title: Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is associated with extracellular matrix remodeling involving atrial fibrosis and atrial dilatation. Angiotensin II mediated pathways and matrix metalloproteinases (MMPs) have been implicated in these processes. Our aim was to study atrial structural remodeling and the expression of the angiotensin receptor subtypes and MMPs and their inhibitors (TIMPs) in patients with mitral valve disease with and without AF.
  
  
  RESULTS
  Biopsies from right and left atrial appendages (RA and LA) were taken from patients undergoing CABG (n=9, all in sinus rhythm (SR)) or mitral valve surgery (MVS; n=19; 9 with permanent AF and 10 in SR). Patients with MVS and AF had significantly larger atria (versus MVS and SR: p=0.02; versus CABG: p<0.01). The MVS patients had significantly more fibrosis than the control CABG group. Fibrosis was increased in both the AF and SR MVS groups in the LA, but only in the MVS-AF group in the RA. These AF patients had significantly more tricuspid regurgitation than SR patients. MMP-1 was down-regulated in LA of MVS patients (p=0.02) independent of the underlying rhythm (SR or AF; p=0.95). In RA biopsies, MMP-1 was down-regulated only in the MVS and AF group. MMP-9 was down-regulated in the MVS patients compared to CABG both in the RA and LA, and without a difference between the SR and AF groups. Protein expression of AT-1, AT-2, MMP-2, TIMP-1, -2 and -4, TNF-alpha, and TNF-alpha-converting enzyme did not differ significantly between the 3 groups.
  
  
  CONCLUSIONS
  Concordant changes between MMP-expression and fibrosis during mitral valve disease, both in LA and RA, suggest involvement of MMPs in structural atrial remodeling. AF itself did not contribute to altered fibrosis or MMP-expression in the LA. The association between AF and RA changes may be precipitated by greater hemodynamic load due to tricuspid regurgitation in these patients.
authors.affiliation: Department of Cardiology, University Hospital Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Anné
authors.forename: Rik
authors.initials: R
authors.lastname: Willems
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Paul
authors.initials: P
authors.lastname: Sergeant
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Patricia
authors.initials: P
authors.lastname: Holemans
authors.forename: Hugo
authors.initials: H
authors.lastname: Ector
authors.forename: Hein
authors.initials: H
authors.lastname: Heidbüchel
mesh_terms: D000368:Aged; D020517:Atrial Appendage / Q000201:enzymology* / Q000473:pathology; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D048429:Cell Size; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008944:Mitral Valve Insufficiency / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2 / Q000032:analysis; D018709:Statistics, Nonparametric; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000097792:Tissue Inhibitor of Metalloproteinase-4