Our science is based on the novel concept of treating atrial fibrillation (AF) by inhibiting the SK channels. SK channels are ion channels present in the heart where they are relevant for regulating the heart rhythm. Several large genome-wide association studies (GWAS) have provided strong genetic validation of the SK channel target by showing strong associations between genes encoding the different subtypes of the channel and AF in humans.1-3
SK channels have been demonstrated to be important for atrial refractoriness, a well-established marker for AF efficacy.4-7,9-11,13
Furthermore, experimental models of AF in isolated perfused heart preparations from rat, guinea pig, and rabbit as well as in in vivo models of AF in rat, dog, pig, goat and horse have demonstrated that SK inhibition can terminate AF or protect against its induction. 4-7,9-11,13
Limiting the effect of drugs for AF to the atria is important for safety. From a functional perspective the SK channels preferentially affect electrical activity in the atria with only minor impact on ventricles.
In heart tissue from patients in normal sinus rhythm (SR), as well as patients with more than six months of AF, SK channel inhibition by the SK channel inhibitor NS8593 prolonged refractory periods in atrial, but not ventricular, tissue.8
1. Ellinor, P. T. et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat.Genet. 42, 240-244 (2010).
2. Ellinor, P. T. et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat.Genet. (2012). doi:10.1038/ng.2261
3. Christophersen, I. E. et al. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat. Genet. (2017). doi:10.1038/ng.3843
4. Diness, J. G. et al. Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation. Circ.Arrhythm.Electrophysiol. 3, 380-390 (2010).
5. Diness, J. G. et al. Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition. Hypertension 57, 1129-35 (2011).
6. Skibsbye, L., Diness, J. G., Sørensen, U. S., Hansen, R. S. & Grunnet, M. The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca(2+)-activated K(+) channels. J. Cardiovasc. Pharmacol. 57, 672-681 (2011).
7. Qi, X.-Y. et al. Role of Small Conductance Calcium-Activated Potassium Channels in Atrial Electrophysiology and Fibrillation in the Dog. Circulation (2013). doi:10.1161/CIRCULATIONAHA.113.003019
8. Skibsbye, L. et al. Small conductance calcium activated potassium (SK) channels contribute to action potential repolarisation in human atria. J. Cardiovacular Res.
9. Giulia Gatta et al. Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction. Europace, 2021 Nov 8;23(11):1847-1859. doi: 10.1093/europace/euab125.
10. Haugaard, M. M. et al. Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm Off. J. Heart Rhythm Soc. 12, 825-835 (2015).
11. Diness, J. G. et al. Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca(2+)-Activated K(+) Channels in Pigs. Circ. Arrhythm. Electrophysiol. 10, (2017).
12. Heijman, J. & Dobrev, D. Inhibition of Small-Conductance Ca2+-Activated K+Channels: The Long-Awaited Breakthrough for Antiarrhythmic Drug Therapy of Atrial Fibrillation? Circ. Arrhythm. Electrophysiol. 10, (2017).
13. Diness JG, Kirchhoff JE, Speerschneider T, Abildgaard L, Edvardsson N, Sørensen US, Grunnet M and Bentzen BH. The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs. Front. Pharmacol. 11:159 (2020). doi: 10.3389/fphar.2020.00159.