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- Title
NS5806 Induces Electromechanically Discordant Alternans and Arrhythmogenic Voltage-Calcium Dynamics in the Isolated Intact Rabbit Heart.
- Authors
Wang, Sufen; Rodríguez-Mañero, Moisés; Ibarra-Cortez, Sergio H.; Kreidieh, Bahij; Valderrábano, Laura; Hemam, Majd; Tavares, Liliana; Blanco, Elvin; Valderrábano, Miguel
- Abstract
Background: NS5806 activates the transient outward potassium current I to, and has been claimed to reproduce Brugada Syndrome (BrS) in ventricular wedge preparations. I to 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.
- Subjects
BRUGADA syndrome; DECAY constants; HEART; RABBITS
- Publication
Frontiers in Physiology, 2019, Vol 10, p1
- ISSN
1664-042X
- Publication type
Article
- DOI
10.3389/fphys.2019.01509