Aging and Heart Failure

Bodh I. Jugdutt Editor

Aging and Heart Failure

Mechanisms and Management

ISBN 978-1-4939-0267-5 ISBN 978-1-4939-0268-2 (eBook) DOI 10.1007/978-1-4939-0268-2 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2014931487

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Editor Bodh I. Jugdutt, MD, MSc, DM, FRCPC, FACC, FACP, FAHA, FESC, FIACS Division of CardiologyDepartment of MedicineMazankowski Alberta Heart Institute University of Alberta and Hospitals Edmonton , AB , Canada

This book is dedicated to:

Catherine Elizabeth Jugdutt (1947–2012 )

who as my friend and wife selfl essly supported me, through many trials and tribulations, in a lifelong pursuit of knowledge and hidden truths that may be applied to improve cardiovascular health and benefi t mankind

and

Dr. Myron L. Weisfeldt

who, as leader and mentor during my fellowship at the Johns Hopkins Hospital, provided me with the inspiration and stimulation to continue on my search for hidden truths and knowledge and undertake this project on aging and heart failure.

vii

Dr. Myron Weisfeldt graduated from Johns Hopkins Medical School and took postdoctoral training at Columbia Presbyterian, the National Institute on Aging of the NIH, and fi nally cardiology fellowship at the Massachusetts General Hospital. Soon after assuming a faculty position at Johns Hopkins, he was named an Established Investigator of the American Heart Association.

One of his areas of research interest has been heart function, particularly with aging. He developed with James Weiss the time constant of isovolumic pressure fall as an independent index of left ventricular relaxation. This index Tau is used to this day as the gold standard index for ventricular relaxation. His research interests have also included treatment and management of acute myocardial infarction. He was the senior author of the fi rst paper to establish the clinical value of TPA in acute myocardial infarction and also the senior author of the fi rst paper describing successful implantation of a defi brillator in human beings. He is perhaps best known for his discovery of the mecha-nism of movement of blood during CPR. The major mechanism is, as a con-sequence of the rise in general intrathoracic pressure, not direct compression of the heart. He currently heads the Resuscitation Outcomes Consortium, an international network of EMS systems in ten major cities or regions spon-sored by NHLBI, the Department of Defense, and Canadian Health Agencies. This is the fi rst major effort to conduct large-scale clinical trials in cardiac arrest victims to improve survival.

From 1975 to 1991 he headed the Division of Cardiology at Johns Hopkins.

Biosk etch

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From 1991 to 2001 he was chair of medicine at Columbia Presbyterian in New York and was the Samuel Bard professor of medicine. Since 2001 he has served as chair of medicine and William Osler professor at Johns Hopkins.

Dr. Weisfeldt received the AHA Award of Merit in 1992 and the AHA Gold Heart in 1998. He received the Dickinson Richards Award of the Council on Cardiopulmonary and Critical Care Medicine in 2001 and the James B. Herrick Award of the Council on Clinical Cardiology in 2004. He was recognized for “outstanding leadership in resuscitation research” by the American Heart Association in 2003. From 1989 to 1990, he was president of the American Heart Association (AHA). During his presidency with the AHA, a successful program was begun to provide the fi rst nutritional food labels on all packaged food products. Also, an AHA Task Force endorsed the manufacture of automatic external defi brillators for public use. During his tenure as president, there was a continuation of programs focusing on Heart Disease in Women, which was begun by Dr. Bernadine Healy who preceded him.

Dr. Weisfeldt is a member of the Institute of Medicine, the American Society for Clinical Investigation, the Association of American Physicians, and the Association of Professors of Medicine.

He received the Diversity Award from the Association of Professors of Medicine in 2008.

Biosketch

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The concept for this book on aging and heart failure (HF) was born in the 1980s with the publication of the book entitled The Aging Heart: Its Function and Responses to Stress , edited by Dr. Myron L. Weisfeldt, MD. It was later fueled along in the early 1990s by the monograph entitled Inclusion of Elderly Individuals in Clinical Trials: Cardiovascular Disease and Cardiovascular Therapy as a Model by Dr. Nanette K. Wenger, MD. Concurrently, observa-tions in population studies and large randomized clinical trials (RCTs) sug-gesting that the elderly patient after myocardial infarction was at higher risk for cardiovascular (CV) complications and adverse left ventricular remodel-ing leading to HF added fuel to the burning fi re.

The concept of cardiac remodeling as a mechanism of heart disease lead-ing to HF has evolved since the mid-1970s following extensive bench-to- bedside and bedside-to-bench research studies. Since the mid-1980s, the initial emphasis on HF related to pressure and volume overload led to theo-ries on adaptive and maladaptive structural and functional remodeling after insults such as myocardial infarction (MI) and hypertension (HTN) and later expanded to pure and mixed pressure/volume overload states and a wide range of cardiomyopathies.

The concept of adverse left ventricular remodeling during acute and sub-acute phases of MI established that adverse cardiac remodeling is a major mechanism for progressive left ventricular enlargement, deterioration of ven-tricular function, increased suffering, and deaths from chronic HF. Concurrently, over the last four decades, expanding knowledge about the biology of aging and the effects of aging on the response to insults by preva-lent CV diseases such as MI and HTN has identifi ed several potential molec-ular pathways and targets that may lead to drug discovery and development and improved therapies for the ravages of these diseases in the elderly patient. A major payoff of the research studies has been the appreciation that lifelong exposure to CV risk factors and cardiotoxic agents from childhood through adulthood and old age fuels the march to HF. This has clearly opened up a new area of research into the biology of CV aging and its impact on cardiac remodeling throughout life.

Despite the advances, a sobering fi nding has been that hearts continue to enlarge and the HF burden continues to increase, especially after ST-segment elevation MI (STEMI). Vast knowledge gaps exist. With the expanded spec-trum of diseases that result in adverse cardiac remodeling, improved

Pref ace

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understanding of the underlying molecular mechanisms through research is crucial. Improvements in medicine, public health, Medicare, and socioeco-nomic conditions in Western countries have extended life span, but the increased longevity is sadly associated with a parallel increase in morbidity due to HF. During the last 20 years, attention has turned to aging-related physiological as well as cellular, subcellular, molecular, and biochemical remodeling that infl uence responses to CV diseases and therapy. An explo-sion in knowledge of molecular and cellular mechanisms, importance of oxi-dative stress, metabolic pathways, extracellular and intracellular matrix remodeling, and the far- reaching effects of infarct and non-infarct zone fi bro-sis in the progression to HF has occurred. The profusion of original scientifi c and review papers dealing with several aspects of molecular mechanisms of adverse cardiac remodeling that impact therapy of HF in the elderly and clini-cal studies on novel therapies and strategies that may benefi t the elderly sug-gested the need to synthesize the main ideas into one book.

In 2008, two special symposium issues of Heart Failure Reviews on aging and HF for which I served as guest editor generated a great deal of interest. The fi rst issue published in 2010 drew attention to the arbitrary nature of the chrono-logical defi nition of elderly in the context of progressive biological aging and the importance of the changing demographics with respect to the growing pop-ulation of elderly people with major aging-related CV changes and diseases that lead to HF such as HTN and MI. The second issue published in 2012 focused on important aging-related issues pertinent to HF therapy in the elderly. In September 2010, I had the opportunity to drive those points home in an invited lecture on “The Biology of Aging in the Cardiac Patient” for a sympo-sium on “Biology of Aging and HF Management” during the 14th Annual Scientifi c Meeting of the Heart Failure Society of America in San Diego.

As the American pop singers Sonny and Cher put it, “ the beat goes on …” And the beat must go on. In this book, a group of invited clinician-scientists discuss pertinent aspects of aging and HF. The book is organized into two sections. Chapters 1 – 20 discuss clinical issues, and Chapters 21 – 32 explore molecular mechanisms. In the chapters in the fi rst section, I deal with the changing demographics in the aging population with HF and the pertinent aspects of the biology of aging in therapy of HF. I address HF prevention strat-egies in the context of the aging continuum and chronological versus biologi-cal aging and discuss promotion of healthy aging through education on CV risk factors and prevention through aggressive CV risk management. There is increasing need for development and discovery of novel targets and therapies pertinent to the growing elderly population in order to ensure that they enjoy the extended life span and continue to contribute meaningfully to society if they so choose. Since the changes with aging are progressive and a host of risk factors damage the CV system during aging, improving the lot of the older, elderly, and oldest elderly segments depends to some extent on the success of preventative measures in the young, beginning in early childhood.

Chapter 3 presents a masterful discussion of HTN and prevention of dia-stolic HF in the aging population. Chapter 4 discusses therapy of systolic HF. Atrial fi brillation in the aging population is explored in Chapter 5 . Chapter 6 discusses optimizing therapy with monitoring in HF clinics. Chapter 7

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addresses cardiac remodeling in aging, HTN, and diastolic HF. Polypharmacy and adverse drug reactions with HF pharmacotherapy in the elderly are high-lighted in Chapter 8 . Chapter 9 presents vascular remodeling with aging and HF. Chapter 10 discusses biomarkers in optimal management of HF in the aging population. Benefi ts of exercise in the elderly and a review of the RAAS in HF are described in Chapters 11 and 12 . Chapter 13 addresses aging and diastolic dysfunction and the interplay with infl ammation and extracellular matrix regulation. We address improving outcome with reperfu-sion and vasodilator therapy in elderly patients with STEMI and HF in Chapter 14 . Erythropoietin therapy and the role of resistin in HF are reviewed in Chapters 15 and 16 . Chapter 17 discusses the role of coronary artery cal-cium in CV risk stratifi cation. We address the remodeling of the RAS, RAAS, and related pathways with aging and implications for therapy in Chapter 18 . The utility of mineralocorticoid receptor antagonists (MRAs) in the very old patient, in whom the age-related decrease in aldosterone levels is balanced by a novel pathway involving decreased 11βHSD-2 levels and cortisol-induced stimulation of the mineralocorticoid receptor, is discussed in Chapter 18 . Chapter 19 aging and right ventricular remodeling and failure secondary to pulmonary artery remodeling and pulmonary hypertension. Biomarkers of CV aging are discussed in Chapter 20 .

In the section on molecular mechanisms, the chapters focus on important translational research areas. Chapter 21 discusses the changes in the heart that accompany aging, from humans to molecules. Cell death and cell survival pathways are explored in Chapter 22 , and Chapter 23 addresses telomeres and telomerases. Chapter 24 discusses changes in infl ammation and fi brosis with aging. Alterations in extracellular matrix and ventricular remodeling after MI and calcium signaling and cardiac function in the aging heart are explored in Chapters 25 and 26 , respectively. Chapter 27 examines integrins and HF failure therapy with aging, and Chapter 28 discusses adipokines as novel biomarkers in aging and HF. Aging-related changes in cellular and molecular mechanisms of post-MI remodeling is addressed in Chapter 29 . Chapter 30 presents aging-related changes in mitochondrial function and implications for HF therapy. Finally, Chapters 31 and 32 , respectively, dis-cuss regulation of SERCA and implications in diastolic dysfunction in the aging heart and SMP-30 and aging-related cardiac remodeling and HF.

These chapters should give the readers an appreciation of the need for more research on the biology of CV aging, more evidence-based clinical trial data on the “older-elderly” HF patients, and new therapies for HF with preserved ejec-tion fraction (HF-PEF) as well as for HF with low ejection fraction (HF-low EF). Together, they point out that while longer life comes at a price, there is still hope and potential for novel targets and therapies in the near future.

In summary, this book provides a high profi le and valuable resource on the major clinical issues facing HF therapy in the elderly and molecular mecha-nisms of the changes with CV aging for both the present and future generations of healthcare professionals including physicians, clinician-scientists, research-ers, teachers, fellows, trainees, and students. It also provides a valuable resource on pertinent aspects of age-related changes in physiology, biochemistry, and pathophysiology that impact HF management in the elderly and important

Preface

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clinical issues in the care of the elderly HF patient. It is hoped that the book will stimulate future translational research targeted towards discovery and develop-ment for preventing, limiting, and reversing changes in pathways leading to the growing HF burden with aging and in the elderly. The invited leaders and established investigators in the fi eld have generously contributed 32 chapters on key topics. The reference lists are comprehensive and include key papers that are currently not easily accessed from PubMed or other search engines. The chapters suggest potential novel strategies that should receive attention in terms of translating basic research knowledge to application in patients at the bedside. I hope that the book will also prove useful for scientists and clinicians, students and teachers, and the industries interested in drug discovery research. While the list of topics is by no means comprehensive, the chapters address some major areas needing attention. To our knowledge, there is no other book on this topic to date.

Edmonton , AB , Canada Bodh I. Jugdutt, MD, MSc, DM, FRCPC, FACC, FACP, FAHA, FESC, FIACS

Preface

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We would like to thank all the contributors for their excellent chapters. We would also like to express our deepest appreciation for the preparation and editorial help provided by Catherine E. Jugdutt and especially Michael D. Sova at Springer.

Acknowledgments

xv

Contents

1 Changing Demographics of the Aging Population with Heart Failure and Implications for Therapy ..................... 1Bodh I. Jugdutt

2 Biology of Aging and Implications for Heart Failure Therapy and Prevention................................. 15Bodh I. Jugdutt

3 Hypertension and Prevention of Diastolic Heart Failure in the Aging Population ........................................ 35Wilbert S. Aronow, Maciej Banach, and Ali Ahmed

4 Aging and Optimal Therapy of Systolic Heart Failure in the Elderly ......................................................... 47Nakul Chander Sharma and Bodh I. Jugdutt

5 Atrial Fibrillation and Heart Failure in the Aging Population ................................................................ 65Pedram Kazemian and Bodh I. Jugdutt

6 Optimizing Therapy of Heart Failure in the Aging Population with Monitoring in Clinics ........................................ 85John R. Dimitry and Justin A. Ezekowitz

7 Cardiac Alterations in Aging, Hypertension, and Diastolic Heart Failure .......................................................... 95Edith Pituskin and D. Ian Paterson

8 Polypharmacy and Adverse Drug Reactions in the Aging Population with Heart Failure ............................... 107Michael W. Rich and William J. Nienaber

9 Age-Related Changes in Vascular Biology and Implications for Heart Failure Therapy in the Aging Population ............................................................... 117Michael Sean McMurtry

10 Biomarkers and Optimal Management of Heart Failure in the Aging Population ................................... 135Hanna K. Gaggin and James L. Januzzi Jr.

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11 Benefi ts of Exercise in the Elderly ............................................... 147Ezra A. Amsterdam and C. Tissa Kappagoda

12 The RAAS in Heart Failure: An Update on Clinical Trials and Opportunities for Therapy......................................... 165C.Tissa Kappagoda and Ezra A. Amsterdam

13 Aging and Diastolic Dysfunction: The Interplay of Infl ammation and Extracellular Matrix Regulation ............ 183Peter Moritz Becher, Dirk Westermann, and Carsten Tschöpe

14 Reperfusion and Vasodilator Therapy in Elderly Patients with STEMI and Heart Failure: Improving Outcomes .................................................................... 199Bodh I. Jugdutt, Anwar Jelani, Seraj Abualnaja, Nakul Chander Sharma, and Joseph Szeman Wong

15 Erythropoietin Therapy for Heart Failure ................................. 221Margarita Borovka and Mathew S. Maurer

16 Role of Resistin in Heart Failure in the Elderly ......................... 243Yasuchika Takeishi

17 Role of Coronary Artery Calcium in Cardiovascular Risk Stratifi cation and Management in the Aging Population ................................................................ 249Craig R. Butler and Paolo Raggi

18 Aging and Remodeling of the RAS and RAAS and Related Pathways: Implications for Heart Failure Therapy ..................................... 259Bodh I. Jugdutt

19 Aging and Right Ventricular Failure from Pulmonary Hypertension: Effect of Right Ventricular and Pulmonary Artery Remodeling ............................................ 291Joseph Szeman Wong and Bodh I. Jugdutt

20 Biomarkers of Cardiovascular Aging .......................................... 305Nirankar S. Neki, Paramjit S. Tappia, and Naranjan S. Dhalla

21 Changes in the Heart That Accompany Advancing Age: Humans to Molecules ....................................... 319Edward G. Lakatta, Harold A. Spurgeon, and Andrzej M. Janczewski

22 Aging-Related Changes in Cell Death and Cell Survival Pathways and Implications for Heart Failure Therapy ............................................................ 339Guido R.Y. De Meyer, Dorien M. Schrijvers, and Wim Martinet

Contents

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23 Aging-Related Changes in Telomeres and Telomerases and Implications for Heart Failure Therapy .............................. 351Pim van der Harst and Dirk J. van Veldhuisen

24 Aging-Associated Alterations in Myocardial Infl ammation and Fibrosis: Pathophysiological Perspectives and Clinical Implications ............................................................. 361Arti V. Shinde and Nikolaos G. Frangogiannis

25 Aging-Related Changes in Extracellular Matrix: Implications for Ventricular Remodeling Following Myocardial Infarction ................................................. 377Nguyen T. Nguyen, Andriy Yabluchanskiy, Lisandra E. de Castro Brás, Yu-Fang Jin, and Merry L. Lindsey

26 Calcium-Handling Defects and Changes in Cardiac Function in the Aging Heart ..................................... 391Adriana Adameova, Nirankar S. Neki, Paramjit S. Tappia, and Naranjan S. Dhalla

27 Integrins: Implications for Aging in Heart Failure Therapy ............................................................. 401Laura L. Daniel, William L. Joyner, Mahipal Singh, and Krishna Singh

28 Adipokines as Novel Biomarkers in Aging and Heart Failure .......................................................................... 411Ken Shinmura

29 Aging-Related Changes in Cellular and Molecular Mechanisms of Postinfarction Remodeling: Implications for Heart Failure Therapy ..................................... 427Henry Han-Jen Shih and Andrew J. Boyle

30 Aging-Related Changes in Mitochondrial Function and Implication for Heart Failure Therapy ............................... 439Satoaki Matoba, Atsushi Hoshino, and Hiroaki Matsubara

31 Regulation of SERCA Via Oxidative Modifi cations: Implications for the Pathophysiology of Diastolic Dysfunction in the Aging Heart ................................................... 449Fuzhong Qin, Richard A. Cohen, and Wilson S. Colucci

32 SMP30 and Aging-Related Cardiac Remodeling and Heart Failure .......................................................................... 457Satoshi Suzuki and Yasuchika Takeishi

Index ....................................................................................................... 465

Contents

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Seraj Abualnaja, MDDS, FRCPC Division of Cardiology, Department of Medicine , University of Alberta , Edmonton , AB , Canada

Adriana Adameova, PharmD, PhD Department of Pharmacology and Toxicology , Comenius University , Bratislava , Slovak Republic

Ali Ahmed, MD, MPH Department of Medicine , University of Alabama School of Medicine at Birmingham , Birmingham , AL , USA

Department of Medicine , Veterans Affairs Medical Center , Birmingham , AL , USA

Ezra A. Amsterdam, MD Department of Internal Medicine , University of California, Davis , Sacramento , CA , USA

Wilbert S. Aronow, MD Department of Medicine , Westchester Medical Center/New York Medical College , Valhalla , NY , USA

Cardiology Division, New York Medical College, Macy Pavilion, Valhalla, NY, USA

Maciej Banach, MD, FAHA, FESC Department of Hypertension , Medical University of Lodz , Lodz , Poland

Peter Moritz Becher, MD Department of General and Interventional Cardiology , University Heart Center Hamburg Eppendorf , Hamburg , Germany

Margarita Borovka, BA University at Buffalo School of Medicine , Staten Island , NY , USA

Andrew J. Boyle, MBBS, PhD Department of Cardiology, University of Newcastle, John Hunter Hospital, Newcastle, NSW, Australia

Craig R. Butler, MSc, MD Division of Cardiology , Mazankowski Alberta Heart Institute , Edmonton , AB , Canada

Richard A. Cohen, MD Department of Medicine , Boston University School of Medicine , Boston , MA , USA

Wilson S. Colucci, MD Boston University Medical Center , Boston , MA , USA

Laura L. Daniel, BS Department of Biomedical Sciences , East Tennessee State University , Johnson City , TN , USA

Contributors

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Lisandra E. de Castro Brás, PhD San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi, Jackson, MS, USA

Guido R.Y. De Meyer, PharmD, PhD Department of Physiopharmacology , University of Antwerp , Antwerp , Belgium

Naranjan S. Dhalla, PhD, MD (Hon), DSc (Hon) Department of Physiology , Faculty of Medicine, Institute of Cardiovascular Sciences, University of Manitoba , Winnipeg , MB , Canada

John R. Dimitry, MD, MPH, FRCPC Division of Cardiology, Department of Medicine, University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, AB, Canada

Justin A. Ezekowitz, MBBCh, MSc Division of Cardiology, Department of Medicine , University of Alberta , Edmonton , AB , Canada

Nikolaos G. Frangogiannis, MD Department of Medicine (Cardiology) , Albert Einstein College of Medicine , Bronx , NY , USA

Hanna K. Gaggin, MD, MPH Department of Medicine, Cardiology Division , Massachusetts General Hospital , Boston , MA , USA

Atsushi Hoshino, MD Department of Cardiovascular Medicine , Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kyoto , Japan

Andrzej M. Janczewski, MD, PhD Department of Internal Medicine, PCK Marine Hospital, Gdynia, Poland

James L. Januzzi Jr ., MD Cardiology Division, Department of Medicine , Massachusetts General Hospital , Boston , MA , USA

Anwar Jelani, MBBS, SBIM, FACC Department of Medicine , Section of Cardiology, King Abdulaziz Hospital , Al-Hasa , Saudi Arabia

Yu-Fang Jin, PhD San Antonio Cardiovascular Proteomics Center, Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, TX, USA

William L. Joyner, PhD Department of Biomedical Sciences , East Tennessee State University , Johnson City , TN , USA

Bodh I. Jugdutt, MD, MSc, DM, FRCPC 2C2 W.C. Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine , Mazankowski Alberta Heart Institute, University of Alberta and Hospitals , Edmonton , AB , Canada

C. Tissa Kappagoda, MBBS, PhD Department of Internal Medicine , University of California, Davis , Sacramento , CA , USA

Pedram Kazemian, MD, MSc Department of Cardiac Electrophysiology , Brigham and Women’s Hospital/Harvard , Newton , MA , USA

Contributors

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Edward G. Lakatta, MD National Institute on Aging/NIH , Baltimore , MD , USA

Merry L. Lindsey, PhD San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi, Jackson, MS, USA

Department of Physiology and Biophysics, University of Mississippi Medical Center, MS, USA

Wim Martinet, PhD Department of Physiopharmacology , University of Antwerp , Antwerp , Belgium

Satoaki Matoba, MD, PhD Department of Cardiovascular Medicine , Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kyoto , Japan

Hiroaki Matsubara, MD, PhD Department of Cardiovascular Medicine , Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kyoto , Japan

Mathew S. Maurer, MD Department of Medicine , Columbia University Medical Center , New York , NY , USA

Michael Sean McMurtry, MD, PhD Division of Cardiology, Department of Medicine , University of Alberta , Edmonton , AB , Canada

Nirankar S. Neki, MD, FRCP, FACP (USA), FAMS Department of Internal Medicine , Government Medical College and Guru Nanak Dev. Hospital , Amritsar , Punjab , India

Nguyen T. Nguyen, MS San Antonio Cardiovascular Proteomics Center, Department of Electrical and Computer Engineering , University of Texas at San Antonio , San Antonio , TX , USA

William J. Nienaber, MD Cheyenne Cardiology Associates , Cheyenne , WY , USA

D. Ian Paterson, MD, FRCPC Department of Cardiology/Medicine , Mazankowski Alberta Heart Institute, University of Alberta , Edmonton , AB , Canada

Edith Pituskin, PhD(c) Department of Oncology , University of Alberta, Cross Cancer Institute , Edmonton , AB , Canada

Fuzhong Qin, MD, PhD Cardiovascular Medicine Section , Boston University Medical Center , Boston , MA , USA

Paolo Raggi, MD Division of Cardiology , Mazankowski Alberta Heart Institute , Edmonton , AB , Canada

Michael W. Rich, MD Washington University School of Medicine , St. Louis , MO , USA

Dorien M. Schrijvers, PhD Department of Physiopharmacology , University of Antwerp , Antwerp , Belgium

Contributors

xxii

Nakul Chander Sharma, MD, FRCP Division of Cardiology, Department of Medicine , Mazankowski Heart Institute , Edmonton , AB , Canada

Henry Han-Jen Shih, MD School of Medicine, Tufts University , Boston , MA , USA

Arti V. Shinde, PhD Department of Medicine (Cardiology) , Albert Einstein College of Medicine , Bronx , NY , USA

Ken Shinmura, MD, PhD, FAHA Division of Geriatric Medicine, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan

Mahipal Singh, PhD Department of Biomedical Sciences , East Tennessee State University , Johnson City , TN , USA

Krishna Singh, PhD Department of Biomedical Sciences , East Tennessee State University , Johnson City , TN , USA

Harold A. Spurgeon, PhD Laboratory of Cardiovascular Science , National Institute on Aging, National Institutes of Health , Baltimore , MD , USA

Satoshi Suzuki, MD, PhD Department of Advanced Cardiac Therapeutics , Fukushima Medical University , Fukushima , Japan

Yasuchika Takeishi, MD, PhD Department of Cardiology and Hematology , Fukushima Medical University , Fukushima , Japan

Paramjit S. Tappia, PhD Offi ce of Clinical Research, Asper Clinical Research Institute, St. Boniface Hospital Research , Winnipeg , MB , Canada

Carsten Tschöpe, MD Department of Cardiology and Angiology , Charité - Universitätsmedizin Berlin , Berlin , Germany

Pim van der Harst, MD, PhD Department of Cardiology , University Medical Center Groningen, University of Groningen , Groningen , Netherlands

Dirk J. van Veldhuisen, MD, PhD Department of Cardiology , University Medical Center Groningen, University of Groningen , Groningen , Netherlands

Dirk Westermann, MD Department of General and Interventional Cardiology , University Heart Center Hamburg Eppendorf , Hamburg , Germany

Joseph Szeman Wong, MBBS, MRCP, FHKCP, FRCPC Division of Cardiology, Department of Medicine , University of Alberta Hospital , Edmonton , AB , Canada

Andriy Yabluchanskiy, MD, PhD San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi, Jackson, MS, USA

Contributors