In our recent report 1, we combined developmental biologyinspired differentiation strategies of human pluripotent stem cells (hPSCs) to derive chamber-specific cardiomyocytes 2 and a collagen-hydrogel-based tissue engineering strategy 3 to generate ring-shaped ventricular and atrial-specific engineered heart tissues (EHTs). Detailed molecular, ultrastructural, and functional phenotyping, together with targeted pharmacology, confirmed the chamber-specific identity of the atrial/ventricular EHTs, and demonstrated the potential of these models for disease modeling and drug testing applications. The latter included the ability to induce reentrant arrhythmias in the atrial EHTs and the ability to terminate such arrhythmias with established anti-arrhythmic agents (flecainide and vernakalant). In the accompanying comment, Christ et al. 4 raise concerns with regards to the relative immature properties of the chamber-specific EHTs and their different response to some of the anti-arrhythmic drugs tested (vernakalant and lidocaine) in comparison to their reported effects in adult human atrial and ventricular heart tissues. The first point raised by Christ 4 relates to vernakalant, a multichannel blocker (that also blocks the atrial-selective ionic currents IKur and IKAch), which is approved in the EU for acute conversion of atrial fibrillation (AF) 5. In Goldfracht et al. 1, we noted significant prolongation of APD90 values following vernakalant administration to atrial EHTs. Christ et al. 4 refer to two studies by Wettwer et al. 6, 7, in which atrial trabecula/myocytes isolated from patients undergoing open-heart surgery were studied. In one study, they noted that vernakalant administration did not lead to APD90 prolongation in isolated atrial trabecula 6. In their second study 7, they suggest that this lack of APD prolongation stems from the inability of IKur blockade to prolong APD90 due to indirect activation of IKr. To address the aforementioned comment, we first aimed to reproduce vernakalant’s APD-prolonging effects in a different hPSC line and using a different experimental model. To this end, we evaluated the effects of vernakalant in a two-dimensional human-induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocyte cell sheet model 8, 9. As shown in Fig. 1, vernakalant also significantly prolonged APD values in this 2D hiPSC-based atrial tissue model. These results were further corroborated in the very recent publication of Gunawan et al. 10. We also noted in Wettwer et al. 6 that although vernakalant did not alter APD in atrial trabecula, this finding was limited to patients with sinus-rhythm. In patients with chronic AF, however, vernakalant significantly prolonged APD90 6. This finding also correlated with the second Wettwer paper, where pharmacological blockade of IKur with either 4-aminopyridine or AVE0118 shortened APD in atrial cells from sinus-rhythm patients, but prolonged APD in AF patients 7. Interestingly, as described in our study 1, in contrast to the ventricular EHTs, which displayed a normal activation pattern (“sinus-rhythm-like”), the vast majority of atrial EHTs displayed continuous fast and irregular arrhythmogenic activity due to multiple reentrant circuits (“AF-like”) 1. This arrhythmogenic activity persisted for weeks but could be terminated, at least temporarily, by electrical cardioversion to allow the drug studies. Hence, one may consider the state of the atrial EHTs more analogous to the atrial cells obtained from the AF, rather than the sinus-rhythm, patients in the Wettwer study 6. Consequentially, vernakalant’s APD-prolonging effects in the atrial EHTs might be in agreement with the human heart tissue studies 6, 7. These results may also open the road to …