The Failing Heart Relies on Ketone Bodies as a Fuel

Gregory Aubert; Ola J. Martin; Julie L. Horton; Ling Lai; Rick B. Vega; Teresa C. Leone; Timothy Koves; Stephen J. Gardell; Marcus Krüger; Charles L. Hoppel; E. Douglas Lewandowski; Peter A. Crawford; Deborah M. Muoio; Daniel P. Kelly

doi:10.1161/CIRCULATIONAHA.115.017355

The Failing Heart Relies on Ketone Bodies as a Fuel

Gregory Aubert, Ola J. Martin, Julie L. Horton, Ling Lai, Rick B. Vega, Teresa C. Leone, Timothy Koves, Stephen J. Gardell, Marcus Krüger, Charles L. Hoppel, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Daniel P. Kelly

Molecular Medicine

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

Abstract

Background-Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results-Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions-These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

Original language	English (US)
Pages (from-to)	698-705
Number of pages	8
Journal	Circulation
Volume	133
Issue number	8
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.115.017355
State	Published - Feb 23 2016

Bibliographical note

Funding Information:
We wish to thank Lorenzo Thomas for assistance with preparation of the manuscript and acknowledge the following Core Facilities at Sanford Burnham Prebys Medical Discovery Institute at Lake Nona: Cardiometabolic Phenotyping and Metabolomics. We wish to thank Olga Ilkayeva and the Duke University School of Medicine''s Proteomics and Metabolomics Shared Resource for metabolomics data; and Lauren Ashley Gabriel and Caron Stonebrook for assistance with the animal studies. This work was supported by NIH grants R01 HL058493 (to Dr Kelly), R01 HL101189 (to Drs Kelly and Muoio), R01 DK091538 (to Dr Crawford), R01 HL062702 (to Dr Lewandowski) and R01 HL49244 (to Dr Lewandowski). Dr Aubert was supported by the Swiss National Science Foundation.

Publisher Copyright:
© 2016 American Heart Association, Inc.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

fatty acids
heart failure
hypertrophy
metabolism
molecular biology

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10.1161/CIRCULATIONAHA.115.017355

http://europepmc.org/articles/pmc4766035

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The Failing Heart Relies on Ketone Bodies as a Fuel. / Aubert, Gregory; Martin, Ola J.; Horton, Julie L.; Lai, Ling; Vega, Rick B.; Leone, Teresa C.; Koves, Timothy; Gardell, Stephen J.; Krüger, Marcus; Hoppel, Charles L.; Lewandowski, E. Douglas; Crawford, Peter A.; Muoio, Deborah M.; Kelly, Daniel P.

In: Circulation, Vol. 133, No. 8, 23.02.2016, p. 698-705.

Research output: Contribution to journal › Article › peer-review

Aubert, Gregory ; Martin, Ola J. ; Horton, Julie L. ; Lai, Ling ; Vega, Rick B. ; Leone, Teresa C. ; Koves, Timothy ; Gardell, Stephen J. ; Krüger, Marcus ; Hoppel, Charles L. ; Lewandowski, E. Douglas ; Crawford, Peter A. ; Muoio, Deborah M. ; Kelly, Daniel P. / The Failing Heart Relies on Ketone Bodies as a Fuel. In: Circulation. 2016 ; Vol. 133, No. 8. pp. 698-705.

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abstract = "Background-Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results-Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions-These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.",

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note = "Funding Information: We wish to thank Lorenzo Thomas for assistance with preparation of the manuscript and acknowledge the following Core Facilities at Sanford Burnham Prebys Medical Discovery Institute at Lake Nona: Cardiometabolic Phenotyping and Metabolomics. We wish to thank Olga Ilkayeva and the Duke University School of Medicine''s Proteomics and Metabolomics Shared Resource for metabolomics data; and Lauren Ashley Gabriel and Caron Stonebrook for assistance with the animal studies. This work was supported by NIH grants R01 HL058493 (to Dr Kelly), R01 HL101189 (to Drs Kelly and Muoio), R01 DK091538 (to Dr Crawford), R01 HL062702 (to Dr Lewandowski) and R01 HL49244 (to Dr Lewandowski). Dr Aubert was supported by the Swiss National Science Foundation. Publisher Copyright: {\textcopyright} 2016 American Heart Association, Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

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The Failing Heart Relies on Ketone Bodies as a Fuel

Abstract

Bibliographical note

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