,436
The residual lumen caliber immediately after reperfusion Collateral Pathways to the Left Anterior Descending
has been used to identify patients at high risk for reclosure Coronary Artery
within the first 2 weeks after thrombolysis. In quantitative
angiographic studies following successful intracoronary 1. From the posterior descending via septal branches or
thrombolysis with streptokinase, rethrombosis occurred around the apex
exclusively in vessels with a minimum lesion cross-sectional 2. From the conal branch of the right coronary artery via
area of <0.4 mm2.432,435,436 In that group, 54% of patients who Vieussens’ ring
had initially successful reperfusion with intracoronary strep- 3. From the acute marginal branch of the right coronary
tokinase developed rethrombosis within 2 weeks.432 Similar artery
conclusions were reached when lesion severity was evaluated 4. From the obtuse marginal branch of the circumflex
by videodensitometry. artery
Data compiled from trials in which thrombolysis was Collateral Pathways to the Right Coronary Artery
achieved using recombinant tissue plasminogen activator (rt-
PA) found that recurrent ischemic events in these patients 1. From the left anterior descending artery via septal
could not be predicted by any angiographic variable: percent branches or around the apex to the posterior descending
diameter stenosis, absolute lesion diameter, angiographically artery
defined thrombus, or stenosis morphology.437 Although the 2. From the distal circumflex or obtuse marginal branches
incidence of recurrent ischemic events was similar to those to the posterolateral branch, at times via the atrioven-
reported for streptokinase (about 20%), after rt-PA reclosure tricular nodal artery
occurred in 8% of patients with a minimum diameter steno- 3. From the conal or right ventricular branch to the more
sis >0.6 mm (about 0.3 mm2) and in patients in whom distal right coronary branches
the residual diameter stenosis was as low as 55%. These 4. From the left atrial circumflex artery
disparate results may be due to fundamental differences Collateral Pathways to the Circumflex Coronary Artery
in the mechanisms of these agents in creating the throm-
bolytic state.438 1. From a diagonal branch of the left anterior descending to
a marginal circumflex branch
2. From a proximal marginal or left atrial circumflex to the
Coronary Collaterals more distal circumflex marginals
A preexisting network of structural connections between 3. From the distal right coronary artery to the distal
various portions of the coronary arterial supply to the heart circumflex
(coronary collaterals) has been recognized for centuries.439 4. From the posterior-lateral branch of the right coronary to
However, the importance of this network in providing a the obtuse marginal branch
degree of structural protection against the effects of ischemia Intermittent or gradual coronary occlusion results in the
due to atherosclerotic coronary obstructions has only recently growth of coronary collaterals.446,447 This maturation process
become clear. involves not only an increase in the lumen of the vessel, but
Where does the human coronary circulation fit in this also the development of new vascular smooth muscle.443 In
species listing? Autopsy studies have shown the presence dogs, at 6 months following coronary occlusion, a well-
of small coronary anastomoses (native collaterals) 50 to developed tunica media is present.448 Collateral vessels
250 μm in diameter in nearly all normal human hearts.440,441 respond to several neurohumoral substances, but the response
In human coronary disease this preexisting collateral of mature coronary collaterals differs substantially from that
network is enhanced by the development of an increased of native coronary arteries and immature collateral vessels.448
plexus of subendocardial collateral vessels that link the Mature collaterals are also responsive to the vasoconstrictor
perfusion field at risk of infarction with other better- effects of vasopressin448 and ergonovine.449
perfused areas.442 In patients with severe coronary athero-
sclerosis, a diffuse subendocardial plexus of collateral
Visible and Recruitable Coronary Collaterals
vessels can be seen angiographically as an outline of the
left ventricular cavity. Human coronary collaterals become demonstrable by coro-
In the human atherosclerotic state, ante- or postmortem nary angiography only when the parent vessel is subtotally
angiograms also often reveal larger epicardial anastomoses or totally occluded. Unfortunately, angiographic grading of
(stimulated collaterals). Such connections often connect coronary collaterals based on collateral caliber is not accu-
proximal and distal segments of the same occluded artery, rate in predicting the functional ability of the collateral to
connect adjacent arteries, or may traverse the atrium to provide coronary perfusion. There are several reasons for
connect two arteries with adjacent atrial branches.443 These this: (1) Coronary collaterals in the 100-μm range are not
connections are more like what is seen in the dog following angiographically visible.450 (2) Angiographic techniques in
the placement of ameroid constrictors, which cause the humans for quantitating collateral function are not well vali-
gradual development of coronary obstruction. dated.450 (3) In the absence of near-total vessel occlusion,
788 chapter 34

collateral vessels are not visible in the resting state (e.g., Collateral Grading
during angiography). They can, however, be rendered visible Rentrop Scale
if contrast is injected into the contralateral artery during
Score Definition
coronary spasm451 or during temporary balloon occlusion of
the recipient artery.452 These collaterals have been termed
“recruitable.”453
It is likely that the above shortcomings in evaluating
0 No collaterals
collateral flow were responsible for much of the controversy
over the past several decades regarding the functional impor-
tance of coronary collaterals in humans. Until the mid-1960s,
the myocardial protective effects of collaterals were accepted
widely.442 In the 1970s, however, these prevailing concepts
1 Faint filling of the distal branch
were called into question,454,455 with the finding of a higher arteries
incidence of wall motion disturbances in patients with versus
those without collaterals. Concepts then shifted to reflect
the view that collaterals were only a marker of severe disease,
which offered no beneficial effects.
At present the pendulum has returned to the conclusions 2 Complete filling of branch arteries
of the earlier era456 as a result of several important observa-
tions. For any given location of acute coronary occlusion, the
degree of deterioration of left ventricular function is inversely
related to the presence of angiographically visible coronary
collaterals.457 In addition, the incidence of late aneurysm
3 Collateral filling of the main artery, in
formation following myocardial infarction is reduced in
addition to the branches
patients with an angiographically significant collateral cir-
culation, with or without successful reperfusion.458 The risk
of hemodynamically severe consequences from acute infarc- FIGURE 34.39. The Rentrop semiquantitative scale for grading col-
tion is mitigated greatly by the presence of a preexisting lateral blood flow to a coronary artery.461
severe stenosis, and thus the protective effect of a developed
collateral circulation. Conversely, when acute coronary 4 mm Hg. Signs and symptoms during angioplasty balloon
occlusion occurs in the presence of a mild stenosis and thus occlusion of ischemia occur with a significantly greater fre-
poor collateral development, it is likely to have more severe quency in patients with a low coronary wedge pressure.
clinical consequences.459 More recently it has been shown Many studies in dogs have shown that even well-
that the presence of angiographically defined coronary col- developed mature collaterals have a minimal vascular resis-
laterals extends the “window of time” for the beneficial tance that is two to four times greater than normal minimal
effect of reperfusion therapy of myocardial infarction and resistance. Thus, coronary flow during maximum dilation
results in greater improvement in cardiac function and to areas supplied by angiographically large-caliber collaterals
reduction in infarct size.460 is usually significantly reduced when compared to regions
Collateral flow can be graded using the following scale supplied by normal coronaries.462 This may explain the fre-
devised by Rentrop et al.461 (Fig. 34.39): quent clinical observation that exertional angina is not infre-
quent when an area of the left ventricle with normal or
Grade 0: No angiographically visible filling of any collateral
minimally impaired contraction is supplied by a totally
channels
occluded coronary, even when large angiographic collaterals
Grade 1: Collateral filling of the distal branches of the
are visible.
recipient artery, but not the epicardial portion of
the artery
Grade 2: Partial collateral filling of the recipient epicardial
artery
Nonatherosclerotic Coronary Artery Disease
Grade 3: Complete collateral filling of the recipient epicar-
dial artery Coronary Vasospasm
Angiographic methods for assessing collateral blood flow The diagnosis of coronary vasospasm can be made at the time
are at best semiquantitative measures. The coronary wedge of angiography by giving drugs that provoke spasm or occa-
pressure (e.g., the distal coronary pressure during transient sionally by observing spontaneous spasm.463–470 The most
balloon occlusion at the time of angioplasty) has been used commonly administered agent is an ergot derivative, usually
to assess more accurately collateral function. Spontaneously ergonovine maleate or ergometrine, although methacholine
visible collaterals are present at angioplasty four times as was used to induce vasospasm in early pioneering studies in
often as recruitable collaterals. Meier et al.453 found the coro- the catheterization laboratory. Ergot derivatives are potent
nary wedge pressure in patients with collaterals of either constrictors of vascular smooth muscle. For over 2000 years,
type to be 44 ± 12 mm Hg (spontaneously visible collaterals ergot drugs have been known to cause gangrene when given
41 ± 12, recruitable collaterals 36 ± 12 mm Hg). The coronary in large doses, but the mechanism of action still is not clear.
wedge pressure in patients without collaterals was 18 ± They appear to have α-adrenergic and serotonin receptor
 corona ry a ngiogr a ph y 789
agonist activity and dopamine antagonist properties, and with spasm induced by ergonovine should have nitroglycerin
may also inhibit central vasomotor centers.471 More recently, or a calcium channel antagonist administered for at least 6
intracoronary acetylcholine (25 to 50 μg and an intracoronary hours after the procedure. An advantage of acetylcholine is
bolus) has been used to provoke spasm.472 Prior to a provoca- its very short half-life and absence of late spasm.
tive test for vasospasm, an electrocardiogram should be Ergonovine provocative studies are relatively safe, with
obtained and a coronary arteriogram should show the absence complication rates comparable to routine angiography. Ven-
of severe coronary obstruction. When vasospasm is suspected, tricular tachycardia or fibrillation, the most common com-
acetylcholine or ergonovine generally is given in incremental plication, occurs in 0.2% to 0.4%, myocardial infarction in
intravenous doses (starting at 50 μg and increasing doses until 0% to 0.03%, and significant heart block or severe bradycar-
a total dose of 350 to 400 μg intravenously for ergonovine) is dia in about 0% to 0.2%.483,484 We do not recommend prophy-
given. Although ergonovine appears safe in doses up to 800 μg, lactic temporary pacemaker insertion unless the patient has
the vast majority of patients with vasospastic angina develop previously developed bradycardia during angina. Platelet
spasm at doses of <200 μg.465–469,473 activation after induction of vasospasm is reported, but its
In normal patients, ergonovine causes an increase in sys- relationship to the induction of or propensity for spasm is
temic arterial pressure (10–20%) and a small increase in left unclear.485,486
ventricular end-diastolic pressure (0 to 4 mm Hg), and does Coronary spasm may be slightly more likely in the right
not change heart rate or lactate extraction.468,470 Normal coronary, followed by the left anterior descending and cir-
patients also exhibit mild, diffuse coronary constriction in cumflex arteries. Vein bypass grafts also can exhibit spasm,
the epicardial arteries (10–20% decrease in diameter).474 The but rarely do.487 Patients with vasospastic angina appear to
response is more pronounced in the distal vessels. have more constriction in nonspastic coronary segments,
In patients with vasospastic angina, ergonovine or acetyl- suggesting a generalized coronary abnormality and also may
choline causes focal, usually severe coronary constriction, have enhanced resting tone, as evidenced by a greater degree
frequently leading to transient, total coronary occlusion of relaxation after nitroglycerin.488–491
(Fig. 34.40). The peak response occurs 2 to 5 minutes after Coronary spasm occurs in two broad settings: spasm
administration, although onset of spasm 15 to 20 minutes associated with atherosclerosis or other arterial diseases, and
later has been reported. In its classic description, coronary spasm that occurs in the absence of identifiable arteriopa-
spasm leads to chest pain, ST-segment elevation on the elec- thy.465,467,484,492,493 The former is common but the latter is
trocardiogram, increased left ventricular end-diastolic pres- not.465 Bertrand et al.484 administered ergonovine to 1089
sure, and myocardial lactate release.470 In as many as half of patients undergoing coronary arteriography and found that
patients with vasospastic angina, the response to ergonovine spasm was more common in patients with recent coronary
is less intense. ST-segment depression (rather than elevation) thrombosis (Fig. 34.41). Vasospasm could be induced in 20%
is often observed in patients with incomplete coronary occlu- of patients with a recent infarction and 38% of patients with
sion with spasm, in patients with collateral arteries to the unstable or rest angina but in only 4.3% of patients with
ischemic bed, and if spasm occurs in a small vessel.475–479 stable exertional angina. Equally important, only 1.2% of
Most authors would consider the test positive if the patient’s patients with chest pain atypical for angina had inducible
symptoms are reproduced, focal spasm >75% is demonstrated, spasm, emphasizing that spasm is not a common cause of
and there are electrocardiographic changes (ST-segment ele- atypical chest pain.
vation or depression).465 Patients with inducible vasospasm and a significant
Coronary spasm induced by ergonovine or acetylcholine (>75%) stenotic lesion have a higher incidence of death,
usually is reversed easily by nitroglycerin, although intra- infarction, and atherosclerosis progression than patients
coronary administration can be required. Vasospasm has with isolated stenotic lesions without inducible vasospasm
been induced while a patient was receiving an intravenous or vasospasm alone.494–496 Harding et al.483 and others497 ret-
infusion of nitroglycerin and nitrate-resistant induced spasm rospectively analyzed ergonovine provocative studies and
can occur, but it is rare.480 It is important to remember that found that smoking (odds ratio 4.7–7.7:1 compared to non-
the blood half-life of ergonovine is 30 to 120 minutes, much smokers) and atherosclerosis were significant risk factors for
longer than that of nitroglycerin.481,482 Consequently, patients inducible spasm.

FIGURE 34.40. An angiogram from a patient with vasospasm rior descending artery develops spasm at the site of the lesion (arrow)
induced by ergonovine. Left panel: Before ergonovine, there is a 50% and there is minimal antegrade blood flow. Right panel: After nitro-
diameter stenosis in the proximal left anterior descending artery. glycerin (200 μg, intracoronary), the spasm is relieved and blood flow
Center panel: After ergonovine (100 μg intravenously), the left ante- is restored.
790 chapter 34

• Atypical chest pain 1.2% in other coronary segments, but the association is with clini-
cal vasospasm is very uncommon.
• Exertional angina 4.3%

• Angina on effort & at rest 13.8% Spontaneous Coronary Artery Dissection

• Angina at rest 38% Naturally occurring coronary artery dissection occurs most
commonly in conjunction with aortic dissection and involves
• Recent myocardial infarct 20%
the right coronary more often than the left. Isolated spontane-
• Oid myocardial infarct 6.2% ous coronary artery dissection, however, is a rare event that
occurs in all coronary arteries with approximately overall
• Valvular disease 2%
equal incidence, although in women it may more frequently
• Cardiomyopathy 0% involve the left coronary and in men the right (Fig. 34.42).501–506
It occurs most frequently in young women, particularly in the
peripartum period, but may also be associated with blunt chest
0 50 100 150 200 250 trauma, atherosclerosis (possibly related to plaque rupture),
FIGURE 34.41. The frequency of coronary vasospasm induced by obstruction immediately above the aortic valve (e.g., an
ergonovine in 1089 patients undergoing cardiac catheterization. The obstructed prosthetic ball valve), and iatrogenic complications
incidence of provokable spasm was high in patients with angina at
of coronary artery cannulation.502,507–511 Histologic examina-
rest and recent myocardial infarction, but spasm was uncommon
in patients with chest pain atypical for myocardial ischemia. tions have shown a variety of abnormalities.502,504,505,509 The
most common observation is a hematoma within the arterial
media and luminal compression.502,505 A rent in the intima
leading to the medial hematoma is observed inconsistently, as
are changes of cystic medial necrosis.504 Atherosclerosis with
aneurysm or plaque rupture has been reported.504 Perivascular
Other agents have also been used to induce spasm at the
eosinophilia has also been found late after dissection but it is
time of catheterization. Muscarinic receptor agonists (acetyl-
not clear whether eosinophils were related to the cause or
choline and methacholine) appear to cause vasospasm in a
occur as a response to the dissection.512
large fraction of patients with ergonovine-induced spasm.498
At angiography, spontaneous dissection appears as a
The specificity and sensitivity of cholinergic agents is not
radiolucent linear filling defect that spirals down the coro-
well described. Induction of vasospasm by muscarinic recep-
nary artery.501,503,506,513–515 After intracoronary contrast injec-
tor agonists suggests the possibility that endothelial dys-
tion, contrast material frequently persists in the false lumen.
function may play a role in coronary spasm.498 Other agents
The dissection may be complicated by total thrombotic coro-
have also been reported to induce spasm (cold pressor test,
nary occlusion. Distal emboli with abrupt vessel cut-offs are
histamine, hyperventilation), but not enough information
common.506 Unless complicated by lumen thrombosis or
is known to assess the potency and specificity of these
death, most spontaneous dissections heal, but permanent
agents.499,500
true and false channel lumina may persist.501,513–515 A similar
dual-lumen vessel can be seen late after angioplasty compli-
Catheter-Induced Vasospasm
cated by a spiral dissection. In one series of patients with
Coronary cannulation can cause vasospasm at the catheter spontaneous dissection, the mortality rate was 18%.501
tip, thought usually to result from mechanical traction on Thrombolytic therapy has been used successfully to treat
the artery. Catheter-induced spasm is much more common acute coronary occlusion related to spontaneous dissec-
in the right compared to the left coronary, and rarely may tion,516 as has stenting.517 Recurrent dissection in another
occur distal to the catheter tip or in vein grafts.145–148 It may artery is uncommon, but may occur more frequently in
occur more frequently in patients with vasospastic disease women.

FIGURE 34.42. Serial angiograms obtained from a patient with a infarction, the angiogram revealed subtotal occlusion of the anterior
spontaneous dissection of the left anterior descending coronary descending and a linear intraluminal filling defect along the occlu-
artery. Left panel: An angiogram obtained before presentation sion. Right panel: Angiography months after presentation and treat-
revealed mild diffuse narrowing of the left anterior descending ment with streptokinase showed healing of the dissection and
artery. Center panel: After developing signs of acute myocardial minimal stenosis.
 corona ry a ngiogr a ph y 7 91

Myocardial Infarction in Patients with at catheterization to have microvascular disease. Hence, it is

Angiographically Normal Coronary Arteries likely that other, still uncharacterized, syndromes alter
microvascular function in these patients.
One to 16 percent of patients with documented acute myo- The function of the microcirculation can be tested in
cardial infarction are found at angiography to have normal several ways at the time of angiography, although the clinical
or nearly normal coronary arteries.518–521 Coronary embo- significance of abnormalities in function in the absence of
lism, in-situ coronary thrombosis with spontaneous lysis, symptoms is not yet certain. Maximal coronary conduc-
and vasospasm have been proposed as possible mecha- tance can be assessed by measurements of coronary flow
nisms.522–525 Compared to patients with infarction associated reserve (the ratio of peak hyperemic blood flow to resting
with coronary atherosclerosis, those with a normal coronary flow).209,388,406,548 In patients with a severe epicardial coronary
angiogram after infarction tend to be younger (16–22% of stenosis (e.g., atherosclerotic stenosis), treadmill exercise
patients are less than 35 years of age), and have fewer performance is reduced proportionately to coronary reserve.549
antecedent symptoms of angina and fewer risk factors for Patients with fixed microvascular disease may have simi-
atherosclerosis.526,527 In contrast to the male predominance larly reduced coronary reserve, suggesting a fixed reduction
of atherosclerosis-associated infarction, men and women in maximal coronary conductance.
are approximately equally affected.524,527 Associations with Cannon et al.534,535,539,540 identified a subgroup of patients
tobacco smoking, a prior history of migraine headaches, with chest pain and angiographically normal arteries who,
Raynaud’s syndrome, mitral valve prolapse, cocaine abuse, after ergonovine administration, failed to normally increase
and birth control pill use have been reported.527–529 Cocaine, coronary blood flow conductance during atrial pacing. The
sumatriptan, nifedipine, or excessive alcohol use also may majority of these patients also had abnormally low maximal
precipitate infarction, presumably by causing vasospasm or coronary conductance after dipyridamole, reduced left ven-
transient thrombosis.530 Coronary spasm induced by ergono- tricular compliance, failure to increase the ventricular ejec-
vine can be demonstrated in a minority of patients, but no tion fraction with exercise, and abnormally low myocardial
definitive underlying mechanism can be found in most.524 lactate uptake (even lactate release) during pacing at a rapid
Sudden sympathetic discharge (e.g., with emotional heart rate. Furthermore, many of these patients also may
stress, shock, or postoperative pain) has also been associated have reduced forearm flow reserve, suggesting a systemic
with transient anterior wall dysfunction, chest pain and deep microvascular abnormality.550 The mechanism of this abnor-
T-wave inversion across the precordial leads on the ECG, in mality is not known.
the presence of normal coronary angiography.531 Although It has been postulated that endothelial dysfunction may
blood markers of infarction are elevated, nearly all patients play an important etiologic role in microvascular disease
have recovery of ventricular function. syndromes.551 The functional integrity of the endothelium
Infarctions associated with a normal coronary angiogram can be tested at the time of angiography by measuring the
tend to be smaller than those associated with atherosclerosis, amount of large vessel dilation and the change in blood flow
and the mortality rate may be lower.527 The long-term prog- (i.e., microvascular dilation) during intracoronary infusion
nosis is generally good in terms of mortality, but recurrent of pharmacologic agents that normally elicit the release of
infarction and stroke may be more common than in patients endothelial dilating factor(s). The responses to two agents
with atherosclerosis.520,527 have been characterized in humans: acetylcholine and sub-
stance P. When normal endothelium is present, acetylcholine
causes a dose-dependent epicardial coronary and microvas-
Microcirculatory Coronary Disease
cular dilation.410 In the absence of endothelium, acetylcho-
Studies in highly selected patient populations suggest that line causes short-acting constriction. Hence, the response to
microvascular coronary dysfunction may be a frequent intracoronary acetylcholine infusion (dilation or no change/
cause of symptoms in the 10% to 25% of patients undergo- constriction) is one marker of endothelial function that can
ing coronary angiography for chest pain in whom no signifi- be tested in humans. The acetylcholine response is abnormal
cant obstruction to blood flow is found in the epicardial in several diseases with known endothelial dysfunction (ath-
vessels.532–536 Of patients with angiographically normal coro- erosclerosis, transplantation).410,552 The endothelial response
nary arteries, Cannon et al.537 reported that 71% had abnor- to acetylcholine also was abnormal in both the large conduit
mal microvascular function, and Geltman et al.538 found coronary arteries and the coronary microcirculation (i.e.,
reduced coronary flow reserve in 50%. It is now accepted constriction, or subnormal dilation) in a series of nine
that microvascular dysfunction can cause clinically impor- patients with anginal symptoms and normal coronary angi-
tant myocardial ischemia, including anginal syndromes, ography even though the response to nonendothelial depen-
exertional dyspnea, and left ventricular dysfunction, but the dent pharmacologic vasodilators was preserved.553 These
mechanism(s) and incidence are unclear.534,535,539–541 One findings suggest that functional as well as fixed abnormali-
investigator has become skeptical of the diagnosis and its ties in the coronary microcirculation may be causes of isch-
clinical importance.542 emia in the absence of epicardial atherosclerosis.
A number of diseases are associated with or cause micro-
vascular dysfunction. These include prolonged hypertension,
Radiation-Induced Coronary Artery Disease
hypertrophy, cardiomyopathies, collagen vascular diseases,
and atherosclerosis,543–547 diseases associated with endothe- Chest irradiation can lead to narrowing or occlusion of the
lial dysfunction. Although common entities, these specific epicardial and intramural coronary arteries, typically pre-
disease entities are present in less than half of patients found senting several months to 12 years after the exposure.554–564
792 chapter 34

Radiation-induced injury usually leads to adventitial fibro-

sis, smooth muscle cell loss in the media, and intimal
proliferation.554,557 Atherosclerotic changes have also been
observed, although lipid deposition is less marked than in
patients with typical atherosclerosis. The angiographic
findings are similar to those of atherosclerosis.559 The coro-
nary lumen can be diffusely narrowed or occluded entirely
from radiation-induced fibrosis. Acute myocardial infarction
is reported.562 The proximal vessels are affected more
commonly.
Generally, a dose of over 3000 R is associated with
increased risk of radiation-induced coronary disease. In one
series of 16 young patients (<33 years of age) who had received
>3500 R to the heart, six had severe focal epicardial coronary
stenoses.559,560 In another series, patients treated for Hodg-
kin’s disease with mantle radiation had a 2.7-fold increase in
risk for coronary disease.556
FIGURE 34.43. An angiogram of the left coronary artery of a patient
with transplant-related vasculopathy. The left anterior descending
Transplant-Related Arteriopathy artery is occluded (open arrow) and fills distally by faint collaterals
(solid arrow). The remainder of the coronary tree has diffuse irregu-
The most persistent problem in patients surviving more than larities and pruning of the distal branches.
1 year after transplantation has been the development of
coronary arteriopathy characterized by diffuse intimal thick-
ening of the transplanted arterial wall.565–569 The process nary dilation and increase in blood flow, suggesting a failure
extends from the large conduit arteries into smaller branch of the endothelium to normally release endothelium-derived
vessels >400μm in diameter. Serial angiographic studies relaxing factor (nitric oxide, NO). Some transplant recipients
demonstrate the development of luminal irregularities or have frank vasoconstriction in response to acetylcholine.
frank stenosis within 3 years of transplantation in 25% to Whether an abnormal endothelial function presages more
45% of patients.570–578 Serial angiographic measurements of severe vasculopathy is unclear, but preliminary studies
coronary luminal cross-sectional area using quantitative suggest a link. Endothelial function testing during angiogra-
angiography show that the large conduit arteries decrease in phy may have a role in research institutions.583
diameter by 6% to 10% in the first year after transplantation, Epicardial coronary tone is also reduced in the first
but thereafter the lumen diameter remains fairly stable until several months after transplantation.584 Tone returns to
more advanced vasculopathy occurs.574 normal by 1 year after transplantation, but the reemergence
The angiographic studies probably underestimate the fre- of normal tone is not related to reinnervation. Spontaneous
quency of arteriopathy because they detect only luminal focal coronary spasm also has been observed during angiog-
encroachment but do not reflect wall thickening, which may raphy in transplanted hearts.585 Tone can be misinterpreted
occur in an abluminal manner.569 Intravascular ultrasound as diffuse narrowing. Nitroglycerin should be administered
imaging of transplanted coronary arteries generally demon- immediately prior to angiography to allow a true assessment
strates a substantially greater degree of intimal thickening of the lumen caliber.
than is observed using angiography.579,580 The presence of
angiographically undetected intimal thickening may predict
Coronary Abnormalities Associated with Vasculitis
progression to more severe arteriopathy over time.581,582 At
the present time, many angiographers routinely image the Coronary vasculitis can result from vascular infection or
coronary arteries at the time of angiography. Nonetheless, collagen vascular diseases and causes four angiographically
development of angiographically detectable vasculopathy is detectable coronary abnormalcies: focal stenotic lesions,
associated with shortened survival.578 diffuse narrowing, thrombosis, and late aneurysmal dila-
In its classic angiographic description, transplant vascu- tion.586,587 Lesions may be located from the aortic origin of
lopathy is characterized by diffuse luminal obliteration, the coronary arteries to the microcirculation. Aortitis asso-
which is most marked in the smaller branch vessels seen on ciated with syphilis, Takayasu’s arteritis, and, more rarely,
angiography (Fig. 34.43). In reality, the process affects the tuberculosis can cause stenosis of the coronary ostia.588
entire conduit artery, and focal stenoses in the large epicar- Involvement of the larger epicardial coronary arteries is
dial arteries—similar in angiographic morphology to athero- reported, but is rare.586,589
sclerotic lesions—are not infrequent (Fig. 34.42). The typical Of the collagen vascular disease, systemic lupus erythe-
patterns of transplant vasculopathy observed in 81 transplant matosus most commonly involves the angiographically
recipients were described by Gao et al.572 Angiographic hall- visible epicardial coronary vessels, although large coronary
marks of vasculitis are absent (FIg. 34.44). involvement can be seen in polyarteritis nodosa, progressive
Several physiologic abnormalities of coronary vasomo- systemic sclerosis, and, more rarely, giant cell arteritis and
tion also have been detected. Endothelial function is rheumatoid arthritis.590–594 The epicardial lesions associated
frequently abnormal.552 In many patients, intracoronary ace- with vasculitis typically resemble atherosclerotic lesions.587
tylcholine administration fails to elicit the expected coro- Diffuse luminal narrowing is less common and the typical
 corona ry a ngiogr a ph y 793

Type A lesion ter) were particularly prone to occlude or develop stenotic

lesions.605 Rarely, aneurysms can rupture.606 Basal coronary
blood flow is usually normal, but coronary flow reserve is
usually reduced in the microvascular bed of arteries affected
Type B1 lesion by Kawasaki disease.607 Kawasaki disease should be consid-
ered in the differential diagnosis of young adults presenting
with aneurysmal coronary artery disease or myocardial
infarction.
Type B2 lesion

Coronary Artery Aneurysms

True aneurysms of the coronary arteries are associated with
Type C lesion thinning of the tunica media and are very uncommon, but
when present can reach over 2 cm in diameter (Fig. 34.45).608–610
FIGURE 34.44. Angiographic morphologies of coronary lesions The angiographic morphology of coronary aneurysms can
associated with transplant vasculopathy. Lesion type A: Discrete
tubular or multiple stenoses. Lesion type B1: Distal concentric nar-
be saccular or fusiform. They frequently contain thrombotic
rowing and obliterated vessels with sparing of proximal vessel. material laminated against the borders of the aneurysm that
Lesion type B2: Diffuse concentric narrowing. Lesion type C: Narrow may not be identifiable on the angiogram. Occasionally, the
irregular distal branches with abrupt terminations. majority of the aneurysmal cavity can be filled with throm-
bus, leaving the angiographic appearance of a normal artery.
After angioplasty or thrombolytic drug treatment, a portion
beaded appearance of vasculitis seen in other vascular beds of the aneurysm cavity can be revealed and at first may
is notably absent, although one case of a huge coronary aneu- resemble a coronary perforation.
rysm associated with systemic lupus erythematosus is Aneurysms can be congenital in origin, or occur as a
reported.590,592,595 Thrombosis of vasculitic segments can result of atherosclerosis, inherited diseases of connective
occur, leading to total arterial occlusion or the typical angio- tissue (e.g., periarteritis nodosa, systemic lupus erythemato-
graphic appearance of a thrombotic lesion. sus), inflammatory arteritis (e.g., Kawasaki disease), mycotic-
The incidence of coronary vasculitis is probably underes- embolic events,611 or coronary trauma (usually iatrogenic).
timated by angiography because the findings are so similar True atherosclerotic coronary aneurysms are very uncom-
to atherosclerosis.590 In young patients with systemic lupus mon, occurring in only 0.2% of coronary arteriographic
erythematosus and no important risk factors for atheroscle- studies,608,612 but the overall incidence from all causes ranges
rosis, coronary lesions and myocardial infarction should be from 0.5% to 1.1% of coronary angiographic studies.613 When
assumed to be due to vasculitic involvement of the coronary associated with atherosclerosis, usually there are coexistent
arteries until shown otherwise, although accelerated athero- stenotic lesions in multiple vessels. Atherosclerotic aneu-
sclerosis due to corticosteroid therapy may also account for rysms almost never rupture, but they may contain throm-
angiographically detected lesions. Late aneurysmal dilation botic material and can cause myocardial infarction by in-situ
of the large coronary arteries, especially in periarteritis thrombosis or embolization. Dissection of atherosclerotic
nodosa, has been reported to occur in nearly all of the vas- aneurysms has been reported, but also is uncommon.505
culitic syndromes, and rupture of the aneurysm has been Congenital disorders of connective tissue are associated
reported as a rare consequence.590,592,596 with multiple aneurysms, particularly of the proximal arter-
Microcirculatory vasculitis occurs frequently in patients ies. Ehlers-Danlos syndrome type IV is characterized by dila-
with systemic lupus erythematosus, scleroderma, and rheu- tion of the proximal and mid-coronary artery.614 One case of
matoid arthritis. In these patients, maximal coronary con-
ductance (e.g., coronary flow reserve) is usually reduced and
ischemia due to microvascular obstruction or dysfunction
has been proposed.597,598
The most common infectious agent to involve the angio-
graphically visible coronary vessels is Kawasaki disease
(mucocutaneous lymph node syndrome). It is characterized
by coronary aneurysmal dilation, stenosis, and thrombosis
occurring primarily in the proximal coronary arteries.599,600
The aneurysms can be huge. Late after the acute illness about
one half of the aneurysms present during the febrile episode
resolve.601,602 In angiographic studies of 1100 patients at an
average of 25 months after disease onset, Suzuki et al.603
found that 36% had frank aneurysms, 28% had coronary
dilation, 24% had localized coronary stenosis, and 8% had
an occluded coronary. Aneurysmal calcification can occur.604
Most of the Kawasaki disease–associated aneurysms were in
the proximal coronary arteries but about one in five was in FIGURE 34.45. A large fusiform aneurysm of the left anterior
the more distal vessels. Large aneurysms (>9 mm in diame- descending coronary artery (arrow).
794 chapter 34

3. Judkins ML. Angiographic equipment; the cardiac catheteriza-

tion laboratory. In: Abrams HL, ed. Coronary Arteriography: A
Practical Approach. Boston: Little, Brown, 1983:1–51.
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7. Holmes DR, Bove AA, Wondrow MA et al. New technique for
decreasing x-ray exposure without decreasing image quality
during cardiac catheterization. Mayo Clin Proc 1986;61:321–
338

FIGURE 34.46. An angiogram of the left coronary artery of a patient Radiation Protection
who underwent angioplasty 6 months previously and developed an
irregular, saccular pseudoaneurysm at the site of dilation (arrow). 8. Judkins MP. Guidelines for radiation protection in the cardiac
catheterization laboratory. Cathet Cardiovasc Diagn 1984;10:
87–92.
9. Miller SW, Castronovo FP. Radiation exposure and protection
in cardiac catheterization laboratories. Am J Cardiol 1985;55:
rupture and another of thrombosis have been reported. Both 171–176.
angiography-related dissection of the coronary ostium and 10. Pitney MR, Allan RM, Giles RW, et al. Modifying fluoroscopic
peripheral vascular pseudoaneurysm have been linked to the views reduces operator radiation exposure during coronary
syndrome. angioplasty. J Am Coll Cardiol 1994;24:1660–1663.
Interventional coronary artery procedures also can result 11. Zorzetto M, Bernardi G, Morocutti G, Fontanelli A. Radiation
exposure to patients and operators during diagnostic catheter-
in true coronary aneurysms, including laser angioplasty,
ization and coronary angioplasty. Cathet Cardiovasc Intervent
atherectomy, stent placement, and balloon dilation.615–617 One 1997;40:348–351.
report suggests that the use of corticosteroids around the 12. Rueter FG. Physician and patient exposure during cardiac cath-
time of the stent placement may promote aneurysm forma- eterization. Circulation 1978;58:135–139.
tion.617 Aneurysms have also developed at the site of coro- 13. Geise RA, Hunter DW. Personnel exposure during fluoroscopy
nary anastomosis of vein bypass grafts.618 Pseudoaneurysms procedures. Postgrad Radiol 1988;8:162–173.
can occur after coronary rupture from balloon dilation 14. National Council on Radiation Protection and Measurements
(Fig. 34.46).619 Recently, paclitaxel-coated stents have rarely (NCRP). Recommendations on Limits for Exposure to Ionizing
caused aneurysms.620 Radiation. Report No. 91. Bethesda, MD: NCRP Publications,
1987.
15. National Council on Radiation Protection and Measurements.
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acute ischemic syndrome, otherwise normal coronary arter- tion laboratory. Cathet Cardiovasc Diagn 1984;10:87–92.
19. National Council on Radiation Protection and Measurements
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 3 Echocardiographic
5 Evaluation of Coronary
Artery Disease
Stephanie A. Coulter

Measurement of Regional Myocardial Function . . . . . . 811 Chronic Complications After a Myocardial

Assessment of Coronary Ischemia/Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813 Prognosis in Acute Myocardial Infarction and
Location of Acute Myocardial Infarction . . . . . . . . . . . . 814 Chronic Coronary Artery Disease . . . . . . . . . . . . . . . 821
Extent of Acute Myocardial Infarction . . . . . . . . . . . . . . 815 Stress Echocardiography: Assessment of Ischemic
Acute Complications of Acute Myocardial and Viable Myocardium . . . . . . . . . . . . . . . . . . . . . . . 823
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815

C
oronary artery disease (CAD) is the most prevalent of cardial motion.1 With echocardiography, a regional wall-
cardiac diseases. Routine evaluation of patients with motion abnormality (RWMA) is characterized as a localized
suspected or known CAD nearly always includes decrease in the rate and amplitude of endomyocardial motion.
echocardiography. Echocardiography is a versatile, low-cost, These abnormalities are accompanied by a reduction
and portable technique that is available clinically in nearly in myocardial thickening during systolic contraction and
all medical centers and subsequently is the most widely uti- by thinning of the myocardial segment after a transmural
lized cardiac testing modality. The diagnosis of CAD by myocardial infarction (MI). The loss of systolic wall
echocardiography is based on the concept that acute myocar- thickening is more specific for myocardial ischemia than
dial ischemia or infarction produces a detectable impairment is the detection of a resting RWMA 2–5 because cardiac
in regional left ventricular (LV) mechanical function. Identi- rotation, translational motion during contraction of border-
fication of patients with suspected CAD and acute coronary ing segments, and loading conditions affect the latter finding.
syndrome is one of the primary indications for echocardiog- An RWMA is not specific for coronary ischemia and also
raphy. Assessment of global LV systolic function and detec- occurs with a previous MI, a previous sternotomy, myocar-
tion of the presence and extent of regional myocardial ditis, cardiomyopathies, left bundle branch block, and
dysfunction are routine clinical indications for echocardiog- preexcitation.
raphy. This method also has an important prognostic value The American Association of Echocardiography rec-
in patients with acute and chronic CAD. When combined ommends a 16-segment standardized format for describing
with exercise or pharmacologic stress testing, echocardiog- RWMAs.5 To update and unify reporting of wall-motion
raphy can identify patients with myocardial ischemia and analysis among disparate cardiac-imaging modalities, in
viability. Because echocardiography can provide a compre- 2002 the American Heart Association (AHA) issued a state-
hensive assessment of cardiac structure, functio