Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

Drug-induced long QT syndrome (diLQTS) is the phenomenon by which the administration of drugs causes prolongation of cardiac repolarisation and leads to an increased risk of the ventricular tachycardia known as torsades de pointes (TdP). In most cases of diLQTS, the primary molecular target is the human ether-à-go-go-related gene protein (hERG) potassium channel, which carries the rapid delayed rectifier current (I(Kr)) in the heart. However, the proarrhythmic risk associated with drugs that block hERG can be modified in patients by a range of environmental- and disease-related factors, such as febrile temperatures, alterations in pH, dyselectrolytaemias such as hypokalaemia and hypomagnesemia and coadministration with other drugs. In this review, we will discuss the clinical occurrence of drug-induced LQTS in the context of these modifying factors as well as the mechanisms by which they contribute to altered hERG potency and proarrhythmic risk.