Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation.

The T618I KCNH2 -encoded hERG mutation is the most frequently observed mutation in genotyped cases of the congenital short QT syndrome (SQTS), a cardiac condition associated with ventricular fibrillation and sudden death. Most T618I hERG carriers exhibit a pronounced U wave on the electrocardiogram and appear vulnerable to ventricular, but not atrial fibrillation (AF). The basis for these effects is unclear. This study used the action potential (AP) voltage clamp technique to determine effects of the T618I mutation on hERG current (I hERG) elicited by APs from different cardiac regions. Whole-cell patch-clamp recordings were made at 37 °C of I hERG from hERG-transfected HEK-293 cells. Maximal I hERG during a ventricular AP command was increased ∼4-fold for T618I I hERG and occurred much earlier during AP repolarization. The mutation also increased peak repolarizing currents elicited by Purkinje fibre (PF) APs. Maximal wild-type (WT) I hERG current during the PF waveform was 87.2 ± 4.5% of maximal ventricular repolarizing current whilst for the T618I mutant, the comparable value was 47.7 ± 2.7%. Thus, the T618I mutation exacerbated differences in repolarizing I hERG between PF and ventricular APs; this could contribute to heterogeneity of ventricular-PF repolarization and consequently to the U waves seen in T618I carriers. The comparatively shorter duration and lack of pronounced plateau of the atrial AP led to a smaller effect of the T618I mutation during the atrial AP, which may help account for the lack of reported AF in T618I carriers. Use of a paired ventricular AP protocol revealed an alteration to protective I hERG transients that affect susceptibility to premature excitation late in AP repolarization/early in diastole. These observations may help explain altered arrhythmia susceptibility in this form of the SQTS. • T618I is a 'hotspot' hERG potassium channel mutation in the congenital short QT syndrome. • Differences in hERG current during ventricular and Purkinje fibre action potentials are exacerbated by the T618I mutation. • T618I has more modest effects on current during atrial action potentials. • T618I modifies the protective response of hERG to premature ventricular excitation. • These alterations to hERG function help explain ECG changes reported in T618I-hERG carriers. [ABSTRACT FROM AUTHOR]