SELECTED METABOLIC ALTERATIONS IN THE ISCHEMIC HEART AND THEIR CONTRIBUTIONS TO ARRHYTHMOGENESIS (REPRINTED FROM MYOCARDIAL-ISCHEMIA-AND-ARRHYTHMIA, 1994)

Myocardial ischemia in vivo is associated with dramatic electrophysiol ogic alterations which occur within minutes of cessation of coronary f low and are rapidly reversible with reperfusion. This suggests that su btle and reversible biochemical and/or ionic alterations within or nea r the sarcolemma may contribute to the electrophysiologic derangements . Our studies have concentrated on 2 amphipathic metabolites, long-cha in acylcarnitines and lysophosphatidylchorine (LPC) which have been sh own to increase rapidly in ischemic tissue in vivo and to elicit elect rophysiologic derangements in normoxic tissue in vitro. Incorporation of these amphiphiles into the sarcolemma at concentrations of 1 to 2 m ol%, elicits profound electrophysiologic derangements analogous to tho se observed in ischemic myocardium in vivo. LPC is produced in endothe lial cells and myocytes in response to thrombin. Thus, activation of t he coagulation system during ischemia may result in extracellular prod uction and accumulation of LPC. The pathophysiological effects of the accumulation of both amphiphiles are thought to be mediated by alterat ions in the biophysical properties of the sarcolemmal membrane, althou gh there is a possibility of a direct effect on ion channels. Inhibiti on of carnitine acyltransferase I in the ischemic cat heart was found to prevent the increase in both long-chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmias includi ng ventricular tachycardia and fibrillation. This review focuses on th e influence of these amphiphiles on cardiac ionic currents observed du ring early ischemia and presents data supporting the concept that accu mulation of these amphiphiles within the sarcolemma contributes to cha nges in ionic conductances leading to electrophysiological derangement s. The contribution and the accumulation of these amphiphiles to alter ations in intracellular Ca2+ as related to changes in Na/K-ATPase acti vity and intracellular Na+ are examined. Other alterations occur durin g early myocardial ischemia in addition to the events reviewed here; h owever, the results of multiple studies over the past 2 decades indica te that accumulation of these amphiphiles contributes importantly to a rrhythmogenesis and that development of specific inhibitors of carniti ne acyltransferase I or phospholipase A,may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.