{"doi":"10.1093/cvr/cvad143","title":"Atrial fibrillation-associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: a novel pathway for antiarrhythmic therapy development","abstract":"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.","journal":"Cardiovascular Research","year":2023,"id":323747,"datarank":0.5416376868966337,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.0,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":725895,"name":"Tony Rubio","orcid":"0000-0001-5118-5330","position":1,"is_corresponding":false},{"id":1039625,"name":"Robin Springer","orcid":null,"position":2,"is_corresponding":false},{"id":1039033,"name":"F. 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Windel","orcid":"0000-0001-9472-0786","position":10,"is_corresponding":false},{"id":1039628,"name":"Núria Díaz i Pedrosa","orcid":null,"position":11,"is_corresponding":false},{"id":1039037,"name":"Markus Rapedius","orcid":"0000-0002-9917-9922","position":12,"is_corresponding":false},{"id":1039629,"name":"Y Doering","orcid":null,"position":13,"is_corresponding":false},{"id":1039038,"name":"Richard Solano","orcid":"0000-0001-7608-6099","position":14,"is_corresponding":false},{"id":1039630,"name":"Robin Hindmarsh","orcid":null,"position":15,"is_corresponding":false},{"id":1039039,"name":"Runzhu Shi","orcid":"0000-0003-3266-1623","position":16,"is_corresponding":false},{"id":1039040,"name":"Malte Tiburcy","orcid":"0000-0002-6942-6275","position":17,"is_corresponding":false},{"id":725628,"name":"Tobias Bruegmann","orcid":"0000-0002-6930-9634","position":18,"is_corresponding":false},{"id":578522,"name":"Ingo Kutschka","orcid":"0000-0002-7358-3513","position":19,"is_corresponding":false},{"id":1039041,"name":"Katrin Streckfuß‐Bömeke","orcid":"0000-0001-5137-7228","position":20,"is_corresponding":false},{"id":1039042,"name":"George Kensah","orcid":"0000-0003-0219-8279","position":21,"is_corresponding":false},{"id":328967,"name":"Lukas Cyganek","orcid":"0000-0001-9120-1382","position":22,"is_corresponding":false},{"id":1039631,"name":"Wolfram H. 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