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

Abstract

Objectives We studied activating autoantibodies to β1-adrenergic (AAβ1AR) and M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves’ hyperthyroidism. Background AF frequently complicates hyperthyroidism. AAβ1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized their co-presence would facilitate AF in autoimmune Graves’ hyperthyroidism. Methods IgG purified from 38 patients with Graves’ hyperthyroidism with AF (n=17) or sinus rhythm (n=21) and 10 healthy controls was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. IgG 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 CHO 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 co-presence of AAβ1AR and AAM2R was the strongest predictor of AF (odds ratio 33.61, 95% CI 1.17 - 964.11, p=0.04). IgG 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. Imunoadsorption studies demonstrated that AAβ1AR and AAM2R were immunologically distinct from TSHR antibodies. Conclusions AAβ1AR and AAM2R when present in patients with Graves’ hyperthyroidism facilitate development of AF.

Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

“…It will be important to elucidate in future studies the precise molecular mechanism how antibodies against these receptors induced a similar phenotypes. Nevertheless, anti-M 2 R antibodies have also been implicated in two additional human diseases, sinus node dysfunction [37] and atrial fibrillation [38,39]. It is thus possible that mechanisms similar to what we observe in our mouse model are operative in humans.…”

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

“…Antibodies for two specific cardiac GPCRs, the b 1 -AR and the M 2 mAChR, are a common feature. IgGs targeting and activating either or even both receptors simultaneously (Elies et al, 1996) have been isolated in patients with idiopathic cardiomyopathy (Wallukat and Wollenberger, 1987;Fu et al, 1993), peripartum cardiomyopathy (Warraich et al, 2005;Stavrakis et al, 2009;Stavrakis et al, 2011;Liu et al, 2014), and in Chagas-induced cardiomyopathy (Sterin-Borda et al, 1976;Borda et al, 1984;Elies et al, 1996;Wallukat et al, 2010;Muñnoz-Saravia et al, 2012).…”

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

“…2,3 Studies with transgenic mouse models have revealed that deregulation of the cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway can cause apoptosis. 4 Specifically, badrenergic receptor (bAR) activation by catecholamines or autoantibodies, as seen in Grave's disease, 5 can cause PKAmediated cardiomyocyte apoptosis, resulting in heart failure (HF). 6 Furthermore, administration of catecholamines, such as epinephrine, is often the last resort for treatment of patients suffering from septic shock, 7 and this is associated with profound alterations in immune function, similar to those observed in haemorrhagic shock where all lymphocyte subsets are decreased owing to excessive apoptosis.…”