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(Circulation. 2005;111:2066-2072.)
© 2005 American Heart Association, Inc.

Heart Failure

Impact of High Glucose/High Insulin and Dichloroacetate Treatment on Carbohydrate Oxidation and Functional Recovery After Low-Flow Ischemia and Reperfusion in the Isolated Perfused Rat Heart

From the Division of Cardiovascular Disease, Department of Medicine (P.W., S.G.L., J.C.C.) and Department of Physiology and Biophysics, Department of Cell Biology (J.C.C.), The Comprehensive Cancer Center, The Clinical Nutrition Research Center (J.C.C.), University of Alabama, Birmingham.

Correspondence to John C. Chatham, University of Alabama at Birmingham, McCallum Bldg, Room 684, 1530 3rd Ave S, Birmingham, AL 35294-0005. E-mail jchatham{at}uab.edu

Received September 21, 2004; revision received November 23, 2004; accepted December 21, 2004.

Background— It is believed that increasing cardiac glucose metabolism in the setting of ischemia and reperfusion is protective because of the resulting decrease in fatty acid oxidation, which improves cardiac efficiency and increases glucose oxidation relative to glycolysis; however, these conclusions are based primarily on studies in which glucose is the only carbohydrate provided. The goal of this study was to examine the effect of stimulating myocardial carbohydrate use either by increasing glucose and insulin levels or by using dichloroacetate on the response to ischemia and reperfusion in hearts perfused with physiological concentrations of lactate and pyruvate plus glucose and fatty acids.

Methods and Results— Metabolic fluxes were determined in hearts from male Sprague-Dawley rats perfused with ¹³C-labeled substrates using ¹³C/¹H-NMR isotopomer analysis after 30 minutes of low-flow ischemia (0.3 mL/min) and 60 minutes of reperfusion. Measurements were made under control conditions: 5 mmol/L glucose, 1 mmol/L lactate, 0.1 mmol/L pyruvate, 0.3 mmol/L palmitate, and 50 µU/mL insulin plus dichloroacetate 5 mmol/L or glucose and insulin increased to 30 mmol/L and 1000 µU/mL, respectively. Dichloroacetate increased carbohydrate oxidation and the ratio of glucose oxidation to glycolysis but did not improve functional recovery or cardiac efficiency; however, elevated glucose and insulin levels improved functional recovery and cardiac efficiency but did not increase carbohydrate oxidation or the ratio of glucose oxidation to glycolysis.

Conclusions— These data support the notion that increasing myocardial glucose use is beneficial in the setting of ischemia and reperfusion; however, the protective effect appears not to be mediated by shifting the balance between carbohydrate and fatty acid oxidation.

Key Words: fatty acids • glucose • ischemia • metabolism • reperfusion

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