ETOMOXIR IMPROVES LEFT-VENTRICULAR PERFORMANCE OF PRESSURE-OVERLOADEDRAT-HEART

Background Numerous studies have demonstrated diverse abnormalities in subcellular structures of pressure-overloaded hypertrophied and faili ng heart. Long-term administration of etomoxir, a carnitine palmitoylt ransferase-1 inhibitor, partially normalized the proportion of myosin isozyme V-1 and number of active Ca2+ pumps in hypertrophied rat myoca rdium. Methods and Results To test the hypothesis that long-term etomo xir treatment improves the performance of hypertrophied ventricle, sha m-operated rats and rats with ascending aorta constriction were treate d with racemic etomoxir (15 mg/kg per day) for 12 weeks. Left ventricu lar geometry, dynamics of isovolumic contractions, as well as myosin i sozymes as marker of etomoxir-induced phenotype changes were assessed. Etomoxir stimulated (P<.05) slight hypertrophic growth in right and l eft ventricles of sham-operated rats as well as in right ventricles bu t not in overloaded left ventricles of rats with aortic constriction. In all treated rats, etomoxir increased (P<.05) maximal developed pres sure, left ventricular pressure-volume area, and +/-dP/dt(max). Enhanc ed values (P<.05) of derived indexes of myocardial performance (normal ized stress-length area, maximal rate of wall stress rise, and decline ) indicated that myocardial changes were responsible for the improved performance. The etomoxir treatment increased selectively (P<.05) the proportion of myosin V-1 in pressure-overloaded left ventricles. Concl usions The long-term treatment with etomoxir improved functional capac ity of pressure-overloaded left ventricle, which can be attributed to an enhanced myocardial performance. Chronic carnitine palmitoyltransfe rase 1 inhibition may thus represent a candidate approach for developi ng novel agents that are useful in the prevention of undesirable conse quences of pressure overload-induced cardiac hypertrophy.