J. Mchowat et al., RECENT INSIGHTS PERTAINING TO SARCOLEMMAL PHOSPHOLIPID ALTERATIONS UNDERLYING ARRHYTHMOGENESIS IN THE ISCHEMIC HEART, Journal of cardiovascular electrophysiology, 4(3), 1993, pp. 288-310
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.