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 1

csBDH1–/– mouse hearts are incapable of oxidizing D-3-hydroxybutyrate.

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csBDH1–/– mouse hearts are incapable of oxidizing D-3-hydroxybutyrate. (...
(A) (Left) The fractional enrichment of acetyl-CoA (Fc), representing oxidation of 13C-labeled D-3-hydroxybutyrate into the TCA cycle, is shown in Bdh1fl/flCre– (control) and csBDH1–/– isolated perfused mouse hearts (12- to 16-week-old male littermates) (n = 6). (Right) Representative in vitro NMR spectra displaying 13C labeling of glutamate at the 4- and 3-carbon (glu C-4 and glu C-3) positions in tissue extract from the hearts of control mice (top) and csBDH1–/– mouse (bottom) is shown. The latter has complete absence of signal (1% natural abundance). (B) Fc for 13C-labeled palmitate perfused isolated mouse hearts is shown (n = 5–6) (12- to 16-week-old male littermates). (C) Levels of myocardial 3-hydroxybutyrate (3OHB) per wet weight (ww) measured in control and csBDH1–/– male mice 8–10 weeks after 4-hour fast (n = 5). Bars represent mean ± SEM; *P < 0.05 control vs. csBDH1–/– using unpaired, 2-tailed Mann-Whitney test.