Our Goals: A novel mechanism of block of electrical propagation in the myocardium may lead to arrhythmias in hearts subjected to ischemia and reperfusion. The mechanism, called the “metabolic sink” hypothesis, is triggered by increased production of reactive oxygen species (ROS) under oxidative stress conditions. This leads to collapse (depolarization) of the mitochondrial membrane potential (ΔΨ_m), additional ROS release, and hence the initiation of a propagating wave of ΔΨ_m depolarization throughout the mitochondrial network. The interplay between cytosolic ROS removal and ROS accumulation in the mitochondrial matrix in turn produces slow oscillation of ΔΨ_m and cytosolic ATP levels. These oscillations of cellular ATP trigger cyclic activation of sarcolemmal potassium channels which can, when conductance is large, reduce or eliminate myocyte excitability. The central hypothesis to be tested in this R33 project is that creation of these spatially and temporally variable “islands of in-excitability” promotes generation of arrhythmias in both the ischemic and the failing heart. Working over a range of biological scales (whole heart, tissue, single cell, and subcellular organelle, namely mitochondria) our aim is to achieve an unprecedented level of integration of structure and function in order to understand and model the ways in which coupling between metabolic and electrophysiological processes in the myocyte contribute to risk of cardiac arrhythmias under conditions of metabolic stress.