Abstract
It has been reported that high intramyocardial peroxisome proliferator-activated receptor alpha (PPARalpha) stimulation or overexpression altered cardiac contractile function in mouse models of cardiac hypertrophy and heart failure. Nevertheless, it has never been demonstrated that clinically relevant doses of drugs stimulating PPARalpha activity such as fenofibrate increase the risk to develop heart failure in humans. To determine if fenofibrate accelerates the development of heart failure in large mammals, we have tested its effects on the progression of left ventricular dysfunction in pacing-induced heart failure in pigs. Fenofibrate treatment blunted reduction in left ventricular ejection fraction, reduced cardiac hypertrophy, and attenuated clinical signs of heart failure. Fenofibrate impeded the increase in atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 plasma levels. The expression of PPARalpha, fatty acyl-CoA-oxidase, and carnitine palmitoyltransferase-Ibeta was reduced at mRNA levels in the left ventricle from untreated heart failure pigs but maintained near normal values with fenofibrate. Fenofibrate prevented heart failure-induced overexpression of TNFalpha mRNA and enhanced catalase activity in left ventricle compared to placebo. These data suggest that a clinically relevant dose of fenofibrate does not accelerate but slows down heart failure development in the model of pacing-induced heart failure in large mammals.
Published Version
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