title: Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes.
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.
  
  
  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.affiliation: 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.
authors.forename: Pietro Enea
authors.initials: PE
authors.lastname: Lazzerini
authors.affiliation: 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.).
authors.forename: Yuankun
authors.initials: Y
authors.lastname: Yue
authors.affiliation: 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.).
authors.forename: Ujala
authors.initials: U
authors.lastname: Srivastava
authors.affiliation: 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.).
authors.forename: Frank
authors.initials: F
authors.lastname: Fabris
authors.affiliation: 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.).
authors.forename: Pier Leopoldo
authors.initials: PL
authors.lastname: Capecchi
authors.affiliation: 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.).
authors.forename: Iacopo
authors.initials: I
authors.lastname: Bertolozzi
authors.affiliation: 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.).
authors.forename: Maria Romana
authors.initials: MR
authors.lastname: Bacarelli
authors.affiliation: 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.).
authors.forename: Gabriella
authors.initials: G
authors.lastname: Morozzi
authors.affiliation: 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.).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Acampa
authors.affiliation: 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.).
authors.forename: Mariarita
authors.initials: M
authors.lastname: Natale
authors.affiliation: 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.).
authors.forename: Nabil
authors.initials: N
authors.lastname: El-Sherif
authors.affiliation: 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.).
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.affiliation: 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.).
authors.forename: Franco
authors.initials: F
authors.lastname: Laghi-Pasini
authors.affiliation: 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.).
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity; D015153:Blotting, Western; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016171:Torsades de Pointes / Q000097:blood / Q000276:immunology* / Q000503:physiopathology
chemical_list: D000974:Antibodies, Antinuclear; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C035356:SS-A antibodies
keywords: arrhythmias, cardiac; autoimmunity; hERG1 potassium channel; immune system; torsade de pointes