title: 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.
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.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Labinskyy
authors.forename: Michelle
authors.initials: M
authors.lastname: Bellomo
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Khaled
authors.initials: K
authors.lastname: Qanud
authors.forename: Federico
authors.initials: F
authors.lastname: Bigazzi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sampietro
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D011345:Fenofibrate / Q000494:pharmacology*; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013318:Stroke Volume / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D044944:Acyl-CoA Dehydrogenases; D011345:Fenofibrate