title: Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.
abstract: BACKGROUND
  Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities.
  
  
  RESULTS
  Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates.
  
  
  CONCLUSIONS
  The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment.
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dodd
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Atherton
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stuckey
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: James A
authors.initials: JA
authors.lastname: West
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Heather
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom (M.S.D., H.J.A., C.A.C., G.K.R., K.C., L.C.H., D.J.T.); Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom (D.J.S.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (J.A.W., J.L.G.).
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019343:Citric Acid / Q000378:metabolism; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D019028:Magnetic Resonance Imaging, Cine; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics / Q000379:methods*; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D011237:Predictive Value of Tests; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D017208:Rats, Wistar; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D015415:Biomarkers; D011768:Pyruvate Dehydrogenase Complex; D019343:Citric Acid; D018698:Glutamic Acid; D000108:Acetylcarnitine
keywords: citric acid cycle; heart; magnetic resonance spectroscopy; metabolism; myocardial infarction