The Heart in Rheumatic, Autoimmune and Inflammatory

Diseases Pathophysiology, Clinical Aspects and Therapeutic

Approaches

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 LIST OF CONTRIBUTORS xiii
Massimo Imazio, MD, FESC Matthew J. Koster, MD
Professor of Physiology Instructor of Medicine
University Cardiology Department of Internal Medicine
Azienda Ospedaliero-Universitaria “Città della Salute Division of Rheumatology
e della Scienza” Mayo Clinic
Torino, Italy Rochester, MN, United States [367]
Department of Public Health and Pediatrics Robert Landewé, MD, PhD
University of Torino Professor of Rheumatology
Torino, Italy [617] Department of Clinical Immunology and
Xiongjing Jiang, MD, PhD Rheumatology Academic Clinical Centre/University of
Professor of Medicine, Division of Hypertension Amsterdam
State Key Laboratory of Cardiovascular Disease Amsterdam, The Netherlands
Fuwai Hospital National Center for Cardiovascular Rheumatologist Department of
Diseases Rheumatology
Peking Union Medical College Atrium Medical Centre
Chines Academy of Medical Sciences Heerlen, The Netherlands [349]
Beijing, People’s Republic of China [389] Avi Livneh, MD
Jorge Kalil, MD, PhD Professor of Medicine
Full Professor of Medicine Medicine F and Heller Institute of Medical
Department of Allergy and Clinical Research
Immunology Sheba Medical Center
Director of Laboratory of Immunology Tel Hashomer, Israel
Heart Institute (InCor) Sackler Faculty of Medicine
School of Medicine of University of São Paulo Tel Aviv University
São Paulo, Brazil [529] Tel Aviv-Yafo, Israel [577]
George D. Kitas, MD, PhD, FRCP Ingrid E. Lundberg, MD, PhD
Professor of Clinical Rheumatology Professor of Rheumatology, Rheumatology Unit
Arthritis Research UK Centre for Epidemiology Department of Medicine, Solna
Centre for Musculoskeletal Research Karolinska Institutet, Rheumatology clinic
University of Manchester Karolinska University Hospital
Manchester Academic Health Science Centre Stockholm, Sweden [327]
Manchester, United Kingdom Silvia Maestroni, MD
NIHR Manchester Musculoskeletal Biomedical Research Department of Internal Medicine
Unit Papa Giovanni XXIII Hospital
University of Manchester Bergamo, Italy [617]
Manchester, United Kingdom
Head of Research and Development – Academic Marek Malik, PhD, MD, DSc, DSc (Med), FACC,
Affairs FESC, FHRS
Dudley Group NHS Foundation Trust Professor of Cardiac Electrophysiology
(teaching) Senior Research Investigator
Russells Hall Hospital National Heart & Lung Institute
Dudley, West Midlands, United Kingdom [129] Imperial College of Science, Technology and Medicine
London, United Kingdom [91]
Karen Francine Köhler, BsC, PhD
Laboratory of Immunology Giacomo Malipiero, MD
Heart Institute (InCor) Allergology and Clinical Immunology
School of Medicine of University of São Paulo Department of Medicine
São Paulo, Brazil [529] Haematology and Clinical Immunology
Unit
Stephanie Könemann, MD
Policlinico Universitario – Azienda Ospedaliera
Department of Internal Medicine B
di Padova
University Medicine Greifswald
University of Padova Medical School
Greifswald, Germany [681]
Padova, Italy [25]
xiv LIST OF CONTRIBUTORS

Renzo Marcolongo, MD Johannes Müller, MD

Haematology and Clinical Immunology Unit Chief Executive Officer
Department of Medicine Berlin Cures GmbH
Policlinico Universitario – Azienda Ospedaliera Berlin, Germany [659]
di Padova Michael T. Nurmohamed, MD, PhD
University of Padova Medical School Professor of Rheumatology
Padova, Italy [25] Department of Rheumatology
Alberto Martini, MD Amsterdam Rheumatology Immunology
Professor of Pediatrics Center
University of Genoa Reade & VUmc
Genoa, Italy Amsterdam, The Netherlands [189]
Istituto Giannina Gaslini U. Nussinovitch, MD, PhD
Genoa, Italy [167] Department of Internal Medicine A
Eric L. Matteson, MD, MPH Rambam Health Care Campus affiliated with the
Professor of Medicine Technion Institute of Technology
Department of Internal Medicine Haifa, Israel [3,91,577]
Division of Rheumatology Miriam O’Sullivan, MB, MMedSc, PhD
Department of Health Sciences Research Consultant Rheumatologist
Division of Epidemiology Department of Rheumatology
Mayo Clinic Sligo University Hospital
Rochester, MN, United States [367] Sligo, Ireland [129]
Clio P. Mavragani, MD, DIC, PhD, FACR Colin K.L. Phoon, MPhil, MD, FAHA, FASE
Assistant Professor of Physiology and Experimental Associate Professor of Pediatrics
Physiology Division of Pediatric Cardiology
Department of Physiology, Faculty of Medicine Department of Pediatrics
National and Kapodistrian University of Athens New York University School of Medicine
Athens, Greece [281] New York, NY, United States
George S. Metsios, PhD Hassenfeld Children’s Hospital of New York
Professor in Clinical Exercise Physiology NYU Langone, New York, NY, United States [269]
School of Sport Nicolò Pipitone, MD, PhD
Performing Arts & Leisure Consultant Rheumatologist
Wolverhampton University Division of Rheumatology
Walsall, West Midlands, United Kingdom [129] Department of Internal Medicine
Christa Miliaresis, MD Arcispedale Santa Maria Nuova – IRCCS
Assistant Professor of Pediatrics Reggio Emilia, Italy [505]
Division of Pediatric Cardiology Mario Plebani, MD
New York Medical College Professor of Clinical Chemistry and Clinical
Valhalla, NY, United States [269] Molecular Biology
Leena B. Mithal, MD, MSCI University of Padova Medical School
Instructor of Pediatrics Padova, Italy
Division of Infectious Diseases Head of the Department of Laboratory
Northwestern University Feinberg School of Medicine Medicine
Chicago, IL, United States University-Hospital of Padova
Ann & Robert H. Lurie Children’s Hospital of Chicago Padova, Italy [25]
Chicago, IL, United States [429] Giacomo Pucci, MD
Haralampos M. Moutsopoulos, MD, FACP, FRCP(hc), Assistant Lecturer of Internal Medicine
Master ACR Unit of Internal Medicine
Professor Emeritus Department of Medicine
Department of Pathophysiology University of Perugia
Faculty of Medicine Perugia, Italy
National University of Athens Terni Hospital
Goudi, Athens, Greece [281] Terni, Italy [213]
 LIST OF CONTRIBUTORS xv
Veronique Ramoni, MD Roney Orismar Sampaio, MD, PhD
Department of Internal Medicine Division of Cardiology and Valvular Heart Disease
Papa Giovanni XXIII Hospital Department
Bergamo, Italy [617] Heart Institute (InCor)
Angelo Ravelli, MD School of Medicine of University of São Paulo
Professor of Pediatrics São Paulo, Brazil [529]
University of Genoa Aamer Sandoo, PhD
Genoa, Italy Lecturer in Cardiovascular Physiology School of Sport
Istituto Giannina Gaslini Health and Exercise Sciences
Genoa, Italy [167] Bangor University
Caroline Reuter, MD Bangor, Gwynedd, Wales, United Kingdom [91, 129]
Fellow, Pediatric Infectious Diseases Helga Sanner, MD, PhD
Northwestern University Feinberg School of Senior consultant, Section of Rheumatology
Medicine Unit of Paediatric Rheumatology, and Advisory Doctor
Chicago, IL, United States Norwegian National Advisory Unit on Rheumatic
Ann & Robert H. Lurie Children’s Hospital of Diseases in Children and Adolescents
Chicago Oslo University Hospital – Rikshospitalet
Chicago, IL, United States [429] Oslo, Norway [327]
Dirk Roggenbuck, MD Benedetta Schiappapietra, MD
Professor of Biotechnology PhD Candidate, University of Genoa
Brandenburg University of Technology Genoa, Italy
Cottbus-Senftenberg Istituto Giannina Gaslini
CSO, Medipan GmbH Genoa, Italy [167]
Dahlewitz, Germany [49] Giuseppe Schillaci, MD
Noel R. Rose, MD, PhD Associate Professor of Internal Medicine
Professor Emeritus, Johns Hopkins Unit of Internal Medicine
University Department of Medicine
Baltimore, MD, United States University of Perugia
Brigham and Women’s Hospital Perugia, Italy
Harvard Medical School Terni Hospital, Terni, Italy [213]
Boston, MA, United States [3] Ingolf Schimke, PhD
Stuart D. Russell, MD Professor of Clinical Chemistry and Senior Scientist
Associate Professor of Medicine Berlin Cures GmbH
Chief, Heart Failure and Transplantation Berlin, Germany [49, 659]
Johns Hopkins School of Medicine Mara Seguso, MSc
Baltimore, MD, United States [645] Clinical Pathologist
Ester Cerdeira Sabino, MD, PhD Department of Laboratory Medicine
Associate Professor of Medicine Autoimmunity Unit
Division of Infectious Diseases University-Hospital of Padova
University of São Paulo Medical School Padova, Italy [25]
São Paulo, São Paulo, Brazil Oded Shamriz, MD
Institute of Tropical Medicine of the University of São Pediatric Division, Hadassah-Hebrew University
Paulo Medical Center
São Paulo, Brazil [553] Ein Kerem, Jerusalem, Israel [3]
Carlo Salvarani, MD Stanford T. Shulman, MD
Professor of Rheumatology Virginia H. Rogers Professor of Pediatric Infectious
Head, Division of Rheumatology Diseases
Department of Internal Medicine Northwestern University Feinberg School of Medicine
Arcispedale Santa Maria Nuova – IRCCS Chicago, IL, United States
Reggio Emilia, Italy Ann & Robert H. Lurie Children’s Hospital of Chicago
Modena and Reggio Emilia University Chicago, IL, United States [429]
Modena, Italy [505]
xvi LIST OF CONTRIBUTORS

Ivar Sjaastad, MD, PhD Department of Laboratory Medicine

Senior Consultant, Institute for Experimental Medical Medical University of Vienna
Research Vienna, Austria [65]
Oslo University Hospital – Ullevål Murray B. Urowitz, MD, FRCP(C)
Oslo, Norway Director, Centre for Prognosis Studies in the Rheumatic
Professor, Institute for Clinical Medicine, Medical Diseases
Faculty Professor Medicine
University of Oslo University of Toronto
Oslo, Norway [327] Toronto Western Hospital
Sarah Skeoch, MBChB (Hons), BSc, MSc, PhD, Toronto, ON, Canada [235]
MRCP Alessandra Vacca, MD
Clinical Lecturer in Rheumatology Consultant Rheumatologist
Arthritis Research UK Centre for Epidemiology Rheumatology Unit
Centre for Musculoskeletal Research University Hospital of Cagliari
University of Manchester Monserrato, Italy [301]
Manchester Academic Health Science Centre
Carlos Henrique Valente Moreira, MD
Manchester, United Kingdom
Attending Physician, Inpatient Unit
NIHR Manchester Musculoskeletal Biomedical
Institute of Infectology Emilio Ribas
Research Unit
São Paulo, Brazil
University of Manchester
Institute of Tropical Medicine of the University of São
Manchester, United Kingdom [129]
Paulo
Alessandra Soriano, MD São Paulo, Brazil [553]
Rheumatology Fellow, Division of Rheumatology
Anna Valenti, MD
Department of Internal Medicine
Department of Internal Medicine
Arcispedale Santa Maria Nuova – IRCCS
Papa Giovanni XXIII Hospital
Reggio Emilia, Italy [505]
Bergamo, Italy [617]
Sobreira Spina Guilherme, MD, PhD
Caroline van Durme, MD
Division of Cardiology and Valvular Heart Disease
Rheumatologist, Department of Internal Medicine
Department
Division of Rheumatology
Heart Institute (InCor)
Maastricht University Medical Centre+
School of Medicine of University of São Paulo
Maastricht, The Netherlands
São Paulo, Brazil [529]
Rheumatologist, Department of Physical Medicine
Flavio Tarasoutchi, MD, PhD Centre Hospitalier Chrétien
Associated Professor of Medicine Liège, Belgium [349]
Director of Division of Cardiology and Valvular Heart
Pieter van Paassen, MD, PhD
Disease Department
Department of Nephrology and Clinical Immunology
Heart Institute (InCor)
Internal Medicine, Maastricht University Medical
School of Medicine of University of São Paulo
Centre
São Paulo, Brazil [529]
Maastricht, The Netherlands [459]
Hans-Joachim Trappe, MD
Sara Verazza, MD
Professor of Medicine
PhD Candidate, University of Genoa
Medical Institute II - Cardiology and Angiology
Genoa, Italy
Marien-Hospital Herne – University Hospital of the
Istituto Giannina Gaslini
Ruhr-University Bochum
Genoa, Italy [167]
Herne, Germany [189]
Gerd Wallukat, PhD
Konstantinos Tselios, MD, PhD
Senior Scientist, Berlin Cures GmbH
Clinical Research Fellow
Berlin, Germany [49, 659]
Toronto Lupus Clinic, University Health Network
Toronto, ON, Canada [235] Kenneth J. Warrington, MD
Associate Professor of Medicine
Dimitrios Tsiantoulas, PhD
Department of Internal Medicine
CeMM Research Center for Molecular Medicine of the
Division of Rheumatology, Mayo Clinic
Austrian Academy of Sciences
Rochester, MN, United States [367]
Vienna, Austria
 LIST OF CONTRIBUTORS xvii
Lirui Yang, MD Huimin Zhang, MD
PhD candidate in Cardiology Professor of Medicine, Division of Hypertension
Division of Hypertension, State Key Laboratory State Key Laboratory of Cardiovascular Disease
of Cardiovascular Disease Fuwai Hospital
Fuwai Hospital, National Center for Cardiovascular National Center for Cardiovascular Diseases
Diseases Chines Academy of Medical Sciences and Peking
Chines Academy of Medical Sciences and Peking Union Medical College
Union Medical College Beijing, People’s Republic of China [389]
Beijing, People’s Republic of China [389]
Marlen Yessirkepov, PhD
Associate Professor, Head of Department of
Biochemistry
Biology and Microbiology
South Kazakhstan State Pharmaceutical Academy
Shymkent, Kazakhstan [129]
 About the Editor

Udi Nussinovitch, MD, PhD graduated from the chapters in scientific textbooks, mostly dealing with
Sackler Faculty of Medicine, Tel Aviv University, train- cardiac autoimmunity.
ing at the Sheba Medical Center, the Rambam Healthcare Dr. Nussinovitch has been the recipient of several
Center, and the Israeli Naval Medical Institute (INMI), awards for his research including the J. Kellerman
while concurrently graduating with a PhD in cardiac Award, the Noyfeld Award, the Lt. Grandir Award, and
electrophysiology from the Technion Institute of Tech- the Britain–Israel Research and Academic Exchange
nology, Israel. Partnership (BIRAX) Annual Award. He serves as a
Dr. Nussinovitch has mainly dedicated his research reviewer for leading rheumatologic and cardiac journals.
to cardiac autoimmunity and autoinflammation, car- Dr. Nussinovitch carries out his clinical work at the
diac manifestations of systemic diseases, cell- and Rambam Health Care Campus, a tertiary medical facility
gene-based cardiac therapies, and the modulation of and leading referral center in northern Israel, academi-
the cardiac electrophysiologic substrate for therapeutic cally affiliated with the Technion Institute of Technol-
purposes. He has published articles in leading rheu- ogy, Israel. Some of his clinical research was conducted
matologic journals and has authored papers dealing in collaboration with the Zabludowicz Center for Auto-
with the cardiovascular system, including publications immune Diseases and the Heller Institute of Medical
in Nature magazines. He has also published several Research, at the Sheba Medical Center, Israel.

xix
 Preface

The prevalence of autoimmune diseases and rheu- substantially contribute to cardiovascular risk factors, as
matic conditions is constantly increasing. Autoimmune well as harbor direct cardiac influences. Interestingly, there
diseases affect approximately 7–10% of the population are several autoantigents shared by the joints and the heart
of the United States, while more than 50,000,000 Ameri- tissue, which may give rise to the involvement of both
can adults suffer from some type of arthritis. Many of these organs. In addition, although infrequent, direct tissue
these clinical conditions are characterized by multiorgan deposits of amyloid or crystals may ultimately manifest as
involvement and systemic inflammation. Cardiac com- cardiac disease in some chronic medical conditions.
plications in rheumatic, autoimmune, or inflammatory In recent years, extensive medical research has
conditions are major influences on the clinical outcome, expanded our understanding of the pathophysiological
quality of life, and overall prognosis of these common dis- mechanisms that mediate cardiac illnesses in systemic
eases, resulting in morbidity, recurrent hospitalizations, and autoimmune diseases. Although a broad review in
decreased quality of life, and early death. Actually, in a medical textbook is needed, more than a decade has
many systemic and inflammatory illnesses (rheumatoid passed since this topic was systemically addressed in
arthritis and others), cardiac disease has become the most a scientific manuscript. The authors herein endeavored
common cause of death. Also, in other cases, unique car- to fill this gap and provide a complete overview of the
diac manifestations may go undetected, mainly due to the current knowledge relating to the role of the immune
lack of medical awareness, high index of suspicion, and processes and inflammation in the pathogenesis of heart
occasionally the need for advanced diagnostic modalities. involvement in rheumatic, systemic autoimmune, and
Researchers have observed that autoimmune and inflammatory diseases. It is hoped that this extensive
inflammatory mechanisms play a pivotal role in athero- collection of data will simplify the comprehension of
sclerosis and ischemic cardiomyopathy. This interplay these complex, yet clinically significant mechanisms.
between immune mechanisms, inflammation, and car- The book is subdivided into three major sections.
diac diseases emerges as a distinct medical field affecting The first section focuses on molecular pathways, auto-
all age groups, genders, and populations. These mecha- immune mechanisms, and the pathogenesis of organ-
nisms are of particular clinical importance in systemic specific, autoimmune-mediated, myocardial injury. A
rheumatic and autoimmune disease. chapter will be devoted to atherosclerosis, within the
Other than a systemic proinflammatory state that context of systemic inflammation. Another chapter will
advances the process of atherosclerosis, there are several describe the battery of cardiac tests that can be employed
main pathways in which cardiac injury may occur. Vascular to identify the risks for an adverse cardiac outcome in
inflammation may involve the coronary vascular tree, thus patients with systemic diseases. This specific chapter will
resulting in many life-threatening medical complications aim at furthering the understanding of the experimental
and distorted coronary anatomy. A directed antiheart auto- results reviewed in the second section of the book (focus-
immune response may aggravate any nonspecific cardiac ing on the specific diseases and medical entities). In addi-
insult. Nonischaemic cardiomyopathy, microvascular dys- tion, this chapter can be used as a guide for conducting
function, valvular damage, and cardiac dysrhythmias may a comprehensive cardiac study in patients with systemic
also appear. Connective tissue disease and systemic vascu- diseases and suspected myocardial involvement.
litis may affect all aspects of cardiac performance including In the second part of the book, various rheumatic,
cardiac perfusion, the contractile function, impulse prop- inflammatory, and autoimmune diseases will be included
agation, induction of arrhythmias, inflammation of the and reviewed in a systemic manner. Chapters are devoted
pericardium, or involvement of the heart valves. A hyper- to inflammatory arthritis (rheumatoid arthritis and juve-
coagulability state may also result from systemic inflam- nile idiopathic arthritis, spondyloarthritides, and poly-
mation and specific immune responses, and consequently myalgia rheumatica), autoimmune and connective tissue
may facilitate ischemic cardiac injury and the development diseases (systemic lupus erythematosus, neonatal lupus,
of nonbacterial thrombotic endocarditis. Therapies used in Sjögren’s syndrome, systemic sclerosis, dermatomyositis,
the treatment of systemic autoimmune conditions may also and polymyositis), and crystal-induced arthritis (gout).

xxi
xxii PREFACE

Vasculitides will also be extensively discussed, including The third section of the book focuses solely on thera-
vasculitis affecting large arteries (giant-cell arteritis and peutics by systemically describing the adverse and
Takayasu’s arteritis), medium-size vessels (polyarteri- desirable cardiovascular effects of different therapeutic
tis nodosa and Kawasaki disease), and small-size vessels approaches used in the aforementioned indications and
(microscopic polyangiitis and Churg-Strauss syndrome, the novel emerging means of treatment and prevention
Wegener’s granulomatosis). Other chapters will focus on of immune-mediated cardiac diseases and atherosclero-
postinfectious autoimmune cardiac diseases (rheumatic sis. Specifically, anti-inflammatory agents, immunosup-
fever and Chagas heart disease) and cardiac manifestations pressive drugs, cardiac immunomodulation approaches,
of systemic autoinflammation found in familial Mediterra- and autoantibody-targeted therapies are described.
nean fever. Importantly, some exciting and recently emerged
In each chapter, the state-of the art knowledge of car- immuno-targeted therapies hold great promise and may
diac manifestations, pathogenesis, and therapeutic aspects revolutionize patient care.
is extensively reviewed and systemically discussed. The It should be noted that autonomic nervous system
aforementioned include clinical topics, present epidemio- abnormalities that may indicate, mediate, or facilitate to
logical data, genetic basis, and diagnostic criteria. The main some extent the progression of cardiac diseases and the
focus of the chapters is the pathophysiology of cardiac development of cardiac arrhythmias is beyond the scope
involvement, different clinical aspects, and the manifesta- of the current manuscript.
tions of cardiac diseases. The covered clinical topics will A comprehensive index was added that will aid in
include endothelial dysfunction and detection of subclinical finding material of theoretical and practical importance
atherosclerosis, ischemic cardiac disease, coronary vasculi- within the book.
tis, pericardial, myocardial and endocardial involvement, Insightful readers are encouraged to contact the
prevalence and markers of ventricular and supraventricu- editor with any suggestions or remarks as to the con-
lar arrhythmias, cardiac amyloidosis, and the overall occur- tent of the book, via email, at:
rence of cardiac-related adverse events and prognosis. Each [email protected].
chapter concludes with a discussion on disease-specific It is my sincere hope that this book will be a valu-
and cardiac-specific therapeutic options. The therapeutic able reference for rheumatologists, cardiologists,
approach for each clinical entity is presented with the level immunologists, and medical practitioners in the con-
of evidence and strength of recommendation according to tinuous pursuit of improving patient care and medical
the following commonly accepted scale: research.

Level of Evidence Strength of Recommendation

A More than one randomized controlled trial Class I Conditions for which there is evidence
(RCT)/meta-analysis and/or general agreement that a given
procedure/therapy is useful and effective
B A single RCT or well-designed nonrandomized Class II Conditions for which there is conflicting
trial, i.e., prospective observational registries evidence and/or divergence of opinion
(case controls, cohorts). regarding the usefulness/efficacy of
­performing the procedure/therapy
C Expert consensus: Includes case reports and Class IIa Weight of evidence/opinion is in favor of
retrospective series; the expert decides based usefulness/efficacy
on his or her experience
Class IIb Usefulness/efficacy is less well established
by evidence/opinion
Class III Conditions for which there is evidence and/
or general agreement that a procedure/
therapy is not useful/effective and in some
cases may be harmful
 Acknowledgments

I wish to thank the distinguished researchers and and Nutrition, Robert H. Smith Faculty of Agriculture,
physicians who graciously accepted the invitation to Food and Environment, The Hebrew University of
contribute their medical knowledge by writing exten- Jerusalem), who has served as my unofficial personal
sive review chapters and sharing their unique perspec- mentor and my role model throughout the years. He has
tives, experiences, and expertise with the readers. always been available for me with practical and smart
I also wish to thank the unbiased experts who advice, insightful opinions, encouraging suggestions
reviewed the scientific content of this book and provided and a witty joke.
beneficial and valuable advice to the authors throughout The following distinguished researchers merit my
the revision process (the list of contributory reviewers is complete gratitude for their contribution to this book by
given below). reviewing and advising on its contents and providing
Special thanks to Shannon M. Stanton, Samuel Young, many valuable suggestions (in alphabetical order):
Julia Haynes and Greg Harris from Elsevier Publishing,
who served as my right-hand people and assisted me
greatly in making this book a reality. Julian L. Ambrus Jr., MD
I also wish to thank Elsevier Publishing who entrusted Professor of Medicine
me with this ambitious project and provided me with all Division of Allergy, Immunology and Rheumatology
the necessary resources for its completion. SUNY at Buffalo School of Medicine
I wish to thank Phyllis Curchack Kornspan for her Buffalo, New York, United States
editorial assistance throughout the years and for her help Paolo Amerio, MD, PhD
during the early editorial stages, and thanks to Hedva Professor of Dermatology and Venereology
Razieli (from the Alfred Goldschmidt Medical Sciences Dermatology Clinic
Library, Technion Institute of Technology, Israel) for her Department of Medicine and Science of Aging
help in locating some of the references incorporated University G. d’Annunzio
within the book. Chieti, Italy
I wish to thank the distinguished professors who
taught me throughout the years, including Prof. Yehuda Elena Bartoloni, MD
Shoenfeld, MD (Director of the Zabludowicz Center for Rheumatology Unit
Autoimmune Diseases, Sheba Medical Center, affiliated Department of Medicine
to Tel Aviv University, Israel), a pioneer and a leader in the University of Perugia
field of autoimmunity, who guided and encouraged me Perugia, Italy
to pursue my cardiac-autoimmunity interest; Prof. Avi Kevin M. Bonney, PhD
Livneh, MD (head of Internal Medicine Department F, Faculty of Arts and Sciences
Sheba Medical Center, the Heller Institute of Medical New York University
Research, affiliated to Tel Aviv University, Israel), an New York, New York, United States
extremely kind and modest person, one of the founding
Wei-Chiao Chang, D. Phil (Oxon)
fathers of FMF research and an exceptional clinician, who
Director, Master Program for Clinical Pharmacogenomics
taught me the principles of clinical research and its trans-
and Pharmacoproteomics
formation into patient care; and Prof. Lior Gepstein, MD,
Taipei Medical University
PhD, a world-leading cardiac researcher, who taught me
Taipei, Taiwan
how to perform high-end basic and translational scientific
research, vastly expanded my perspective of cardiac Arrigo F.G. Cicero, MD, PhD
electrophysiology, and always encouraged me to “focus Atherosclerosis and Metabolic disease Research Unit
on the big questions”. President of the Italian Nutraceutical Society (SINut)
Finally, I wished to thank Prof. Amos Nussinovitch, Medicine and Surgery Sciences Department
PhD (from the Institute of Biochemistry, Food Science Bologna, Italy

xxiii
xxiv ACKNOWLEDGMENTS

Antoinette Cilliers, MD Haner Direskeneli, MD

Professor of Pediatric Cardiology Professor of Rheumatology
Chris Hani Baragwanath Academic Hospital Chief, Division of Rheumatology
University of the Witwatersrand Department of Internal Medicine
Johannesburg, South Africa Marmara University School of Medicine
Kaynarca, Pendik, Istanbul, Turkey
Coziana Ciurtin, MSc, PhD
Consultant Rheumatologist James V. Dunne, MB BCh, FRCPC
Principal Research Investigator—Clinical Trials in Clinical Assistant Professor of Medicine
Rheumatology Dept of Medicine, University of British Columbia
Department of Rheumatology St. Paul’s Hospital
University College London Vancouver BC, Canada
London, United Kingdom
Despina Eleftheriou, MBBS, MRCPCH, PhD
Madeleine W. Cunningham, PhD Senior Lecturer in Pediatric Vasculitis
George Lynn Cross Research Professor UCL Institute of Child Health
Presbyterian Health Foundation Presidential Professor London, United Kingdom
Microbiology and Immunology
Frank Flachskampf, MD, PhD
Director, Immunology Training Program
Professor of Cardiology
University of Oklahoma Health Sciences Center
Department of Medical Sciences
Oklahoma City, Oklahoma, United States
Uppsala University
Michael Czihal, MD Uppsala, Sweden
Senior Angiologist
Annarosa Floreani, MD
Vascular Center
Associate Professor of Gastroenterology
Medical Clinic and Policlinic IV
Department of Surgery, Oncology and Gastroenterology
University Hospital
University of Padova
Munich, Germany
Padova, Italy
Maria Giovanna Danieli, MD, PhD
Adam Hancock, MBChB, MPhil
Associate Professor of Applied Technical Medical
Researcher at the Arthritis Research UK Primary Care
Sciences
Sciences Center
Clinical and Molecular Sciences Department
Keele University
Polytechnic University of Marche
Staffordshire, United Kingdom
Marche, Italy
Andrés F. Henao-Martínez, MD
Katalin Dankó, MD, PhD, DSc
Instructor, Attending Physician
Professor of Medicine; Specialist of Internal
Infectious Diseases Division
Medicine Clinical Immunology, and Rheumatology
University of Colorado School of Medicine,
University of Debrecen
Aurora, Colorado, United States
Medical and Health Science Center
Third Dept. of Internal Medicine Johan Hoebeke, PhD
Division of Immunology CNRS Research Director (retired) in the Department
Debrecen, Hungary of Immunological and Chemical Therapeutics at
the Institute of Molecular and Cell Biology at the
Michel de Bandt, MD, PhD
University of Strasbourg, France
Head of Unit
Rheumatology and Internal Medicine Lisa K. Hornberger, MD
P Z Quitman, University Hospital Professor of Pediatrics
French West Indies Adjunct Professor of Obstetrics & Gynecology
Director, Fetal & Neonatal Cardiology
Antonio Carlos Campos de Carvalho, MD, PhD, FAHA
Section Head, Pediatric Echocardiography
Professor of Physiology and Biophysics
Division of Cardiology, Department of Pediatrics
Biophysics Institute Carlos Chagas FIlho
University of Alberta
Federal University of Rio de Janeiro
Alberta, Canada
Rio de Janeiro, Brazil
Shaye Kivity, MD
Alexandre Wagner Silva de Souza, MD, PhD
Deputy Head Internal Medicine Department A
Rheumatology Division Department of Internal Medicine
Zabludovitz Center of Autoimmune Diseases
Universidade Federal de São Paulo Brazil
Sheba Medical Center, Tel Hashomer
São Paulo-SP, Brazil
Ramat Gan, Israel
 ACKNOWLEDGMENTS xxv

Alessandro Cavalcanti Lianza, MD, PhD Nancy Olsen, MD

Pediatric and Fetal Echocardiographer Professor of Medicine
Division of Radiology, Instituto da Criança HC-FMUSP Division of Rheumatology
São Paulo-Brazil Penn State MS Hershey Medical Center
Division of Echocardiography of Hospital Israelita Albert Hershey, Pennsylvania, United States
Einstein
Dr. John Pauling, BMed Sci BMBS MRCP
São Paulo, Brazil
(Rheumatology), PhD
M.Yassine Mallem, DVM, PhD Consultant Rheumatologist
Associate Professor of Pharmacology Royal National Hospital for Rheumatic Diseases
Nantes-Atlantic National College of Veterinary Medicine Upper Borough Walls
Food Science, and Engineering, Oniris—La Chantrerie Bath, United Kingdom
Nantes, France
Roberto Coury Pedrosa, MD, PhD
William John Martin, PhD Professor of the Heart Institute Edson Saad from Federal
Inflammation Division, Walter & Eliza Hall Institute of University of Rio de Janeiro
Medical Research, Parkville, Australia University Hospital Clementino Fraga Filho
Department of Medical Biology, University of Melbourne Rio de Janeiro, Brazil
Parkville, Australia
Tânia Pereira, PhD
Jaime Mas-Oliva, MD, PhD Biomedical Engineering Researcher
Professor of Biochemistry Electronics and Instrumentation Group Instrumentation
Institute of Cellular Physiology Center
National Autonomus University of Mexico Physics Department, University of Coimbra
Mexico Coimbra, Portugal
Adolfo Gabriele Mauro, MS Andrea Péter, MD
Research Fellow Cardiologist at the Institute of Cardiology
Department of Internal Medicine, Division of Cardiology University of Debrecen, Hungary
Virginia Commonwealth University
Sergei N. Pokrovsky, PhD
Richmond, Virginia, United States
Professor of Biochemistry, Department of Atherosclerosis
Sophie I. Mavrogeni, MD, FESC Institute Experimental Cardiology
Consultant Cardiologist Cardiology Research Center
Onassis Cardiac Surgery Center, Athens, Greece Moscow, Russia
Scientific Collaborator of A Pediatric Clinic
Jonathan L. Respress, PhD
University of Athens
Assistant Principal Investigator Chagas Cardiomyopathy
Athens, Greece
Program
Juan Diego Maya, MD, PhD, MSc Southwest Electronic Energy Medical Research Institute
Associate Professor Research Associate Section of Pediatric Tropical Medicine
Molecular and Clinical Pharmacology Program Biomedical Department of Pediatrics—Tropical Medicine
Sciencies Institute Baylor College of Medicine
Faculty of Medicine, University of Chile, Santiago, Chile Center for Vaccine Development
Texas Children’s Hospital
Sofia Gabriela Azevedo Morais, MD
Houston, Texas, United States
Bissaya Barreto Maternity, Neonatology, Coimbra, Portugal
Joan L. Robinson, MD, FRCPC
Daiji Nagayama, MD, PhD
Professor of Pediatrics
Director, Center of Endocrinology and Metabolism,
Division of Infectious Diseases
Shin-Oyama City Hospital
University of Alberta
Oyama-City, Tochigi, Japan
Edmonton, Alberta, Canada
Stefan Mark Nidorf, MD, MBBS, FRACP, FACC
Gloria Salazar, MD
Heart Care Western Australia
Assistant Professor
Perth, Western Australia
Division of Rheumatology
Giuseppe Danilo Norata, PhD University of Texas Medical School
Associate Professor of Pharmacology Houston, Texas, United States
Department of Pharmacological and Biomolecular Sciences
Ignacio M. Seropian, MD
University of Milan, Italy;
Interventional Cardiology Department
SISA Center for the Study of Atherosclerosis, Bassini
Hospital Italiano de Buenos Aires
Hospital
Buenos Aires, Argentina
Cinisello B, Italy
xxvi ACKNOWLEDGMENTS

Milena Botelho Pereira Soares, BSc, PhD Miguel Hernán Vicco, MRes, MD, PhD
Senior Researcher Clinical Assistant Professor
Gonçalo Moniz Research Center Department of Internal Medicine
Oswaldo Cruz Foundation Faculty of Medical Sciences, National University of the
Salvador, Bahia, Brazil Littoral
Santa Fe, Argentina
Lee Stoner, PhD, MA, BSc (Hons), FRSPH, SFHEA
Senior Lecturer Antje Voigt, MD, PhD
College of Health, Massey University Associate Professor of Molecular Medicine
Wellington, New Zealand Institute for Biochemistry at the Charité Center for Basic
Sciences
Andre Talvani, BSc, MSc, PhD
Charité—Universitätsmedizin
Associate Professor in Immunology & Parasitology
Berlin, Germany
Department of Biological Sciences
Federal University of Ouro Preto Kenneth J. Warrington, MD, FACP, FACR
Ouro Preto, MG, Brazil Associate Professor of Medicine
Division of Rheumatology, Mayo Clinic, College of
Stefano Toldo, PhD
Medicine
Assistant Professor of Medicine
Rochester, Minnesota, United States
VCU Pauley Heart Center, Department of Internal
Medicine and Department of Surgery Ryu Watanabe, MD, PhD
Virginia Commonwealth University Professor of Medicine
Richmond, Virginia, United States Tohoku University Graduate School of Medicine Sendai
Japan
Juan Torrado, MD
and Visiting Assistant Professor at Department of
Research Associate
Medicine
Division of Cardiology—VCU Pauley Heart Center
Division of Immunology and Rheumatology
Virginia Commonwealth University Medical Center
Stanford University School of Medicine
Richmond, VA, United States
California, United States
Robert M. R. Tulloh, BM BCh MA DM FRCPCH
Wen Zhang, MD, PhD
Professor of Congenital Cardiology
Professor of Medicine
School of Clinical Sciences
Department of Rheumatology and Clinical Immunology
University of Bristol, Bristol, United Kingdom
Peking Union Medical College Hospital
Patompong Ungprasert, MD Beijing, China
Instructor of Medicine
Division of Rheumatology, Department of Internal    
Medicine
Mayo Clinic
Rochester, Minnesota, United States
 C H A P T E R

1
Pathophysiology of Autoimmunity
and Immune-Mediated Mechanisms
in Cardiovascular Diseases
O. Shamriz1, U. Nussinovitch2, N.R. Rose3,4
1Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Rambam Health Care Campus, Affiliated With the
Technion Institute of Technology, Haifa, Israel; 3Johns Hopkins University, Baltimore, MD, United States; 4Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, United States

1. PATHOPHYSIOLOGY OF Herein, we will discuss the multifactorial etiology of

AUTOIMMUNITY autoimmune diseases.
1.1.1 Environmental Factors
1.1 Etiology of Autoimmunity Several environmental factors contribute to the devel-
A common etiology of virtually all autoimmune dis- opment of autoimmune diseases, eg, occupational expo-
eases is a dysregulated and uncontrolled self-reactive sures, drugs, tobacco smoke, silica, organic solvents,
CD4 T-cell response [1]. Several factors are known to affect dietary intake of certain elements, and exposure to UV
autoimmunity, including immunologic, infectious, and light [5,6]. This association was validated in 2010 by an
genetic predispositions. Researchers have acknowledged expert panel workshop of the National Institute of Envi-
that many triggers may contribute to the development ronmental Health Sciences (NIEHS) deliberating on the
of autoimmune diseases in susceptible individuals [2]. role of the environment in the development of autoim-
In recent years we have acquired a better understanding mune disease [7].
of the pathogenesis of autoimmunity. Although in some Drugs are important environmental triggers of auto-
cases, the link between specific triggers and an autoim- immunity. The hallmark of drug-induced autoimmu-
mune disease has been established (ie, the poststrepto- nity (DIA) is a systemic lupus erythematosus (SLE)-like
coccal pharyngitis development of acute rheumatic fever phenotype. First described in 1945 in the context of sul-
(RF)), in most cases the etiology remains elusive and is fadiazine, it is now recognized that over 90 drugs can
considered multifactorial. Autoimmunity may be con- induce SLE and other autoimmune diseases, such as
fined to a specific organ or be associated with a systemic vasculitis and arthritis [8,9]. The highest risk for drug-
disease with various different clinical manifestations. induced lupus erythematosus (DILE) is attributed to
Importantly, there is an outstanding difference in the procainamide and hydralazine, while quinidine and
prevalence of different autoimmune diseases reported other drugs are associated with moderate and low risk,
in different countries, further supporting the association respectively [8]. Recently, biological treatments such
between ethnogeographical factors (and presumably dif- as the tumor necrosis factor-α (TNF-α) inhibitors and
ferent exposure to infectious agents) and autoimmunity interferon (IFN) have been identified as causing DILE in
[3]. Diabetes mellitus (DM) type 1 is an example of an some patients [9]. As DILE is often reversible, once the
immune-mediated organ-specific disease that is charac- offending drug has been removed, early diagnosis and
terized by a diverse global prevalence. For undetermined distinguishing DILE from SLE is important [9,10]. How-
reasons, prevalence appears to be higher in North Amer- ever, currently, there are no diagnostic criteria for DILE
ica, northern Europe, and Australia/New Zealand [4]. [8,9]. Identification of a temporal relationship between

The Heart in Rheumatic, Autoimmune and Inflammatory Diseases 3

http://dx.doi.org/10.1016/B978-0-12-803267-1.00001-6 © 2017 Elsevier Inc. All rights reserved.