Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome

Abstract

Background-Drugs with I Kr -blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results-Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, Pϭ0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, PϽ0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions-dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I Kr -blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)Key Words: long-QT syndrome Ⅲ secondary Ⅲ drug Ⅲ electrophysiology Ⅲ ion channel C ongenital long-QT syndrome (cLQTS) is characterized by abnormally prolonged ventricular repolarization and familial inheritance, leading to polymorphic ventricular tachycardia (torsades de pointes [TdP]), causing sudden cardiac death. 1,2 In contrast, secondary long-QT syndrome can be induced by a variety of commercially available drugs, including antiarrhythmic drugs, antihistamines, antibiotics, Clinical Perspective on p 523and major tranquilizers. 3 In patients with drug-induced long-QT syndrome (dLQTS), after a washout period of the culprit drugs, the QT interval usually returns to within normal range. Genetic factors may underlie the susceptibility to drug-induced serious adverse reactions such as a long QT Received February 29, 2008; accepted July 6, 2009. (eg, drugs, hypokalemia, or bradycardia). Among the subjects, 20 probands had drug-induced cardiac events (10.2% of long-QT syndrome probands). Their clinical information was collected, including family history of sudden death age 30 years or younger and long-QT syndrome members, previ...

Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

“…We demonstrate that the occurrence of LQTS/TdP required the presence of increased susceptibility to the LQTS-inducing potential of these drugs. 21,22 In the index patient, such susceptibility was provided by the K422T mutation in KCNQ1.…”

Atrioventricular Block-Induced Torsades de Pointes With Clinical and Molecular Backgrounds Similar to Congenital Long QT Syndrome

“…11, 12 The ratio of IKr and IKs conductance was set at 23:1, 17:1, and 19:1 in the epicardium, endocardium, and M cell layer, respectively. Based on the experimental data of voltageclamp recordings of KCNH2 channels heterologously expressed in CHO cells, we constructed Markov or Hodgkin-Huxley models for simulated mutant channels as compared with mutants associated with congenital LQTS.…”

Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

“…[39][40][41][42][43] Of note, functional analysis revealed that KCNQ1 or KCNH2 mutations identified in dLQTS showed no dominant-negative suppression or only a relatively mild decreased current density compared with those identified in congenital LQTS (cLQTS). 42 Drugs that have an IKr-blocking effect lead to further reductions of the repolarizing currents in patients with a latent genetic background of mildly reduced repolarizing currents, thus unmasking dLQTS. Interestingly, colleagues have reported that K + channel regulator-1 (KCR1), homologous to yeast α-1,2-glucosyltransferase ALG10, protects KCNH2 currents from pharmacological block by QT-prolonging antiarrhythmic drugs through enhancing of cellular glycosylation by acting as an α-1,2-glucosyltransferase.…”