Atrial fibrillation-Associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: A novel pathway for antiarrhythmic therapy development

Aims: Atrial fibrillation (AF) is associated with tachycardia-induced cellular electrophysiology alterations which promote AF chronification and treatment resistance. Development of novel antiarrhythmic therapies is hampered by the absence of scalable experimental human models that reflect AF-Associated electrical remodelling. Therefore, we aimed to assess if AF-Associated remodelling of cellular electrophysiology can be simulated in human atrial-like cardiomyocytes derived from induced pluripotent stem cells in the presence of retinoic acid (iPSC-ACM), and atrial-engineered human myocardium (aEHM) under short term (24 h) and chronic (7 days) tachypacing (TP). Methods and results: First, 24-h electrical pacing at 3 Hz was used to investigate whether AF-Associated remodelling in iPSC-ACM and aEHM would ensue. Compared to controls (24 h, 1 Hz pacing) TP-stimulated iPSC-ACM presented classical hallmarks of AF-Associated remodelling: (i) decreased L-Type Ca2+ current (ICa,L) and (ii) impaired activation of acetylcholine-Activated inward-rectifier K+ current (IK,ACh). This resulted in action potential shortening and an absent response to the M-receptor agonist carbachol in both iPSC-ACM and aEHM subjected to TP. Accordingly, mRNA expression of the channel-subunit Kir3.4 was reduced. Selective IK,ACh blockade with tertiapin reduced basal inward-rectifier K+ current only in iPSC-ACM subjected to TP, thereby unmasking an agonist-independent constitutively active IK,ACh. To allow for long-Term TP, we developed iPSC-ACM and aEHM expressing the light-gated ion-channel f-Chrimson. The same hallmarks of AF-Associated remodelling were observed after optical-TP. In addition, continuous TP (7 days) led to (i) increased amplitude of inward-rectifier K+ current (IK1), (ii) hyperpolarization of the resting membrane potential, (iii) increased action potential-Amplitude and upstroke velocity as well as (iv) reversibly impaired contractile function in aEHM. Conclusions: Classical hallmarks of AF-Associated remodelling were mimicked through TP of iPSC-ACM and aEHM. The use of the ultrafast f-Chrimson depolarizing ion channel allowed us to model the time-dependence of AF-Associated remodelling in vitro for the first time. The observation of electrical remodelling with associated reversible contractile dysfunction offers a novel platform for human-centric discovery of antiarrhythmic therapies.