Abstract Body: Background: Brugada syndrome (BrS) is traditionally considered a pure channelopathy, yet the efficacy of epicardial ablation implies a structural substrate. The molecular composition of the BrS epicardial microenvironment remains unknown.
Objective: To characterize the pericardial fluid (PF) proteome in BrS vs healthy controls and identify tissue components released during epicardial ablation.
Methods: PF was collected from BrS patients (pre-ablation, n=11) and controls (n=11). Paired pre/post-ablation samples were obtained intra-procedurally (n=39). Label-free LC-MS/MS, Ingenuity Pathway Analysis, and cell-type deconvolution were performed.
Results: BrS PF showed downregulation of desmosomal proteins (desmoglein-1, desmocollin-1, plakoglobin; p<0.01) and cytoskeletal markers (cytokeratin-78, S100-A14, calretinin, FABP5). Classical complement components were upregulated (C1q, C4-A, CFHR1; p<0.05) along with macrophage receptor MARCO. TRIM21 intracellular antibody signaling was the top enriched pathway, followed by BCR signaling and complement cascade, indicating local immune complex activation. Pre/post-ablation analysis showed that ablation released cardiac proteins (troponin T2, myoglobin, tropomyosin-1), extracellular matrix components (collagen I, fibromodulin, lumican), and metabolic enzymes. Cell-type deconvolution confirmed contributions from cardiomyocytes, adipocytes, fibroblasts, neurons, and immune cells.
Conclusions: The BrS epicardial microenvironment features desmosomal disorganization, echoing the molecular hallmark of arrhythmogenic cardiomyopathy, coupled with classical complement activation. Epicardial ablation targets a composite neuro-adipo-fibro-myocardial niche in an immunologically active milieu, redefining BrS as a disease with a distinct structural and immune epicardial substrate.