Pathophysiology and Pharmacotherapy of Cardiovascular Disease

Gowraganahalli Jagadeesh • Pitchai Balakumar Khin Maung-U Editors

Pathophysiology and Pharmacotherapy of Cardiovascular Disease

Adis

ISBN 978-3-319-15960-7 ISBN 978-3-319-15961-4 (eBook) DOI 10.1007/978-3-319-15961-4

Library of Congress Control Number: 2015937615

Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The opinions expressed are those of the respective chapter authors and do not necessarily represent those of their employers or the editors and their employers. The editors, publisher or any other party involved in the preparation of this work are not responsible for any inaccurate or incomplete information provided in this book. Readers should confi rm the accuracy of the information contained in the book from other currently available sources considering the fact that the drug related information might change over the time. The editors and publisher of this book do not undertake any liability for any inconvenience arising from use of this book, either print or electronic media.

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Editors Gowraganahalli Jagadeesh Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products US Food and Drug Administration Silver Spring , MD USA

Pitchai Balakumar Pharmacology Unit AIMST University Bedong Malaysia

Khin Maung-U Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products US Food and Drug Administration Silver Spring , MD USA

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Pref ace

With the advance of modern civilization, the historical causes of death in human populations such as war, drought, famine and the spread of microbes have been replaced by a new wave of global killers: ‘non-communicable diseases (NCDs)’. According to the World Health Organization report, NCDs kill 38 million people each year, with cardiovascular diseases (CVDs) accounting for most NCD deaths (17.5 million deaths, or 46.2 % of NCD deaths). Urbanization, industrialization, globalization and a larger ageing population have amplifi ed the role of NCDs in global mortality and morbidity. NCDs affect both men and women, devastating both rich and poor nations alike, although more people in poor nations are more likely to die as they lack access to lifesaving medicines. In the past, we tussled against nature to combat communicable diseases; now, it is a battle against the lifestyles, dietary habits and indulgences of human nature to combat these NCDs, of which one important battlefront is to prevent, delay and effectively treat CVDs and promote global cardiovascular health.

While we are acquainted with a lot of information about CVDs and relevant treatment strategies, we still need to know more about current advances in CVD patterns, pathophysiology, diagnosis and pharmacotherapy. In addition, there is a constant stream of newly approved medicines entering the pharmaceutical drug market necessitating periodical updates in drug information to meet the rational use of drugs. We have attempted to collate here the knowledge of experts in different aspects of CVDs. This effort has been an innovative collaboration of global clini-cians and scientists with the goal of advancing our thinking and testing new approaches to combat CVDs. Keeping these principles in mind, our authors have narrated the basic understanding of physiology and pathophysiology of the cardio-vascular system, its regulation, and its excessive indulgence or over-activation caus-ing an imbalance in the neural and hormonal systems to release harmful factors/chemicals changing the integrity of the cells, tissues and organs to precipitate disease(s). Applying the fi ndings from these studies, treatment algorithms were generated by the authors, giving detailed descriptions of complex cellular mecha-nisms of drug action for the CVDs described in each chapter.

vi

The book has eight major sections comprising 62 chapters. The emphasis is clinical, covering all key areas such as heart failure, cardiac hypertrophy and cardiomyopathy, coronary heart disease, atherosclerosis and hyperlipidemia, hypertension, cardiac arrhythmias, valvular heart diseases and cardiovascular conditions of childhood and pregnancy. Emerging areas of cardiovascular therapies such as cell and gene therapy, microRNA therapeutics, biomarkers, devices and mechanical approaches to control diseases are presented in addition to classic pharmacologic and therapeutic approaches. The editors are greatly indebted to all authors and co- authors for the expert write-up of their respective chapters in a fi eld that is dynamic and ever growing.

Our objective is to provide meaningful guidance in understanding and treating CVDs. This book is not just a database of therapeutics for CVDs. This book is particularly intended for pharmaceutical, biomedical and health science professionals. We have tried our level best to make the subject contents interesting and thought provoking. This book offers an opportunity for readers to keep abreast of recent advances in the practice of cardiovascular medicine. We sincerely welcome comments and suggestions from readers.

We are grateful to Dr. Amitabh Prakash, Editor of Clinical Pharmacokinetics and the American Journal of Cardiovascular Drugs for having initiated the project and for his timely advice in the preparation of the book. We are also pleased to acknowledge the indispensable role played by Ms. Lorna Venter-Lewis, Ms. Ursula Gramm, Mr. Gurunadham Prasad and Mr. PremLal Prejith of Springer in the prepa-ration of this book.

The opinions expressed in the book are those of the respective chapter authors and do not necessarily represent those of the editors and their employers.

Silver Spring , MD , USA Gowraganahalli Jagadeesh Bedong , Malaysia Pitchai Balakumar Silver Spring , MD , USA Khin Maung-U

Preface

vii

Contents

Part I Heart Failure

1 Heart Failure, Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Tina Shah, Nicholas Palaskas, and Biykem Bozkurt

2 Cardiac Prevention Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21John W. McEvoy, Roger S. Blumenthal, and Erin D. Michos

3 Pathophysiology of Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Leany Capote, Ruth Nyakundi, Brandon Martinez, and Anastasios Lymperopoulos

4 Calcium Signaling in Cardiovascular Physiology and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Nadjib Hammoudi and Djamel Lebeche

5 Sympathetic Nervous System Signaling in Heart Failure and Cardiac Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Gaetano Santulli

6 The Parasympathetic Nervous System and Heart Failure: Pathophysiology and Potential Therapeutic Modalities for Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Brian Olshansky, Renee M. Sullivan, Wilson S. Colucci, and Hani N. Sabbah

7 Risk for Sudden Cardiac Death in Heart Failure: Underlying Mechanisms and Therapeutic Modalities . . . . . . . . . . . . 129Philip B. Adamson, Emilio Vanoli, and Eduardo Gronda

8 Pharmacological Management of Heart Failure and Device Therapy in Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . . 151Jens Jakob Thune and Finn Gustafsson

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9 Exercise in Heart Failure: Effectiveness Versus Safety . . . . . . . . . . . 165Stuart D. Russell

10 Cardiac Muscle and the Troponins . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Elizabeth A. Hausner

11 Circulating Cardiac Troponins as Specifi c Biomarkers of Myocardial Damage: Clinical Considerations . . . . . . . . . . . . . . . . 193Karen A. Hicks

12 Natriuretic Peptides and Biomarkers in the Diagnosis of Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Nicholas Phreaner, Kevin Shah, and Alan Maisel

13 MicroRNAs in Cardiovascular Disease: From Pathogenesis to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Ioana Barb, Britta Vogel, Hugo A. Katus, and Benjamin Meder

14 MicroRNA Therapeutics in Cardiovascular Disease . . . . . . . . . . . . . 253Antoine Bril

15 Gene Therapy in Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . 265Michael G. Katz, Anthony S. Fargnoli, Andrew P. Kendle, and Charles R. Bridges

Part II Cardiac Hypertrophy and Cardiomyopathy

16 Cardiac Hypertrophy and Hypertrophic Cardiomyopathy: Introduction and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291Roy Beigel, Robert J. Siegel, and Florian Rader

17 Myocardial Metabolic Abnormalities and Cardiac Dysfunction . . . 325Petra C. Kienesberger

18 Molecular Targets in the Treatment of Cardiac Hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Christian Kuhn, Susanne Hille, and Norbert Frey

Part III Coronary Heart Disease

19 Acute Coronary Syndromes: Introduction and Pathophysiologic Classifi cation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Kjell Nikus and Yochai Birnbaum

20 Pathophysiology and Management of Myocardial Infarction . . . . . . 397Mahmoud H. Abdou, Niels Engberding, and Nanette K. Wenger

21 Pathophysiology and Lifetime Risk Factors for Atherosclerosis and Coronary Artery Disease in Women and in the Elderly . . . . . . . 425Stacy Westerman, Niels Engberding, and Nanette K. Wenger

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22 Medical Management of Chronic Stable Angina . . . . . . . . . . . . . . . . 443John D. Parker

23 Therapy for Acute Coronary Syndrome and Unstable Angina. . . . . 467Daniel M. Shivapour and A. Michael Lincoff

24 Drug-Eluting Stents and Coronary Artery Disease . . . . . . . . . . . . . . 495Eliano Pio Navarese, Mariusz Kowalewski, and Michalina Kołodziejczak

Part IV Atherosclerosis and Hyperlipidemia

25 Atherosclerosis, Introduction and Pathophysiology . . . . . . . . . . . . . . 527Kazuyuki Yahagi, Harry R. Davis, Michael Joner, and Renu Virmani

26 Vascular Endothelial Dysfunction and Atherosclerosis: Role of Nitric Oxide System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547Estelle R. Simo Cheyou and Ashok K. Srivastava

27 Cardioprotective Role of Omega-3 Polyunsaturated Fatty Acids Through the Regulation of Lipid Metabolism . . . . . . . . . . . . . 563Kayode A. Balogun and Sukhinder K. Cheema

28 Prevention and Treatment of Atherosclerotic Vascular Disease: Hypolipidemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589Antonio M. Gotto Jr. and Henry J. Pownall

29 Prevention of Cardiovascular Disease: The Polypill Concept . . . . . . 613Prem Pais, Deepak Y. Kamath, Alben Sigamani, and Denis Xavier

Part V Hypertension

30 Hypertension: Introduction, Types, Causes, and Complications . . . . 635Yoshihiro Kokubo, Yoshio Iwashima, and Kei Kamide

31 Pathophysiology of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655Michel Burnier and Grégoire Wuerzner

32 Blood Pressure Genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685Georg B. Ehret

33 Hypertension and Vascular Endothelial Growth Factors . . . . . . . . . 695Marcelo Rizzatti Luizon and Valeria Cristina Sandrim

34 Role of Gi Proteins in Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . 709Yuan Li and Madhu B. Anand-Srivastava

35 Sympathetic and Renin–Angiotensin Activity in the Pathophysiology of Hypertension . . . . . . . . . . . . . . . . . . . . . . . 723Adrian Covic and Liviu Segall

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36 Drugs Targeting RAAS in the Treatment of Hypertension and Other Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 751Pitchai Balakumar and Gowraganahalli Jagadeesh

37 Calcium Channel Blockers in the Treatment of Hypertension . . . . . 807Yoshihiko Kanno, Yoichi Ohno, and Tsuneo Takenaka

38 Diuretics for the Treatment of Hypertension . . . . . . . . . . . . . . . . . . . 823Domenic A. Sica

39 Centrally Acting Antihypertensive Agents in the Treatment of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853Domenic A. Sica

40 Vasodilators and Management of Hypertensive Emergencies. . . . . . 869Jaya Mallidi, C. Gabriela Macías, and Amir S. Lotfi

41 Combination Therapy for the Clinical Management of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887Giuliano Tocci and Massimo Volpe

42 Resistant Hypertension: Defi nition, Prevalence, and Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903Anthony J. Viera

43 Drug Adherence in Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919Michel Burnier

44 The Glycemic Consequences of Antihypertensive Medications . . . . 935Joshua I. Barzilay, Paul K. Whelton, and Barry R. Davis

45 Pathophysiology and Treatment of Pulmonary Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949Nina Rol, Christophe Guignabert, and Harm Jan Bogaard

Part VI Cardiac Arrhythmias

46 Cardiac Arrhythmias: Introduction, Electrophysiology of the Heart, Action Potential and Membrane Currents . . . . . . . . . . 977Norbert Jost, Danina M. Muntean, and Torsten Christ

47 Pathophysiology of Cardiac Arrhythmias: Arrhythmogenesis and Types of Arrhythmias . . . . . . . . . . . . . . . . . . 1003Peter P. Karpawich

48 Proarrhythmic Effects of Antiarrhythmic and Non-antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015J. William Schleifer and Komandoor Srivathsan

Contents

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49 Drug-Induced Prolongation of the QT Interval: Present and Future Challenges for Drug Discovery . . . . . . . . . . . . . . 1039Gary Gintant and Jean-Pierre Valentin

50 Treatment of Atrial Fibrillation and Atrial Flutter . . . . . . . . . . . . . . 1059Torsten Christ, Simon Pecha, and Norbert Jost

51 Use of Mechanical Devices to Reduce Stroke in Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081Peter Pollak and David Holmes

52 Antiarrhythmic Drugs and Management of Ventricular Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101J. William Schleifer and Komandoor Srivathsan

53 Cardiac Arrest and Cardiopulmonary Resuscitation: Recent Advances in Management Approach for Cardiopulmonary Resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . 1135Allan R. Mottram and Karen Serrano

Part VII Valvular Heart Disease

54 Valvular Heart Disease: Introduction, Clinical Pathogenesis, and Management . . . . . . . . . . . . . . . . . . . . . . . 1151Siri Kunchakarra, Jyothy Puthumana, and Kameswari Maganti

55 Mitral Regurgitation in Heart Failure: Mechanisms and Therapeutic Options. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187Michael Huntgeburth and Volker Rudolph

56 Pathophysiology and Management of Functional Tricuspid Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201Jason H. Rogers and Steven F. Bolling

57 Aortic Valve Stenosis and Aortic Regurgitation: Pathophysiology and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221Wilbert S. Aronow

58 Induction of Valvular Heart Disease by Pharmacological Interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247Steven Droogmans and Bernard Cosyns

Part VIII Cardiovascular Conditions of Childhood and Pregnancy

59 Pathophysiology and Pharmacotherapy of Adult Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1269Anushree Agarwal, Saurabh Aggarwal, and Ian S. Harris

Contents

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60 Cardiac Disease in Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1293Henry Boardman and Lucy Mackillop

61 Placental Insuffi ciency: The Impact on Cardiovascular Health in the Mother and Her Offspring Across the Lifespan. . . . . . . . . . . . 1315John Henry Dasinger, Suttira Intapad, and Barbara T. Alexander

62 miRNAs in Cardiovascular Development . . . . . . . . . . . . . . . . . . . . . . 1331Katharina K. Wystub and Thomas Boettger

Contents

xiii

Contributors

Mahmoud H. Abdou , MD Cardiology Fellow, Division of Cardiology, Department of Medicine , Emory University School of Medicine , Atlanta , GA , USA

Philip B. Adamson , MD, FACC Director, Heart Failure Institute, Oklahoma Heart Hospital , Oklahoma City , OK , USA

Adjunct Associate Professor, Department of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City , OK , USA

Anushree Agarwal , MD Advanced Fellow in Adult Congenital Cardiology, Division of Cardiology, University of California School of Medicine , San Francisco , CA , USA

Saurabh Aggarwal , MD Cardiology Fellow, Division of Cardiology, Creighton University School of Medicine , Omaha , NE , USA

Barbara T. Alexander , PhD Professor, Department of Physiology and Biophysics, Director, Basic Research Center for Developmental Disorders Research , Center for Cardiovascular and Renal Research, Women’s Health Research Center, University of Mississippi Medical Center , Jackson , MS , USA

Madhu B. Anand-Srivastava , PhD Professor, Department of Molecular and Integrative Physiology, Faculty of Medicine , University of Montreal , Montreal , QC , Canada

Wilbert S. Aronow , MD, FACC, FAHA Professor, Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine , New York Medical College , Valhalla , NY , USA

Pitchai Balakumar , PhD Associate Professor and Head, Pharmacology Unit, Faculty of Pharmacy , AIMST University , Bedong , Kedah Darul Aman , Malaysia

Kayode A. Balogun , PhD Department of Biochemistry , Memorial University , St. John’s , NL , Canada

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Ioana Barb , MD Department of Internal Medicine III , University of Heidelberg, University Hospital of Heidelberg , Heidelberg , Germany

Joshua I. Barzilay , MD Kaiser Permanente of Georgia and Emory University School of Medicine , Duluth , GA , USA

Roy Beigel , MD Division of Cardiology, Department of Medicine , The Heart Institute Cedars Sinai Medical Center , Los Angeles , CA , USA

The Leviev Heart Center, Sheba Medical Center , Tel Hashomer , Israel

The Sackler School of Medicine, Tel Aviv University , Tel Aviv , Israel

Yochai Birnbaum , MD, FACC, FAHA Professor of Medicine, John S. Dunn Chair in Cardiology Research and Education, Section of Cardiology, Department of Medicine , Baylor College of Medicine , Houston , TX , USA

Roger S. Blumenthal , MD Director, Division of Cardiology, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Professor of Medicine, Johns Hopkins University School of Medicine , Baltimore , MD , USA

Henry Boardman , MBBS, BSc Cardiovascular Clinical Research Facility, Department of Cardiovascular Medicine , University of Oxford, John Radcliffe Hospital , Headley Way, Oxford , UK

Thomas Boettger , PD Dr. rer. nat. Max-Planck-Institut fuer Herz- und Lungenforschung , Department of Cardiac Development and Remodelling , Bad Nauheim , Germany

Harm Jan Bogaard , MD Associate Professor, Department of Pulmonary Medicine , VU University Medical Center , Amsterdam , The Netherlands

Steven F. Bolling , MD Professor of Cardiac Surgery, University of Michigan Cardiovascular Center, University of Michigan , Ann Arbor , MI , USA

Biykem Bozkurt , MD, PhD, FACC, FAHA Professor of Medicine, Cardiology Section, Department of Medicine , Michael E. DeBakey Veterans Affairs Medical Center, Winters Center for Heart Failure Research, Cardiovascular Research Institute, Baylor College of Medicine , Houston , TX , USA

Charles R. Bridges , MD, ScD, FACC, FACS Professor and Chairman, Department of Cardiovascular Surgery , Sanger Heart and Vascular Institute, Carolinas HealthCare System , Charlotte , NC , USA

Antoine Bril , PharmD, PhD Scientifi c Director Research and Partnerships , Institut de Recherches Internationales Servier , Suresnes Cedex , France

Michel Burnier , MD Professor, Service of Nephrology and Hypertension, Department of Medicine , Centre Hospitalier Universitaire Vaudois (CHUV) , Lausanne , Switzerland

Leany Capote Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences , Nova Southeastern University College of Pharmacy , Ft. Lauderdale , FL , USA

Contributors

xv

Sukhinder K. Cheema , PhD Professor & Deputy Head (Graduate Studies), Department of Biochemistry , Memorial University , St. John’s , NL , Canada

Estelle R. Simo Cheyou , PhD Laboratory of Cell Signaling , Research Center of the University of Montreal Hospital, Center Department of Nutrition , Montreal , QC , Canada

Department of Nutrition, University of Montreal , Montreal , QC , Canada

Torsten Christ , MD Associate professor, Department of Experimental Pharmacology and Toxicology , University Medical Center, Hamburg-Eppendorf , Hamburg , Germany

Wilson S. Colucci , MD Professor, Department of Medicine, Boston University , Boston , MA , USA

Bernard Cosyns , MD, PhD Professor, In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Department of Cardiology, Vrije Universiteit Brussel , Jette , Belgium

Adrian Covic , MD, PhD, FRCP (London), FERA Nephrology Clinic, Parhon University Hospital, Gr. T. Popa University of Medicine and Pharmacy , Iasi , Romania

John Henry Dasinger , PhD Department of Physiology and Biophysics , Center for Cardiovascular and Renal Research, Women’s Health Research Center, University of Mississippi Medical Center , Jackson , MS , USA

Barry R. Davis , MD, PhD Guy S. Parcel Chair in Public Health, University of Texas School of Public Health , Houston , TX , USA

Harry R. Davis , PhD CVPath Institute, Inc. , Gaithersburg , MD , USA

Steven Droogmans , MD, PhD Department of Cardiology , UZ Brussel , Jette , Belgium

In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Department of Cardiology, Vrije Universiteit Brussel , Jette , Belgium

Georg B. Ehret , MD Department of Cardiology , Geneva University Hospitals, Rue Gabrielle-Perret-Gentil , Geneva , Switzerland

Center for Complex Disease Genomics , McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine , Baltimore , MD , USA

Niels Engberding , MD, FACC, FESC Assistant Professor, Division of Cardiology, Department of Medicine , Emory University School of Medicine , Atlanta , GA , USA

Anthony S. Fargnoli , PhD Department of Cardiovascular Surgery , Sanger Heart and Vascular Institute, Carolinas HealthCare System , Charlotte , NC , USA

Norbert Frey , MD Professor and Chair, Department of Internal Medicine III – Cardiology and Angiology , University Medical Center of Schleswig-Holstein , Kiel , Germany

Contributors

xvi

Gary Gintant , PhD Department of Integrative Pharmacology , Integrated Science and Technology , North Chicago , IL , USA

Antonio M. Gotto Jr. , MD, DPhil Dean Emeritus and Co-Chair of the Board of Overseers, Lewis Thomas University Professor, Houston Methodist Research Institute , Weill Cornell Medical College , New York , NY , USA

Vice President and Provost for Medical Affairs Emeritus, Department of Medicine , Cornell University , New York , NY , USA

Eduardo Gronda , MD Department of Cardiovascular Medicine , IRCCS, MultiMedica , Sesto San Giovanni , Italy

Christophe Guignabert , PhD INSERM U999 , Université Paris Sud , Le Plessis- Robinson , France

Finn Gustafsson , MD, PhD, DMSci Consultant cardiologist, Medical director cardiac transplantation and MCS, Department of Cardiology B2142 , Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark

Nadjib Hammoudi , MD Institut de Cardiologie , Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris , Paris , France

Ian S. Harris , MD, FACP, FACC Associate Professor of Medicine, Director, Adult Congenital Cardiology Program, Division of Cardiology , University of California School of Medicine , San Francisco , CA , USA

Elizabeth A. Hausner , DVM, DABT, DABVT Senior Pharmacologist, Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research (CDER) , US Food and Drug Administration , Silver Spring , MD , USA

Karen A. Hicks , MD Medical Offi cer, Division of Cardiovascular and Renal Products , Center for Drug Evaluation and Research (CDER), US Food and Drug Administration , Silver Spring , MD , USA

Susanne Hille Department of Internal Medicine III – Cardiology and Angiology , University Medical Center of Schleswig-Holstein , Kiel , Germany

David Holmes , MD Division of Cardiology , Mayo Clinic , Rochester , MN , USA

Michael Huntgeburth , MD Department of Cardiology , Clinic III for Internal Medicine, Heart Center, University of Cologne , Cologne , Germany

Suttira Intapad , PhD Department of Physiology and Biophysics , Center for Cardiovascular and Renal Research, Women’s Health Research Center, University of Mississippi Medical Center , Jackson , MS , USA

Yoshio Iwashima , MD, PhD, FAHA Divisions of Hypertension and Nephrology , National Cerebral and Cardiovascular Center , Suita , Osaka , Japan

Gowraganahalli Jagadeesh , PhD Senior Expert Pharmacologist, Division of Cardiovascular and Renal Products , Center for Drug Evaluation and Research, US Food and Drug Administration (FDA) , Silver Spring , MD , USA

Contributors

xvii

Michael Joner , MD CVPath Institute, Inc. , Gaithersburg , MD , USA

Norbert Jost , PhD Associate professor, Division of Cardiovascular Pharmacology, Department of Pharmacology and Pharmacotherapy , University of Szeged , Szeged , Hungary

Department of Pharmacology, “Victor Babes” University of Medicine and Pharmacy , Timisoara , Romania

Deepak Y. Kamath , MD Division of Clinical Research and Training, Department of Medicine , St. John’s Research Institute and Medical College , Bengaluru , India

Kei Kamide , MD, PhD, FAHA Division of Health Science , Osaka University Graduate School of Medicine , Suita , Osaka , Japan

Yoshihiko Kanno , MD Department of Nephrology , Tokyo Medical University , Shinjuku , Tokyo , Japan

Peter P. Karpawich , MSc, MD, FACC, FAHA, FHRS Section of Cardiology, Department of Pediatrics , The Children’s Hospital of Michigan, Wayne State University School of Medicine , Detroit , MI , USA

Hugo A. Katus , MD Department of Internal Medicine III , University of Heidelberg, University Hospital of Heidelberg , Heidelberg , Germany

DZHK (German Centre for Cardiovascular Research) , Heidelberg , Germany

Klaus Tschira Institute for Computational Cardiology, University of Heidelberg , Heidelberg , Germany

Michael G. Katz , MD, PhD Senior Scientist, Department of Cardiovascular Surgery , Sanger Heart and Vascular Institute, Carolinas HealthCare System , Charlotte , NC , USA

Andrew P. Kendle , BS Department of Cardiovascular Surgery , Sanger Heart and Vascular Institute, Carolinas HealthCare System , Charlotte , NC , USA

Petra C. Kienesberger , PhD Professor, Department of Biochemistry and Molecular Biology , Dalhousie University, Dalhousie Medicine New Brunswick , Saint John , New Brunswick , Canada

Yoshihiro Kokubo , MD, PhD, FAHA, FACC, FESC, FESO Chief Doctor, Department of Preventive Cardiology , National Cerebral and Cardiovascular Center , Suita , Osaka , Japan

Michalina Kołodziejczak , MD Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine , Heinrich-Heine-University , Düsseldorf , Germany

Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network , Düsseldorf , Germany

Contributors

xviii

Mariusz Kowalewski , MD Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine , Heinrich-Heine-University , Düsseldorf , Germany

Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network , Düsseldorf , Germany

Christian Kuhn , MD Department of Internal Medicine III – Cardiology and Angiology , University Medical Center of Schleswig-Holstein , Kiel , Germany

Siri Kunchakarra , MD Division of Cardiology, Department of Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Djamel Lebeche , PhD Professor, Department of Medicine , Cardiovascular Research Institute, Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai , New York , NY , USA

Yuan Li , MD Department of Molecular and Integrative Physiology, Faculty of Medicine , University of Montreal , Montreal , QC , Canada

A. Michael Lincoff , MD Vice Chairman, Department of Cardiovascular Medicine , Director, Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland Clinic , Cleveland , OH , USA

Amir S. Lotfi , MD Vice Chair, Cardiology, Director, Heart and Vascular Inpatient, Director, Regional MI program, Division of Cardiology , Baystate Medical Center, Tufts University , Springfi eld , MA , USA

Marcelo Rizzatti Luizon , PhD Department of Pharmacology , Institute of Biosciences, Universidade Estadual Paulista (UNESP) , Botucatu , SP , Brazil

Anastasios Lymperopoulos , BPharm, MSc, PhD, FAHA Assistant Professor of Pharmacology, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences , Nova Southeastern University College of Pharmacy , Ft. Lauderdale , FL , USA

C. Gabriela Macías, PharmD, BCPS Heart and Vascular Clinical Pharmacy Specialist , Baystate Medical Center, Acute Care Pharmacy Services , Springfi eld , MA , USA

Lucy Mackillop , MA, FRCP Consultant Obstetric Physician, Department of Obstetric Medicine , University of Oxford, Women’s Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital , Headley Way, Oxford , UK

Kameswari Maganti , MD Director of Cardiac Rehabilitation, Associate Professor of Medicine, Division of Cardiology, Department of Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Alan Maisel , MD, FACC Professor, Division of Cardiovascular Medicine, Department of Medicine , San Diego Veterans Affairs Healthcare System , San Diego , CA , USA

Contributors

xix

Jaya Mallidi , MD, MHS Cardiology Fellow, Division of Cardiology , Baystate Medical Center, Tufts University , Springfi eld , MA , USA

Brandon Martinez Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences , Nova Southeastern University College of Pharmacy , Ft. Lauderdale , FL , USA

John W. McEvoy , MB BCh, BAO, MRCPI Chief Fellow, Division of Cardiology , Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine , Baltimore , MD , USA

Benjamin Meder , MD Professor, Department of Internal Medicine III , University of Heidelberg, University Hospital of Heidelberg , Heidelberg , Germany

DZHK (German Centre for Cardiovascular Research) , Heidelberg , Germany

Klaus Tschira Institute for Computational Cardiology, University of Heidelberg , Heidelberg , Germany

Erin D. Michos , MD Division of Cardiology , Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine , Baltimore , MD , USA

Allan R. Mottram , MD Professor, Emergency Department , William S. Middleton Memorial Veterans Hospital, Madison, University of Wisconsin , Madison , WI , USA

Danina M. Muntean , MD Professor, Department of Pathophysiology , “Victor Babes” University of Medicine and Pharmacy , Timisoara , Romania

Eliano Pio Navarese , MD, PhD, FESC Professor, Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine , Heinrich-Heine-University , Düsseldorf , Germany

Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network , Düsseldorf , Germany

Kjell Nikus , MD, PhD Department of Cardiology , Tampere University Hospital and University of Tampere, Medical School , Tampere , Finland

Ruth Nyakundi , PhD Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences , Nova Southeastern University College of Pharmacy , Ft. Lauderdale , FL , USA

Yoichi Ohno , MD Department of Nephrology , Saitama Medical University , Iruma , Saitama , Japan

Brian Olshansky , MD Professor Emeritus, Division of Cardiology , University of Iowa Hospitals , Iowa City , IA , USA

Prem Pais , MD Professor of Medicine, Former Dean, St John’s Medical College, Head, Division of Clinical Research and Training , St John’s Medical College and Research Institute , Bangalore , India

Contributors

xx

Nicolas Palaskas , MD Cardiology Section 3C-332E , Michael E. DeBakey Veterans Affairs Medical Center, Winters Center for HF Research, Baylor College of Medicine , Houston , TX , USA

John D. Parker , MD, FRCP (C) Professor of Medicine and Pharmacology, Department of Medicine , Mount Sinai and University Health Network Hospitals, University of Toronto , Toronto , ON , Canada

Simon Pecha , MD Department of Cardiovascular Surgery, University Heart Center Hamburg , University Medical Center, Hamburg-Eppendorf , Hamburg , Germany

Nicholas Phreaner , MD Internal Medicine, Division of Cardiovascular Medicine, Department of Medicine , San Diego Veterans Affairs Healthcare System , San Diego , CA , USA

Peter Pollak , MD Director of Structural Heart Disease, Division of Cardiology , Mayo Clinic Florida , Jacksonville , FL , USA

Henry J. Pownall , PhD Director, Atherosclerosis and Lipoprotein Research, Houston Methodist Research Institute, Department of Cardiology , Weill Cornell Medical College , Houston , TX , USA

Jyothy Puthumana , MD Division of Cardiology, Department of Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Florian Rader , MD, MSc Cardiac Non-Invasive Lab, Division of Cardiology, Department of Medicine , Hypertension Center of Excellence, The Heart Institute Cedars Sinai Medical Center , Los Angeles , CA , USA

Jason H. Rogers , MD, FACC, FSCAI Director, Interventional Cardiology, Division of Cardiovascular Medicine , University of California, Davis Medical Center , Sacramento , CA , USA

Nina Rol , MD Department of Pulmonary Medicine , VU University Medical Center , Amsterdam , The Netherlands

Volker Rudolph , MD Department of Cardiology , Clinic III for Internal Medicine, Heart Center, University of Cologne , Cologne , Germany

Stuart D. Russell , MD Associate Professor of Medicine, Department of Medicine , Johns Hopkins University School of Medicine , Baltimore , MD , USA

Hani N. Sabbah , PhD Department of Medicine , Henry Ford Hospital , Detroit , MI , USA

Valeria Cristina Sandrim , PhD Department of Pharmacology , Institute of Biosciences, Universidade Estadual Paulista (UNESP) , Botucatu , SP , Brazil

Contributors

xxi

Gaetano Santulli , MD, PhD Department of Advanced Biomedical Sciences , “Federico II” University , Naples , Italy

College of Physicians and Surgeons, Columbia University Medical Center , New York , NY , USA

Liviu Segall , MD Nephrology Clinic, Parhon University Hospital, Gr. T. Popa University of Medicine and Pharmacy , Iasi , Romania

Karen Serrano , MD Department of Emergency Medicine, University of Wisconsin , Madison , WI , USA

Kevin Shah , MD Assistant Professor, Division of Cardiovascular Medicine, Department of Medicine , San Diego Veterans Affairs Healthcare System , San Diego , CA , USA

Tina Shah , MD Assistant Professor, Cardiology Section 3C-332E , Michael E. DeBakey Veterans Affairs Medical Center, Winters Center for HF Research, Baylor College of Medicine , Houston , TX , USA

Daniel M. Shivapour , MD Clinical and Research Fellow, Department of Cardiovascular Medicine , Cleveland Clinic , Cleveland , OH , USA

Domenic A. Sica , MD President, American Society of Hypertension, Professor of Medicine and Pharmacology, Chairman, Clinical Pharmacology and Hypertension, Section of Clinical Pharmacology and Hypertension, Division of Nephrology , Virginia Commonwealth University Health System , Richmond , VA , USA

Robert J. Siegel , MD, FACC Director, Cardiac Noninvasive Laboratory, Division of Cardiology, Department of Medicine , The Heart Institute Cedars Sinai Medical Center , Los Angeles , CA , USA

Alben Sigamani , MD, MSc (Clin. trials) Associate Professor, Department of Pharmacology , St. John’s Medical College and Research Institute, St. John’s National Academy of Health Sciences , Bengaluru , India

Ashok K. Srivastava , PhD Professor, Laboratory of Cell Signaling , Research Center of the University of Montreal Hospital Center , Montreal , QC , Canada

Department of Nutrition and Medicine , University of Montreal , Montreal , QC , Canada

Komandoor Srivathsan , MD Assistant Professor of Medicine, Division of Cardiovascular Diseases , Mayo Clinic Arizona , Phoenix , AZ , USA

Renee M. Sullivan , MD Covance, Princeton , NJ , USA

Tsuneo Takenaka , MD, PhD Professor, Department of Medicine , International University of Health and Welfare, Clinical Research Center , Minato Tokyo , Japan

Contributors

xxii

Jens Jakob Thune , MD, PhD Department of Cardiology B2142 , Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark

Giuliano Tocci , MD, PhD Assistant Professor in Cardiology, Hypertension Unit, Division of Cardiology, Department of Clinical and Molecular Medicine , University of Rome “Sapienza”, Sant’Andrea Hospital , Rome , Italy

Jean-Pierre Valentin , PhD Senior Director, Investigative Toxicology , UCB Biopharma SPRL , Braine-l’Alleud , Belgium

Emilio Vanoli , MD Department of Physiology , University of Oklahoma Health Sciences Center , Oklahoma City , OK , USA

Department of Molecular Medicine , University of Pavia , Sesto San Giovanni , Italy

Department of Cardiovascular Medicine , IRCCS, MultiMedica , Sesto San Giovanni , Italy

Anthony J. Viera , MD, MPH, FAHA Department of Family Medicine, Hypertension Research Program , University of North Carolina at Chapel Hill School of Medicine , Chapel Hill , NC , USA

Renu Virmani , MD Director, CVPath Institute, Inc. , Gaithersburg , MD , USA

Britta Vogel , MD Department of Internal Medicine III , University of Heidelberg, University Hospital of Heidelberg , Heidelberg , Germany

Massimo Volpe , MD, FAHA, FESC Professor and .Chair, Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology , University of Rome “Sapienza”, Sant’Andrea Hospital , Rome , Italy

IRCCS Neuromed , Pozzilli , Italy

Nanette K. Wenger , MD, MACC, MACP, FAHA Professor Emeritus, Division of Cardiology, Department of Medicine , Emory University School of Medicine , Atlanta , GA , USA

Emory Heart and Vascular Center , Lawrenceville , GA , USA

Stacy Westerman , MD, MPH Fellow, Cardiovascular Disease, Division of Cardiology, Department of Medicine , Emory University School of Medicine , Atlanta , GA , USA

Paul K. Whelton , MB, MD, MSc Show Chwan Professor of Global Public Health, Tulane University School of Public Health and Tropical Medicine , New Orleans , LA , USA

J. William Schleifer , MD Division of Cardiovascular Diseases , Mayo Clinic Arizona , Phoenix , AZ , USA

Grégoire Wuerzner , MD Service of Nephrology and Hypertension, Department of Medicine , Centre Hospitalier Universitaire Vaudois (CHUV) , Lausanne , Switzerland

Contributors

xxiii

Katharina K. Wystub , PD Dr. rer. nat. Department of Cardiac Development and Remodelling , Max-Planck-Institute of Heart and Lung Research , Bad Nauheim , Germany

Denis Xavier , MD, MSc (Clin Epi) Professor and Head, Department of Pharmacology, St. John’s Medical College , Bangalore , India

Division of Clinical Research and Training , St. John’s Research Institute and Medical College, St. John’s National Academy of Health Sciences , Bangalore , India

Kazuyuki Yahagi , MD Cardiovascular Research Fellow, CVPath Institute, Inc. , Gaithersburg , MD , USA

Contributors