Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events.
SK-channel
arrhythmia
atrial fibrillation
novel pharmacological treatment
obstructive sleep apnea
Journal
Journal of cardiovascular electrophysiology
ISSN: 1540-8167
Titre abrégé: J Cardiovasc Electrophysiol
Pays: United States
ID NLM: 9010756
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
revised:
02
11
2022
received:
14
05
2022
accepted:
07
11
2022
pubmed:
10
12
2022
medline:
18
1
2023
entrez:
9
12
2022
Statut:
ppublish
Résumé
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 Ca 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. 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. 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.
Sections du résumé
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 Ca
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.
Identifiants
pubmed: 36482155
doi: 10.1111/jce.15769
pmc: PMC10107889
doi:
Substances chimiques
AP14145
0
isonitrosoacetophenone
532-54-7
Acetamides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
126-134Informations de copyright
© 2022 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.
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