title: Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study.
abstract: Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Lydia M
authors: LM
authors: Le Page
authors: Division of Cardiovascular Medicine, University of Oxford, Oxford, U.K.
authors: Oliver J
authors: OJ
authors: Rider
authors: Division of Cardiovascular Medicine, University of Oxford, Oxford, U.K.
authors: Andrew J
authors: AJ
authors: Lewis
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Vicky
authors: V
authors: Ball
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Kieran
authors: K
authors: Clarke
authors: AstraZeneca, Mölndal, Sweden.
authors: Edvin
authors: E
authors: Johansson
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Carolyn A
authors: CA
authors: Carr
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
authors: Lisa C
authors: LC
authors: Heather
authors: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K. damian.tyler@dpag.ox.ac.uk.
authors: Damian J
authors: DJ
authors: Tyler
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D004452:Echocardiography; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid