title: Atrial fibrosis and atrial fibrillation: the role of the TGF-β1 signaling pathway.
abstract: BACKGROUND
  Atrial fibrosis concurs with chronic atrial fibrillation (AF), a phenomenon that contributes to the resistance to restore and maintain sinus rhythm (SR). Fibrogenesis represents a complex process in which the transforming growth factor-β1 (TGF-β1) pathway may play a major role, e.g. in the setting of myocardial infarction. The present study addresses the potential contribution of the TGF-β1 signaling pathway to atrial fibrosis in patients with AF.
  
  
  RESULTS
  Right atrial appendages of 163 patients were excised during heart surgery and grouped according to rhythm (SR vs. AF) and AF duration. Five groups were defined: SR, paroxysmal/chronic persistent AF (<6 months), chronic permanent AF (CAF) of 7-24 months, 25-60 months, and >60 months duration. Collagen content of atria, determined morphometrically, revealed a steady and significant increase in patients with SR (14.6±8.9%) up to patients with CAF of >60 months (28.1±7.1%). Likewise, expression of TGF-β1 mRNA and protein, TGF-β-receptor-II protein, profibrotic phospho-Smad-2 and -4 proteins increased. However, the TGF-β(1) effect appeared to decline with increasing AF duration, characterized by a decrease in TGF-β-receptor-I protein, increases of TGF-β inhibiting Smad-7 protein and a reduction of ph-Smad-2.
  
  
  CONCLUSIONS
  Human atrial fibrogenesis in patients with atrial fibrillation is accompanied by a biphasic response, an early increase and later loss of responsiveness to TGF-β(1). It appears that fibrosis progresses despite compensatory changes in the TGF-β-signaling pathway. The sequential changes in the contribution of different profibrotic processes during the establishment of AF may offer the opportunity to selectively interfere with the atrial remodeling process at different stages.
authors.affiliation: Department of Cardiology and Vascular Medicine, Mainz University, Germany. gramley@hotmail.com
authors.forename: Felix
authors.initials: F
authors.lastname: Gramley
authors.forename: Johann
authors.initials: J
authors.lastname: Lorenzen
authors.forename: Eva
authors.initials: E
authors.lastname: Koellensperger
authors.forename: Klaus
authors.initials: K
authors.lastname: Kettering
authors.forename: Christian
authors.initials: C
authors.lastname: Weiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Munzel
mesh_terms: D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism / Q000473:pathology; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology*; D001706:Biopsy; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C497806:SMAD7 protein, human; D051898:Smad1 Protein; D051901:Smad4 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1