{"id":13254,"date":"2023-11-08T10:01:00","date_gmt":"2023-11-08T10:01:00","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&p=13254"},"modified":"2024-01-08T12:05:43","modified_gmt":"2024-01-08T12:05:43","slug":"2023-atrial-fibrillation-associated-electrical-remodelling-in-human-induced-pluripotent-stem-cell-derived-atrial-cardiomyocytes-a-novel-pathway-for-antiarrhythmic-therapy-development","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-atrial-fibrillation-associated-electrical-remodelling-in-human-induced-pluripotent-stem-cell-derived-atrial-cardiomyocytes-a-novel-pathway-for-antiarrhythmic-therapy-development\/","title":{"rendered":"2023 – Atrial fibrillation-associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: a novel pathway for antiarrhythmic therapy development"},"content":{"rendered":"
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Aims<\/strong><\/div>\n
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).<\/div>\n<\/div>\n
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Methods and results<\/strong><\/div>\n
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+\u00a0current (ICa,L) and (ii) impaired activation of acetylcholine-activated inward-rectifier K+\u00a0current (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\u00a0blockade with tertiapin reduced basal inward-rectifier K+\u00a0current 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+\u00a0current (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.<\/div>\n
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Conclusions<\/strong><\/div>\n
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\u00a0in vitro\u00a0for the first time. The observation of electrical remodelling with associated reversible contractile dysfunction offers a novel platform for human-centric discovery of antiarrhythmic therapies.<\/div>\n<\/div>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[53,76,77],"therapeutic_areas":[54,143],"target_categories":[61],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-13254","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-assay-development-and-validation","application_areas-drug-discovery","application_areas-cell-ipscs-profiling","therapeutic_areas-cardiac-safety-cipa","therapeutic_areas-assay-development-and-validation","target_categories-voltage-gated-ion-channels"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/13254","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=13254"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=13254"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=13254"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=13254"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=13254"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=13254"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=13254"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=13254"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=13254"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}