title: 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)-beta1 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-beta1 contributes to atrial fibrosis via TGF-beta1-Smad pathway by phosphorylating Smad2. These processes culminate in accumulations of fibrillar and non-fibrillar collagens leading to excessive atrial fibrosis and maintainance of AF.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Core Lab for Molecular and Structural Biology, Bad Nauheim, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Polyakova
authors.forename: S
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Z
authors.initials: Z
authors.lastname: Szalay
authors.forename: J
authors.initials: J
authors.lastname: Risteli
authors.forename: S
authors.initials: S
authors.lastname: Kostin
mesh_terms: D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism* / Q000473:pathology; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C115460:RECK protein, human; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9