© 1999 American Heart Association, Inc.
Brief Reviews |
Plasminogen Activator Inhibitor Type 1 in Ischemic Cardiomyopathy
From the Department of Clinical and Experimental Medicine, University of Padua Medical School, Padua, Italy.
Correspondence to G.P. Rossi, MD, FACC, Clinica Medica 4, Department of Clinical and Experimental Medicine, University Hospital, Via Giustiniani, 2, 35126 Padova, Italy. E-mail gprossi{at}ux1.unipd.it
Key Words: plasminogen activator inhibitor • myocardial infarction • coronary artery disease • gene polymorphism
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Introduction |
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 Top Introduction Biochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Plasminogen activator inhibitor type 1 (PAI-1) is a proteinase inhibitor1 constituting the key regulator2 of the activity of the fibrinolytic system, an important protective mechanism against thrombosis. Because a reduced fibrinolytic activity, mainly caused by increased plasma levels of PAI-1, was a common finding in cross-sectional studies of patients with coronary artery disease (CAD),3 high PAI-1 levels have been regarded as a risk factor for recurrent myocardial infarction (MI).4 5 6 It has also been proposed that a reduced fibrinolytic activity may have a role in atherosclerotic plaque formation and in a prothrombotic state, carrying an increased risk of arterial occlusion. Accordingly, over the last few years, several studies have been performed to investigate the role of plasma PAI-1 levels in the development of CAD and MI. Moreover, the observation that polymorphisms of the PAI-1 gene exist, some of which apparently associated with increased plasma PAI-1 levels, stimulated studies aiming at investigating the potential relation between PAI-1 genotypes and ischemic cardiomyopathy.
Thus, we shall focus on recent advances in the knowledge of the role of PAI-1 and its gene in the development of ischemic cardiomyopathy.
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Biochemical Features |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Intravascular fibrinolytic activity results from a balance between plasminogen activators, such as the tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and inhibitors, such as PAI-1 and
2-antiplasmin. PAI-1 is a
glycoprotein with a molecular mass of 
54 kDa that
belongs to the serine protease inhibitor superfamily
(serpins). Its primary structure was deduced from the sequence of its
cDNA.7 It is considered the major
physiological inhibitor of t-PA and
urokinase, because plasmin formation and fibrinolysis,
as well as formation of other extracellular proteases, strongly depend
on PAI-1 levels.8 Although the principal source of plasma
PAI-1 is unknown, available evidence indicates that several cell types,
including endothelial and vascular smooth muscle cells
(VSMCs), platelets, hepatocytes, fibroblasts, and
adipocytes, can all produce PAI-1.9 10 Furthermore, the
finding of immunocytochemical localization of PAI-1 in human
endothelial cells and VSMCs suggests an action of the
peptide not only in the vessel lumen, but also in the vascular
wall.
Plasma levels of PAI-1 can be measured either as activity or as
immunoreactive (ir) PAI-1 (PAI-1 antigen). Both measurements require
utmost care in blood collection and sample handling because PAI-1 is a
labile molecule. In addition, precautions must be taken to avoid
release of PAI-1 from the platelets, which contain a large amount
of mostly the inactive form (see below). PAI-1 reacts rapidly with t-PA
and u-PA, forming very stable stoichiometric 1:1 complexes, as
do many serpins.11 A unique feature of PAI-1 among serpins
is its spontaneous transition into an inactive "latent" form, which
can be reactivated by treatment with denaturing
agents.12 13 It has been established that denaturing
agents lead to an exposure of the scissile bond at the surface
of PAI-1, making it available for interaction with
plasminogen activators. Crystallographic
studies have clarified the three-dimensional structure of the latent
form of PAI-1.13 Elegant, limited proteolysis studies have
allowed detection of conformational differences between the different
forms, ie, latent, active and complexed PAI-1, as well as
identification of some flexible regions that seem to be implicated in
the conformational changes during the inhibitory reaction
of PAI-1 on plasminogen
activators.8 In plasma,
vitronectin forms a relatively tight complex via its
NH2-terminal domain with PAI-1 and this
interaction may contribute to stabilize PAI-1 in its functional
state.14 The differential proteolytic susceptibility of
the aforementioned flexible joint region is likely to affect affinity
to vitronectin.8 Although the half-life for
the transformation into the inactive latent form is 4 hours in
vitro,3 at neutral pH and 37°C the half-life of PAI-1
activity is very short (2 hours), and the in vivo half-life is even
shorter (<10 minutes).15 Therefore, samples for PAI-1
activity measurements must be handled and plasma frozen as quickly as
possible.
The PAI-1 activity (PAI-1act) assay detects free active PAI-1, whereas PAI-1 antigen (PAI-1ag) assay measures free active PAI-1, inactive latent PAI-1, and also inactive (complexed with t-PA or u-PA) PAI-1.
Many studies, performed in healthy subjects or patients with CAD, showed a correlation between t-PA antigen (t-PAag) and PAI-1ag, with coefficients ranging between 0.36 and 0.86. These proteins are highly correlated with each other also in the circadian variation, but the real value of this relation is still unclear. It has recently been proposed that t-PAag could accumulate in the presence of a high concentration of PAI-1 because of the delayed clearance of the t-PA/PAI-1 complex.16 It is our opinion that the aforementioned potential problems in sample handling and processing, as well as differences in the type of assay used, may contribute to explaining the discrepant results obtained in different studies, as discussed later in this review. We did our best to specify whether PAI-1ag or PAI-1act were measured in the studies that are reviewed in this article; however, the generic term PAI-1 levels was used whenever it was not possible to determine which type of assay was used.
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Environmental Influences on Plasma PAI-1 Levels |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Plasma PAI-1 levels show an intrinsic within-individual variability over time, and are affected by several environmental factors, which are summarized in Table 1
.
It has been shown that in vitro the expression of PAI-1 is regulated by
glucocorticoids,17 thrombin,18
platelet-derived growth factor,19
angiotensin II (Ang II),20 and oxidized
LDLs.21 In particular, various cytokines are known
to affect PAI-1 expression. Interleukin-1, transforming growth
factor-ß, and tumor necrosis factor- were found to enhance the
secretion of PAI-1 in vitro,18 22 23 and tumor necrosis
factor- also increases PAI-1 plasma levels when injected in healthy
men.24 Interferon-
has only a small direct effect on
PAI-1ag expression in vitro, but may downregulate both basal and
thrombin- or endotoxin-induced PAI-1 expression in cultured human
endothelial cells.25 26 It is likely that
the regulation occurs at the level of transcription, because sequence
elements mediating the response to different regulators have been
identified within the promoter region of the PAI-1 gene.27
With regard to other growth factors, in contrast to the results of in
vitro experiments, endothelin-1 infusion does not appear to affect
fibrinolysis in healthy men,28 and
insulin-like growth factor-1 was not found to induce PAI-1 synthesis in
vivo when infused in type II diabetic patients.29
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Bacteremia and endotoxemia were also found to affect PAI-1 in vivo. Both the infusion of endotoxin in animals and the intravenous injection of lipopolysaccharides in healthy men induce a rapid increase in PAI-1 plasma levels, suggesting a role for PAI-1 in the development of disseminated intravascular coagulation occurring during Gram-negative sepsis.30 31
Moderate physical activity lowers PAI-1ag after 30 and 60 minutes in normotensive and hypertensive men.32 Physical training also decreases PAI-1act, but not PAI-1ag, in men with and without a history of MI.33
With regard to sex, PAI-1 levels are higher in men than in women, but it is noteworthy that testosterone is inversely associated with plasma PAI-1 levels.34 Hypogonadism in males is associated with an increased synthesis of PAI-1, and androgen medication, with stanozolol and danazol, was found to reduce PAI-1 plasma levels,34 whereas estrogens seem to lower plasma PAI-1 levels.35 A significant non–dose-dependent decrease in PAI-1 activity in fertile women taking oral contraceptives, at estrogen doses ranging between 30 and 50 µg, compared with nonusers, was observed.36 Moreover, hormone replacement therapy in postmenopausal women with estrogen alone or estrogen plus progesterone lowers the morning values of PAI-1.37 These findings may explain both the low and high cardiovascular risk profile of premenopausal and postmenopausal women, respectively.
Insulin and triglycerides were found to stimulate PAI-1 production by human cultured endothelial cells or hepatocytes (for review, see Juhan-Vague et al38 ), but acute infusions of either insulin or triglycerides in humans did not increase PAI-1 levels.39 Glucose can also increase PAI-1 release in the medium of cultured human endothelial cells; however, there is only a weak association between glycemia and PAI-1 levels in vivo and a short-term glucose infusion did not change PAI-1 concentration.39 Nonetheless, according to some reports, plasma PAI-1 levels would be higher in non–insulin-dependent diabetic (NIDDM) patients than in nondiabetic subjects.40 41 Collectively, available findings suggest that the increase in PAI-1 level in NIDDM patients is not related to hyperinsulinemia per se, but rather to insulin resistance, a contention also supported by the observation that the increase of insulin sensitivity because of weight loss or metformin treatment lowers PAI-1ag levels.41 42 Epidemiological studies have also shown a strong positive correlation between plasma PAI-1act and markers of insulin resistance, such as plasma insulin and proinsulin-like molecules (intact proinsulin and des 31.32 proinsulin) levels, body mass index, (VLDL) triglycerides, and ApoB, in healthy subjects and in patients with NIDDM and CAD.43 44 45 46 Therefore, it has been proposed that increased PAI-1 levels may be a component of the "insulin resistance syndrome,"47 a metabolic disorder characterized by upper body obesity, hypertriglyceridemia, and hyperinsulinemia, which may correspond to a prediabetic stage with an increased cardiovascular risk.
The effect of cigarette smoking on PAI-1 plasma levels is still debated. Increased PAI-1act has been observed in healthy smokers and in both smokers and past smokers with CAD,48 49 and in cigarette smokers compared with pipe/cigar smokers.50 However, no influence of cigarette smoking was found in a series of monozygotic twins discordant for smoking, and in 228 healthy families of the Stanislas cohort.51 52 Therefore, it is not inconceivable that increased PAI-1 plasma levels are related to the presence of atherosclerosis in smokers and past smokers, rather to cigarette smoking itself.
The renin–angiotensin–aldosterone system (RAAS) has recently been found to exert important effects on PAI-1. Ang II has been shown to induce PAI-1 mRNA expression in cultured rat astrocytes and VSMCs20 with a time-dependent increase in PAI-1act in the medium. When infused in healthy human volunteers at doses capable to attain physiological levels similar to those generated by standing up, Ang II caused a dose-dependent increase in plasma PAI-1 levels (but not in t-PA levels), thereby suggesting a role of Ang II in regulating basal PAI-1 expression in healthy tissues.53 The increased PAI-1 expression in response to Ang II was specific20 and not prevented in vitro by inhibitors of both AT1 and AT2 receptors, suggesting a role for additional receptor subtypes. Elegant in vitro experiments with different inhibitors of angiotensin biosynthesis pointed to Ang IV (Ang 3 to 8) and the recently identified AT4 receptors as the most likely mediators of the effect of the RAAS on PAI-1.54 55 Of interest, treatment with angiotensin-converting enzyme inhibitors was found either to lower or to unaffect plasma levels of PAI-1act or PAI-1ag (for review, see Lottermoser et al56 ). The effect of the AT1 receptor antagonist losartan on plasma levels of PAI-1act and PAI-1ag has been investigated only in 1 study to date.57 Although, by displacing Ang II from the AT1 receptors, this agent might theoretically be expected to enhance the effects of angiotensin peptides on the other angiotensin receptor subtypes, including AT4 and thereby to increase PAI-1 levels, no significant change on PAI-1act and PAI-1ag was seen after 4 weeks of treatment.57
Bradykinin administration in human hypertensives dose-dependently increases plasma t-PA levels by stimulating t-PA secretion from vascular endothelium. Because this effect occurred only after angiotensin-converting enzyme inhibition,58 a role of angiotensin-converting enzyme in maintaining the physiological balance between PAI-1 and t-PA is suggested.55
Of the other hormones, plasma aldosterone levels and renin, but not catecholamines atrial natriuretic factor and arginine-vasopressin, significantly correlated with plasma PAI-1 levels in a subset of patients enrolled in the SAVE (Survival and Ventricular Enlargement) study.59 This finding further supports the contention of a link between the RAAS and the fibrinolytic cascade.
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Genetic Influence on Plasma PAI-1 Levels |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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The human PAI-1 gene has been mapped on chromosome 7 (q21.3-q22) and contains 9 exons and 8 introns.27 60 At present, 8 different polymorphisms of the PAI-1 gene are known (Table 2
).61 The 4G/5G
polymorphism in the promoter region was found to affect plasma
PAI-1 antigen and activity levels in some, but not all,
studies.45 61 62 63 64 65 66 Furthermore, in vitro studies
demonstrated enhanced cytokine-stimulated gene transcription
associated with the 4G, compared with the 5G,
allele.22 According to the results of a transfection
assay, the 5G allele would bind factor B, a nuclear protein acting
as a transcriptional repressor, present in the human hepatocellular
carcinoma cell line HepG2, human umbilical vein
endothelial cells, and VSMCs.65 Both
healthy subjects and patients with CAD or NIDDM, who were 4G
homozygotes, were found to have the highest mean plasma PAI-1 antigen
or activity levels.45 62 63 64 65 Thus, these data would
suggest a direct relation between the plasma levels of PAI-1 and the
number of 4G alleles, but discordant results are also available. In
fact, no significant association was found between PAI-1act levels and
the 4G/5G polymorphism or the HindIII restriction
fragment length polymorphism [in strong linkage disequilibrium
with both 4G/5G and (CA)n repeat polymorphisms] in 189 patients
with NIDDM, and between PAI-1act levels and the 4G/5G polymorphism
and other recently identified 4 polymorphisms in 256 healthy men,
aged 50 to 59 years old.61 66
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There is also preliminary evidence that the genotype at the PAI-1 gene may affect the relation between PAI-1 antigen and activity levels and serum triglycerides, the association being stronger in 4G/4G than 5G/5G in patients with high triglycerides levels, NIDDM, or CAD.45 62 63 66 Because this gene-environment interaction was not confirmed in a large population of the ECTIM (Etude Cas Temoins de l'Infarctus du Myocarde) study,64 nor in healthy families52 and men,61 this issue remains controversial.
Two recent studies investigated the influence of environment and genetic background on the total variability of PAI-1 plasma levels.52 67 In Swedish middle-aged and elderly twins, a genetic effect on PAI-1 levels, comprising 42% of PAI-1act variability, was reported.67 At variance, in 228 healthy French nuclear families, a low (3%) influence of the genotype was found only in women, and a greater importance of the environmental factors, namely, of markers of the insulin resistance syndrome, comprising the 49% in fathers and 29% in mothers of the total PAI-1 variability, was described.52 It is likely, therefore, that in subjects with more pronounced features of the insulin resistance syndrome, the proportion of variance of PAI-1 plasma levels caused by genetic factors is minimized. In agreement with this contention, we recently found that in young, healthy, normotensive twins with no features of insulin resistance syndrome, a predominant additive genetic component accounts for the largest proportion (70%) of variance of plasma levels of PAI-1.68
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PAI-1 Plasma Levels and Coronary Heart Disease |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Several pieces of evidence suggest that high local levels of PAI-1 might play a role in development of CAD. Increased PAI-1 mRNA expression was found in VSMCs and macrophages of human atherosclerotic lesions.69 70 This is not surprising because cytokines and thrombin can increase local synthesis of PAI-1,28 71 with ensuing increased fibrin deposition, incorporation into the intima, and subsequent plaque growth. Local PAI-1 can also affect VSMC migration or proliferation after vascular injury, as suggested by experiments in PAI-1–deficient mice, where vascular wound healing was found to be improved.72 73 74 Because adenoviral PAI-1 gene transfer was also shown to suppress luminal stenosis after vascular injury, it was concluded that PAI-1 plays an inhibitory role in arterial neointima formation after injury.72 73
In atherosclerotic plaque, VSMC migration is accompanied by production and accumulation of matrix molecules, such as collagen and glycoproteins, and it is known that matrix deposition depends on the balance between protease and antiprotease activity. Therefore, it is conceivable that an increase in PAI-1 expression in the thickened media of atherosclerotic arteries can reduce local plasmin activity and therefore the activation of matrix metallopeptidases, protecting the vessel wall after damage.69 74 Thus, although after plaque rupture an increased local PAI-1 expression may facilitate thrombosis, it is possible that local PAI-1 generation contributes to ensure plaque stabilization.
With regard to the relation between atherosclerosis and plasma levels of PAI-1, some evidence that an impaired fibrinolysis could play a role in the early stage of atherosclerosis has emerged from the ARIC study (Atherosclerosis Risk in Communities), a biracial prospective multicenter study in asymptomatic subjects with intima-media thickening of carotid arteries.75 A cross-sectional case–control study in 455 pairs from this cohort showed a relation between PAI-1ag plasma levels and the intima-media thickness of carotid arteries, although only in white subjects.75 Cross-sectional studies in coronary atherosclerosis have also shown a decreased fibrinolytic activity, associated with elevated PAI-1ag and t-PAag plasma levels in patients with angina pectoris, compared with healthy controls.76 77 78 79 80 In the European Concerted Action on Thrombosis and Disabilities (ECAT) prospective study, where the relation of increased circulating PAI-1ag and t-PAag plasma levels with coronary stenosis was investigated in 2578 patients undergoing coronary angiography, although slightly but significantly higher PAI-1ag (P=0.0004) and PAI-1act (P=0.0008) levels were found in patients with 1 to 4 stenosed or occluded vessels, compared with the subjects without stenoses >50%, no significant relation between PAI-1 plasma level and the extent of coronary disease, measured in term of involved vessels, was detected.50 This was consistent with the results of a more recent study on 453 Yorkshire patients, classified at angiography as having normal vessels or single-vessel or multivessel coronary disease, that showed only a borderline significant (P=0.06) relation between PAI-1ag level and coronary artery stenoses.45 Thus, at the present time there is no conclusive evidence of a relation between PAI-1ag plasma level and the extent of coronary atherosclerosis, and further studies are needed.
No relation between coronary atherosclerosis and the 4G/5G polymorphism was found,45 despite the contention that the 4G/4G homozygotes would have the highest PAI-1 plasma levels. This would also challenge the hypothesis of a role for PAI-1 plasma levels in the development of coronary atherosclerotic lesions, and might suggest that the increased PAI-1 plasma levels in patients with CAD may simply be a consequence of the presence of atheroma.45 However, it must be emphasized that it is not known whether the 4G/5G polymorphism has any relation with the local (arterial wall) levels of PAI-1 and whether the increased plasma levels of PAI-1 reflect an enhanced release of the inhibitor from endothelial cells. Thus, although it has been hypothesized that an increase in local levels of PAI-1 might contribute to the pathogenesis of atherosclerosis, it is still unclear whether the increase in PAI-1 plasma levels observed in this pathological condition represents cause, effect, or both. In our view, the cause–effect relation must be demonstrated in prospective studies of healthy populations before PAI-1 can be considered a risk factor for coronary atherosclerosis, because it is evident that PAI-1 can play an ambivalent role, either by contributing plaque stabilization or by enhancing the risk of thrombosis after plaque rupture.
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PAI-1 Plasma Levels and Complications of Coronary Heart Disease (CHD) |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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In animals, disruption of the PAI-1 gene induces a mild hyperfibrinolytic state and a greater resistance to venous thrombosis,73 and conversely transgenic mice engineered to overexpress PAI-1 were found to develop spontaneous venous, but not arterial, thrombosis.81 In a canine model of coronary artery thrombosis, PAI-1act was shown to enhance both thrombosis and thrombus growth.82 Most PAI-1 found in occlusive platelet-rich clots comes from platelets and approximately one-third of PAI-1 in porcine coronary artery thrombi is active.83 As already mentioned, tumor necrosis factor-
can induce PAI-1 secretion from endothelial
cells in vitro and in vivo23 24 and other
cytokines produced in the atherosclerotic plaque can induce
adjacent endothelial cells in vivo to secrete PAI-1,
with subsequent clot stabilization.84 Thus, experimental
studies suggest an independent pathogenetic role of PAI-1 in the
development of complications of CHD, such as MI and stable or unstable
angina. It has been shown that predisposition to formation of an abnormal fibrin gel structure in vitro is associated with premature MI in humans.85 This could be the result of an increase in PAI-1act, because a strong inverse correlation between plasma PAI-1act and fibrin gel porosity, or fiber mass–length ratio, was seen in men with premature MI.85 Over the past few years, cross-sectional studies in patients with stable and unstable angina and MI showed a decreased fibrinolytic activity, with increased PAI-1ag and t-PAag levels, to be related with CHD, increased PAI-1act being more strongly associated with MI than with angina or CAD.76 The first evidence of a link between increased plasma PAI-1 levels and CHD was provided by a study in young survivors of MI.5 Elevated PAI-1act levels were also observed in diabetic and nondiabetic MI patients,41 86 for up to 1 to 3 months after MI, despite normalization of other acute-phase proteins.87 In 62 nondiabetic patients with premature MI, plasma levels of triglycerides, cholesterol, fasting insulin, proinsulin-like molecules, and PAI-1act were higher than in age-matched healthy men.46 In the already mentioned ECAT study, slightly but significantly (P<0.0001) higher plasma PAI-1ag and PAI-1act levels were found in patients with a history of MI and diabetes.50
Plasma PAI-1act, but not t-PAag, was significantly higher in offspring of men with premature MI than in controls88 ; however, it is unclear whether PAI-1act is a heritable risk factor for CAD in males, because in the European Atherosclerosis Research Study (EARS) PAI-1act did not differ between 682 offspring of men with premature MI and 1312 controls.89 In 165 patients with previous MI studied with coronary angiography, only a trend toward higher levels of PAI-1ag (22.2 versus 18.6 ng/mL; P=0.1), after adjustment for age, sex, body mass index, and triglycerides level, was found.45 (It must be acknowledged that with multivariate analyses, adjustments of particular variable values for all related parameters may cause a highly significant difference found in a univariate analysis to lose its significance. This may lead to underestimation of the importance of risk factors identified as significant in univariate analyses. Although these factors cannot be regarded as "independent" statistically speaking, they may well retain their relevance as markers of increased cardiovascular risk.) In the ECTIM study, a large 4-center case–control study of MI in patients aged 25 to 64 years, PAI-1act levels were higher in cases than in controls only in the North Irish cohort, whereas in the 3 French cohorts the opposite was found, a difference that cannot be explained by assay variability or blood handling.64
Collectively, available data suggest that in men with a high metabolic risk because of insulin resistance, increase of ApoB, fasting insulin, triglycerides, body mass index, and reduced HDL cholesterol, who suffer premature MI, increased PAI-1 levels are likely to be present. Whether this is simply a consequence of the increase of insulin and triglycerides, which stimulate in vitro the synthesis of the peptide, remains to be clarified.
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Prognostic Value of PAI-1 |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Reduced fibrinolytic activity has been linked to the risk of CHD-related events and mortality in several studies of patients with unstable and stable angina pectoris, and in healthy, middle-aged men,90 91 92 93 94 95 96 but the prognostic value of fibrinolytic variables is still controversial, because prospective cohort studies have given conflicting results. In a longitudinal study of 109 men with premature MI, evidence of a cause and effect relation between PAI-1act and risk of recurrent MI was found.6 In keeping with this finding, in the prospective trial Angina Prognosis Study in Stockholm (APSIS),94 PAI-1act was found to be an independent predictor for death or nonfatal MI, albeit only in male patients with angina. Elevation of PAI-1act was also found to be related to cardiac death within 6 to 9 years in a prospective study in 108 nondiabetic men with premature MI,97 and to development of a thrombotic event after 1-year follow-up in a smaller case–control study of patients with atherosclerotic disease in the PLAT study.98
However, other studies have given opposite results,93 99 possibly because, as fibrinolytic parameters are strongly related to other risk factors such as insulin resistance and inflammation markers, the adjustment for these variables could reduce the prognostic value of PAI-1. This explanation is also supported by the results of the previously mentioned ECAT study.100 In this study, 10 fibrinolytic variables were measured in >3000 patients (men and women) with angina pectoris, followed up for 2 years. Of these variables, 3 (t-PAag, P=0.0002; PAI-1act, P=0.02; and PAI-1ag, P=0.001) were found to be associated with an increased incidence of subsequent coronary events. However, after adjustment for markers of insulin resistance, PAI-1 antigen and activity could no longer be considered independent risk factors.100 [See note about multivariate analyses under section "PAI-1 Plasma Levels and Complications of Coronary Heart Disease (CHD)."]
With regard to the influence of PAI-1 on reperfusion after thrombolytic therapy, it had been established that the level of PAI-1 decreases slightly immediately after thrombolytic therapy, increases again several hours after therapy, and returns to normal 4 to 7 days after thrombolysis,101 and that raised PAI-1act in MI patients on admission would be associated with reduced likelihood of reperfusion.102 It has therefore been proposed that increased PAI-1act on day 3 may predict an increased risk of reinfarction,102 because an elevated PAI-1 level contributes to a prothrombotic state, increasing the likelihood of coronary thrombosis.
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PAI-1 Gene Polymorphisms and Ischemic Cardiomyopathy |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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As already mentioned, 8 polymorphisms were found in the PAI-1 gene and there is preliminary evidence of a direct association of genotypes, particularly of the 4G allele, with plasma PAI-1ag and PAI-1act levels.45 64 This led to hypothesize that the 4G/5G polymorphism may be related to the occurrence of ischemic heart disease. This hypothesis has been investigated mainly in small and cross-sectional studies that seem to support the contention of a significant association of the 4G allele with MI,22 45 64 65 65 103 although this relation was not confirmed in other studies. In an earlier study, no difference in frequency of 4G or 5G allele between long-term survivors of MI and controls was found.22 However, because patients were studied 5 to 7 years after MI, a selection bias caused by the early mortality of 4G/4G patients, who might be at highest risk, might have occurred.6 In the previously mentioned ECTIM study, no association was found between PAI-1 genotypes and MI in 476 cases compared with 601 controls.64 In the 374 middle-aged men of the American Physicians Health Study (APHS) who developed MI during the 8 years of follow-up, the distribution of the three 4G/5G genotypes was identical to those who remained free of cardiovascular disease.104 Thus, although this issue is still controversial, a bulk of evidence supports the contention that the 4G/5G polymorphism in the promoter of the PAI-1 gene is not a major risk factor for MI. In keeping with this view is also the finding that in healthy ultracentenarians the 4G/4G genotype was significantly more frequent than in younger healthy individuals, indicating that the 4G homozygosity is compatible with successful aging.105
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PAI-1 and Restenosis After Percutaneous Transluminal Coronary Angioplasty (PTCA) |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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Impaired fibrinolysis, by influencing proteolysis and neointima formation in the arterial wall, has been suspected to participate in the mechanism of restenosis occurring in as many as 25% to 40% of patients within the first 6 months after PTCA. Studies investigating whether PAI-1 levels before and after PTCA can predict the development of restenosis have shown increased PAI-1 levels after PTCA in patients who develop late restenosis. Three and 6 months after PTCA, plasma PAI-1act was significantly higher (P<0.005) in 34 patients who develop coronary restenosis than in 70 who did not, although PAI-1act was similar before the procedure.106 At variance, t-PAag levels did not differ in these patients at any stage during the whole observation period. In a subsequent clinical trial, fibrinolytic factors of 73 patients were studied before and within 6 months after elective PTCA.107 PAI-1 levels after PTCA were higher in the 27 patients with restenosis than in those without restenosis, despite similar levels before PTCA.107 PAI-1 levels were also assessed in 35 patients before and after directional coronary atherectomy. In 8 patients with late (within 6 months) restenosis, PAI-1 levels increased from 2.4 to 4.9 U/mL (P<0.05) 24 hours after directional coronary atherectomy, whereas there were no changes in patients without restenosis.108
These findings are probably because immediately after the vascular injury there is an inflammatory reaction with recruitment of leukocytes, activation of the coagulation and fibrinolytic cascade, and thrombin production and formation of a platelet-rich thrombus. The increase in PAI-1 plasma levels may therefore be regarded as a reactive phenomenon.
Early reocclusion caused by this increased thrombogenic reaction after endothelial damage and plaque rupture, which occurs within days after PTCA, does not seem to be influenced by PAI-1 levels. At variance, late restenosis, which is mainly caused by cytokine production, fibroblast and VSMC migration and proliferation, and synthesis of the extracellular matrix with subsequent intimal hyperplasia, is likely to be affected by PAI-1 levels. The increase in plasma PAI-1 levels 3 to 6 months after PTCA, or during the first 48 hours after directional coronary atherectomy in patients who developed late restenosis, may be a consequence of the local inflammatory process with an increase of mediators such as interleukin-1, platelet-derived growth factor, transforming growth factor, and tissue RAAS, which are known to stimulate PAI-1 synthesis. Thus, PAI-1 has been proposed to be an indirect marker of late restenosis.
Conclusions
The advancement of our knowledge on the biology of the clotting
and fibrinolytic cascade, and of its role in
cardiovascular disease, is the result of studies
performed, to a large extent, in the past decade. Although several
factors, some of which are known cardiovascular risk
factors, have been found to affect PAI-1 synthesis, whether PAI-1
carries, per se, an increased risk of cardiovascular
disease remains to be determined, perhaps with the exception of
late restenosis after PTCA. The fact that increased plasma
levels of PAI-1 are likely to be part of the insulin resistance
syndrome ("metabolic" syndrome X) has contributed to
complicate many studies aimed at clarifying the role of PAI-1. In
addition, as for other "players" acting locally as
autocrine/paracrine factors, the relation between circulating (plasma)
and local (tissue) levels of PAI-1 must be taken into consideration,
and it has been neglected in most available studies. Conflicting
results are available concerning the genetic determinants of plasma
levels of PAI-1 antigen and activity, despite intensive investigative
efforts. It can be anticipated that a better understanding of the role
of PAI-1 in the different cardiovascular diseases,
which might be relevant for the development of novel therapeutic
strategies, is likely to be attained in the next decade with the use of
molecular techniques, which are becoming increasingly available to most
clinical research laboratories.
Received October 23, 1998; accepted December 2, 1998.
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References |
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TopIntroductionBiochemical FeaturesEnvironmental Influences on...Genetic Influence on Plasma...PAI-1 Plasma Levels and...PAI-1 Plasma Levels and...Prognostic Value of PAI-1PAI-1 Gene Polymorphisms and...PAI-1 and Restenosis After...References |
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1. Kruithof EKO, Ransijn A, Bachmann F. Inhibition of tissue plasminogen activator by human plasma. In: Davidson JF, Bachmann F, Bouvier CA, Kruithof EKO, eds. Progress in Fibrinolysis. Edinburgh, Scotland: Churchill Livingstone; 1983:362–366.
2. Chandler WL. A kinetic model of the circulatory regulation of tissue plasminogen activator. Thromb Haemost. 1991;66:321–328.[Medline] [Order article via Infotrieve]
3. Wiman B. Plasminogen activator inhibitor 1 (PAI-1) in plasma: its role in thrombotic disease. Thromb Haemost. 1995;74:71–76.[Medline] [Order article via Infotrieve]
4.
Hamsten A, Blombäck M, Wiman B, Svensson J,
Szamosi A, de Faire U, Mettinger L. Haemostatic function in myocardial
infarction. Br Heart J. 1986;55:58–66.
5. Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985;313:1557–1563.[Abstract]
6. Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3–9.[Medline] [Order article via Infotrieve]
7.
Ny T, Sawdey M, Lawrence D, Millan JL, Loskutoff DJ.
Cloning and sequence of a cDNA coding for the human beta-migrating
endothelial-cell-type plasminogen
activator inhibitor. Proc Natl Acad Sci
U S A. 1986;83:6776–6780.
8. Egelund R, Schousboe SL, Sottrup-Jensen L, Rodenburg KW, Andreasen PA. Type-1 plasminogen-activator inhibitor–conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility. Eur J Biochem. 1997;248:775–785.[Medline] [Order article via Infotrieve]
9. Booth NA, Simpson AJ, Croll A, Bennett B, MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol. 1988;70:327–333.[Medline] [Order article via Infotrieve]
10. Chomiki N, Henry M, Alessi MC, Anfosso F, Juhan-Vague I. Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls. Thromb Haemost. 1994;72:44–53.[Medline] [Order article via Infotrieve]
11. Lindahl TL, Ohlsson PI, Wiman B. The mechanism of the reaction between human plasminogen-activator inhibitor 1 and tissue plasminogen activator. Biochem J. 1990;265:109–113.[Medline] [Order article via Infotrieve]
12. Kruithof EK, Ransijn A, Bachmann F. Influence of detergents on the measurement of the fibrinolytic activity of plasminogen activators. Thromb Res. 1982;28:251–260.[Medline] [Order article via Infotrieve]
13. Mottonen J, Strand A, Symersky J, Sweet RM, Danley DE, Geoghegan KF, Gerard RD, Goldsmith EJ. Structural basis of latency in plasminogen activator inhibitor-1. Nature. 1992;355:270–273.[Medline] [Order article via Infotrieve]
14.
Seiffert D, Ciambrone G, Wagner NV, Binder BR,
Loskutoff DJ. The somatomedin B domain of vitronectin:
structural requirements for the binding and stabilization of active
type 1 plasminogen activator
inhibitor. J Biol Chem. 1994;269:2659–2666.
15. Lindahl TL, Sigurdardottir O, Wiman B. Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb Haemost. 1989;62:748–751.[Medline] [Order article via Infotrieve]
16.
Chandler WL, Alessi MC, Aillaud MF, Henderson P,
Vague P, Juhan-Vague I. Clearance of tissue plasminogen
activator (TPA) and TPA/plasminogen
activator inhibitor type 1 (PAI-1) complex:
relationship to elevated TPA antigen in patients with high PAI-1
activity levels. Circulation. 1997;96:761–768.
17.
Heaton JH, Gelehrter TD. Glucocorticoid induction of
plasminogen activator and
plasminogen activator-inhibitor
messenger RNA in rat hepatoma cells. Mol Endocrinol. 1989;3:349–355.
18.
Hopkins WE, Fujii S, Sobel BE. Synergistic induction
of plasminogen activator inhibitor
type-1 in HEP G2 cells by thrombin and transforming growth factor-beta.
Blood. 1992;79:75–81.
19.
Reilly CF, McFall RC. Platelet-derived growth
factor and transforming growth factor-beta regulate
plasminogen activator inhibitor-1
synthesis in vascular smooth muscle cells. J Biol Chem. 1991;266:9419–9427.
20.
van Leeuwen RT, Kol A, Andreotti F, Kluft C, Maseri
A, Sperti G. Angiotensin II increases
plasminogen activator inhibitor
type 1 and tissue-type plasminogen activator
messenger RNA in cultured rat aortic smooth muscle cells.
Circulation. 1994;90:362–368.
21.
Latron Y, Chautan M, Anfosso F, Alessi MC, Nalbone G,
Lafont H, Juhan-Vague I. Stimulating effect of oxidized low density
lipoproteins on plasminogen activator
inhibitor-1 synthesis by endothelial cells.
Arterioscler Thromb. 1991;11:1821–1829.
22.
Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S,
Henney AM. The two allele sequences of a common polymorphism in
the promoter of the plasminogen activator
inhibitor-1 (PAI-1) gene respond differently to
interleukin-1 in HepG2 cells. J Biol Chem. 1993;268:10739–10745.
23.
van Hinsbergh VW, Kooistra T, van den Berg EA,
Princen HM, Fiers W, Emeis JJ. Tumor necrosis factor increases the
production of plasminogen activator
inhibitor in human endothelial cells in
vitro and in rats in vivo. Blood. 1988;72:1467–1473.
24.
van der Poll T, Levi M, Büller HR, van Deventer
SJ, de Boer JP, Hack CE, ten Cate JW. Fibrinolytic response to tumor
necrosis factor in healthy subjects. J Exp Med. 1991;174:729–732.
25. Gallicchio M, Hufnagl P, Wojta J, Tipping P. IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. J Immunol. 1996;157:2610–2617.[Abstract]
26. Arnman V, Stemme S, Rymo L, Risberg B. Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. Thromb Res. 1995;77:431–440.[Medline] [Order article via Infotrieve]
27. Follo M, Ginsburg D. Structure and expression of the human gene encoding plasminogen activator inhibitor, PAI-1. Gene. 1989;84:447–453.[Medline] [Order article via Infotrieve]
28.
Kapiotis S, Jilma B, Szalay T, Dirnberger E, Wagner
O, Eichler HG, Speiser W. Evidence against an effect of endothelin-1 on
blood coagulation, fibrinolysis, and
endothelial cell integrity in healthy men.
Arterioscler Thromb Vasc Biol. 1997;17:2861–2867.
29. Padayatty SJ, Orme S, Zenobi PD, Stickland MH, Belchetz PE, Grant PJ. The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies. Thromb Haemost. 1993;70:1009–1013.[Medline] [Order article via Infotrieve]
30. Biemond BJ, Levi M, ten Cate H, van der Poll T, Büller HR, Hack CE, ten Cate JW. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci. 1995;88:587–594.[Medline] [Order article via Infotrieve]
31.
van der Poll T, Levi M, Dentener M, Jansen PM, Coyle
SM, Braxton CC, Buurman WA, Hack CE, ten Cate JW, Lowry SF.
Epinephrine exerts anticoagulant effects during human
endotoxemia. J Exp Med. 1997;185:1143–1148.
32.
DeSouza CA, Dengel DR, Rogers MA, Cox K, Macko RF.
Fibrinolytic responses to acute physical activity in older hypertensive
men. J Appl Physiol. 1997;82:1765–1770.
33.
Fernhall B, Szymanski LM, Gorman PA, Milani J, Paup
DC, Kessler CM. Fibrinolytic activity is similar in physically active
men with and without a history of myocardial infarction.
Arterioscler Thromb Vasc Biol. 1997;17:1106–1113.
34. Winkler UH. Effects of androgens on haemostasis. Maturitas. 1996;24:147–155.[Medline] [Order article via Infotrieve]
35.
Gebara OCE, Mittleman MA, Sutherland P, Lipinska I,
Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler GH.
Association between increased estrogen status and increased
fibrinolytic potential in the Framingham Offspring Study.
Circulation. 1995;91:1952–1958.
36. Scarabin PY, Plu-Bureau G, Zitoun D, Bara L, Guize L, Samama MM. Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb Haemost. 1995;74:928–932.[Medline] [Order article via Infotrieve]
37.
Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F,
Guetta V, Waclawiw, M, Cannon RO III. Effects of hormone-replacement
therapy on fibrinolysis in postmenopausal women.
N Engl J Med. 1997;336:683–690.
38. Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost. 1997;78:656–660.[Medline] [Order article via Infotrieve]
39. Grant PJ, Kruithof EK, Felley CP, Felber JP, Bachmann F. Short-term infusions of insulin, triacylglycerol and glucose do not cause acute increases in plasminogen activator inhibitor-1 concentrations in man. Clin Sci. 1990;79:513–516.[Medline] [Order article via Infotrieve]
40.
Panahloo A, Andres C, Mohamed-Ali V, Gould MM, Talmud
P, Humphries SE, Yudkin JS. The insertion allele of the ACE gene
I/D polymorphism: a candidate gene for insulin resistance?
Circulation. 1995;92:3390–3393.
41.
Gray RP, Patterson DL, Yudkin JS.
Plasminogen activator inhibitor
activity in diabetic and nondiabetic survivors of myocardial
infarction. Arterioscler Thromb. 1993;13:415–420.
42. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabete Metab. 1991;17:168–173.[Medline] [Order article via Infotrieve]
43. Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metab. 1987;13:331–336.[Medline] [Order article via Infotrieve]
44. Gray RP, Panahloo A, Mohamed-Ali V, Patterson DL, Yudkin JS. Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction. Atherosclerosis. 1997;130:171–178.[Medline] [Order article via Infotrieve]
45.
Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson
IJ, Grant PJ. Plasminogen activator
inhibitor-1 promoter 4G/5G genotype and plasma
levels in relation to a history of myocardial infarction in patients
characterized by coronary angiography. Arterioscler
Thromb Vasc Biol. 1997;17:33–37.
46. Båvenholm P, Proudler A, Silveira A, Crook D, Blombäck M, de Faire U, Hamsten A. Relationships of insulin and intact and split proinsulin to haemostatic function in young men with and without coronary artery disease. Thromb Haemost. 1995;73:568–575.[Medline] [Order article via Infotrieve]
47.
Juhan-Vague I, Thompson SG, Jespersen J.
Involvement of the hemostatic system in the insulin resistance
syndrome: a study of 1500 patients with angina pectoris—the ECAT
Angina Pectoris Study Group. Arterioscler Thromb. 1993;13:1865–1873.
48. Haire WD, Goldsmith JC, Rasmussen J. Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors. Am J Haematol. 1989;31:36–40.[Medline] [Order article via Infotrieve]
49. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet. 1987;2:986–988.[Medline] [Order article via Infotrieve]
50.
ECAT Angina Pectoris Study Group. Baseline
associations of haemostatic factors with extent of coronary
arteriosclerosis and other coronary risk
factors in 3000 patients with angina pectoris undergoing
coronary angiography. Eur Heart J. 1993;14:8–17.
51. Calori G, D'Angelo A, Della Valle P, Ruotolo G, Ferini-Strambi L, Giusti C, Errera A, Gallus G. The effect of cigarette-smoking on cardiovascular risk factors: a study of monozygotic twins discordant for smoking. Thromb Haemost. 1996;75:14–18.[Medline] [Order article via Infotrieve]
52.
Henry M, Tregouët DA, Alessi MC, Aillaud MF,
Visvikis S, Siest G, Tiret L, Juhan-Vage I. Metabolic
determinants are much more important than genetic polymorphisms in
determining the PAI-1 activity and antigen plasma concentrations.
Arterioscler Thromb Vasc Biol. 1998;18:84–91.
53.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams
GH, Vaughan DE. Stimulation of plasminogen
activator inhibitor in vivo by infusion of
angiotensin II: evidence of a potential interaction between
the renin-angiotensin system and fibrinolytic function.
Circulation. 1993;87:1969–1973.
54. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 1995;95:995–1001.
55. Vaughan DE. The renin-angiotensin system and fibrinolysis. Am J Cardiol. 1997;79:12–16.
56. Lottermoser K, Weisser B, Hertfelder HJ, Wostmann B, Vetter H, Dusing R. Antihypertensive drug treatment and fibrinolytic function. Am J Hypertens. 1998;11:378–384.[Medline] [Order article via Infotrieve]
57.
Seljeflot I, Moan A, Kjeldsen S, Sandvik E, Arnesen
H. Effect of angiotensin II receptor blockade on
fibrinolysis during acute
hyperinsulinemia in patients with essential
hypertension. Hypertension. 1996;27:1299–1304.
58. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost. 1997;77:522–525.[Medline] [Order article via Infotrieve]
59. Vaughan DE, Rouleau JL, Pfeffer MA. Role of the fibrinolytic system in preventing myocardial infarction. Eur Heart J. 1995;16(suppl K):31–36.
60.
Bosma PJ, van den Berg EA, Kooistra T, Siemieniak DR,
Slightom JL. Human plasminogen activator
inhibitor-1 gene: promoter and structural gene
nucleotide sequences. J Biol Chem. 1988;263:9129–9141.
61.
Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti
F, Arveiler D, Ferriéres J, Evans A, Amouyel P, Poirier O,
Cambien F, Juhan-Vague I. Five frequent polymorphisms of the PAI-1
gene: lack of association between genotypes, PAI activity, and
triglyceride levels in a healthy population.
Arterioscler Thromb Vasc Biol. 1997;17:851–858.
62.
Dawson S, Hamsten A, Wiman B, Henney A, Humphries S.
Genetic variation at the plasminogen activator
inhibitor-1 locus is associated with altered levels of
plasma plasminogen activator
inhibitor-1 activity. Arterioscler Thromb. 1991;11:183–190.
63. Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes. 1995;44:37–42.[Abstract]
64. Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study: Etude Cas Temoins de l'Infarctus du Myocarde. Thromb Haemost. 1995;74:837–841.[Medline] [Order article via Infotrieve]
65.
Eriksson P, Kallin B, van `t Hooft FM, Båvenholm P,
Hamsten A. Allele-specific increase in basal transcription of the
plasminogen-activator inhibitor 1
gene is associated with myocardial infarction. Proc Natl Acad Sci
U S A. 1995;92:1851–1855.
66. Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost. 1995;74:842–847.[Medline] [Order article via Infotrieve]
67.
Hong Y, Pedersen NL, Egberg N, de Faire U. Moderate
genetic influences on plasma levels of plasminogen
activator inhibitor-1and evidence of genetic
and environmental influences shared by plasminogen
activator inhibitor-1,
triglycerides, and body mass index. Arterioscler
Thromb Vasc Biol. 1997;17:2776–2782.
68.
Cesari M, Sartori MT, Patrassi GM, Vettore S, Rossi
GP. Determinants of plasma levels of plasminogen
activator inhibitor-1 (PAI-1): a study of
normotensive twins. Arterioscler Thromb Vasc Biol. 1999;19:316–320.
69.
Lupu F, Heim DA, Bachmann F, Hurni M, Kakkar VV,
Kruithof EK. Plasminogen activator expression
in human atherosclerotic lesions. Arterioscler Thromb Vasc
Biol. 1995;15:1444–1455.
70.
Schneiderman J, Sawdey MS, Keeton MR, Bordin GM,
Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1
plasminogen activator inhibitor
gene expression in atherosclerotic human arteries. Proc Natl Acad
Sci U S A. 1992;89:6998–7002.
71. de Boer JP, Abbink JJ, Brouwer MC, Meijer C, Roem D, Voorn GP, Lambers JWJ, van Mourik JA, Hack CE. PAI-1 synthesis in the human hepatoma cell line HepG2 is increased by cytokines-evidence that the liver contributes to acute phase behaviour of PAI-1. Thromb Haemost. 1991;65:181–185.[Medline] [Order article via Infotrieve]
72.
Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F,
Collen D, Gerard RD. Inhibitory role of
plasminogen activator inhibitor-1
in arterial wound healing and neointima
formation: a gene targeting and gene transfer study in mice.
Circulation. 1997;96:3180–3191.
73. Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993;92:2756–2760.
74.
Hasenstab D, Forough R, Clowes AW.
Plasminogen activator inhibitor
type 1 and tissue inhibitor of metalloproteinases-2
increase after arterial injury in rats. Circ
Res. 1997;80:490–496.
75.
Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE,
Wu KK. Association of fibrinolytic parameters with early
atherosclerosis: the ARIC
Study—Atherosclerosis Risk in Communities Study.
Circulation. 1995;91:284–290.
76.
Aznar J, Estellés A, Tormo G, Sapena P, Tormo
V, Blanch S, España F. Plasminogen
activator inhibitor activity and other
fibrinolytic variables in patients with coronary artery
disease. Br Heart J. 1988;59:535–541.
77.
Olofsson BO, Dahlen G, Nilsson TK. Evidence for
increased levels of plasminogen activator
inhibitor and tissue plasminogen
activator in plasma of patients with angiographically
verified coronary artery disease. Eur Heart J. 1989;10:77–82.
78. Huber K, Resch I, Stefenelli T, Lang I, Probst P, Kaindl F, Binder BR. Plasminogen activator inhibitor-1 levels in patients with chronic angina pectoris with or without angiographic evidence of coronary sclerosis. Thromb Haemost. 1990;63:336–339.[Medline] [Order article via Infotrieve]
79. Francis RB Jr, Kawanishi D, Baruch T, Mahrer P, Rahimtoola S, Feinstein DI. Impaired fibrinolysis in coronary artery disease. Am Heart J. 1988;115:776–780.[Medline] [Order article via Infotrieve]
80. Held C, Hjemdahl P, Rehnqvist N, Wallén NH, Forslund L, Björkander I, Angelin B, Wiman B. Haemostatic markers, inflammatory parameters and lipids in male and female patients in the Angina Prognosis Study in Stockholm (APSIS): a comparison with healthy controls. J Intern Med. 1997;241:59–69.[Medline] [Order article via Infotrieve]
81. Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature. 1990;346:74–76.[Medline] [Order article via Infotrieve]
82.
Biemond BJ, Levi M, Coronel R, Janse MJ, ten Cate JW,
Pannekoek H. Thrombolysis and reocclusion in experimental
jugular vein and coronary artery thrombosis: effects of a
plasminogen activator inhibitor
type 1-neutralizing monoclonal antibody. Circulation. 1995;91:1175–1181.
83.
Fay WP, Murphy JG, Owen WG. High concentrations of
active plasminogen activator
inhibitor-1 in porcine coronary artery thrombi.
Arterioscler Thromb Vasc Biol. 1996;16:1277–1284.
84.
Handt S, Jerome WG, Tietze L, Hantgan RR.
Plasminogen activator inhibitor-1
secretion of endothelial cells increases fibrinolytic
resistance of an in vitro fibrin clot: evidence for a key role of
endothelial cells in thrombolytic
resistance. Blood. 1996;87:4204–4213.
85. Fatah K, Silveira A, Tornvall P, Karpe F, Blombäck M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost. 1996;76:535–540.[Medline] [Order article via Infotrieve]
86. Almér LO, Ohlin H. Elevated levels of the rapid inhibitor of plasminogen activator (t-PAI) in acute myocardial infarction. Thromb Res. 1987;47:335–339.[Medline] [Order article via Infotrieve]
87. Chandler WL, Stratton JR. Laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction. Am J Clin Pathol. 1994;102:248–252.[Medline] [Order article via Infotrieve]
88. Rallidis LS, Megalou AA, Papageorgakis NH, Trikas AG, Chatzidimitriou, GI, Tsitouris GK. Plasminogen activator inhibitor 1 is elevated in the children of men with premature myocardial infarction. Thromb Haemost. 1996;76:417–421.[Medline] [Order article via Infotrieve]
89. Bara L, Nicaud V, Tiret L, Cambien F, Samama MM. Expression of a paternal history of premature myocardial infarction on fibrinogen, factor VIIC and PAI-1 in European offspring: the EARS study—European Atherosclerosis Research Study Group. Thromb Haemost. 1994;71:434–440.[Medline] [Order article via Infotrieve]
90. Benchimol D, Dartigues JF, Benchimol H, Drouillet F, Lauribe P, Marazanof M, Couffinhal T, Bonnet J. Predictive value of hemostatic factors for sudden death in patients with stable angina pectoris. Am J Cardiol. 1995;76:241–244.[Medline] [Order article via Infotrieve]
91.
Munkvad S, Gram J, Jespersen J. A depression of
active tissue plasminogen activator in plasma
characterizes patients with unstable angina pectoris who develop
myocardial infarction. Eur Heart J. 1990;11:525–528.
92. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet. 1993;342:1076–1079.[Medline] [Order article via Infotrieve]
93.
Thompson SG, Kienast J, Pyke SD, Haverkate F, van de
Loo JCW. Hemostatic factors and the risk of myocardial infarction or
sudden death in patients with angina pectoris: European Concerted
Action on Thrombosis and Disabilities Angina Pectoris Study Group.
N Engl J Med. 1995;332:635–641.
94.
Held C, Hjemdahl P, Rehnqvist N, Wallén NH,
Björkander I, Eriksson SV, Forslund L, Wiman B. Fibrinolytic
variables and cardiovascular prognosis in patients
with stable angina pectoris treated with verapamil or
metoprolol: results from the Angina Prognosis study in Stockholm.
Circulation. 1997;95:2380–2386.
95.
Jansson JH, Olofsson BO, Nilsson TK. Predictive value
of tissue plasminogen activator mass
concentration on long-term mortality in patients with coronary
artery disease: a 7-year follow-up. Circulation. 1993;88:2030–2034.
96. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet. 1993;341:1165–1168.[Medline] [Order article via Infotrieve]
97. Malmberg K, Båvenholm P, Hamsten A. Clinical and biochemical factors associated with prognosis after myocardial infarction at a young age. J Am Coll Cardiol. 1994;24:592–599.[Abstract]
98.
Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L,
Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G,
Tavazzi L, Tremoli E, Pozzoli E, Turri M, for the PLAT Group. Increased
fibrin turnover and high PAI-1 activity as predictors of
ischemic events in atherosclerotic patients: a case-control
study—The PLAT Group. Arterioscler Thromb. 1993;13:1412–1417.
99.
Jansson JH, Nilsson TK, Olofsson BO. Tissue
plasminogen activator and other risk factors as
predictors of cardiovascular events in patients with
severe angina pectoris. Eur Heart J. 1991;12:157–161.
100.
Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F,
Thompson SG. Fibrinolytic factors and the risk of myocardial infarction
or sudden death in patients with angina pectoris: ECAT Study
Group—European Concerted Action on Thrombosis and Disabilities.
Circulation.. 1996;94:2057–2063.
101. Goto S, Kawai Y, Handa S, Abe S, Takahashi E, Watanabe K, Hori S, Ikeda Y. Serial changes in plasma concentration of plasminogen activator inhibitor-1 before and serially after thrombolytic therapy for acute myocardial infarction. Cardiology. 1993;82:280–285.[Medline] [Order article via Infotrieve]
102.
Gray RP, Yudkin JS, Patterson DL. Enzymatic evidence of
impaired reperfusion in diabetic patients after
thrombolytic therapy for acute myocardial infarction: a
role for plasminogen activator
inhibitor? Br Heart J. 1993;70:530–536.
103. Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost. 1995;74:1032–1034.[Medline] [Order article via Infotrieve]
104.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ,
Miletich JP. Arterial and venous thrombosis is not
associated with the 4G/5G polymorphism in the promoter of the
plasminogen activator inhibitor
gene in a large cohort of US men. Circulation. 1997;95:59–62.
105.
Mannucci PM, Mari D, Merati G, Peyvandi F, Tagliabue L,
Sacchi E, Taioli E, Sansoni P, Bertolini S, Franceschi C. Gene
polymorphisms predicting high plasma levels of coagulation and
fibrinolysis proteins: a study in centenarians.
Arterioscler Thromb Vasc Biol. 1997;17:755–759.
106. Huber K, Jörg M, Probst P, Schuster E, Lang I, Kaindl F, Binder BR. A decrease in plasminogen activator inhibitor-1 activity after successful percutaneous transluminal coronary angioplasty is associated with a significantly reduced risk for coronary restenosis. Thromb Haemost. 1992;67:209–213.[Medline] [Order article via Infotrieve]
107. Ishiwata S, Tukada T, Nakanishi S, Nishiyama S, Seki A. Postangioplasty restenosis: platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis. Am Heart J. 1997;133:387–392.[Medline] [Order article via Infotrieve]
108. Lins M, Zurborn KH, Dau O, Nagel E, Muurling S, Herrmann G, Simon R. Coagulation activation in patients undergoing directional coronary atherectomy. Thromb Res. 1997;86:433–441.[Medline] [Order article via Infotrieve]
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