Inhibition of Small-Conductance Calcium-Activated Potassium Current (I K,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

Merle Friederike Fenner,Jonas Goldin Diness,Arne Van Hunnik,Sander Verheule,Morten Smerup,Stefan Sattler,Ulrik Sørensen,Ulrich Schotten,Rikke Buhl,Giulia Gatta,Marion Kuiper,Thomas Jespersen,Eva Melis Hesselkilde,Ditte M T Adler

doi:10.3389/fphys.2021.614483

Abstract

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Highlights

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which poses a serious public health issue in Western societies as its prevalence increases drastically with age (Heeringa et al, 2006)
AF became sustained after 6 ± 4 days of pacing at 10 Hz (Figure 2A)
AF stabilization was accompanied by a progressive reduction in AF cycle length (AFCL), from 209 (55) ms on day 3 to 169 (17) ms on day 29 (p < 0.05; Figure 2B), which indicated the progression of atrial electrical remodeling (Fenner et al, 2020)

Summary

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which poses a serious public health issue in Western societies as its prevalence increases drastically with age (Heeringa et al, 2006). Small-conductance Ca2+-activated K+ (KCa2) channels have recently been proposed as a possible atrial-selective target to pharmacologically terminate AF (Diness et al, 2010). Small-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. It has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling. Experimental Approach and Methods: To address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring

Methods

Results

Discussion

Conclusion