XAF-1407 decreased atrial fibrillatory rate by ~20% and successfully cardioverted tachypacing-induced persistent atrial fibrillation in horses, although with decreasing efficacy over time.
Does XAF-1407 improve cardioversion success and alter electrophysiological properties in an equine model of tachypacing-induced persistent atrial fibrillation?
XAF-1407, a novel IK,ACh inhibitor, successfully cardioverted tachypacing-induced persistent AF in an equine model, highlighting its potential as an atrial-selective anti-arrhythmic strategy.
Background and Purpose Inhibition of the G‐protein gated ACh‐activated inward rectifier potassium current, I K,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 I K,ACh inhibitor, XAF‐1407 (3‐methyl‐1‐5‐phenyl‐4‐[4‐(2‐pyrrolidin‐1‐ylethoxymethyl)‐1‐piperidylthieno2,3‐dpyrimidin‐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 the I K,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 I K,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
Fenner et al. (Thu,) conducted a other in Persistent atrial fibrillation (n=11). XAF-1407 vs. Baseline was evaluated on Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology. XAF-1407 decreased atrial fibrillatory rate by ~20% and successfully cardioverted tachypacing-induced persistent atrial fibrillation in horses, although with decreasing efficacy over time.
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