When does spontaneous sarcoplasmic reticulum CA(2+) release cause a triggered arrythmia? Cellular versus tissue requirements.

Abstract

Ventricular arrhythmias are a major cause of sudden premature death in patients with ischemic heart disease, hypertrophy, and congestive heart failure. The processes that initiate these arrhythmias include reentry, abnormal automaticity, and triggered activity.1 2 In the past three decades, there has been substantial investigation into each of these processes.3 4 This discussion will focus on triggered activity caused by delayed afterdepolarizations (DADs). Triggered activity has been widely studied for more than 20 years in whole hearts, isolated myocytes, and muscle and in Purkinje fiber preparations.5 6 Two general types of triggered afterdepolarizations have been observed and characterized. Early afterdepolarizations occur during the plateau phase of long-duration action potentials (APs). These secondary depolarizations involve either reactivation of the L-type Ca2+ channel or Na+ channel.6 7 DADs occur after repolarization of the AP to the resting potential and are caused by spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR).6 8 9 10 11 12 The resulting elevation of cytosolic free Ca2+ activates inward current(s) that causes diastolic depolarization. When DADs are of a sufficient magnitude, an AP is induced. In the intact heart, these APs can propagate throughout the myocardium to cause extra heartbeats. In addition, if they find the ventricle in a partially refractory state or with conduction abnormalities, these APs can lead to tachyarrhythmias and fibrillation. It is well established that DADs result from spontaneous Ca2+ release from a Ca2+-overloaded SR.9 10 11 Many early studies of DADs used cardiac glycosides to increase cellular and SR Ca2+ and induce Ca2+ overload. It is now clear that many other factors including hypoxia, ischemia, increased sympathetic nerve activity, sympathomimetic drugs, hypertrophy, and heart failure can produce Ca2+ overload and DADs.10 In whole hearts, …