We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and
activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial
fibrillation (AF) in Graves' hyperthyroidism.
Atrial fibrillation frequently complicates hyperthyroidism. Both AAbeta1AR 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.
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 AAbeta1AR 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.
The frequency of AAbeta1AR and/or AAM2R differed significantly between patients with
AF and sinus rhythm (AAbeta1AR=94% vs. 38%, p<0.001; AAM2R=88% vs. 19%, p<0.001; and
AAbeta1AR+AAM2R=82% vs. 10%, p<0.001). The copresence of AAbeta1AR 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 AAbeta1AR and AAM2R were immunologically distinct
from TSHR antibodies.
When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate
development of AF.