Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/− murine hearts modelling the Brugada syndrome

摘要

Brugada syndrome (BrS) is associated with a loss of Na+ channel function and an increased incidence of rapid polymorphic ventricular tachycardia (VT) and sudden cardiac death. A programmed electrical stimulation (PES) technique assessed arrhythmic tendency in Langendorff-perfused wild-type (WT) and genetically modified (Scn5a+/−) ‘loss-of-function’ murine hearts in the presence and absence of flecainide and quinidine, and the extent to which Scn5a+/− hearts model the human BrS. Extra-stimuli (S2), applied to the right ventricular epicardium, followed trains of pacing stimuli (S1) at progressively reduced S1–S2 intervals. These triggered VT in 16 out of 29 untreated Scn5a+/− and zero out of 31 WT hearts. VT occurred in 11 out of 16 (10 μm) flecainide-treated WT and nine out of the 13 initially non-arrhythmogenic Scn5a+/− hearts treated with (1.0 μm) flecainide. Quinidine (10 μm) prevented VT in six out of six flecainide-treated WT and 13 out of the 16 arrhythmogenic Scn5a+/− hearts in parallel with its clinical effects. Paced electrogram fractionation analysis demonstrated increased electrogram durations, expressed as electrogram duration (EGD) ratios, with shortening S1–S2 intervals in arrhythmogenic Scn5a+/− hearts, and prolonged ventricular effective refractory periods (VERPs) in non-arrhythmogenic Scn5a+/− hearts. Flecainide increased EGD ratios in WT (at 10 μm) and non-arrhythmogenic Scn5a+/− hearts (at 1.0 μm), whereas quinidine (10 μm) reduced EGD ratios and prolonged VERPs in WT and arrhythmogenic Scn5a+/− hearts. However, epicardial and endocardial monophasic action potential recordings consistently demonstrated positive gradients of repolarization in WT, arrhythmogenic and non-arrhythmogenic Scn5a+/− hearts under all pharmacological conditions. Together, these findings demonstrate proarrhythmic effects of flecainide in WT and Scn5a+/− murine hearts that recapitulate its clinical effects. They further attribute the arrhythmogenic phenomena observed here to re-entrant substrates resulting from delayed epicardial activation despite an absence of transmural heterogeneities of repolarization, in sharp contrast to recent characterizations in ‘gain-of-function’ Scn5a+/Δ murine hearts modelling the long-QT(3) syndrome.