Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress.

Ali A Sovari

doi:10.1155/2016/9656078

Abstract

Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca2+/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia.

Highlights

Cardiac Electrophysiology Section, Heart Institute, Cedars Sinai Medical Center, 127 S
Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets
Chronic treatment of Atrial fibrillation (AF) with current antiarrhythmic drugs has not been more effective than a rate control strategy in reducing thromboembolism [10] which may suggest the ineffectiveness of the antiarrhythmic drugs in maintaining the sinus rhythm

Summary

Scope of the Problem in Treatment of Arrhythmias

Cardiovascular disorders are the most common cause of death in the United States and most of the developed countries [1]. Current therapies for treatment of arrhythmias are antiarrhythmic drugs, catheter ablation, and implantable cardioverter defibrillators (ICDs) for VT/VF. These therapies have had some success, they have limitations. The Cardiac Arrhythmia Suppression Trial (CAST) showed that treatment of premature ventricular contractions (PVCs) with class IC antiarrhythmic drugs may increase cardiovascular mortality in patients with myocardial infarction (MI) [9]. Defibrillation has shown success in terminating VT/VF It does not prevent the occurrence of arrhythmia, and frequent ICD shocks worsen the quality of life and may even increase mortality [16]. Despite considerable evidence that ROS play an important role in the genesis of arrhythmia, limited clinical studies using conventional antioxidants have shown conflicting results [26]. The study of mechanisms by which ROS elevation may result in arrhythmia may lead to the discovery of novel therapeutic targets for treatment of arrhythmia

Oxidative Stress Facilitating Focal Activity and Reentry

Arrhythmogenic Ionic Effects of Oxidative Stress

Oxidative Stress and Cell Coupling

Molecular Mechanisms of ROS-Induced Arrhythmia

Findings

Conclusion