Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation

Abstract

Background Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored. Research aims (a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF. Methods Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF). Results The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03). Conclusion In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.

Unraveling cardiomyocyte responses and intercellular communication alterations in primary carnitine deficiency cardiomyopathy via single-nucleus RNA sequencing

“…3 I). We further identified genes associated with fibrosis, including FN1 (encoding fibronectin), GAS6 (encoding growth arrest-specific 6), COL1A2 (encoding collagen, type I, alpha 2), ACTA2 (encoding actin alpha 2), and POSTN (encoding periostin) [ [30] , [31] , [32] , [33] ], which were significantly increased in the OCTN2-deficient group ( Fig. 3 J).…”

Deciphering the Involvement of the Epicardium in Cardiac Diseases

“…Similarly, inflammatory processes in EAT have been recently associated with AF onset [77][78][79][80]. EAT adiponectin signaling [81] and EAT-driven endothelial dysfunction [82] can influence AF vulnerability.…”

The Role of Immune Cells Driving Electropathology and Atrial Fibrillation

“…In addition to their interaction with endothelial cells, neutrophils can also interact with cardiomyocytes, promoting apoptosis and activating atrial fibroblasts, which results in increased fibrous tissue [95,96]. Recent studies utilizing single-cell transcriptomics have identified different subpopulations of neutrophils at various stages of healing after myocardial infarction, all of which share a unique sialic acid binding Ig-like lectin F (SiglecFhi) signature [97].…”