Abstract 18188: Ito Enhancement Leads to Electromechanically Discordant Alternans and Conduction Block Due Ca-Induced Postrepolarization Refractoriness: Arrhythmogenesis in Brugada Syndrome

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Introduction: The mechanisms of arrhtyhmogenesis in Brugada Syndrome (BrS) involve the transient outward current Ito.NS5806 (NS, an Ito activator) has been reported to reproduce BrS. Itois known to modulate electromechanical (EM) coupling.

Hypothesis: Ito enhancement leads to arrhythmogenic disruption of EM coupling.

Methods: We optically mapped action potential (AP) and Ca2+ transient (Ca) in isolated rabbit hearts using incremental pacing protocols to induce alternans and ventricular tachycardia/fibrillation (VT/VF). Alternans spatial and EM (AP and Ca) phase concordance was assessed. NS5806 (15-45 μM, NS) was used as an Ito activator.

Results: At baseline, alternans was induced at pacing cycle length (PCL) of 215±7ms, of which became spatially discordant in 70% and EM discordant in 20% at PCL(128±15ms). NS facilitated the occurrence of alternans at slower PCL (301±12), and made alternans EM discordant from its onset (Figure). Pacing induced VT/VF in 10/13 after NS vs 6/20 at BL (all p <0.05). EM discordance led to conduction block in regions of short AP duration (postrepolarization refractoriness) that had persistently elevated Ca, leading to VF induction.

Conclusions: Ito enhancement leads to EM discordant alternans, Ca-induced postrepolarization refractoriness and VF. Altered EM coupling may contribute to arrhythmogenesis in BrS.

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