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

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.