Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events

BackgroundObstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. We investigated atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+-activated K+ (SK)-channel inhibition in a porcine model for obstructive respiratory events. MethodsIn spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 s, every 10 min, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (pre-INAP), during (INAP) and after (post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) shortening. ResultsDuring vehicle infusion, INAP transiently shortened AERP (pre-INAP: 135 +/- 10 ms vs. post-INAP 101 +/- 11 ms; p = .008) and increased AF-inducibility. QT-paced prolonged during INAP (pre-INAP 270 +/- 7 ms vs. INAP 275 +/- 7 ms; p = .04) and EMW shortened progressively throughout INAP and post-INAP (pre-INAP 80 +/- 4 ms; INAP 59 +/- 6 ms, post-INAP 46 +/- 10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did not alter QT-paced at baseline (pre-AP14145 270 +/- 7 ms vs. AP14145 268 +/- 6 ms, p = .83) or QT-paced and EMW-shortening during INAP. ConclusionIn a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Whether SK-channels represent a target for OSA-related AF in humans warrants further study.