{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:19:12Z","timestamp":1785449952112,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T00:00:00Z","timestamp":1634515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL147044"],"award-info":[{"award-number":["R01 HL147044"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.<\/jats:p>","DOI":"10.3390\/ijms222011249","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T22:52:47Z","timestamp":1634683967000},"page":"11249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart"],"prefix":"10.3390","volume":"22","author":[{"given":"Md. Kamrul Hasan","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0291-7683","authenticated-orcid":false,"given":"Laura","family":"Martinez-Mateu","sequence":"additional","affiliation":[{"name":"Signal Theory, Communications, Telematic Systems and Computation Department, Telecommunications Engineers School, King Juan Carlos University, 28942 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Do","sequence":"additional","affiliation":[{"name":"Masonic Medical Research Institute, Utica, NY 13501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"Aromolaran","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Saiz","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n e Innovaci\u00f3n en Bioingenier\u00eda, Universitat Polit\u00e8cnica de Val\u00e8ncia, 46022 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ademuyiwa S.","family":"Aromolaran","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Masonic Medical Research Institute, Utica, NY 13501, USA"},{"name":"Division of Cardiothoracic Surgery & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1161\/01.ATV.0000216787.85457.f3","article-title":"Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of weight loss","volume":"26","author":"Poirier","year":"2006","journal-title":"Arter. 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