Atrial hiPSC-CM as a pharmacological model to evaluate anti-AF drugs: Some lessons from IKur

Human induced pluripotent stem cells (hiPSC) and atrial hiPSC-derived cardiomyocytes (hiPSC-CM) have entered the arena of preclinical AF research. A central question is whether they reproduce the physiological contribution of atrial selective potassium currents (such as the ultrarapid potassium current, I Kur ) to repolarization. Of note, two studies in single atrial hiPSC-CM reported prolongation of action potential duration by I Kur block indicating that I Kur might in fact represent a valuable target for the treatment of human AF. However, the results and interpretation are at odds with the literature on I Kur block in human atria and the results of clinical studies. We believe that the discrepancies indicate that experiments in single atrial CM (both adult atrial CM and atrial hiPSC-CM) might be misleading. Under particular experimental conditions, atrial hiPSC-CMs may not closely resemble the electrophysiology of the human atrium. Therefore, we recapitulate here methodological issues evaluating potential value of the I Kur as an antiarrhythmic target when investigated in animal models, in human atrial tissues and finally in atrial hiPSC-CM.