title: Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study.
abstract: BACKGROUND
  Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD.
  
  
  METHODS
  Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk.
  
  
  RESULTS
  PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113).
  
  
  CONCLUSIONS
  PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.
authors.affiliation: Royal North Shore Hospital, Sydney University, Australia. Electronic address: Geoffrey.Tofler@health.nsw.gov.au.
authors.forename: G H
authors.initials: GH
authors.lastname: Tofler
authors.affiliation: Boston University, United States.
authors.forename: J
authors.initials: J
authors.lastname: Massaro
authors.affiliation: The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health, United States; The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States; Massachusetts General Hospital, United States.
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Emory University, United States.
authors.forename: P W F
authors.initials: PWF
authors.lastname: Wilson
authors.affiliation: The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health, United States.
authors.forename: R S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health, United States; The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: P A
authors.initials: PA
authors.lastname: Sutherland
authors.affiliation: Massachusetts General Hospital, United States.
authors.forename: J B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health, United States; The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: D
authors.initials: D
authors.lastname: Levy
authors.affiliation: Boston University, United States.
authors.forename: R B
authors.initials: RB
authors.lastname: D'Agostino
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D011446:Prospective Studies; D012307:Risk Factors; D010959:Tissue Plasminogen Activator / Q000097:blood
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator
keywords: Cardiovascular diseases; Myocardial infarction; Plasminogen activator inhibitor 1; Tissue plasminogen activator