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Oxford Textbook of

Advanced Heart
Failure and Cardiac
Transplantation
Oxford Textbook of

Advanced
Heart Failure
and Cardiac
Transplantation
Edited by
Michael J. Domanski
Division of Cardiology, Peter Munk Center, University Health Network; the University
of Toronto School of Medicine, Toronto, Canada; the Ichan School of Medicine at
Mount Sinai, New York, NY, USA

Mandeep R. Mehra
Harvard Medical School; BWH Heart and Vascular Center, Brigham and Women’s
Hospital, Boston, MA, USA

Marc A. Pfeffer
Harvard Medical School; Cardiovascular Division, Brigham and Women’s Hospital,
Boston, MA, USA

1
1
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 Foreword

During the last half century there have been extraordinary advances patients who survive to develop failure of the myocardial pump.
in the diagnosis and management of many forms of heart disease. Co-morbidities such as diabetes mellitus, obesity, atrial fibrilla-
A variety of drugs, devices, surgical and catheter-based interven- tion, chronic obstructive lung disease and severely reduced renal
tions have resulted in dramatic reductions of morbidity and mor- function, which are common in the elderly, increase the risk of
tality of many cardiovascular disorders. For example, in the early heart failure in patients with the aforementioned underlying car-
1960s, the one year mortality in patients with acute myocardial diac disorders.
infarction who reached the hospital was about 50% and has been Fortunately, there has been progress in the treatment of one form
reduced to 10% since then. Surgical and catheter-based interven- of heart failure—that which occurs in patients with reduced ejec-
tions have prolonged the lives of most patients with valvular and tion fraction. However, while the prognosis in such patients has
congenital heart disease. Hypertension can now be controlled with improved, this improvement is usually temporary, and after several
pharmacotherapy in the majority of patients. Patients at high risk years, the condition often progresses. Treatment of patients with
of sudden cardiac death can be identified and this outcome can be heart failure and preserved ejection fraction as well as of patients
prevented in many patients. with acute decompensated heart failure has improved relatively lit-
Concomitant with these spectacular advances, there has been tle in the last few decades. As a consequence, many patients with a
a progressive and alarming increase in the prevalence of heart history of heart failure enter a phase commonly known as advanced
failure, which has become the most frequent diagnosis of hospital heart failure. This pre-morbid condition is the subject of this excel-
admission in Medicare patients. The development of heart failure lent book, edited by Michael Domanski, Marc Pfeffer, and Mandeep
has actually become the price of successful treatment of heart dis- Mehra, three acknowledged leaders of this field. They have been
ease, and for many patients this price has been high indeed. How joined by a team of expert co-authors and have produced a volume
can this seeming paradox be explained? While the life of patients which reviews the fundamental pathobiology and pathophysiology
with most forms of heart disease has certainly been prolonged and of advanced heart failure, including right heart failure. It then goes
its quality improved, with some exceptions the underlying condi- on to describe and assess diagnostic procedures, pharmacologic
tion is rarely cured. For example, while most patients with acute and device management, and treatment with mechanical circula-
myocardial infarction now survive for years after the event, they tory support and cardiac transplantation.
often develop additional episodes of myocardial infarction which This well written, carefully edited book will be of great interest to
“chip away” at their remaining viable myocardium leading to left clinicians faced with the challenge of caring for the growing num-
ventricular dysfunction and ultimately to heart failure. Similar ber of patients with advanced heart failure. It will be of particular
scenarios play out in patients with hypertension, who might have value to trainees who will join the ranks of specialists in advanced
died as a consequence of a hemorrhagic stroke in 1960, but who heart failure. It is this next generation who, in addition to provid-
now develop heart failure later in life as a consequence of pro- ing care to these patients, will advance this importance branch of
longed and progressive ventricular hypertrophy despite receiving cardiology, and this book will help them on their journey.
antihypertensive drugs. While the development and more wide-
spread use of implanted cardiac defibrillators has reduced sud- Eugene Braunwald, M.D.
den cardiac death, this treatment has increased the prevalence of Boston, MA, USA
 Contents

Contributors ix 11 Cardiac resynchronization 179

James P. Daubert, Brett Atwater, and Kevin Jackson
Abbreviations xi
12 Advanced heart failure in
valvular heart disease 202
1 Advanced heart failure in perspective 1
Blase A. Carabello
Marc A. Pfeffer, Michael J. Domanski,
and Mandeep R. Mehra 13 High-risk heart failure surgery: Strategies
for coronary artery bypass grafting
2 Cell biology of heart failure 12
and valve surgery in patients with
Kenneth B. Margulies and J. Eduardo Rame
reduced ejection fraction 215
3 Physiology and hemodynamic assessment Marzia Leacche, Garrick C. Stewart, and John G. Byrne
of the failing heart: Current knowledge and
14 Mechanical circulatory support: Patient
unmet needs for advanced heart failure 43
selection, optimization, and in-patient
J. Julia Shin, Mandeep R. Mehra, and Ileana L. Piña
management of the patient with a
4 Transplantation immunology 57 left ventricular assist device 231
James F. George Michael J. Domanski and Mandeep R. Mehra
5 Implantable devices for 15 Mechanical circulatory support: Outpatient
cardiovascular monitoring 74 management 248
Max J. Liebo and W. H. Wilson Tang Mandeep R. Mehra and Michael J. Domanski
6 Endomyocardial biopsy in the 16 Cardiac transplantation: Overview 255
failing heart 92 Josef Stehlik MD, PhD and Joann Lindenfeld MD
Michael J. Domanski, Mark Halushka,
and Sean P. Pinney
17 Immunosuppression strategies 279
Jon A. Kobashigawa
7 Imaging in advanced heart failure 102
Mayank Kansal, Manish Bansal,
18 Rejection surveillance: Types and treatment 307

Jagat Narula, and Partho P. Sengupta Natasha Lipson Altman and Sean P. Pinney

8 Pharmacologic management of 19 Complications after cardiac transplantation 314

advanced heart failure 137 Howard J. Eisen

Akshay S. Desai and Marc A. Pfeffer 20 Right heart failure: Anatomy,
9 Arrhythmias in heart failure: The physiology, and pathobiology 329

atrioventricular node and above 153 Thomas G. Di Salvo and Simon Maltais
Steven Stevens, Kalyanam Shivkumar, 21 Right ventricular failure: Clinical
and Noel G. Boyle features and management 346
10 Ventricular arrhythmias in heart failure 165 Thomas G. Di Salvo and Simon Maltais
John D. Ferguson and John P. DiMarco
viii contents

22 Pulmonary arterial hypertension 385 24 Future directions in advanced heart failure 427
Myung H. Park Michael J. Domanski, Mark A. Pfeffer,
and Mandeep R. Mehra
23 End of life care in advanced heart failure 420
Jessi Khangura and Sarah J. Goodlin Index 433
 Contributors

Natasha Lipson Altman University of Colorado Hospital, Aurora, Jon A. Kobashigawa Cedars-Sinai Heart Institute, Los Angeles,
CO, USA CA, USA
Brett Atwater Duke University Medical Center, Durham, NC, Marzia Leacche Brigham and Women’s Hospital, Boston, MA,
USA USA
Manish Bansal Baptist Medical Center Jacksonville, Jacksonville, Max J. Liebo Stritch School of Medicine, Loyola University
Florida, USA Chicago, Maywood, IL, USA
Noel G. Boyle David Geffen School of Medicine at UCLA, Joann Lindenfeld Vanderbilt University, Nashville, TN, USA
Los Angeles, CA, USA Simon Maltais Vanderbilt University Medical Center, Nashville,
John G. Byrne Brigham and Women's Hospital, Boston, MA, USA TN, USA
Blase A. Carabello Mount Sinai Beth Israel, NY, USA Kenneth B. Margulies Perelman School of Medicine at the
James P. Daubert Duke University Medical Center, Durham, NC, University of Pennsylvania, Philadelphia, PA, USA
USA Mandeep R. Mehra Brigham and Women’s Hospital, Boston, MA,
Akshay S. Desai Brigham and Women’s Hospital, Boston, MA, USA
USA Jagat Narula Mount Sinai School of Medicine, New York
John P. DiMarco University of Virginia School of Medicine, Myung H. Park University of Maryland Medical Center,
Charlottesville, VA, USA Baltimore, MD, USA
Thomas G. Di Salvo Vanderbilt Heart and Vascular Institute, Ileana L. Piña Montefiore Einstein Center for Heart and Vascular
Nashville, TN, USA Care, NY, USA
Michael J. Domanski Icahn School of Medicine and Mount Sinai Marc A. Pfeffer Brigham and Women’s Hospital, Boston, MA,
School of Medicine, NY, USA and Peter Munk Cardiac Centre, USA
University of Toronto, Canada Sean P. Pinney Mount Sinai School of Medicine, NY, USA
Howard J. Eisen Drexel University College of Medicine, J. Eduardo Rame Perelman School of Medicine at the University
Philadelphia, PA, USA of Pennsylvania, Philadelphia, PA, USA
John D. Ferguson University of Virginia School of Medicine, Partho P. Sengupta Mount Sinai School of Medicine, NY, USA
Charlottesville, VA, USA
J. Julia Shin Montefiore Medical Center, NY, USA
James F. George University of Alabama at Birmingham,
Birmingham, AL, USA Kalyanam Shivkumar David Geffen School of Medicine at UCLA,
Los Angeles, CA, USA
Sarah J. Goodlin Oregon Health and Science University,
Portland, OR, USA Josef Stehlik University of Utah School of Medicine, Salt Lake
City, UT, USA
Mark Halushka The John Hopkins Hospital, Baltimore, MD, USA
Steven Stevens David Geffen School of Medicine at UCLA, Los
Kevin Jackson Duke University Medical Center, Durham, NC, Angeles, CA, USA
USA
Garrick C. Stewart Brigham and Women’s Hospital, Boston, MA,
Mayank Kansal University of Illinois at Chicago, Chicago, IL, USA
USA
W.H. Wilson Tang Clever Clinic Lerner Research Institute,
Jessi Khangura Oregon Health and Science University, Cleveland, OH, USA
Portland, OR, USA
 Abbreviations

ABIM American Board of Internal Medicine BR breathing reserve

AC adenylyl cyclase BTT bridge to transplant
AC arrhythmogenic cardiomyopathy BUN blood urea nitrogen
ACC American College of Cardiology CABG coronary artery bypass grafting
ACE angiotensin converting enzyme CAD coronary artery disease
ACEI angiotensin converting enzyme inhibitor CARE cholesterol and recurrent events
ACHD adult congenital heart disease CARP cardiac ankyrin repeat protein
ACLS adult cardiac life support CAV cardiac allograft vasculopathy
ACR acute cellular rejection cCTGA congenitally corrected transposition of the great
ACT activated clotting time arteries
ADCC antibody-dependent cellular cytotoxicity CDC complement-dependent cytotoxicity
ADHF acute decompensated heart failure CHD congenital heart disease
ADL activities of daily living CHF congestive heart failure
AF atrial fibrillation CI cardiac index
AHA American Heart Association CICR calcium-induced calcium release
AHG anti-human globulin CIED cardiovascular implantable electronic devices
AMPK AMP-sensitive kinase CK creatine kinase
AMR antibody-mediated rejection CMR cardiac magnetic resonance
ANS autonomic nervous system CMV cytomegalovirus
APC antigen presenting cells CNI calcineurin inhibitor
AR aortic regurgitation CO cardiac output
ARB angiotensin receptor blocker COPD chronic obstructive pulmonary disease
ARVC arrhythmogenic right ventricular cardiomyopathy CPAP continuous positive airway pressure
AS aortic stenosis CPET cardiopulmonary exercise testing
ASD atrial septal defect CREB CAMP response binding
ASE American Society of Echocardiography CRT cardiac resynchronization therapy
ASO arterial switch operation CS coronary sinus
AT atrial tachycardia CSA cyclosporine
ATG anti-thymocyte globulin CTD connective tissue disease
ATP anti-tachycardia pacing CTEPH chronic thromboembolic pulmonary hypertension
ATR atrial tachycardia remodeling CTL cytotoxic T lymphocyte
AUC area under the curve CTPH chronic thromboembolic pulmonary hypertension
AV atrioventricular CTRD cardiac transplant research database
AVA aortic valve area CVP central venous pressure
AVM arteriovenous malformations CXR chest radiograph
AVR aortic valve replacement DAMPS damage-associated molecular patterns
AZA azathioprine DAVID dual-chamber and vvi implantable defibrillator
BiVAD biventricular assist device DC dendritic cell
BiVP biventricular pacing DCD donation after circulatory death
BMI body mass index DENSE displacement encoding with stimulated echoes
BMV balloon mitral valvotomy DSA donor-specific antibodies
BNP brain natriuretic peptide DSE dobutamine stress-echocardiography
xii abbreviations

EBV Epstein–Barr virus IVUS intravascular ultrasound

ECG electrocardiography JNK jun N-terminal kinases
ECMO extracorporeal membrane oxygenation JVP jugular venous pressure
EDV end-diastolic volume KIR killer immunoglobulin-like receptors
EEPV end-ejection pressure/volume LA left atrium
EF ejection fraction LAD left anterior descending
EGFR epidermal growth factor receptor LAO left anterior oblique
ELISA enzyme-linked immunosorbent assay LAP left atrial pressure
EMB endomyocardial biopsy LAS lung allocation score
EPR external pressure reference LBBB left bundle branch block
ER endoplasmic reticulum LDH lactate dehydrogenase
ERA endothelial receptor antagonist LFT liver function test
ESC European Society of Cardiology LGE late gadolinium enhancement
ESV end-systolic volume LIMA left internal mammary artery
EVR everolimus LM lateral marginal
FAC fractional area change LV left ventricle
FC functional class LVAD left ventricular assist device
FDA food and drug administration LVEDP left ventricular end-diastolic pressure
FDG fluorodeoxyglucose LVEDV left ventricular end-diastolic volume
FFA free fatty acid LVEF left ventricular ejection fraction
FHF first heart field LVFP left ventricular filling pressure
FI fluid index LVH left ventricular hypertrophy
FSV forward stroke volume LVOT left ventricular outflow tract
FVC forced vital capacity LVP left ventricular pacing
GALT gut-associated lymphoid tissue MAC membrane attack complex
GCM giant cell myocarditis MAP mean arterial pressure
GEP gene expression profiling MAPK mitogen-activated protein kinase
GFR glomerular filtration rate MBL mannose-binding lectin
GI gastrointestinal MCS mechanical circulatory support
GLS global longitudinal strain MCV middle cardiac vein
GPCR G-protein-coupled receptors MHC major histocompatibility complex
H&E hematoxylin and eosin (strain) MI myocardial infarction
HBV hepatitis B virus MMF mycophenolate mofetil
HCV hepatitis C virus MPI myocardial performance index
HF heart failure MPT mitochondrial permeability transitions
HFpEF heart failure with preserved ejection fraction MR mitral regurgitation
HFrEF heart failure with reduced ejection fraction MRS magnetic resonance spectroscopy
HIT heparin-induced thrombocytopenia MS mitral stenosis
HLA human leukocyte antigen MSCT multislice CT
HMR heart-to-mediastinum ratio MUGA Multi Gated Acquisition Scan
HPV human papillomavirus MV minute ventilation
HRS Heart Rhythm Society MVR mitral valve repair/replacement
HRV heart rate variability MVV maximum voluntary ventilation
HTLV human T-lymphotropic virus NAION nonarteritic anterior ischemic optic neuropathy
IABP intra-aortic balloon pump NAT nucleic acid testing
ICD implantable cardioverter defibrillator NEM necrotizing eosinophilic myocarditis
ICU intensive care unit NFAT nuclear factor of activated transcription
IDC interdigitating dendritic cell NHLBI National Heart, Lung, and Blood Institute
IHM implantable hemodynamic monitors NHR nighttime heart rate
INR international normalized ratio NIH National Institutes of Health
INTERMACS Interagency Registry for Mechanically Assisted NODM new-onset diabetes mellitus
Circulatory Support NPV negative predictive value
IPAH idiopathic pulmonary arterial hypertension NSAID nonsteroidal anti-inflammatory drug
IR insulin resistance NYHA New York Heart Association
IRIS immediate risk stratification improves survival OPCAB off-pump coronary artery bypass
ISHLT International Society for Heart and Lung PA pulmonary artery
Transplantation PAC pulmonary artery catheter
ITAMS immune-receptor tyrosine based activation motifs PAD peripheral arterial disease
IVC inferior vena cava PAH pulmonary arterial hypertension
 abbreviations xiii

PAM patient advisory module RVSWI right ventricular stroke work index
PAP pulmonary artery pressure RVWS right ventricular wall stress
PAWP pulmonary arterial wedge pressure SAI systolic area index
PBMC peripheral blood mononuclear cell SCD sudden cardiac death
PCI percutaneous coronary intervention SDI systolic dyssynchrony index
PCR polymerase chain reaction SERCA sarcoplasmic reticulum calcium ATPase
PCWP pulmonary capillary wedge pressure SFI standard fluorescent intensity
PDA patent ductus arteriosus SHF second heart field; systolic heart failure
PDA posterior descending artery SM sensor module
PDGF platelet-derived growth factor SMVT sustained monomorphic ventricular tachycardia
PE pulmonary embolism SPECT single photcon emission CT
PEA peak endocardial acceleration SPI solid-phase immunoassays
PEEP positive end-expiratory pressure SR sarcoplasmic reticulum; sinus rhythm
PEP pre-ejection period SSRI selective serotonin reuptake inhibitor
PET positron emission tomography STAR speckle tracking and resynchronization
PFT pulmonary function test STE speckle tracking echocardiography
PH pulmonary hypertension STS Society of Thoracic Surgeons
PI pulmonic insufficiency SV stroke volume
PI pulsatility index SVC superior vena cava
PKA protein kinase A SVR systemic vascular resistance
PKC protein kinase C SVT supraventricular tachycardia
PMA phorbol myristate acetate SWI stroke work index
PND paroxysmal nocturnal dyspnea TAC transverse aortic constriction
PPH primary pulmonary hypertension TAH total artificial heart
PR pulmonary regurgitation TAP transporter associated with antigen processing
PRA panel reactive antibody TAPSE tricuspid annular plane systolic excursion
PRES posterior reversible encephalopathy syndrome TARP total atrial refractory period
PS pulmonic stenosis TAVR transcatheter aortic valve replacement
PTLD post-transplantation lymphoproliferative disorder TCE threshold-crossing event
PVC premature ventricular contraction TCR T cell receptor
PVI pulmonary vascular impedance TDI tissue Doppler imaging
PVOD pulmonary venous occlusive disease TEE transesophageal echocardiography
PVR pulmonary vascular resistance TNF tumor necrosis factor
QOL quality of life TOF tetralogy of Fallot
RA right atrium TOR target of rapamycin
RAAS renin–angiotensin–aldosterone system TP tachycardia pacing
RAP right atrial pressure TPG transpulmonary gradient
RAVI right atrial volume index TPR total pulmonary resistance
RBBB right bundle branch block TR tricuspid regurgitation
RBC red blood cells TRP transient receptor potential
RCA right coronary artery TTE transthoracic echocardiography
RCT randomized controlled trial TV tricuspid valve
RER respiratory exchange ratio TVM tissue velocity mapping
RHC right heart catheterization UNOS United Network for Organ Sharing
RIMA right internal mammary artery VA ventricular arrhythmias
RIP receptor-interacting protein VAD ventricular assist device
RLC regulatory light chain VCF velocity of circumferential fiber
ROC receiver operating characteristic VEGF vascular endothelial growth factor
RV right ventricle VER ventricular evoked response
RVA right ventricular apex VF ventricular fibrillation
RVAD right ventricular assist device VIP vasoactive intestinal peptide
RVDP right ventricular diastolic pressure VS ventricular sensing
RVEF right ventricular ejection fraction VSD ventricular septal defect
RVFW right ventricular free wall VT ventricular tachycardia
RVMI right ventricular myocardial infarction WHO World Health Organization
RVOT right ventricular outflow tract WMA wall motion abnormality
RVSP right ventricular systolic pressure
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