TY - JOUR

T1 - Effect of Selective IK,ACh Inhibition by XAF-1407 in an Equine Model of Tachypacing-induced Persistent Atrial Fibrillation (AF)

AU - Fenner, M F

AU - Carstensen, H

AU - Nissen, S D

AU - Hesselkilde, E Z

AU - Lunddahl, C

AU - Jensen, Maja Adler Hess

AU - Loft-Andersen, A V

AU - Sattler, S M

AU - Platonov, P G

AU - El-Haou, S

AU - Jackson, C

AU - Tang, R

AU - Kirby, R

AU - Ford, J W

AU - Schotten, U

AU - Milnes, J T

AU - Sørensen, U S

AU - Jespersen, T

AU - Buhl, R

N1 - This article is protected by copyright. All rights reserved.

PY - 2020

Y1 - 2020

N2 - BACKGROUND AND PURPOSE: Inhibition of the G-protein gated acetylcholine-activated inward rectifier potassium (K+ ) current, IK,ACh , may be an effective atrial selective treatment strategy for atrial fibrillation. Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in an in vivo equine, atrial-tachypacing-induced model of persistent AF in the following.EXPERIMENTAL APPROACH: The in vitro ion channel pharmacological profile of XAF-1407, was investigated using cell lines stably expressing Kir 3.1/3.4, Kir 3.4/3.4, Kir 2.1, Kir 6.2/SUR2A, hERG, Kv 1.5, Kv 4.3 and Nav 1.5. A tachypacing induced model of persistent AF in the horse, a large animal model suited to pre-clinical investigations of longer duration AF, was employed to study the in vivo electrophysiological and anti-arrhythmic profile of XAF-1407. Eleven horses were implanted with implantable cardioverter defibrillators (ICD) enabling atrial-tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated at different time points over a period of one month. Cardioversion success, drug induced changes of atrial tissue refractoriness and ventricular electrophysiology were assessed at baseline (day 0) and at day 3, 5, 11, 17 and 29 after AF induction.KEY RESULTS: XAF-1407 potently and selectively inhibited Kir 3.1/3.4 hetero- and Kir 3.4 homotetramers, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period (aERP) as well as decreased atrial fibrillatory rate (AFR) significantly by approximately 20% and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened AV-nodal refractoriness, without effect on the QRS duration. A QTc prolongation of 4% within 15 minutes of drug infusion was observed, however, without any evidence of ventricular arrhythmia.CONCLUSION AND IMPLICATIONS: XAF-1407 efficiently cardioverted sustained tachypacing induced AF of short duration in horses without notable side effects. The study supports IK,ACh inhibition as a potentially safe treatment modality of paroxysmal AF in horses and suggests potential clinical value for other species including humans.

AB - BACKGROUND AND PURPOSE: Inhibition of the G-protein gated acetylcholine-activated inward rectifier potassium (K+ ) current, IK,ACh , may be an effective atrial selective treatment strategy for atrial fibrillation. Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in an in vivo equine, atrial-tachypacing-induced model of persistent AF in the following.EXPERIMENTAL APPROACH: The in vitro ion channel pharmacological profile of XAF-1407, was investigated using cell lines stably expressing Kir 3.1/3.4, Kir 3.4/3.4, Kir 2.1, Kir 6.2/SUR2A, hERG, Kv 1.5, Kv 4.3 and Nav 1.5. A tachypacing induced model of persistent AF in the horse, a large animal model suited to pre-clinical investigations of longer duration AF, was employed to study the in vivo electrophysiological and anti-arrhythmic profile of XAF-1407. Eleven horses were implanted with implantable cardioverter defibrillators (ICD) enabling atrial-tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated at different time points over a period of one month. Cardioversion success, drug induced changes of atrial tissue refractoriness and ventricular electrophysiology were assessed at baseline (day 0) and at day 3, 5, 11, 17 and 29 after AF induction.KEY RESULTS: XAF-1407 potently and selectively inhibited Kir 3.1/3.4 hetero- and Kir 3.4 homotetramers, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period (aERP) as well as decreased atrial fibrillatory rate (AFR) significantly by approximately 20% and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened AV-nodal refractoriness, without effect on the QRS duration. A QTc prolongation of 4% within 15 minutes of drug infusion was observed, however, without any evidence of ventricular arrhythmia.CONCLUSION AND IMPLICATIONS: XAF-1407 efficiently cardioverted sustained tachypacing induced AF of short duration in horses without notable side effects. The study supports IK,ACh inhibition as a potentially safe treatment modality of paroxysmal AF in horses and suggests potential clinical value for other species including humans.

U2 - 10.1111/bph.15100

DO - 10.1111/bph.15100

M3 - Journal article

C2 - 32436234

VL - 177

SP - 3778

EP - 3794

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 16

ER -