Pietro Enea Lazzerini1, Yuankun Yue2, Ujala Srivastava2, Frank Fabris2, Pier Leopoldo Capecchi2, Iacopo Bertolozzi2, Maria Romana Bacarelli2, Gabriella Morozzi2, Maurizio Acampa2, Mariarita Natale2, Nabil El-Sherif2, Mauro Galeazzi2, Franco Laghi-Pasini2, Mohamed Boutjdir2. 1. From the Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy (P.E.L., P.L.C., M.R.B., G.M, M.A., M.N., M.G., F.L.-P.); VA New York Harbor Healthcare System and Department of Medicine, Cell Biology and Pharmacology, SUNY Downstate Medical Center, NY (Y.Y., U.S, F.F., N.E.-S., M.B.); Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara, Carrara, Italy (I.B.); Stroke Unit, University Hospital of Siena, Siena, Italy (M.A.); and Department of Medicine, New York University School of Medicine, NY (M.B.). lazzerini7@unisi.it. 2. From the Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy (P.E.L., P.L.C., M.R.B., G.M, M.A., M.N., M.G., F.L.-P.); VA New York Harbor Healthcare System and Department of Medicine, Cell Biology and Pharmacology, SUNY Downstate Medical Center, NY (Y.Y., U.S, F.F., N.E.-S., M.B.); Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara, Carrara, Italy (I.B.); Stroke Unit, University Hospital of Siena, Siena, Italy (M.A.); and Department of Medicine, New York University School of Medicine, NY (M.B.).
Abstract
BACKGROUND: In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. METHODS AND RESULTS: Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. CONCLUSIONS: Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk.
BACKGROUND: In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. METHODS AND RESULTS: Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. CONCLUSIONS: Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk.
Authors: John Szendrey; Shawn M Lamothe; Stephanie Vanner; Jun Guo; Tonghua Yang; Wentao Li; Jordan Davis; Mala Joneja; Adrian Baranchuk; Shetuan Zhang Journal: Cardiovasc Res Date: 2019-08-01 Impact factor: 10.787
Authors: Laura Geraldino-Pardilla; Yevgeniya Gartshteyn; Paloma Piña; Marina Cerrone; Jon T Giles; Afshin Zartoshti; Joan M Bathon; Anca D Askanase Journal: Lupus Sci Med Date: 2016-12-16