Mechanisms of gefitinib-induced QT prolongation.

Gefitinib, a tyrosine kinase inhibitor, was the first targeted therapy for non-small cell lung cancer (NSCLC). Gefitinib could block human Ether-à-go-go-Related Gene (hERG) channel, an important target in drug-induced long QT syndrome. However, it is unclear whether gefitinib could induce QT interval prolongation. Here, whole-cell patch-clamp technique was used for evaluating the effect of gefitinib on rapidly-activating delayed rectifier K+ current (IKr), slowly-activating delayed rectifier K+ current (IKs), transient outward potassium current (Ito), inward rectifier K+ current (IK1) and on action potentials in guinea pig ventricular myocytes. The Langendorff heart perfusion technique was used to determine drug effect on the ECG. Gefitinib depressed IKr by binding to open and closed hERG channels in a concentration-dependent way (IC50: 1.91 µM). The inhibitory effect of gefitinib on wildtype hERG channels was reduced at the hERG mutants Y652A, S636A, F656V and S631A (IC50: 8.51, 13.97, 18.86, 32.99 µM), indicating that gefitinib is a pore inhibitor of hERG channels. In addition, gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation. Gefitinib also decreased IKs with IC50 of 23.8 µM. Moreover, gefitinib increased action potential duration (APD) in guinea pig ventricular myocytes and the corrected QT interval (QTc) in isolated perfused guinea pig hearts in a concentration-dependent way (1-30 µM). These findings indicate that gefitinib could prolong QTc interval by potently blocking hERG channel, modulating kinetic properties of hERG channel. Partial block of KCNQ1/KCNE1 could also contribute to delayed repolarization and prolonged QT interval. Thus, caution should be taken when gefitinib is used for NSCLC treatment.

Sustained localized reentry within the left atrial appendage as a mechanism of recurrent arrhythmia following atrial fibrillation ablation.

The current study investigated the electrophysiological characteristics and radiofrequency ablation in patients with localized reentry within the left atrial appendage during repeated ablation for recurrent atrial fibrillation (AF). A total of 76 patients (21 paroxysmal, 55 persistent) undergoing repeated catheter ablation for recurrent AF were enrolled in this study. Local reentry tachycardia within the left atrial appendage (LAA) was identified through combining activation and entrainment mapping. Left atriography was performed prior to radiofrequency ablation to identify the focus in the LAA. Three patients (1 paroxysmal, 2 persistent) with sustained atrial tachycardias (ATs) were identified during repeated ablation in this cohort. Combined activation and entrainment mapping were applied to localize the reentry. Postpacing interval-tachycardia cycle length differences were <30 msec at the possible site of reentry in varying segments with macro-reentry. This difference was only determined at the base of LAA for local reentry within the LAA. All 3 patients were free of atrial arrhythmias without any complications at the 6-month follow-up following the ablation in the LAA. Combining activation and entrainment mapping were necessary in approaching ATs within the LAA. Performing entrainments in opposite segments of possible loops were valuable in precluding macro-reentry. Focal ablation was safe and effective in this cohort. Therefore localized reentry within the LAA was not uncommon during repeat AF ablation. The present study may thus provide valuable information for clinicians to manage this type of arrhythmia.