Advertisement

Pathogenesis of Autoimmune-Associated Long QT Syndrome

  • Mohamed Boutjdir
  • Pietro Enea Lazzerini
  • Pier Leopoldo Capecchi
  • Franco Laghi-Pasini
  • Nabil El-Sherif
Chapter

Abstract

The impact of autoimmunity on the heart electrical activity is being more and more recognized, as clinical and experimental evidences demonstrate the association between the presence of pathogenic autoantibodies and cardiac repolarization. Long QT syndrome (LQTS) which manifests as prolongation of the repolarization measured as QT interval on the surface electrocardiogram, increases risk for ventricular arrhythmia particularly torsades de pointes. Here, we discuss current knowledge in the functional and molecular basis of autoantibody (anti-Ro/SSA antibodies)-induced QTc prolongation in patients with autoimmune diseases particularly connective tissue disease as well as in the general population subjects with torsades de pointes. Specifically, in vitro and in vivo experimental evidence is provided demonstrating that the human Ether-à-go-go-Related Gene, hERG, potassium channel conducting the rapidly activating delayed potassium current, IKr, is a target for anti-Ro/SSA antibodies, leading to action potential duration prolongation and QT interval lengthening on the surface electrocardiogram, thus predisposition to torsades de pointes. The predicted anti-Ro/SSA antibody binding sites have been identified on the hERG extracellular loop between S5/S6, thereby opening new avenues in the development of decoy peptide-based therapeutic approaches.

Keywords

Autoimmune disease Anti-Ro/SSA antibodies Long QT syndrome Potassium channels Cardiac arrhythmia 

Notes

Acknowledgement

Supported in part by Cardiovascular Research program, a MERIT Award Number I01BX007080 from Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development (MB), and the Narrows Institute for Biomedical Research and Education (NES).

References

  1. 1.
    El-Sherif N, Turitto G, Boutjdir M. Congenital long QT syndrome and torsade de pointes. Ann Noninvasive Electrocardiol. 2017;22(6):e12481.CrossRefGoogle Scholar
  2. 2.
    El-Sherif N, Turitto G, Boutjdir M. Acquired long QT syndrome and torsade de pointes. Pacing Clin Electrophysiol. 2018;41:414.CrossRefGoogle Scholar
  3. 3.
    El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol. 2003;18(1):6–13.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am Heart J. 1975;89(3):378–90.CrossRefGoogle Scholar
  5. 5.
    Roden DM. Cellular basis of drug-induced torsades de pointes. Br J Pharmacol. 2008;154(7):1502–7.CrossRefGoogle Scholar
  6. 6.
    Farkas AS, Nattel S. Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice. Drugs. 2010;70(5):573–603.CrossRefGoogle Scholar
  7. 7.
    Lerner MR, Boyle JA, Hardin JA, Steitz JA. Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus. Science. 1981;211(4480):400–2.CrossRefGoogle Scholar
  8. 8.
    Yoshimi R, Ueda A, Ozato K, Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system. Clin Dev Immunol. 2012;2012:606195.CrossRefGoogle Scholar
  9. 9.
    Sim S, Wolin SL. Emerging roles for the Ro 60-kDa autoantigen in noncoding RNA metabolism. Wiley Interdiscip Rev RNA. 2011;2(5):686–99.CrossRefGoogle Scholar
  10. 10.
    Kong HJ, Anderson DE, Lee CH, Jang MK, Tamura T, Tailor P, et al. Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol. 2007;179(1):26–30.CrossRefGoogle Scholar
  11. 11.
    Higgs R, Lazzari E, Wynne C, Ni Gabhann J, Espinosa A, Wahren-Herlenius M, et al. Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One. 2010;5(7):e11776.CrossRefGoogle Scholar
  12. 12.
    Higgs R, Ni Gabhann J, Ben Larbi N, Breen EP, Fitzgerald KA, Jefferies CA. The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol. 2008;181(3):1780–6.CrossRefGoogle Scholar
  13. 13.
    Lee AYS. A review of the role and clinical utility of anti-Ro52/TRIM21 in systemic autoimmunity. Rheumatol Int. 2017;37(8):1323–33.CrossRefGoogle Scholar
  14. 14.
    Lee HC, Huang KT, Wang XL, Shen WK. Autoantibodies and cardiac arrhythmias. Heart Rhythm. 2011;8(11):1788–95.CrossRefGoogle Scholar
  15. 15.
    Lazzerini PE, Capecchi PL, Laghi-Pasini F, Boutjdir M. Autoimmune channelopathies as a novel mechanism in cardiac arrhythmias. Nat Rev Cardiol. 2017;14(9):521–35.CrossRefGoogle Scholar
  16. 16.
    Bornholz B, Roggenbuck D, Jahns R, Boege F. Diagnostic and therapeutic aspects of beta1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev. 2014;13(9):954–62.CrossRefGoogle Scholar
  17. 17.
    Patel PA, Hernandez AF. Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy. Eur J Heart Fail. 2013;15(7):724–9.CrossRefGoogle Scholar
  18. 18.
    Matsui S, Fu M. Pathological importance of anti-G-protein coupled receptor autoantibodies. Int J Cardiol. 2006;112(1):27–9.CrossRefGoogle Scholar
  19. 19.
    Li J, Seyler C, Wiedmann F, Schmidt C, Schweizer PA, Becker R, et al. Anti-KCNQ1 K(+) channel autoantibodies increase IKs current and are associated with QT interval shortening in dilated cardiomyopathy. Cardiovasc Res. 2013;98(3):496–503.CrossRefGoogle Scholar
  20. 20.
    Lazzerini PE, Acampa M, Guideri F, Capecchi PL, Campanella V, Morozzi G, et al. Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases. Arthritis Rheum. 2004;50(4):1248–52.CrossRefGoogle Scholar
  21. 21.
    Lazzerini PE, Capecchi PL, Acampa M, Morozzi G, Bellisai F, Bacarelli MR, et al. Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity. Arthritis Care Res (Hoboken). 2011;63(10):1463–70.CrossRefGoogle Scholar
  22. 22.
    Lazzerini PE, Capecchi PL, Guideri F, Bellisai F, Selvi E, Acampa M, et al. Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol. 2007;100(6):1029–34.CrossRefGoogle Scholar
  23. 23.
    Lazzerini PE, Yue Y, Srivastava U, Fabris F, Capecchi PL, Bertolozzi I, et al. Arrhythmogenicity of anti-Ro/SSA antibodies in patients with torsades de pointes. Circ Arrhythm Electrophysiol. 2016;9(4):e003419.CrossRefGoogle Scholar
  24. 24.
    Cimaz R, Stramba-Badiale M, Brucato A, Catelli L, Panzeri P, Meroni PL. QT interval prolongation in asymptomatic anti-SSA/Ro-positive infants without congenital heart block. Arthritis Rheum. 2000;43(5):1049–53.CrossRefGoogle Scholar
  25. 25.
    Bourré-Tessier J, Clarke AE, Huynh T, Bernatsky S, Joseph L, Belisle P, et al. Prolonged corrected QT interval in anti-Ro/SSA-positive adults with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2011;63(7):1031–7.CrossRefGoogle Scholar
  26. 26.
    Hayashi N, Koshiba M, Nishimura K, Sugiyama D, Nakamura T, Morinobu S, et al. Prevalence of disease-specific antinuclear antibodies in general population: estimates from annual physical examinations of residents of a small town over a 5-year period. Mod Rheumatol. 2008;18(2):153–60.CrossRefGoogle Scholar
  27. 27.
    Satoh M, Chan EK, Ho LA, Rose KM, Parks CG, Cohn RD, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012;64(7):2319–27.CrossRefGoogle Scholar
  28. 28.
    Guo YP, Wang CG, Liu X, Huang YQ, Guo DL, Jing XZ, et al. The prevalence of antinuclear antibodies in the general population of China: a cross-sectional study. Curr Ther Res Clin Exp. 2014;76:116–9.CrossRefGoogle Scholar
  29. 29.
    Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Selvi E, Bisogno S, et al. Autoantibody-mediated cardiac arrhythmias: mechanisms and clinical implications. Basic Res Cardiol. 2008;103(1):1–11.CrossRefGoogle Scholar
  30. 30.
    Boutjdir M, Lazzerini PE, Capecchi PL, Laghi-Pasini F, El-Sherif N. Potassium channel block and novel autoimmune-associated long QT syndrome. Card Electrophysiol Clin. 2016;8(2):373–84.CrossRefGoogle Scholar
  31. 31.
    Yue Y, Castrichini M, Srivastava U, Fabris F, Shah K, Li Z, et al. Pathogenesis of the novel autoimmune-associated long-QT syndrome. Circulation. 2015;132(4):230–40.CrossRefGoogle Scholar
  32. 32.
    Nakamura K, Katayama Y, Kusano KF, Haraoka K, Tani Y, Nagase S, et al. Anti-KCNH2 antibody-induced long QT syndrome: novel acquired form of long QT syndrome. J Am Coll Cardiol. 2007;50(18):1808–9.CrossRefGoogle Scholar
  33. 33.
    Suzuki S, Satoh T, Yasuoka H, Hamaguchi Y, Tanaka K, Kawakami Y, et al. Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis. J Neuroimmunol. 2005;170(1–2):141–9.CrossRefGoogle Scholar
  34. 34.
    Suzuki S, Baba A, Kaida K, Utsugisawa K, Kita Y, Tsugawa J, et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur J Neurol. 2014;21(2):223–30.CrossRefGoogle Scholar
  35. 35.
    Romi F, Suzuki S, Suzuki N, Petzold A, Plant GT, Gilhus NE. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J Neurol. 2012;259(7):1312–6.CrossRefGoogle Scholar
  36. 36.
    Fabris F, Yue Y, Qu Y, Chahine M, Sobie E, Lee P, et al. Induction of autoimmune response to the extracellular loop of the HERG channel pore induces QTc prolongation in guinea pigs. J Physiol. 2016;594(21):6175–87.CrossRefGoogle Scholar
  37. 37.
    Karnabi E, Boutjdir M. Role of calcium channels in congenital heart block. Scand J Immunol. 2010;72(3):226–34.CrossRefGoogle Scholar
  38. 38.
    Strandberg LS, Cui X, Rath A, Liu J, Silverman ED, Liu X, et al. Congenital heart block maternal sera autoantibodies target an extracellular epitope on the alpha1G T-type calcium channel in human fetal hearts. PLoS One. 2013;8(9):e72668.CrossRefGoogle Scholar
  39. 39.
    Ambrosi A, Sonesson SE, Wahren-Herlenius M. Molecular mechanisms of congenital heart block. Exp Cell Res. 2014;325(1):2–9.CrossRefGoogle Scholar
  40. 40.
    Qu Y, Baroudi G, Yue Y, Boutjdir M. Novel molecular mechanism involving alpha1D (Cav1.3) L-type calcium channel in autoimmune-associated sinus bradycardia. Circulation. 2005;111(23):3034–41.CrossRefGoogle Scholar
  41. 41.
    Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52(2):402–11.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Mohamed Boutjdir
    • 1
    • 2
    • 3
  • Pietro Enea Lazzerini
    • 4
  • Pier Leopoldo Capecchi
    • 4
  • Franco Laghi-Pasini
    • 4
  • Nabil El-Sherif
    • 5
  1. 1.Department of Medicine and Physiology, SUNY Downstate Medical CenterBrooklynUSA
  2. 2.State University of New York Downstate Medical CenterNew YorkUSA
  3. 3.NYU School of MedicineNew YorkUSA
  4. 4.Department of Medical Sciences, Surgery and NeurosciencesUniversity of SienaSienaItaly
  5. 5.Department of Medicine and PhysiologyState University of New York Downstate Medical Center, VA New York Harbor Healthcare CenterBrooklynUSA

Personalised recommendations