Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction

Abstract

Aims Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145. Methods and results Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred. Conclusion AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.

Enhanced Ca 2+ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

“…Several SK-channel inhibitors have demonstrated pronounced antiarrhythmic potential in large animal models, both for acute cardioversion and for prevention of AF reinduction, suggesting a potential for SK-channel inhibition in rhythm control of patients with AF. 7,[9][10][11][12][13] Ventricular effective refractory period is largely unchanged by SK-channel inhibition in most large animal models, therefore, atrial selectivity is likely a beneficial characteristic of I SK blockers. [11][12][13]16 AF is associated with pronounced electrical, structural and Ca 2+ -handling remodeling (reviewed in [59][60][61] ).…”

“…6 SK-channel expression and current (I SK ) are upregulated in several animal models of AF, including dogs with 7-days of electrically maintained AF 7 and rabbits with 3-hour intermittent atrial-burst pacing. 8 SK-channel inhibitors prolong atrial repolarization, promote AF-termination in rats, 9 dogs, 7 goats, 10 horses, 11 and pigs 12,13 and reduce the likelihood of subsequent AF-reinduction. 13 Moreover, SK-channel inhibition in pigs can successfully terminate more persistent forms of AF that are resistant to cardioversion by vernakalant, 13 an AAD clinically approved in Europe and several other jurisdictions, suggesting a robust antiarrhythmic efficacy in large animals with remodeled atria.…”

SK Channels and Heart Disease

“…The authors found that AP14145 produced dose-dependent prolongation of AF cycle length and increased the effective refractory period of atrial impulses [102]. Interestingly, atrial conduction velocity in AF following AP14145 treatment remained unchanged until the final seconds before AF termination, where sudden organization of fibrillatory conduction occurred prior to AF cardioversion [102].…”

“…In a recent study, Gatta et al conducted a detailed examination of the effects of SK channel inhibitor AP14145 on goat hearts induced to AF after 30 days of burst-pacing stimulation delivered by pericardial electrodes implanted above the left atria [102]. The authors found that AP14145 produced dose-dependent prolongation of AF cycle length and increased the effective refractory period of atrial impulses [102].…”

“…In a recent study, Gatta et al conducted a detailed examination of the effects of SK channel inhibitor AP14145 on goat hearts induced to AF after 30 days of burst-pacing stimulation delivered by pericardial electrodes implanted above the left atria [102]. The authors found that AP14145 produced dose-dependent prolongation of AF cycle length and increased the effective refractory period of atrial impulses [102]. Interestingly, atrial conduction velocity in AF following AP14145 treatment remained unchanged until the final seconds before AF termination, where sudden organization of fibrillatory conduction occurred prior to AF cardioversion [102].…”