Novel Therapeutic Targets for Antiarrhythmic Drugs

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.

Table of Contents

1. Introduction.

Part 1: Basic physiology/pharmacology.

• 2. Myocardial potassium channels: primary determinants of action potential repolarization.
• 2.1 Introduction.
• 2.2 Action Potential Waveforms and Repolarizing K+ Currents.
• 2.3 Functional Diversity of Repolarizing Myocardial K+ Channels.
• 2.4 Molecular Diversity of K+ Channel Subunits.
• 2.5 Molecular Determinants of Functional Cardiac Ito Channels.
• 2.6 Molecular Determinants of Functional Cardiac IK Channels.
• 2.7 Molecular Determinants of Functional Cardiac Kir Channels.
• 2.8 Other Potassium Currents Contributing to Action Potential Repolarization.
• 2.9 Myocardial K+ channels functioning in macromolecular protein complexes.
• 3. The "funny" pacemaker current.
• 3.1 Introduction: the mechanism of cardiac pacemaking.
• 3.2 The "funny" current.
• 3.3 Historical background.
• 3.4 Biophysical properties of the If current.
• 3.5 Cardiac distribution of If.
• 3.6 Molecular determinants of the If current.
• 3.7 HCN clones and pacemaker channels.
• 3.8 Identification of structural elements involved in channel gating.
• 3.9 Regulation of pacemaker channel activity: "context" dependence and protein-protein interactions.
• 3.10 "HCN gene regulation".
• 3.11 Blockers of funny channels.
• 3.12 Alinidine (ST567).
• 3.13 Falipamil (AQ-A39), Zatebradine (UL-FS 49) and Cilobradine (DK-AH269).
• 3.14 ZD7288.
• 3.15 Ivabradine (S16257).
• 3.16 Effects of the heart rate reducing agents on HCN isoforms.
• 3.17 Genetics of HCN channels.
• 3.18 HCN-KO models.
• 3.19 Pathologies associated to HCN dysfunctions.
• 3.20 HCN-based biological pacemakers.
• 4. Arrhythmia mechanisms in ischemia and infarction.
• 4.1 Introduction.
• 4.2 Arrhythmogenesis in Acute Myocardial Ischemia.
• 4.3 Arrhythmogenesis during the first week post MI.
• 4.4 Arrhythmia mechanisms in chronic infarction.
• 5. Antiarrhythmic drug classification.
• 5.1 Introduction.
• 5.2 Sodium Channel Blockers.
• 5.3 IKur Blocker.
• 5.4 Inhibitors of Calcium Channels.
• 5.5 Inhibitors of Adrenergically-modulated electrophysiology.
• 5.6 Adenosine.
• 5.7 Digoxin.
• 5.8 Conclusions.

Part 2: Safety Pharmacology.

• 6. Repolarization reserve and proarrhythmic risk.
• 6.1 Definitions and Background.
• 6.2 The Major Players Contributing to Repolarization Reserve.
• 6.3 Mechanism of Arrhythmia due to Decreased Repolarization Reserve.
• 6.4 Clinical Significance of the Reduced Repolarization Reserve.
• 6.5 Repolarization Reserve as a Dynamically Changing Factor.
• 6.6 How to measure Repolarization Reserve.
• 6.7 Pharmacological Modulation of the Repolarization Reserve.
• 6.8 Conclusion.
• 7. Safety Challenges in the development of novel antiarrhythmic drugs.
• 7.1 Introduction.
• 7.2 Review of Basic Functional Cardiac Electrophysiology.
• 7.3 Safety Pharmacology Perspectives on Developing Antiarrhythmic Drugs.
• 7.4 Proarrhythmic Effects of Ventricular Antiarrhythmic Drugs.
• 7.5 Ranolazine: an Anti-anginal Agent with a Novel Electrophysiologic.
• 7.6 Avoiding Proarrhythmia with Atrial Antiarrhythmic Drugs.
• 7.7 The quest for atrial selective ion channel blocking drugs..
• 7.8 Conclusions- Present-day Safety Challenges in the Development of Novel Antiarrhythmic Drugs.
• 8. Safety Pharmacology and regulatory issues in the development of antiarrhythmic medications.
• 8.1 Introduction.
• 8.2 Basic Physiological Considerations.
• 8.3 Historical Considerations.
• 8.4 Opportunities for Antiarrhythmic Drug Development in the Present Regulatory Environment.

Part 3: Novel targets for anitarrhythmic drugs.

Pharmacological interventions.

• 9. Ion channel remodeling and arrhythmias.
• 9.1 Introduction.
• 9.2 Cellular and molecular basis for cardiac excitability.
• 9.3 Heart failure - epidemiology and arrhythmia connection.
• 9.4 K+ remodeling and heart failure.
• 9.5 Ca2+ handling and arrhythmia risk.
• 9.6 Intracellular [Na+] in heart failure.
• 9.7 Gap junctions and connexins.
• 9.8 Autonomic signaling.
• 9.10 Calmodulin kinase.
• 9.11 Conclusions.
• 10. Redox modification of ryanodine receptors by heart failure and cardiac arrhythmias: a potential therapeutic target.
• 10.1 Introduction.
• 10.2 Activation and deactivation of ryanodine receptors during normal excitation-contraction coupling.
• 10.3 Defective ryanodine receptor function is linked to proarrhythmic delayed afterdepolarizations and calcium alternans.
• 10.4 Genetic and acquired defects in ryanodine receptors.
• 10.5 Effects of thiol modifying agents on ryanodine receptors.
• 10.6 Reactive oxygen species production and oxidative stress in cardiac disease.
• 10.7 Redox modification of ryanodine receptors in cardiac arrhythmia and heart failure.
• 10.8 Therapeuntic potential of normalizing ryanodine receptor function.
• 11. Targeting sodium/calcium exchange as an antiarrhythmic strategy.
• 11.1 Introduction.
• 11.2 Why target NCX in arrhythmias?
• 11.3 When do we see triggered arrhythmias?
• 11.4 What drugs are available?
• 11.5 Experience with NCX inhibitors.
• 11.6 Caveat - the consequences on Calcium Handling.
• 11.7 Needs for further development.
• 12. Calcium/calmodulin-dependent protein kinase II (CaMKII) - Modulation of ion currents and potential role for arrhythmias.
• 12.1 Introduction.
• 12.2 Evolving role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the heart.
• 12.3 Activation of CaMKII.
• 12.4 Role of CaMKII in excitation-contraction coupling (ECC).
• 12.5 Role of CaMKII for arrhythmias.
• 12.6 Summary.
• 13. Selective targeting of ventricular potassium channels for arrhythmia suppression: feasible or risible?
• 13.1 Introduction.
• 13.2 Effects of K+ channel blockade on APD and arrhythmogenesis.
• 13.3 Conclusion and Future Directions.
• 14. Cardiac sarcolemmal ATP-sensitive potassium channel antagonists: a class of drugs that may selectively target the ischemic myocardium.
• 14.1 Introduction.
• 14.2 Extracellular Potassium and Myocardial Ischemia.
• 14.3 Extracellular Potassium and Ventricular Arrhythmias.
• 14.4 Effect of ATP-sensitive Potassium Channel Antagonists.
• 5. Summary.
• 15. Mitochondrial Origin of Ischemia-Reperfusion Arrhythmias: cardiac mitochondria as a novel target for antiarrhythmic drugs.
• 15.1 Introduction.
• 15.2 Mechanisms of Arrhythmias.
• 15.3 Ischemia-reperfusion arrhythmias.
• 15.4 Mitochondrial Criticality: the root of ischemia-reperfusion arrhythmias.
• 15.5 KATP activation and Arrhythmias.
• 15.6 Metabolic Sinks and Reperfusion arrhythmias.
• 15.7 Antioxidant depletion.
• 15.8 Mitochondria as therapeutic targets.
• 16. Cardiac gap junction modulators: a new target for antiarrhythmic drugs.
• 16.1 Introduction.
• 16.2 The development of gap junction modulators and Antiarrhythmic Peptides (AAPs).
• 16.3 Molecular mechanisms of action of AAPs.
• 16.4 Antiarrhythmic effects of AAPs.
• 16.5 Site- and condition-specific effects of AAPs; effects in ischemia or simulated ischemia.
• 16.6 Chemistry of AAPs.
• 16.7 Short overview over cardiac gap junctions.
• 16.8 Gap Junction Modulation as a new antiarrhythmic principle.
• 17. Novel Pharmacological Targets for the Management of Atrial Fibrillation.
• 17.1 Introduction.
• 17.2 Novel Ion Targets for Atrial Fibrillation Treatment.
• 17.3 Upstream Targets for Atrial Fibrillation.
• 17.4 Gap Junctions as Targets for Atrial Fibrillation Therapy.
• 17.5 Intracellular Calcium Handling and Atrial Fibrillation.
• 18. Ultra-rapid delayed rectifier potassium current, IKur: a therapeutic target for atrial arrhythmias.
• 18.1 Introduction.
• 18.2 Molecular Biology of the Kv1.5.
• 18.3 IKur as a therapeutic target.
• 18.4 Organic Blockers of IKur.
• 18.5 Conclusions.

Non-Pharmacological Interventions.

• 19. Non-pharmacologic manipulation of the autonomic nervous system in man for the prevention of life-threatening arrhythmias.
• 19.1 Introduction.
• 19.2 Sympathetic nervous system.
• 19.3 Parasympathetic nervous system.
• 19.4 Conclusion.
• 20. Effects of endurance exercise training on cardiac autonomic regulation and susceptibility to sudden cardiac death: a non-pharmacological approach for the prevention of ventricular fibrillation.
• 20.1 Introduction.
• 20.2 Exercise and Susceptibility to Sudden Death.
• 20.3 Cardiac Autonomic Neural Activity and Sudden Cardiac Death.
• 20.4 ß-adrenergic receptor Activation and Susceptibility to Ventricular Fibrillation.
• 20.5 Effect of Exercise Conditioning on Cardiac Autonomic Regulation.
• 20.6 Effect of Exercise Training on Myocyte Calcium Regulation.
• 20.7 Summary and Conclusions.
• 21. Dietary Omega-3 fatty acids as a Non-pharmacological Antiarrhythmic Intervention.
• 21.1 Introduction.
• 21.2 Fatty Acid Metabolism.
• 21.3 Cellular Mechanisms.
• 21.4 Animal Studies.
• 21.5 Clinical Studies.
• 21.6 Future Directions.