Basic/Translational Science -> Whole Animal Electrophysiology and Pharmacology (includes Neurohumoral Modulation) D-PO01 - Featured Poster Session (ID 11) Poster

D-PO01-217 - The Acetylcholine-activated Potassium Current Inhibitor XAF-1407 Terminates Atrial Fibrillation In Goats (ID 147)

Abstract

Background: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF).
Objective: To investigate the effect of IKACh inhibition using novel selective IKACh inhibitor XAF-1407.
Methods: Nine goats (56±6kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during IV infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before (normal atria) and after 2 days of AF-induced remodeling (electrically remodeled atria). Following further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or vernakalant (3.7 followed by 4.5 mg/kg). During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns. AF cardioversion was attempted with XAF-1407 (0.3 followed by 3 mg/kg).
Results: XAF-1407 significantly prolonged atrial effective refractory period (aERP; Fig. A). It showed higher cardioversion efficacy than vernakalant, with shorter time to cardioversion (Fig. B) and shorter AF cycle length prior to cardioversion (135±39 vs. 162±25 ms, p<0.05). XAF-1407 decreased the number of waves per AF cycle in the last 2 seconds prior to cardioversion but not in the last 2-12 seconds prior to cardioversion (Fig. D). There was a minor increase in QTc (Fig. C) but no ventricular proarrhythmic events were observed.
Conclusion: Inhibition of IKACh by XAF-1407 has an anti-arrhythmic effect in a goat model of AF. Cardioversion of AF to SR was associated with reduced complexity of AF only during last 2 seconds before termination.
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