title: Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrosis has been shown to concur with the persistence of atrial fibrillation (AF) and is only incompletely reversible, thus counteracting attempts to restore and maintain sinus rhythm (SR). Besides the angiotensin system, the matrix metalloproteinases (MMP) play a major role in the pathogenesis of fibrosis. Thus, the present study investigated changes of the MMP system during the development of human AF.
  
  
  RESULTS
  Right atrial appendages of 146 patients were excised during heart surgery and grouped according to rhythm (SR vs AF) and AF duration. Hydroxyproline as a surrogate for collagen content and morphometrically determined collagen content increased significantly from SR (14.3 +/- 7.7%) to chronic permanent AF (CAF) of 6-24 months (21.2 +/- 9.2%, P = 0.02), and CAF of > 60 months (25.3 +/- 4.7%, P < 0.01). From SR to paroxysmal and chronic persistent AF (CPAF) and to CAF MMP-2 and MMP-9 activity rose, while their mRNA and protein levels were not altered significantly. Plasminogen activator inhibitor (PAI), an inhibitor of a potent activator of many MMPs, was significantly decreased with increasing duration of AF. In parallel, the mRNA levels of the tissue inhibitors of MMPs TIMP-1 and -2 decreased significantly.
  
  
  CONCLUSIONS
  Human atrial fibrogenesis is enhanced with increasing duration of AF: a longer AF duration is associated with elevated atrial interstitial MMP activity, but decreased PAI and TIMP expression.
authors.affiliation: Department of Cardiology, Technical University Aachen, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gramley
authors.forename: Johann
authors.initials: J
authors.lastname: Lorenzen
authors.forename: Jurgita
authors.initials: J
authors.lastname: Plisiene
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Rakauskas
authors.forename: Rimantas
authors.initials: R
authors.lastname: Benetis
authors.forename: Michael
authors.initials: M
authors.lastname: Schmid
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Autschbach
authors.forename: Christian
authors.initials: C
authors.lastname: Knackstedt
authors.forename: Thomas
authors.initials: T
authors.lastname: Schimpf
authors.forename: Karl
authors.initials: K
authors.lastname: Mischke
authors.forename: Axel
authors.initials: A
authors.lastname: Gressner
authors.forename: Peter
authors.initials: P
authors.lastname: Hanrath
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Patrick
authors.initials: P
authors.lastname: Schauerte
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D015849:Plasminogen Inactivators / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015849:Plasminogen Inactivators; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases