title: Hyperpolarized (13)C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart.
abstract: OBJECTIVE
  Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.
  
  
  RESULTS
  Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.
  
  
  CONCLUSIONS
  Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression.
authors.affiliation: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room M326A, Toronto, Ontario M4N 3M5, Canada. marie.schroeder@dpag.ox.ac.uk
authors.forename: Marie A
authors.initials: MA
authors.lastname: Schroeder
authors.forename: Angus Z
authors.initials: AZ
authors.lastname: Lau
authors.forename: Albert P
authors.initials: AP
authors.lastname: Chen
authors.forename: Yiping
authors.initials: Y
authors.lastname: Gu
authors.forename: Jeevan
authors.initials: J
authors.lastname: Nagendran
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barry
authors.forename: Xudong
authors.initials: X
authors.lastname: Hu
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Graham A
authors.initials: GA
authors.lastname: Wright
authors.forename: Charles H
authors.initials: CH
authors.lastname: Cunningham
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002247:Carbon Isotopes; D002304:Cardiac Pacing, Artificial; D002306:Cardiac Volume / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002952:Citric Acid Cycle / Q000502:physiology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D026901:Membrane Transport Proteins / Q000502:physiology; D047493:PPAR alpha / Q000235:genetics; D010725:Phosphocreatine / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D013552:Swine; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology
chemical_list: D001639:Bicarbonates; D002247:Carbon Isotopes; D026901:Membrane Transport Proteins; D047493:PPAR alpha; D011768:Pyruvate Dehydrogenase Complex; C021723:oxoglutarate translocator; D010725:Phosphocreatine; D018698:Glutamic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4