PubMed Health⌕ Search

Biomedical subjects

Wiek H van Gilst

Publications and source records attributed to Wiek H van Gilst.

At least 19 recordsLinked to original sources
PubMed2007

Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.

Bradykinin↗
PubMed2006

Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well.

AIMS: Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients. METHODS AND RESULTS: We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels. CONCLUSION: Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.

Adolescent↗
PubMed2006

C-reactive protein and angiographic characteristics of stable and unstable coronary artery disease: data from the prospective PREVEND cohort.

AIMS: High sensitive-C-reactive protein (hs-CRP) is associated with coronary risk, which may be explained by an association with (unstable) coronary artery disease (CAD). Until now, histopathological and angiographic studies have failed to consistently demonstrate a strong relationship. However, most of these studies were limited by a cross-sectional design. Our aim was to prospectively evaluate the association between hs-CRP and plaque instability. Therefore, firstly, we investigated the relation between hs-CRP measured long before coronary angiography (CAG) and angiographic characteristics of stable and unstable CAD. In addition, we investigated the association with coronary events during follow up in the total PREVEND population. METHODS AND RESULTS: Of the population based Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 8139 subjects without previous documented CAD were followed for the incidence of CAG and coronary events from 1997 to 2003. For the qualitative angiographic analysis, 216 CAGs were available. Mean time to CAG was 37+/-19 months. The 864 coronary vessels were graded as follows: 436 coronary vessels as normal, 175 as non-obstructive CAD, 179 as stable obstructive CAD and 74 as unstable obstructive CAD. Multilevel ordinal regression analysis was performed to study associations between baseline clinical variables and angiographic findings. Hs-CRP contributed significantly to the multivariate model after adjustment for age, gender, smoking, lipids and blood pressure. In 8139 subjects, 201 (2.5%) first coronary events occurred during follow up. Cox survival analysis showed age- and sex-adjusted hazard ratios for hs-CRP 1-3 and >3mg/L of, respectively, 1.26 (95% CI 0.67-2.40) and 3.16 (95% CI 1.26-3.16), relative to hs-CRP <1mg/L. CONCLUSION: In the prospective PREVEND study of subjects without previous documented CAD, hs-CRP levels at baseline were associated with angiographic characteristics and clinical consequences of plaque instability during follow up. This observation supports the concept that hs-CRP significantly contributes to coronary atherogenesis.

Aged↗
PubMed2006

Long-term effects of pravastatin and fosinopril on peripheral endothelial function in albuminuric subjects.

The purpose of this double-blind, randomized, placebo-controlled trial was to determine the long-term effects of pravastatin and fosinopril treatment on peripheral endothelial function in subjects with albuminuria. Subjects (mean age 51 years, 63% male) were randomized to pravastatin 40 mg or matching placebo and to fosinopril 20mg or matching placebo. Using high resolution ultrasound, flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) was assessed at baseline and after 4 years of treatment in a total of 276 subjects. At baseline, mean+/-standard error FMD was 4.73+/-0.49% and NID was 10.86+/-0.67%. Pravastatin significantly reduced total cholesterol and LDL cholesterol (p<0.01) and randomization to pravastatin was associated with a non-significant improvement of 18.9% in FMD (+0.80+/-0.95, p=0.09), without a significant change in NID. Interestingly, pravastatin significantly increased FMD by 34.9% in men (+1.23, p=0.04), but only 1.1% in women (+0.06, p=0.95). Fosinopril was not associated with a change in FMD or NID despite significantly decreasing urinary albumin excretion, systolic and diastolic blood pressure (all p<0.01). In conclusion, after 4 years of follow-up, pravastatin treatment tended to increase FMD and this effect was predominantly present in men. Fosinopril treatment did not modify FMD during long-term follow-up.

Adult↗
PubMed2006

Protective effects of erythropoietin in cardiac ischemia: from bench to bedside.

Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells and cardiomyocytes. In animal studies, treatment with EPO during ischemia/reperfusion in the heart has been shown to limit the infarct size and the extent of apoptosis. In the longer term, EPO may promote ischemia-induced neovascularization, either by stimulating endothelial cells in situ or by mobilizing endothelial progenitor cells from bone marrow. The effects of EPO in the ischemic heart support the concept of EPO as a pleiotropic, tissue-protective agent for other organs expressing the EPO receptor. We recently performed a first randomized clinical study showing the safety and feasibility of EPO administration in patients with acute myocardial infarction. Future clinical studies are warranted to translate the beneficial effects of EPO from basic experiments to cardiac patients.

Animals↗
PubMed2006

Predictors of angiotensin-converting enzyme inhibitor-induced reduction of urinary albumin excretion in nondiabetic patients.

Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1+/-11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (beta(standardized)=0.161; P=0.006), urinary sodium excretion (beta(standardized)=0.154; P=0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months (P<0.001). Fosinopril use and blood pressure reduction independently predicted the change in urinary albumin excretion. Baseline urinary albumin excretion independently predicted the antialbuminuric effect of fosinopril (beta(standardized)=-0.303; P<0.001). In conclusion, at baseline, sodium intake and blood pressure were positively associated with urinary albumin excretion. Fosinopril reduced albuminuria more than might be expected from its blood pressure-lowering effect alone, and this effect was more outspoken in subjects with higher baseline albumin excretion. Based on our data, we hypothesize that angiotensin-converting enzyme inhibition may result in superior cardiovascular protection when compared with other blood pressure-lowering agents in subjects with higher baseline levels of albuminuria.

Albuminuria↗
PubMed2006

Effects of C-reactive protein and cholesterol on responsiveness in vitro of the internal thoracic artery to angiotensin II in patients having coronary artery bypass grafting.

The renin-angiotensin system is critically involved in the pathogenesis of atherosclerosis. Cholesterol increases vascular responsiveness to angiotensin II by upregulation of the angiotensin II type 1 receptor. However, the effects of C-reactive protein (CRP) on vascular responsiveness to angiotensin II are unknown. We evaluated, in vitro, the vascular responsiveness of the internal thoracic artery to angiotensin II in patients who underwent coronary bypass grafting. We observed that increased preoperative CRP and increased cholesterol levels were strongly related to increased vascular responsiveness to angiotensin II (p <0.001 for the 2 comparisons). However, angiotensin II-mediated contraction was increased only when levels of CRP and cholesterol were jointly increased. In conclusion, our results suggest that CRP and cholesterol act synergistically on vascular responsiveness to angiotensin II.

Angina Pectoris↗
PubMed2006

The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study.

BACKGROUND: Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis. METHODS: We used data from the Prevention of REnal and Vascular ENd-stage Disease Intervention trial (PREVEND-IT) and the PREVEND cohort study. The PREVEND-IT subjects (788 with a UAE 15-300 mg/day) received pravastatin 40 mg/day vs placebo and/or fosinopril 20 mg/day vs placebo in a 2x2 factorial-RCT design. Of the 3440 cohort subjects, 469 used statins during the 4-year follow-up period. Multivariate-regression adjusted for confounding factors and the propensity score was used to estimate the relation between statin use and UAE and GFR. RESULTS: In the RCT, pravastatin did not change UAE or GFR, neither in fosinopril yes/no subgroups. In the observational cohort, statin use was associated with a rise in UAE (+12.1%), compared with statin non-use (+3.6%, P<0.001). This rise was most pronounced in those on statins prior to the first screening [+24.8% (95% CI: 11.9-39.2)], those using statins>3 years [+18.5% (7.3-30.8)] and those with >1 or >2 defined daily doses (+15.7 and +17.3%, respectively). These differences remained significant after adjustment for relevant variables and propensity score. The rise in UAE could not be attributed to a higher dose or a specific statin. GFR fell in 4 years in both statin users and non-users (4.6+/-13.5 and 2.4+/-11.2, respectively). The fall in GFR between groups was not different after adjustment (P=0.11). CONCLUSIONS: We conclude from the RCT data that statins do not lower UAE in subjects selected because of an elevated UAE instead of hyperlipidaemia. In the observational cohort study, the use of statins similarly was not associated with a fall in UAE; UAE instead increased. Statin treatment was not associated with a significant change in GFR in these subjects with only modestly impaired GFR.

Adult↗
PubMed2006

Statins in the treatment of chronic heart failure: biological and clinical considerations.

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.

Animals↗
PubMed2006

Usefulness of preoperative C-reactive protein and soluble intercellular adhesion molecule-1 level for predicting future cardiovascular events after coronary artery bypass grafting.

High levels of C-reactive protein and soluble intercellular adhesion molecule-1 are associated with increased risk for cardiovascular events. No long-term data are available on predictive value of preoperative levels of C-reactive protein and soluble intercellular adhesion molecule-1 on outcome after coronary artery bypass grafting. We measured baseline levels of C-reactive protein and soluble intercellular adhesion molecule-1 in preoperative serum stored at -80 degrees C in 87 patients with coronary artery disease before undergoing isolated coronary artery bypass grafting. Follow-up was performed after a mean duration of 7.6+/-0.1 years, and all cardiovascular events were recorded. Data were analyzed by categorizing patients into 2 groups according to median value of C-reactive protein and soluble intercellular adhesion molecule-1. During follow-up, 16 patients developed a cardiovascular event. In patients with C-reactive protein above the median (1.9 mg/L), the cumulative cardiovascular event incidence was 29% compared with 9% in patients with levels below the median (p=0.048). In Cox regression analysis that was corrected for age, gender, and conventional risk factors, the adjusted relative risk of cardiovascular events of C-reactive protein above the median was 3.9 (95% confidence interval 1.1 to 13.9, p <0.05). Soluble intercellular adhesion molecule-1 level above the median (136 microg/L) was associated with a cumulative cardiovascular event incidence of 21% versus 16% below the median (p=0.48). In conclusion, in patients who undergo coronary artery bypass grafting, high preoperative levels of C-reactive protein levels, but not of soluble intercellular adhesion molecule-1, were associated with long-term risk of cardiovascular events, independent of other cardiac risk factors.

Angioplasty, Balloon, Coronary↗
PubMed2006

A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study.

BACKGROUND: Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. METHODS: A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included. RESULTS: Subjects with AF had a higher prevalence of electrocardiographic left ventricular hypertrophy, ischemic heart disease, hypertension, renal dysfunction, elevated levels of C-reactive protein (CRP) and increased urinary albumin excretion as compared to controls. The polymorphisms of the Renin-angiotensin system and Bradykinin gene did not show a significant association with AF (p > 0.05). The TaqIB polymorphism of the CETP gene was significantly associated with the presence of AF (p < 0.05). Using the MDR method, the best genotype-phenotype models included the combination of micro- or macroalbuminuria and CETP TaqIB polymorphism, CRP >3 mg/L and CETP TaqIB polymorphism, renal dysfunction and the CETP TaqIB polymorphism, and ischemic heart disease and CETP TaqIB polymorphism (1000 fold permutation testing, P < 0.05). Interaction entropy graph showed that the combination of albuminuria and CETP TaqIB polymorphism removed the most entropy. CONCLUSION: CETP TaqIB polymorphism is significantly associated with the presence of AF in the context of micro- or macroalbuminuria, elevated C-reactive protein, renal dysfunction, and ischemic heart disease.

Atrial Fibrillation↗
PubMed2006

A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study.

AIMS: Besides stimulating hematopoiesis, erythropoietin (EPO) protects against experimental ischemic injury in the heart. The present study evaluated the safety and tolerability of EPO treatment in non-anemic patients with acute myocardial infarction (MI). METHODS AND RESULTS: In this single-center, investigator-initiated, prospective study, patients with a first acute MI were randomized to one bolus of 300 microg darbepoetin alfa or no additional medication before primary coronary intervention. Twenty-two patients (mean age 59 +/- 2 years) were included. In the darbepoetin group, serum EPO-levels increased to 130-270 times that of controls, within the first 24 h. After darbepoetin administration, only small and non-significant changes in hematocrit levels were observed, while endothelial progenitor cells (EPCs, CD34+/CD45-) were increased at 72 h (2.8 vs. 1.0 cells/microl in control group, p < 0.01). No adverse events were recorded during the 30-day follow-up. After 4 months, left ventricular ejection fraction was similar in the two groups (52 +/- 3% in darbepoetin vs. 48 +/- 5% in control group, p = NS). CONCLUSIONS: Intravenous single high-dose darbepoetin alfa in acute MI is both safe and well tolerated. Darbepoetin treatment after MI stimulates EPCs mobilization. The results of this first pilot study support a larger scale clinical trial to establish efficacy of EPO administration in patients after acute MI.

Angioplasty, Balloon, Coronary↗
PubMed2006

Angiotensin-converting enzyme inhibition in patients with coronary artery disease and preserved left ventricular function Ischemia Management with Accupril post-bypass graft via inhibition of angiotensin-converting enzyme (IMAGINE) compared with the other major trials in coronary artery disease.

It has been hypothesized that angiotensin-converting enzyme (ACE) inhibition, independent from its effect on ventricular function and blood pressure, could affect the atherosclerotic process and reduce the incidence of ischemic events and its complications. Several large clinical outcome trials were designed to test this hypothesis: QUIET, HOPE, EUROPA, PEACE, and IMAGINE. The results of the PEACE study were recently reported, leaving the IMAGINE study as the last chapter in our efforts to evaluate the role of ACE inhibition in coronary artery disease with preserved left ventricular function. In this report, we compare these studies with respect to their methodology and patient population and analyze the unique nature of the last ongoing study, IMAGINE. The reported studies show that patients with coronary artery disease who are at low-to-moderate or high risk should receive an ACE inhibitor if tolerated. However, when the absolute risk of a patient decreases, and intensive contemporary management is given, with good control of risk factors, the absolute and perhaps relative benefits of an ACE inhibitor decrease and their routine use in these patients may not be warranted. The role of ACE inhibition started early post-coronary artery bypass graft in patients with preserved left ventricular function, and intensive contemporary management remains to be determined and should get answered by the IMAGINE study. Moreover, the IMAGINE population is not only a lower risk population than those enrolled in HOPE or EUROPA, but also the risk for this population is bimodal in nature (early post-revascularization inflammation and thrombosis vs long-term atherosclerosis progression) and may provide further insight into underlying mechanisms.

Aged↗
PubMed2006

Cost-effectiveness of screening for albuminuria with subsequent fosinopril treatment to prevent cardiovascular events: A pharmacoeconomic analysis linked to the prevention of renal and vascular endstage disease (PREVEND) study and the prevention of renal and vascular endstage disease intervention trial (PREVEND IT).

OBJECTIVE: This study estimated the cost-effectiveness,from the Dutch health care perspective, of screening for albuminuria in the general Dutch population to prevent cardiovascular events (CVEs) with subsequent angiotensin-converting enzyme inhibitor treatment, using data from the Prevention of REnal and Vascular ENdstage Disease Intervention Trial (PREVEND IT). METHODS: PREVEND IT was a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design within the larger observational Prevention of REnal and Vascular ENdstage Disease (PREVEND) study. The PREVEND IT study was conducted to assess the effects of fosinopril 20 mg and pravastatin 40 mg on CVEs in subjects with specific inclusion criteria: urinary albumin excretion (UAE) rate in the range from 15 to 300 mg/d, blood pressure <160/100 mm Hg, and plasma cholesterol level <8.0 mmol/L. Cost-effectiveness estimates for the Dutch population were expressed in euros (2002; 1 euro = US 1.01 dollars) as net costs per life-year gained (LYG) in the baseline and sensitivity (stochastic) analyses. RESULTS: Data were assessed for 864 subjects, with a mean (SD) follow-up of 46 (7) months. CVEs occurred in 45 (5.2%) subjects. Subjects who received fosinopril had a 40% lower incidence of CVEs than subjects in the placebo group (3.9% vs 6.5%, respectively; P = NS). The cost-effectiveness of screening for albumnuria was determined to be euro 16,700/LYG for the study population. Stochastic analysis indicated that the probability of the cost-effectiveness being below the suggested Dutch threshold of euro 20,000/LYG was 59% in the baseline analysis. The probability of cost-effectiveness below euro 20,000/LYG would increase to 91% if only subjects with UAE >50 mg/d were treated with fosinopril. Limiting the screening to subjects aged >50 years and >60 years also improved cost-effectiveness. CONCLUSIONS: The results of our study suggest that screening the general Dutch population for albuminuria and subsequently treating those found positive with fosinopril may be cost-effective compared with no screening and adopting the Dutch health care perspective. However, confirmation from larger multicenter trials is needed.

Adult↗
PubMed2006

Statins in the treatment of chronic heart failure: a systematic review.

BACKGROUND: The efficacy of statin therapy in patients with established chronic heart failure (CHF) is a subject of much debate. METHODS AND FINDINGS: We conducted three systematic literature searches to assess the evidence supporting the prescription of statins in CHF. First, we investigated the participation of CHF patients in randomized placebo-controlled clinical trials designed to evaluate the efficacy of statins in reducing major cardiovascular events and mortality. Second, we assessed the association between serum cholesterol and outcome in CHF. Finally, we evaluated the ability of statin treatment to modify surrogate endpoint parameters in CHF. Using validated search strategies, we systematically searched PubMed for our three queries. In addition, we searched the reference lists from eligible studies, used the "see related articles" feature for key publications in PubMed, consulted the Cochrane Library, and searched the ISI Web of Knowledge for papers citing key publications. Search 1 resulted in the retrieval of 47 placebo-controlled clinical statin trials involving more than 100,000 patients. CHF patients had, however, been systematically excluded from these trials. Search 2 resulted in the retrieval of eight studies assessing the relationship between cholesterol levels and outcome in CHF patients. Lower serum cholesterol was consistently associated with increased mortality. Search 3 resulted in the retrieval of 18 studies on the efficacy of statin treatment in CHF. On the whole, these studies reported favorable outcomes for almost all surrogate endpoints. CONCLUSIONS: Since CHF patients have been systematically excluded from randomized, controlled clinical cholesterol-lowering trials, the effect of statin therapy in these patients remains to be established. Currently, two large, randomized, placebo-controlled statin trials are under way to evaluate the efficacy of statin treatment in terms of reducing clinical endpoints in CHF patients in particular.

Anticholesteremic Agents↗
PubMed2006

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

Adult↗