Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure Academic Article uri icon

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abstract

  • 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 Oxct1), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific Oxct1Muscle-/- 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 (P=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, P=0.011; mitral E/A, P=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.

authors

  • Byrne, Nikole J
  • Soni, Shubham
  • Takahara, Shingo
  • Ferdaoussi, Mourad
  • Al Batran, Rami
  • Darwesh, Ahmed M
  • Levasseur, Jody L
  • Beker, Donna
  • Vos, Dyonne Y
  • Schmidt, Mya A
  • Alam, Abrar S
  • Maayah, Zaid H
  • Schertzer, Jonathan
  • Seubert, John M
  • Ussher, John R
  • Dyck, Jason RB

publication date

  • June 2020

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