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1 Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA
2 Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
3 Louis Stokes Dept of Veteran Affairs Medical Center, Medical Research Service, Cleveland, OH, USA
4 Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA
5 Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Dept of Veteran Affairs Medical Center, Medical Research Service, Cleveland, OH, USA
6 Department of Medicine, Henry Ford Heart & Vascular Institute, Detroit, MI, USA
7 Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA; Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: wcs4{at}po.cwru.edu.
Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by down regulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation was measured in normal dogs (n=8) and dogs with microembolization-induced HF (n=18, EF=28%) by infusing three isotopic tracers ([9,10- 3H]oleate, [U-14C]glucose and [1-13C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl- CoA between groups, however malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Km and Vmax for malonyl CoA decarboxylase as neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF, and that the downregulation of fatty acid oxidation enzymes and switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomemon.
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