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

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-alpha 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Lionetti V,Linke A,Chandler MP,Young ME,Penn MS,Gupte S,d'Agostino C,Hintze TH,Stanley WC,Recchia FA

doi

10.1016/j.cardiores.2005.02.004

subject

Has Abstract

pub_date

2005-06-01 00:00:00

pages

454-61

issue

3

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(05)00081-7

journal_volume

66

pub_type

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