|Morgan, Eric - CASE WESTERN RESERVE UNIV|
|Rennison, Julie - CASE WESTERN RESERVE UNIV|
|Mcelfresh, Tracy - CASE WESTERN RESERVE UNIV|
|Kung, Theodore - CASE WESTERN RESERVE UNIV|
|Tserng, Kou-Yi - VET AFFAIRS MED RES CNTR|
|Hoit, Brian - CASE WESTERN RESERVE UNIV|
|Stanley, William - CASE WESTERN RESERVE UNIV|
|Chandler, Margaret - CASE WESTERN RESERVE UNIV|
Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 6, 2005
Publication Date: May 1, 2006
Citation: Morgan, E.E., Rennison, J.H., Young, M.E., McElfresh, T.A., Kung, T.A., Tserng, K.Y., Hoit, B.D., Stanley, W.C., Chandler, M.P. 2006. Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure. American Journal of Physiology - Heart and Circulatory Physiology. 290(5):H1899-H1904. Interpretive Summary: The heart uses both fat and carbohydrates as fuels for continued beating. During heart disease (for example, heart failure), the heart appears to increase use of carbohydrate, and simultaneously decreases use of fat, as fuel sources. It is not known whether this shift in fuel preference during heart disease is beneficial or detrimental. This study therefore forced the heart (in an animal model that mimics heart failure) to use fat as a fuel by either increasing fat in the diet, or by treatment with a drug that stimulates fat use. The results show that forcing the heart to use fat as a fuel in this disease state does not have any effect on heart function.
Technical Abstract: Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPAR agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPAR-alpha agonist fenofibrate (150 mg·kg(–1)·day(–1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 ± 6%) compared with sham operated (86 ± 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPAR-alpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPAR-alpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.