Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

Abstract Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially e...

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Autores principales:	Zachary Laksman, Marianne Wauchop, Eric Lin, Stephanie Protze, Jeehoon Lee, Wallace Yang, Farzad Izaddoustdar, Sanam Shafaattalab, Lior Gepstein, Glen F. Tibbits, Gordon Keller, Peter H. Backx
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/de4c7f423d3d4347aaa96056d0036cc4
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spelling	oai:doaj.org-article:de4c7f423d3d4347aaa96056d0036cc42021-12-02T15:06:24ZModeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue10.1038/s41598-017-05652-y2045-2322https://doaj.org/article/de4c7f423d3d4347aaa96056d0036cc42017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05652-yhttps://doaj.org/toc/2045-2322Abstract Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.Zachary LaksmanMarianne WauchopEric LinStephanie ProtzeJeehoon LeeWallace YangFarzad IzaddoustdarSanam ShafaattalabLior GepsteinGlen F. TibbitsGordon KellerPeter H. BackxNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zachary Laksman Marianne Wauchop Eric Lin Stephanie Protze Jeehoon Lee Wallace Yang Farzad Izaddoustdar Sanam Shafaattalab Lior Gepstein Glen F. Tibbits Gordon Keller Peter H. Backx Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
description	Abstract Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.
format	article
author	Zachary Laksman Marianne Wauchop Eric Lin Stephanie Protze Jeehoon Lee Wallace Yang Farzad Izaddoustdar Sanam Shafaattalab Lior Gepstein Glen F. Tibbits Gordon Keller Peter H. Backx
author_facet	Zachary Laksman Marianne Wauchop Eric Lin Stephanie Protze Jeehoon Lee Wallace Yang Farzad Izaddoustdar Sanam Shafaattalab Lior Gepstein Glen F. Tibbits Gordon Keller Peter H. Backx
author_sort	Zachary Laksman
title	Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
title_short	Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
title_full	Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
title_fullStr	Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
title_full_unstemmed	Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue
title_sort	modeling atrial fibrillation using human embryonic stem cell-derived atrial tissue
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/de4c7f423d3d4347aaa96056d0036cc4
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Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

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