The heart has the highest energy demand in the body and relies on a variety of fuel sources, including glucose, fatty acids and ketone bodies, to meet its metabolic needs. Previous studies have shown beneficial effects of ketone administration in heart failure with preserved ejection fraction (HFpEF). In a recent study published in Circulation Research, Koay et al. demonstrate the intrinsic ability of the heart to produce its own ketones and the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which prevents the accumulation of acetyl-CoA that could acetylate and impair functions of mitochondrial proteins. O’Sullivan, one of the corresponding authors of the study, notes that “treating heart failure with metabolic therapies such as SGLT2i and GLP-1 has reinvigorated the research community to study metabolism and bioenergetics in heart failure. Therefore, I wanted to study the potential role of perturbed energy metabolism as a casual factor in HFpEF”.
To study cardiac energy metabolism, the authors used an established mouse model of HFpEF and demonstrated that in the myocardial proteome of HFpEF mice, levels of glucose transporters and enzymes that are crucial for the regulation of glucose uptake, glucose phosphorylation and the conversion of pyruvate to acetyl-CoA (which fuels the tricarboxylic acid cycle) were decreased, whereas levels of HMGCS2, fatty acid transporters and enzymes that catalyze the first steps in mitochondrial fatty acid β-oxidation (FAO) were increased. HMGCS2 served as a transition point, in which levels of upstream enzymes were increased, and downstream enzymes including enzymes involved in ketone body utilization were unchanged or decreased.
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