Yuankun Yue1, Monica Castrichini1, Ujala Srivastava1, Frank Fabris1, Krupa Shah1, Zhiqiang Li1, Yongxia Qu1, Nabil El-Sherif1, Zhengfeng Zhou1, Craig January1, M Mahmood Hussain1, Xian-Cheng Jiang1, Eric A Sobie1, Marie Wahren-Herlenius1, Mohamed Chahine1, Pier-Leopoldo Capecchi1, Franco Laghi-Pasini1, Pietro-Enea Lazzerini1, Mohamed Boutjdir2. 1. From Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn (Y.Y., U.S., F.F., K.S., Z.L., Y.Q., N.E.-S., M.M.H., X.-C.J., M.B.); Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy (M.C., P.-L.C., F.L.-P., P.-E.L.); Departments of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn (U.S., F.F., Z.L., Y.Q., M.M.H., X.-C.J., M.B.); Knight Cardiovascular Institute, Oregon Health & Science University, Portland (Z.Z.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (C.J.); Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York (E.A.S.); Unit of Experimental Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden (M.W.-H.); Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Laval University, Quebec City, Canada (M.C.); and Department of Medicine, New York University School of Medicine, New York (M.B.). 2. From Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn (Y.Y., U.S., F.F., K.S., Z.L., Y.Q., N.E.-S., M.M.H., X.-C.J., M.B.); Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy (M.C., P.-L.C., F.L.-P., P.-E.L.); Departments of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn (U.S., F.F., Z.L., Y.Q., M.M.H., X.-C.J., M.B.); Knight Cardiovascular Institute, Oregon Health & Science University, Portland (Z.Z.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (C.J.); Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York (E.A.S.); Unit of Experimental Rheumatology, Department of Medicine, Karolinska Institute, Stockholm, Sweden (M.W.-H.); Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Laval University, Quebec City, Canada (M.C.); and Department of Medicine, New York University School of Medicine, New York (M.B.). mohamed.boutjdir@va.gov.
Abstract
BACKGROUND: 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, IKr, 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 IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit IKr 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 IKr and cross-reacted with guinea pig ERG channel. CONCLUSIONS: The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit IKr 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.
BACKGROUND: 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, IKr, 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 IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit IKr 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 IKr and cross-reacted with guinea pig ERG channel. CONCLUSIONS: The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit IKr 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.
Authors: John Szendrey; Shawn M Lamothe; Stephanie Vanner; Jun Guo; Tonghua Yang; Wentao Li; Jordan Davis; Mala Joneja; Adrian Baranchuk; Shetuan Zhang Journal: Cardiovasc Res Date: 2019-08-01 Impact factor: 10.787
Authors: Laura Geraldino-Pardilla; Yevgeniya Gartshteyn; Paloma Piña; Marina Cerrone; Jon T Giles; Afshin Zartoshti; Joan M Bathon; Anca D Askanase Journal: Lupus Sci Med Date: 2016-12-16