Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.
Hypoxia in isolated myocytes results in accumulation of long-chain acylcarnitines (LCA) in sarcolemma. Inhibition of carnitine acyltransferase I (CAT-I) with sodium 2-[5-(4-chlorophenyl)-pentyl]-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 (3.3 +/- 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.
Corr
P B
PB
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Creer
M H
MH
Yamada
K A
KA
Saffitz
J E
JE
Sobel
B E
BE
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001783:Blood Flow Velocity; D002331:Carnitine / Q000378:metabolism*; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors*; D002415:Cats; D002851:Chromatography, High Pressure Liquid; D003326:Coronary Circulation; D003327:Coronary Disease / Q000150:complications* / Q000503:physiopathology; D003331:Coronary Vessels / Q000378:metabolism; D004852:Epoxy Compounds / Q000627:therapeutic use*; D004988:Ethers, Cyclic / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism; D006439:Hemodynamics; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D005227:Fatty Acids; D008244:Lysophosphatidylcholines; C033891:ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate; D000217:Acyltransferases; D002333:Carnitine Acyltransferases; D002331:Carnitine