新型自身免疫相关性长 QT 综合征的发病机制。
Pathogenesis of the Novel Autoimmune-Associated Long-QT Syndrome.
机构信息
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.).
出版信息
Circulation. 2015 Jul 28;132(4):230-40. doi: 10.1161/CIRCULATIONAHA.115.009800. Epub 2015 May 20.
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.
背景
新兴的临床证据表明，抗 Ro 抗体（抗 Ro Ab）阳性自身免疫性疾病患者的 QTc 延长和复杂室性心律失常发生率较高。我们检验了这样一个假设，即抗 Ro Ab 靶定 HERG（人类 ether-a-go-go 相关基因）K(+)通道，该通道传导快速激活延迟 K(+)电流，即 IKr，从而导致心电图上 QTc 延长所见到的延迟复极。
方法和结果
使用表达 HERG 通道的 HEK293 细胞和天然心肌细胞，对来自自身免疫性疾病和 QTc 延长患者的抗 Ro Ab 阳性血清、纯化 IgG 和亲和纯化的抗 52kDa Ro Ab 进行了 IKr 检测。电生理和生化数据表明，抗 Ro Ab 通过直接结合 HERG 通道蛋白来抑制 IKr，从而延长动作电位时程。在产生高滴度抗 Ro Ab 后，52kDa Ro 抗原免疫豚鼠的心电图出现 QTc 延长，这表明天然 IKr 受到抑制，并且与豚鼠 ERG 通道发生交叉反应。
结论
这些数据表明，自身免疫性疾病患者的抗 Ro Ab 通过与 HERG 通道发生交叉反应抑制 IKr，可能发生在同源性存在于抗 52kDa Ro 抗原和 HERG 通道的孔区。自身免疫性相关 QTc 延长的动物模型首次为抗 Ro Ab 在 QTc 延长发展中的致病作用提供了强有力的证据。据推测，具有抗 Ro Ab 的成年患者可能受益于常规心电图筛查，而那些 QTc 延长的患者应该接受关于可能增加致命性心律失常风险的药物的咨询。
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