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Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation

Fenner, Merle Friederike ; Carstensen, Helena ; Dalgas Nissen, Sarah ; Melis Hesselkilde, Eva ; Scott Lunddahl, Christine ; Adler Hess Jensen, Maja ; Loft-Andersen, Ameli Victoria ; Sattler, Stefan Michael ; Platonov, Pyotr LU and El-Haou, Said , et al. (2020) In British Journal of Pharmacology 177(16). p.3778-3794
Abstract

Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). 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 horses with persistent AF. Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses... (More)

Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). 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 horses with persistent AF. Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. Key Results: XAF-1407 potently and selectively inhibited Kir3.1/3.4 and Kir3.4/3.4, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min 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. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

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@article{25565699-72d1-4acb-b46a-b5c51aa90a2c,
  abstract     = {{<p>Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I<sub>K,ACh</sub> may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific I<sub>K,ACh</sub> 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 horses with persistent AF. Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. Key Results: XAF-1407 potently and selectively inhibited K<sub>ir</sub>3.1/3.4 and K<sub>ir</sub>3.4/3.4, underlying the I<sub>K,ACh</sub> current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min 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. This supports I<sub>K,ACh</sub> inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.</p>}},
  author       = {{Fenner, Merle Friederike and Carstensen, Helena and Dalgas Nissen, Sarah and Melis Hesselkilde, Eva and Scott Lunddahl, Christine and Adler Hess Jensen, Maja and Loft-Andersen, Ameli Victoria and Sattler, Stefan Michael and Platonov, Pyotr and El-Haou, Said and Jackson, Claire and Tang, Raymond and Kirby, Robert and Ford, John and Schotten, Ulrich and Milnes, James and Svane Sørensen, Ulrik and Jespersen, Thomas and Buhl, Rikke}},
  issn         = {{0007-1188}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{3778--3794}},
  publisher    = {{Wiley}},
  series       = {{British Journal of Pharmacology}},
  title        = {{Effect of selective I<sub>K,ACh</sub> inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation}},
  url          = {{http://dx.doi.org/10.1111/bph.15100}},
  doi          = {{10.1111/bph.15100}},
  volume       = {{177}},
  year         = {{2020}},
}