Cellular basis for dispersion of repolarization underlying reentrant arrhythmias

Substantial heterogeneity in ion channel density and expression exists in cells isolated from various regions of the heart. Cell-to-cell coupling in the intact heart, however, is expected to attenuate the functional expression of the ion channel heterogeneities. Due to limitations of conventional electrophysiological recording techniques, the extent to which cellular electrical heterogeneities are functionally present in intact myocardium remains unknown. High-resolution optical mapping with voltage-sensitive dyes was used to measure transepicardial and transmural repolarization gradients in the Langendorff perfused guinea pig ventricle and the canine wedge preperation, respectively. Diversity of repolarization kinetics in the transepicardial direction modulated dispersion of repolarization in a biphasic fashion as premature coupling interval was shortened. Moreover, modulation of repolarization paralleled arrhythmia vulnerability in a predictable fashion. Transmural optical mapping revealed significant gradients of repolarization across the ventricular wall that were markedly increased in a surrogate model of LQTS. Transmural gradients of repolarization in LQTS were associated with an enhanced susceptibility to TdP. Therefore, despite strong cell-to-cell coupling in the normal heart, heterogeneities in the ionic make-up of cells across the epicardial and transmural surfaces result in functional heterogeneities of repolarization leading to arrhythmias.