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Medicinal spices and vegetables from Africa therapeutic

potential against metabolic inflammatory infectious and
systemic diseases 1st Edition Victor Kuete

Drug Delivery Challenges and Novel Therapeutic Approaches

for Retinal Diseases Christopher L. Cioffi

Antiphospholipid Syndrome in Systemic Autoimmune Diseases

Ricard Cervera
Congenital Heart Diseases The Broken Heart Clinical
Features Human Genetics and Molecular Pathways 1st Edition
Silke Rickert-Sperling

Chronic Lung Diseases Pathophysiology and Therapeutics

Sheikh Rayees

Pediatrics in Systemic Autoimmune Diseases Rolando Cimaz

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Epigenetics and Gene Expression in Cancer Inflammatory and

Immune Diseases 1st Edition Barbara Stefanska

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Diseases: Multiple Sclerosis 1st Edition Ronald Ross
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 Dedication

To my parents, Naomi and Moshe Nussinovitch,

for their unconditional love, guidance, and support throughout my life.
THE HEART IN RHEUMATIC,
AUTOIMMUNE AND
INFLAMMATORY DISEASES

PATHOPHYSIOLOGY, CLINICAL ASPECTS

AND THERAPEUTIC APPROACHES
Edited by

Udi Nussinovitch, MD, PhD

Rambam Health Care Campus, affiliated with the Technion Institute of Technology, Haifa, Israel
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About the cover

The left upper panel of images exhibit giant coronary aneurysms, a possible result of coronary vasculitis (modified with permission
from van Beek et al, Neth Heart J 2012;20:42–43) and mitral regurgitant flow (upper right image), a consequence of rheumatic heart
disease (modified with permission, from Huang et al; ECR 2013. DOI:10.1594/ecr2013/C-1218). The lower left image demonstrates an
example of nonbacterial endocardial involvement (modified with permission; http://www.wikidoc.org/index.php/Endocarditis_patho
logy) and the right lower image is a histologic example of Churg-Strauss vasculitis (modified with permission; http://commons.wikim
edia.org/wiki/File:Churg-Strauss_syndrome_-_very_high_mag.jpg).
 List of Contributors

Carlo Agostini, MD Jürgen Braun, MD

Professor of Internal Medicine Professor of Rheumatology
Director Postgraduate School of Clinical Immunology Center for rheumatic diseases in the Ruhr
and Allergology area, Herne
Department of Medicine Ruhr-University Bochum
Policlinico Universitario – Azienda Ospedaliera di Bochum, Germany [189]
Padova Antonio Brucato, MD
University of Padova Medical School Department of Internal Medicine
Padova, Italy [25] Papa Giovanni XXIII Hospital
Alessia Alunno, MD Bergamo, Italy [617]
Research Associate, Rheumatology Unit Jill P. Buyon, MD
Department of Medicine Professor of Medicine
University of Perugia Division of Rheumatology
Perugia, Italy [213] Department of Medicine
Lilit Ayvazyan, PhD New York University School of
Associate Professor Medicine
Department of Medical Chemistry New York, NY, United States [269]
Yerevan State Medical University Alida L.P. Caforio, MD, PhD, FESC
Yerevan, Armenia [129] Division of Cardiology
João Marcos Barbosa-Ferreira, MD, PhD Department of Cardiological Thoracic and Vascular
Associate Professor of Medicine Sciences
Division of Cardiology Policlinico Universitario – Azienda Ospedaliera di
University of the State of Amazonas Padova
Manaus, Amazonas, Brazil [553] University of Padova Medical
Elena Bartoloni, MD School
Assistant Professor of Rheumatology Padova, Italy [25]
Rheumatology Unit, Department of Medicine Robert Dennert, MD, PhD
University of Perugia Department of Cardiology
Perugia, Italy [213] Maastricht University Medical
Christoph J. Binder, MD, PhD Centre
Principal Investigator, Professor of Atherosclerosis Maastricht, The Netherlands [459]
Research Louise Pyndt Diederichsen, MD, PhD
CeMM Research Center for Molecular Medicine Associate Professor of Rheumatology
of the Austrian Academy of Sciences Department of Rheumatology
Vienna, Austria Odense University Hospital
Department of Laboratory Medicine Odense, Denmark [327]
Medical University of Vienna Theodoros Dimitroulas, MD, MSc, PhD
Vienna, Austria [65] Academic Lecturer in Rheumatology
Beatrice Bornholz, PhD 4th Department of Internal Medicine
Junior Scientist Hippokration Hospital, Thessaloniki
Medipan GmbH, Blankenfelde-Mahlow Aristotle University of Thessaloniki
Germany [49] Greece [129]

xi
xii LIST OF CONTRIBUTORS

Marcus Dörr, MD Roberto Gerli, MD

Professor of Medicine Full Professor of Rheumatology, Rheumatology
Department of Internal Medicine B Unit
University Medicine Greifswald Department of Medicine
Greifswald, Germany University of Perugia
DZHK (German Center for Cardiovascular Perugia, Italy [213]
Research) Sabrina Gruber, MSc
Partner Site Greifswald CeMM Research Center for Molecular Medicine
Greifswald, Germany [681] of the Austrian Academy of Sciences
Stephan B. Felix, MD Vienna, Austria
Professor of Medicine Department of Laboratory Medicine
Department of Internal Medicine B Medical University of Vienna
University Medicine Greifswald Vienna, Austria [65]
Greifswald, Germany Luiza Guilherme, PhD
DZHK (German Center for Cardiovascular Professor in Immunology
Research) Laboratory of Immunology
Partner Site Greifswald Heart Institute (InCor)
Greifswald, Germany [681] School of Medicine of University of São Paulo
Fabio Fernandes, MD, PhD São Paulo, Brazil [529]
Associate Professor of Medicine Loïc Guillevin, MD
Division of Cardiomyopathy Professor of Medicine
Heart Institute, University of São Paulo Medical Department of Internal Medicine
School Referral Center for Rare Autoimmune and Systemic
São Paulo, São Paulo, Brazil [553] Diseases
Sofia Fragkioudaki, MD, PhD candidate French Vasculitis Study Group
Department of Physiology Hôpital Cochin, University Paris Descartes
National and Kapodistrian University of Athens Paris, France [419]
Athens, Greece [281] Mark Hazebroek, MD
Samar Freschi de Barros, BsC, PhD Department of Cardiology
Laboratory of Immunology Maastricht University Medical Centre
Heart Institute (InCor) Maastricht, The Netherlands [459]
School of Medicine of University of São Sjoerd C. Heslinga, MD
Paulo Department of Rheumatology
São Paulo, Brazil [529] Amsterdam Rheumatology Immunology Center
Deborah M. Friedman, MD, FAAP, FACC Reade & VUmc
Professor of Pediatrics Amsterdam, The Netherlands [189]
Division of Pediatric Cardiology Stephane Heymans, MD, PhD
New York Medical College Professor of Cardiomyopathies
Valhalla, NY, United States [269] Head of the Centre for Heart Failure Research
Nicoletta Gallo, MD Department of Cardiology
Clinical Pathologist at the Department of Laboratory Maastricht University Medical Centre
Medicine, Autoimmunity Unit Maastricht, The Netherlands [459]
University Hospital of Padova Sabino Iliceto, MD, FESC, FACC
Padova, Italy [25] Professor of Cardiology and Head of Department
Armen Yuri Gasparyan, MD, PhD, FESC Division of Cardiology, and Department
Associate Professor, Research Fellow of Cardiological Thoracic and Vascular
Departments of Rheumatology and Research and Sciences
Development Policlinico Universitario – Azienda Ospedaliera di
Dudley Group NHS Foundation Trust Padova
Russells Hall Hospital University of Padova Medical School
Dudley, West Midlands, United Kingdom [129] Padova, Italy [25]
 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.
4 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

drug administration and symptom development, as A possible mechanism is the inhibition of T-cell DNA
well as symptom resolution after cessation of the drug, methylation by UV radiation, which can convert normal
is required for diagnosis [10]. antigen-specific CD4+ T lymphocytes into autoreactive,
Exposure to silica and organic solvents are associated cytotoxic, proinflammatory cells [16]. The role of DNA
with systemic sclerosis (SSc). Silica may also be associ- methylation modulation in the pathogenesis of autoim-
ated with the development of rheumatoid arthritis (RA), munity is further indicated by the presence of immune
systemic lupus erythematosus (SLE), and antineutro- dysregulation in two rare congenital diseases: Russel–
phil-cytoplasmic antibody (ANCA)-associated vasculitis Silver and Beckwith–Wiedemann syndromes [7]. Other
[6,7]. Suggested mechanisms for silica-induced autoim- studies have suggested that UV light causes a clinically
munity include adjuvant effects of apoptotic debris, dys- significant autoimmune disease only in individuals with
regulation of apoptosis, altered CD4+/CD4+ CD25+ T-cell a genetic predisposition to SLE [16]. UV radiation plays
ratio, and induction of circulating autoantibodies (such a role in the pathogenesis of cutaneous lupus erythema-
as anti-dsDNA, anti-Ro/SSA, anti-La/SSB antibodies in tosus (CLE) by triggering keratinocyte apoptosis and
silica associated SLE) [7]. Solvents were found to be asso- externalization of nucleoprotein autoantigens, such as
ciated with circulating SSc autoantibodies (anti-Scl-70), Ro/SSa, to the keratinocyte cell surface and exposing
increased IFN-γ, and reduced interleukin (IL)-4 produc- them to circulating autoantibodies [17,18]. Exposure to
tions [7]. Other substances, such as aromatic amines, UV light is also known to be associated with the release
hydrazines, hair dyes, aliphatic chlorinated hydrocar- of proinflammatory cytokines, thus contributing to the
bons (vinyl chloride, trichloroethylene, and perchloro- pathogenesis and progression of SLE. These cytokines
ethylene), environmental estrogens (such as bisphenol include IFNs, TNFα, and IL-1, IL-6, IL-8, IL-10, and
A), inorganic mercury, and the mineral oil component IL-17, among others [18].
2-, 6-, 10-, 14-tetramethylpentadecane (TMPD or pris- Vitamin D, another solar exposure byproduct (due to
tine, which was found to induce acute inflammatory its production in the skin and the kidneys in a bipha-
arthritis in rats), are acquired due to occupational expo- sic process; although it may be externally derived
sure, which can also trigger autoimmunity in predis- from nutritional sources), is considered an important
posed individuals [7,11,12]. One suggested mechanism immune modulator. Interestingly, low levels of vitamin
for these substance-induced autoimmune responses is D were observed in various autoimmune conditions
the estrogenic influences on the immune system, which and were reported to be associated with more advanced
use binding to self-antigens and the creation of neoanti- disease stage and adverse clinical outcomes [19–22].
gens for which immune tolerance is lacking [3]. Tobacco Other dietary exposures were also suggested to miti-
smoking has been known to be associated with autoim- gate autoimmunity, such as the development of gluten-
munity and connective tissue diseases. For instance, the sensitive enteropathy, eosinophilia-myalgia syndrome,
odds ratio (OR) for developing SLE increases by 50% in and toxic oil syndrome as a result of ingestion of glu-
smokers compared with nonsmokers. The association ten, L-Tryptophan and 1, 2-di-oleyl ester (DEPAP), and
with RA is even higher (OR of 2.6–3.8 compared with oleic anilide-contaminated rapeseed oil, respectively
nonsmokers). Conjugation of smoking and a specific [7]. Furthermore, cow milk proteins introduced into
genetic background (HLA-DR alleles) produces a syn- the diet at a young age were reported to be linked to
ergistic effect and a higher risk of developing RA [13]. the development of DM. Excessive iodine consumption
Grave’s disease is also remarkably susceptible to smok- was found to be associated with autoimmune thyroid-
ing [14]. The exact mechanisms by which tobacco smok- itis [7]. Similarly, animal meat, fat, sweets, and sugar
ing affects autoimmunity are not fully understood but were suggested as a trigger for inflammatory bowel
increased tissue damage, generation of free radicals, and ­disease (IBD), although the latter association has yet to
increased systemic inflammation seems to mediate its be proven. Many of the environmental possible effectors
unfavorable immune effects [5]. Suggested mechanisms have been linked to the Western lifestyle [4].
for tobacco smoking-induced RA include post-transla-
tional modification of antigen citrullination and anti- 1.1.2 Infectious Agents
cyclic citrullinated peptide (CCP) antibodies, T helper Molecular mimicry between human and pathogenic
(Th)-17 activation by nicotine, and upregulation of heat (bacterial, viral, parasitic, and fungal) antigens has been
shock gene expression and circulating autoantibodies suggested as a possible trigger or aggravator of auto-
(such as rheumatoid factor and antiheat shock protein immune diseases. Chagas heart disease (CHD) and RF
70 (HSP70)) [7]. are good examples of autoimmune diseases triggered
Interestingly, among other factors, SLE is influenced by infectious agents, ie, Trypanosoma cruzi and group A
and exacerbated by ultraviolet (UV) radiation [15]. Ani- Streptococcus, respectively. Both pathogens are related
mal models suggest that exposure to UV radiation can to cardiac damage, but as the former affects mostly the
also lead to the development of an SLE-like disease. myocardial tissue, the latter may be associated with

I. CARDIAC INJURY, ATHEROSCLEROSIS AND CARDIAC INVOLVEMENTS IN SYSTEMIC DISEASES

 1. Pathophysiology of Autoimmunity 5
pancarditis and the development of valvulopathy, probable triggers of multiple sclerosis (MS). Coxsackie
which may result in progressive heart failure [23,24]. virus B (CVB), cytomegalovirus, and mumps were iden-
Molecular mimicry, epitope spreading, bystander acti- tified as triggers of type 1 DM, and CVB, EBV and hepa-
vation, polyclonal activation, and other mechanisms of titis C virus (HCV) are likely to be triggers of Sjögren’s
action were all found to induce autoimmunity following syndrome (SS) [6].
infections [25]. There are many experimental models in animals dem-
“Molecular mimicry” is the presence of cross-reactiv- onstrating an autoimmune response following exposure
ity between infectious and self-epitopes. Subsequently, to infectious antigens. For instance, immunizing animals
naïve autoreactive T cells recognize self-antigens and with EBV nuclear antigen 1 (EBNA-1) fragments were
initiate or facilitate tissue damage. This mechanism may found to induce a serological response similarly found
be proven by disease induction in animal models follow- in SLE patients [25]. CVB3, a common viral cause of
ing immunization, or by disease induction following the acute myocarditis, is another example. Mice models pre-
transfer of sensitized T cells or autoantigens. “Epitope viously demonstrated that CVB3 can induce a chronic
spreading” is a process in which a dominant epitope is organ-specific immune response to cardiac myosin
metabolized and presented to the immune system as [26,27]. One study demonstrated the generation of myo-
a neoepitope, thus eliciting an autoimmune response. sin heavy chain (MyHC)-α-autoreactive CD4 T cells in
This immune mechanism appears to play a pivotal role myocarditis-susceptible mice infected with CVB3. This
in the pathogenesis of many autoimmune diseases and autoreactive T-cell repertoire appears to contain high
cardiac-related immune damage [2]. “Bystander acti- levels of IL-17-producing cells capable of inducing myo-
vation” is a term describing infection-mediated tissue carditis [28]. Importantly, infections were reported to
damage (either direct or immune-mediated), thus elicit- affect the clinical presentation of systemic autoimmune
ing exposure of self-antigens, an immune presentation, and rheumatologic disease. For instance, in SLE patients
and an autoimmune response. Infection-mediated non- who were also exposed to rubella (with high IgM), neu-
specific macrophage activation and cytokine secretion ropsychiatric lupus usually developed.
by specific T cells (directed against the infectious agent) In contrast, high titers of anti-EBV antibodies were
also further facilitate the tissue damage induced by auto- reported to correlate with skin and joint manifesta-
reactive T cells. tions [25]. Interestingly, Strachan et al. demonstrated
Many infectious agents are known to produce specific an inverted correlation between exposure to certain
molecules, also known as pathogen-associated molecu- infectious agents and development of autoimmu-
lar patterns (PAMPs). PAMPs are able to bind to toll-like nity. This negative association is also known as the
receptors (TLRs) and thereby activate T, B, and antigen “hygiene hypothesis” [29]. The correlation is mostly
presenting cells (APCs). Importantly, infections may related with type 1 DM, IBD, and MS, which explains
result in cell apoptosis and a release of endogenous dam- in part the increase in their incidence during the last
age-associated molecular patterns (DAMPs), which may century in the Western world. This hypothesis is also
further induce immune activation via TLRs pathways corroborated by the lower levels of antibodies against
[2]. Constant immune activation may result in immune- Helicobacter pylori, CMV, EBV, and toxoplasma in the
complex-mediated tissue damage, and eventually in serum of patients with type 1 DM [25]. It is not fully
organ dysfunction [25]. understood as to why certain infectious agents pro-
Notably, superantigens can be produced by certain mote an autoimmune response and others produce
infectious agents, thus resulting in nonspecific T-cell the opposite immune-protective effect. It may be asso-
activation, with potential T-cell self-reactivity. Viruses ciated with specific characteristics of the infectious
may also induce TLRs activation via an overexpres- agents, or due to host response-related mechanisms
sion of type 1 INF genes (INF and INF-related cytokines and genetic predisposition. Certain viral and fungal
and chemokines), which may further contribute to the infections are capable of promoting Treg cells (CD4+/
pathogenesis of autoimmunity. Certain infections pro- CD25+ positive cells), which play a role in immune
mote IL-17 secretion and a Th17-mediated immune regulation and may suppress autoimmune mecha-
response, another important contributor to autoimmu- nisms [2].
nity [2]. It has been suggested that in most patients not Atherosclerosis, an inflammatory process involving
a single infection, but rather the “burden of infections” the vascular wall, was suggested as one of the multi-
affecting an individual throughout his lifetime, advocate factorial pathophysiological processes resulting in part
an autoimmune response. More than a few infectious from an infections-associated cumulating effect. Interest-
agents have been identified in this context including the ingly, certain infectious agents were found to be linked
Epstein Barr virus (EBV), parvo B19, and the hepatitis with accelerated atherosclerosis, including Helicobacter
C virus (HCV); all were reported as possible triggers of pylori, Chlamydia pneumoniae, herpes-simplex type 2, and
RA. EBV and Chlamydia pneumonia were also reported as CMV [30].

I. CARDIAC INJURY, ATHEROSCLEROSIS AND CARDIAC INVOLVEMENTS IN SYSTEMIC DISEASES

6 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

1.1.3 Hormonal Associations presentation of autoimmune diseases are attributed to

For an undetermined reason, most autoimmune dis- sex hormones [33]. Sex hormones are known to affect the
eases are much more common in females than in males function of immune cells. Estrogens increase the Th2-type
[31]. This prevalence exists in patients with MS, hyperthy- immune response (associated with increased secretion of
roidism/Graves’ disease, RA, Hashimoto’s disease, and IFNγ, tumor-necrosis factor TNFα, TGFβ, and IL-1, 4, 5,
many other immune-mediated diseases (Table 1.1) [31]. and 10) and increases the autoreactive B-cell count, while
Autoimmune diseases among males are characterized androgen and progesterone may downregulate immune
by a lower incidence rate and a more severe phenotype, mechanisms via the Th1 immune response and decreased
as compared to females. A wide range of female-to-male levels of proinflammatory cytokines [33]. Thus the bal-
prevalence has been reported in the medical literature ance between estrogen and progesterone can possibly
for certain diseases, which may be attributed to various influence presentation of autoimmune diseases [31].
geoepidemiologic factors, prevalence of possible trig- Interestingly, patients with autoimmune diseases
gers, and possibly to diagnostic factors [32]. However, have no altered hormonal profile compared with healthy
there are a few diseases where no gender-association individuals of the same sex. There are several other gen-
was found (ie, DM and Beçhet’s Disease, which occurs der-related immune differences. Females have increased
equally in both species) [4]. Furthermore, exacerbation IgM levels, higher CD4+ T-cell counts, and a tendency
of autoimmune diseases appears more commonly dur- toward increased secretion of IL-4, IFNγ, and IL-1 com-
ing puberty, pregnancy and postpartum periods, all life pared with males [32].
events that are characterized with gender-related hor- Suggested mechanisms in SLE that account for the
monal alterations. Ovarian stimulation may be associated female predominance in this disorder are presented in
with increased expression of autoimmunity, as well as Fig. 1.1 [31].
exogenous estrogen supplementation (oral contraceptive Specifically, in the context of immune mediated car-
or hormonal replacement therapy) that may be associ- diac injury, sex hormones modulate postviral myocardi-
ated with disease flare-ups [5]. Shoenfeld et al. suggested tis tissue damage induced by anticardiac autoimmune
that the sex-related differences in prevalence and clinical responses. Unlike most systemic autoimmune and rheu-
matologic diseases, pure autoimmune cardiac damage is
more common in males by 1.2–2 folds [35,36]. Males also
TABLE 1.1 Female-to-Male Prevalence Ratio in Several
tend to experience a more severe cardiac injury, more
Immune-Mediated Disorders
global cardiac involvement and a higher rate of fibro-
Disease F:M ratio References sis, resulting in a grave prognosis in some patients [44].
Ankylosing spondylitis 1:3 [34] Some of the gender-related models associated with car-
diac injury in a postmyocarditis mouse model are found
Autoimmune myocarditis 1:1.2–2 [35,36]
in Table 1.2 [32]. Testosterone was reported to promote
Beçhet’s disease 1:1 [37] a cell-mediated immune response, whereas female mice
Mixed Connective tissue 8:1 [35]
demonstrated a dominant Th2 response manifested by
Diseasea B-cell predominance [32].
Polymyositis/ 2:1 [38] 1.1.4 Psychological Effectors
dermatomyositisa
Psychological mechanisms may produce profound
Rheumatoid arthritisa 2.7–4:1 [34,35,37–40] physiological effects. Reports of exaggerated emo-
Sclerodermaa 2.7–4:1 [34,35,37–40] tional stress preceding autoimmune disease onset is not
Sjögren’s syndromea 4-20:1 [34,35,38,40]
uncommon and were reported in up to 80% of patients,
according to some case series [5]. Furthermore, emotional
Systemic lupus 7.4–9:1 [34,35,37–40] stress was reported prior to disease exacerbation. Impor-
erythematosusa
tantly, the disease itself may cause abundant physical
Addison’s diseasea 12.3:1 [38] and emotional distress, thus inducing a “vicious cycle”
Celiac diseasea 1.8–3.3:1 [34,41,42] cumulating in disease aggravation. Stress may affect the
neuroendocrine system, activate the hypothalamic-pitu-
Grave’s diseasea 3.5–7.2:1 [34,35,38]
itary-adrenal axis, and induce the release of proinflam-
Hashimoto thyroiditisa 5.2–50:1 [34,35,37,38] matory cytokines, such as IL-1, IL-6, IL-8, IL-18, TNF-α,
Myasthenia gravisa 1.6–3:1 [34,35,39,43] and C-reactive protein (CRP) [45]. Therefore emotional
stress management is considered an integral component
Primary biliary cirrhosisa 7.8–10:1 [34,35,38–40]
of autoimmunity treatment and patient management [5].
aCharacteristic
female predominance. Major depression (MD) is a hallmark for the bidirec-
Adapted from Nussinovitch and Shoenfeld [32]. tional relationship between psychological diseases and

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 1. Pathophysiology of Autoimmunity 7
Immune
complex

pDC
IgG+

IFN-γ MPA

IFN-α
Feed-forward
loop

Naive
Mature TH1 CD4+
B cell T cell

IL-12

Feed-forward
Immature loop IFN-β mDC/
B cell macrophage

Pathogenic IgG autoantibody Autoantigen

IgM autoantibody Oestrogen Self-antigens
FcR Progesterone Commensal bacteria

FIGURE 1.1 Potential mechanisms through which estrogen and progesterone might modulate the loss of immune tolerance and regulate the
production of pathogenic autoimmune autoantibodies in SLE. Adapted from Hughes and Choubey [31].

TABLE 1.2 Hormonal influences in a CVB-3 mediated autoimmune myocarditis mouse model
Estrogen (dominant Th2 response) Testosterone (dominant Th1/Th17 response)

Polarization of macrophages into M2 response and increased M2 Increased number of macrophages, neutrophils and cell-mediated
response autoimmunity

Upregulation of the M2 marker Arg1 and increased markers of Elevated levels of TLR4, caspase-1
M2 differentiation (Dectin-1, CD169, galcatin-3, CCL-2, CCL-7,
CXCL-3)

Increased IL-1β, IL-4, IFNγ, TNFα, TGFβ, IL-5, and IL-10 secretion Enhanced necrosis of cardiomyocytes

Greater percentage of B-cells and CD25, FOXp3, and Treg Autoreactive cytolytic T cells in the spleen

Increased Tim-3 expression in mast cells, macrophages, and T cells Increased CD8-cell activation

Increased fibrosis Decreased levels of IL-1β, IL-4, IL-5, IL-6, and TNFα

Increased antibody-mediated and immune complex-associated tissue Increased secretion of IL-10

damage

Adapted from Nussinovitch and Shoenfeld [32].

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8 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

autoimmunity. Two important factors found in this rela- protease, is the main inducer of the alternative pathway.
tionship are cytokine dysregulation and the presence It cleaves to factor B, which forms a complex with the
of autoantibodies [46]. Cytokine dysregulation plays a hydrolyzed iC3b, thus leading to the formation of Ba
role in patients with MD, as high levels of proinflam- and Bb. Bb and C3b generate the C3 convertase of the
matory cytokines, including CRP, IL-6, and TNF-α, were alternative pathway, C3bBb [60,64]. Enzyme activation
detected [47]. This proinflammatory process appears to of C5 by C3bC4bC2a (lectin or classical pathway) or by
play a role in the pathogenesis of MD [46]. As a result, C3bBbC3b (alternative pathway) leads to the formation
these patients may be at risk for autoimmune disorders, of C5a and C5b, which in turn form the MAC C5b-9, thus
as was previously demonstrated in a large-scale epide- causing cell lysis [60]. Further effects of the complement
miological study [47]. Interestingly, this proinflamma- system include the MAC’s activation of granulocytes and
tory state may link MD with cardiovascular diseases endothelium; increased opsonization and phagocytosis
(CVD) [48]. Several studies describing MD patients to by the deposition of C3 fragments on the membranes;
have increased risk for hypertension and stroke, as well clearance of immune complex and apoptotic bodies; and
as studies that found MD to be an independent risk fac- alterations in immune cell signal transduction, adhesion
tor for CVD, support this notion [49]. activation, and cytokine production [60].
Several studies have suggested that an autoimmune Defects in the complement system or in its regulatory
mechanism triggers the development of MD via the pro- proteins may contribute to the development of autoim-
duction of autoantibodies. In SLE, antiribosomal P anti- mune diseases. Herein, we will explore the association
bodies (anti-P antibodies) were found associated with between the complement system and autoimmunity.
neuropsychiatric manifestations [50–53]. Moreover, they
were linked to hepatic involvement and acceleration 1.2.1 Complement Compound Deficiency and
of glomerulonephritis in these patients [54,55]. How- Autoimmunity
ever, it appears that anti-P antibodies may play a role The complement system’s role in tissue repair may
in the development of MD as well. In one study, anti-P be responsible for autoimmune response [60]. Although
antibodies were injected intracerebra-ventricularly into hypocomplementemia was associated with primary SS
mice, inducing a depressive-like behavior. Treatment and SSc [60], the hallmark autoimmune disease affected
with fluoxetine succeeded in relieving the symptoms by complement deficiency is SLE [61]. Complement defi-
[56]. This intriguing association between anti-P antibod- ciency was in fact identified as the strongest genetic sus-
ies, SLE, and MD implies that the presence of MD may ceptibility factor in humans for SLE [65,66]. In particular,
affect the development of autoimmune diseases. How- the deficiency of C1 (C1q, C1r, C1s), C4, and C2 were asso-
ever, a causal relationship has yet to be proven. ciated with high, moderate, and low risk for the develop-
ment of SLE, respectively [60,61,65]. This may result from
bypass mechanisms absent in C1q and C4 [67].
1.2 Complement System and Autoimmunity In the case of C3 deficiency, the clinical picture is dif-
The complement system was discovered over ferent, rarely associated with SLE, and more commonly
100 years ago [57]. At first, it was considered only to par- characterized by recurrent pyogenic infections, membra-
ticipate in the recognition and destruction of pathogens. noproliferative glomerulonephritis, and rash [60]. Preva-
At present, it is known to possess regulatory functions lence of SLE development in patients with C1q, C1r/C1s,
in adaptive [58], humoral [59], and T-cell immunity [57]. C4, and C2 deficiencies is estimated at 93%, 57%, and
There are three complement-cascade activating path- 75%, respectively [65,68,69]. The exact estimation of SLE
ways: the classical, lectin, and alternative pathways (Fig. development in C2 deficiency is more difficult than in
1.2 [57]). All three pathways lead to the cleavage of C3 other complement deficiencies due to higher prevalence
into the opsonin C3b and the anaphylatoxins C3a, which of heterozygosity in these patients. In one study it was
activates the C5 with formation of a membrane attack found to be 30% [65]. These clinical observations were
complex (MAC) [60,61]. The classical pathway is trig- further confirmed by mice models deficient in C1q-, C4-,
gered by the binding of immunoglobulin (Ig)-M and IgG C3-, and CD35/CD21 (CR1/2) and were shown to pre-
to the C1 complex [60,62]. The binding of C1q to an anti- dispose the subjects for autoimmune diseases [61].
body further activates C4 and C2 and induces the forma- In addition to complement compound deficiency
tion of the C4bC2a complex, a C3 convertase [60,63]. The anti-C1q autoantibodies also appear to play a role in the
lectin pathway facilitates recognition of microbial car- development of SLE. Present in up to one-third of SLE
bohydrate patterns either by a mannose-binding lectin patients, these autoantibodies create immune complexes,
(MBL) or ficolins. This leads to the activation of C2 and which are correlated with more severe disease [65,70].
C4 through the MBL-associated serine proteases (MASP) Anti-C1q antibodies may play a promising future role
and the formation of the C4bC2a complex, similar to in the early detection and monitoring of SLE patients,
that of the classic pathway [60,62]. Factor D, a serine especially in those with renal involvement [71].

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 1. Pathophysiology of Autoimmunity 9

1. Lectin 2. Classical 3. Alternative

MBL/carbohydrates Antibody/antigen ‘Tick over’

Amplification loop
MASPS C1 C3b

C4, C2

CD55 (DAF),
C3 CR1,
Convertases fH or C4bp

C3
CD46 (MCP),
CR1,
fH C3b C3a

C5
Convertases
Opsonin Chemoaractant
CD46 ligand Smooth muscle cell contraction
T cell activation Vasodilation
C5 Neutrophil/phagocyte/mast cell activation
Degranulation
T cell activation
C5b C5a

MAC Chemoaractant
Vasodilation
Neutrophil/phagocyte/mast cell activation
Endothelial cell activation
Degranulation
T cell activation

CD59, S protein

FIGURE 1.2 Complement system, regulation, and function. In red are the major effectors of C3a, C3b, and C5a. Adapted from Heeger and
Kemper [57].

Three suggested hypotheses for the mechanism of receptor 1, CR1), and the complement receptor 1-related
SLE development in complement deficiency include gene/protein y (Crry) [72,73]. Other regulators involved
impaired clearance of immune complexes, apoptotic in autoimmune diseases are membrane soluble and can
cells, and abnormal B- and T-cell activation, which may be found in plasma or lymphatic fluid. These proteins
cause a defective tolerance in self-antigens. However, include factor H (fH), C4b-binding protein (C4bp), vit-
none of these hypotheses have been completely proven ronectin (S protein), clusterin (apolipoprotein J), and the
[61,65]. C1 inhibitor (C1-INH) [72]. Herein, we will elaborate
on five main regulator proteins: the CD55, CD59, CD46,
1.2.2 Impaired Function of Regulatory Proteins of Crry, and C1-INH.
the Complement System
The complement system has over 30 membrane- 1.2.2.1 CD55
bound regulator proteins that interact with different cells This glycosylphosphatidylinositol (GPI)-anchored
of the immune system [57,61]. Important regulators in membrane protein inhibits the formation and accelerates
the pathogenesis of autoimmunity include CD46 (mem- the decay of C3 and C5 convertases in all pathways [73].
brane cofactor protein, MCP), CD55 (decay accelerat- Paroxysmal nocturnal hemoglobinuria (PNH) is charac-
ing factor, DAF), CD59 (protectin), CD35 (complement terized by susceptibility of platelets and erythrocytes to

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10 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

a complement attack. It was previously demonstrated demonstrated in patients with C1-INH deficiencies suf-
that CD55 deficiency in patients with PNH is responsible fering from hereditary angioedema (HAE). Up to 12%
for the lack of inhibition of the complement system and of HAE patients suffer from autoimmune diseases [84].
thus to an autoreactive complement response [73]. An association between SLE and acquired C1-INH defi-
ciency was previously reported, suggesting the presence
1.2.2.2 CD59 of anti-C1-INH autoantibodies as a possible etiology
Similar to CD55, CD59 is a GPI-anchored membrane [84]. However, SLE patients presenting with C1-INH
protein [74], expressed on red blood cells (RBC). It deficiency and angioedema without circulating anti-C1-
regulates the terminal step in the complement system INH antibodies were also reported [85].
by inhibiting MAC formation [73,74]. Furthermore, Other autoimmune diseases linked to HAE include
recent studies have suggested a direct inhibitory role SS, autoimmune thyroiditis, RA, DILE, pernicious ane-
of CD59a on T-cell activation, as demonstrated by the mia, IBD, celiac disease, MS-like syndrome and mixed
increased Vaccinia-specific CD4+ T-cell responses in connective tissue disease [84]. Suggested mechanism
CD59-knockout mice [73,75]. In murine models of SLE, include the defective clearance of immune-complexes
a CD59a deficiency was found to exacerbate skin auto- and apoptotic cells, which cause inflammatory damage
immune diseases, increase antichromatin autoantibody and trigger autoimmune responses [84]. Moreover, HAE
titers, and cause higher levels of proteinuria in male patients were found to have autoreactive B cells, which
mice [74]. CD59 deficiency has also been associated produce autoantibodies such as antinuclear, rheuma-
with PNH, autoimmune-hemolytic anemia (AIHA), toid factor, anticardiolipin, antitissue transglutaminase,
RA, MS, and SS [73,76–78]. antiendomysial, anti-Saccharomyces cerevisiae, antithy-
roid, antineutrophil cytoplasmic antibodies and others
1.2.2.3 CD46 [84,86–89]. Even anticholesterol autoantibodies were iso-
CD46 is a transmembrane glycoprotein, which lated in HAE patients, suggesting a major role of autore-
binds, inactivates C3b and C4b [79], and plays a major active B cells in HAE pathogenesis [90]. The presence of
role in downregulating the Th1 response by substitut- increased levels of TLR-9 in HAE patients may account
ing IFNγ + IL-10 - CD4+ T cells into IFNγ + IL-10 + cells for this phenomenon [86].
[72,79]. This regulatory process is mediated by IL-2 and
allows for an anti-inflammatory, IL-10-mediated, T-cell
1.3 Autoantibodies and Autoantigens
response [79]. Involvement of CD46 has been demon-
strated in MS, RA, and SLE [72]. Autoantibodies play a major role in the pathogenesis
An interesting study suggests that in MS, errors of immune diseases and are considered a hallmark of
in CD46 signaling may be associated with dendritic autoimmunity. In some instances, autoantibodies can
cells (DC) in IL-23 production, which in turn induces be used as a marker for disease activity, may have prog-
IL-17 production and thus accelerates an autoimmune nostic significance, and may appear in the sera of unaf-
response [72,80]. fected patients’ years prior to clinical presentation. Their
positive predictive value may be near 100% according
1.2.2.4 Crry to some reports. For instance, rheumatoid factor (anti-
Crry includes both CD46 and CD55 functions [73]. In IgG) and anti-CCP predict RA, whereas anti-SSA (Ro)
fact, it coexpresses with CD55 and thus differentiation and anti-SSB (La) are associated with SS. SLE occurrence
between the two molecules’ functions may be difficult is also associated with many preceding autoantibodies
[73]. Crry seems to play a special and critical role in feto- including antiphospholipids (PL), anti-Ro, anti-La, anti-
maternal tolerance [73]. SLE mice models treated with dsDNA, anti-Sm, antinuclear ribonucleoprotein, anti-
Crry were found to have reduced serum anti-dsDNA heparan sulfate (HS), antinucleosome, antihistone, and
antibody levels and trends toward reduced glomerular antiribosomal P protein [91].
IgG deposition levels [81,82]. Moreover, Crry improved In the context of heart diseases, dilated cardiomy-
survival and reduced proteinuria, glomerular C3 deposi- opathy (DCM) is commonly mediated by autoimmune
tion, circulating immune complexes levels, the presence mechanisms (and may evolve in patients with sys-
of skin lesions, lung bronchiolar, and vascular inflamma- temic autoimmune\inflammatory conditions). Several
tion [82,83]. antiheart antibodies have been found in cardiac dis-
eases such as DCM, as well as in healthy individuals
1.2.2.5 C1-INH [92,93]. Autoantibodies can be reactive to all cardiac
C1-INH is a glycosylated serine protease inhibitor components including contractile proteins, receptors,
displaying a regulatory role in the complement and con- intracellular antigens, and connective tissue elements
tact systems as well as the intrinsic coagulation cascade [94,95]. However, their clinical significance and role in
[84]. A tendency toward autoimmunity was previously pathogenesis is a matter of debate and remains to be

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 1. Pathophysiology of Autoimmunity 11
explored. This topic is extensively covered in Chapters production, IL-17 was found to be a disease mediator in
2 and 3 of this book. MS, RA, SLE, IBD, EAE, psoriasis, DM type 1, SS, auto-
immune uveitis, and autoimmune DCM, via production
of IL-17, IL-22, and CCL20 [98–100]. Interestingly, some
1.4 T helper Balance and Autoimmunity studies support the view of an overlap between the four
T-cell mediated adaptive immunity has classically CD4 subsets, since a group of CD4+ T cells, which pro-
been divided into Th1- and Th2-dominant responses duces both IFNγ and IL-17 (Th1 and Th17 cytokines,
[96,97]. While Th1 cells were found to be key players respectively), was found [101,102].
in immune protection against intracellular organisms Since the balance between the four CD4+ T-cell sub-
and in autoimmunity pathogenesis, the Th2 response sets has an important role in autoimmunity pathogen-
was found to protect against extracellular organisms esis, its modulation may have therapeutic potential.
and helminths and to participate in the pathogenesis of IL-4-producing Th2 cells and IL-10-producing CD4+
inflammation and allergy [96]. The two groups of CD4+ CD25+ forkhead box p3 (Foxp3+) iTreg cells inhibit both
T cells produce different cytokines, comparable to Th1 Th17 and Th1 cells [98].
cells, which produce IFN-γ, lymphotoxin-α (LTα) and It seems that a balance between IL-10 and IFN-γ regu-
IL-2 and the Th2 cells, which produce IL-4, IL-5, IL-9, lates the Th1’s normal/autoreactive response. IFN-γ is
IL-10, IL-13, IL-25, and amphiregulin [96]. These two a key cytokine in Th1-mediated autoimmunity develop-
parts of the adaptive immune system are assumed to ment [79,96]. On the other hand, Th1 autoreactivity was
interact in a delicate balance. Thus autoimmunity and found to be attenuated by IL-10, which is produced by
allergy development were thought to be a result of a both iTreg and Th1 cells themselves, and inhibits Th1
shift toward Th1- and Th2-dominanat response, respec- proliferation and IL-2 production [79]. Regulation of this
tively [97]. However, it seems that the exact picture is balance is complex and involves the CD46 regulatory
more complex. It is now known that naive CD4+ T cells protein of the complement system [79].
actually split into four subgroups: Th1, Th2, Th17, and Th17 regulation is complex. Differentiation of Th17
induced Treg (iTreg) cells. Each lymphocyte subset has is mediated by the transcription factor retinoid-related
its own features, cytokine production, immunological orphan receptor γt (RORγt) and induced by TGF-β and
pathways, and roles in disease pathogenesis (see Fig. 1.3) IL-6 via the activation of a signal transducer and acti-
[96]. Similar to Th1, IL-17 producing Th17 cells also play vator of transcription (STAT) 3 [101]. However, it was
a role in autoimmunity, although some studies suggest previously demonstrated that TGF-β induction of Th17
different clinical and histological phenotypes of autoim- differentiation is a concentration-dependent process. At
mune diseases in the two groups [98]. Induced by IL-23 low concentrations, TGF-β induces Th17 differentiation

Extracellular bacteria Intracellular pathogens

Fungi Autoimmunity
Autoimmunity

IL-21 IFNγ
IL-17a IL-2
Th17 TG Th1 LTα
IL-17f
IL Fβ 12 (IL-10)
IL-22 -6, (IL
21 -1 +I L-
(IL-10) ,23 )+ Nγ
RORγt/STAT-3 IF T-bet/STAT-4

Naїve
CD4 T

Foxp3/STAT-5 IL GATA-3/STAT-5
2 -4
- +I IL-4
β +IL L-
2
TGFβ F IL-5
TG
IL-35 Th2 IL-13
iTreg
IL-10 IL-25
Amphiregulin
IL-10
Immune tolerance
Lymphocyte homeostasis Extracellular parasites
Regulation of immune responses Allergy and asthma

FIGURE 1.3 A summary of CD4+ T-cells subsets roles in adaptive immunity. Adapted from Zhu and Paul [96].

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12 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

by synergy with IL-6 and IL-21 and upregulates the IL-23 mechanisms that underlay the pathogenesis. Based on
receptor (IL-23r). On the other hand, high concentrations the criteria of Rose et al., we suggest five minor cri-
of TGF-β downregulates the IL-23r expression and thus teria for the diagnosis of autoimmune DCM [1]. The
induces Foxp3+ Treg cells by inhibiting Th17 differentia- criteria are either immunohistochemical histological
tion [103]. Predicting autoimmunity development, as the data (mononuclear cell infiltrates with an abnormal
end result of this balance between Th1, Th17, Th2, and human leukocyte antigen presentation; autoreactive
iTreg, is difficult. Previous studies have targeted several lymphocytes and/or autoantibodies in cardiac tissue);
molecules in Th1- and Th17-mediated responses in order serological (circulating antiheart autoantibodies or
to attenuate autoimmune disease pathogenesis. These autoreactive lymphocytes); animal-model based (dis-
attempts include blocking RORγt, transfer of polyclonal ease induction in animals following a transfusion of
Treg cells, and inhibition of STAT3 by small interfer- the patient’s serum, antibodies, or lymphocytes); or
ing (si) RNA and of proinflammatory cytokines, such clinical (clinical or echocardiographic improvement
as IL-6 and IL-17A, using monoclonal antibodies [101]. following immunoadsorption or immunosuppressive
However, in order to carefully evaluate the efficacy and therapy). Several findings may provide supporting
safety of these therapeutic modalities, further studies are evidence but are inadequate as criteria, since one may
needed. find a clinical course of exacerbation and remissions,
positive HLA DR4 (which was reported to be weakly
associated with autoimmune DCM), and familial clus-
1.5 Diagnostic Criteria for Immune-Mediated
tering of autoimmune diseases and/or family history
Diseases of DCM [92].
There has been an ongoing attempt to identify the
diagnostic criteria for autoimmune diseases. In 1993,
Rose et al. [1] suggested three types of evidence in order 2. IMMUNE-MEDIATED MECHANISMS OF
to establish an autoimmune pathogenesis: direct proof, CARDIOVASCULAR DISEASES
indirect evidence, and circumstantial evidence. Direct
evidence for autoimmunity can be found in disease 2.1 Systemic Inflammation and the Vascular
induction following a transfusion of autoantibodies or
Wall
autoreactive T cells [1]. On rare occasions, autoimmune
diseases may also be transferred following bone mar- The endothelium is a cell monolayer lining the blood
row transplantation [104]. Direct proof for autoimmu- vessels’ lumens [107]. Several functions have been attrib-
nity may also be found in the transplacental migration uted to the endothelium such as participation in vascular
of pathogenic IgG, which are well known for their abil- metabolism, acting as a selective barrier, and maintain-
ity to induce many neonatal illnesses including myas- ing and regulating vasoconstriction/vasodilation bal-
thenia gravis and Graves’ disease. Direct experimental ance [107].
proof for autoimmunity may be achieved by inducing a Triggers for vascular wall inflammation include
disease in animals following a transfusion of pathogenic aging, dyslipidemia, hypertension, hyperglycemia,
autoantibodies or the patient’s serum. obesity, oxidative stress, smoking, and other car-
In cases of a T-cell mediated autoimmune disease, diovascular risk factors [107,108]. As inflammation
the pathogenic T cells can be transfused into rodents occurs, the integrity and function of the endothelial
with severe combined immune deficiency (SCID). Indi- cells become damaged. As a result, endothelial repair
rect proof of autoimmunity may be achieved by disease mechanisms including local replication of endothelial
induction following the immunization of animals with cells and the incorporation of circulating progenitor
equivalent antigens known to induce disease in humans. cells are activated [109]. However, chronic exposure to
Indirect proof of autoimmunity may also be generated cardiovascular risk factors can eventually overwhelm
from the isolation of autoantibodies or autoreactive T this repair system, resulting in endothelial dysfunc-
cells in the affected organ. Circumstantial evidence for tion (ED), damage to endothelial continuity, and the
autoimmunity includes factors such as the appearance detachment of endothelial cells or microparticles into
of an autoimmune disease in a close family member or a the circulation [107,109]. Once ED develops, progres-
statistical association with a particular MHC haplotype sion to atherogenesis may occur [107,108]. Inflamma-
[1]. In most autoimmune diseases only some of the afore- tion involvement in atherogenesis consists of three
mentioned criteria by Rose et al. can be found (Table 1.3). stages: leukocyte adhesion to the intima layer, pen-
A few years ago, we proposed a new criteria sys- etration to the media layer, and plaque rupture and
tem for autoimmune-mediated DCM (Table 1.4) [92]. thrombus formation [108].
The system mandated echocardiographic evidence Inflammation of the vascular wall induces expression
of DCM, and the exclusion of other nonimmune of several molecules promoting the binding of blood

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TABLE 1.3 Evidence of Autoimmunity in Various Clinical Diseases

Direct proof Indirect proof

Induction Identification within Transfer of

Transfer of disease by Ab Transfer of of disease lesions of: the disease by
disease by in animals lymphocytes in Autoantibodies

2. Immune-Mediated Mechanisms of Cardiovascular Diseases

cells to SCID by an experimental Genetic or self-reactive
Disease Experimental Maternal To animals mice autoantigen Ab T cells models models T cells

Rheumatoid X X X X X
arthritis

Sjögren’s X X
syndrome

Systemic lupus X X X X X
erythematosus

Systemic X X X X
sclerosis

Polymyositis X

Myocarditis X X X

Myasthenia X X X X X X
gravis

Graves’ X X X X X
disease

Type 1 X X X
Diabetes
mellitus

Addison’s X
disease

Adapted from Rose and Bona [1].

13
14 1. PATHOPHYSIOLOGY OF AUTOIMMUNITY AND IMMUNE-MEDIATED MECHANISMS IN CARDIOVASCULAR DISEASES

TABLE 1.4 Proposed Diagnostic Criteria for Autoimmune DCMa

Supporting evidence but not
Major criteria Minor criteria considered criteria

1. Fulfilment of accepted echocardiographic criteria 1. Proven mononuclear cell infiltrate with abnormal 1. Clinical course of
of DCM [105,106] human leukocyte antigen (HLA) presentation exacerbation and remissions

2. Excluding secondary cardiac injury due to 2. Circulating antiheart autoantibodies or 2. Positive HLA DR4
infections, alcohol, toxins or chemotherapeutic autoreactive lymphocytes in patients and in
drugs, metabolic abnormalities, nutritional unaffected family members
deficiencies, neuromuscular diseases, or collagen
vascular disorders

3. Familial Clustering of autoimmune diseases and/ 3. In situ evidence of autoreactive lymphocytes
or family history of DCM (two or more affected and/or autoantibodies in cardiac tissue
individuals or sudden cardiac death in a first-
degree relative <35 years old) 4. Disease induction in animals following
transfusion of the patient’s serum, antibodies, or
lymphocytes

5. Proven clinical or echocardiographic

improvement following immunoadsorption or
immunosuppressive therapy
aDiagnosis requires two major and at least one minor criterion.
Adapted from Nussinovitch and Shoenfeld [92].

leukocytes to the endothelium. This includes molecules Immune-mediated accelerated atherosclerosis is dis-
that enable adhesion, rolling, and attachment of leuko- cussed in detail in Chapter 4 of this book.
cytes to the vascular wall endothelium (ie, vascular cell
adhesion molecule-1 (VCAM-1), selectins, and integrins,
respectively) [108]. 2.2 Pro- and Anti-inflammatory Cytokines
This is followed by leukocyte penetration into the Balance and Cardiovascular Diseases
media layer, the formation of macrophages foam cells,
and replication of smooth muscle cells (SMC), all of Recent studies have evaluated the efficacy of cytokine
which account for the propagation of the atheroscle- modulation as a therapeutic modality to CVD, such as
rotic plaque [108]. Several key molecules mediate heart failure and myocardial infraction [114,115]. Balanc-
this process, such as CXC chemokines (IFN-inducible ing pro- and anti-inflammatory cytokines is a compli-
protein 10 (IP-10), monokine induced by IFN-γ (Mig), cated process. Overlapping pro- and anti-inflammatory
and IFN-inducible T-cell α chemoattractant (I-TAC)) activities of certain cytokines such as IL-6 accounts for
[110], monocyte chemoattractant protein-1 (MCP-1) the difficulty in identifying the outcome [116].
[111], and macrophage colony-stimulating factor Fig. 1.4 demonstrates the balance between pro- and
(M-CSF) [112]. Finally, the thinning of the fibrous anti-inflammatory cytokines, whose effects on the car-
cap and release of prothrombotic factors by macro- diovascular system are discussed herein. Most cytokines
phages foam cells all promote plaque rupture and have both cardioprotective and cardiotoxic functions.
thrombus formation [108]. Therefore it seems that The net impact on cardiac tissue is often unpredictable
restoring endothelial function and targeting vascular and may be related to the duration of plasma level eleva-
wall inflammation may hold the key for preventing tions [116,117]. Herein, we will explore and clarify the
atherosclerosis and CVD. available data.
Lifestyle modification, including exercise and weight
control, smoking cessation, lipid-lowering agents, such 2.2.1 Anti-inflammatory Cytokines
as statins, better glycemic control in diabetic patients, Major anti-inflammatory cytokines involved in car-
and other methods, reduce vascular wall inflammation, diovascular diseases (CVD) include IL-4, IL-10, IL-11,
improve endothelial function, and prevent atherosclero- IL-13, and the transforming growth factor (TGF)-β [116].
sis [107]. Other therapeutic modalities shown to improve
endothelial function involve the use of angiotensin- 2.2.1.1 IL-4
converting enzyme (ACE) inhibitors, renin antago- IL-4 is an STAT-6 signaling-dependent 20-kd glycopro-
nist, endothelin-1 antagonists, and β-blockers [107]. tein, which shifts the Th balance toward a Th2-­mediated
Development of new therapies for ED, including vita- response. Other activities include downregulation of
min D administration, is under investigation [113]. IL-12 production, the Th1 suppression response, and

I. CARDIAC INJURY, ATHEROSCLEROSIS AND CARDIAC INVOLVEMENTS IN SYSTEMIC DISEASES

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