Luke Bailey

 Introduction: Atrial fibrillation (AF) is the most common cardiac arrythmia in which the atria are rapidly excited without constant rate or rhythm. There are approximately over 3 million adults in the United States being affected by AF¹ There is approximately a 25% increase in risk of cardiovascular related death within 1 year after getting diagnosed with AF.² Atrial fibrillation is precipitated by the inappropriate atrial depolarizations, specifically through small conductance calcium-activated potassium channels. The purpose of these channels is to allow potassium ions to cross the membrane and cause hyperpolarization.^3,4 This research is intended to investigate the effects of blocking these channels in relation to AF, and to investigate potential pharmacological treatments.

Objective: In this literature review, the connection and involvement of small conductance calcium activated potassium channels was investigated to see if there were any connections between inhibiting these and atrial fibrillation outcomes.

Methods: A PubMed search was completed, and multiple experiments were examined. The effective refractory period (ERP) was measured in three different groups: including a group that was administered a SK_Ca channel inhibitor.⁴ Another study utilized isochronal high-density maps and measured atrial fibrillation cycle length (AFCL).⁵ The effectiveness of SK_Ca channel inhibitors NS 8593 and UCL 1684 were measured by examining AFCL, and ERP.⁶ Lastly, the novel SK_Ca channel inhibitor, AP 30663, was tested to see if it was safe and tolerable to administer to patients.⁷

Results: When the SK_Ca channels were inhibited with TRAM-34, there was a significant increase in ERP which would increase atrial contraction time gaps.⁴ Administration of SK_Ca channel blocker NS 8593 resulted in an increase in the AFCL, however there were divergent effects observed in the left and right atria, which most likely caused the drug to fail in producing cardioversion.^5,6 The ERP was increased as well when UCL 1684 was tested as a treatment method, however this method also was not able to be successful at cardioversion, most likely due to not affecting the action potential duration.⁶ A transient dose dependent QT interval prolongation was found to occur with AP 30663 administration, however this was the only pharmacological method that was successful at cardioversion.⁷

Conclusion: SK_Ca channels play an important role in AF and inhibition of these channels yields desirable therapeutic characteristics for treating AF. These characteristics include increased AFCL and ERP, while decreasing the atrial conduction velocity.⁵ While some of these favorable markers were achieved through NS 8593 and UCL 1684, the only SK_Ca channel inhibitor that was successful at cardioversion was AP 30663, which should be further investigated as a pharmacological treatment for AF.⁷

Works Cited

1. Wijesurendra RS, Casadei B. Mechanisms of atrial fibrillation. Heart. 2019;105(24):1860-1867. doi:10.1136/heartjnl-2018-314267

2. Schüttler D, Bapat A, Kääb S, et al. Animal Models of Atrial Fibrillation. Circ Res. 2020;127(1):91-110. doi:10.1161/CIRCRESAHA.120.316366
3. Brundel BJJM, Ai X, Hills MT, Kuipers MF, Lip GYH, de Groot NMS. Atrial fibrillation. Nat Rev Dis Primers. 2022;8(1):21. Published 2022 Apr 7. doi:10.1038/s41572-022-00347-9
4. Ma Y, Fu Y, Wang Y, et al. Blocking Intermediate-Conductance Calcium-Activated Potassium Channels in the Macrophages Around Ganglionated Plexi Suppresses Atrial Fibrillation Vulnerability in Canines with Rapid Atrial Pacing. Front Physiol. 2022;13:837412. Published 2022 Apr 1. doi:10.3389/fphys.2022.837412
5. Fenner MF, Gatta G, Sattler S, et al. 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. 2021;12:614483. Published 2021 Feb 9. doi:10.3389/fphys.2021.614483
6. Burashnikov A, Barajas-Martinez H, Hu D, Robinson VM, Grunnet M, Antzelevitch C. The Small Conductance Calcium-Activated Potassium Channel Inhibitors NS8593 and UCL1684 Prevent the Development of Atrial Fibrillation Through Atrial-Selective Inhibition of Sodium Channel Activity. J Cardiovasc Pharmacol. 2020;76(2):164-172. doi:10.1097/FJC.0000000000000855
7. Gal P, Klaassen ES, Bergmann KR, et al. First Clinical Study with AP30663 – a K_Ca2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation. Clin Transl Sci. 2020;13(6):1336-1344. doi:10.1111/cts.12835