Fibrinolysis, inflammation and cardiovascular disease; Epidemiological studies on Plasminogen activator inhibitor-type 1 and C-reactive protein

Plasminogen activator inhibitor-type 1 (PAI-1) is the main inhibitor of fibrinolysis and a potential risk factor for cardiovascular disease. In addition to its regulating role in fibrinolysis, PAI-1 may have detrimental effects in the cardiovascular system also through other processes, e.g. inflammation. Although PAI-1 is generally elevated in the presence of cardiovascular disease, it is not yet clear whether it is a causal risk factor. A polymorphism in the promoter region of the PAI-1 gene, the 4G/5G-polymorphism, affects the transcription of the PAI-1 gene, yielding higher blood levels of PAI-1 for the 4G-allele. In case of a causal role of PAI-1 in cardiovascular disease, an increased cardiovascular risk would be expected for the 4G-allele.The general objective of the studies in this thesis was to examine whether PAI-1 and the 4G/5G-polymorphism are associated with cardiovascular risk. Both associations with markers of atherosclerosis and clinical end points were studied. Because of the acute-phase properties of PAI-1, we additionally examined the role of C-reactive protein (CRP), a sensitive marker of inflammation.In the Arnhem Elderly Study, comprising 641 subjects aged 65-84 years, we observed a strong daytime fluctuation in PAI-1 activity with peak levels in the early morning. The diurnal pattern was clearly present for the 4G/4G and 4G/5G-genotypes, but not for the 5G/5G-genotype. These findings raised the hypothesis that 5G-homozygotic persons may be relatively protected from the early morning peak incidence in cardiovascular events.In a population of 208 smoking men the 4G/5G-polymorphism was not associated with two non-invasive markers of atherosclerosis, i.e. common carotid intima-media thickness and the ankle-brachial index. Neither did we observe consistent associations between the 4G/5G-polymorphism and coronary stenosis after pooling three similar case-control studies (n = 776) with angiographically determined coronary atherosclerosis.In the Arnhem Elderly Study we investigated whether PAI-1 and the 4G/5G-polymorphism were associated with mortality and incidence of cardiovascular events during 7.8 years of follow-up. We observed that the 4G/4G-genotype was protective against incident stroke and transient ischemic attack (relative risks of 0.4 and 0.3 respectively), which is in contrast to the generally accepted hypothesis that the 4G-allele would increase cardiovascular risk. For PAI-1 levels, an increased risk of stroke and ischemic attacks was observed in the highest tertile.In the Arnhem Elderly Study, PAI-1 and CRP were inter-related, but only in lean elderly. The associations between CRP and other components of the metabolic syndrome were also predominantly present in lean elderly. In elderly men, CRP was predictive for future cardiovascular events, but not in women.Overall, PAI-1 and the 4G/5G-polymorphism do not appear to play a major role in atherosclerosis, but the effects on thrombosis are still controversial. Causality of PAI-1 was not supported by an increased risk of cardiovascular events for the 4G/4G-genotype. In contrast, subjects with the 4G/4G-genotype were relatively protected against stroke.