Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart.

Abstract Type2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolicstiffness in response to pressure overloading. Pressure–volume relationships (PVRs) and myocardial metabolomeswere determined at baseline and during elevation of aortic pressureby phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloadingaugmented diastolicstiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end- diastolicPVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titinremodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolomeanalyses revealed impaired glycolysis and facilitation of the pentose phosphate pathwayin OLETF. Pressure overloadingsignificantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD + ratios were similar in the two groups. The decline in ATP by pressure overloadingin OLETF was associated with increased inosine5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminasein OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminaseunderlies ventricular stiffening during acute pressure overloadingin T2DM hearts.