|Labinskyy, Volodymyr - NY MEDICAL COLLEGE|
|Bellomo, Michelle - NY MEDICAL COLLEGE|
|Chandler, Margaret - CASE WESTERN RESERVE UNIV|
|Lionetti, Vincenzo - CONSIGLIO NAZIONALE RES|
|Qanud, Khaled - NY MEDICAL COLLEGE|
|Bigazzi, Federico - CONSIGLIO NAZIONALE RES|
|Sampietro, Tiziana - CONSIGLIO NAZIONALE RES|
|Stanley, William - CASE WESTERN RESERVE UNIV|
|Recchia, Fabio - NY MEDICAL COLLEGE|
Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 8, 2007
Publication Date: January 10, 2007
Citation: Labinskyy, V., Bellomo, M., Chandler, M.P., Young, M.E., Lionetti, V., Qanud, K., Bigazzi, F., Sampietro, T., Stanley, W.C., Recchia, F.A. 2007. Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure. Journal of Pharmacology and Experimental Therapeutics. 321(1):165-171. Interpretive Summary: Fenofibrate is a commonly prescribed drug given to patients with elevated ‘bad’ fats in their blood (called dyslipidemia). Fenofibrate acts by accelerating fat usage by organs, such as the heart. However, several studies suggest that stimulating fat usage in the heart during heart disease is detrimental. The present study shows that treating dogs with fenofibrate at doses given to humans does not accelerate heart failure progression. These results suggest that treating heart failure patients with fenofibrate is not likely to be detrimental.
Technical Abstract: 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-alpha, 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 beta-oxidation pathway, was reduced in HF versus control (1.46 +/- 0.25 versus 2.42 +/- 0.24 micromol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 +/- 0.18 micromol/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.