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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Merle Friederike Fenner
  • Helena Carstensen
  • Sarah Dalgas Nissen
  • Eva Melis Hesselkilde
  • Christine Scott Lunddahl
  • Maja Adler Hess Jensen
  • Ameli Victoria Loft-Andersen
  • Stefan Michael Sattler
  • Pyotr Platonov
  • Said El-Haou
  • Claire Jackson
  • Raymond Tang
  • Robert Kirby
  • John Ford
  • Ulrich Schotten
  • James Milnes
  • Ulrik Svane Sørensen
  • Thomas Jespersen
  • Rikke Buhl
Organisations
External organisations
  • University of Copenhagen
  • Copenhagen University Hospital
  • University Hospital Munich
  • Skåne University Hospital
  • Ludwig-Maximilian University of Munich
  • Xention Ltd
  • Maastricht University
  • Acesion Pharma
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
  • Cardiac and Cardiovascular Systems
Original languageEnglish
JournalBritish Journal of Pharmacology
Publication statusE-pub ahead of print - 2020 May 20
Publication categoryResearch
Peer-reviewedYes