Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure

Academic Article

Abstract

  • Objective: Experimental evidence suggests that modulation of myocardial substrate metabolism can markedly affect the progression of chronic heart failure (HF). We tested whether the inhibition of carnitine palmitoyl transferase-I (CPT-I), the enzyme regulating mitochondrial fatty acid oxidation, slows left ventricular remodeling and deterioration of function in pacing-induced HF. Methods: Normal dogs (n=9) were compared to untreated dogs with pacing-induced HF (n=9) and HF dogs treated with 65 mg/kg/day of oxfenicine (HF+Oxf, n=9), a CPT-I inhibitor. Results: HF+Oxf reached terminal failure (LV end-diastolic pressure=25 mm Hg) 6 days later than untreated HF (P<0.05). At 28 days of pacing, hemodynamic alterations and LV dilation were significantly attenuated and the 25% decrease in LV wall thickness was completely prevented in HF+Oxf vs. untreated HF, as was the activation of matrix metalloproteinase-2 and -9, markers of tissue remodeling. Oxfenicine also prevented HF-induced transcriptional down-regulation of CPT-I, medium chain acyl-CoA dehydrogenase, GAPDH and citrate synthase, key enzymes of cardiac energy metabolism. In addition, mRNA, but not protein levels of the nuclear receptor peroxisome proliferator-activated receptor-α were reduced in untreated HF, while they did not change significantly in HF+Oxf, as compared to control. Conclusions: CPT-I inhibition early in the development of HF prevented LV wall thinning and delayed the time to end-stage failure. While these results are limited to an experimental model of disease, they nevertheless suggest that CPT-I inhibition might be effective for slowing the progression of clinical HF. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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    Author List

  • Lionetti V; Linke A; Chandler MP; Young ME; Penn MS; Gupte S; D'Agostino C; Hintze TH; Stanley WC; Recchia FA
  • Start Page

  • 454
  • End Page

  • 461
  • Volume

  • 66
  • Issue

  • 3