Populations of in silico myocytes and tissues reveal synergy of multiatrial-predominant K+ -current block in atrial fibrillation.

ABSTRACT

BACKGROUND AND PURPOSE: Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial-predominant ion-channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast and minimal effects at slow rates are desirable. We present a novel systems pharmacology framework to quantitatively evaluate synergistic anti-AF effects of combined block of multiple atrial-predominant K+ currents (ultra-rapid delayed rectifier K+ current, IKur , small conductance Ca2+ -activated K+ current, IKCa , K2P 3.1 2-pore-domain K+ current, IK2P ) in AF. EXPERIMENTAL APPROACH: We constructed experimentally calibrated populations of virtual atrial myocyte models in normal sinus rhythm and AF-remodelled conditions using two distinct, well-established atrial models. Sensitivity analyses on our atrial populations was used to investigate the rate dependence of action potential duration (APD) changes due to blocking IKur , IK2P or IKCa and interactions caused by blocking of these currents in modulating APD. Block was simulated in both single myocytes and one-dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti-arrhythmic effects of multi-atrial-predominant K+ current block in single cells and coupled tissue. KEY RESULTS: In both virtual atrial myocytes and tissues, multiple atrial-predominant K+ -current block promoted favourable positive rate-dependent APD prolongation and displayed positive rate-dependent synergy, that is, increasing synergistic antiarrhythmic effects at fast pacing versus slow rates. CONCLUSION AND IMPLICATIONS Simultaneous block of multiple atrial-predominant K+ currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.