Novel Targets for Cardiac Antiarrhythmic Drug Development

John   Christian   Hesketh; Daniel      Herrera; Stephen      Zicha; Stanley      Nattel

Abstract

Cardiac arrhythmias remain a major source of morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of cardiac arrhythmia treatment; however, drug therapy of cardiac arrhythmias has been plagued by incomplete efficacy and by potentially serious adverse reactions, of which the most worrisome has been a potential for malignant proarrhythmia and related effects to increase cardiac mortality. This article reviews the principal arrhythmia mechanisms and their ionic determinants, and discusses potential innovative approaches to new antiarrhythmic drug development, including the consideration of novel ionic targets, potential biophysical approaches and non-channel components involved in composing the arrhythmic substrate.

Keywords: sinoatrial node (san), pacemaker, re-excitation, early afterdepolarizations(eads), sarcoplasmic reticulum (sr), automaticity, sodium current, channels, ultra rapid delayed rectifier, antiarrhythmic therapy