A peptidomimetic inhibitor suppresses the inducibility of β1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit

Abstract

Purpose Previous studies demonstrated that burst pacing and subthreshold infusion of acetylcholine in β1-adrenergic receptor (β1AR)-immunized rabbits induced sustained sinus tachycardia. The aim of this study was to examine the anti-arrhythmogenic effect of a newly designed retro-inverso (RI) peptidomimetic inhibitor that specifically targets the β1AR antibodies in the rabbit. Methods Six New Zealand white rabbits were immunized with a β1AR second extracellular loop peptide to produce sympathomimetic β1AR antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with the RI peptide inhibitor. Each rabbit served as its own control. Results No sustained arrhythmias were induced at preimmune baseline. At 6 weeks after immunization, there was a marked increase in induced sustained tachyarrhythmias, predominantly sinus tachycardia, which was largely suppressed by the RI peptide. The atrial effective refractory period was shortened significantly in immunized rabbits compared to their preimmune state. The RI peptide reversed and prolonged this shortening. β1AR antibody levels were negatively correlated with the atrial effective refractory period. Postimmune sera-induced β1AR activation in transfected cells in vitro was also blocked by the RI peptide. Conclusions β1AR-activating autoantibodies are associated with reduction of the atrial effective refractory period and facilitate arrhythmia induction in this model. The RI peptide reversal may have important therapeutic implications in subjects who harbor these autoantibodies.

Association of β1‐Adrenergic, M2‐Muscarinic Receptor Autoantibody with Occurrence and Development of Nonvalvular Atrial Fibrillation

“…Li et al demonstrated that expression of sympathomimetic β-AR-activating antibodies in rabbit model led to a significant reduction of atrial ERP. 23 Stavrakis et al have shown that seropositivity for anti-β1-R differed significantly between patients with AF and sinus rhythm in Graves' hyperthyroidism (94% vs 38%, P < 0.001). In a small study, anti-β1-R positivity was detected in 41.6% of patients with AF and 10% of patients in the healthy control group.…”

“…Li et al. demonstrated that expression of sympathomimetic β‐AR‐activating antibodies in rabbit model led to a significant reduction of atrial ERP . Stavrakis et al.…”

Elevated β1-Adrenergic Receptor Autoantibody Levels Increase Atrial Fibrillation Susceptibility by Promoting Atrial Fibrosis

“…Sixteen male New Zealand white rabbits (each weighing 3.0-3.5 kg at baseline) were obtained from the Experimental Animal Center of Xinjiang Medical University (Urumqi, China) and were randomly divided into two groups: a control group and an immune group. The generation of the animal model followed the protocols of previous studies (Li et al, 2014(Li et al, , 2015(Li et al, , 2016, and a flow chart of the experimental design is shown in Figure 1A. The immune group was initially FIGURE 1 | Schematic of the study process.…”

“…Rabbits in the control group received an equal amount of adjuvant without the β1AR ECL2 peptide at the same time points. Blood samples were collected from both groups every 2 weeks in an awake state before injection, and the serum β1ARAb levels were measures by ELISA and expressed as optical density values based on previous studies (Li et al, 2015). Transthoracic echocardiographic examination was performed at baseline and repeated at 8 weeks after the first immunization.…”

“…Evidence from experiments in a rabbit autoimmune model showed that animals developed high titers of β1ARAbs after immunization with the second extracellular loop (ECL2) peptide of β1AR, and elevated β1ARAbs reduced the atrial effective refractory period (AERP) and facilitated AF induction Abbreviations: AERP, atrial effective refractory period; AF, atrial fibrillation; β1AR, beta 1-adrenergic receptor; β1ARAb, beta 1-adrenergic receptor autoantibody; CV, conduction velocity; ECG, electrocardiogram; ECL2, second extracellular loop; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; Gal3, galectin-3; H&E, hematoxylin and eosin; LA, left atrial; LAD, left atrial diameter; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; MEA, multielectrode array; PAF, paroxysmal atrial fibrillation; PIIINP, procollagen type III N-terminal peptide; PICP, procollagen type I C-terminal peptide; RAD, right atrial diameter; RT-PCR, real-time polymerase chain reaction; RVD, right ventricular diameter; TGF-β1, transforming growth factor-β1. (Li et al, 2015(Li et al, , 2016. However, the underlying pathogenetic mechanisms of β1ARAb-mediated AF remains unclear.…”