Stem Cell–Derived Cardiomyocytes as a Tool for Studying Proarrhythmia

Abstract

Proarrhythmia is a leading cause of hospitalization for adverse drug events, and screening for proarrhythmic potential resulting from QT interval prolongation has become a major component of the development process for any new drug candidate. Conventional wisdom, now embedded in regulatory guidelines from the Food and Drug Administration and other regulatory agencies, holds that drug block of the rapid component of the cardiac delayed-rectifier potassium current, I Kr, is the major proximate mechanism underlying prolongation of cardiac action potentials, an effect that leads to early afterdepolarizations in vitro and is manifest on the surface ECG as QT prolongation and occasionally torsades de pointes.1,2 As a result, regulatory guidance suggests an early look at I Kr blocking potency of new drug entities, even recognizing that other mechanisms, some newly described,3,4 may contribute. Article see p 1677 However, the correlation between I Kr block and QT interval prolongation is imperfect. Multiple mechanisms may underlie this “disconnect,” and a reasonable generalization is that I Kr is but one (albeit important) component of normal cardiac repolarization, and abnormalities in expression or function of other components of repolarization may, in turn, modulate the net effect of I Kr block on action potentials in cardiac myocytes and on QT interval and arrhythmia susceptibility in the whole heart. The logical extension of this line of reasoning is that screening for proarrhythmic potential should include the evaluation of not only drug effects on individual ionic currents such as I Kr contributing to repolarization but also the integrated effect of drugs on action potentials in vitro and on the QT interval in animal models and in humans. In conventional drug development programs, this is commonly accomplished by comparing the effects of a candidate drug molecule on QT intervals in human subjects with …