Pathogenesis of the Novel Autoimmune-Associated Long-QT Syndrome. Issue 4 (28th July 2015)

• Record Type: Journal Article
• Authors: Yue, Yuankun; Castrichini, Monica; Srivastava, Ujala; Fabris, Frank; Shah, Krupa; Li, Zhiqiang; Qu, Yongxia; El-Sherif, Nabil; Zhou, Zhengfeng; January, Craig; Hussain, M. Mahmood; Jiang, Xian-Cheng; Sobie, Eric A.; Wahren-Herlenius, Marie; Chahine, Mohamed; Capecchi, Pier-Leopoldo; Laghi-Pasini, Franco; Lazzerini, Pietro-Enea; Boutjdir, Mohamed
• Is Part Of: Circulation. Volume 132:Issue 4(2015)
• Publication Date: 2015-07-28
• Subjects: Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.115.009800
• Languages: English
• ISSNs: 0009-7322

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>Emerging clinical evidence demonstrates high prevalence of QTc prolongation and complex ventricular arrhythmias in patients with anti-Ro antibody (anti-Ro Ab)–positive autoimmune diseases. We tested the hypothesis that anti-Ro Abs target the HERG (human ether-a-go-go–related gene) K<sup>+</sup> channel, which conducts the rapidly activating delayed K<sup>+</sup> current, <italic>I</italic><sub>Kr</sub>, thereby causing delayed repolarization seen as QT interval prolongation on the ECG.</p> </sec> <sec> <title>Methods and Results—</title> <p>Anti-Ro Ab–positive sera, purified IgG, and affinity-purified anti-52kDa Ro Abs from patients with autoimmune diseases and QTc prolongation were tested on <italic>I</italic><sub>Kr</sub> using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit <italic>I</italic><sub>Kr</sub> to prolong action potential duration by directly binding to the HERG channel protein. The 52-kDa Ro antigen–immunized guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro Abs, which inhibited native <italic>I</italic><sub>Kr</sub> and cross-reacted with guinea pig ERG channel.</p> </sec> <sec> <title>Conclusions—</title> <p>The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit <italic>I</italic><sub>Kr</sub> by cross-reacting with the HERG channel likely at the pore region where homology between anti–52-kDa Ro antigen and HERG channel is present. The animal model of autoimmune-associated QTc prolongation is the first to provide strong evidence for a pathogenic role of anti-Ro Abs in the development of QTc prolongation. It is proposed that adult patients with anti-Ro Abs may benefit from routine ECG screening and that those with QTc prolongation should receive counseling about drugs that may increase the risk for life-threatening arrhythmias.</p> </sec> </abstract>