Heart failure is characterized by changes in myocardial fuel metabolism and bioenergetics, and the heart shifts from utilizing fatty acids as its main fuel source to more oxygen-sparing carbohydrate metabolism. Two studies published in Circulation now show that ketone utilization is increased in both animal models of heart failure and the human failing heart.
Numerous studies using animal models of heart disease have demonstrated that the failing heart shifts from fatty acid oxidation (FAO) to increased reliance on glycolysis for energy production. The pathways through which the heart compensates for reduced FAO are unknown, and an integrated signature of metabolism in the human nondiabetic failing heart is yet to be defined.
Aubert et al. aimed to identify mitochondrial energy abnormalities in heart failure using mice with pressure-overload-induced hypertrophy and heart failure. Using quantitative mitochondrial proteomics, the investigators demonstrated that the proteins required for cellular fatty acid utilization were reduced in myocardial samples from both hypertrophied and failing hearts. Meanwhile, gene and protein expression of β-hydroxybutyrate dehydrogenase 1, an important enzyme in the ketone oxidation pathway, was elevated in failing hearts. Ex vivo 13C-nuclear magnetic resonance studies in the hypertrophied heart, and assessment of myocardial levels of metabolites indicating ketone body oxidation in the failing heart, consistently demonstrated a reduction in FAO and an increase in the oxidation of ketone bodies.
Aubert et al. conclude that “these results provide evidence that myocardial ketone body utilization is increased in the heart failure mice through several potential mechanisms including increased delivery of ketone bodies and gene regulatory reprogramming of ketone uptake and oxidation”. Further studies to determine the effect of chronic ketone utilization on cardiac metabolism and function are warranted.
In a separate study, Bedi et al. aimed to elucidate the metabolic signature in the human nondiabetic failing heart using a case–control study. Unbiased and targeted myocardial lipid surveys were performed in nondiabetic patients with heart failure using liquid chromatography–mass spectroscopy. Long-chain acylcarnitine, the primary lipid substrate for mitochondrial fatty acid oxidation, was substantially reduced in failing hearts, along with other myocardial lipids. Decreased levels of acyl-CoA species were incorporated into the Krebs cycle, in contrast to an increase in acetyl-CoA concentration in the failing heart, reflecting dysregulation in energy metabolism. Furthermore, the investigators found evidence for increased utilization of β-hydroxybutyrate (βOHB), in addition to increased myocardial gene expression of the gene encoding the rate limiting enzyme for myocardial oxidation of βOHB and acetoacetate.
In this case–control study of nondiabetic heart failure, Bedi and colleagues identified an aberrant metabolic signature associated with an increase in acetyl-CoA and a reduction in Krebs cycle intermediates. The investigators conclude that these results “support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaption in the failing human heart”.
Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 10.1161/CIRCULATIONAHA.115.017355
Bedi, K. C. Jr et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 10.1161/CIRCULATIONAHA.115.017545
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Huynh, K. Ketone bodies as fuel in heart failure. Nat Rev Cardiol 13, 123 (2016). https://doi.org/10.1038/nrcardio.2016.22
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