Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study

• Type of Material: Article
• Authors: G.H. Tofler, University of Sydney; J. Massarob, Boston University; C.J. O'Donnell, National Institutes of Health; Peter Wilson, Emory University; R.S. Vasan, National Institutes of Health; P.A. Sutherland, National Institutes of Health; J.B. Meigs, Massachusetts General Hospital; D. Levy, National Institutes of Health; R.B. D'Agostino, Boston University
• Language: English
• Date: 2016-04-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Ltd. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.thromres.2016.02.002
• Title of Journal or Parent Work: Thrombosis Research
• ISSN: 0049-3848
• Volume: 140
• Start Page: 30
• End Page: 35
• Grant/Funding Information: This work was supported by an AHA Grant-in-Aid (92011960), the National Institutes of Health (RO1-HL-48157), the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), the Ducker Bequest and Heart Research Australia.
• Keywords: CORONARY-ARTERY-DISEASE; Science & Technology; MYOCARDIAL-INFARCTION; Peripheral Vascular Disease; Plasminogen activator inhibitor 1; Cardiovascular System & Cardiology; Myocardial infarction; Tissue plasminogen activator; EVENTS; WOMEN; PLASMA; PREDICTION; LEFT-VENTRICULAR HYPERTROPHY; FIBRINOLYTIC FACTORS; LINKED-IMMUNOSORBENT-ASSAY; Hematology; PAI-1; Life Sciences & Biomedicine; Cardiovascular diseases
• Research Categories: Health Sciences, General

Abstract

Introduction 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). Conclusion 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.