Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology

Abstract Drugs targeting atrial‐specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non‐cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)‐derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial‐like (hESC‐atrial) and ventricular‐like (hESC‐ventricular) CMs. We found the expression of atrial‐specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC‐atrial CMs and further demonstrated that these ion channel genes are regulated by COUP‐TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN‐D0101, hESC‐atrial but not hESC‐ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC‐atrial CMs, XEN‐R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN‐R0703 had an effect on hESC‐ventricular CMs. In summary, we demonstrate that hESC‐atrial CMs are a robust model for pre‐clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.