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(Kur)) and the Na(+) current (I(Na)) 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(Kur) 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(Kur)-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(Kur) blokers, and (ii) evaluate the antiarrhythmic effect of blocking I(Kur) and I(Na), 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(Kur) while less potently blocking I(to), I(Kr), and I(Ks)). Rate- and atrial-selective inhibition of I(Na) 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(Kur) 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(Na) and combined I(Kur)/K(+)-channels were also observed. The attainable maximal AF-selectivity of I(Na) inhibition was greatly augmented by blocking I(Kur) 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(Na) blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of I(Kur) and I(Na), as well as those of I(Na) 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.