Mechanisms of ventricular arrhythmogenesis in mice following targeted disruption of KCNE1 modelling long QT syndrome 5.

Mutations within KCNE1 encoding a transmembrane protein which coassembles with K+ channels mediating slow K+, I(Ks), 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 murine KCNE1-/- 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 (DeltaAPD90: 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 5 KCNE1-/- 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 5 KCNE1-/- hearts, following premature stimuli but not WT (n = 5). (5) Epicardial APD alternans. Perfusion of KCNE1-/- hearts with 1 mum nifedipine 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 DeltaAPD90 to 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 in KCNE1-/- hearts and their abolition by antagonism of inward L-type Ca2+ current.