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

Autor:	Seibertz F; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Rubio T; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Springer R; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Popp F; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Ritter M; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Liutkute A; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Bartelt L; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Stelzer L; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Haghighi F; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Pietras J; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Windel H; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Pedrosa NDI; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Rapedius M; Nanion Technologies GmbH, Munich, Germany., Doering Y; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Solano R; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Hindmarsh R; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University Göttingen, Germany., Shi R; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Institute for Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany., Tiburcy M; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany., Bruegmann T; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; Institute for Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany., Kutschka I; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Streckfuss-Bömeke K; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University Göttingen, Germany.; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany., Kensah G; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Department of Cardiothoracic and Vascular Surgery, Georg-August-University Göttingen, Göttingen, Germany., Cyganek L; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University Göttingen, Germany., Zimmermann WH; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Göttingen, Germany.; Campus-Institute Data Science (CIDAS), University of Göttingen, Göttingen, Germany., Voigt N; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Dec 19; Vol. 119 (16), pp. 2623-2637.
DOI:	10.1093/cvr/cvad143
Abstrakt:	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. Competing Interests: Conflict of interest: W.H.Z. is founder and advisor of Repairon GmbH and myriamed GmbH. M.T. is advisor of Repairon GmbH and myriamed GmbH. myriamed GmbH commercializes iPSC-based cell and tissue models for drug discovery. M.Rap. is an employee of Nanion Technologies GmbH. This manuscript was handled by Consulting Editor David Eisner. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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