Abstract 9384: Normalizing Myocardial Carbohydrate Metabolism Reverses Energetic Impairment and Diastolic Dysfunction in a Rodent Model of Obesity
Background: The role of abnormal cardiac substrate metabolism in the development of obesity cardiomyopathy and the therapeutic potential of interventions targeting substrate metabolism are unknown. We hypothesised; (1) that obesity would impair both myocardial carbohydrate metabolism and energetics resulting in diastolic dysfunction and (2) that normalisation of carbohydrate metabolism would reverse these changes.
Methods: Obese (n=36, 471±45g) and normal weight Long Evans rats (n=12, 383±34g) were diet standardized (67% carbohydrate, ≥5 days). We then performed in vivo hyperpolarized [1-13C] and [2-13C] magnetic resonance spectroscopy (MRS), echocardiography and perfused heart 31P MRS to evaluate myocardial metabolism, structure and function. Two obese groups were subsequently treated with either Liraglutide (a GLP-1 analogue, 0.2mg/kg twice daily, 7 days, n=12) or calorie restriction (70% usual intake, 28 days, n=12) and then restudied.
Results: Obesity caused left ventricular (LV) hypertrophy (2.1 vs 1.8mm, P<0.05), diastolic dysfunction (E/E’ 26 vs 14, P<0.05), reduced myocardial pyruvate dehydrogenase (PDH) flux (by 40%, P<0.01) and increased PDH kinase 4 (PDK4) expression (P=0.01). The PCr/ATP ratio and free energy change of ATP hydrolysis were also impaired (by 13% and 5% respectively, both P<0.05). Calorie restriction reduced weight versus age-matched obese controls (by 14%, P<0.0001). Both Liraglutide and calorie restriction normalised PDH flux, PDK4 expression, myocardial energetics and diastolic function whilst calorie restriction also reduced LV wall thickness (all P<0.05).
Conclusions: Treatment with either Liraglutide (weight-neutral) or calorie restriction normalized myocardial carbohydrate metabolism, energetics and diastolic function. These findings suggest a key role for myocardial metabolism in the development of obesity cardiomyopathy and identify PDH as a potential clinical therapeutic target.
Author Disclosures: A.J. Lewis: Other Research Support; Modest; Our laboratory has received equipment support from GE Healthcare. M.S. Dodd: None. J. Sourdon: None. K. Clarke: None. S. Neubauer: None. D.J. Tyler: Other Research Support; Modest; Our laboratory has received equipment support from GE Healthcare.
- © 2014 by American Heart Association, Inc.