Atrial extracellular matrix remodelling in patients with atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most frequent clinical arrhythmia. Atrial fibrosis is an important factor in initiating and maintaining AF. However, the collagen turnover and its regulation in AF has not been completely elucidated. We tested the hypothesis that the extracellular matrix changes are more severe in patients with permanent AF in comparison with those in patients in sinus rhythm (SR). Intraoperative biopsies from the right atrial appendages (RAA) and free walls (RFW) from 24 patients with AF undergoing a mini-Maze procedure and 24 patients in SR were investigated with qualitative and quantitative immunofluorescent and Western blot analyses. As compared with SR, all patients with AF exhibited dysregulations in collagen type I and type III synthesis/degradation. Tissue inhibitors of metalloproteinases (TIMP2) was significantly enhanced only in RAA-AF. As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05). The level of transforming growth factor (TGF)-β1 was higher in AF than SR. Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05). Conclusions: Atrial fibrosis in AF is characterized by severe alterations in collagen I and III synthesis/degradation associated with disturbed MMP/TIMP systems and increased levels of RECK. TGF-β1 contributes to atrial fibrosis via TGF-β1-Smad pathway by phospho-rylating Smad2. These processes culminate in accumulations of fibrillar and non-fibrillar collagens leading to excessive atrial fibrosis and maintainance of AF.

Chronic hypoxia increases peroxynitrite, MMP9 expression, and collagen accumulation in fetal guinea pig hearts

“…Furthermore, the increase in MMP9 and/or MMP2 expression has been shown to contribute to an increase in cardiac fibrosis in adult hearts (39,40). The current study indicates that both iNOS-derived NO and reactive oxygen species are sufficient to induce MMPs because each inhibitor (i.e., LNIL and NAC) was capable of inhibiting MMP9 expression individually.…”

“…Although MMP9 can degrade collagen via its gelatinolytic activity, we measured a paradoxical increase in collagen levels. This may occur if chronic exposure to hypoxia disrupts the balance between collagen synthesis and degradation as a result of time-dependent generation of matrikines (subfragments of collagen degradation), which stimulates further collagen synthesis (39,40). We hypothesize that chronic hypoxia is sufficient to generate collagen accumulation in fetal hearts with increased MMP activation, although the causal relationship remains unknown.…”

TGF‐β1 Expression and Atrial Myocardium Fibrosis Increase in Atrial Fibrillation Secondary to Rheumatic Heart Disease

“…10,11 Homogeneity conduction of atrial actuation depends not only on synchronized actuation of cardiocytes, but also on the concordance of matrix and cardiomyocyte. 12,13 Collagens I and III, the major matrix proteins of cardiocytes, constitute 85% of the content of the myocardial matrix. Atrial fibrosis, which hinders conduction in the atrium, leads to asynechia conduction and diffusion of conduction, further initiating and sustaining atrial fibrillation.…”

Oncostatin M Induces FGF23 Expression in Cardiomyocytes

“…Immunoreactive proteins were analyzed with the QuantityOne software (BioRad) after visualization on the VersaDoc system (BioRad). Tissue samples were processed for immunocytochemistry and immunofluorescence analysis as reported previously [19]. Anti-FGF23 antibodies were obtained from R&D Systems, Inc (614 McKinley Place NE, Minneapolis, MN, 55413, United States).…”