The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats
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The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats. / Sobota, Vladimír; Gatta, Giulia; van Hunnik, Arne; van Tuijn, Iris; Kuiper, Marion; Milnes, James; Jespersen, Thomas; Schotten, Ulrich; Verheule, Sander.
In: Frontiers in Pharmacology, Vol. 11, 608410, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats
AU - Sobota, Vladimír
AU - Gatta, Giulia
AU - van Hunnik, Arne
AU - van Tuijn, Iris
AU - Kuiper, Marion
AU - Milnes, James
AU - Jespersen, Thomas
AU - Schotten, Ulrich
AU - Verheule, Sander
PY - 2021
Y1 - 2021
N2 - Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF. Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
AB - Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF. Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
KW - acetylcholine-activated potassium channel
KW - atrial fibrillation
KW - cardioversion
KW - mapping
KW - remodeling
UR - http://www.scopus.com/inward/record.url?scp=85101028818&partnerID=8YFLogxK
U2 - 10.3389/fphar.2020.608410
DO - 10.3389/fphar.2020.608410
M3 - Journal article
C2 - 33584287
AN - SCOPUS:85101028818
VL - 11
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - 608410
ER -
ID: 279431172