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

• Published in: Journal of cardiovascular electrophysiology Vol. 34; no. 1; pp. 126 - 134
• Main Authors: Linz, Benedikt, Hesselkilde, Eva M., Skarsfeldt, Mark A., Hertel, Julie N., Sattler, Stefan M., Yan, Yannan, Tfelt‐Hansen, Jacob, Diness, Jonas G., Bentzen, Bo H., Linz, Dominik, Jespersen, Thomas
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-01-2023; John Wiley and Sons Inc
• Subjects: Acetamides; Animal models; Animals; Apnea; arrhythmia; atrial fibrillation; Atrial Fibrillation - prevention & control; Calcium conductance; Electrophysiology; Heart rate; Humans; Intubation; novel pharmacological treatment; obstructive sleep apnea; Original; ORIGINAL ARTICLES; Potassium conductance; SK‐channel; Sleep apnea; Sleep Apnea, Obstructive; Sleep disorders; Swine; Ventricle; obstructive sleep apnea; SK-channel; atrial fibrillation; novel pharmacological treatment; arrhythmia
• DOI: 10.1111/jce.15769
• EISSN: 1540-8167
• ISSN: 1045-3873

Background
Obstructive 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.
Methods
In 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.
Results
During 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.
Conclusion
In 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.
Obstructive respiratory events, shortening of atrial refractoriness and efficacy of AAD: Obstructive respiratory events may be associated with venous preload, arousal, thoracic pressure swings and asphyxic blood gas changes (hypoxia and hypercapnia). These pathophysiological elements may contribute to shortened atrial refractoriness in the setting of OSA. While established AADs could not blunt apnea‐related shortening in atrial refractoriness, AP14145, as a novel SK‐channel inhibitor could. Nevertheless, SK‐channel involvement in OSA‐related AF remains putative and further investigations are warranted. AAD, atrial antiarrhythmic drugs, OSA, obstructive sleep apnea.