PT - JOURNAL ARTICLE AU - Volodymyr Labinskyy AU - Michelle Bellomo AU - Margaret P. Chandler AU - Martin E. Young AU - Vincenzo Lionetti AU - Khaled Qanud AU - Federico Bigazzi AU - Tiziana Sampietro AU - William C. Stanley AU - Fabio A. Recchia TI - Chronic Activation of Peroxisome Proliferator-Activated Receptor-α with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure AID - 10.1124/jpet.106.116871 DP - 2007 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 165--171 VI - 321 IP - 1 4099 - http://jpet.aspetjournals.org/content/321/1/165.short 4100 - http://jpet.aspetjournals.org/content/321/1/165.full SO - J Pharmacol Exp Ther2007 Apr 01; 321 AB - Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-α, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of high-frequency left ventricular pacing (HF + Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. [3H]Oleate and [14C]Glucose were infused intravenously to measure the rate of substrate oxidation. At 21 days of pacing, left ventricular end-diastolic pressure was significantly lower in HF + Feno (14.1 ± 1.6 mm Hg) compared with HF (18.7 ± 1.3 mm Hg), but it increased up to 25 ± 2 mm Hg, indicating end-stage failure, in both groups after 29 ± 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA β-oxidation pathway, was reduced in HF versus control (1.46 ± 0.25 versus 2.42 ± 0.24 μmol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 ± 0.18 μmol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation. The American Society for Pharmacology and Experimental Therapeutics