title: Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension.
abstract: The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH.
  
  
  
  We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4±1.3% triglyceride versus 0.22±0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV.
  
  
  
  Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation.
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.). evan.brittain@vanderbilt.edu.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Brittain
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Megha
authors.initials: M
authors.lastname: Talati
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: He
authors.initials: H
authors.lastname: Zhu
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Niki
authors.initials: N
authors.lastname: Penner
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: M Wade
authors.initials: MW
authors.lastname: Calcutt
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Mitch
authors.initials: M
authors.lastname: Funke
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Pugh
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: From Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN (E.L.B.); Vanderbilt Translational and Clinical Cardiovascular Center, Vanderbilt University Medical Center, Nashville, TN (E.L.B.); Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN (M.T., J.P.F., N.P., J.D.W., M.F., M.E.P., J.H.N., A.R.H.); Vanderbilt University Institute of Imaging Science, Nashville, TN (H.Z.); Department of Biochemistry; Vanderbilt University, Nashville, TN (M.W.C.); Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (D.G.L., R.E.G.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L., R.E.G.); Broad Institute of MIT and Harvard, Cambridge, MA (R.E.G.); Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (R.H.); and Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (E.D.A.).
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism; D015331:Cohort Studies; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011446:Prospective Studies; D014280:Triglycerides / Q000378:metabolism*; D018497:Ventricular Dysfunction, Right / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D014280:Triglycerides
keywords: fatty acids; heart ventricles; hypertension, pulmonary; lipid metabolism; lipids; magnetic resonance spectroscopy; pulmonary circulation