The medium-chain fatty acid octanoate is a beneficial fuel for the failing heart.

Abstract

The failing heart displays marked alterations of energy substrate metabolism, with a reduced oxidation of long-chain fatty acids (FA) associated with increased glucose oxidation. Recent preclinical and human studies have shown that the delivery of ketone bodies as an alternative substrate reduces pathological cardiac remodeling and dysfunction in heart failure. However, chronic administration of ketone bodies is challenging. Therefore, using a clinically relevant canine model of tachypacing-induced dilated cardiomyopathy, we tested the hypothesis that other shorter-chain FA may also be beneficial. Seven dogs received cardiac tachypacing and continuous infusion of sodium octanoate, a medium-chain FA, starting after 2 wk of pacing when cardiac dysfunction was still moderate. Six dogs received cardiac pacing with no octanoate infusion. Octanoate did not significantly alter circulating levels of ketone bodies, whereas it still exerted protection, resulting in a delayed progression of systolic and diastolic cardiac dysfunction and normalized myocardial metabolism. These results identify the delivery of medium-chain FA as a potential actionable therapeutic for heart failure with reduced ejection fraction. Octanoate has translational promise due to proven methods of dietary supplementation with no need for parenteral administration.Provision of the medium-chain fatty acid octanoate prevented or reversed key metrics of cardiac functional and metabolic deterioration in a large animal model of dilated cardiomyopathy. Our results demonstrate the cardiac benefits of supplementing a medium-chain FA independent of ketosis in a translational model of heart failure. These findings encourage mechanistic and next-stage translational studies into metabolic interventions for the treatment of heart failure.