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

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. 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. 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. 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.