Short Chain Fatty Acids Outpace Ketone Oxidation in the Failing Heart

Background: The failing heart is energy-starved with impaired oxidation of long chain fatty acids (LCFA) at the level of reduced carnitine palmitoyltransferase 1 (CPT1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short chain carbon source, short chain fatty acids (SCFA) that bypass CPT1, could similarly support energy production in failing hearts. Methods: Cardiac hypertrophy and dysfunction was induced in rats by transverse-aortic constriction (TAC). 14 weeks after TAC or sham-operation, isolated hearts were perfused with either the four carbon, 13C-labeled ketone (D3-hydroxybutyrate) or the four carbon, 13C -labeled SCFA, butyrate in the presence of glucose and the LCFA, palmitate. Oxidation of ketone and SCFA was compared by in vitro13C NMR spectroscopy, as was the capacity for short chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts. Results: TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl CoA production in the tricarboxylic acid cycle (0.60±0.02 sham ketone vs 0.70±0.02 TAC ketone, p