Advertisement

Endocrine

, Volume 49, Issue 2, pp 457–463 | Cite as

Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism

  • Allison Galloway
  • Hongliang Li
  • Megan Vanderlinde-Wood
  • Muneer Khan
  • Alexandria Benbrook
  • Campbell Liles
  • Caitlin Zillner
  • Veitla Rao
  • Madeleine W. Cunningham
  • Xichun Yu
  • David C. Kem
Original Article

Abstract

We have previously demonstrated that activating autoantibodies to β1-adrenergic receptor (β1AR) and M2 muscarinic receptor (M2R) facilitate atrial fibrillation (AF) in patients with Graves’ disease (GD). The objectives of this expanded study were to examine the prevalence of β1AR, β2AR, and M2R autoantibodies in hyperthyroidism subjects. Sera from 81 patients including 31 with GD and AF, 36 with GD and sinus rhythm, 9 with toxic multinodular goiter, 5 with subacute thyroiditis, and 10 control subjects were examined for these autoantibodies by ELISA. Sera from 20 ELISA-positive GD subjects, 10 with AF and 10 with sinus rhythm, were assayed for autoantibody bioactivity using cell-based bioassays. In patients with GD and AF, 45, 65, and 77 % were ELISA positive for β1AR, M2R, and β2AR autoantibodies, respectively. In patients with GD and sinus rhythm, 17, 39, and 75 % were ELISA positive for β1AR, M2R, and β2AR autoantibodies, respectively. β1AR and M2R autoantibodies were co-present in 39 % of patients with GD and AF compared to 14 % in GD with sinus rhythm (p = 0.026). Patients with toxic multinodular goiter or subacute thyroiditis had a low prevalence of autoantibodies. The mean β1AR and M2R autoantibody activity was elevated in both GD groups but higher in those with AF than those with sinus rhythm. β2AR autoantibody activity was also increased in both groups. In conclusion, β1AR, β2AR, and M2R autoantibodies were elevated in GD. β1AR and M2R autoantibodies appear to be related to concurrent AF, while β2AR autoantibodies were equally prevalent in those with a sinus tachycardia and those with AF.

Keywords

Activating autoantibodies β-Adrenergic receptors M2 muscarinic receptor Hyperthyroidism Atrial tachyarrhythmias 

Notes

Acknowledgments

This work was supported by funding from a VA Merit Review grant, NIH HL056267, an American Heart Association Postdoctoral Fellowship, and individual grant support from Will and Helen Webster.

Conflict of interest

The authors have no conflict of interest to disclose.

References

  1. 1.
    A.P. Weetman, Graves’ disease. N. Engl. J. Med. 343, 1236–1248 (2000)CrossRefPubMedGoogle Scholar
  2. 2.
    C. Selmer, J.B. Olesen, M.L. Hansen, J. Lindhardsen, A.M. Olsen, J.C. Madsen, J. Faber, P.R. Hansen, O.D. Pedersen, C. Torp-Pedersen, G.H. Gislason, The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study. BMJ 345, e7895 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    I. Klein, K. Ojamaa, Thyroid hormone and the cardiovascular system. N. Engl. J. Med. 344, 501–509 (2001)CrossRefPubMedGoogle Scholar
  4. 4.
    I. Klein, S. Danzi, Thyroid disease and the heart. Circulation 116, 1725–1735 (2007)CrossRefPubMedGoogle Scholar
  5. 5.
    C.T. Sawin, A. Geller, P.A. Wolf, A.J. Belanger, E. Baker, P. Bacharach, P.W. Wilson, E.J. Benjamin, R.B. D’Agostino, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N. Engl. J. Med. 331, 1249–1252 (1994)CrossRefPubMedGoogle Scholar
  6. 6.
    Y.C. Chen, S.A. Chen, Y.J. Chen, M.S. Chang, P. Chan, C.I. Lin, Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes. J. Am. Coll. Cardiol. 39, 366–372 (2002)CrossRefPubMedGoogle Scholar
  7. 7.
    S. Stavrakis, X. Yu, E. Patterson, S. Huang, S.R. Hamlett, L. Chalmers, R. Pappy, M.W. Cunningham, S.A. Morshed, T.F. Davies, R. Lazzara, D.C. Kem, Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves’ hyperthyroidism. J. Am. Coll. Cardiol. 54, 1309–1316 (2009)CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    J. Perez-Schindler, A. Philp, J. Hernandez-Cascales, Pathophysiological relevance of the cardiac beta2-adrenergic receptor and its potential as a therapeutic target to improve cardiac function. Eur. J. Pharmacol. 698, 39–47 (2013)CrossRefPubMedGoogle Scholar
  9. 9.
    P.A. Chiale, H.A. Garro, J. Schmidberg, R.A. Sanchez, R.S. Acunzo, M. Lago, G. Levy, M. Levin, Inappropriate sinus tachycardia may be related to an immunologic disorder involving cardiac beta andrenergic receptors. Heart Rhythm 3, 1182–1186 (2006)CrossRefPubMedGoogle Scholar
  10. 10.
    E.N. Pearce, A.P. Farwell, L.E. Braverman, Thyroiditis. N. Engl. J. Med. 348, 2646–2655 (2003)CrossRefPubMedGoogle Scholar
  11. 11.
    H. Li, D.C. Kem, S. Reim, M. Khan, M. Vanderlinde-Wood, C. Zillner, D. Collier, C. Liles, M.A. Hill, M.W. Cunningham, C.E. Aston, X. Yu, Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Hypertension 59, 402–408 (2012)CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    H. Li, X. Yu, C. Liles, M. Khan, M. Vanderlinde-Wood, A. Galloway, C. Zillner, A. Benbrook, S. Reim, D. Collier, M.A. Hill, S.R. Raj, L.E. Okamoto, M.W. Cunningham, C.E. Aston, D.C. Kem, Autoimmune basis for postural tachycardia syndrome. J. Am. Heart Assoc. 3, e000755 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    P.S. Chen, A.Y. Tan, Autonomic nerve activity and atrial fibrillation. Heart Rhythm 4, S61–S64 (2007)CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    B. Olshansky, Interrelationships between the autonomic nervous system and atrial fibrillation. Prog. Cardiovasc. Dis. 48, 57–78 (2005)CrossRefPubMedGoogle Scholar
  15. 15.
    S.S. Po, B.J. Scherlag, W.S. Yamanashi, J. Edwards, J. Zhou, R. Wu, N. Geng, R. Lazzara, W.M. Jackman, Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 3, 201–208 (2006)CrossRefPubMedGoogle Scholar
  16. 16.
    E. Patterson, S.S. Po, B.J. Scherlag, R. Lazzara, Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2, 624–631 (2005)CrossRefPubMedGoogle Scholar
  17. 17.
    H. Li, B.J. Scherlag, D.C. Kem, C. Zillner, S. Male, S. Thirunavukkarasu, X. Shen, J.V. Pitha, M.W. Cunningham, R. Lazzara, X. Yu, Atrial tachycardia provoked in the presence of activating autoantibodies to beta2-adrenergic receptor in the rabbit. Heart Rhythm 10, 436–441 (2013)CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    H. Li, B.J. Scherlag, D.C. Kem, A. Benbrook, X. Shen, M.W. Cunningham, R. Lazzara, C.E. Aston, X. Yu, Inducible cardiac arrhythmias caused by enhanced beta1-adrenergic autoantibody expression in the rabbit. Am. J. Physiol. Heart Circ. Physiol. 306, H422–H428 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    H. Li, B.J. Scherlag, D.C. Kem, C. Zillner, S. Male, S. Thirunavukkarasu, X. Shen, A. Benbrook, J.V. Pitha, R. Lazzara, X. Yu, The propensity for inducing atrial fibrillation: a comparative study on old versus young rabbits. J. Aging Res. 2014, 684918 (2014)CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    H. Li, B.J. Scherlag, D.C. Kem, A. Benbrook, L. Zhang, B. Huang, M.W. Cunningham, R. Lazzara, X. Yu, Atrial tachyarrhythmias induced by the combined effects of beta1/2-adrenergic autoantibodies and thyroid hormone in the rabbit. J. Cardiovasc. Trans. Res. 7, 581–589 (2014)CrossRefGoogle Scholar
  21. 21.
    M.D. Rodefeld, S.L. Beau, R.B. Schuessler, J.P. Boineau, J.E. Saffitz, Beta-adrenergic and muscarinic cholinergic receptor densities in the human sinoatrial node: identification of a high beta 2-adrenergic receptor density. J. Cardiovasc. Electrophysiol. 7, 1039–1049 (1996)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Allison Galloway
    • 1
  • Hongliang Li
    • 1
    • 2
  • Megan Vanderlinde-Wood
    • 1
  • Muneer Khan
    • 1
  • Alexandria Benbrook
    • 1
  • Campbell Liles
    • 1
  • Caitlin Zillner
    • 1
  • Veitla Rao
    • 1
  • Madeleine W. Cunningham
    • 3
  • Xichun Yu
    • 1
    • 2
  • David C. Kem
    • 1
    • 2
  1. 1.Endocrinology and the Harold Hamm Diabetes CenterUniversity of Oklahoma Health Sciences Center and Veterans Affairs Medical CenterOklahoma CityUSA
  2. 2.Heart Rhythm Institute and EndocrinologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Department of Microbiology and ImmunologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations