MedicalResearch.com Interview with:
Mohamed Boutjdir, PhD, FAHA
Director of the Cardiovascular Research Program
VA New York Harbor Healthcare System
Professor, Depts of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Medical Center and
NYU School of Medicine, New York, NY
Medical Research: What is the background for this study? What are the main findings?
Dr. Boutjdir: Patients with autoimmune diseases including Sjogren’s syndrome, systemic lupus erythematosus and other connective tissue diseases who are seropositive for anti-SSA/Ro antibodies may present with corrected QTc prolongation on the surface ECG. This QTc prolongation can be arrhythmogenic and lead to Torsades de Pointes fatal arrhythmia.
In our study, we established for the first time an animal model for this autoimmune associated QTc prolongation that is reminiscent of the clinical long QT2 syndrome. We also demonstrated the functional and molecular mechanisms by which the presence of the anti-SSA/Ro antibodies causes QTc prolongation by a direct cross-reactivity and then block of the hERG channel (Human ether-a-go-go-related gene). This hERG channel is responsible for cardiac repolarization and its inhibition causes QTc prolongation. We were able to pinpoint to the target epitope at the extracellular pore forming loop between segment 5 and segment 6 of the hERG channel.
Medical Research: What should clinicians and patients take away from your report?
Dr. Boutjdir: 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. QTc prolongation associated with anti-SSA/Ro antibodies per se may confer an increased risk for developing ventricular arrhythmias and represents an additional risk factor for patients with drug-induced or congenital QTc prolongation.
The finding from the present study supports the recommendations that adult patients with anti-Ro antibodies may benefit from routine ECG screening for QTc prolongation and that those already identified with anti-Ro antibodies associated QTc prolongation should receive counseling, including education about avoiding drugs and other conditions known to prolong the QT interval.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Boutjdir: Large multicenter clinical trials with thousands of patients with autoimmune diseases are warranted to confirm or infirm whether the anti-SSA/Ro antibodies are associated with QTc prolongation and under which circumstances. Similarly, the molecular mechanisms underlying the absence of QTc prolongation in certain cohorts of patients despite the presence of anti-SSA/Ro antibodies need be elucidated.
Yue, M. Castrichini, U. Srivastava, F. Fabris, K. Shah, Z. Li, Y. Qu, N. El-Sherif, Z. Zhou, C. January, M. M. Hussain, X.-C. Jiang, E. A. Sobie, M. Wahren-Herlenius, M. Chahine, P.-L. Capecchi, F. Laghi-Pasini, P.-E. Lazzerini, M. Boutjdir. Pathogenesis of the Novel Autoimmune-Associated Long QT Syndrome. Circulation, 2015; DOI: 10.1161/CIRCULATIONAHA.115.009800
Mohamed Boutjdir, PhD, FAHADirector of the Cardiovascular Research Program (2015). Autoimmune Antibodies Can Lead To EKG Abnormalities and Ventricular Arrhythmias