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

Haibo Ni,Sanjiv M Narayan,Wei Wang,Dominic G Whittaker,Henggui Zhang,Wayne R Giles

doi:10.3389/fphys.2017.00946

Abstract

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

Highlights

Despite recent advances in the management of Atrial fibrillation (AF), the world’s most common cardiac arrhythmia (Dobrev et al, 2012; Nattel and Dobrev, 2017), developing effective and safe antiarrhythmic drugs for treatment of AF remains challenging (Aguilar-Shardonofsky et al, 2012; Aguilar et al, 2015)
The updated Colman et al human atrial model was first used to simulate effects cAF-induced remodeling on the action potential (AP) and calcium transient (CaT)
The results showed that applying Bl·IKur or Comb·Bl·IX alone both abolished the AP alternans while prolonging the action potential durations (APDs) to 116.3 and 126.3 ms and reducing the peak INa by 5.9 and 20.1%, respectively

Summary

Introduction

Despite recent advances in the management of Atrial fibrillation (AF), the world’s most common cardiac arrhythmia (Dobrev et al, 2012; Nattel and Dobrev, 2017), developing effective and safe antiarrhythmic drugs for treatment of AF remains challenging (Aguilar-Shardonofsky et al, 2012; Aguilar et al, 2015) These antiarrhythmic agents promote ventricular arrhythmias (Dobrev et al, 2012; Woods and Olgin, 2014; Voigt and Dobrev, 2016) by prolonging cellular action potential durations (APDs). Previous simulation studies have demonstrated that by optimizing state-dependent Na+-channel blocking dynamics (i.e., drug-channel interaction parameters), atrial-selective block of INa could be achieved and that could maximize pharmaceutical effects on the atria while minimizing their proarrhythmic actions in the ventricles (Aguilar-Shardonofsky et al, 2012; Aguilar et al, 2015)

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