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A key issue in the development of atrial-selective antiarrhythmic drugs is the limited access to human heart tissue. Goldfracht et al. have used atrialand ventricular-differentiated human embryonic stem cell‐derived cardiomyocytes (hESC-CMs) to dissect chamber-selective actions of clinically relevant antiarrhythmic drugs1. This is plausible, but we want to point to remaining differences between the electrophysiological properties the atrial hESCCMs presented in the study and adult human atrial cardiomyocytes. We believe that further refinement and in-depth comparison of atrialand ventricular-differentiated hESC-CM with adult human cardiomyocytes and tissue is warranted before these models can be safely used for the development of atrial-selective antiarrhythmics. There is an unmet need to find new drugs to stop atrial fibrillation (AF) without inducing ventricular arrhythmias. However, access to atrial and even more to ventricular human tissue is limited, both of which could be principally solved by the widespread availability of human induced pluripotent stem cell‐ derived cardiomyocytes (hiPSC-CM) or hESC-CMs, which are limited to some countries due to ethical requirements. Indeed, protocols to generate atrial hiPSC-CM or hESC-CM have been established2,3. However, differences in antiarrhythmic drug response between atrial and ventricular EHTs have only scarcely been investigated3,4. Therefore, the study by Goldfracht et al. using established antiarrhythmic drugs is very welcomed1. The authors used the early method of ring-shaped EHTs5, which allowed the induction of macro reentry arrhythmia, visualized by voltage sensitive dyes, and the exploration of activation maps and drug effects. Goldfracht et al. used vernakalant, a compound approved in the EU since 2010 as an antiarrhythmic drug in AF. The authors used this multichannel blocker because it blocks, amongst others, two ion currents selectively present in the atria and not in the ventricle: the ultrarapidly activating potassium outward rectifier current (IKur) and the acetylcholine-activated potassium inward rectifier current (IK,ACh). The underlying hypothesis was that effects of vernakalant in atrial, but not ventricular EHTs are indicative of a truly atrial phenotype. Indeed, vernakalant (30 μM) increased action potential duration at 90% percent of repolarization (APD90) in atrial EHTs by about 100% (~200 ms), while it was reported ineffective in ventricular EHTs. Of note, however, the large effect of vernakalant on APD90 in atrial EHTs is in stark contrast to results obtained in human atrial tissue, where the same concentration of vernakalant did not prolong APD90 at all6. Inefficacy of IKur block to prolong APD90 in human atrium is a common finding and is explained by indirect activation of the rapid component of the delayed rectifier potassium current (IKr). Thus, one has to consider block of another potassium channel to underlie the marked prolongation of APD90 in atrial EHT upon vernakalant. Contribution of IK,ACh to repolarization normally requires G protein-coupled inwardly rectifying potassium channels to be open, e.g., by stimulation of muscarinic or adenosine receptors. However, agonists should be absent under in vitro conditions. Thus, other scenarios have to be considered. Atrial hiPSC-CMs or hESC-CMs could differ from human atrium with respect to repolarization reserve (similar to what we have reported for ventricular EHTs8), enabling block of IKur to prolong APD90. A high baseline activity of IK,ACh could result either from acetylcholine or adenosine present in these cultures or from constitutively active IK,ACh, as reported in human AF9. Alternatively, vernakalant could have induced APD90 prolongation in atrial hESC-CM by blocking ion channels normally absent from adult CM, but present in immature hESC/hiPSCCM, an example for this phenomenon was reported recently10. In contrast to the unusual effect in atrial EHTs, the reported absence of effects of vernakalant on repolarization in ventricular EHTs appears, at first sight, to match the reported vernakalant https://doi.org/10.1038/s41467-021-21949-z OPEN