Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse model

Abstract

Two major mechanisms have been postulated for the arrhythmogenic tendency observed in Brugada Syndrome (BrS): delays in conduction or increased heterogeneities in repolarization. We use a contact mapping system to directly investigate the interacting roles of these two mechanisms in arrhythmogenesis using a genetic murine model for BrS for the first time. Electrograms were obtained from a multielectrode recording array placed against the left ventricle and right ventricle (RV) of spontaneously beating Langendorff-perfused wild type (WT) and Scn5a+/− mouse hearts. Scn5a+/− hearts showed activation waves arriving at the epicardial surface consistent with slowed conduction, which was exacerbated in the presence of flecainide. Lines of conduction block across the RV resulting from premature ventricular beats led to the formation of reentrant circuits and polymorphic ventricular tachycardia. WT hearts showed an inverse relationship between activation times and activation recovery intervals measured at the epicardial surface, which resulted in synchronicity of repolarization times. In contrast, Scn5a+/− hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT. Isochronal maps showed that their normal activation recovery interval gradients at the epicardial surface were disrupted, leading to heterogeneity in repolarization times. We thus directly demonstrate the initiation of arrhythmia in the RV of Scn5a+/− hearts. This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits. The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

“…The cellular and molecular experiments described here correlate with work performed in the whole heart, especially mapping experiments that have localized both conduction slowing and heterogeneity of repolarization, and subsequent initiation of arrhythmias through re-entrant phenomena, to the RV [8]. Computer simulations could provide a potential means to further explore the pro-arrhythmic consequences of RV/LV differences in ionic currents, particularly employing whole heart models [60–63].…”

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias

“…The timing of emergence and spatial orientation of the excitation wave fronts of ectopic beats are key factors in arrhythmia initiation. In Scn5a +/− mice, PVCs play important roles in initiating re-entrant, spontaneous polymorphic VT 31 . In Scn2b null hearts, every recorded VT episode occurred following a PVC, suggesting a requirement for PVCs to serve as triggers.…”

Refractory dispersion promotes conduction disturbance and arrhythmias in a Scn5a +/− mouse model

“…We have previously demonstrated both depolarization abnormalities, in the form of delayed conduction latencies [27] and slowed activation patterns [25], and repolarization abnormalities, in the form of heterogeneities in APDs and steep restitution curves with high incidences of discordant alternans [24]. However, the evidence in the present studies links these two mechanisms by correlating the arrhythmic propensity shown by Scn5a +/− hearts with reentrant arrhythmias attributable to enhanced RV transmural refractory gradients, in turn leading to slowed conduction.…”