Metabolic Inefficiences and the Response to Ischemia Reperfusion in the Diabetic Heart

The heart relies heavily on oxidative metabolism to meet the high energy demand of constant contractile function. Among the fuels available for the oxidative, ATP generating pathways in cardiac mitochondria, the heart relies most on long chain fatty acids (LCFA). In comparison to carbohydrates, like glucose and lactate, oxidation of the energy rich LCFA holds a greater oxygen demand for ATP production, but offers a much higher yield of ATP. Thus, each fuel source offers a different cost/benefit ratio under normal versus ischemic conditions. In the pathological heart, inefficiencies in the oxidative, intermediary pathways occur as a consequence of metabolic remodeling. For example, the diabetic heart is more susceptible to ischemic damage than the normal heart. Diabetic hearts display chronic upregulation of PPARa, increasing reliance on LCFA oxidation and thus higher oxygen use. Upon reperfusion, diabetic hearts also have increased demands on flux through the citric acid cycle because of elevated uncoupling protein and limited transfer of cytosolic reducing equivalents into the mitochondria. Interestingly, the limitation of LCFA oxidation during hypoperfusion via coronary artery stenosis is not necessarily due to anoxia during reduced blood flow. In the in vivo pig heart, oxidation of fatty acids during low flow ischemia can be sustained, particularly during the second window of preconditioning. Thus, the efficiency of oxidative metabolism in the heart in either diabetes or ischemia/reperfusion is influenced by regulatory mechanisms for LCFA entry into mitochondrial oxidation beyond oxygen availability alone and fundamental changes in the metabolic efficiency of the cardiomyocytes.