(Circulation. 1997;96:3681-3686.)
© 1997 American Heart Association, Inc.
Articles |
Etomoxir Improves Left Ventricular Performance of Pressure-Overloaded Rat Heart
From the Institute of Pathophysiology, Medical School, Comenius University, Bratislava, Slovak Republic, and Molecular Cardiology Lab, Division of Cardiology, Philipps University of Marburg (Germany).
Correspondence to Marian Turcani, MD, Institute of Pathophysiology, Medical School, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic. E-mail turcani{at}medik.fmed.uniba.sk
Background Numerous studies have demonstrated diverse abnormalities in subcellular structures of pressure-overloaded hypertrophied and failing heart. Long-term administration of etomoxir, a carnitine palmitoyltransferase-1 inhibitor, partially normalized the proportion of myosin isozyme V1 and number of active Ca2+ pumps in hypertrophied rat myocardium.
Methods and Results To test the hypothesis that long-term etomoxir treatment improves the performance of hypertrophied ventricle, sham-operated rats and rats with ascending aorta constriction were treated with racemic etomoxir (15 mg/kg per day) for 12 weeks. Left ventricular geometry, dynamics of isovolumic contractions, as well as myosin isozymes as marker of etomoxir-induced phenotype changes were assessed. Etomoxir stimulated (P<.05) slight hypertrophic growth in right and left ventricles of sham-operated rats as well as in right ventricles but not in overloaded left ventricles of rats with aortic constriction. In all treated rats, etomoxir increased (P<.05) maximal developed pressure, left ventricular pressure-volume area, and ±dP/dtmax. Enhanced values (P<.05) of derived indexes of myocardial performance (normalized 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 V1 in pressure-overloaded left ventricles.
Conclusions The long-term treatment with etomoxir improved functional capacity of pressure-overloaded left ventricle, which can be attributed to an enhanced myocardial performance. Chronic carnitine palmitoyltransferase-1 inhibition may thus represent a candidate approach for developing novel agents that are useful in the prevention of undesirable consequences of pressure overload–induced cardiac hypertrophy.
Key Words: etomoxir • heart failure • hypertrophy • ventricular function • myosin isozymes
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