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

Abstract

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.

Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts

“…Slowed conduction is a possible arrhythmogenic mechanism in pathological conditions such as myocardial ischaemia [31], ventricular hypertrophy [32], heart failure [33], and the Brugada syndrome [10]. This study therefore investigated whether slowed conduction can induce arrhythmogenic effects in the absence of the remaining repolarization abnormalities previously also implicated in arrhythmogenesis.…”

“…Increases in both the EGDs and the ratios of EGDs obtained at the longest S1S2 interval to those obtained at the shortest S1S2 interval were observed for heptanol-treated hearts. Our results were, therefore, similar to those also indicative of increases in EGD ratios in KCNE1 -/- [21], Scn5a ?/D [20], and Scn5a ?/- [10] hearts. Furthermore, we demonstrated for the first time that there was a significant and positive linear relationship between latency and EGDs that was not altered by heptanol.…”

“…They extend previous findings that heptanol at 0.05 mM increases arrhythmogenicity but at 0.1-1 mM reduces arrhythmogenicity in the ischaemic rat heart [16]. Our results also complement reports associating slowed conduction with increased arrhythmogenicity in mXina ?/- [8], Scn5a ?/- [10,19], and Cx43 ?/-hearts [7,38,39]. The arrhythmogenesis observed in heptanol-treated hearts was further analysed by application of paced electrogram fractionation analysis (PEFA) [18,26] to the BEG recordings obtained during PES.…”

“…In mXina ?/-hearts with a deficiency of Xina, a protein located in gap junctions, prolonged APDs and slowed conduction are observed [8], predisposing the hearts to triggered and re-entrant arrhythmias. In Scn5a ?/-hearts with a targeted disruption of the gene coding for the a-subunit of the sodium channel, shortened APDs, altered repolarization gradients [9], and slowed conduction [10] are observed, predisposing the hearts to re-entrant arrhythmias.…”

Mouse models of SCN5A-related cardiac arrhythmias

“…To elucidate the arrhythmogenic mechanisms in Scn5a ± mice programmed electrical stimulation, monophasic action potential (MAP) recording, and bipolar electrogram recording was performed on Langendorffperfused hearts. These experiments showed that Scn5a ± mice were characterized by increased electrogram duration with shortening extrasystoles intervals, especially in the right ventricular outflow tract, and increased transmural and regional heterogeneity of MAP duration and refractory periods in the right ventricle with the shortest in the right ventricular outflow tract (Stokoe et al, 2007a;Martin et al, 2010Martin et al, , 2011a. Scn5a ± mice also exhibited increased incidence of MAP alternans.…”