Atrial tachycardia provoked in the presence of activating autoantibodies to β2-adrenergic receptor in the rabbit

Abstract

Background: A recent clinical study of patients with inappropriate sinus tachycardia reported that autoantibodies to β-adrenergic receptors (β2ARs) could act as agonists to induce atrial arrhythmias.

Objective: To test the hypothesis that activating autoantibodies to the β2AR in the rabbit atrium are arrhythmogenic.

Methods: Five New Zealand white rabbits were immunized with a β2AR second extracellular loop peptide to raise β2AR antibody titers. A catheter-based electrophysiologic study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after the infusion of acetylcholine in incremental concentrations of 10 μM, 100 μM, and 1 mM at 1 mL/min.

Results: In the preimmune studies when β2AR antibody titers were undetectable, of a total of 20 events, only 3 episodes of nonsustained (<10 seconds) atrial arrhythmias were induced. In the postimmune studies when β2AR antibody titers ranged from 1:160,000 to 1:1.28 million, burst pacing induced 10 episodes of nonsustained or sustained (≥10 seconds) arrhythmias in 20 events (P = .04 vs preimmune; χ(2) and Fisher exact test). Taking into account only the sustained arrhythmias, there were 6 episodes in 20 events in the postimmune studies compared with 0 episodes in 20 events in the preimmune studies (P = .02). Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of β2AR in transfected cells in vitro compared to the preimmune sera.

Conclusions: Enhanced autoantibody activation of β2AR in the rabbit atrium leads to atrial arrhythmias mainly in the form of sustained atrial tachycardia.

Figure 1

Examples are shown of the various cardiac arrhythmias that were seen as nonsustained and sustained forms in the present study. See section “Definition of arrhythmias in the rabbit heart” for further descriptions of panels A–F.

Figure 2

In vivo immunoglobulin G (IgG) deposition in the rabbit atria. Rabbits immunized with β2-adrenergic receptor peptide demonstrated IgG deposition in the atrial myocytes (right), while no atrial tissue-bound IgG was detected in the preimmune rabbits (left) (20× magnification).

Figure 3

Rabbit sera-induced cyclic adenosine monophosphate (cAMP) production in Chinese hamster ovary cells transfected with β2-adrenergic receptor (β2AR). Rabbit anti-β2AR sera significantly increased cAMP production (*β < .01 vs preimmune sera; n = 3), while β2 selective blocker ICI-118551 and preincubation with the second extracellular loop (ECL2) peptide for β2AR both effectively blocked the sera-induced β2AR activation (**P < .01, n = 3). RLU = relative luminescence unit.