High Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma Precede a First Acute Myocardial Infarction in Both Men and Women

Abstract

Background-In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1. Methods and Results-The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men. Conclusions-The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors. (Circulation. 1998;98:2241-2247.)

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…A pooled meta‐analysis shows the highest quantile (ie, tertile, quartile, or quintile) of blood PAI‐1 levels is associated with higher risk of CHD incidence compared with the lowest quantile (OR=2.17; 95% CI: 1.53, 3.07; Figure 2A) in an age‐and sex‐adjusted model 11, 12, 13, 14, 15, 16, 17, 18, 19, 22. The overall heterogeneity across studies is high (I 2 =71.5%, P <0.001; Figure 2A).…”

“…The association of elevated plasma PAI‐1 levels with CHD incidence has been reported in longitudinal studies 11, 12, 13, 14, 15, 16, 17, 18, 19. However, this association did not always remain consistent after adjusting for cardiovascular risk factors 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23. On the one hand, these inconsistencies could be due to small sample sizes and/or restricted study populations (eg, type 2 diabetes mellitus patients, obese individuals, or HIV patients) 20, 24.…”

“…Ten studies that adjusted only for age and sex reported association between PAI‐1 and CHD incidence (Table S1), while 13 studies found the same association following adjustment for multiple covariates (eg, BMI, blood glucose, blood lipids, and blood pressure; Table S1). 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 31 Covariates used in each study that included multivariable‐adjusted models are shown in Table S1. Detailed literature screening procedure is presented in Figure 1.…”

Local Production of Soluble Urokinase Plasminogen Activator Receptor and Plasminogen Activator Inhibitor‐1 in the Coronary Circulation Is Associated With Coronary Endothelial Dysfunction in Humans

“…Inhibition of fibrinolysis due to elevated PAI‐1 levels has been associated with atherosclerotic plaque development, accelerated coronary atherosclerosis, thrombus formation, and an increased risk of recurrent myocardial infarctions 14, 41, 46, 47, 48, 49. Moreover, elevated levels of PAI‐1 have been documented in metabolic syndrome,50 diabetes mellitus,51 and obesity, all of which have been closely associated with endothelial dysfunction.…”

Biomarkers as Surrogates for Coronary Endothelial Dysfunction in Patients With Nonobstructive Coronary Artery Disease

“…Plasminogen activator inhibitor‐1 (PAI‐1) is an inhibitor of fibrinolysis with diurnal circadian variation, and higher serum PAI‐1 levels are associated with greater myocardial infarction risk 6, 7. Soluble urokinase plasminogen activator receptor (suPAR) is a proinflammatory marker with evidence suggesting it can outperform traditional markers of inflammation, such as C‐reactive protein, in prognosticating cardiovascular events 8.…”