Abstract
Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardio-gram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing. QTc and TpTe increased by 5.5±3.5% and 15±19.6%, respectively, and TAmp decreased by 13.2±15.5%. A principal-component analysis derived from the latter ECG changes was performed. A random subsample of 489 individuals were subjected to a genome-wide-association analysis where 8,306,856 imputed single nucleotide polymor-phisms (SNPs) were tested for association with QTc, TpTe and TAmp modulations, as well their derived principal-components, to search for common genetic variants associated with sotalol-induced IKr inhibition. None of the studied SNPs reached the statistical threshold for genome-wide significance. This study supports the lack of common variants with larger effect sizes than one would expect based on previous ECG genome-wide-association studies.
Highlights
Torsade de pointes (TdP) is a life-threatening arrhythmia occurring in the setting of marked prolongation of the ventricular repolarization, as assessed by prolongation of QT interval on the electrocardiogram
The main electrophysiological process leading to drug-induced long QT is inhibition of the transmembrane potassium channel IKr [1,2], which results in prolongation of ventricular repolarization
As drug-induced long QT (diLQT) induced by sotalol represents the equivalent of a iatrogenic form of congenital LQT2 syndrome [3,4], we evaluated the apparition of its classical ECG features between baseline and three hours post sotalol (H3)
Summary
Torsade de pointes (TdP) is a life-threatening arrhythmia occurring in the setting of marked prolongation of the ventricular repolarization, as assessed by prolongation of QT interval on the electrocardiogram. The main electrophysiological process leading to drug-induced long QT (diLQT) is inhibition of the transmembrane potassium channel IKr [1,2] (encoded by KCNH2), which results in prolongation of ventricular repolarization. On the electrocardiogram (ECG), as observed in patients with type 2 congenital long QT, IKr inhibition increases the duration of ventricular repolarization (QTc), in the terminal phase (Tpeak-Tend, i.e. TpTe), decreases T wave maximal amplitude (TAmp) and alters T-wave morphology by producing notches [3,4]. Notches corresponds to an additional deflection with inverse polarity during the repolarization phase and is associated, among patients with LQTS, with a further increase of ventricular arrhythmia risk [5,6]
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