Primary and Secondary Effects of K+-Channels Block During Atrial Fibrillation and Its Rate Dependency

Selective inhibition of atrial fibrillation (AF) can be of therapeutic benefit for reducing the AF burden. The concept of atrial-selective block of K+ channels mainly ultra-rapidly activating and delayed-rectifier (IKur) and transient outward (Ito) current may suppress AF without the risk of ventricular proarrhythmic effects. K+-channels block alters electrophysiology through a combination of primary and secondary effects. In addition, the underlying mechanisms behind the rate dependent response of such blockers both under sinus rhythm (SR) and AF condition is not yet fully clear. In this work, we have dissociated the primary and secondary response of low dose concentration of K+channel block (4-AP and AVE0118) on human atrial electrophysiology by clamping one current at a time. As a result, under SR condition, 4-AP abbreviates the AP duration (APD) and that was because of the secondary rise of the IKr current. In contrast, during AF, the lengthening of APD in response to 4-AP was because of AP mediated rise in ICaL current. At higher rates, in SR but not in AF condition, both drugs perturb the rate dependent shortening of APD and slows the AP upstroke velocity at higher rates because of unavailability of Na+ channels. Our analysis suggest that K+-channel block can AF induced burden.