Key result
Anti-Ro antibodies inhibit IKr and prolong QTc in animal models by directly binding HERG channels.
Why the study?
Clinical evidence shows high prevalence of QTc prolongation and complex ventricular arrhythmias in anti-Ro Ab-positive autoimmune diseases, leading investigators to test whether anti-Ro Abs directly target the HERG channel.
Do anti-Ro antibodies cause QTc prolongation by inhibiting the HERG K+ channel in experimental models?
Do anti-Ro antibodies cause QTc prolongation by inhibiting the HERG K+ channel in experimental models?
This study provides strong evidence that anti-Ro antibodies directly inhibit the HERG channel, establishing a pathogenic mechanism for autoimmune-associated Long-QT syndrome.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We discovered that antibodies called anti-SSA/Ro antibodies picked up in laboratory testing and found in adult patients with connective tissue diseases actually block a specific cardiac channel (called the hERG channel), preventing potassium ions from going out of the cell and resulting in abnormal ECG (Long QT). The concern is that patients with these 'bad' antibodies can be at risk for even worse heartbeat abnormalities if their electrolytes are abnormal or if they are taking medications such as some anti-histamine or anti-depressant drugs known to cause Long QT on their own.”
“QT prolongation has been attributed to either a congenital origin resulting from ion channel mutations or an acquired origin generally resulting from QT-prolonging drugs. Patients with QTc prolongation are prone to complex ventricular arrhythmias, including Torsade de Pointes, syncope, and sudden death. Here, we propose a novel form of acquired QT prolongation of autoimmune origin induced by anti-SSA/Ro antibodies.”
May prompt QTc monitoring in anti-Ro Ab-positive patients; hypothesis-generating for HERG blockade as modifiable target.
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.
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Yue et al. (2015) studied Autoimmune-associated Long-QT syndrome. Anti-Ro antibodies was evaluated on Inhibition of IKr and QTc prolongation. Anti-Ro antibodies from patients with autoimmune diseases inhibit IKr by directly binding to the HERG channel, causing QTc prolongation in an animal model.
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