Editorial [Hot topic: Drug-Induced QT Interval Prolongation: Clinical, Safety and Regulatory Update (Guest Editor: Guillermo Di Girolamo)]

This issue of Current Drug Safety includes a review of scientific and regulatory implications of QT interval prolongation by drugs and the mechanisms involved for several drug classes: like cardiovascular, metabolic, endocrine, anti-infectives, antineoplastic chemotherapy, antihistamines, prokinetic agents and drugs affecting the Central Nervous System. In normal healthy subjects, the normal range of the QTc interval is quite broad ranging from 0.38 to 0.45 seconds, with age and gender modifying the range. Furthermore, in any given subject, the QTc interval can be different from one day to the next, even when taken at the same time of the day and at the same heart rate. In addition, the formulae for correction of the QT interval for heart rate are problematic, especially at heart rates either low (<50 bpm.) or high (>90 bpm). Syncope associated with the initiation of quinidine therapy has been recognized since the 1920s.The electrocardiographic monitoring in the 1960s led to the identification of pause-dependent polymorphic ventricular tachycardia as the underlying mechanism. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ether-a-go-go-related gene (HERG) channel that contributes prominently to terminal (phase 3) repolarization in human ventricular myocytes, and thus lengthen the QT interval. At least ten separate genes, if mutated, can cause the congenital long-QT syndrome (cLQTS) [1]. Among them the HERG gene, which encodes a potassium-channel protein, is especially relevant for drug-associated torsades de pointes (TdP). HERG controls an important repolarizing current (IKr). Mutations in HERG reduce IKr causing the cLQTS [2]. In addition, virtually all drugs that prolong the QT interval and cause TdP also block IKr. Unfortunately, this finding is not specific, since many drugs that do not appear to cause TdP also block this current. Such mechanisms will be reviewed in depth by Ponte et al. in his article in this issue of Current Drug Safety. Although the risk of TdP for noncardiac medication is generally lower than for antiarrhythmic drugs, it is difficult to estimate the actual incidence of acquired LQTS. A number of noncardiovascular drugs have been recently withdrawn from the market because of unexpected postmarketing reports of sudden cardiac death associated with prolongation of QT interval and TdP. Most drug classes involved will be also reviewed in several articles of this issue.