title: Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.
abstract: BACKGROUND
  The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se.
  
  
  RESULTS
  We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate.
  
  
  CONCLUSIONS
  These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Bedi
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Brandimarto
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Moez
authors.initials: M
authors.lastname: Aziz
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Clementina
authors.initials: C
authors.lastname: Mesaros
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Linda L
authors.initials: LL
authors.lastname: Wang
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Ali
authors.initials: A
authors.lastname: Javaheri
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.).
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: From Cardiovascular Institute University of Pennsylvania Perelman School of Medicine, Smilow Translational Research Center, Philadelphia, PA (K.C.B., J.B., A.J., K.B.M., J.E.R.); A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA (N.W.S.); and Center of Cancer Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (M.A., C.M., A.J.W., L.L.W., I.A.B.). Eduardo.rame@uphs.upenn.edu.
authors.forename: J Eduardo
authors.initials: JE
authors.lastname: Rame
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000175:diagnosis* / Q000378:metabolism*; D006801:Humans; D007659:Ketones / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D007659:Ketones
keywords: cardiomyopathies; heart failure; ketones; lipids; metabolism
references.citation: Cell Metab. 2010 Dec 1;12(6):654-61
references.pmid: 21109197
references.citation: J Clin Invest. 1991 Feb;87(2):384-90
references.pmid: 1671390
references.citation: Anal Biochem. 2015 Apr 1;474:59-65
references.pmid: 25572876
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2356-60
references.pmid: 10051646
references.citation: Anal Chem. 2011 Feb 15;83(4):1363-9
references.pmid: 21268609
references.citation: J Cardiovasc Transl Res. 2010 Dec;3(6):643-51
references.pmid: 20842468
references.citation: Chem Res Toxicol. 2011 Oct 17;24(10):1630-2
references.pmid: 21950265
references.citation: J Biol Chem. 2014 Sep 26;289(39):26895-903
references.pmid: 25122772
references.citation: J Am Coll Cardiol. 1996 Sep;28(3):665-72
references.pmid: 8772754
references.citation: Nat Protoc. 2012 Jan;7(1):1-12
references.pmid: 22157971
references.citation: Anal Chem. 2011 Sep 1;83(17):6648-57
references.pmid: 21774539
references.citation: Circ Cardiovasc Imaging. 2014 Nov;7(6):895-904
references.pmid: 25201905
references.citation: Eur J Heart Fail. 2013 Feb;15(2):130-40
references.pmid: 23258802
references.citation: Physiol Rev. 2010 Jan;90(1):207-58
references.pmid: 20086077
references.citation: J Card Fail. 2006 Oct;12(8):644-52
references.pmid: 17045185
references.citation: Circ Heart Fail. 2014 Nov;7(6):1022-31
references.pmid: 25236884
references.citation: Biochim Biophys Acta. 2007 Sep;1767(9):1134-42
references.pmid: 17692817
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W127-33
references.pmid: 22553367
references.citation: J Biol Chem. 2010 Aug 6;285(32):24447-56
references.pmid: 20529848
references.citation: Mol Metab. 2014 Aug 13;3(7):754-69
references.pmid: 25353003
references.citation: Circulation. 2012 Jun 12;125(23):2844-53
references.pmid: 22586279
references.citation: J Clin Invest. 1992 Mar;89(3):968-73
references.pmid: 1541685
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):243-51
references.pmid: 14769483
references.citation: Circ Cardiovasc Genet. 2014 Jun;7(3):266-76
references.pmid: 24825877
references.citation: Trends Endocrinol Metab. 2008 May-Jun;19(4):130-7
references.pmid: 18337116
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6601-6
references.pmid: 23576753
references.citation: FASEB J. 2004 Nov;18(14):1692-700
references.pmid: 15522914
references.citation: Rapid Commun Mass Spectrom. 2014 Aug 30;28(16):1840-8
references.pmid: 25559454
references.citation: Biochem J. 2005 Apr 1;387(Pt 1):185-93
references.pmid: 15535801
references.citation: Circulation. 2013 May 14;127(19):1957-67
references.pmid: 23589024
references.citation: FASEB J. 2009 Feb;23(2):586-604
references.pmid: 18945875
references.citation: Cell Metab. 2013 Dec 3;18(6):920-33
references.pmid: 24315375
references.citation: Am J Pathol. 2011 Jun;178(6):2547-59
references.pmid: 21641380
references.citation: J Vis Exp. 2013;(75):e50433
references.pmid: 23711563
references.citation: Int J Cardiovasc Imaging. 2010 Apr;26(4):459-68
references.pmid: 20107905
references.citation: Ann Endocrinol (Paris). 2002 Apr;63(2 Pt 1):86-90
references.pmid: 11994667
references.citation: J Mol Cell Cardiol. 2009 Feb;46(2):201-12
references.pmid: 19061896