Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events
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Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events. / 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.
In: Journal of Cardiovascular Electrophysiology, Vol. 34, No. 1, 2023, p. 126-134.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events
AU - Linz, Benedikt
AU - Hesselkilde, Eva M.
AU - Skarsfeldt, Mark A.
AU - Hertel, Julie N.
AU - Sattler, Stefan M.
AU - Yan, Yannan
AU - Tfelt-Hansen, Jacob
AU - Diness, Jonas G.
AU - Bentzen, Bo H.
AU - Linz, Dominik
AU - Jespersen, Thomas
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - arrhythmia
KW - atrial fibrillation
KW - novel pharmacological treatment
KW - obstructive sleep apnea
KW - SK-channel
KW - CA2+-ACTIVATED K+ CHANNELS
KW - SLEEP-APNEA
KW - PIG MODEL
KW - FIBRILLATION
KW - DENERVATION
KW - MECHANISMS
KW - SEVERITY
KW - PRESSURE
KW - RISK
U2 - 10.1111/jce.15769
DO - 10.1111/jce.15769
M3 - Journal article
C2 - 36482155
VL - 34
SP - 126
EP - 134
JO - Journal of Cardiovascular Electrophysiology
JF - Journal of Cardiovascular Electrophysiology
SN - 1045-3873
IS - 1
ER -
ID: 332618545