Novel therapeutic targets for antiarrhythmic drugs

著者

• Billman, George Edward

書誌事項

Novel therapeutic targets for antiarrhythmic drugs

edited by George Edward Billman

J. Wiley, c2010

• : cloth

注記

"A John Wiley & Sons, Inc., publication"

Includes bibliographical references and indexes

収録内容

• Myocardial K+ channels : primary determinants of action potential repolarization / Noriko niwa and Jeanne Nerbonne
• The "funny" pacemaker current / Andrea Barbuti ... [et al.]
• Arrhythmia mechanisms in ischemia and infarction / Ruben Coronel ... [et al.]
• Antiarrhythmic drug classification / Cynthia A. Carnes
• Repolarization reserve and proarrhythmic risk / András Varró
• Safety challenges in the development of novel antiarrythmic drugs / Gary Gintant and Zhi Su
• Safety pharmacology and regulatory issues in the development of antiarrhythmic medications / Armando Lagrutta and Joseph J. Salata
• Ion channel remodeling and arrhythmias / Takeshi Aiba and Gordon F. Tomaselli
• Redox modification of ryanodine receptors in cardiac arrhythmia and failure : a potential therapeutic target / Andriy E. Belevych, Dmitry Terentyev, and Sandor Györke
• Targeting Na+/Ca2+ exchange as an antiarrhythmic strategy / Gudrun Antoons, Rik Willems, and Karin R. Sipido
• Calcium/calmodulin-dependent protein kinase II (CaNKII) - modulation of ion currents and potential role for arrhythmias / Lars S. Maier
• Selective targeting of ventricular potassium channels for arrhythmia suppression : feasible or risible? / Hugh Clements-Jewery and Michael Curtis
• Cardiac sarcolemmal ATP-sensitive potassium channel antagonists : aclass of drugs tha may selectively target the ischemic myocardium / George E. Billman
• Mitochondrial origin of ischemia-reperfusion arrhythmias / Brian O'Rourke
• Cardiac Gap Junctions : a new target for new antiarrhythmic drugs : gap junction modulators / Anja Hagen and Stefan Dhein
• Novel pharmacological targets for the management of artial fibrillation / Alexander Burashnikov and Charles Antzelevitch
• IKur, ultra-rapid delayed rectifier potassium current : a therapeutic target for artial arrhythmias / Arun Sridhar and Cynthia A. Carnes
• Non-pharmacologic manipulation of the autonomic nervous system in human for the prevention of life-thereatening arrhythmias / Peter J. Schwartz
• Effects of endurance exercise training on cardiac autonomic regulation and susceptibility to sudden cardiac death : a nonpharmacological approach for the prevention of ventricular fibrillation / George E. Billman
• Dietary omega-3 fatty acids as a nonpharmacological antiarrhythmic intervention / Barry London and J. Michael Frangiskakis

内容説明・目次

内容説明

PROFILES POTENTIAL TREATMENT APPROACHES FOR CARDIAC ARRHYTHMIAS Cardiac arrhythmias of ventricular origin are responsible for the deaths of nearly half a million Americans each year while atrial fibrillation accounts for about 2.3 million cases per year, a rate that is projected to increase 2.5 fold over the next half century. Effectively managing these cardiac rhythm disorders remains a major challenge for both caregivers and the pharmaceutical industry. Filling a gap in the current literature, Novel Therapeutic Targets for Antiarrhythmic Drugs presents the latest treatments for cardiac arrhythmias alongside comprehensive presentations of basic cardiac physiology and pharmacology. Written by leading experts in their research areas, this invaluable resource offers both practitioners and researchers a one-stop guide that brings together previously dispersed information. The text consists of four sections: Section One comprehensively reviews basic cardiac electrophysiology, the mechanisms responsible for arrhythmias in the setting of ischemia, and basic pharmacology of antiarrhythmic drugs. Section Two addresses safety pharmacology, including the concept of "repolarization reserve," safety challenges, and regulatory issues for the development of novel antiarrhythmic drugs. Section Three describes several novel pharmacological targets for antiarrhythmic drugs, including both ion channel and non-ion channel targets. Section Four describes promising non-pharmacological antiarrhythmic interventions including selective cardiac neural disruption or nerve stimulation, aerobic exercise training, and diet (omega-3 fatty acids). Offering an unparalleled look at the current state and future direction of cardiac arrhythmia treatment, Novel Therapeutic Targets for Antiarrhythmic Drugs provides an important resource to advanced students, working researchers, and busy professionals alike.

目次

• Acknowledgments xix Contributors xxi 1. Introduction 1 George E. Billman References 3 2. Myocardial K+ Channels: Primary Determinants of Action Potential Repolarization 5 Noriko Niwa and Jeanne Nerbonne 2.1 Introduction 5 2.2 Action Potential Waveforms and Repolarizing K+ Currents 7 2.3 Functional Diversity of Repolarizing Myocardial K+ Channels 9 2.4 Molecular Diversity of K+ Channel Subunits 12 2.5 Molecular Determinants of Functional Cardiac Ito Channels 16 2.6 Molecular Determinants of Functional Cardiac IK Channels 18 2.7 Molecular Determinants of Functional Cardiac Kir Channels 23 2.8 Other Potassium Currents Contributing to Action Potential Repolarization 27 2.8.1 Myocardial K+ Channel Functioning in Macromolecular Protein Complexes 28 References 32 3. The ''Funny'' Pacemaker Current 59 Andrea Barbuti, Annalisa Bucchi, Mirko Baruscotti, and Dario DiFrancesco 3.1 Introduction: The Mechanism of Cardiac Pacemaking 59 3.2 The ''Funny'' Current 60 3.2.1 Historical Background 60 3.2.2 Biophysical Properties of the If Current 61 3.2.3 Autonomic Modulation 63 3.2.4 Cardiac Distribution of If 63 3.3 Molecular Determinants of the If Current 64 3.3.1 HCN Clones and Pacemaker Channels 64 3.3.2 Identification of Structural Elements Involved in Channel Gating 66 3.3.3 Regulation of Pacemaker Channel Activity: "Context" Dependence and Protein-Protein Interactions 70 3.3.4 HCN Gene Regulation 71 3.4 Blockers of Funny Channels 72 3.4.1 Alinidine (ST567) 73 3.4.2 Falipamil (AQ-A39), Zatebradine (UL-FS 49), and Cilobradine (DK-AH269) 73 3.4.3 ZD7288 75 3.4.4 Ivabradine (S16257) 75 3.4.5 Effects of the Heart Rate Reducing Agents on HCN Isoforms 78 3.5 Genetics of HCN Channels 78 3.5.1 HCN-KO Models 78 3.5.2 Pathologies Associated with HCN Dysfunctions 79 3.6 HCN-Based Biological Pacemakers 81 References 84 4. Arrhythmia Mechanisms in Ischemia and Infarction 101 Ruben Coronel, Wen Dun, Penelope A. Boyden, and Jacques M.T. de Bakker 4.1 Introduction 101 4.1.1 Modes of Ischemia, Phases of Arrhythmogenesis 102 4.1.2 Trigger-Substrate-Modulating Factors 103 4.2 Arrhythmogenesis in Acute Myocardial Ischemia 103 4.2.1 Phase 1A 103 4.2.2 Phase 1B 113 4.2.3 Arrhythmogenic Mechanism: Trigger 114 4.2.4 Catecholamines 115 4.3 Arrhythmogenesis During the First Week Post MI 115 4.3.1 Mechanisms 115 4.3.2 The Subendocardial Purkinje Cell as a Trigger 24-48 H Post Occlusion 116 4.3.3 Five Days Post-Occlusion: Epicardial Border Zone 120 4.4 Arrhythmia Mechanisms in Chronic Infarction 128 4.4.1 Reentry and Focal Mechanisms 128 4.4.2 Heterogeneity of Ion Channel Expression in the Healthy Heart 129 4.4.3 Remodeling in Chronic Myocardial Infarction 131 4.4.4 Structural Remodeling 133 4.4.5 Role of the Purkinje System 135 References 136 5. Antiarrhythmic Drug Classification 155 Cynthia A. Carnes 5.1 Introduction 155 5.2 Sodium Channel Blockers 155 5.2.1 Mixed Sodium Channel Blockers (Vaughan Williams Class Ia) 156 5.3 Inhibitors of the Fast Sodium Current with Rapid Kinetics (Vaughan Williams Class Ib) 158 5.3.1 Lidocaine 158 5.3.2 Mexiletine 159 5.4 Inhibitors of the Fast Sodium Current with Slow Kinetics (Vaughan Williams Class Ic) 159 5.4.1 Flecainide 159 5.4.2 Propafenone 160 5.5 Inhibitors of Repolarizing K+ Currents (Vaughan Williams Class III) 160 5.5.1 Dofetilide 160 5.5.2 Sotalol 161 5.5.3 Amiodarone 161 5.5.4 Ibutilide 162 5.6 IKur Blockers 162 5.7 Inhibitors of Calcium Channels 162 5.7.1 Verapamil and Diltiazem 162 5.8 Inhibitors of Adrenergically-Modulated Electrophysiology 163 5.8.1 Funny Current (If) Inhibitors 163 5.8.2 Beta-Adrenergic Receptor Antagonists 164 5.9 Adenosine 164 5.10 Digoxin 165 5.11 Conclusions 165 References 165 6. Repolarization Reserve and Proarrhythmic Risk 171 Andras Varro 6.1 Definitions and Background 171 6.2 The Major Players Contributing to Repolarization Reserve 175 6.2.1 Inward Sodium Current (INa) 175 6.2.2 Inward L-Type Calcium Current (ICa,L) 176 6.2.3 Rapid Delayed Rectifier Outward Potassium Current (IKr) 177 6.2.4 Slow Delayed Rectifier Outward Potassium Current (IKs) 178 6.2.5 Inward Rectifier Potassium Current (Ik1) 179 6.2.6 Transient Outward Potassium Current (Ito) 180 6.2.7 Sodium-Potassium Pump Current (INa/K) 180 6.2.8 Sodium-Calcium Exchanger Current (NCX) 180 6.3 Mechanism of Arrhythmia Caused By Decreased Repolarization Reserve 182 6.4 Clinical Significance of the Reduced Repolarization Reserve 183 6.4.1 Genetic Defects 184 6.4.2 Heart Failure 185 6.4.3 Diabetes Mellitus 185 6.4.4 Gender 186 6.4.5 Renal Failure 187 6.4.6 Hypokalemia 187 6.4.7 Hypothyroidism 187 6.4.8 Competitive Athletes 188 6.5 Repolarization Reserve as a Dynamically Changing Factor 188 6.6 How to Measure the Repolarization Reserve 189 6.7 Pharmacological Modulation of the Repolarization Reserve 191 6.8 Conclusion 193 References 194 7. Safety Challenges in the Development of Novel Antiarrhythmic Drugs 201 Gary Gintant and Zhi Su 7.1 Introduction 201 7.2 Review of Basic Functional Cardiac Electrophysiology 202 7.2.1 Normal Pacemaker Activity 203 7.2.2 Atrioventricular Conduction 204 7.2.3 Ventricular Repolarization: Effects on the QT Interval 204 7.2.4 Electrophysiologic Lessons Learned from Long QT Syndromes 205 7.3 Safety Pharmacology Perspectives on Developing Antiarrhythmic Drugs 206 7.3.1. Part A. On-Target (Primary Pharmacodynamic) versus Off-Target (Secondary Pharmacodynamic) Considerations 206 7.3.2 Part B. General Considerations 207 7.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs 208 7.4.1 Sodium Channel Block Reduces the Incidence of Ventricular Premature Depolarizations But Increases Mortality 208 7.4.2 Delayed Ventricular Repolarization with d-Sotalol Increases Mortality in Patients with Left Ventricular Dysfunction and Remote Myocardial Infarction: The SWORD and DIAMOND Trials 210 7.4.3 Ranolazine: An Antianginal Agent with a Novel Electrophysiologic Action and Potential Antiarrhythmic Properties 213 7.5 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs 217 7.5.1 Introduction 217 7.5.2. Lessons Learned with Azimilide, a Class III Drug that Reduces the Delayed Rectifier Currents IKr and IKs 218 7.5.3 Atrial Repolarizing Delaying Agents. Experience with Vernakalant, a Drug that Blocks Multiple Cardiac Currents (Including the Atrial-Specific Repolarizing Current IKur) 220 References 222 8. Safety Pharmacology and Regulatory Issues in the Development of Antiarrhythmic Medications 233 Armando Lagrutta and Joseph J. Salata 8.1 Introduction 233 8.2 Basic Physiological Considerations 234 8.2.1 Ion Channels and Arrhythmogenesis 234 8.2.2 Antiarrhythmic Agents 236 8.3 Historical Considerations 237 8.3.1 CAST: Background, Clinical Findings, and Aftermath 237 8.3.2 Torsades de Pointes and hERG Channel Inhibition: Safety Pharmacology Concern with Critical Impact on Antiarrhythmic Development 239 8.3.3 Recent Clinical Trials 242 8.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment 244 8.4.1 ICH-S7A and S7B
• E14 245 8.4.2 Additional Regulatory Guidance 248 8.4.3 Clinical Management Guidelines and Related Considerations About Patient Populations 250 8.4.4 Consortia Efforts to Address Safety Concerns Related to Antiarrhythmic Drug Development 253 8.4.5 The Unmet Medical Need: Challenges and Opportunities 254 References 256 9. Ion Channel Remodeling and Arrhythmias 271 Takeshi Aiba and Gordon F. Tomaselli 9.1 Introduction 271 9.2 Molecular and Cellular Basis for Cardiac Excitability 271 9.3 Heart Failure-Epidemiology and the Arrhythmia Connection 272 9.4 K+ Channel Remodeling in Heart Failure 274 9.4.1 Transient Outward Current (Ito) 274 9.4.2 Inward Rectifier K+ Current (IK1) 276 9.4.3 Delayed Rectifier K Currents (IKr and IKs) 277 9.5 Ca2+ Handling and Arrhythmia Risk 278 9.5.1 L-type Ca2+ Current ICa-L 278 9.5.2 Sarcoplasmic Recticulum Function 278 9.6 Intracellular [Na+] in HF 282 9.6.1 Cardiac INa in HF 282 9.6.2 Na+/K+ ATPase 283 9.7 Gap Junctions and Connexins 283 9.8 Autonomic Signaling 284 9.9 Calmodulin Kinase 285 9.10 Conclusions 286 References 286 10. Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Failure: A Potential Therapeutic Target 299 Andriy E. Belevych, Dmitry Terentyev, and Sandor Gyoerke 10.1 Introduction 299 10.2 Activation and Deactivation of Ryanodine Receptors During Normal Excitation-Contraction Coupling 300 10.3 Defective Ryanodine Receptor Function is Linked to Proarrhythmic Delayed Afterdepolarizations and Calcium Alternans 301 10.4 Genetic and Acquired Defects in Ryanodine Receptors 302 10.5 Effects of Thiol-Modifying Agents on Ryanodine Receptors 303 10.6 Reactive Oxygen Species Production and Oxidative Stress in Cardiac Disease 304 10.7 Redox Modification of Ryanodine Receptors in Cardiac Arrhythmia and Heart Failure 305 10.8 Therapeutic Potential of Normalizing Ryanodine Receptor Function 306 References 308 11. Targeting Na+/Ca2+ Exchange as an Antiarrhythmic Strategy 313 Gudrun Antoons, Rik Willems, and Karin R. Sipido 11.1 Introduction 313 11.2 Why Target NCX in Arrhythmias? 314 11.3 When Do We See Triggered Arrhythmias? 317 11.4 What Drugs are Available? 318 11.5 Experience with NCX Inhibitors 321 11.6 Caveat-the Consequences on Ca2+ Handling 328 11.7 Need for More Development 331 References 332 12. Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII)-Modulation of Ion Currents and Potential Role for Arrhythmias 339 Dr. Lars S. Maier 12.1 Introduction 339 12.2 Evolving Role of Ca2+/CaMKII in the Heart 340 12.3 Activation of CaMKII 340 12.4 Role of CaMKII in ECC 342 12.4.1 Ca2+ Influx and ICa Facilitation 343 12.4.2 SR Ca2+ Release and SR Ca Leak 344 12.4.3 SR Ca2+ Uptake, FDAR, Acidosis 346 12.4.4 Na+ Channels 348 12.4.5 K+ Channels 353 12.5 Role of CaMKII for Arrhythmias 354 12.6 Summary 355 Acknowledgments 356 References 356 13. Selective Targeting of Ventricular Potassium Channels for Arrhythmia Suppression: Feasible or Risible? 367 Hugh Clements-Jewery and Michael Curtis 13.1 Introduction 367 13.2 Effects of K+ Channel Blockade on APD and Arrhythmogenesis 371 13.2.1 IKur Blockade 371 13.2.2 IKr Blockade 371 13.2.3 IKs Blockade 372 13.2.4 IK1 Blockade 372 13.2.5 Ito Blockade 373 13.2.6 IKATP Blockade 374 13.3 Conclusions/Future Directions 375 References 375 14. Cardiac Sarcolemmal ATP-sensitive Potassium Channel Antagonists: A Class of Drugs that May Selectively Target the Ischemic Myocardium 381 George E. Billman 14.1 Introduction 381 14.2 Effects of Myocardial Ischemia on Extracellular Potassium 382 14.3 Effect of Extracellular Potassium on Ventricular Rhythm 386 14.4 Effect of ATP-sensitive Potassium Channel Antagonists on Ventricular Arrhythmias 387 14.4.1 Nonselective ATP-sensitive Potassium Channel Antagonists 387 14.4.2 Selective ATP-sensitive Potassium Channel Antagonist 390 14.4.3 Proarrhythmic Effects of ATP-sensitive Potassium Channel Agonists 397 14.5 Summary 401 References 401 15. Mitochondrial Origin of Ischemia-Reperfusion Arrhythmias 413 Brian O'Rourke, PHD 15.1 Introduction 413 15.2 Mechanisms of Arrhythmias 414 15.2.1 Automacity 414 15.2.2 Triggered Arrhythmias 415 15.3 Ischemia-Reperfusion Arrhythmias 417 15.4 Mitochondrial Criticality: The Root of Ischemia-Reperfusion Arrhythmias 418 15.5 KATP Activation and Arrhythmias 420 15.6 Metabolic Sinks and Reperfusion Arrhythmias 422 15.7 Antioxidant Depletion 423 15.8 Mitochondria as Therapeutic Targets 423 References 424 16. Cardiac Gap Junctions: A New Target for New Antiarrhythmic Drugs: Gap Junction Modulators 431 Anja Hagen and Stefan Dhein 16.1 Introduction 431 16.2 The Development of Gap Junction Modulators and AAPs 433 16.3 Molecular Mechanisms of Action of AAPs 436 16.4 Antiarrhythmic Effects of AAPs 439 16.4.1 Ventricular Fibrillation and Ventricular Tachycardia 444 16.4.2 Atrial fibrillation 444 16.4.3 Others 445 16.5 Site- and Condition-Specific Effects of AAPs
• Effects in Ischemia or Simulated Ischemia 446 16.6 Chemistry of AAPs 447 16.7 Short Overview About Cardiac Gap Junctions 447 16.8 Gap Junction Modulation as a New Antiarrhythmic Principle 452 References 453 17. Novel Pharmacological Targets for the Management of Atrial Fibrillation 461 Alexander Burashnikov and Charles Antzelevitch 17.1 Introduction 461 17.2 Novel Ion Channel Targets for Atrial Fibrillation Treatment 462 17.2.1 The Ultrarapid Delayed Rectifier Potassium Current (IKur) 462 17.2.2 The Acetylcholine-Regulated Inward Rectifying Potassium Current (IK-ACh) and the Constitutively Active (CA) IK-ACh 464 17.2.3 The Early Sodium Current (INa) 464 17.2.4 Block IKr and Its Relation to Atrial Selectivity of INa Blockade 467 17.2.5 Other Potential Atrial-Selective Ion Channel Targets for the Treatment AF 467 17.2.6 Influence of Atrial- Selective Agents on Ventricular Arrhythmias? 468 17.3 Upstream Therapy Targets for Atrial Fibrillation 468 17.4 Gap Junction as Targets for AF Therapy 469 17.5 Intracellular Calcium Handling and AF 470 References 471 18. IKur, Ultra-rapid Delayed Rectifier Potassium Current: A Therapeutic Target for Atrial Arrhythmias 479 Arun Sridhar and Cynthia A. Carnes 18.1 Introduction 479 18.2 Molecular Biology of the Kv 1.5 Channels: 480 18.2.1 Kv 1.5 Activation and Inactivation 480 18.2.2 Where Does IKur Fit Into the Cardiac Action Potential? 482 18.2.3 Adrenergic Modulation of IKur 485 18.3 IKur as a Therapeutic Target 485 18.4 Organic Blockers of IKur 486 18.4.1 Mixed Channel Blockers 486 18.4.2 Mixed Channel Blockers 487 18.4.3 Selective Kv 1.5 Blockers 488 18.5 Conclusions 490 References 490 19. Non-Pharmacologic Manipulation of the Autonomic Nervous System in Human for the Prevention of Life-Threatening Arrhythmias 495 Peter J. Schwartz 19.1 Introduction 495 19.2 Sympathetic Nervous System 496 19.2.1 Experimental Background 496 19.2.2 Clinical Evidence 497 19.3 Parasympathetic Nervous System 500 19.3.1 Experimental Background 500 19.3.2 Clinical Evidence 501 19.4 Conclusion 504 Acknowledgement 504 References 504 20. Effects of Endurance Exercise Training on Cardiac Autonomic Regulation and Susceptibility to Sudden Cardiac Death: A Nonpharmacological Approach for the Prevention of Ventricular Fibrillation 509 George E. Billman 20.1 Introduction 509 20.2 Exercise and Susceptibility to Sudden Death 510 20.2.1 Clinical Studies 510 20.2.2 Experimental Studies 515 20.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death 518 20.4 2-Adrenergic Receptor Activation and Susceptibility to VF 521 20.5 Effect of Exercise Conditioning on Cardiac Autonomic Regulation 523 20.6 Effect of Exercise Training on Myocyte Calcium Regulation 528 20.7 Summary and Conclusions 530 References 531 21. Dietary Omega-3 Fatty Acids as a Nonpharmacological Antiarrhythmic Intervention 543 Barry London and J. Michael Frangiskakis 21.1 Introduction 543 21.2 Fatty Acid Metabolism 544 21.2.1 Nomenclature 544 21.2.2 Dietary Fatty Acids 544 21.2.3 Roles of Polyunsaturated Fatty Acids 545 21.3 Cellular Mechanisms 545 21.3.1 Ion Channel Blockade 545 21.3.2 Direct Membrane Effects 547 21.3.3 Phosphorylation 548 21.3.4 Inflammation 548 21.3.5 Summary 548 21.4 Animal Studies 548 21.4.1 Acute Intravenous Effects of n-3 PUFAs 549 21.4.2 Dietary Supplementation with n-3 PUFAs 549 21.5 Clinical Studies 550 21.5.1 Observational Studies 550 21.5.2 Randomized Trials 551 21.5.3 Surrogate Markers for Arrhythmias 555 21.5.4 Summary 555 21.6 Future Directions 556 References 556 General Index 567 Index of Drug and Chemical Names 575

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詳細情報

• NII書誌ID(NCID): BB08565444
• ISBN:
  • 9780470261002
• LCCN: 2009020796
• 出版国コード: us
• タイトル言語コード: eng
• 本文言語コード: eng
• 出版地: Hoboken, N.J.
• ページ数/冊数: xxiv, 578 p., [8] p. of plates
• 大きさ: 25 cm
• 分類:
  • LCC : RM347
  • DC22 : 616.1/28061
• 件名:
  • LCSH : Myocardial depressants
  • LCSH : Arrhythmia -- Chemotherapy
  • MESH : Anti-Arrhythmia Agents
  • MESH : Arrhythmias, Cardiac -- drug therapy