Basic Research in Cardiology

, Volume 103, Issue 1, pp 1–11 | Cite as

Autoantibody-mediated cardiac arrhythmias: mechanisms and clinical implications

  • Pietro Enea Lazzerini
  • Pier Leopoldo Capecchi
  • Francesca Guideri
  • Maurizio Acampa
  • Enrico Selvi
  • Stefania Bisogno
  • Mauro Galeazzi
  • Franco Laghi-Pasini


Cardiac arrhythmias, including conduction defects and tach- yarrhythmias, represent an important source of morbidity and mortality in industrialized countries. Among the different pathophysiological mechanisms involved in the arrhythmogenesis, an inappropriate activation of the immune system represents a field of recent increasing interest. In fact, a large amount of studies suggest that specific autoantibody may be significantly involved in the pathogenesis of cardiac arrhythmias not only in the course of systemic autoimmune disease, but also in a number of rhythm disorders currently classified as “idiopathic.” Although the strongest evidence concerns the relationship between anti-Ro/SSA antibodies and the development of congenital heart block in foetus and newborn, other specific autoantibodies demonstrated the aptitude to affect directly the myocardial tissue, thus producing interference in its bioelectric activity thereby leading to rhythm disorders, also life-threatening. The identification of an immunological autoantibody-mediated mechanism opens new perspectives in the treatment and prevention of cardiac arrhythmias in such patients, including the use of immunosuppressive agents and/or the removal of autoantibodies by immuno-adsorption technique.

Key words

arrhythmias conduction defects autoimmunity autoantibodies anti-Ro/SSA 


  1. 1.
    Antzelevitch C, Fish J (2001) Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 96:517–527PubMedCrossRefGoogle Scholar
  2. 2.
    Baba A, Yoshikawa T, Chino M, Murayama A, Mitani K, Nakagawa S, Fujii I, Shimada M, Koyama T, Akaishi M, Mitamura H, Ogawa S, Keio International Cardiology Study Group (2002) Autoantibodies: new upstream targets of paroxysmal atrial fibrillation in patients with congestive heart failure. J Cardiol 40:217–223PubMedGoogle Scholar
  3. 3.
    Baba A, Yoshikawa T, Fukuda Y, Sugiyama T, Shimada M, Akaishi M, Tsuchimoto K, Ogawa S, Fu M (2004) Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy. Eur Heart J 25:1108–1115PubMedCrossRefGoogle Scholar
  4. 4.
    Baba A, Yoshkawa T, Ogawa S (2002) Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy. J Am Coll Cardiol 40:1153–1159PubMedCrossRefGoogle Scholar
  5. 5.
    Benitah JP, Gomez AM, Fauconnier J, Kerfant BG, Perrier E, Vassort G, Richard S (2002) Voltage-gated Ca2+ currents in the human pathophysiologic heart: a review. Basic Res Cardiol 97(Suppl 1):I11–I18PubMedGoogle Scholar
  6. 6.
    Brette F, Leroy J, Le Guennec JY, Salle L (2006) Ca2+ currents in cardiac myocytes: old story, new insights. Prog Biophys Mol Biol 91:1–82PubMedCrossRefGoogle Scholar
  7. 7.
    Buyon JP, Clancy R, Di Donato F, Miranda-Carus ME, Askanase AD, Garcia J, Qu Y, Hu K, Yue Y, Chan EKL, Boutjdir M (2002) Cardiac 5-HT4 serotoninergic receptors, 52 kD SSA/Ro and autoimmune associated congenital heart block. J Autoimmun 19:79–86PubMedCrossRefGoogle Scholar
  8. 8.
    Chiale PA, Ferrari I, Mahler E, Vallazza MA, Elizari M, Rosenbaum M, Levin MJ (2001) Differential profile and biochemical effects of antiautonomic membrane receptor antibodies in ventricular arrhythmias and sinus node dysfunction. Circulation 103:1765–1771PubMedGoogle Scholar
  9. 9.
    Chiale PA, Garro HA, Schmidberg J, Sanchez RA, Acunzo RS, Lago M, Levy G, Levin M (2006) Inappropriate sinus tachicardia may be related to an immunologic disorder involving cardiac β adrenergic receptors. Heart Rhythm 3:1182–1186PubMedCrossRefGoogle Scholar
  10. 10.
    Chiale PA, Rosenbaum MB, Elizari MV, Hjalmarson A, Magnusson I, Wallukat G, Hoebeke J (1995) High prevalence of antibodies against beta1- and beta2-adrenoceptors in patients with primary electrical cardiac abnormalities. J Am Coll Cardiol 26:864–869PubMedCrossRefGoogle Scholar
  11. 11.
    Christ T, Wettwer E, Dobrev D, Adolph E, Knaut M, Wallukat G, Ravens U (2001) Autoantibodies against the beta1 adrenoceptor from patients with dilated cardiomyopathy prolong action potential duration and enhance contractility in isolated cardiomyocytes. J Mol Cell Cardiol 33:1515–1525PubMedCrossRefGoogle Scholar
  12. 12.
    Costedoat-Chalumeau N, Amoura Z, Hulot JS, Ghillani P, Lechat P, Funck-Brentano C, Piette JC (2005) Letter in response to “Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases” by Lazzerini et al. Arthritis Rheum 52:676–677; author reply 677–678PubMedCrossRefGoogle Scholar
  13. 13.
    Del Corsso C, Campos De Carvalho AC, Martino HF, Varanda WA (2004) Sera from patients with idiopathic dilated cardiomyopathy decrease l-type calcum currents in cardiomyocytes isolated from rabbits. Am J Physiol Heart Circ Physiol 287:H1928–H1936PubMedCrossRefGoogle Scholar
  14. 14.
    Eftekhari P, Roegel JC, Lezoualc’h F, Fischmeister R, Imbs JL, Hoebeke J (2001) Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotoninergic 5-HT4 receptor. Eur J Immunol 31:573–579PubMedCrossRefGoogle Scholar
  15. 15.
    Eftekhari P, Salle L, Lezoualc’h F, Mialet J, Gastineau M, Briand JP, Isenberg DA, Fournie GJ, Argibay J, Fischmeister R, Muller S, Hoebeke J (2000) Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 30:2782–2790PubMedCrossRefGoogle Scholar
  16. 16.
    Escobar AL, Fernandez-Gomez R, Peter JC, Mobini R, Hoebeke J, Mijares A (2006) IgGs and Mabs against the β2-adrenoceptor block A-V conduction in mouse hearts: a possible role in the pathogenesis of ventricular arrhythmias. J Cell Mol Cardiol 40:829–837CrossRefGoogle Scholar
  17. 17.
    Fairfax A, Doniach D (1976) Autoantibodies to cardiac conducting tissue and their characterization by immunofluorescence. Clin Exp Immunol 23:1–8PubMedGoogle Scholar
  18. 18.
    Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A (1997) Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96:1180–1187PubMedGoogle Scholar
  19. 19.
    Fukuda Y, Miyoshi S, Tanimoto K, Oota K, Fujikura K, Iwata M, Baba A, Hagiwad Chagas’ra Y, Yoshikawa T, Mitamura H, Ogawa S (2004) Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits. J Am Coll Cardiol 43:1090–1100PubMedCrossRefGoogle Scholar
  20. 20.
    Goin JC, Borda ES, Auger S, Storino R, Sterin-Borda L (1999) Cardiac M2 muscarinic cholinoceptor activation by human chagasic autoantibodies: association with bradycardia. Heart 82:273–278PubMedGoogle Scholar
  21. 21.
    Gordon PA, Khamashta MA, Rosenthal E, Simpson JM, Sharland G, Brucato A, Franceschini F, De Bosschere K, Meheus L, Meroni PL, Hughes GRV, Buyon J (2004) Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus. J Rheumatol 31:2480–2487PubMedGoogle Scholar
  22. 22.
    Gordon PA, Rosenthal E, Khamashta MA, Hughes GR (2001) Absence of conduction defects in the electrocardiograms [correction of echocardiograms] of mothers with children with congenital heart block. J Rheumatol 28:366–369PubMedGoogle Scholar
  23. 23.
    Hariman RJ, Zeiler RH, Gough WB, El-Sherif N (1985) Enhancement of triggered activity in ischemic Purkinje fibers by ouabain: a mechanism of increased susceptibility to digitalis toxicity in myocardial infarction. J Am Coll Cardiol 5:672–679PubMedCrossRefGoogle Scholar
  24. 24.
    Hu K, Qu Y, Boutjdir M (2004) Functional basis of sinus bradycardia in congenital heart block. Circ Res 94:e32–e38PubMedCrossRefGoogle Scholar
  25. 25.
    Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S (2001) Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiophatic dilated cardiomyopathy. J Am Coll Cardiol 37:418–424PubMedCrossRefGoogle Scholar
  26. 26.
    Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, Lohse MJ (2004) Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113:1419–1429PubMedCrossRefGoogle Scholar
  27. 27.
    Kamel R, Eftekhari P, Clancy R, Buyon JP, Hoebeke J (2005) Autoantibodies against the serotoninergic 5-HT4 receptor and congenital heart block: a reassessment. J Autoimmun 25:72–76PubMedCrossRefGoogle Scholar
  28. 28.
    Kaplan D, Ferrari I, Bergami P, Mahler E, Levitus G, Chiale P, Hoebeke J, Van Regenmortel MH, Levin MJ (1997) Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus. Proc Natl Acad Sci USA 16:10301–10306CrossRefGoogle Scholar
  29. 29.
    Lazzerini PE, Acampa M, Guideri F, Capecchi PL, Campanella V, Morozzi G, Galeazzi M, Marcolongo R, Laghi Pasini F (2004) Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases. Arthritis Rheum 50:1248–1252PubMedCrossRefGoogle Scholar
  30. 30.
    Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Galeazzi M, Laghi Pasini F (2006) Connective tissue diseases and cardiac rhythm disorders: an overview. Autoimmun Rev 5:306–313PubMedCrossRefGoogle Scholar
  31. 31.
    Lazzerini PE, Capecchi PL, Guideri F, Bellisai F, Selvi E, Acampa M, Costa A, Maggio R, Garcia-Gonzalez E, Bisogno S, Morozzi G, Galeazzi M, Laghi Pasini F (2007) Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol 100:1029–1034PubMedCrossRefGoogle Scholar
  32. 32.
    Lazzerini PE, Capecchi PL, Laghi Pasini F (2007) Arrhythmogenicity of anti-Ro/SSA antibodies: from the newborn to the adult? In: Tarkowicz IR (Ed) Progress in cardiac arrhythmias research. Nova Science Publishers, New York [in press]Google Scholar
  33. 33.
    Low PA (2002) Autonomic neuropathies. Curr Opin Neurol 15:605–609PubMedCrossRefGoogle Scholar
  34. 34.
    Magnusson Y, Hjalmarson A, Hoebeke J (1996) Beta1-adrenoceptor autoimmunity in cardiomyopathy. Int J Cardiol 54:137–141PubMedCrossRefGoogle Scholar
  35. 35.
    Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J (1994) Autoimmunity in idiophatic dilated cardiomyopathy: characterization of antibodies against the beta1-adrenoceptor with positive chronotropic effect. Circulation 89:2760–2767PubMedGoogle Scholar
  36. 36.
    Maisch B, Lotze U, Schneider J, Kochsiek K (1986) Antibodies to human sinus node in sick sinus syndrome. Pacing Clin Electrophysiol 9:1101–1109PubMedCrossRefGoogle Scholar
  37. 37.
    Maixent JM, Paganelli F, Scaglione J, Levy S (1998) Antibodies against myosin in sera of patients with idiopathic paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 9:612–617PubMedCrossRefGoogle Scholar
  38. 38.
    Mandal K, Jahangiri M, Mulhin M, Poloniecki J, Camm AJ, Xu Q (2004) Association of anti-heat shock protein 65 antibodies with development of postoperative atrial fibrillation. Circulation 110:2588–2590PubMedCrossRefGoogle Scholar
  39. 39.
    Medei E, Pedrosa RC, Benchimol Barbosa PR, Costa PC, Hernandez CC, Chaves EA, Linhares V, Masuda MO, Nascimento JH, Campos de Carvalho AC (2007) Human antibodies with muscarinic activity modulate ventricular repolarization: basis for electrical disturbance. Int J Cardiol 115:373–380PubMedCrossRefGoogle Scholar
  40. 40.
    Neumann DA, Rose NR, Ansari AA, Herskowitz A (1994) Induction of multiple heart autoantibodies in mice with coxsackie virus B3- and cardiac myosin-induced autoimmune myocarditis. J Immunol 152:343–350PubMedGoogle Scholar
  41. 41.
    Obbiassi M, Brucato A, Meroni PL, Vismara A, Lettino M, Poloni F, Finzi A, Fenini MG, Rossi L (1987) Antibodies to cardiac Purkinje cells: further characterization in autoimmune disease and atrioventricular heart block. Clin Immunol Immunopathol 42:141–150PubMedCrossRefGoogle Scholar
  42. 42.
    Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Matsumori A, Miato N, Honjo T (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483PubMedCrossRefGoogle Scholar
  43. 43.
    Oliveira SF, Pedrosa RC, Nascimento JH, Campos de Carvalho AC, Masuda MO (1997) Sera from chronic chagasic patients with complex cardiac arrhythmias depress electrogenesis and conduction in isolated rabbit hearts. Circulation 96:2031–2037PubMedGoogle Scholar
  44. 44.
    Pineau CA, Huynh T, Bernatsky S, St.Pierre Y, Joseph L, Clarke AE (2005) Prolongation of the corrected QT interval in anti-Ro/SSA positive adults with systemic lupus erithematosus. American College of Rheumatology, San Diego (USA); 12–17 November, program number 1213 [Abstract]Google Scholar
  45. 45.
    Qu Y, Baroudi G, Yue Y, Boutjdir M (2005) Novel molecular mechanism involving α1D (Cav 1.3) L-Type calcium channel in autoimmune-associated sinus bradycardia. Circulation 111:3034–3041PubMedCrossRefGoogle Scholar
  46. 46.
    Ristic AD, Maisch B (2000) Cardiac rhythm and conduction disturbances: what is the role of autoimmune mechanisms? Herz 3:181–188CrossRefGoogle Scholar
  47. 47.
    Rosenbaum MB, Chiale PA, Schejtman D, Levin M, Elizari MV (1994) Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas’ heart disease. J Cardiovasc Electrophysiol 5:367–375PubMedCrossRefGoogle Scholar
  48. 48.
    Shah M, Akar FG, Tomaselli GF (2005) Molecular basis of arrhythmias. Circulation 112:2517–2529PubMedCrossRefGoogle Scholar
  49. 49.
    Smulski C, Labovsky V, Levy G, Hontebeyrie M, Hoebeke J, Levin MJ (2006) Structural basis of the cross-reaction between an antibody to the Trypanosoma cruzi ribosomal P2β protein and the human β1 adrenergic receptor. FASEB J 20:1396–1406PubMedCrossRefGoogle Scholar
  50. 50.
    Tincani A, Biasini-Rebaioli C, Cattaneo R, Riboldi P (2005) Nonorgan specific autoantibodies and heart damage. Lupus 14:656–659PubMedCrossRefGoogle Scholar
  51. 51.
    Veres A, Fust G, Smiela M, McQueen M, Horvath A, Yi Q, Biro A, Pogue J, Romics L, Karadi I, Singh M, Gnarpe J, Prohaszka Z, Yusuf S, Heart Outcomes Prevention evaluation (HOPE) Study Investigators (2002) Relationship of anti-60 kDa heat shock protein and anti-cholesterol antibodies to cardiovascular events. Circulation 106:2775–2780PubMedCrossRefGoogle Scholar
  52. 52.
    Villecco AS, de Liberali E, Bianchi FB, Pisi E (1983) Antibodies to cardiac conducting tissue and abnormalities of cardiac conduction in rheumatoid arthritis. Clin Exp Immunol 53:536–540PubMedGoogle Scholar
  53. 53.
    Wallukat G, Nissen E, Morwinski R, Muller J (2000) Autoantibodies against the beta- and muscarinic receptors in cardiomyopathy. Herz 25:261–266PubMedCrossRefGoogle Scholar
  54. 54.
    Wang ZH, Liao YH, Fu M (2001) The frequency of occurrence of autoantibodie against beta1-adrenoceptors and its clinical relevance in patients with hepatitis virus myocarditis. Autoimmunity 34:241–245PubMedCrossRefGoogle Scholar
  55. 55.
    Xiao GQ, Hu K, Boutjdir M (2001) Direct inhibition of expressed cardiac L- and T-type calcium channels by IgG from mothers whose children have congenital heart block. Circulation 103:1599–1604PubMedGoogle Scholar
  56. 56.
    Zaho R, wang W, Wu B, Hoebeke J, Hjalmarson A, Fu ML (1996) Effects of anti-peptide antibodies against the second extracellular loop of human M2 muscarinic acetylcholine receptors on transmembrane potentials and currents in guinea pig ventricular myocytes. Mol Cell Biochem 163–164:185–193CrossRefGoogle Scholar
  57. 57.
    Zheng Z, Croft J, Giles W, Mensah G (2001) Sudden cardiac death in the United States, 1989 to 1998. Circulation. 104:2158–2163PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Pietro Enea Lazzerini
    • 1
  • Pier Leopoldo Capecchi
    • 1
  • Francesca Guideri
    • 1
  • Maurizio Acampa
    • 2
  • Enrico Selvi
    • 3
  • Stefania Bisogno
    • 3
  • Mauro Galeazzi
    • 3
  • Franco Laghi-Pasini
    • 1
  1. 1.Dept. of Clinical Medicine and Immunological Sciences, Division of Clinical ImmunologyUniversity of SienaSienaItaly
  2. 2.Division of Internal MedicineUniversity of SienaSienaItaly
  3. 3.Division of RheumatologyUniversity of SienaSienaItaly

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