Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome.

Abstract The gain-of-function Scn5a +/ΔKPQ mutation in the cardiac Na + channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K ATP channel-opener nicorandil (20 μM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a +/Δ hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD 90 ) that (2) restored transmural repolarization gradients, ΔAPD 90 . Scn5a +/Δ hearts showed longer epicardial but not endocardial APD 90 s, giving shorter ΔAPD 90 s than WT hearts. Nicorandil reduced epicardial APD 90 in both Scn5a +/Δ and WT hearts thereby increasing ΔAPD 90 . (3) Reduced epicardial critical intervals for re-excitation; Scn5a +/Δ hearts showed greater differences between APD 90 and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD 90 alternans. Scn5a +/Δ hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a +/Δ hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a +/Δ hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a +/Δ and WT hearts. The presence or absence of arrhythmogenesis in Scn5a +/Δ and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.