The contribution of fatty acid and ketone body oxidation to energy production increases in the failing heart and is associated with a decrease in cardiac efficiency

Abstract

Background: The failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Since recent evidence suggests that ketone body oxidation increases in the failing heart as an adaptive mechanism to counteract reductions in fatty acid oxidation, our aim was to assess overall cardiac metabolism in heart failure, to establish what metabolic alterations contribute to reduced cardiac efficiency. Methods: C57BL/6J male mice (12 wk old) underwent either sham surgery, or transverse aortic constriction (TAC) surgery to induce pressure overload hypertrophy over a 4 wk period. Isolated working hearts from these mice were then perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and ß-hydroxybutyrate (0.6 mM) to assess oxidative metabolism and glycolysis. Results: A 45% reduction in %EF was seen in intact TAC mice and a 54% decrease in cardiac work was seen in isolated working hearts from TAC mice. However, normal cardiac Krebs Cycle acetyl CoA production was seen compared to sham mice, reflecting a reduction in cardiac efficiency. Correspondingly, absolute glucose oxidation rates decreased in TAC compared to sham hearts, whereas absolute rates of fatty acid and ketone body oxidation were similar. However, normalization to cardiac work revealed that glucose oxidation was not depressed in failing hearts, although glycolysis was increased. Conversely, both fatty acid and ketone body oxidation increased in TAC hearts when normalized to cardiac work. This increased reliance on fatty acid oxidation challenges the current dogma suggesting that fatty acid oxidation is depressed in the failing heart. Conclusion: In the failing heart, a decreased cardiac efficiency is associated with increases in the contributions of ketone body and fatty acid oxidation to energy production. The latter observation suggests that normalizing excessive fatty acid oxidation in the failing heart may be a novel approach to improve cardiac efficiency.