Mechanisms of ventricular arrhythmogenesis in mice following targeted disruption ofKCNE1modelling long QT syndrome 5

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Abstract
Mutations withinKCNE1encoding a transmembrane protein which coassembles with K+channels mediating slow K+,IKs, currents are implicated in cardiac action potential prolongation and ventricular arrhythmogenicity in long QT syndrome 5. We demonstrate the following potentially arrhythmogenic features in simultaneously recorded, left ventricular, endocardial and epicardial monophasic action potentials from Langendorff‐perfused murineKCNE1−/− hearts for the first time. (1) Prolonged epicardial (57.1 ± 0.5 ms cf. 36.1 ± 0.07 ms in wild‐type (WT),P< 0.001;n= 5) and endocardial action potential duration at 90% repolarication (APD90) (54.4 ± 2.4 ms cf. 48.5 ± 0.3 ms,P< 0.05;n= 5). (2) Negative transmural repolarization gradients (ΔAPD90: endocardial minus epicardial APD90) (−2.5 ± 2.4 ms, compared with 12.4 ± 1.1 ms in WT,P< 0.001;n= 5). (3) Frequent epicardial early afterdepolarizations (EADs) and spontaneous ventricular tachycardia (VT) in 4 out of 5KCNE1−/− hearts but not WT (n= 5). EADs were especially frequent following temporary cessations of ventricular pacing. (4) Monomorphic VT lasting 1.36 ± 0.2 s in 5 out of 5KCNE1−/− hearts, following premature stimuli but not WT (n= 5). (5) Epicardial APD alternans. Perfusion ofKCNE1−/− hearts with 1 μmnifedipine induced potentially anti‐arrhythmic changes including: (1) restored epicardial APD90(from 57.1 ± 0.5 ms to 42.3 ± 0.4 ms,P< 0.001;n= 5); (2) altered ΔAPD90to values (11.2 ± 2.6) close to WT (P> 0.05;n= 5); (3) EAD suppression during both spontaneous activity and following cessation of ventricular pacing (n= 5) to give similar features to WT controls (n= 5); (4) suppression of programmed electrical stimulation‐induced VT; and (5) suppression of APD alternans. These findings suggest arrhythmic effects of reduced outward currents expected inKCNE1−/− hearts and their abolition by antagonism of inward L‐type Ca2+current.