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

Abstract

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, IKur) to repolarization. Of note, two studies in single atrial hiPSC-CM reported prolongation of action potential duration by IKur block indicating that IKur 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 IKur 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 IKur as an antiarrhythmic target when investigated in animal models, in human atrial tissues and finally in atrial hiPSC-CM.