Heart failure (HF) remains the leading cause of morbidity and mortality in the developed world, highlighting the urgent need for novel, effective therapeutics. Recent studies support the proposition that improved myocardial energetics as a result of ketone body (KB) oxidation may account for the intriguing beneficial effects of sodium-glucose cotransporter-2 inhibitors in patients with HF. Similar small molecules, short-chain fatty acids (SCFAs) are now realized to be preferentially oxidized over KBs in failing hearts, contradicting the notion of KBs as a rescue "superfuel." In addition to KBs and SCFAs being alternative fuels, both exert a wide array of nonmetabolic functions, including molecular signaling and epigenetics and as effectors of inflammation and immunity, blood pressure regulation, and oxidative stress. In this review, the authors present a perspective supported by new evidence that the metabolic and unique nonmetabolic activities of KBs and SCFAs hold promise for treatment of patients with HF with reduced ejection fraction and those with HF with preserved ejection fraction.
Keywords: BP, blood pressure; CPT1, carnitine palmitoyltransferase I; CoA, coenzyme A; FFAR, free fatty acid receptor; GPR, G protein–coupled receptor; HF, heart failure; HFpEF; HFpEF, heart failure with preserved ejection fraction; HFrEF; KB, ketone body; LCFA, long-chain fatty acid; SCFA, short-chain fatty acid; SGLT2, sodium-glucose cotransporter-2; heart failure; ketones; short-chain fatty acids; β-HB, β-hydroxybutyrate.
© 2022 The Authors.