title: Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.
abstract: BACKGROUND
  Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy.
  
  
  RESULTS
  We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69).
  
  
  CONCLUSIONS
  This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.
authors.affiliation: Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. Yamanim@ccf.org
authors.forename: Mohamad H
authors.initials: MH
authors.lastname: Yamani
authors.forename: Randall C
authors.initials: RC
authors.lastname: Starling
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cook
authors.forename: E Murat
authors.initials: EM
authors.lastname: Tuzcu
authors.forename: Ashraf
authors.initials: A
authors.lastname: Abdo
authors.forename: Philip
authors.initials: P
authors.lastname: Paul
authors.forename: Kimerly
authors.initials: K
authors.lastname: Powell
authors.forename: Norman B
authors.initials: NB
authors.lastname: Ratliff
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McCarthy
authors.forename: James B
authors.initials: JB
authors.lastname: Young
mesh_terms: D000328:Adult; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D003327:Coronary Disease / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D014019:Tissue Donors; D014463:Ultrasonography
chemical_list: D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9