{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:05:49Z","timestamp":1792631149832,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pre-existing Ca<jats:sup>2+<\/jats:sup> handling abnormalities constitute the arrhythmogenic substrate in patients developing postoperative atrial fibrillation (POAF), a common complication after cardiac surgery. Postoperative interleukin (IL)-6 levels are associated with atrial fibrosis in several animal models of POAF, contributing to atrial arrhythmias. Here, we hypothesize that IL-6-mediated-Ca<jats:sup>2+<\/jats:sup> handling abnormalities contribute to atrial fibrillation (AF) in sterile pericarditis (SP) rats, an animal model of POAF. SP was induced in rats by dusting atria with sterile talcum powder. Anti-rat-IL-6 antibody (16.7 \u03bcg\/kg) was administered intraperitoneally at 30 min after the recovery of anesthesia. <jats:italic>In vivo<\/jats:italic> electrophysiology, <jats:italic>ex vivo<\/jats:italic> optical mapping, western blots, and immunohistochemistry were performed to elucidate mechanisms of AF susceptibility. IL-6 neutralization ameliorated atrial inflammation and fibrosis, as well as AF susceptibility <jats:italic>in vivo<\/jats:italic> and the frequency of atrial ectopy and AF with a reentrant pattern in SP rats <jats:italic>ex vivo<\/jats:italic>. IL-6 neutralization reversed the prolongation and regional heterogeneity of Ca<jats:sup>2+<\/jats:sup> transient duration, relieved alternans, reduced the incidence of discordant alternans, and prevented the reduction and regional heterogeneity of the recovery ratio of Ca<jats:sup>2+<\/jats:sup> transient. In agreement, western blots showed that IL-6 neutralization reversed the reduction in the expression of ryanodine receptor 2 (RyR2) and phosphorylated phospholamban. Acute IL-6 administration to isolated rat hearts recapitulated partial Ca<jats:sup>2+<\/jats:sup> handling phenotype in SP rats. In addition, intraperitoneal IL-6 administration to rats increased AF susceptibility, independent of fibrosis. Our results reveal that IL-6-mediated-Ca<jats:sup>2+<\/jats:sup> handling abnormalities in SP rats, especially RyR2-dysfunction, independent of IL-6-induced-fibrosis, early contribute to the development of POAF by increasing propensity for arrhythmogenic alternans.<\/jats:p>","DOI":"10.3389\/fimmu.2021.758157","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T05:25:21Z","timestamp":1639632321000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":72,"title":["Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats"],"prefix":"10.3389","volume":"12","author":[{"given":"Jie","family":"Liao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoshao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaitao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0166-5","article-title":"Postoperative Atrial Fibrillation: Mechanisms, Manifestations and Management","volume":"16","author":"Dobrev","year":"2019","journal-title":"Nat Rev Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e137528","DOI":"10.1172\/jci.insight.137528","article-title":"TRPV4 Blockade Suppresses Atrial Fibrillation in Sterile Pericarditis Rats","volume":"5","author":"Liao","year":"2020","journal-title":"JCI Insight"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110384","article-title":"Colchicine Prevents Atrial Fibrillation Promotion by Inhibiting IL-1\u03b2-Induced IL-6 Release and Atrial Fibrosis in the Rat Sterile Pericarditis Model","volume":"129","author":"Wu","year":"2020","journal-title":"BioMed Pharmacother"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e3396","DOI":"10.1161\/CIRCEP.115.003396","article-title":"Signal Transducer and Activator of Transcription 3\/MicroRNA-21 Feedback Loop Contributes to Atrial Fibrillation by Promoting Atrial Fibrosis in a Rat Sterile Pericarditis Model","volume":"9","author":"Huang","year":"2016","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3892\/ijmm.2015.2204","article-title":"Interleukin-17a Contributes to the Development of Post-Operative Atrial Fibrillation by Regulating Inflammation and Fibrosis in Rats With Sterile Pericarditis","volume":"36","author":"Fu","year":"2015","journal-title":"Int J Mol Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.trsl.2021.01.007","article-title":"Mechanism of IL-6-Related Spontaneous Atrial Fibrillation After Coronary Artery Grafting Surgery: IL-6 Knockout Mouse Study and Human Observation","volume":"233","author":"Liu","year":"2021","journal-title":"Transl Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000087441.48566.0d","article-title":"The -174g\/C Interleukin-6 Polymorphism Influences Postoperative Interleukin-6 Levels and Postoperative Atrial Fibrillation. 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