QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.116871v1 321/1/165    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Labinskyy, V. Articles by Recchia, F. A. Search for Related Content PubMed PubMed Citation Articles by Labinskyy, V. Articles by Recchia, F. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Medline Plus Health Information Heart Failure

CARDIOVASCULAR

Chronic Activation of Peroxisome Proliferator-Activated Receptor- with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure

Department of Physiology, New York Medical College, Valhalla, New York (V.L., M.B., K.Q., F.A.R.); Sector of Medicine, Scuola Superiore Sant'Anna, Pisa, Italy (V.L., F.A.R.); Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas (M.E.Y.); Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy (V.L., F.B., T.S.); and Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (M.P.C., W.C.S.)

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-, 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 -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.

Address correspondence to: Dr. Fabio A. Recchia, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail: fabio_recchia{at}nymc.edu

This article has been cited by other articles:

				Z. Gao, A. S. Barth, D. DiSilvestre, F. G. Akar, Y. Tian, A. Tanskanen, D. A. Kass, R. L. Winslow, and G. F. Tomaselli Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling Physiol Genomics, November 12, 2008; 35(3): 222 - 230. [Abstract] [Full Text] [PDF]

				D. J. Chess and W. C. Stanley Role of diet and fuel overabundance in the development and progression of heart failure Cardiovasc Res, July 15, 2008; 79(2): 269 - 278. [Abstract] [Full Text] [PDF]

				N. K. LeBrasseur, T.-A. S. Duhaney, D. S. De Silva, L. Cui, P. C. Ip, L. Joseph, and F. Sam Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension Hypertension, September 1, 2007; 50(3): 489 - 496. [Abstract] [Full Text] [PDF]

				G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]