Validation of quantitative measure of repolarization reserve as a novel marker of drug induced proarrhythmia

Abstract

Repolarization reserve, the robustness of a cell to repolarize even when one of the repolarization mechanisms is failing, has been described qualitatively in terms of ionic currents, but has not been quantified by a generic metric that is applicable to drug screening. Prolonged repolarization leading to repolarization failure is highly arrhythmogenic. It may lead to ventricular tachycardia caused by triggered activity from early afterdepolarizations (EADs), or it may promote the occurrence of unidirectional conduction block and reentry. Both types of arrhythmia may deteriorate into ventricular fibrillation (VF) and death. We define the Repolarization Reserve Current (RRC) as the minimum constant current necessary to prevent normal repolarization of a cell. After developing and testing RRC for nine computational ionic models of various species, we applied it experimentally to atrial and ventricular human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), and isolated guinea-pig ventricular cardiomyocytes. In simulations, repolarization was all-or-none with a precise, model-dependent critical RRC, resulting in a discrete shift in the Action Potential Duration (APD) - RRC relation, in the occurrence of EADs and repolarization failure. These data were faithfully reproduced in cellular experiments.RRC allows simple, fast, unambiguous quantification of the arrhythmogenic propensity in cardiac cells of various origins and species without the need of prior knowledge of underlying currents and is suitable for high throughput applications, and personalized medicine applications.