Abstract
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 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) 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) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. 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, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) 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%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic 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.
Highlights
Atrial fibrillation (AF) is the most common clinically diagnosed cardiac arrhythmia, affecting approximately 3% of the population aged 20 years and older (Kirchhof et al, 2016)
A dose-dependent prolongation of atrial effective refractory period (aERP) in left atrial (LA) was observed after the administration of XAF-1407 in normal atria as well as in electrically remodeled atria at all pacing rates (Figure 2A)
A small prolongation of PQ by 10% (7–11%) in normal atria and by 4% (3–18%) in electrically remodeled atria was observed after the administration of 3.0 mg/kg of XAF-1407 (Figure 3C)
Summary
Atrial fibrillation (AF) is the most common clinically diagnosed cardiac arrhythmia, affecting approximately 3% of the population aged 20 years and older (Kirchhof et al, 2016) It is associated with increased risk for stroke and death (Kirchhof et al, 2016). The rapid process of electrical remodeling (hours to days) entails shortening of the atrial effective refractory period (aERP), whereas the much slower process of structural remodeling (weeks to years) refers to alterations in atrial tissue structure. Both processes contribute to the gradual progression of AF, to increasing AF episode duration and to decreasing the efficacy of antiarrhythmic drugs. There is an unmet need for development of new antiarrhythmic therapies that are atrial-specific, with fewer side effects
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