Drug-Induced Torsade de Pointes: From Molecular Biology to Bedside

ABSTRACT

A progressively increasing number of cardiac and noncardiac drugs prolong the ventricular action potential duration (QT interval of the electrocardiogram) and cause a distinctive polymorphic ventricular tachycardia termed torsades de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Drugs prolong the QT interval and cause TdP by blocking cardiac K⁺ channels in general and selectively blocking the rapidly activating delayed rectifier channel Ι_Kr· Coassembly of HERG (human-ether-ago-go-related gene) α-subunits and MiRPl (MinK-related peptide 1) β-subunits recapitulate the behavior of native human I_Kr and mutations of HERG and MiRPl decrease the repolarizing current, delay ventricular repolarization and prolong the QT. Thus, drug-induced QT prolongation and TdP might represent an iatrogenic reproduction of the congenital LQTS. In patients with silent forms of the congenital LQTS associated with mutations in I_Kr, arrhythmic symptoms developed almost exclusively after exposure to QT-prolonging drugs. This review centers on the possible cellular mechanisms underlying drug-induced QT prolongation and TdP, the description of specific drugs and risk factors facilitating the development of TdP, and the recommendations for preventing and treating this potentially fatal arrhythmia.