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.
Abstract: 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. However, it has been hypothesized that the importance of the KCa2 current-and thereby the efficacy of small-conductance Ca2+-activated K+ current (I K,Ca) inhibition-might be negatively related to AF duration and the extent of AF-induced remodeling. Unassigned: To address the hypothesis of the efficacy of I K,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the I K,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. Results: I K,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. Conclusions: Intra-atrial heterogeneity in response to I K,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, I K,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.
Copyright © 2021 Fenner, Gatta, Sattler, Kuiper, Hesselkilde, Adler, Smerup, Schotten, Sørensen, Diness, Jespersen, Verheule, Van Hunnik and Buhl.
Publication Date: 2021-02-09 PubMed ID: 33633584PubMed Central: PMC7900437DOI: 10.3389/fphys.2021.614483Google Scholar: Lookup
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Summary
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The research investigates the effect of inhibiting small-conductance calcium-activated potassium current (I K,Ca) on atrial electrophysiological properties in horses having persistent atrial fibrillation. The study reveals that I K,Ca inhibition through NS8593 doesn’t result in cardioversion, instead causes differential responses in the right and left atrium.
Objective of the Study
- The main aim of this research is to understand the efficiency of inhibiting the I K,Ca in the context of atrial fibrillation (AF) duration.
- The research uses an equine model where persistent AF is induced, to study the anti-arrhythmic properties of the I K,Ca inhibitor, NS8593, and its impact on atrial conduction behaviour.
Methodology
- The research used eleven Standardbred mares who were induced with persistent AF.
- An open-chest experiment was conducted, wherein the high-density contact maps from unipolar AF electrograms were analysed for understanding patterns and changes in electrophysiological parameters such as atrial conduction velocity and AF cycle length.
- Continuous surface ECG monitoring was performed to evaluate the atrial anti-arrhythmic properties and any adverse effects of I K,Ca inhibition by NS8593 on ventricular electrophysiology.
Findings
- The results indicate that inhibiting I K,Ca with NS8593 led to different impacts on the complexity and propagation properties of AF in the right and left atriums.
- While the AF cycle length was globally prolonged, the right atrium showed a slowing of conduction leading to increased anisotropy and electrical dissociation, thereby increasing AF complexity.
- However, no significant change in AF complexity was observed in the left atrium, and cardioversion of AF was not achieved.
Conclusions
- The research concluded that there was intra-atrial heterogeneity in response to I K,Ca inhibition by NS8593.
- The dose of NS8593 used in the study increased the AF cycle length, yet it did not induce cardioversion.
- It further highlights that the I K,Ca inhibitor, NS8593, impacted the propagation properties differently in the right and left atrium during AF, contributing to an unsuccessful cardioversion.
Cite This Article
APA
Fenner MF, Gatta G, Sattler S, Kuiper M, Hesselkilde EM, Adler DMT, Smerup M, Schotten U, Sørensen U, Diness JG, Jespersen T, Verheule S, Van Hunnik A, Buhl R.
(2021).
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.
Front Physiol, 12, 614483.
https://doi.org/10.3389/fphys.2021.614483 Publication
Researcher Affiliations
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Cardiothoracic Surgery, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.
- Acesion Pharma ApS, Copenhagen, Denmark.
- Acesion Pharma ApS, Copenhagen, Denmark.
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
Conflict of Interest Statement
USø and JD are co-founders of Acesion Pharma ApS and USø was one of the inventors of NS8593. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, as the anti-arrhythmic compound NS8593 was provided free of charge solely for academic purposes.
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