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(Circulation. 1998;98:2241-2247.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

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

Evidence for the Fibrinolytic System as an Independent Primary Risk Factor

Anna M. Thögersen, MD; Jan-Håkan Jansson, MD; Kurt Boman, MD; Torbjörn K. Nilsson, MD; Lars Weinehall, MD; Fritz Huhtasaari, MD; ; Göran Hallmans, MD

From the Department of Medicine (A.M.T.), Department of Clinical Chemistry (T.K.N.), and Departments of Nutritional Research and Pathology (G.H.), Umeå University Hospital; Department of Medicine-Geriatric, Skellefteå County Hospital (J.-H.J., K.B.) and Department of Epidemiology and Public Health (L.W.), University of Umeå; and Department of Medicine, Luleå Hospital (F.H.), Sweden.

Correspondence to Anna Margrethe Thögersen, Department of Medicine, Umeå University Hospital, Umeå, S-901 85 Sweden. E-mail anna.margrethe.thogersen{at}medicin.umu.se

	Abstract

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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.

Key Words: myocardial infarction • risk factors • plasminogen activators • von Willebrand factor

	Introduction

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In northern Sweden, a high incidence of myocardial infarction has been reported,¹ but traditional risk factors such as hypercholesterolemia, hypertension, and smoking explain only part of the individual risk of cardiovascular events.^{2 3} Because plaque rupture and thrombus formation have been identified as the most common mechanistic events in myocardial infarction,⁴ recent studies have focused particularly on various components of the hemostatic system.⁵ Initially, several cross-sectional studies of patients with angina pectoris or previous myocardial infarction suggested that such patients had an impaired fibrinolytic system, and a few prospective cohort studies later supported the idea that fibrinolytic factors such as plasminogen activator inhibitor (PAI-1) and tissue-type plasminogen activator (tPA) mass concentrations were predictors of future events in this type of patient.^{5 6} In contrast, prospective studies of initially healthy individuals assessing the predictive value of specific components of the fibrinolytic system are sparse,⁷ and there are no such reports on thrombomodulin (TM) and PAI-1. Controversy also still exists over the influence of dehydroepiandrosterone sulfate (DHEAS) and the development of coronary artery disease.

The aim of the present study was to test whether disturbances in endothelium-derived hemostatic factors (PAI-1, tPA, von Willebrand factor [vWF], and TM) or DHEAS preceded a first myocardial infarction in a north Swedish population with a high incidence of cardiovascular events and whether measurements of these factors could improve the prediction of subjects at risk in addition to established risk factors. Some of the data have been published previously in abstract form.⁸

	Methods

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Study Cohort
As a part of an ongoing community intervention program on cardiovascular disease and diabetes prevention in the county of Västerbotten in northern Sweden, the Västerbotten Intervention program (VIP), and the World Health Organization (WHO) MONICA study in Västerbotten and Norrbotten, the 2 northernmost counties in Sweden, 78 cases fulfilled the inclusion criteria of a first myocardial infarction but no cancer as earlier described.⁹ In brief, the VIP study was launched 1985, and men and women 30, 40, 50, and 60 years of age were invited to a health survey at their local primary healthcare centers. We used a prospective nested case-control design in which incident cases were defined by the northern Sweden MONICA incidence registry¹⁰ and the controls are randomly selected from the population-based health surveys in VIP or from the MONICA screenings. For the present study, they were matched for sex, age (±2 years), date of health survey (±1 year), and geographical region. Controls were excluded if they had died before September 30, 1994; if they had moved out from the MONICA region before that date; if they had reported a prior acute myocardial infarction or stroke according to the survey questionnaire; or if acute myocardial infarction or stroke before the health survey could not be excluded from the case records. The participants of the health survey were asked to complete a questionnaire with items on, among other things, social background, smoking habits, medical history, and intake of drugs. Up to September 30, 1994, we had screened 36 405 subjects in northern Sweden for cardiovascular risk factors, and >91% of the participants had donated blood samples. The study was approved by the Research Ethics Committee of Umeå University, and the data handling procedures were approved by the National Computer Data Inspection Board. All participants gave informed consent.

Clinical Variables and End Points
Hypertension was defined as systolic blood pressure >160 mm Hg and/or diastolic blood pressure >95 mm Hg or defined because the patient reported taking antihypertensive medication during a period of 14 days before the health survey. Smokers were divided into daily smokers and nonsmokers. Statements on diabetes were obtained from the questionnaire. Body mass index (BMI) was calculated, after measurement of body weight and height, as weight (kilograms) divided by height (meters squared).

A diagnosis of myocardial infarction was confirmed if the event met WHO criteria.¹¹ For fatal myocardial infarctions, we also accepted diagnoses based on necropsies and on deaths confirmed by records as being caused by coronary heart disease (ICD-9 411–414). Silent myocardial infarctions found on routine examination were not included because they could not be assigned an accurate date of occurrence.

Blood Sampling and Laboratory Procedures
Venous blood samples for hemostatic assays, DHEAS, and apolipoprotein (apo) A-1 were drawn without stasis after 5 minutes of bed rest into evacuated glass tubes (Venoject) containing 1/100 volume of 0.5 mmol/L EDTA. Plasma was obtained by centrifugation at 1500g for 15 minutes, placed in aliquots, and stored frozen within 1 hour at -80°C until analysis. In some instances, the samples were temporarily stored at -20°C for up to 1 week but then transferred to -80°C. Most of the health surveys were done between 7 and 11 AM. Blood specimens from cases and controls were analyzed in triplets of 1 case and 2 controls; the position of the cases was varied at random within triplets to avoid systemic bias and interassay variability. The investigators and laboratory staff had no knowledge of case or control status.

The mass concentrations of tPA and PAI-1 in plasma were determined with an ELISA.¹² Reagent kits (Imulyse) were purchased from Biopool AB. For tPA mass concentration, the coefficient of variation (CV) at 8 µg/L was 9.5% in our hands (n=34) and 10% according to the manufacturer. For PAI-1 mass concentration, the CV is 9% according to the manufacturer.

vWF was measured with an ELISA¹³ by use of reagents purchased from DAKO. The values are expressed as percent of the value obtained in a pool of normal subjects (n=20). For vWF, the CV at a level of 138% was 11.7% in our hands (n=41).

TM was measured with an ELISA method¹⁴ purchased from STAGO.

Plasma DHEAS was measured directly in diluted plasma with a radioimmunoassay with an antiserum obtained from Endocrine Sciences and raised against DHEA-SO₄-17-oxime-BSA; 7-³H-DHEAS was used as tracer, and free and bound radioactivities were separated by means of ammonium sulfate precipitation.

Serum samples for lipid measurements were obtained after 4 hours of fasting. Total cholesterol was measured by enzymatic methods with Reflotron bench-top analyzers (Boehringer Mannheim GmbH) at each health survey center at the time of the health survey. The mean interassay CV was 2.6%. ApoA-I was measured with a commercial radioimmunoassay research kit (RIA-100, Kabi Pharmacia).

Statistical Analysis
We compared mean values and proportions of various cardiovascular risk factors between cases and controls by unpaired t tests and Fisher's exact test as appropriate. To test the relation between increasing levels of risk factors and the risk of acute myocardial infarction, the sample was categorized a priori for TM, vWF, and mass concentrations of tPA and PAI-1 into quartiles or tertiles or dichotomized by the distribution of the control values or to clinically defined levels. To account for the matching variables, conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% CIs. To account for the matching variables and potential confounding factors simultaneously, we performed conditional logistic regression analysis, using the EGRET software package to estimate relative risks by calculating the ORs.¹⁵

A ² test for trends was used to assess any relationship between increasing levels of tPA, PAI-1, vWF, TM, and DHEAS and the risk of first myocardial infarction after the samples were categorized. Thus, fewer assumptions about the shape of the curve relating hemostatic factors and DHEAS to the risk of myocardial infarction were required. With a total of 78 cases and 156 controls, it is estimated that for a statistical power of 80%, ORs >3.0 will be significant at the 5% level when exposure prevalence is 10% and those >2.3 will be significant at the 5% level when exposure prevalence is 30%.

Missing Values
The number of individuals with missing values per variable was as follows: smoking, 17; diabetes, 11; BMI, 4; hypertension, 7; and different plasma analyses, at most 7. In the conditional logistic regression tests, missing values (besides smoking and diabetes) were replaced by the mean value for the control group in the continuous variables and in the categorical variables by the value representing nonexposed. Missing values for smoking and diabetes were categorized in a separate group. This allowed all subjects to be included in the conditional logistic regression analyses. Specifically, nonexposed meant the lowest quartiles for the variables tPA, PAI-1, vWF, and TM; for apoA-1 and DHEAS, the highest quartile or tertile; for BMI, the value <27 kg/m²; and for hypertension, normotensive.

ApoB was excluded as a traditional risk factor because of high correlation with serum cholesterol (r=0.78).

	Results

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Acute myocardial infarction events for the 78 cases occurred on average 18 months after their participation in the health survey (median, 15 months). Baseline characteristics for the 16 women and 62 men who developed a myocardial infarction and for the matched controls are shown in Table 1. Established cardiovascular risk factors such as smoking, hypertension, and diabetes were more common in the cases, and they had higher mean levels of BMI, systolic and diastolic blood pressures, and serum cholesterol concentrations but lower mean concentrations of apoA-I. Moreover, in the group with myocardial infarction, the mass concentrations of PAI-1, tPA, and vWF were significantly higher, whereas TM and DHEAS did not differ compared with the reference group.

View this table: [in this window] [in a new window]   Table 1. Mean Baseline Characteristics for Patients and Control Subjects by Use of an Unpaired t Test and Fisher's Exact Test for Comparison

Several variables differed between men and women. Comparison of men and women by unpaired t test analysis and Fisher's exact test including only the controls showed that women had significantly higher levels of apoA-I, lower diastolic blood pressure, and lower concentrations of DHEAS and TM than men.

In conditional univariate logistic regression analysis in which numerical data were treated as continuous values and with myocardial infarction as an outcome variable, there were significant associations with the plasma concentrations of PAI-1, tPA, and vWF and with smoking, hypertension, diabetes, hypercholesterolemia, BMI, systolic and diastolic blood pressures, and apoA-1 concentration (Table 2). The same analysis in the subgroup of men showed significant associations of outcome with mass concentration of tPA and PAI-1, smoking, BMI, and apoA-1 concentration (data not shown). In the subgroup of women, there were significant associations with mass concentrations of PAI-1 and tPA, BMI, systolic blood pressure, hypertension, and apoA-1 concentration (data not shown).

View this table: [in this window] [in a new window]   Table 2. Relative Risk of Myocardial Infarction in 78 Case-Control Triplets by Use of Discrete Numerical Data and Continuous Variables, Respectively, and Conditional Logistic Regression for Comparison

Data for the total study population and the probability value for the test for trends across the stratification are shown in Tables 3 and 4. High plasma levels of PAI-1, tPA, and vWF mass concentrations; obesity; and high levels of cholesterol were all associated with significant increases in the risk of myocardial infarction. High levels of apoA-I were associated with a markedly reduced risk, whereas only nonsignificant trends for increased risk were seen for high levels of TM and low levels of DHEAS.

View this table: [in this window] [in a new window]   Table 3. Relative Risk of Myocardial Infarction From a Matched Analysis of 78 Case-Control Triplets With Conditional Logistic Regression and Adjustment for Traditional Risk Factors

View this table: [in this window] [in a new window]   Table 4. Relative Risk of Myocardial Infarction From a Matched Analysis of 78 Case-Control Triplets With Conditional Logistic Regression and Adjustment for Traditional Risk Factors

To visually illustrate the strength of these relationships, the ORs through quartiles 1 through 4 of the distributions of mass concentrations of tPA, PAI-1, and vWF are shown in the Figure. Subgroup analysis on men showed that higher levels of cholesterol and mass concentrations of tPA and PAI-1 and lower levels of apoA-I were associated with significant increases in the risk of myocardial infarction, whereas no significant trend was found for BMI, vWF, TM, or DHEAS (data not shown).

View larger version (30K): [in this window] [in a new window]   Figure 1. Relative risk of myocardial infarction in all subjects for quartiles 1 through 4 of mass concentrations in plasma of t-PA, PAI-1, and vWF.

Variables for women were only dichotomized because of the small number of cases. In women, high levels of TM and mass concentrations of tPA and PAI-1 and low levels of apoA-I were associated with significant increases in the risk of myocardial infarction (Table 5).

View this table: [in this window] [in a new window]   Table 5. Subgroup Analyses on 16 Women With First Myocardial Infarction and 32 Age- and Sex-Matched Control Subjects on Relative Risk of Myocardial Infarction With Conditional Logistic Regression

In multivariate conditional logistic regression analysis on all cases of both sexes, when all the traditional atherosclerotic risk factors available in this study were simultaneously controlled for, the relative risk in the highest quartile of tPA mass concentration was only slightly reduced to 5.42 (95% CI, 1.75 to 16.79) compared with 5.89 (95% CI, 2.38 to 14.57) in univariate analysis (Table 4). Low levels of apoA-I and high cholesterol levels also remained significantly associated with myocardial infarction in this analysis with tPA (Table 3).

Also, when the parameters were treated as continuous variables, including tPA and the established risk factors, in a conditional logistic regressions analysis, ORs for tPA remained significant (OR, 1.22; 95% CI, 1.09 to 1.36) together with apoA-I (OR, 1.00; 95% CI, 0.99 to 1.00) and cholesterol (OR, 1.36; CI, 1.02 to 1.83). When PAI-1, vWF, TM, and DHEAS were included in the same multivariate analysis together with the established risk factors diabetes, smoking, hypertension, BMI, cholesterol, and apoA-I, the significant associations of these former variables to myocardial infarction disappeared (data not shown). Subgroup analysis on men showed a significant association of tPA and diabetes, smoking, hypertension, BMI, cholesterol, and apoA-I in multivariate conditional logistic regression, whereas no significant association could be shown when PAI-1, vWF, TM, or DHEAS was included in the model (data not shown). Multivariate subgroup analysis on women were not done because the statistical power was too small owing to the limited number of women.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present population-based study was designed to evaluate certain hemostatic factors and DHEAS as putative new predictors of a first myocardial infarction in subjects without prior myocardial infarction or cancer. Our findings are consistent with the hypothesis that high PAI-1 and tPA mass concentrations are associated with increased risk of a first myocardial infarction in both men and women. For tPA, the association is strong, especially in women; is independent of established cardiovascular risk factors; and is continuous across the tPA strata. Increased levels of PAI-1 were also associated with first myocardial infarctions in both sexes in univariate but not multivariate analyses when adjusted for traditional risk factors.

The prognostic value of the concentration of the vWF antigen in patients with ischemic heart disease was recently reported by us¹⁶ and others.^{17 18} Thompson et al¹⁷ found vWF, fibrinogen, and tPA antigen to be directly and independently correlated with the risk of subsequent coronary events in patients with angina pectoris. Here, we report the prognostic value of vWF in a population without previous myocardial infarction. Cases had higher mean vWF values than controls, and this difference was also significant in subgroup analysis of women but not in men. vWF was predictive of a future myocardial infarction, and its OR actually increased slightly after adjustment for traditional risk factors. The predictive value of vWF may thus be real in the type of subjects studied here, although the introduction of confounding variables in multivariate analyses resulted in too great a loss of statistical power to achieve statistical significance. vWF may be even more useful in evaluating risk of relapse in patients with known ischemic heart disease, as suggested by previous studies.^{16 17 18}

For 2 of the studied putative risk factors, no significant differences in the mean levels of plasma TM and DHEAS were found between the case and control groups, although TM tended to be higher in subgroup analysis of male cases compared with controls (Table 1). However, in a stratified subgroup analysis of women, high levels of TM were predictive of future myocardial infarction. Specially designed studies are therefore necessary to confirm the possibility that TM may indeed be a risk factor, albeit a weak one, of a first myocardial infarction. A low level of DHEAS has been reported to be a predictor of cardiovascular death in a long-term follow-up of survivors of acute myocardial infarction.¹⁹ However, no cardioprotective effect of high levels of DHEAS was shown for women.¹⁹ In the present study, no predictive value of DHEAS regarding risk of a first myocardial infarction was found for either men or women.

Our finding that a high mass concentration of PAI-1 predicts a first myocardial infarction resolves the objection against prior secondary-risk-factor studies,⁵ namely that the high PAI-1 levels may have been caused by the first infarction, rather than preceding it. PAI-1 mass concentration level was not predictive of cardiac events in a previous study.²⁰ A reason for this could be that the present study is larger with more end points and includes individuals without known heart disease. The remaining major difficulty in the assessment of our new finding that PAI-1 and tPA are predictors of a first myocardial infarction is the fact that these fibrinolytic variables are closely related to several other established cardiovascular risk factors. In the prospective US Physicians' Study, mass concentration of tPA was associated with subsequent myocardial infarction in men, a relation that vanished after adjustment for BMI, blood pressure, exercise frequency, parental history of myocardial infarction before 60 years of age, diabetes, and total and HDL cholesterol.⁷ Our finding that tPA but not PAI-1 mass concentration remains a significant predictor after adjustment for apoA-I (measured in this study instead of HDL cholesterol), among other things, supports the idea that fibrinolysis is part of a complex interrelation with lipoproteins, cholesterol, diabetes, smoking, hypertension, blood pressure, and BMI.

High levels of tPA, PAI-1, and vWF have also been shown to predict cardiovascular complications in persons with various vascular disorders.^{16 17 18 21 22 23 24} In the Northwick Park Heart Study,²⁵ low fibrinolytic activity measured with a global assay was associated with a high risk of future coronary artery disease in apparently healthy young men; this relation was independent of fibrinogen. Juhan-Vague et al²³ reported the prognostic value of fibrinolytic factors in patients with angina pectoris and found that PAI-1 is related to insulin resistance, whereas that of tPA mass concentration could be explained only by its relationship with a combination of different mechanisms, including insulin resistance, inflammation, and endothelial cell damage. The mechanisms by which the endothelial cells of atherosclerotic blood vessels are stimulated are multifaceted, but there is evidence that endothelial cells covering the walls of atherosclerotic vessels are likely to be constantly activated by macrophages/cytokines and become dysfunctional.^{26 27 28 29 30} However, the question of whether increased tPA antigen levels are the result of prevalent endothelial dysfunction or represent a net activation of endogenous fibrinolysis in response to underlying atherosclerosis, increased inhibition of fibrinolysis, or delayed turnover is unlikely to be resolved in an epidemiological setting and will require direct experimental testing.^{31 32}

In conclusion, the levels of PAI-1 and tPA mass concentrations and vWF were associated with the incidence of a first myocardial infarction. For PAI-1 and tPA mass concentrations, this was found in both men and women, but only tPA remained independently related after adjustment for other confounding factors. Altogether, there is now good evidence that the fibrinolytic system, measured with various methods, may be implicated in the arsenal of new important cardiovascular markers for risk.

	Acknowledgments

 
This research was supported by grants from the Swedish Council for Planning and Coordination of Research, the Swedish National Public Health Institute, the Swedish Council for Forestry and Agriculture, and Umeå University. We especially thank research assistant Åsa Ågren, Department of Nutrition, Umeå University, for her untiring performance in preparing data for this study. We also thank the County Council of Västerbotten for its persistence in maintaining the community promotion program care and thereby creating and guaranteeing the study base. We are indebted to Hans Stenlund, PhD, for his expert help with the statistical analyses.

Received January 6, 1998; revision received July 17, 1998; accepted July 30, 1998.

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				R. R. S. Packard and P. Libby Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction Clin. Chem., January 1, 2008; 54(1): 24 - 38. [Abstract] [Full Text] [PDF]

				R. L.C. Hoo, W.S. Chow, M.H. Yau, A. Xu, A. W.K. Tso, H.F. Tse, C. H.Y. Fong, S. Tam, L. Chan, and K. S.L. Lam Adiponectin Mediates the Suppressive Effect of Rosiglitazone on Plasminogen Activator Inhibitor-1 Production Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2777 - 2782. [Abstract] [Full Text] [PDF]

				P.E. Morange, N. Saut, M.C. Alessi, J.S. Yudkin, M. Margaglione, G. Di Minno, A. Hamsten, S.E. Humphries, D.A. Tregouet, and I. Juhan-Vague Association of Plasminogen Activator Inhibitor (PAI)-1 (SERPINE1) SNPs With Myocardial Infarction, Plasma PAI-1, and Metabolic Parameters: The HIFMECH Study Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2250 - 2257. [Abstract] [Full Text] [PDF]

				A. A. Komissarov, A. Zhou, and P. J. Declerck Modulation of Serpin Reaction through Stabilization of Transient Intermediate by Ligands Bound to {alpha}-Helix F J. Biol. Chem., September 7, 2007; 282(36): 26306 - 26315. [Abstract] [Full Text] [PDF]

				S. Thalmann and C. A. Meier Local adipose tissue depots as cardiovascular risk factors Cardiovasc Res, September 1, 2007; 75(4): 690 - 701. [Abstract] [Full Text] [PDF]

				K.-J. Chuang, C.-C. Chan, T.-C. Su, C.-T. Lee, and C.-S. Tang The Effect of Urban Air Pollution on Inflammation, Oxidative Stress, Coagulation, and Autonomic Dysfunction in Young Adults Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 370 - 376. [Abstract] [Full Text] [PDF]

				D. G. Yanbaeva, M. A. Dentener, E. C. Creutzberg, G. Wesseling, and E. F. M. Wouters Systemic Effects of Smoking Chest, May 1, 2007; 131(5): 1557 - 1566. [Abstract] [Full Text] [PDF]

				A. Barac, U. Campia, and J. A. Panza Methods for Evaluating Endothelial Function in Humans Hypertension, April 1, 2007; 49(4): 748 - 760. [Full Text] [PDF]

				N. N. Lang and D. E. Newby Emerging Thrombotic Effects of Drug Eluting Stents Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 261 - 262. [Full Text] [PDF]

				T. J. Wang, P. Gona, M. G. Larson, G. H. Tofler, D. Levy, C. Newton-Cheh, P. F. Jacques, N. Rifai, J. Selhub, S. J. Robins, et al. Multiple Biomarkers for the Prediction of First Major Cardiovascular Events and Death N. Engl. J. Med., December 21, 2006; 355(25): 2631 - 2639. [Abstract] [Full Text] [PDF]

				M.-C. Alessi and I. Juhan-Vague PAI-1 and the Metabolic Syndrome: Links, Causes, and Consequences Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2200 - 2207. [Abstract] [Full Text] [PDF]

				T. Yokoi, K. Fukuo, O. Yasuda, M. Hotta, J. Miyazaki, Y. Takemura, H. Kawamoto, H. Ichijo, and T. Ogihara Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells Diabetes, June 1, 2006; 55(6): 1660 - 1665. [Abstract] [Full Text] [PDF]

				K. Niwano, M. Arai, N. Koitabashi, S. Hara, A. Watanabe, K. Sekiguchi, T. Tanaka, T. Iso, and M. Kurabayashi Competitive Binding of CREB and ATF2 to cAMP/ATF Responsive Element Regulates eNOS Gene Expression in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1036 - 1042. [Abstract] [Full Text] [PDF]

				N. J. Brown, J. A.S. Muldowney III, and D. E. Vaughan Endogenous NO Regulates Plasminogen Activator Inhibitor-1 During Angiotensin-Converting Enzyme Inhibition Hypertension, March 1, 2006; 47(3): 441 - 448. [Abstract] [Full Text] [PDF]

				S. Kathiresan, P. Gona, M. G. Larson, J. A. Vita, G. F. Mitchell, G. H. Tofler, D. Levy, C. Newton-Cheh, T. J. Wang, E. J. Benjamin, et al. Cross-Sectional Relations of Multiple Biomarkers From Distinct Biological Pathways to Brachial Artery Endothelial Function Circulation, February 21, 2006; 113(7): 938 - 945. [Abstract] [Full Text] [PDF]

				F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]

				D. Feinbloom and K. A. Bauer Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2043 - 2053. [Abstract] [Full Text] [PDF]

				S. Kathiresan, S. B. Gabriel, Q. Yang, A. L. Lochner, M. G. Larson, D. Levy, G. H. Tofler, J. N. Hirschhorn, and C. J. O'Donnell Comprehensive Survey of Common Genetic Variation at the Plasminogen Activator Inhibitor-1 Locus and Relations to Circulating Plasminogen Activator Inhibitor-1 Levels Circulation, September 20, 2005; 112(12): 1728 - 1735. [Abstract] [Full Text] [PDF]

				J. Ma, F. Albornoz, C. Yu, D. W. Byrne, D. E. Vaughan, and N. J. Brown Differing Effects of Mineralocorticoid Receptor-Dependent and -Independent Potassium-Sparing Diuretics on Fibrinolytic Balance Hypertension, August 1, 2005; 46(2): 313 - 320. [Abstract] [Full Text] [PDF]

				Y. Rikitake and J. K. Liao Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells Circulation, June 21, 2005; 111(24): 3261 - 3268. [Abstract] [Full Text] [PDF]

				A. Garcia-Touchard, T. D. Henry, G. Sangiorgi, L. G. Spagnoli, A. Mauriello, C. Conover, and R. S. Schwartz Extracellular Proteases in Atherosclerosis and Restenosis Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1119 - 1127. [Abstract] [Full Text] [PDF]

				C. B Ebbeling, M. M Leidig, K. B Sinclair, L. G Seger-Shippee, H. A Feldman, and D. S Ludwig Effects of an ad libitum low-glycemic load diet on cardiovascular disease risk factors in obese young adults Am. J. Clinical Nutrition, May 1, 2005; 81(5): 976 - 982. [Abstract] [Full Text] [PDF]

				E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]

				A M Smith, K M English, C J Malkin, R D Jones, T H Jones, and K S Channer Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina Eur. J. Endocrinol., February 1, 2005; 152(2): 285 - 291. [Abstract] [Full Text] [PDF]

				D. J. Brotman, E. Walker, M. S. Lauer, and R. G. O'Brien In Search of Fewer Independent Risk Factors Arch Intern Med, January 24, 2005; 165(2): 138 - 145. [Abstract] [Full Text] [PDF]