Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart

Abstract

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1–2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A 2 (PLA 2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by β-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia. Inhibition of CAT-I prevents not only the accumulation of long-chain acylcarnitine but also the accumulation of LPC and the occurrence of ventricular tachycardia or fibrillation during a 5-min ischemic interval. These results indicate that inhibition of CAT-I may be a promising therapeutic strategy to modify the incidence of lethal arrhythmias associated with ischemic heart disease in man.