THE RELATIONSHIP BETWEEN IMPAIRED FIBRINOLYSIS AND CORONARY HEART-DISEASE - A ROLE FOR PAI-1

Several studies have evaluated the possible relationship between deficient fibrinolysis and ischaemic heart disease. Case-control and cross-sectional studies in patients with angiographically proved coronary disease have shown a significant increase of PAI-1 levels as compared with a control group. A significant increase of PAI-1 activity and antigen has also been demonstrated in patients with acute myocardial infarction (AMI) either during the acute event (3 h-3 days) or longer than one month after the acute event. It was suggested that the impairment of fibrinolytic activity in patients studied few days after the acute event is the consequence rather than the cause of AMI. Furthermore, the high PAI-1 levels would be non specific since they may reflect an acute phase reactant behaviour. It is, therefore, difficult to establish whether reduced fibrinolytic activity plays a role in the pathogenesis of AMI, although the fact that PAI-1 is still elevated months after the acute episode seems to support this hypothesis. In order to clarify this point the analysis of reports evaluating the predictive role of impaired fibrinolysis in the appearance of a first AMI episode is important, as well as in the recurrence of infarction. Two cohort studies explored the relationship between fibrinolytic activity and the incidence of cardiovascular disease and found similar baseline fibrinolytic activity among subjects dying from cardiovascular diseases and those who survived during the follow-up period. However, only global fibrinolytic activity was measured, so there is a possibility that levels of specific components of the fibrinolytic system might be predictors of AMI. Several studies have explored the fibrinolytic activity as a predictor of the recurrent AMI and various others have shown that elevated PAI-1 levels are associated with a higher incidence of recurrent infarction. The role of the fibrinolytic system in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty and the possible association between preoperative hypofibrinolysis and postoperative graft occlusion in patients undergoing coronary revascularization procedures has also been investigated. It has been known for considerable time that several of the well-established risk factors for coronary heart disease (CHD) such as obesity, smoking, hypertension and hyperlipoproteinemia are associated with decreased fibrinolytic activity. The positive relationship between serum triglycerides and PAI-1 levels in plasma is of particular interest, since it raises the possibility that hypertriglyceridemia confers predisposition to coronary thrombosis. Patients with diabetes mellitus, mainly of the non insulin-dependent type, show an increase of PAI-1 levels and a high incidence of atherosclerosis and CHD. Finally, some authors have found increased expression of PAI-1 mRNA in segments of human arteries from atherosclerotic patients compared with normal arteries. It can be concluded that high PAI-1 would induce hypofibrinolysis contributing to the fibrin deposition and subsequent atheroma plaque growth as well as to thrombus formation on atheroma plaque. The results of interventional studies on the modulation of endogenous fibrinolysis will convincingly establish the definitive role of fibrinolysis in the pathogenesis of atherosclerosis and CHD.