Synergistic Anti-arrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Developing effective and safe anti-AF drugs remains an unmet challenge. Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K) current (I) and the Na current (I) has been hypothesized to be anti-AF, without inducing significant QT prolongation and ventricular side effects. However, the antiarrhythmic advantage of simultaneously blocking these two channels vs. individual block in the setting of AF-induced electrical remodeling remains to be documented. Furthermore, many I blockers such as acacetin and AVE0118, partially inhibit other K currents in the atria. Whether this multi-K-block produces greater anti-AF effects compared with selective I-block has not been fully understood. The aim of this study was to use computer models to (i) assess the impact of multi-K-block as exhibited by many I blokers, and (ii) evaluate the antiarrhythmic effect of blocking I and I, either alone or in combination, on atrial and ventricular electrical excitation and recovery in the setting of AF-induced electrical-remodeling. Contemporary mathematical models of human atrial and ventricular cells were modified to incorporate dose-dependent actions of acacetin (a multichannel blocker primarily inhibiting I while less potently blocking I, I, and I). Rate- and atrial-selective inhibition of I was also incorporated into the models. These single myocyte models were then incorporated into multicellular two-dimensional (2D) and three-dimensional (3D) anatomical models of the human atria. As expected, application of I blocker produced pronounced action potential duration (APD) prolongation in atrial myocytes. Furthermore, combined multiple K-channel block that mimicked the effects of acacetin exhibited synergistic APD prolongations. Synergistically anti-AF effects following inhibition of I and combined I/K-channels were also observed. The attainable maximal AF-selectivity of I inhibition was greatly augmented by blocking I or multiple K-currents in the atrial myocytes. This enhanced anti-arrhythmic effects of combined block of Na- and K-channels were also seen in 2D and 3D simulations; specially, there was an enhanced efficacy in terminating re-entrant excitation waves, exerting improved antiarrhythmic effects in the human atria as compared to a single-channel block. However, in the human ventricular myocytes and tissue, cellular repolarization and computed QT intervals were modestly affected in the presence of actions of acacetin and I blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of I and I, as well as those of I and combined multi K-current block of acacetin, without significant alterations of ventricular repolarization and QT intervals. This approach may be a valuable strategy for the treatment of AF.