Inhibition of the acetylcholine-regulated potassium current prevents transient apnoea-related atrial arrhythmogenic changes in a porcine model.

BACKGROUND:More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient vagally-mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. OBJECTIVE:To study the effect of pharmacological inhibition of the G-protein-gated acetylcholine-regulated potassium current (IK,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. METHODS:In pigs (n=21) SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF-inducibility and atrial effective refractory periods (aERP) were determined before and during INAP by a S1S2 atrial pacing-protocol. Pigs were randomised into three groups. Group 1: vehicle (n=4); Group 2: XAF-1407 (IK,ACh-inhibitor) (n=7); Group 3: Nicotine followed by XAF-1407 (n=10). RESULTS:In Group 1, INAP shortened the aERP (ΔaERP: -42.6 ms (p=0.004) and transiently increased AF-inducibility from 0 to 31%. In Group 2, XAF-1407 prolonged the aERP by 25.2 ms (p=0.005) during normal breathing and prevented INAP-induced aERP-shortening (ΔaERP: -3.6 ms, p=0.3) and AF-inducibility. In Group 3, INAP transiently shortened the aERP during nicotine perfusion (ΔaERP: -33.6 ms, p=0.004) and increased AF-inducibility up to 61%, which were both prevented by XAF-1407. CONCLUSION:Simulated obstructive respiratory events transiently shorten the aERP and increase AF-inducibility, which can be prevented by the IK,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether IK,ACh-channels represent a target for SDB-related AF in humans warrants further study.