Investigating the contribution of the rs13376333 genetic variant to lone atrial fibrillation in human induced pluripotent stem cell-derived atrial cardiomyocytes

Atrial fibrillation (AF), the most common arrhythmia globally, is characterized by irregular and rapid electrical activity in the atria. AF is linked to increased morbidity, mortality, and decreased quality of life. Although multiple modifiable risk factors have been associated with a higher incidence of AF, there is a strong genetic component in the development of lone AF. The effect of the intronic rs13376333 variant located within the KCNN3 gene encoding for the small-conductance Ca2+-activated K+ channel 3 (SK3) was investigated with multielectrode array and optical mapping. Gene-edited human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs) harboring the rs13376333 variant exhibited a prolonged action potential duration and a diminished response to apamin, an SK channel blocker, compared to the isogenic wild-type hiPSC-aCMs measured with optical mapping. The results of this project suggest that SK channels could be a potential and more specific novel therapeutic target for the treatment of AF.