Pathogenesis of the Novel Autoimmune-Associated Long-QT Syndrome
2015; Lippincott Williams & Wilkins; Volume: 132; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.115.009800
ISSN1524-4539
AutoresYuankun Yue, Monica Castrichini, Ujala Srivastava, Frank Fabris, Krupa Shah, Zhiqiang Li, Yongxia Qu, Nabil El‐Sherif, Zhengfeng Zhou, Craig T. January, M. Mahmood Hussain, Xian-Cheng Jiang, Eric A. Sobie, Marie Wahren‐Herlenius, Mohamed Chahine, Pier-Leopoldo Capecchi, Franco Laghi‐Pasini, Pietro‐Enea Lazzerini, Mohamed Boutjdir,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoBackground— 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 + channel, which conducts the rapidly activating delayed K + current, I Kr , thereby causing delayed repolarization seen as QT interval prolongation on the ECG. Methods and Results— 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 I Kr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit I Kr 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 I Kr and cross-reacted with guinea pig ERG channel. Conclusions— The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit I Kr 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.
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