Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure

Pathophysiological remodeling of cardiac function occurs at multiple levels, spanning the spectrum from molecular and sub-cellular changes to those occurring at the organ-system levels. Of key importance to arrhythmias are changes in the electrophysiological substrate at the tissue level. In this manuscript, we provide an overview of mechanisms by which heterogeneous remodeling of ion channels, calcium handling proteins, gap junctions, and stretch-activated pathways produce functionally significant repolarization gradients across regions (anterior vs lateral) and muscle layers (epicardial vs midmyocardial vs endocardial) of the left ventricule. These repolarization gradients form an electrophysiological substrate that predisposes to arrhythmias and sudden cardiac death in heart failure.