Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism.
OBJECTIVE
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.


BACKGROUND
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.


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 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.


RESULTS
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.


CONCLUSIONS
When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate development of AF.
Department of Medicine, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104, USA.
Stavros
S
Stavrakis
Xichun
X
Yu
Eugene
E
Patterson
Shijun
S
Huang
Sean R
SR
Hamlett
Laura
L
Chalmers
Reji
R
Pappy
Madeleine W
MW
Cunningham
Syed A
SA
Morshed
Terry F
TF
Davies
Ralph
R
Lazzara
David C
DC
Kem
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000276:immunology*; D001285:Atropine / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis*; D016022:Case-Control Studies; D006224:Cricetinae; D004285:Dogs; D005260:Female; D006111:Graves Disease / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D043585:Receptor, Muscarinic M2 / Q000276:immunology*; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology*
D000889:Anti-Arrhythmia Agents; D001323:Autoantibodies; D007074:Immunoglobulin G; D043585:Receptor, Muscarinic M2; D018342:Receptors, Adrenergic, beta-1; D001285:Atropine