New findings: What is the central question of this study? Do autoantibodies to the M2 muscarinic receptor (M2R-AAbs) have the potential to facilitate specific sustained tachyarrhythmias in the presence of thyroxine (T4 ) in rabbits? What is the main finding and its importance? The M2R-AAb and T4 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 T4 in arrhythmia induction and might provide an innovative option for treatment of Graves' disease with rhythm disturbance.
Abstract: Activating autoantibodies toward the β1/2 -adrenergic receptors (β1/2AR-AAbs) and M2 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 (T4 ) increased the induction of sustained tachyarrhythmias in an autoimmune rabbit model. However, the separate role of M2R-AAbs and their interaction with T4 are not clear. The aim of this study was to investigate the impact of M2R-AAbs and T4 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 T4 treatment. In group B (n = 4), the rabbits were treated only with T4 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+T4 treatment) in group A and at 0 (baseline) and 8 weeks (T4 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, T4 predominantly induced sustained sinus tachycardia. This study demonstrated that M2R-AAbs and T4 jointly increased the susceptibility to both sinus and atrial tachyarrhythmias. The data supported the pathophysiological role of M2R-AAbs in hyperthyroidism-associated supraventricular tachyarrhythmias.
Keywords: M2 muscarinic receptor; activating autoantibodies; atrial fibrillation; sinus tachycardia; thyroid hormone.
© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.