Abstract

BACKGROUND AND PURPOSE: Current pharmacological therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, remain unsatisfactory due to low efficacy and safety concerns. New promising strategies for AF pharmacotherapy include targeting atrial-predominant ion-channels and multi-channel block (poly)therapy. Further, as AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast rates 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 both normal sinus rhythm (nSR) and AF-remodeled conditions using two distinct, well-established atrial models. Next, we conducted sensitivity analyses on our atrial populations to investigate the rate dependence of action potential duration (APD) changes due to blocking IKur , IK2P or IKCa , and uncover interactions among block of these three 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 favorable positive rate-dependent APD prolongation and displayed positive rate-dependent synergy, i.e., increasing synergistic antiarrhythmic effects at fast pacing vs slow rates.CONCLUSION AND IMPLICATIONS: Simultaneous block of multiple atrial-predominant K+ currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.

View details for DOI 10.1111/bph.15198

View details for PubMedID 32667679