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

Fenner, Merle Friederike; Carstensen, Helena; Nissen, Sarah Dalgas; Hesselkilde, Eva Melis; Lunddahl, Christine Scott; Jensen, Maja Adler Hess; Loft-Andersen, Ameli Victoria; Sather, Stefan Michael; Platonov, Pyotr; El-Haou, Said; Jackson, Claire; Tang, Raymond; Kirby, Robert; Ford, John; Schotten, Ulrich; Milnes, James; Sorensen, Ulrik Svane; Jespersen, Thomas und Buhl, Rikke (2020): Effect of selective I-K,I-ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation. In: British Journal of Pharmacology, Bd. 177, Nr. 16: S. 3778-3794

Abstract

Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I-K,I-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 specificI(K,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 K(ir)3.1/3.4 and K(ir)3.4/3.4, underlying theI(K,ACh)current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (similar to 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 supportsI(K,ACh)inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0007-1188
• Sprache: Englisch