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 6

3OHB augments respiratory efficiency in isolated heart mitochondria.

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3OHB augments respiratory efficiency in isolated heart mitochondria. Fre...
Freshly isolated mitochondria from heart ventricles of C57BL/6N mice were utilized to assess the impact of 3-hydroxybutyrate (3OHB) on the relationship between (A) oxygen consumption rate (JO2) (B) mitochondrial membrane potential (ΔΨ) in millivolts (mV), and (C) NAD(P)H/NAD(P)+ redox state versus the estimated Gibbs energy of ATP hydrolysis (ΔGATP). Mitochondria were fueled with pyruvate + malate (P/M, 110 μM each) and increasing concentrations of L-octanoylcarnitine (OC; 10, 50, or 100 μM) in the absence (purple) or presence (red) of 2 mM 3OHB. (D) Mitochondrial respiratory efficiency was evaluated by plotting JO2 against ΔΨ in the presence of P/M + 10–100 μM OC ± 3OHB. Dotted lines separate the submaximal and maximal portions of JO2 vs. ΔGATP. Triangle denotes the changing concentrations of ATP relative to ADP (ATP/ADP), resulting in a reciprocal change in energy demand. Data are mean ± SEM (n = 5). Measurements made at submaximal JO2 (A–C) were analyzed by 2-way ANOVA (†main effect of ketone; ‡ketone, ΔGATP interaction; P < 0.05), whereas those representing maximal JO2 (ΔGATP = –12.95) were analyzed via t test (*P < 0.05).