Molecular Predictors of Drug-induced Prolongation of the QT Interval

Abstract

One of the most common causes of drug withdrawal from the market is the prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsade de pointes (TdP) that can degenerate into ventricular fibrillation and sudden cardiac death. Cardiac and non-cardiac 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. Co-assembly of HERG (human-ether-a-go-go-related gene) alpha-subunits and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate the behavior of native human IKr, and the majority of 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 long-QT syndrome (LQTS). Current evidence suggests that 5 to 10% of persons in whom TdP develops on exposure to QT-interval prolonging drugs harbor mutations associated with the LQTS and can therefore be viewed as having a subclinical form of the congenital syndrome. This clinical observation is entirely consistent with the concept of reduced repolarization reserve arising from a mutation in an ion-channel gene, which predisposes the carrier to drug-induced TdP. This review centers on the possible molecular 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.

Clarithromycin treatment and QT prolongation in childhood

“…The gene encodes MinK‐related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore‐forming protein, to alter its function [10]. Mutations in HERG (LQTS2) and in MiRP1 (LQTS6) can lead to a marked increase in QT prolongation, and these patients are at a potential risk when exposed to clarithromycin, as is any person with long‐QT syndrome [10,11].…”

“…Clarithromycin, a widely prescribed antibiotic for community‐acquired respiratory tract infections, is associated with drug‐induced QT prolongation [1] which, on rare occasions, results in the occurrence of life‐threatening arrhythmias [2–4]. The co‐adminis‐tration of other QT‐prolonging drugs [5–9], or its administration on genetically susceptible patients [10,11], increases the risk of drug‐induced arrhythmias. Clinical data from the paediatric population are lacking.…”

Iatrogenic QT Abnormalities and Fatal Arrhythmias: Mechanisms and Clinical Significance

“…The low incidence and often-unpredictable emergence of TdP may result from individual differences in pharmacokinetics and/or pharmacogenomics. In this regard, it has been proposed that subjects susceptible to drug-induced TdP (i.e, low repolarization reserve) may have mutations in the HERG K + channel, which would become apparent when exposed to a QT-prolonging drug [5, 50]. Up to 20% of people developing drug-induced TdP were found to have a low repolarization reserve due to subclinical ion-channel mutations [51].…”

Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology

“…Candidate gene studies have been undertaken to investigate if mutations in fLQTS genes can also explain diLQTS. Up-to-date mutations in the six genes of fLQTS could only be found in a small fraction (5 -10%) of individuals with diLQTS [67], but the results of exhaustive and unbiased assessments of the entire genome, powered by new technologies of genotyping, are still outstanding in the field of diLQTS. If diLQTS is more frequent in individuals with a longer QT interval at baseline, the determinants of baseline QT length would impact on the frequency in diLQTS.…”