The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense
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
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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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 7

The effects of 3OHB on mitochondrial respiratory efficiency depend on BDH1 flux.

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The effects of 3OHB on mitochondrial respiratory efficiency depend on BD...
(A–C) Freshly isolated mitochondria from heart ventricles of BDH1fl/fl (controls), csBDH1–/–, or WT C57BL/6N mice were used to assess the impact of 3OHB on the relationship between (A) oxygen consumption rate (JO2), (B) 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 (110 μM each) and 50 μM L-octanoylcarnitine in the absence (purple) or presence of 2 mM of the (R, red) or (S, green) enantiomer of 3OHB, or acetoacetate (AcAc, gray). (D) Mitochondrial respiratory efficiency was evaluated by plotting JO2 against ΔΨ. 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 represent mean ± SEM (n = 4–6). Comparisons between BDH1fl/fl versus csBDH1–/– mitochondria were analyzed by 3-way ANOVA followed by Tukey HSD (#ketone/genotype interaction; §ketone effect; P< 0.05 and family-wise error rate [FWER] < 0.05) using measurements (A–C) made at submaximal JO2. Energy fluxes representing maximal JO2 (ΔGATP = –12.95) were analyzed by 2-way ANOVA and Tukey HSD (*FWER < 0.05, relative to vehicle control). Comparison of R and S enantiomers were analyzed by 2-way ANOVA (submaximal JO2) and 1-way ANOVA (maximal JO2) each followed by Tukey HSD (§effect of R at submaximal JO2; ¤effect of S at maximal JO2; FWER < 0.05). Effects of AcAc were analyzed by 2-way ANOVA at submaximal JO2 (†main effect of ketone; ‡ketone/ΔGATP interaction, P < 0.05) and t test at maximal JO2 (*P < 0.05).