Abstract
Background: NS5806 activates the transient outward potassium current Ito, and has been claimed to reproduce Brugada Syndrome (BrS) in ventricular wedge preparations. Ito modulates excitation-contraction coupling, which is critical in alternans dynamics. We explored NS5806-arrhythmogenic effects in the intact whole heart and its impact on alternans.Methods: Langendorff-perfused rabbit hearts (n = 20) underwent optical AP and Ca mapping during pacing at decremental cycle lengths (CL). Spontaneous arrhythmias and pacing-induced alternans was characterized at baseline (BL), after perfusing with NS5806, before and after adding verapamil (VP), and SEA0400 (SEA, n = 5 each), to modulate Ca-current and Na-Ca exchange, the main AP-Ca coupling mechanisms.Results: NS5806 induced BrS-like ECG features in 6 out of 20 hearts. NS5806 prolonged steady-state (3 Hz) action potential duration (APD) by 16.8%, Ca decay constant by 34%, and decreased conduction velocity (CV) by 52.6%. After NS5806 infusion, spontaneous ventricular ectopy (VE) and AP/Ca alternans occurred. Pacing-induced alternans during NS5806 infusion occurred at longer CL and were AP/Ca discordant from its onset. Spatially discordant alternans after NS5806 infusion had non-propagation-driven nodal line distribution. No spontaneous phase-2 reentry occurred. Under NS5806 + VP, alternans became AP/Ca concordant and only induced in two out of five; NS5806 + SEA did not affect alternans but suppressed spontaneous ectopy.Conclusions: NS5806 disrupts AP-Ca coupling and leads to Ca-driven, AP/Ca-discordant alternans and VE. Despite BrS-like ECG features, no spontaneous sustained arrhythmias or phase-2 reentry occurred. NS5806 does not fully reproduce BrS in the intact rabbit heart.
Highlights
We found that 5 μM NS5806 neither changed ECG morphology, nor the characteristics of action potential duration (APD) or Ca transient
We did not find any loss of action potential (AP) dome, spontaneous sustained arrhythmias, phase-2 reentry or otherwise using any of the aforementioned doses of NS5806 in this whole heart preparation
The salient results of our studies are that NS5806 leads to: (1) steady-state APD prolongation with pause-dependent APD shortening; (2) conduction velocity (CV) slowing; (3) prolongation of the Ca decay
Summary
NS5806, an activator of the transient outward potassium channel, Ito, has been used as an experimental model of Brugada Syndrome (BrS) in both right and left ventricular wedge preparations (Calloe et al, 2009; Minoura et al, 2013) alone or in combination with verapamil (VP) (Szel et al, 2013; Szel and Antzelevitch, 2014; Patocskai et al, 2016, 2017; Yoon et al, 2018). Epicardial shortening of the action potential duration (APD) due to unopposed Ito leads to transmural repolarization gradients that give rise to the characteristic ECG changes (Calloe et al, 2009) and set the stage for phase-2 reentry and ventricular fibrillation (VF) (Yan and Antzelevitch, 1999). We explored NS5806arrhythmogenic effects in the intact whole heart and its impact on alternans
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