The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats

Aims The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF. Methods Ten goats (57±5kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg·kg-1) in conscious animals before and after 2 days of electrically-induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg·kg-1) or with vernakalant (3.7 followed by 4.5 mg·kg-1), a class III antiarrhythmic drug that inhibits several potassium currents and the fast sodium current. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg·kg-1, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodelling) and showed higher cardioversion efficacy than vernakalant (8/9 vs 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%), and no ventricular proarrhythmic events were observed. Conclusion XAF-1407 showed an anti-arrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.