The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense
Julie L. Horton, … , Fabio A. Recchia, Daniel P. Kelly
Julie L. Horton, … , Fabio A. Recchia, Daniel P. Kelly
Published January 22, 2019
Citation Information: JCI Insight. ;4(4):e124079. https://doi.org/10.1172/jci.insight.124079.
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Research Article Cardiology Metabolism

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

Abstract

Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in the heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared with WT controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.

Authors

Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, Daniel P. Kelly

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Figure 5

Impact of 3OHB infusion on cardiac substrate utilization.

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Impact of 3OHB infusion on cardiac substrate utilization. Cardiac substr...
Cardiac substrate utilization measured at the last day of the cardiac pacing protocol in dogs without (HF) or with infusion of 3-hydroxybuytrate (HF + 3OHB) compared with nonpaced controls. The set of data for HF and nonpaced controls was randomly selected from historical pools. (A) Cardiac uptake of ketone bodies. (B and C) Myocardial oxidation of (B) FFA and (C) glucose. (D and E) Cardiac uptake of (D) glucose and (E) FFA. (F) Cardiac uptake of lactate. (G) Myocardial oxygen consumption (MVO2). Bars represent mean ± SEM (n = 6 for all groups), *P < 0.05 vs. Control; #P < 0.05 HF vs. HF + 3OHB by 1-way ANOVA followed by Student-Newman test for multiple comparisons.