Pathogenesis of the novel autoimmune-associated long-QT syndrome

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, 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.