Background— Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia–reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia–reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. Methods and Results— We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia–reperfusion, with greater action potential duration shortening ( P <0.001 at 8-minute ischemia; P =0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P <0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. Conclusions— We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia–reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes.