Clinical meaning
Long QT syndrome (LQTS) encompasses a group of inherited and acquired disorders characterized by delayed ventricular repolarization, manifesting as prolonged QTc interval on ECG and predisposing to torsades de pointes (TdP), a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden cardiac death. At the cellular level, the QT interval represents the duration of the ventricular action potential (phases 0 through 3). Normal repolarization requires a precise balance between inward depolarizing currents that prolong the action potential (late INa, ICa,L) and outward repolarizing currents that shorten it (IKr, IKs, IK1). LQTS results from either gain-of-function mutations in depolarizing channels (increased INa in LQT3 via SCN5A) or loss-of-function mutations in repolarizing channels (reduced IKs in LQT1 via KCNQ1, reduced IKr in LQT2 via KCNH2/hERG). Acquired LQTS (drug-induced) most commonly involves blockade of the hERG potassium channel (IKr), which has an unusually large inner vestibule that accommodates many structurally diverse drug molecules. When IKr is blocked, repolarization is prolonged, and early afterdepolarizations (EADs) can develop during phase 2 or 3 of the action potential. EADs occur when L-type calcium channels...