M₂ muscarinic autoantibodies and thyroid hormone promote susceptibility to atrial fibrillation and sinus tachycardia in an autoimmune rabbit model

New Findings What is the central question of this study? Do autoantibodies to the M 2 muscarinic receptor (M2R‐AAbs) have the potential to facilitate specific sustained tachyarrhythmias in the presence of thyroxine (T 4 ) in rabbits? What is the main finding and its importance? The M2R‐AAb and T 4 jointly destabilized the electrophysiological properties, thus promoting the occurrence of atrial and sinus tachyarrhythmias in rabbits. These findings provide a practical basis for understanding the pathophysiological role of M2R‐AAb alone and with T 4 in arrhythmia induction and might provide an innovative option for treatment of Graves’ disease with rhythm disturbance. Abstract Activating autoantibodies toward the β 1/2 ‐adrenergic receptors (β1/2AR‐AAbs) and M 2 muscarinic receptor (M2R‐AAbs) are present in a high proportion of patients with Graves’ disease. We previously demonstrated that β1/2AR‐AAbs with or without the presence of M2R‐AAbs in combination with excessive thyroxine (T 4 ) increased the induction of sustained tachyarrhythmias in an autoimmune rabbit model. However, the separate role of M2R‐AAbs and their interaction with T 4 are not clear. The aim of this study was to investigate the impact of M2R‐AAbs and T 4 on the induction of cardiac arrhythmias in a similar rabbit model. Ten New Zealand White rabbits were randomly divided into two groups. In group A ( n = 6), the rabbits were immunized with the second extracellular loop peptide of M2R and subjected to 2 weeks of T 4 treatment. In group B ( n = 4), the rabbits were treated only with T 4 for 2 weeks. After induction of general anaesthesia, rabbits were subjected to an electrophysiological study at 0 (pre‐immune), 6 (post‐immune) and 8 weeks (post‐immune+T 4 treatment) in group A and at 0 (baseline) and 8 weeks (T 4 treatment) in group B. Each rabbit served as its own control. In group A, high levels and activity of M2R‐AAbs were detected in all immunized animals. Thyroxine in combination with immunization significantly increased induction of sustained sinus tachycardia and atrial fibrillation in comparison to the pre‐immune state. In group B, T 4 predominantly induced sustained sinus tachycardia. This study demonstrated that M2R‐AAbs and T 4 jointly increased the susceptibility to both sinus and atrial tachyarrhythmias. The data supported the pathophysiological role of M2R‐AAbs in hyperthyroidism‐associated supraventricular tachyarrhythmias.