RECENT INSIGHTS PERTAINING TO SARCOLEMMAL PHOSPHOLIPID ALTERATIONS UNDERLYING ARRHYTHMOGENESIS IN THE ISCHEMIC HEART

Myocardial ischemia in vivo is associated with dramatic electrophysiol ogic alterations that occur within minutes of cessation of coronary fl ow and are rapidly reversible with reperfusion. This suggests that sub tle and reversible biochemical alterations within or near the sarcolem ma may contribute to the electrophysiologic derangements. Our studies have concentrated on two amphipathic metabolites, long-chain acylcarni tines and lysophosphatidylcholine (LPC), which have been shown to incr ease rapidly in ischemic tissue in vivo and to elicit electrophysiolog ic derangements in normoxic tissue in vitro. Incorporation of these am phiphiles into the sarcolemma at concentrations of 1 to 2 mole %, elic its profound electrophysiologic derangements analogous to those observ ed in ischemic myocardium in vivo. The pathophysiological effects of t he accumulation of these amphiphiles are thought to be mediated by alt erations in the biophysical properties of the sarcolemmal membrane, al though there is a possibility of a direct effect upon ion channels. In hibition of carnitine acyltransferase I (CAT-I) in the ischemic cat he art was found to prevent the increase in long-chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmia s including ventricular tachycardia and fibrillation. This review focu ses on the electrophysiologic derangements that are observed during ea rly ischemia and presents data supporting the concept that accumulatio n of these amphiphiles within the sarcolemma contributes to these chan ges. The potential contribution of these amphiphiles to the increases in extracellular potassium and intracellular calcium are examined. Fin ally, recent data pertaining to the accumulation of long-chain acylcar nitines on cell-to-cell uncoupling are presented. In addition to the e vents reviewed here, there are many other alterations that occur durin g early myocardial ischemia, but the results from multiple studies ove r the past two decades indicate that the accumulation of these amphiph iles contributes importantly to arrhythmogenesis and that development of specific inhibitors of CAT-I or phospholipase A2 may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.