Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.

Abstract

Hypoxia in isolated myocytes results in accumulation of longchain acylcarnitines (LCA) in sarcolemma. nhibition of carnitine acyltransferase I (CAT-I) with sodium 2-15-(4-chlorophenyl)-pentyll-oxirane-2-carboxylate (POCA) prevents both the accumulation of LCA in the sarcolemma and the initial electrophysiologic derangements associated with hypoxia. Another amphiphilic metabolite, lysophosphatidylcholine (LPC), accumulates in the ischemic heart in vivo, in part because of inhibition of its catabolism by accumulating LCA. It induces electrophysiologic alterations in vitro analogous to early changes induced by ischemia in vivo. The present study was performed to determine whether POCA could prevent accumulation of both LCA and LPC induced by ischemia in vivo and if so, whether attenuation of early arrhythmogenesis would result. LAD coronary artery occlusions were induced for 5 min in chloralose-anesthetized cats. Coronary occlusion in untreated control animals elicited prompt, threefold increases of LCA (73±8 to 286±60 pmol/mg protein) and twofold increase of LPC (33±0.4 to 7.5±0.9 nmol/mg protein) selectively in the ischemic zone, associated with ventricular tachycardia (VT) or ventricular fibrillation (VF) occurring within the 5-min interval before acquisition of myocardial samples in 64% of the animals. POCA prevented the increase of both LCA and LPC. It also prevented the early occurrence of VT or VF (within 5 min of occlusion) in all animals studied. The antiarrhythmic effect of POCA was not attributable to favorable hemodynamic changes or to changes in myocardial perfusion measured with radiolabeled microspheres. Thus, inhibition of CAT-I effectively reduced the incidence of lethal arrhythmias induced early after the onset of ischemia. Accordingly, pharmacologic inhibition of this enzyme provides a promising approach for prophylaxis of sudden cardiac death, that typically occurs very soon after the onset of acute ischemia, in man.

Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients.

“…The impaired long-chain fatty acid 13-oxidation activity in the patients would cause the shortage of energy owing to the inadequate muscle fat utilization and the deficient production of ketone bodies, normally the preferential fuel for myocardium and skeletal muscle. It would also cause accumulation of long-chain triglycerides and long-chain acylcarnitines, which may be toxic to cardiac muscle (43). These unfavorable factors may relate to the occurrence of cardiac diseases such as arrhythmia, cardiomegaly, and cardiomyopathy, and muscular disorders such as episodic muscle pain, rhabdomyolysis, and progressive muscular weakness.…”

Hypoxia Inhibits the Peroxisome Proliferator-activated Receptor α/ Retinoid X Receptor Gene Regulatory Pathway in Cardiac Myocytes

“…Additionally, under limited oxygen availability, reduced cardiac mitochondrial ␤-oxidation predisposes to the accumulation of upstream extramitochondrial LCFA intermediates, such as long-chain acylcarnitine (LCAC), the product of the reaction catalyzed by M-CPT I. LCACs have been demonstrated to impair cardiac function through effects on cellular coupling, ion channel function, and sodium/potassium ATPase activity (36 -38). Previous studies (38) have shown that pharmacologic inhibition of LCAC accumulation in cells subjected to hypoxia prevents electrophysiologic derangements and improves cell survival. Given that CPT I catalyzes a rate-limiting step in mitochondrial FAO, down-regulation of M-CPT I expression would lead to a reduction of substrate flux into reactive oxygen species and LCACgenerating mitochondrial pathways.…”

Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

“…Second, administration of 5 pM palmitoyl-L-carnitine may inflict damage to the heart to an extent similar to that induced by ischemia in terms of tissue accumulation of long-chain acylcarnitines (8). Last, 5 pM palmitoyl-L carnitine produces not only mechanical dysfunction and energy deficiency but also membrane damage (8), and it induces electrophysiological alterations (1,3) in the heart. We observed that palmitoyl-L-carnitine produced mechanical dysfunction (as evidenced by an increase in LVEDP and a decrease in LVDP) and metabolic damage (as evidenced by a decrease in the tissue ATP level and an increase in the tissue AMP level).…”