MYOCARDIAL ISCHEMIA
From mechanisms to therapeutic potentials
BASIC SCIENCE FOR THE CARDIOLOGIST
1. B. Swynghedauw (ed.): Molecular Cardiology for the Cardiologist Second Edition. 1998 ISBN 0-7923-8323-0 2. B. Levy, A. Tedgui (eds.): Biology of the Arterial Wall 1999
ISBN 0-7923-845 8-X 3. M.R. Sanders, J.B. Kostis (eds.): Molecular Cardiology in Clinical
Practice. 1999 ISBN 0-7923-8602-7 4. B.Ostadal, F. Kolar (eds.): Cardiac Ischemia: From Injury to Protection. 1999
ISBN 0-7923-8642-6 5. H. Schunkert, G.A.J. Riegger (eds.): Apoptosis in Cardiac Biology. 1999
ISBN 0-7923-8648-5 6. A. Malliani, (ed.): Principles of Cardiovascular Neural Regulation in Health
and Disease. 2000 ISBN 0-7923-7775-3 7. P. Benlian: Genetics of Dyslipidemia. 2001 ISBN 0-7923-7362-6 8. D. Young: Role of Potassium in Preventive Cardiovascular Medicine. 2001
ISBN 0-7923-7376-6 9. E. Carmeliet, J. Vereecke: Cardiac Cellular Electrophysiology. 2001
ISBN 0-7923-7544-0 10. C. Holubarsch: Mechanics and Energetics of the Myocardium. 2002
ISBN 0-7923-7570-X 11. J.S, Ingwall: ATP and the Heart. 2002 ISBN 1-4020-7093-4 12. W.C. De Mello, M.J. Janse: Heart Cell Coupling and Impuse Propagation in
Health and Disease. 2002 ISBN 1 -4020-7182-5 13. P.P.-Dimitrow: Coronary Flow Reserve - Measurement and Application: Focus
on transthoracic Doppler echocardiography. 2002 ISBN 1-4020-7213-9 14. G.A. Danieli: Genetics and Genomics for the Cardiologist. 2002
ISBN 1-4020-7309-7 15. F.A. Schneider, I.R. Siska, J. A. Avram: Clinical Physiology of the Venous System.
2003. ISBN 1-4020-7411-5 16. Can Ince: Physiological Genomics of the Critically III Mouse. 2004
ISBN 1-4020-7641-X 17. Wolfgang Schaper, Jutta Schaper: Arteriogenesis. 2004
ISBN 1-4020-8125-1 elSBN 1-4020-8126-X
18. Nico Westerhof, Nikos Stergiopulos, Mark I.M. Noble: Snapshots of Hemodynamics:
An aid for clinical research and graduate education. 2005
ISBN 0-387-23345-8 elSBN 0-387-23346-6 19. Toshio Nishikimi: Adrenomedullin in Cardiovascular Disease. 2005
ISBN 0-387-25404-8 elSBN 0-387-25405-6 20. Edward D. Frohlich, Richard N. Re: The Local Cardiac Renin Angiotensin-
Aldosterone System. 2005 ISBN 0-387-27825-7 elSBN 0-387-27826-5
21. D.V. Cokkinos, C. Pantos, G. Heusch, H. Taegtmeyer: Myocardial Ischemia: From mechanisms to therapeutic potentials. 2005
ISBN 0-387-28657-8 elSBN 0-387-28658-6
MYOCARDIAL ISCHEMIA
From mechanisms to therapeutic potentials
Edited by
Dennis V. Cokkinos, MD, PhD University of Athens
Athens, Greece
Constantinos Pantos, MD, PhD University of Athens
Athens, Greece
Gerd Heusch, MD, PhD University of Essen
Essen, Germany
Heinrich Taegtmeyer, MD, DPhil The University of Texas Medical School
Houston, Texas, USA
1 3
Dennis V. Cokkinos Constantinos Pantos
Prof. of Cardiology Assistant Professor of Pharmadcology University of Athens Depart. Of Pharmacology, Medical School Chairman Cardiology Dept. University of Athens
Onassis Cardiac Surgery Center Athens, Greece Athens, Greece
Gerd Heusch Heinrich Taegtmeyer
Professor of Medicine Professor of Medicine
Director, Institute of Pathophysiology Co-Director, Division of Cardiology Department of Internal Medicine The University of Texas
University of Essen Houston Medical School
Essen, Germany Houston, Texas
USA
Library of Congress Cataloging-in-Publication Data
Myocardial ischemia: from mechanisms to therapeutic potentials / edited by D.V. Cokkinos, C. Pantos, G. Heusch and H. Taegtmeyer
p. ; cm. – (Basic science for the cardiologist ; 21) Includes bibliographical references and index.
ISBN-13: 978-0-387-28657-0 (alk. paper) ISBN-10: 0-387-28657-8 (alk. paper)
1. Coronary heart disease—Pathophysiology. 2. Coronary heart disease—Treatment. I.
Cokkinos, Dennis V. II. Series
[DNLM: 1. Myocardial Ischemia—physiopathology. 2. Myocardial Ischemia—therapy.
WG 300 M99764 2005]
RC685.C6M9585 2005 616.1’23—dc22
2005051640 ISBN -10 0-387-28657-8 e-ISBN 0-387-28658-6
ISBN -13 978-0-387-28657-0 e-ISBN 978-0-387-28658-7 Printed on acid-free paper.
¤ 2006 Springer Science+Business Media, Inc.
All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.
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CONTENTS
PREFACE ix INTRODUCTION: FROM FETAL TO FATAL. Metabolic adaptation
of the heart to environmental stress 1 Heinrich Taegtmeyer
1. THE LOGIC OF METABOLISM 2 2. SUBSTRATE SWITCHING AND METABOLIC FLEXIBILITY 2
3. PLEIOTROPIC ACTIONS OF METABOLISM 5 CHAPTER 1: MYOCARDIAL ISCHEMIA. Basic concepts 11 Constantinos Pantos, lordanis Mourouzis, Dennis V. Cokkinos
1. THE PATHOPHYSIOLOGY OF ISCHEMIA
AND REPERFUSION INJURY 11
1.1. Cellular injury 14 1.2. Spread of cell injury 14
1.2.1 Gap junctions; cell to cell communication 14
1.2.2 The inflammatory response 14
1.3. Microvascular injury 16 1.4. Biochemical aspects of ischemia-reperfusion 17
1.5. Contractile dysfunction 20 1.5.1 Ischemic contracture 20 1.5.2 Hypercontracture 22 1.5.3 Myocardial Stunning 24 1.5.4 Myocardial Hibernation 25 1.6. Ischemia-reperfusion induced arrhythmias 27
2. STRESS SIGNALING IN MYOCARDIAL ISCHEMIA 29
2.1. Membrane bound receptors 30 2.2. Triggers of cell signaling 34
2.2.1. Receptor dependent endogenous triggers 34 2.2.2. Non receptor triggers; reactive oxygen species
and nitric oxide 36
vi CONTENTS
2.3. Intracellular Pathways and End-Effectors 41
2.3.1. Protein kinase A 41 2.3.2. Protein kinase C 41 2.3.3. The Rho signaling 43 2.3.4. The Ras/Raf signaling 44 2.3.5 The PI3K signaling 45 2.3.6 The JAK/STAT signaling 47
2.3.7 Calcineurin 47 2.4. Transcription 47
2.4.1 Hypoxia inducible factor 50 2.4.2 Heat shock factor- Heat shock proteins 51
3. THE ADAPTED HE ART 53 3.1. Ischemic preconditioning 53 3.2 Heat stress induced 'cross tolerance' to myocardial ischemia 55
3.3 Chronic hypoxia 55 4. THE DISEASED AND AGEING HEART 56
4.1 Cardiac hypertrophy 56 4.2 Heart failure 56 4.3. Diabetes 57 4.4 Hypercholesterolemia 57
4.5 Post-infarcted heart... 58
4.6. Ageing heart 58 5. EXPERIMENTAL MODELS 59
6. TREATMENT STRATEGIES 62 6.1. Pharmacological treatments 62 6.2. Gene and cell based therapies 63 CHAPTER 2: HORMONES SIGNALING AND MYOCARDIAL
ISCHEMIA 77 Constantinos Pantos, Dennis V. Cokkinos
1. ESTROGENS 77 2. ANDROGENS 78 3. GROWTH HORMONE 79
4. GHRELIN 79 5. GLUCOCORTICOIDS 80
6. UROCORTIN 80 7. MELANOCORTIN PEPTIDES 80
8. MELATONIN 81 9. ERYTHROPOIETIN 81
10. NATRIURETIC PEPTIDES 81 11. PTH - PARATHYROID HORMONERELATED PEPTIDE (PTHrP).... 82
12. ALDOSTERONE 82
13. LEPTIN 83 14. INSULIN 83 15. INSULIN LIKE GROWTH FACTOR (IGF-1) 85
16. PEROXISOME PROLIFERATED -ACTIVATED
RECEPTORS (PPARS) 85
MYOCARDIAL ISCHEMIA: FROM MECHANISMS TO THERAPEUTIC POTENTIALS vii
17. THYROID HORMONE 86 17.1 Thyroid hormone receptors 89 CHAPTER 3: ISCHEMIC PRECONDITIONING 99
James M. Downey, Michael V. Cohen
1. INTRODUCTION 99 2. ISCHEMIC PRECONDITIONING 100
3. ISCHEMIC PRECONDITIONING IS RECEPTOR-MEDIATED 100
4. ATP-SENSITIVE POTASSIUM CHANNELS 102 5. MITOCHONDRIAL K^^p OPENING TRIGGERS ENTRANCE
INTO THE PRECONDITIONED STATE 103 6. THE TRIGGER PATHWAYS ARE DIVERGENT 104 7. IPC APPEARS TO EXERT ITS PROTECTION DURING
REPERFUSION BY PREVENTING MPT PORE OPENING 107 8. DRUGS THAT PROTECT AT REPERFUSION TARGET
THE SAME PATHWAYS AS IPC 108 9. DOES REPERFUSION INJURY EXIST? 108
10. CLINICAL IMPLICATIONS 108 CHAPTER 4: CONNEXIN 43 AND ISCHEMIC PRECONDITIONING ... 113
Rainer Schulz, Gerd Heusch
1. INTRODUCTION 113 2. REGULATION OF HEMICHANNELS AND GAP JUNCTIONS 114
2.1. Protein kinase A (PKA) 114 2.2. cGMP-dependent protein kinases (PKG) 115
2.3. Protein kinase C (PKC) 115 2.4. Protein tyrosine kinase (PTK) 115 2.5. Mitogen activated protein kinases (MAPKs) 115
2.6. Casein kinase (CasK) 115 2.7. Protein phosphatases 115 2.8. Proton and calcium concentration 116
3. MYOCARDIAL ISCHEMIA/REPERFUSION INJURY AND
ITS MODIFICATION BY ISCHEMIC PRECONDITIONING 117
4. ALTERATIONS IN CX43 DURING ISCHEMIA 117 5. CX43 AND ISCHEMIC PRECONDITIONING 119
6. CLINICAL IMPLICATIONS 120 CHAPTER 5: CORONARY MICROEMBOLIZATION 127
Andreas Skyschally, Rainer Schulz, Michael Haude, Raimund Erbel, Gerd Heusch
1. INTRODUCTION 127 2. CORONARY BLOOD FLOW RESPONSE AND EXPERIMENTAL
CORONARY MICROEMBOLIZATION 128 3. PLATELETS, CYCLIC CORONARY FLOW VARIATIONS AND
EXPERIMENTAL CORONARY MICROEMBOLIZATION 129
viu CONTENTS
4. CORONARY MICROEMBOLIZATION AS AN EXPERIMENTAL MODEL OF UNSTABLE ANGINA: THE ROLE
OF INFLAMMATORY CYTOKINES 130 5. CORONARY MICROEMBOLIZATION AND ISCHEMIC
PRECONDITIONING 133 6. SOURCE AND CONSEQUENCES OF POTENTIAL
THROMBOEMBOLI IN PATIENTS 135 7. PROTECTION DEVICES AGAINST CORONARY
MICROEMBOLIZATION 136 8. CONCLUSIONS AND REMAINING QUESTIONS 137
CHAPTER 6: FIBROBLAST GROWTH FACTOR-2 145 Elissavet Kardami, Karen A. Detillieux, Sarah K. Jimenez, Peter A. Cattini
1. INTRODUCTION 145 2. FGF-2 IN THE HEART 146 3. PRECONDITIONING-LIKE CARDIOPROTECTION BY FGF-2 148
4. REPERFUSION (SECONDARY) INJURY PREVENTION 149
5. THERAPEUTIC ANGIOGENESIS AND FGF-2 152 6. REPAIR AND REGENERATION: REBUILDING, IN ADDITION
TO PRESERVING, THE DAMAGED MYOCARDIUM 152
7. CLINICAL APPLICATIONS 156 7.1. Delivery Methods 156 7.2. Safety considerations 157 7.3. Clinical Trial Design 157 CHAPTER 7: MYOCARDIAL PROTECTION -
FROM CONCEPTS TO CLINICAL PRACTICE 167 Dennis V. Cokkinos
1. BACKGROUND 167 2. MYOCARDIAL PROTECTION 167
2.1. Patient status 168 2.1.1 Diabetes mellitus 168
2.1.2 Hypercholesterolemia-atherosclerosis 168
2.1.3 Hyperthyroidism 168 2.1.4 Hypothyroidism 169 2.2. Myocardial status 170
2.2.1 Myocardial hypertrophy 170 2.2.2 Myocardial dysfunction 170 3. THE STAGE OF THE ISCHEMIA-REPERFUSION
INJURY CASCADE 171 4. CARDIOPROTECTIVE AGENTS 174
5. SYNTHESIS 181 CHAPTER 8: A SYNOPSIS 199
INDEX 201
PREFACE
Effective new treatments of heart disease are based on a refined understanding of cellular function and the heart's response to environmental stresses. Not surprisingly therefore, the field of experimental cardiology has experienced a phase of rapid expo- nential growth during the last decade. The acquisition of new knowledge has been so fast that textbooks of cardiology or textbooks of cardiovascular physiology are often hard-pressed to keep up with the most important conceptual advances. Witness the explosive increase in knowledge about signaling pathways of cardiac growth, transcrip- tional regulation of cardiac metabolism, hormonal signaling, and the complex responses of the heart to ischemia, reperfusion, or ischemic preconditioning. This book is meant to bridge the gap between original literature and textbook reviews. It brings together inves- tigators of various backgrounds who share their expertise in the biology of myocardial ischemia. Each chapter is a self-contained mini-review, but it will soon become apparent to the reader that there is also a common thread: Molecular and cellular cardiology has never been more exciting than now, but ever more exciting times are yet to come.
The Editors
ACKNOWLEDGEMENTS
- Publication of this book was generously supported by Sanofi-Aventis Hellas.
- Eikon creative team provided the technical assistance in preparing the manuscripts.
- We thank Dr. Bernard Swynghedauw for all his scientific support.
