{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:32:10Z","timestamp":1790404330215,"version":"4.1.0"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100010447","name":"DZHK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"German Center for Cardiovascular Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G&gt;A and c.3749G&gt;A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euz122","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T18:22:29Z","timestamp":1554315749000},"page":"1410-1421","source":"Crossref","is-referenced-by-count":41,"title":["A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes"],"prefix":"10.1093","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-1045","authenticated-orcid":false,"given":"Ibrahim","family":"El-Battrawy","sequence":"first","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Albers","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Cyganek","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Zhao","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Lan","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Kleinsorge","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Huang","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxing","family":"Liao","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rujia","family":"Zhong","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Rudic","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Dinkel","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Lang","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Diecke","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram-Hubertus","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Institute of Pharmacology and Toxicology, University of G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Utikal","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wieland","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Borggrefe","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Zhou","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Akin","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,5,18]]},"reference":[{"key":"2019091012210959400_euz122-B1","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1046\/j.1540-8167.2002.00816.x","article-title":"Spontaneous T wave alternans and premature ventricular contractions during febrile illness in a patient with Brugada syndrome","volume":"13","author":"Morita","year":"2002","journal-title":"J Cardiovasc Electrophysiol"},{"key":"2019091012210959400_euz122-B2","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1161\/01.CIR.0000104568.13957.4F","article-title":"Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest","volume":"108","author":"Brugada","year":"2003","journal-title":"Circulation"},{"key":"2019091012210959400_euz122-B3","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.jacc.2016.05.073","article-title":"Long-term trends in newly diagnosed Brugada syndrome: implications for risk stratification","volume":"68","author":"Casado-Arroyo","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2019091012210959400_euz122-B4","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/j.jacc.2016.07.779","article-title":"Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome","volume":"68","author":"Liang","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2019091012210959400_euz122-B5","doi-asserted-by":"crossref","first-page":"11246.","DOI":"10.1038\/s41598-018-29574-5","article-title":"Identification of an INa-dependent and Ito-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient","volume":"8","author":"Ma","year":"2018","journal-title":"Sci Rep"},{"key":"2019091012210959400_euz122-B6","doi-asserted-by":"crossref","first-page":"e007394","DOI":"10.1161\/JAHA.117.007394","article-title":"Modeling short QT syndrome using human-induced pluripotent stem cell-derived cardiomyocytes","volume":"7","author":"El-Battrawy","year":"2018","journal-title":"J Am Heart Assoc"},{"key":"2019091012210959400_euz122-B7","doi-asserted-by":"crossref","first-page":"e001893","DOI":"10.1161\/CIRCGEN.117.001893","article-title":"Ion channel dysfunctions in dilated cardiomyopathy in Limb-Girdle muscular dystrophy","volume":"11","author":"El-Battrawy","year":"2018","journal-title":"Circ Genom Precis Med"},{"key":"2019091012210959400_euz122-B8","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa0908679","article-title":"Patient-specific induced pluripotent stem-cell models for long-QT syndrome","volume":"363","author":"Moretti","year":"2010","journal-title":"N Engl J Med"},{"key":"2019091012210959400_euz122-B9","doi-asserted-by":"crossref","first-page":"e004725","DOI":"10.1161\/CIRCEP.116.004725","article-title":"Patient-specific drug screening using a human induced pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia type 2","volume":"10","author":"Maizels","year":"2017","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2019091012210959400_euz122-B10","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/pcmr.12369","article-title":"NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model","volume":"28","author":"Larribere","year":"2015","journal-title":"Pigment Cell Melanoma Res"},{"key":"2019091012210959400_euz122-B11","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.stem.2008.08.003","article-title":"A high-efficiency system for the generation and study of human induced pluripotent stem cells","volume":"3","author":"Maherali","year":"2008","journal-title":"Cell Stem Cell"},{"key":"2019091012210959400_euz122-B12","doi-asserted-by":"crossref","first-page":"99941","DOI":"10.1172\/jci.insight.99941","article-title":"Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes","volume":"3","author":"Cyganek","year":"2018","journal-title":"JCI Insight"},{"key":"2019091012210959400_euz122-B13","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1161\/CIRCULATIONAHA.106.668392","article-title":"Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death","volume":"115","author":"Antzelevitch","year":"2007","journal-title":"Circulation"},{"key":"2019091012210959400_euz122-B14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1161\/CIRCRESAHA.112.274035","article-title":"Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology","volume":"111","author":"Verkerk","year":"2012","journal-title":"Circ Res"},{"key":"2019091012210959400_euz122-B15","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1161\/CIRCULATIONAHA.112.000604","article-title":"Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk","volume":"127","author":"Ritchie","year":"2013","journal-title":"Circulation"},{"key":"2019091012210959400_euz122-B16","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ng.716","article-title":"Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction","volume":"42","author":"Sotoodehnia","year":"2010","journal-title":"Nat Genet"},{"key":"2019091012210959400_euz122-B17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jacc.2014.04.032","article-title":"Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome","volume":"64","author":"Hu","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2019091012210959400_euz122-B18","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/cvr\/cvv042","article-title":"Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study","volume":"106","author":"Behr","year":"2015","journal-title":"Cardiovasc Res"},{"key":"2019091012210959400_euz122-B19","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1172\/JCI73140","article-title":"A common genetic variant within SCN10A modulates cardiac SCN5A expression","volume":"124","author":"van den Boogaard","year":"2014","journal-title":"J Clin Invest"},{"key":"2019091012210959400_euz122-B20","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/hmg\/11.3.337","article-title":"Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome","volume":"11","author":"Vatta","year":"2002","journal-title":"Hum Mol Genet"}],"container-title":["EP Europace"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/europace\/advance-article-pdf\/doi\/10.1093\/europace\/euz122\/28670733\/euz122.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/europace\/article-pdf\/21\/9\/1410\/29581893\/euz122.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T20:40:48Z","timestamp":1569271248000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/21\/9\/1410\/5491508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,18]]},"references-count":20,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,5,18]]},"published-print":{"date-parts":[[2019,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euz122","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,9]]},"published":{"date-parts":[[2019,5,18]]}}}