{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T14:41:53Z","timestamp":1780497713837,"version":"3.54.1"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"crossref","award":["CSDA-2020098"],"award-info":[{"award-number":["CSDA-2020098"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01-HL160654,R01-HL166217"],"award-info":[{"award-number":["R01-HL160654,R01-HL166217"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["T32 GM007171"],"award-info":[{"award-number":["T32 GM007171"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,8]]},"abstract":"<jats:p>\n                    Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    -ATPase function, causing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMs\n                    <jats:sup>D801N<\/jats:sup>\n                    ), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca\u00b2\n                    <jats:sup>+<\/jats:sup>\n                    influx via the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    exchanger (NCX1) during depolarization was observed in iPSC-CMs\n                    <jats:sup>D801N<\/jats:sup>\n                    . Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.197721","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T18:00:46Z","timestamp":1775584846000},"source":"Crossref","is-referenced-by-count":1,"title":["D801N in ATP1A3-encoded Na\/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger\u2013mediated calcium overload"],"prefix":"10.1172","volume":"11","author":[{"given":"Minu-Tshyeto K.","family":"Bidzimou","sequence":"first","affiliation":[{"name":"Department of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmapriya","family":"Muralidharan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhushan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyal","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Needs","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin M.","family":"Perelli","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Moya-Mendez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.K. Rakesh","family":"Manivannan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsen S.","family":"Hunanyan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbigail","family":"Helfer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine Q.","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-966X","authenticated-orcid":true,"suffix":"Jr.","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":true,"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5688-6061","authenticated-orcid":true,"given":"Nenad","family":"Bursac","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad A.","family":"Mikati","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University, Durham, North Carolina, USA."},{"name":"Department of Neurobiology, Duke University, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and"},{"name":"Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2022.101978"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-017-1094-1"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00149"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2008.06.003"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.05.020"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/HCG.0000000000000086"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.10.025"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2008.01169.x"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.03.038"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2017.10.035"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.282319"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25116122"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2021.05.004"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0335-5"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab128"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.019887"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2024.6832"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S210325"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.03.002"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(96)00259-3"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00089.2015"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48890"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.322847"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000062469.83985.9B"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000095274.72486.94"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12228"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/CRD.0b013e3181c07592"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.668392"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(76)90017-5"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)21811-0"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00144"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-011-4146-1"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(00)76783-X"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00362.2023"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2020.06.022"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/biom13081259"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00314"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.12.002"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.01.010"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2358"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012264"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2013.02.024"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15257"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2022.03.007"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2023.12.002"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.7572"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s13760-019-01182-8"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18236"},{"key":"B50","doi-asserted-by":"crossref","unstructured":"Srour MK, et al. Children and adolescent patients with variants in the ATP1A3 -encoded sodium-potassium ATPase Alpha-3 subunit demonstrate an impaired QT response to bradycardia and predisposition to sinus node dysfunction [preprint]. https:\/\/doi.org\/10.1101\/2024.08.31.24312446 Posted on medRxiv October 31, 2024","DOI":"10.1101\/2024.08.31.24312446"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2025.03.027"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1111\/pace.70018"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.05.013"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.02.002"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx151"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/197721\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:16:45Z","timestamp":1778872605000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/197721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":55,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,2,19]]},"published-print":{"date-parts":[[2026,4,8]]}},"alternative-id":["10.1172\/jci.insight.197721"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.197721","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]},"article-number":"e197721"}}