Predicting drug-induced QT prolongation and torsades de pointes

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Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia (‘torsades de pointes’). This syndrome of drug-induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (IKr) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarizations thought to trigger torsades de pointes. This review describes the evidence in support of this construct, and describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.

The chain of molecular and cellular events that culminate in drug-induced torsades de pointes. The first event (A) is drug block of the Kv11.1 (‘HERG’) channel, leading to decreased IKr; recent evidence has also suggested an increase in late sodium current may contribute. This in turn results in prolongation of action potentials and generation of triggered activity from early afterdepolarization(s) (B), QT interval prolongation (C), and torsades de pointes (D).

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