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

doi:10.1172/jci.insight.124079

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

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237 Scopus citations

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.

Original language	English (US)
Journal	JCI Insight
Volume	4
Issue number	4
DOIs	https://doi.org/10.1172/jci.insight.124079
State	Published - Feb 21 2019

Keywords

Cardiology
Heart failure
Metabolism
Mitochondria
Mouse models

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10.1172/jci.insight.124079

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title = "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.",

keywords = "Cardiology, Heart failure, Metabolism, Mitochondria, Mouse models",

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

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AU - Horton, Julie L.

AU - Davidson, Michael T.

AU - Kurishima, Clara

AU - Vega, Rick B.

AU - Powers, Jeffery C.

AU - Matsuura, Timothy R.

AU - Petucci, Christopher

AU - Lewandowski, E. Douglas

AU - Crawford, Peter A.

AU - Muoio, Deborah M.

AU - Recchia, Fabio A.

AU - Kelly, Daniel P.

PY - 2019/2/21

Y1 - 2019/2/21

N2 - 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.

AB - 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.

KW - Cardiology

KW - Heart failure

KW - Metabolism

KW - Mitochondria

KW - Mouse models

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

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