Juan Tamargo
Department of Pharmacology, School of Medicine, Universidad Complutense,
28040 Madrid, Spain
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 IKr. Coassembly
of HERG (human-ether-a-go-go-related gene) a-subunits
and MiRP1 (MinK-related peptideﾊ1) b-subunits
recapitulate the behavior of native human IKr and mutations of
HERG and MiRP1 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 IKr,
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.
Keywords: Potassium channel, HERG (human-ether-a-go-go-related gene),
MiRP1 (MinK-related peptideﾊ1), Long QT syndrome, Cardiac arrhythmia, Torsade
de pointes