Leptin is associated with increased risk of myocardial infarction

OBJECTIVES AND DESIGN: Leptin is involved in the regulation of bodyweight and metabolism in man and might also be involved in the pathophysiology of the insulin resistance syndrome, which is associated with the development of cardiovascular diseases. We tested whether leptin is a risk factor for acute myocardial infarction (AMI) in a nested case-referent study. SUBJECTS AND METHODS: Sixty-two men with first-ever AMI were identified who, prior to AMI, had participated in population-based health surveys in Northern Sweden. Referents were matched for sex, age, date and type of health survey, and geographical region. Blood pressure, body mass index (BMI) and the presence of smoking, diabetes and hypertension were recorded. Total cholesterol, apolipoprotein A-1 (apo A-1), apolipoprotein B (apo B), plasminogen activator inhibitor (PAI-1), insulin, and leptin were analysed in stored samples. Their influences on first-ever AMI were analysed by conditional logistic regression analysis. RESULTS: Men with first-ever AMI had higher BMI, plasma insulin and leptin, and diastolic blood pressure than the referents. Furthermore, they had lower plasma apo A-1 and were more often smokers. Smoking, high leptin, PAI-1 and cholesterol, and low apo A-1 levels were significant risk factors for first-ever AMI in univariate analysis. High leptin (OR 8.97; 95% CI: 1.73-46.5) and cholesterol (OR 5.18; 95% CI: 1.34-20.0) levels remained significant risk factors for AMI in a multivariate model. High apo A-1 was protective (OR = 0.13; 95% CI: 0.03-0.55). The combination of high leptin and low apo A-1 was associated with a particularly pronounced increased risk for AMI. CONCLUSION: Plasma leptin strongly predicts first-ever AMI. Our data support the hypothesis that leptin is an important link in the development of cardiovascular disease in obesity.     

Low level of tissue plasminogen activator activity in non-diabetic patients with a first myocardial infarction

OBJECTIVE: To explore the role of tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) in survivors of a first myocardial infarction (MI). Insulin and proinsulin were analysed as potential risk factors. DESIGN: Case-control study in northern Sweden. SUBJECTS: A total of 115 patients under 65 years of age with a first MI were enrolled and recalled for further examination 3 months later. Twenty-seven patients were excluded, 17 with known diabetes and 10 who did not come to the follow-up, giving a final number of 88 patients, 73 men and 15 women. Patients were age- and sex-matched with control subjects drawn from the local cohort in the MONICA population survey 1994. MAIN OUTCOME MEASURES: We compared MI patients and controls using univariate and multiple regression analyses including odds ratios (OR). RESULTS: PAI-1 activity, fibrinogen, postload insulin and -proinsulin were significantly higher and tPA activity significantly lower in MI patients in the univariate analysis. In a multiple regression analysis, including also age, sex and cardiovascular risk factors, these parameters were divided in quartiles. The lowest quartile of tPA activity was significantly associated with MI (OR = 19.1; CI 3.0-123) together with the highest quartiles of fibrinogen (OR = 25; CI 5.2-120) but other variables were not. CONCLUSION: Low tPA activity, i.e. low fibrinolytic activity, characterized nondiabetic subjects after a first MI which is not explained by concomitant disturbances in metabolic and anthropometric variables.     

冠心病患者血清脂蛋白(a)与纤溶功能的变化及其相关性

目的:观察冠心病(CHD)患者血清脂蛋白a[Lp(a)]、血浆组织型纤溶酶原激活剂(tPA)与纤溶酶原激活剂抑制物-1(PAI-1)活性的变化特点,并探讨它们之间的关系。方法:对124例CHD患者和26例正常人采用双抗体ELISA法测定Lp(a)浓度,发色底物法测定tPA、PAI-1活性。结果:CHD患者中,急性心肌梗死(AMI)和不稳定性心绞痛(UAP)组患者Lp(a),浓度和PAI-1活性均非常显著高于对照组(P<0.01):tPA活性显著低于对照组(P<0.01);陈旧性心肌梗死(OMI)和稳定性心绞痛(SAP)组患者Lp(a)浓度和PAI-1活性均亦高于对照组(P<0.05);tPA活性亦低于对照组(P<0.05)。124例CHD患者相关分析显示:Lp(a)与PAI-1活性呈显著正相关,与tPA活性呈显著负相关(P均<0.001)。结论:冠心病患者Lp(a)显著升高,且与tPA、PAI-1活性有密切相关关系。     

Anti-inflammatory effects of troglitazone in nondiabetic obese subjects independent of changes in insulin sensitivity

BACKGROUND: Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers. We investigated whether, in the absence of changes in glucose, thiazolidinediones (TZDs) have anti-inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers. METHODS: We performed a randomised double-blind placebo-controlled crossover study with troglitazone (400 mg daily for eight weeks) in 15 normoglycaemic obese subjects. We measured plasma high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), leptin, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and tumour necrosis factor-alpha (TNF-alpha) after each of the two treatment periods and in 13 age- and sex-matched lean individuals. RESULTS: Obese subjects were insulin resistant (decreased glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp) and had higher plasma levels of hsCRP, IL-6, leptin, tPA, and PAI-1 compared with lean subjects. TNF-alpha also tended to be higher. Troglitazone improved insulin sensitivity (mean increase in whole body glucose uptake 23.1 +/- 10.5% (p = 0.047)) and normalised plasma concentrations of hsCRP, tPA and TNF-alpha, whereas it did not significantly change IL-6, leptin and PAI-1. Changes in GIR did not correlate with changes in inflammatory markers. CONCLUSION: Troglitazone induces suppression of some of the inflammatory markers that are elevated in normoglycaemic obese subjects. The suppression of inflammatory markers, however, does not correlate with improvement in insulin sensitivity, suggesting involvement of partially differential mechanisms in these effects of TZDs.     

Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study

An impaired fibrinolytic function due to elevated plasma levels of plasminogen activator inhibitor (PAI)-1 activity or tissue plasminogen activator (tPA) antigen is correlated with the development of myocardial infarction (MI) in patients with manifest coronary heart disease. Recently, methods for determining the specific tPA/inhibitor complexes constituting tPA antigen in plasma have become available. In the Stockholm Heart Epidemiology Program (SHEEP) study, 86 of 1212 MI patients, subjected to blood sampling in a metabolically stable period, suffered reinfarction before the end of 1996. These individuals have been compared with an approximately equal number of matched MI patients without recurrence and a group of matched healthy control subjects regarding the plasma concentrations of some hemostatic factors. The hemostatic compounds studied (fibrinogen, von Willebrand factor, tPA antigen, PAI-1, and the tPA/PAI-1 complex) were typically higher in the groups (men and women) with recurrence of MI compared with those without. The plasma concentrations were also typically higher in the pooled groups of patients compared with the groups of healthy control subjects. The largest between-group differences were found for the plasma tPA/PAI-1 complex. The crude odds ratio for reinfarction associated with higher concentration (>/=75th percentile among the control subjects) of tPA/PAI-1 was 1.8 (95% CI 1.1 to 3.1); the corresponding crude odds ratio for von Willebrand factor was 2.3 (1. 3 to 4.0). The tPA/PAI-1 complex correlated strongly with PAI-1 and tPA antigen in all groups and with serum triglycerides and body mass index in all groups except for women with reinfarction. An increased plasma level of tPA/PAI-1 complex is a novel risk marker for recurrent MI in men and women. Most likely, increased plasma levels of tPA/PAI-1 complex reflect impaired fibrinolysis, because the correlation with PAI-1 is strong. Further support is obtained indicating that the plasma concentration of von Willebrand factor is also an important risk marker for recurrent MI.     

C-reactive protein in offspring is associated with the occurrence of myocardial infarction in first-degree relatives

The relevance of elevated levels of C-reactive protein (CRP) in cardiovascular disease is gaining increasing recognition. A family history of coronary artery disease is a major determinant of coronary artery disease in the offspring. In a cohort of 1048 individuals without clinical evidence of atherosclerosis, we investigated the relationships between CRP levels and a family history of myocardial infarction. We measured CRP, fibrinogen, plasminogen activator inhibitor-1, total cholesterol, triglycerides, and some genetic polymorphisms: plasminogen activator inhibitor-1 (4G/5G), fibrinogen (Bbeta-chain G-->A(-455)), and angiotensin-converting enzyme insertion/deletion (I/D). Clinical data were collected by a World Health Organization-modified questionnaire for cardiovascular disease. When compared with subjects without first-degree relatives who had suffered a myocardial infarction (n=867), subjects with such first-degree relatives (n=181) were older (P=0.001), more often hypertensive (P<0. 001), and homozygous for the 4G allele (4G/4G) of the plasminogen activator inhibitor-1 gene (P=0.003). In addition, they had a higher body mass index (P=0.036), raised plasma fibrinogen (P<0.007) and total cholesterol (P<0.001) concentrations, and CRP levels >0.33 mg/L (P=0.005). In a multiple logistic regression analysis, age (odds ratio [OR] 1.03, 95% confidence interval [95% CI] 1.01 to 1. 05), total cholesterol (OR 1.35, 95% CI 1.11 to 1.65), plasminogen activator inhibitor-1 4G/4G (OR 1.72, 95% CI 1.20 to 2.45), and CRP levels >0.33 mg/L (OR 1.75, 95% CI 1.05 to 2.91) were all independently associated with a positive family history of myocardial infarction. We therefore conclude that raised levels of CRP independently identify the offspring of patients with a myocardial infarction.     

Thrombogenic factors and recurrent coronary events.

BACKGROUND: Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS: We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS: Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.     

Sex-related differences in the associations between hyperleptinemia, insulin resistance and dysfibrinolysis

The adipocyte-derived hormone leptin is associated with insulin resistance and reduced fibrinolytic status--or dysfibrinolysis--in humans. As leptin associates differentially to the development of cardiovascular disease and diabetes in men and women, we hypothesized that leptin and insulin sensitivity are related to dysfibrinolysis in a sex-dependent manner. Thirty-two men and 40 women were recruited from the Monitoring of trends and determinants in Cardiovascular disease (MONICA) population sample, representing the highest and lowest quartiles of fasting insulin levels. Lipids, fibrinolytic status [plasminogen activator inhibitor 1 (PAI-1) activity, tissue plasminogen activator (tPA) mass and activity, and tPA-PAI complex], leptin, testosterone and sex-hormone-binding globulin were measured. Insulin sensitivity was estimated using the euglycaemic clamp technique. Body composition was determined by bioimpedance. Determinants for circulating levels of fibrinolytic factors were explored in a multivariate linear regression analysis. Levels of fibrinolytic variables and estimated insulin sensitivity did not differ between men and women. Leptin was independently associated with reduced fibrinolytic status (high PAI-1 activity, low tPA activity, high tPA mass, and high tPA-PAI complex) in men (P < 0.001-0.002). In women, fat mass and/or insulin sensitivity were related to these factors (P < 0.001-0.03), and leptin only to reduced tPA activity (P = 0.002). Hyperleptinemia, dysfibrinolysis, insulin sensitivity and androgenicity associate differentially in men and women.     

同型半胱氨酸对人脐静脉内皮细胞纤溶系统的影响

目的探讨同型半胱氨酸（homocysteine,Hcy）对血管内皮细胞纤溶系统影响。方法（1）将体外培养的人脐静脉血管内皮细胞（HUVEC）分为10个实验组（0、10、50、200、500μmol／L Hcy组及叶酸和上述各Hcy点共同培养组）,培养24h后,酶联免疫吸附实验法（ELISA）测定各组细胞上清液中纤溶酶原激活剂（plasminogen activator,tPA）及纤溶酶原激活物抑制剂1（plasminogen activator inhibitor1,PAI-1）抗原含量,逆转录聚合酶链反应分析（RT-PCR）法分析各组tPA及PAI-1的mRNA表达水平。（2）急性心肌梗死（AMI）患者53例及健康对照组48例,ELISA测定空腹血浆tPA及PAI-1含量,高效液相色谱法测定血浆Hcy水平。结果（1）500μmoL／L Hcy组PAI-1抗原及mRNA表达水平均明显增高（P〈0．05）。（2）以单纯培养基为对照组,生理浓度Hcy组内皮细胞tPA抗原合成及mRNA表达明显增高（P〈0．05）,而以10μmoL／L Hcy组为对照组时,500μmoL／L Hcy组tPA抗原合成及mRNA表达水平则明显减少（P〈0．05）。（3）500μmoL／L Hcy与叶酸共同培养组和单纯Hcy组相比,可以明显提高内皮细胞tPA抗原的合成及mRNA表达,减少PAI-1抗原合成及mRNA表达（P〈0、05）。（4）AMI组Hcy、tPA及PAI-1均明显高于健康对照组（P〈0．05）。结论在体外细胞时,超生理浓度Hcy可以通过下调tPA、上调PAI-1的mRNA表达,减少内皮细胞tPA抗原的分泌及增加PAI-1抗原的合成,可能降低纤溶系统的活性。叶酸则可以减少Hcy引起内皮细胞纤溶系统的损害,起到保护作用。Hcy是AMI的一个独立危险因素。     

Fibrinolytic function and coronary risk

Plasminogen activation potential in the blood is controlled by an equilibrium between plasminogen activators, mainly tissue-type plasminogen activator (t-PA), and inhibitors, mainly plasminogen activator inhibitor (PAI)-1. In cardiovascular practice, imbalance of this fibrinolytic potential is encountered primarily in the insulin-resistance syndrome. This syndrome leads to increased plasma PAI-1 and t-PA antigen levels (reflecting inactive t-PA/PAI-1 complexes) with a consequent decrease in fibrinolytic activity. Increased plasma PAI-1 and t-PA antigen both are predictive of myocardial infarction. The prognostic value of PAI-1 disappears after adjustments for insulin resistance markers, whereas the prognostic value of t-PA antigen disappears after simultaneous adjustments for insulin resistance and inflammation markers, suggesting an additive role of inflammation in inducing plasma fibrinolytic markers. Recently the production of PAI-1 by adipose tissue, in particular by tissue from the omentum, has been shown. PAI-1 produced in this way could be an important contributor to the elevated plasma PAI-1 levels observed in insulin-resistant patients. These results support the notion that PAI-1 may be a link between obesity, insulin resistance, and cardiovascular disease. Genetic control of PAI-1 expression has also been shown, involving a -675 4G/5G polymorphism, the 4G/4G genotype being associated with higher plasma PAI-1 levels; its proper influence on the development of myocardial infarction is still debated.     

Low-grade systemic inflammation, hypoadiponectinemia and a high concentration of leptin are present in very young obese children, and correlate with metabolic syndrome

OBJECTIVE: To determine the concentration levels of C-reactive protein (CRP), leptin and adiponectin in obese pre-pubertal children, and their possible relation with metabolic syndrome, fibrinogen and plasminogen activator inhibitor-1. METHODS: A study was carried out in 51 obese children (aged 6 to 9 years) and the same number of non-obese children (control group), matched by age and sex. (Cross-sectional study of obese children). Body mass index (BMI), waist/hip ratio (WHR) and blood pressure were determined for each child. Serum CRP, leptin, adiponectin, glucose, insulin, lipid profile, plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were all measured. RESULTS: The levels of CRP serum (1.67+/-0.222 vs 0.92+/-0.16 mg/l) and leptin (15.56+/-1.27 vs 4.68+/-0.62 ng/ml) were significantly higher in obese children. The adiponectin level was significantly higher in non-obese children (11.58+/-0.63 vs 9.64+/-0.49 microg/dl). In the obese group, log. CRP showed a positive correlation with BMI, insulin, homeostasis model assessment (HOMA), triglycerides, alanine aminotransferase (ALT), uric acid, PAI-1, fibrinogen and interleukin 6 (IL-6), and correlated negatively with apolipoprotein A-I and high-density lipoprotein cholesterol (HDL-C). The leptin was positively correlated with BMI, insulin, HOMA, triglycerides and PAI-1 and negatively with Apo A-I and HDL-C. Adiponectin correlated negatively with BMI, insulin, HOMA, and triglycerides. CONCLUSIONS: Low-grade systemic inflammation, elevated leptin concentration and low adiponectin level are described in very young obese children, correlating with a range of variables of metabolic syndrome. Inflammation and adipocytokines can play an important role in the etiopathogeny of metabolic syndrome.     

Protection by α2-macroglobulin of tissue plasminogen activator against inhibition by plasminogen activator inhibitor-1

Tissue plasminogen activator (tPA) is widely used in the treatment of acute myocardial infarction (MI). However, its thrombolytic efficacy does not correlate with the dose administered. The interactions between tPA, α2-macroglobulin (α2-M), and plasminogen activator inhibitor-1 (PAI-1) were investigated both in vitro and in patients undergoing tPA therapy for MI in an attempt to identify variables that might affect the clinical efficacy of tPA.
Purified α2-M (5.4 mg/ml) protected 16.0% or 22.4% of tPA (12.5 IU/ml) activity from inhibition by PAI-1 at 4 or 8 IU/ml in vitro . Of nine patients treated with 5–20 mega IU of tPA for MI, the plasma activity of tPA remained increased for 15–30 min after the cessation of infusion in eight; the patient who failed to exhibit a persistent increase in tPA activity had a low plasma concentration of α2-M. Total tPA activity, derived from the area under the activity-versus-time curve (AUC), showed a significant inverse correlation with the ratio of the plasma PAI-1 activity to the plasma α2-M concentration. Total tPA activity did not correlate with plasma PAI-1 activity or plasma α2-M concentration alone. Results suggest that α2-M, by binding to tPA, protects the latter against inhibition by PAI-1.     

Quantitative measurement of carotid atherosclerosis in relation to levels of von Willebrand factor and fibrinolytic variables in plasma--a 2-year follow-up study

BACKGROUND: It has been proposed that the mechanism of action of the new risk factors for myocardial infarction and stroke, von Willebrand factor (vWF), tissue plasminogen activator (tPA) and tissue plasminogen activator inhibitor-1 (PAI-1) could possibly be mediated via a primary effect on atherogenesis but there is little data to substantiate this. DESIGN: A prospective single-centre cohort study of progression of atherosclerosis. METHODS: Carotid plaque area was quantitated by two-dimensional (2D) ultrasound in 258 subjects at entry and after 1 and 2 years. Plasma and serum samples were drawn at baseline and serum lipids and plasma levels of haemostatic factors were measured. RESULTS: The traditional risk factors, smoking, total cholesterol, hypertension and male gender explained 51% of the variance in plaque area at baseline and 48% at 1-year follow-up. There were small positive associations of plaque area with vWF, tPA and tPA/PAI-1 complex and a tendency to negative associations with PAI-1 levels, independent from the traditional risk factors. The additional explanatory power of the haemostatic factors did not exceed 3%. CONCLUSION: The data accord with a marginal role in atherogenesis of vWF and tPA, and underline the major impact of smoking, hypertension and cholesterol on carotid plaque area progression.     

Hyperinsulinemia predicts low tissue plasminogen activator activity in a healthy population: The Northern Sweden MONICA study

Fibrinogen levels predict atherothrombotic disease, and impaired fibrinolysis has been proposed as a risk factor for myocardial infarction. Fibrinolysis is mainly dependent on the activity of tissue plasminogen activator (tPA) and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). Oral glucose tolerance tests were performed in 318 randomly selected healthy men and 324 women aged 25 to 64 years. tPA activity was strongly predicted by fasting insulin in both univariate analysis (r = −.37 and −.34 in men and women, respectively) and multivariate analysis with age, anthropometric measurements, lipids, and blood pressure included. Fasting insulin was the strongest predictor of PAI-1 activity (r = .49 and .51). In women, the influence of fasting insulin level on tPA and PAI-1 activity was consistently stronger after than before menopause, and a threshold effect was seen with distinctly lower fibrinolytic activity in the highest quartile of insulin (>7.0 mU/L). In men, the relation between insulin and fibrinolytic variables was linear. Fibrinogen levels were not related to insulin or glucose levels after adjustment for age and other risk factors in a multiple regression. Subjects with previously unknown diabetes or impaired glucose tolerance tended to have elevated fibrinogen and PAI-1 activity and decreased tPA activity. Our data support previous findings of a strong correlation between insulin and PAI-1 activity in small highly selected groups, and extend them to randomly selected population samples. The strong inverse relation between endogenous insulin levels and tPA activity has not previously been demonstrated in a healthy population.     

Plasmin Activation System in Restenosis: Role in Pathogenesis and Clinical Prediction?

During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis and restenosis. Responsible pathophysiologic mechanisms, however, remain elusive. This review focuses primarily on the clinicians, point of view, suggesting that increases in plasminogen activator inhibitor type-1 (PAI-1) plasma levels after balloon angioplasty or permanently elevated lipoprotein (a) (Lp(a)) plasma levels might be helpful in the prediction of restenosis after coronary angioplasty. In contrast, tissue-type plasminogen activator (tPA) plasma levels appear unrelated to restenosis, and data regarding a possible role of urokinase-type plasminogen activator (uPA) in circulation are not available at present. Furthermore, a new hypothesis on the pathophysiological role of local PAI-1 overexpression as a beneficial negative feedback mechanism to limit excess cellular proliferation in atherogenesis and restenosis is presented.     

Bio-available testosterone levels fall acutely following myocardial infarction in men: association with fibrinolytic factors

The effect of acute myocardial infarction on plasma levels of testosterone in men is unclear. No previous studies have evaluated the bio-available fraction of testosterone. Low plasma testosterone levels have been associated with several risk factors for myocardial infarction, including an unfavorable fibrinolytic profile. In a prospective, case control study, we examined changes in plasma levels of sex hormones, including bio-available testosterone, in patients with acute myocardial infarction and in control subjects. In addition, changes in hormone levels in patients were compared with alterations in the fibrinolytic profile. Thirty male patients admitted with chest pain were studied. Twenty two had acute myocardial infarction and eight had non-specific chest pain. Plasma levels of total and bio-available testosterone, 17beta-estradiol, sex hormone binding globulin and insulin were measured at baseline and throughout admission. In addition, fibrinolytic factors (plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen) were measured in patients who received fibrinolysis. Height and weight, and the subsequent development of heart failure or myocardial dysfunction were also recorded. Patients had lower levels of bio-available testosterone (2.07 +/- 0.75 nmol/L vs. 5.3 +/- 1.7 nmol/L, p < 0.05) and higher levels of 17beta-estradiol (87.9 +/- 39.5 pmol/L vs. 48.1 +/- 18.4 pmol/L, p < 0.001) than controls. Total and bio-available testosterone levels fell acutely following myocardial infarction (11.9 +/- 3.8 nmol/L to 9.7 +/- 3.3 nmol/L, p < 0.05; 1.95 +/- 0.76 nmol/L to 1.55 +/- 0.67 nmol/L, p < 0.05). This reduction was associated with elevation of PAI-I activity and reduction of tPA activity, independent of changes in plasma insulin levels. Patients with lower baseline levels of testosterone and higher levels of 17beta-estradiol had a relatively pro-thrombotic fibrinolytic profile and increased risk of complications. In conclusion, total and bio-available levels of testosterone fall following acute myocardial infarction in men, in association with adverse changes in fibrinolytic profile. It is not clear whether this association represents a direct effect of testosterone on thrombotic tendency but warrants further investigation.     

Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a north Swedish population

Serum lipids, lipoprotein (a), plasminogen activator inhibitor and tissue plasminogen activator levels were measured in 260 subjects, constituting a cross-section sample of 30-60-year-old men and women. For Lp(a), there were positive correlations with age and cholesterol, but not with any of other measured parameters. Triglyceride, cholesterol, and HDL-cholesterol (inversely) levels were associated with waist-to-hip girth circumference ratio: this variable remained significant in a multiple regression model. PAI-1 activity and tPA antigen levels were positively associated with triglycerides and inversely associated with HDL-cholesterol. Moreover, tPA antigen was positively related to total cholesterol level. In multiple regression analysis, however, only triglycerides were found to contribute significantly to the variance of tPA antigen and PAI-1 activity levels, when BMI (in men) and abdominal skinfold thickness (in women) were entered into the model. Insulin or glucose postload responses to an OGTT were not independently related to any lipid or fibrinolytic variable. These data demonstrate the importance of anthropometric variables both for fibrinolytic variables and traditional lipid risk factors. Only Lp(a) was found to be largely unrelated to the endocrine-metabolic and anthropometric variables.     

Normal plasminogen activator inhibitor levels at long-term follow-up after jejuno-ileal bypass surgery in morbidly obese individuals.

Forty-five patients who had been subjected to jejuno-ileal bypass (JIB) surgery for morbid obesity and 10 obese nonsurgery subjects were studied. The former group was examined 14 to 20 years after surgery, and was found to have lower mean plasminogen activator inhibitor type 1 (PAI-1) activity (8.4 v 32 U/mL, P < .001), tissue plasminogen activator (tPA) antigen concentrations (7.2 v 12 micrograms/L, P < .01), body mass index (BMI), and fasting plasma insulin, triglyceride, and cholesterol levels. The PAI-1 levels were correlated with BMI, waist to hip ratio, and insulin, triglyceride, and cholesterol levels. Thus, previously obese subjects have normal PAI levels 14 to 20 years after treatment with JIB surgery, in contrast to the high PAI-1 levels in nonsurgery obese subjects.     

Lp(a) lipoprotein levels as a predictor of risk for thrombogenic events in patients with Beh?et's disease.

OBJECTIVES--To investigate whether plasma levels of Lp(a) lipoprotein (Lp(a)) are predictors of defective fibrinolytic activity, leading to thrombosis, in patients with Behçet's disease. METHODS--Plasma Lp(a) was measured by enzyme linked immunosorbent assay, lipids and lipoproteins by enzymatic methods, and apolipoproteins A-I and B, fibrinogen (turbidimetric method), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and D-dimer levels by enzyme immunoassay. Their levels and interactions were evaluated in 33 patients with Behçet's disease (including five with thrombotic complications) and 30 healthy control subjects. RESULTS--Plasma Lp(a) concentration was significantly greater in the patients than in controls. Nine patients (27%) had levels > 0.30 microgram. There was no correlation between Lp(a) and other lipids and lipoproteins apart from apolipoprotein B. Lp(a) showed inverse correlation with t-PA (r = -0.34, p < 0.05) and D-dimer (r = 0.35, p < 0.05). Patients with thrombotic complications had significantly greater Lp(a) and PAI-1, and lower D-dimer concentrations than control subjects. CONCLUSIONS--Measurement of plasma Lp(a) levels in patients with Behçet's disease may provide useful information regarding the potential development of thrombotic events, because of its possible role in defective fibrinolysis.     

ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. METHODS: The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). RESULTS: Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. CONCLUSIONS: Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.