title: Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart.
abstract: BACKGROUND
  Alterations in the balance of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) are involved in left ventricular (LV) remodeling. Whether their expression is related to interstitial fibrosis or LV dysfunction in patients with chronic pressure overload-induced LV hypertrophy, however, is unknown.
  
  
  RESULTS
  Therefore, cardiac biopsies were taken in 36 patients with isolated aortic stenosis (AS) and in 29 control patients without LV hypertrophy. Microarray analysis revealed significantly increased mRNA expression of collagen types I, III, and IV and transcripts involved in collagen synthesis, including procollagen endopeptidase and lysine and proline hydroxylases, in AS compared with control patients. Collagen deposition was greater in AS than in control patients and was most pronounced in AS patients with severe diastolic dysfunction. Cardiac mRNA expression of TIMP-1 and TIMP-2 was significantly increased in AS compared with control patients (mRNA transcript levels normalized to GAPDH: TIMP-1, 0.67+/-0.1 in AS versus 0.37+/-0.08 in control patients; TIMP-2, 9.5+/-2.6 in AS versus 1.6+/-0.4 in control patients; P<0.05 for both) but did not differ significantly for MMP-1, -2, or -9. Cardiac TIMP-1 and -2 transcripts were significantly related to the degree of interstitial fibrosis and proportional to diastolic dysfunction in AS patients.
  
  
  CONCLUSIONS
  Cardiac expression of TIMP-1 and TIMP-2 is significantly increased in chronic pressure-overloaded human hearts compared with controls and is related to the degree of interstitial fibrosis.
authors.affiliation: CARIM, University Hospital Maastricht, Maastricht, The Netherlands. s.heymans@cardio.unimaas.nl
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeersch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.forename: Fangye
authors.initials: F
authors.lastname: Gao
authors.forename: Astrid
authors.initials: A
authors.lastname: Kassner
authors.forename: Hilde
authors.initials: H
authors.lastname: Gillijns
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Willem
authors.initials: W
authors.lastname: Flameng
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
mesh_terms: D001024:Aortic Valve Stenosis / Q000473:pathology / Q000503:physiopathology; D001706:Biopsy; D002908:Chronic Disease; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000235:genetics; D001026:Coronary Artery Bypass; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D017725:Ventricular Pressure
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9