A novel acquired autoimmune-associated LQTS has been recently reported in adult patients carrying anti-Ro antibodies (anti-Ro Abs), 7-10 which result from an autoimmune response against the intracellular ribonucleoprotein, SSA/Ro antigen (Ro). The detection of circulating anti-Ro Abs is relatively 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 crossreacted 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. (QTc prolongation) 7-10 but not with conduction abnormalities (complete atrioventricular block), which is well described in children born to mothers with anti-Ro Abs.13,14 Accordingly, it is assumed that the adult heart does not represent an immunological target for anti-Ro Abs. However, emerging clinical observations suggest that anti-Ro Abs may be arrhythmogenic for the adult heart by causing QT interval prolongation.7-10 Specifically, in a cohort of CTD patients, more than half (58%) of patients with anti-Ro Abs displayed a prolonged QTc, with a mean QTc duration significantly longer in anti-Ro Ab-positive versus anti-Ro Ab-negative patients. 7 In a subsequent study, patients with CTD and anti-Ro Ab showed 5-fold higher incidence of complex ventricular arrhythmias compared with anti-Ro Ab-negative patients.9 Despite this high incidence of QTc prolongation and ventricular arrhythmias in patients with CTD, the pathogenesis of this autoimmuneassociated QTc prolongation in the adult remains poorly understood.
Methods
Study PopulationSe...