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.