title: The Failing Heart Relies on Ketone Bodies as a Fuel.
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.
  
  
  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.
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Gregory
authors.initials: G
authors.lastname: Aubert
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Ola J
authors.initials: OJ
authors.lastname: Martin
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Julie L
authors.initials: JL
authors.lastname: Horton
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Rick B
authors.initials: RB
authors.lastname: Vega
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Koves
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crawford
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.).
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: From Cardiovascular Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (G.A., O.J.M., J.L.H., L.L., R.B.V., T.C.L., S.J.G., P.A.C., D.P.K.); Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (T.K., D.M.M.); CECAD Research Center, Institute for Genetics, University of Cologne, Cologne, Germany (M.K.); Departments of Pharmacology and Medicine, Case Western Reserve University, Cleveland, OH (C.L.H.); College of Medicine, University of Illinois at Chicago, Chicago, IL (E.D.L.); and Department of Medicine, Washington University School of Medicine, St. Louis, MO (P.A.C.). dkelly@sbpdiscovery.org.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D055423:Diet, Ketogenic / Q000379:methods*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology*; D007657:Ketone Bodies / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies
keywords: fatty acids; heart failure; hypertrophy; metabolism; molecular biology
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