Primary and Secondary Effects of IKur Block Response During Atrial Fibrillation and its Rate Dependency

Fazeelat Mazhar, Chiara Bartolucci, Stefano Severi
University of Bologna


Abstract

Selective inhibition of atrial fibrillation (AF) can be of therapeutic benefit for reducing the AF burden. The concept of atrial-selective block of ultra-rapidly activating and delayed-rectifier K+ current (IKur) may suppress AF without the risk of ventricular proarrhythmic effects. The primary and secondary effects on electrophysiology and contractility by IKur specific blocker are not yet fully understood. In addition, the mechanism behind the rate dependent IKur block response under sinus rhythm (SR) and AF condition is still not known. In this work, we have dissociated the primary and secondary responses upon IKur block using action potential (AP)-clamp under SR and AF conditions. The results show the prolongation of AP duration (APD) was associated with the prolongation of the ERP under both SR and AF conditions. In SR but not in AF condition, 4-AP perturbs the rate dependent shortening of APD and slows the AP upstroke velocity at higher rates because of unavailability of Na+ channels. AP-clamp has shown that the currents still active during plateau decides the response of APD which is biphasic under SR and always lengthening under AF. This work can be used as a framework to quantify the performance of IKur specific blockers towards the treatment of AF.