Cellular basis for dispersion of repolarization underlying reentrant arrhythmias

Substantial heterogeneity in ion channel density and expression exists in c ells isolated from various regions of the heart. Cell-to-cell coupling in t he intact heart, however, is expected to attenuate the functional expressio n of the ion channel heterogeneities. Due to limitations of conventional el ectrophysiological recording techniques, the extent to which cellular elect rical heterogeneities are functionally present in intact myocardium remains unknown. High-resolution optical mapping with voltage-sensitive dyes was u sed to measure transepicardial and transmural repolarization gradients in t he Langendorff perfused guinea pig ventricle and the canine wedge preperati on, respectively. Diversity of repolarization kinetics in the transepicardi al direction modulated dispersion of repolarization in a biphasic fashion a s premature coupling interval was shortened. Moreover, modulation of repola rization paralleled arrhythmia vulnerability in a predictable fashion. Tran smural optical mapping revealed significant gradients of repolarization acr oss the ventricular wall that were markedly increased in a surrogate model of LQTS. Transmural gradients of repolarization in LQTS were associated wit h an enhanced susceptibility to TdP. Therefore, despite strong cell-to-cell coupling in the normal heart, heterogeneities in the ionic make-up of cell s across the epicardial and transmural surfaces result in functional hetero geneities of repolarization leading to arrhythmias.