Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models

Abstract

Background: Autoimmune disorder is the emerging mechanism of atrial fibrillation (AF).The β1-adrenergic receptor antibody (β1-AAb) is associated with AF progress. Our study aims to investigate whether β1-AAbs involves in atrial vulnerable substrate by mediating Ca2+ mishandling and atrial fibrosis in autoimmune associated AF. Methods: Active immunization models were established via subcutaneous injection of the second extracellular loop (ECL2) peptide for β1 adrenergic receptor (β1AR). Invasive electrophysiologic study and ex vivo optical mapping were used to evaluate the changed electrophysiology parameters and calcium handling properties. Phospho-proteomics combined with molecular biology assay were performed to identify the potential mechanisms of remodeled atrial substrate elicited by β1-AAbs. Exogenous β1-AAbs were used to induce the cellular phenotypes of HL-1 cells and atrial fibroblasts to AF propensity. Results: β1-AAbs aggravated the atrial electrical instability and atrial fibrosis. Bisoprolol alleviated the alterations of action potential duration (APD), Ca2+ transient duration (CaD) and conduction heterogeneity challenged by β1-AAbs. β1-AAbs prolonged calcium transient refractoriness and promoted arrhythmogenic atrial alternans and spatially discordant alternans, which were partly counteracted through blocking β1AR. Its underlying mechanisms are related to β1AR-drived CaMKII/RyR2 activation of atrial cardiomyocytes and the myofibroblasts phenotype formation of fibroblasts. Conclusion: Suppressing β1-AAbs effectively protects the atrial vulnerable substrate by ameliorating intracellular Ca2+ mishandling and atrial fibrosis, preventing the process of the autoimmune associated AF.

Bioinformatics analysis reveals the potential common genes and immune characteristics between atrial fibrillation and periodontitis

“…Electrophysiological parameters were measured in our previous work 11 . Briefly, the AERP was measured as follows:…”

“…Electrophysiological parameters were measured in our previous work. 11 Briefly, the AERP was measured as follows: An output voltage, set at four times the pacing threshold and a pulse width of 0.5 ms, was administered. Stimulation was induced at a rate of 120 beats per minute using the S1S1 method (S1S1 interval = 200 ms) and maintained at an S1:S2 ratio of 8:1.…”

Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old

“…It has been shown that the β 1 -adrenergic receptor autoantibodies (β 1 -AAb) contribute to the development of autoimmunity-associated AF by targeting the functional domain on the second extracellular loop of the receptor itself. In vivo models revealed that β 1 -AAb contribute to atrial electrical instability through the activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and phosphorylation of the ryanodine receptor (RyR2) [5]. These mechanisms prolong transient calcium refractoriness and promote arrhythmogenic and spatially discordant atrial alternans.…”

β1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues

“…Induction of β1AR-AAbs aggravated atrial electrical instability and atrial fibrosis in rabbits. Further, in vitro experiments revealed that β 1 AR-AAb induced calmodulin kinase and ryanodine receptor 2 activation in atrial cardiomyocytes and the myofibroblasts phenotype formation [ 97 ]. β 1 AR-AAbs with thyroid hormone supplementation induced sustained AF in rabbits.…”