Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice

Abstract

1Altered cardiac metabolism and function (diabetic cardiomyopathy) has been observed in diabetes. We hypothesize that cardiac efficiency, the ratio of cardiac work (pressurevolume area [PVA]) and myocardial oxygen consumption (MVO 2 ), is reduced in diabetic hearts. Experiments used ex vivo working hearts from control db/؉, db/db (type 2 diabetes), and db/؉ mice given streptozotocin (STZ; type 1 diabetes). PVA and ventricular function were assessed with a 1.4-F pressure-volume catheter at low (0.3 mmol/l) and high (1.4 mmol/l) fatty acid concentrations with simultaneous measurements of MVO 2 . Substrate oxidation and mitochondrial respiration were measured in separate experiments. Diabetic hearts showed decreased cardiac efficiency, revealed as an 86 and 57% increase in unloaded MVO 2 in db/db and STZ-administered hearts, respectively. The slope of the PVA-MVO 2 regression line was increased for db/db hearts after elevation of fatty acids, suggesting that contractile inefficiency could also contribute to the overall reduction in cardiac efficiency. The end-diastolic and end-systolic pressure-volume relationships in db/db hearts were shifted to the left with elevated end-diastolic pressure, suggesting left ventricular remodeling and/or myocardial stiffness. Thus, by means of pressure-volume technology, we have for the first time documented decreased cardiac efficiency in diabetic hearts caused by oxygen waste for noncontractile purposes. Diabetes 55: 466 -473, 2006 C ardiac efficiency is the ratio between energy output (work) and energy input (myocardial oxygen consumption [MVO 2 ]) for the heart. Currently, the most accepted definition of total cardiac work is pressure-volume area (PVA), the sum of external mechanical work and the potential energy triangle (1). Importantly, MVO 2 is linearly related to PVA. Extrapolation of this linear relationship to 0 work gives unloaded (PVA independent) MVO 2 , the oxygen cost of excitation-contraction coupling and basal metabolism.Furthermore, the inverse slope of the MVO 2 -PVA relationship defines the contractile efficiency.Recently, How et al. (2) demonstrated that pressurevolume loops and resulting determinations of PVA can be obtained with ex vivo perfused working mouse hearts, using a combined micromanometer (pressure)-conductance (volume) catheter. A fiber-optic oxygen probe gave simultaneous measurements of MVO 2 . An elevation in perfusate fatty acid concentration resulted in augmented fatty acid oxidation and reduced cardiac efficiency (increased MVO 2 with no change in work), manifested as increased unloaded MVO 2 (2).Perfused hearts from db/db mice, a monogenic model of type 2 diabetes with obesity and insulin resistance, have been characterized as having an early increase in fatty acid oxidation that precedes the onset of contractile dysfunction (3). Because elevated rates of fatty acid oxidation produce a decrease in cardiac efficiency in control hearts (2), the objective of the current investigation was to test the hypothesis that cardiac efficiency will be r...

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