{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:02:55Z","timestamp":1788667375781,"version":"build-2803163510"},"reference-count":64,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"50","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:p>\n            Long QT syndrome (LQTS) is a cardiovascular disease characterized by QT interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in\n            <jats:italic>KCNH2<\/jats:italic>\n            , the gene that encodes for hERG (Kv11.1), which lead to onset of LQTS type 2 (LQTS2). In this work, we developed a LQTS2-diseased tissue-on-a-chip model, using 3D coculture of isogenic stem cell\u2013derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily, we created a hiPSC line with R531W mutation in\n            <jats:italic>KCNH2<\/jats:italic>\n            using CRISPR-Cas9 gene-editing technique and characterized the resultant differentiated CMs and CFs. A deficiency in hERG trafficking was identified in\n            <jats:italic>KCNH2<\/jats:italic>\n            -edited hiPSC-CMs, revealing a possible mechanism of R531W mutation in LQTS2 pathophysiology. Following creation of a 3D LQTS2 tissue-on-a-chip, the tissues were extensively characterized, through analysis of calcium handling and response to \u03b2-agonist. Furthermore, attempted phenotypic rescue via pharmacological intervention of LQTS2 on a chip was investigated.\n          <\/jats:p>","DOI":"10.1126\/sciadv.abq6720","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T18:58:39Z","timestamp":1671217119000},"source":"Crossref","is-referenced-by-count":24,"title":["Modeling long QT syndrome type 2 on-a-chip via in-depth assessment of isogenic gene-edited 3D cardiac tissues"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3373-5022","authenticated-orcid":true,"given":"Jaimeson","family":"Veldhuizen","sequence":"first","affiliation":[{"name":"School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0839-4038","authenticated-orcid":true,"given":"Helen F.","family":"Mann","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3730-0210","authenticated-orcid":true,"given":"Nina","family":"Karamanova","sequence":"additional","affiliation":[{"name":"Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-5578","authenticated-orcid":true,"given":"Wade D.","family":"Van Horn","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA."},{"name":"Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond Q.","family":"Migrino","sequence":"additional","affiliation":[{"name":"Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA."},{"name":"University of Arizona College of Medicine, Phoenix, AZ 85004, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brafman","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5970-7666","authenticated-orcid":true,"given":"Mehdi","family":"Nikkhah","sequence":"additional","affiliation":[{"name":"School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ 85287, USA."},{"name":"Biodesign Center for Personalized Diagnostics, Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0b013e31820a55f5"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.04.044"},{"key":"e_1_3_3_4_2","unstructured":"M. Alders H.\u00a0Bikker I.\u00a0Christiaans Long QT syndrome GeneReviews [Internet] (2003)."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00036.2011"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00139"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1681.2000.03337.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411042200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.05.021"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40949-020-00037-9"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6535"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00052.2004"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.08.002"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.4.H1748"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000128561.28701.ea"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206569200"},{"key":"e_1_3_3_17_2","first-page":"H1643","article-title":"Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells","volume":"274","author":"Chandra R.","year":"1998","unstructured":"R.\u00a0Chandra, C. F.\u00a0Starmer, A. O.\u00a0Grant,Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am.\u00a0J.\u00a0Physiol.274,H1643\u2013H1654 (1998).","journal-title":"Am.\u00a0J.\u00a0Physiol."},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2012.09.006"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00210"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09747"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr073"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.008409"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55837-w"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2017.04.038"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.240"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2017.0172"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.06.007"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40064-016-1889-y"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.04.041"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.19-0340"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1179555"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231143"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.021"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0059-1"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cr.2019.08.001"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0561-9"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2019.0001"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20170793"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-015-1874-6"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.12.013"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz713"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00552-y"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu060"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2020.10.005"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.04.057"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120195"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.121336"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.570200"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305787200"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511765200"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2006.05.013"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.15.11241"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199206203-00002"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-019-02151-x"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2021.113055"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-013-9539-6"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1159\/000113745"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200409119"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-005-0812-1"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.062588"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1151526"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124633"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09831-5"},{"key":"e_1_3_3_65_2","first-page":"e62539","article-title":"Developing 3D organized human cardiac tissue within a microfluidic platform","volume":"172","author":"Veldhuizen J.","year":"2021","unstructured":"J.\u00a0Veldhuizen, M.\u00a0Nikkhah,Developing 3D organized human cardiac tissue within a microfluidic platform. J. Vis. Exp.172,e62539 (2021).","journal-title":"J. Vis. Exp."}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.abq6720","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T23:12:16Z","timestamp":1704841936000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.abq6720"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,16]]},"references-count":64,"journal-issue":{"issue":"50","published-print":{"date-parts":[[2022,12,16]]}},"alternative-id":["10.1126\/sciadv.abq6720"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.abq6720","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,16]]},"article-number":"eabq6720"}}