{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:13:14Z","timestamp":1773285194040,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2016,7,26]],"date-time":"2016-07-26T00:00:00Z","timestamp":1469491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Biomedical Laboratory Research & Development Service of the Veterans Affairs Office of Research and Development"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Channelopathies of autoimmune origin are novel and are associated with corrected QT (QTc) prolongation and complex ventricular arrhythmias.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We have recently demonstrated that anti\u2010SSA\/Ro antibodies from patients with autoimmune diseases and with QTc prolongation on the ECG target the human ether\u2010\u00e0\u2010go\u2010go\u2010related gene (HERG) K<jats:sup>+<\/jats:sup> channel by inhibiting the corresponding current, <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>, at the pore region.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Immunization of guinea\u2010pigs with a peptide (E\u2010pore peptide) corresponding to the extracellular loop region connecting the S5 and S6 segments of the HERG channel induces high titres of antibodies that inhibit <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>, lengthen the action potential and cause QTc prolongation on the surface ECG. In addition, anti\u2010SSA\/Ro\u2010positive sera from patients with connective tissue diseases showed high reactivity to the E\u2010pore peptide.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The translational impact is the development of a peptide\u2010based approach for the diagnosis and treatment of autoimmune\u2010associated long QT syndrome.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>We recently demonstrated that anti\u2010SSA\/52\u00a0kDa Ro antibodies (Abs) from patients with autoimmune diseases and corrected QT (QTc) prolongation directly target and inhibit the human ether\u2010\u00e0\u2010go\u2010go\u2010related gene (HERG) K<jats:sup>+<\/jats:sup> channel at the extracellular pore (E\u2010pore) region, where homology with SSA\/52\u00a0kDa Ro antigen was demonstrated. We tested the hypothesis that immunization of guinea\u2010pigs with a peptide corresponding to the E\u2010pore region (E\u2010pore peptide) will generate pathogenic inhibitory Abs and cause QTc prolongation. Guinea\u2010pigs were immunized with a 31\u2010amino\u2010acid peptide corresponding to the E\u2010pore region of HERG. On days 10\u201362 after immunization, ECGs were recorded and blood was sampled for the detection of E\u2010pore peptide Abs. Serum samples from patients with autoimmune diseases were evaluated for reactivity to E\u2010pore peptide by enzyme\u2010linked immunosorbent assay (ELISA), and histology was performed on hearts using Masson's Trichrome. Inhibition of the HERG channel was assessed by electrophysiology and by computational modelling of the human ventricular action potential. The ELISA results revealed the presence of high titres of E\u2010pore peptide Abs and significant QTc prolongation after immunization. High reactivity to E\u2010pore peptide was found using anti\u2010SSA\/Ro Ab\u2010positive sera from patients with QTc prolongation. Histological data showed no evidence of fibrosis in immunized hearts. Simulations of simultaneous inhibition of repolarizing currents by anti\u2010SSA\/Ro Ab\u2010positive sera showed the predominance of the HERG channel in controlling action potential duration and the QT interval. These results are the first to demonstrate that inhibitory Abs to the HERG E\u2010pore region induce QTc prolongation in immunized guinea\u2010pigs by targeting the HERG channel independently from fibrosis. The reactivity of anti\u2010SSA\/Ro Ab\u2010positive sera from patients with connective tissue diseases with the E\u2010pore peptide opens novel pharmacotherapeutic avenues in the diagnosis and management of autoimmune\u2010associated QTc prolongation.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272151","type":"journal-article","created":{"date-parts":[[2016,6,14]],"date-time":"2016-06-14T09:38:02Z","timestamp":1465897082000},"page":"6175-6187","source":"Crossref","is-referenced-by-count":22,"title":["Induction of autoimmune response to the extracellular loop of the HERG channel pore induces QTc prolongation in guinea\u2010pigs"],"prefix":"10.1113","volume":"594","author":[{"given":"Frank","family":"Fabris","sequence":"first","affiliation":[{"name":"Cardiovascular Research Program VA New York Harbor Healthcare System  Brooklyn NY USA"},{"name":"Department of Medicine State University of New York Downstate Medical Center  Brooklyn NY 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