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CLINICAL RESEARCH: HEART RHYTHM DISORDER

Activating Autoantibodies to the Beta-1 Adrenergic and M2 Muscarinic Receptors Facilitate Atrial Fibrillation in Patients With Graves' Hyperthyroidism

Stavros Stavrakis, MD^_*,, Xichun Yu, MD^_*,,, Eugene Patterson, PhD^,, Shijun Huang, MD^_*,,, Sean R. Hamlett, MD^_*,, Laura Chalmers, MD^_*,, Reji Pappy, MD^_*, Madeleine W. Cunningham, PhD^||, Syed A. Morshed, PhD^¶, Terry F. Davies, MD^¶, Ralph Lazzara, MD^_*, and David C. Kem, MD^_*,,,_*

^_* Department of Medicine, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma
Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
^|| Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
^¶ Thyroid Research Unit, Mount Sinai School of Medicine, James J. Peters Veterans Affairs Medical Center, New York, New York

Manuscript received May 18, 2009; revised manuscript received June 29, 2009, accepted July 13, 2009.

^_* Reprint requests and correspondence: Dr. David C. Kem, Heart Rhythm Institute, TCH6E103, 1200 Everett Drive, Oklahoma City, Oklahoma 73104 (Email: david-kem{at}ouhsc.edu).

This paper was presented in part at the Annual Meeting of the American College of Cardiology, March 2008, Chicago, Illinois; and at the Annual Meeting of the Endocrine Society, June 2008, San Francisco, California.

Objectives: We studied activating autoantibodies to beta-1 adrenergic receptors (AAβ1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism.

Background: Atrial fibrillation frequently complicates hyperthyroidism. Both AAβ1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized that their copresence would facilitate AF in autoimmune Graves' hyperthyroidism.

Methods: Immunoglobulin G purified from 38 patients with Graves' hyperthyroidism with AF (n = 17) or sinus rhythm (n = 21) and 10 healthy control subjects was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. Immunoglobulin G electrophysiologic effects were studied using intracellular recordings from isolated canine pulmonary veins. Potential cross-reactivity of AAβ1AR and AAM2R with stimulating thyrotropin receptor (TSHR) antibodies was evaluated before and after adsorption to Chinese hamster ovary cells expressing human TSHRs using flow cytometry and enzyme-linked immunosorbent assays.

Results: The frequency of AAβ1AR and/or AAM2R differed significantly between patients with AF and sinus rhythm (AAβ1AR = 94% vs. 38%, p < 0.001; AAM2R = 88% vs. 19%, p < 0.001; and AAβ1AR+AAM2R = 82% vs. 10%, p < 0.001). The copresence of AAβ1AR and AAM2R was the strongest predictor of AF (odds ratio: 33.61, 95% confidence interval: 1.17 to 964.11, p = 0.04). Immunoglobulin G from autoantibody-positive patients induced hyperpolarization, decreased action potential duration, enhanced early afterdepolarization formation, and facilitated triggered firing in pulmonary veins by local autonomic nerve stimulation. Immunoadsorption studies showed that AAβ1AR and AAM2R were immunologically distinct from TSHR antibodies.

Conclusions: When present in patients with Graves' hyperthyroidism, AAβ1AR and AAM2R facilitate development of AF.

Key Words: activating autoantibodies • β-adrenergic receptors • M2 muscarinic receptor • atrial fibrillation • Graves' hyperthyroidism

Abbreviations and Acronyms   AAβ1AR = activating autoantibodies to beta-1 adrenergic receptor   AAM2R = activating autoantibodies to M2 muscarinic receptor   AF = atrial fibrillation   CHO-TSHR = Chinese hamster ovary cells expressing full-length thyrotropin receptor   CI = confidence interval   DT = deceleration time of mitral E flow velocity   E = early diastolic velocity of mitral inflow   E/E' = ratio between the early diastolic velocity of mitral inflow and that of mitral annulus   ELISA = enzyme-linked immunosorbent assay   Ig = immunoglobulin   M2R = M2 muscarinic receptor   TSHR = thyrotropin receptor

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