Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.

BACKGROUND

Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown.

METHODS

To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by ), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific knockout (n=32) mice and littermate controls (wild type; WT; n=35) were subjected to transverse aortic constriction (TAC) surgery to induce HF.

RESULTS

Deletion of SCOT in skeletal, but not cardiac muscle resulted in elevated concentrations of fasted circulating β-hydroxybutyrate in knockout mice compared with WT mice (=0.030). Five weeks following TAC, WT mice progressed to HF, whereas knockout mice with elevated fasting circulating ketones were largely protected from the TAC-induced effects observed in WT mice (ejection fraction, =0.011; mitral E/A, =0.012). Furthermore, knockout mice with TAC had attenuated expression of markers of sterile inflammation and macrophage infiltration, which were otherwise elevated in WT mice subjected to TAC. Lastly, addition of β-hydroxybutyrate to isolated hearts was associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3)-inflammasome activation, which has been previously shown to play a role in contributing to HF-induced cardiac inflammation.

CONCLUSIONS

These data show that chronic elevation of circulating ketones protects against the development of HF that is associated with the ability of β-hydroxybutyrate to directly reduce inflammation. These beneficial effects of ketones were associated with reduced cardiac NLRP3 inflammasome activation, suggesting that ketones may modulate cardiac inflammation via this mechanism.