Regular ArticleThe complex between tPA and PAI-1: risk factor for myocardial infarction as studied in the SHEEP project
Introduction
An impaired fibrinolytic function, mainly due to increased plasma PAI-1 levels, is strongly correlated to the development of MI. This has been clearly demonstrated in several prospective [1], [2], [3], [4], [5], [6] and retrospective [7], [8] studies. It has also been found that tPA antigen [9], [10] or tPA/PAI-1 complex [11] in plasma might be an even better predictor of MI. The reason for this is not well understood, but tPA/PAI-1 complex in plasma, which constitutes the most important part of tPA antigen, correlates very well to the plasma PAI-1 activity concentrations [12]. On the other hand, it does not correlate at all with tPA activity, which constitutes only a few % of the total tPA in plasma. The active PAI-1 molecule is not stable at physiological conditions, but is slowly transformed into a latent inactive form. Also, it is subjected to quite an extensive diurnal variation, with the highest levels in the very early morning. At the time when blood samples are normally taken in patients, between 8 and 10 am, the concentration of PAI-1 is rapidly declining. The complex between tPA and PAI-1 is also subjected to a diurnal variation, but much less as compared to PAI-1. Therefore it seems that the complex between tPA and PAI-1 is a more reliable way to get a true estimate of the PAI-1 levels in plasma. Recently we were able to demonstrate that tPA/PAI-1 complex is a quite strong predictor of reinfarction among the patients in the Stockholm Heart Epidemiology Program (SHEEP) study that already had a first cardiovascular event prior to inclusion in the study [11]. The SHEEP study consists of virtually all patients (45–70 years old) of Swedish origin in the Stockholm County with a first MI between 1992 and 1993 (men) or 1992 and 1994 (women). 1267 of these patients, who survived until at least 3 months after the first event, was subjected to blood sampling and compared with a control group, matched for age, sex and living area within the Stockholm County [13].
In the present study we decided to explore more closely the distribution of plasma concentrations of tPA/PAI-1 complex in all patients and controls included in the SHEEP study. This provides data regarding a primary infarction, which has not been published previously. This is important, especially since the mechanism for reinfarction and a primary infarction might be different. In addition, we also investigated its distribution in subpopulations of the SHEEP material and evaluated correlations and possible interactions. Since the tPA/PAI-1 complex seems to be one of the most important biochemical markers for MI, it was considered important to put it into perspective of other factors of importance for the development of this disease.
Section snippets
Patients and controls
The Stockholm Heart Epidemiology Program (SHEEP) is a case-control study in which 2246 patients (1485 men and 761 women) with a first MI were identified. From the survivors 1267 (893 men and 374 women) were subjected to blood sampling about 3 months after the primary event. They were compared with 1563 (1054 men and 509 women) control subjects matched for age, sex and hospital catchments area. All individuals were subjected to a health control at the same time as the blood sampling was carried
Characteristics of the study group
Basic characteristics in the different study groups are presented in Table 1. On the average, men were about four years younger as compared to the women. As expected, higher BMI values and higher W/H ratios were observed in the patients as compared to the controls. Also, diabetes mellitus was more common in the patient groups of both sexes as compared to the groups of controls. Hypertension, on the other hand, was equally frequent among patients and controls in both sexes. Physical inactivity
Discussion
Today many different types of risk factors for MI has been described including several laboratory parameters, such as serum cholesterol fractions, apolipoproteins and fibrinogen. Inflammatory markers have also become increasingly interesting. In addition to this, an impaired fibrinolytic function due to increased plasma levels of PAI-1, the most important inhibitor of the physiological plasminogen activator tPA, has been demonstrated to correlate to the development of MI in several prospective
Acknowledgements
We thank Professor Kerstin Brismar, Institution for Molecular Medicine, Karolinska Institutet for performing the serum insulin analyses. Skilful technical assistance by Ms Anette Dahlin in analysing tPA/PAI-1 complex is gratefully acknowledged.
Financial support was obtained from the Swedish Research Council (project nos. 05193 and 09533), Heart and Lung Foundation and funds from Karolinska Institutet.
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