{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T06:15:24Z","timestamp":1771049724947,"version":"3.50.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T00:00:00Z","timestamp":1653523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the promotion of Science","doi-asserted-by":"crossref","award":["17K09501"],"award-info":[{"award-number":["17K09501"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Brugada syndrome (BrS) can be diagnosed by a type 1 BrS tracing in a 12-lead electrocardiogram (ECG). However, there are daily variations in the ECGs of BrS patients, which presents a challenge when diagnosing BrS. Although many susceptibility genes have been identified, the <jats:italic>SCN5A<\/jats:italic> gene is reportedly the main causative gene of BrS. However, most patients do not have an evidence of genetic predisposition to develop BrS. In addition, the diagnosis and risk stratification for ventricular fibrillation (VF) in patients with BrS presents some problems. Meanwhile, circulating micro RNAs (miRNAs) have drawn increased attention as potential biomarkers of various diseases. We hypothesize that circulating miRNAs may be potential diagnostic biomarkers for BrS.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We enrolled 70 Japanese BrS patients and 34 controls for the screening cohort. A total of 2,555 miRNA sequences were detected using the 3D-Gene miRNAs labeling kit and 3D-Gene Human miRNAs Oligo Chip. We compared the expression of the miRNAs between the BrS patients and the controls. We validated whether the miRNA were significantly up- or downregulated in the screening cohort using RT-PCR. We also enrolled 72 Japanese BrS patients and 56 controls to replicate these miRNAs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Eight miRNAs (hsa-miR-223-3p, hsa-miR-22-3p, hsa-miR-221-3p, hsa-miR-4485-5p, hsa-miR-550a-5p, hsa-miR-423-3p, hsa-miR-23a-3p, and hsa-miR-30d-5p) were downregulated, and one miRNA (hsa-miR-873-3p) was upregulated by more than 3-fold in BrS patients. The multivariate logistic regression analysis determined that hsa-miR-423-3p, hsa-miR-223-3p, and hsa-miR-23a-3p were independently associated with BrS (P &lt; 0.0001). The AUC based on cross validation was 0.871 with a sensitivity and specificity of 83.5% and 81.1%, respectively.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The plasma miRNAs are potential noninvasive biomarkers of BrS, and the constructed logistic model was useful for discriminating BrS.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0261390","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T17:31:11Z","timestamp":1653586271000},"page":"e0261390","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Plasma MicroRNAs as noninvasive diagnostic biomarkers in patients with Brugada syndrome"],"prefix":"10.1371","volume":"17","author":[{"given":"Yoshihiro","family":"Ikeuchi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenori","family":"Ochi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikaaki","family":"Motoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehito","family":"Tokuyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yousaku","family":"Okubo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sho","family":"Okamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syunsuke","family":"Miyauchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shogo","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukimi","family":"Uotani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Onohara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidetoshi","family":"Tahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuaki","family":"Chayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuki","family":"Kihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5373-5164","authenticated-orcid":true,"given":"Yukiko","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"key":"pone.0261390.ref001","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/0735-1097(92)90253-J","article-title":"Right bundle branch block persistent ST segment elevation sudden cardiac death: a distinct clinical electrocardiographic syndrome","volume":"20","author":"P Brugada","year":"1992","journal-title":"J Am Coll Cardiol"},{"key":"pone.0261390.ref002","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.hrthm.2005.01.005","article-title":"Brugada syndrome. 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Biochem"},{"issue":"23","key":"pone.0261390.ref023","doi-asserted-by":"crossref","first-page":"469","DOI":"10.21037\/atm.2016.11.39","article-title":"RNAs that make a heart beat","volume":"4","author":"M Mitra","year":"2016","journal-title":"Ann Transl Med"},{"issue":"12","key":"pone.0261390.ref024","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.2169\/internalmedicine.44.1224","article-title":"The Brugada syndrome--an update","volume":"44","author":"W Shimizu","year":"2005","journal-title":"Intern Med"},{"issue":"2","key":"pone.0261390.ref025","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1046\/j.1540-8167.2001.00268.x","article-title":"The Brugada syndrome: ionic basis and arrhythmia mechanisms","volume":"12","author":"C Antzelevitch","year":"2001","journal-title":"J Cardiovasc Electrophysiol"},{"issue":"12","key":"pone.0261390.ref026","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/nrcardio.2017.103","article-title":"Unmasking the molecular 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in cultured cardiac myocytes","volume":"105","author":"PY Sato","year":"2009","journal-title":"Circ Res"},{"key":"pone.0261390.ref030","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1161\/CIRCEP.114.002342","article-title":"Epicardial ventricular tachycardia ablation in a patient with Brugada ECG pattern and mutation of PKP2 and DSP genes","volume":"8","author":"M Forkmann","year":"2015","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"pone.0261390.ref031","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1007\/s00415-017-8414-2","article-title":"Juvenile myoclonic epilepsy and Brugada type 1 ECG pattern associated with (a novel) plakophillin 2 mutation","volume":"264","author":"L Gigli","year":"2017","journal-title":"J Neurol"},{"issue":"30","key":"pone.0261390.ref032","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1093\/eurheartj\/ehaa383","article-title":"An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins","volume":"41","author":"D Chatterjee","year":"2020","journal-title":"European Heart Journal"},{"key":"pone.0261390.ref033","article-title":"Regulation of Connexins Expression Levels by MicroRNAs, an Update","author":"JF Calder\u00f3n","year":"2016","journal-title":"Front. 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