(Circulation. 1996;94:2052-2054.)
© 1996 American Heart Association, Inc.
Articles |
Impaired Fibrinolysis and the Risk for Coronary Heart Disease
the Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Correspondence to D. Collen, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail desire.collen@med.kuleuven.ac.be.
Key Words: fibrinolysis • coronary disease • plasminogen activators • Editorials
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Introduction |
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 Top Introduction References |
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Ischemic heart disease is most frequently caused by coronary atherosclerosis. The main triggering event of unstable coronary heart disease is rupture of an atherosclerotic plaque with superimposed thrombosis.1 Reduced fibrinolytic capacity is presumed to be involved in the development and/or progression of atherosclerotic plaque, but its pathogenetic role is not fully established. This may be due in part to complex interrelations of fibrinolysis with lipoproteins, with insulin or insulinlike peptides, and with different cell types in the normal and atherosclerotic vessel wall. Specific assays for antigen and activity levels of the main components of the fibrinolytic system have recently made it possible to establish an association between low fibrinolytic activity and atherothrombosis.2 Prospective studies have revealed correlations between changes in fibrinolytic parameters and coronary disease, but it appeared to be difficult to identify independent risk factors. The article by Juhan-Vague et al3 (on behalf of ECAT) sheds a new light on the confounding variables governing the correlation between PAI-1 and TPA antigen on the one hand and coronary disease on the other.
The fibrinolytic system, which is responsible for the removal of fibrin from the circulation, contains an inactive proenzyme, plasminogen, which is activated to the serine proteinase plasmin by plasminogen activators, which comprise TPA and UPA. Plasmin degrades fibrin as well as extracellular matrix proteins. Inhibition of the fibrinolytic system may occur at the level of the plasminogen activator (by specific plasminogen activator inhibitors, mainly PAI-1) or at the level of plasmin, mainly by 
2-antiplasmin. TPA-mediated plasminogen activation is involved primarily in the dissolution of fibrin. UPA binds to a specific cellular receptor and may participate in pericellular proteolysis via degradation of matrix components or via activation of latent proteinases or growth factors. Binding of plasminogen and of the physiological plasminogen activators to fibrin or to different cell types results in enhanced plasminogen activation, whereas bound plasmin is protected from rapid inhibition by 2-antiplasmin. The fibrinolytic system is regulated by specific molecular interactions between its main components and by controlled cellular synthesis and release of plasminogen activators and plasminogen activator inhibitors.4 5
The physiological importance of the fibrinolytic system in humans is demonstrated by associations between impaired fibrinolysis and thrombotic events and between excessive fibrinolysis and bleeding complications. Clinical and epidemiological studies suggested that impairment of fibrinolytic activity, resulting in enhanced fibrin deposition, is a significant contributor to the development of atherothrombosis.1 2
Decreased fibrinolytic capacity occurs in several thrombotic disease states, including venous thromboembolism, coronary artery disease and acute myocardial infarction, sepsis, and the insulin-resistance syndrome (which includes a cluster of abnormalities such as obesity, glucose intolerance, hypertension, hyperinsulinemia, and lipid disorders with elevated triglyceride levels and decreased HDL cholesterol).6 7 High plasma PAI-1 levels in patients with acute myocardial infarction or unstable angina were predictive for recurrent (within 3 years) myocardial infarction in some studies8 9 but not in others.10 11 In a prospective study in patients with angina pectoris, high basal levels of TPA antigen but not plasminogen activator inhibitor activity were associated with an increased risk of myocardial infarction.12 13 In the ECAT angina pectoris study (see below) in 3043 patients, higher TPA antigen, von Willebrand factor, fibrinogen, and C reactive protein levels were associated with an increased risk for a subsequent coronary event, whereas PAI-1 activity or antigen levels had a weaker predictive value that disappeared after adjustment for other known risk factors (smoking, body mass index, triglycerides, cholesterol, blood pressure, diabetes, history of myocardial infarction, extent of coronary artery disease, drug use).14 15 In the Physician's Health Study,16 increased TPA antigen levels were predictive for myocardial infarction within the 5-year follow-up period, but this association disappeared after adjustment for the known risk factors (body mass index, HDL cholesterol, blood pressure). In the ARIC (Atherosclerosis Risk in Communities)17 study, high baseline PAI-1 levels were correlated with vessel wall thickness, suggesting a relationship between PAI-1 levels and the severity of vessel wall damage. Local high concentrations of PAI-1 have also been observed in coronary arteries with atherogenic lesions and may contribute to the development of vessel wall damage.18 19 20 21 However, enhanced local expression of plasminogen activators was observed within the atherosclerotic plaque, which may contribute to destabilization and rupture of the plaque.21 22
In patients with insulin resistance syndrome, interventions aimed at improving the lipid profile also enhanced fibrinolytic activity. Thus, treatment with gemfibrozil reduces the risk for coronary events23 ; it induces an improvement of the lipid profile, in association with enhanced fibrinolytic activity as a result of reduced PAI-1 levels.24 25 Increased insulin sensitivity as a result of dietary interventions in obese women is associated with an improvement of the lipid profile (lower total cholesterol and triglyceride levels) and enhanced fibrinolytic activity due to reduced PAI-1 activity.26 In postmenopausal women, hormone replacement therapy is associated with increased fibrinolytic activity and improved endothelial healing.27
Several clinical and epidemiological studies have shown that increased PAI-1 antigen and, more so, increased TPA antigen levels are predictors of coronary events. Because of complex interrelations between impaired fibrinolytic activity and several metabolic and inflammatory disorders, however, the identification of independent risk factors with prognostic value is determined largely by the selection of confounding variables. In the prospective ECAT study, 10 fibrinolytic variables were measured in 3043 patients with angina pectoris recruited from 18 European centers.14 15 A first analysis after adjustment for other nonfibrinolytic coronary risk factors (body mass index, triglyceride levels, diabetes, systolic blood pressure) revealed that an increased risk of coronary events within 2 years was associated with higher baseline concentrations of TPA antigen but not of PAI-1 activity and antigen levels. Well-known interrelations between TPA and PAI-1 levels, however, have led to the notion that PAI-1 is the most determining factor in the balance of fibrinolytic activity. Indeed, several studies, including the ECAT study itself, have reported strong correlations between TPA and PAI-1 antigen levels, in healthy populations as well as in patients with coronary heart disease.2 6 7 It should be kept in mind that assays of TPA antigen measure mainly inactive TPA/PAI-1 complexes and that PAI-1 antigen assays detect not only free active PAI-1 but also TPA/PAI-1 complexes and latent PAI-1 that may be secreted by platelets. Furthermore, many triggers, both physiological and pharmacological, simultaneously induce enhanced TPA secretion from endothelial cells and enhanced PAI-1 secretion from a variety of cell types.28 Because of this strong association, it appeared surprising that in the ECAT study, only TPA antigen and not PAI-1 was identified as a predictive risk factor for coronary heart disease.14
In the analysis by Juhan-Vague et al,3 the prognostic value of the fibrinolytic variables determined in the ECAT study was reexamined after separate adjustment for clusters of markers of insulin resistance, inflammation, or endothelial cell damage. These adjustments affected the prognostic value of PAI-1 and TPA levels differently. Factors involved in the insulin-resistance syndrome strongly affect PAI-1 and to a lesser extent TPA antigen; the latter is influenced primarily by inflammation and endothelial cell damage. The mechanisms by which enhanced PAI-1 levels are linked with the insulin-resistance syndrome are not well understood. In vitro data indicate that PAI-1 synthesis by endothelial cells and hepatocytes could be affected by insulin, proinsulin, and atherogenic lipoproteins.29 30 31 Other experimental studies have shown that binding of Lp(a) to endothelium results in enhanced PAI-1 expression, which may contribute to the development of a prothrombotic endothelial phenotype.32 Increased production of PAI-1 by adipocytes was recently observed in response to cytokines or transforming growth factor-ß, which may explain the high PAI-1 levels in insulin-resistant obese patients.33 34
In view of the multifactorial nature of atherothrombotic disease and the resulting variety of confounding variables that may be controlled for, the analysis of the ECAT data by Juhan-Vague et al would suggest that TPA antigen levels constitute a biological marker of coronary heart disease, influenced by a variety of pathophysiological pathways, including inflammation. In contrast, plasminogen activator inhibitor levels, which determine fibrinolytic activity and which are dependent mainly on the metabolic status, emerge as a risk factor predictive for the future development of atherothrombosis. The main message of this analysis seems to be that because of the strong interrelations between different fibrinolytic parameters and between fibrinolytic parameters and other coronary risk markers, the choice of confounding variables controlled for largely determines which fibrinolytic parameters emerge as risk factors for coronary heart disease.
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Selected Abbreviations and Acronyms |
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References |
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TopIntroductionReferences |
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