Atrial selective I_K,ACh Inhibition in an equine model of persistent AF

Principal Investigators: Rikke Buhl and Thomas Jespersen

Study Director: Merle Friederike Fenner

Master students: Sarah Dalgas Nissen, Maja Adler Hess Jensen, Christine Scott Lunddahl 

Background:

Inhibition of the G-protein gated acetylcholine-activated inward rectifier potassium (K⁺) current, I_K,ACh, has been proposed to be an effective atrial selective treatment strategy for atrial fibrillation. Therefore, the anti-arrhythmic and electrophysiological properties of a novel potent and highly specific I_K,ACh inhibitor, XAF-1407, 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:

Subsequent to profound electrophysiological and pharmacological in vitro selectivity profiling of XAF-1407, the horse, as a large animal model for preclinical investigations in AF of longer duration, was employed. In this model 11 horses were equipped with implantable cardioverter defibrillators (ICD) enabling atrial-tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 (3 mg kg^-1) 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 (day₀) and at day 3, 5, 11, 17 and 29 after AF induction.

Results:

XAF-1407 inhibited K_ir3.1/3.4 hetero- and K_ir3.4 homotetramers, underlying the I_K,ACh current, with the same potency and at high specificity. XAF-1407 treatment in horses prolonged atrial effective refractory period (aERP), decreased atrial fibrillatory rate (AFR) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened AV-nodal refractoriness, and provided a minor QT prolongation but did not affect QRS duration. Ventricular pro-arrhythmicity was not observed.

Conclusion and implication:

Treatment with XAF-1407 was found to efficiently cardiovert shorter duration AF of tachypacing induced AF in horses and did not induce noteworthy safety compromising side effects. The study thereby suggests that I_K,ACh inhibition may constitute a potentially potent and safe treatment modality of paroxysmal AF in horses, indicating clinical value for other species including humans.

Funding:

This project has received funding from the European Union’s Horizon 2020 MSCA ITN under Grant Agreement No. 675351.