Platelet aggregability is modulated by eNOS locus in non-type 2 diabetic patients with acute coronary syndrome.

BACKGROUND AND AIM: Platelet nitric oxide (NO) synthesis is compromised in patients with acute coronary syndrome (ACS), and platelet NO availability may be critically relevant in determining the extent of thrombosis in ACS patients. It has been demonstrated that an impaired responsiveness to the antiaggregatory effects of NO may affect platelet dysfunction in diabetic patients with ACS. Since NO availability may be genetically determined, we have investigated the role of endothelial nitric oxide synthase (eNOS) gene in influencing platelet aggregability in relation to the presence (n=247) or absence (n=883) of type 2 diabetes in ACS patients. METHODS AND RESULTS: We have genotyped 1130 consecutive high risk ACS patients on dual antiplatelet therapy, previously investigated in relation to platelet function. eNOS 4a allele frequency was significantly higher in diabetic vs. non-diabetic patients (p=0.02). In non-diabetic patients the eNOS 4a allele significantly modulated platelet aggregability in response to arachidonic acid (AA), but not to collagen and adenosine diphosphate (ADP) stimulus, after Bonferroni correction for multiple testing. After adjustment for age, gender, smoking habit, hypertension and ejection fraction ≤40%, the eNOS 4a allele remained significantly and independently associated with platelet aggregability in response to AA stimulus [ß (SE)=0.17 (0.07), p=0.01]. When platelet aggregation values were considered according to the presence or absence of high residual platelet reactivity (RPR) eNOS 4a, but not -786C and 894T, allele was significantly associated with RPR by AA stimulus. The haplotype reconstruction analysis for eNOS gene showed that the -786C/894G/4a and -786C/894G/4b haplotypes significantly influenced platelet aggregation after AA stimulus. CONCLUSIONS: Our study indicates that eNOS 4a allele, may be a determinant of higher platelet aggregability and residual platelet reactivity in non-diabetic ACS patients.

Blood rheology and renal transplantation: an intriguing relationship for assessing cardiovascular risk.

Renal transplant recipients (RTRs) are at increased risk of cardiovascular complications. An altered hemorheological profile may determine both cardiovascular complications and progression of renal failure in RTRs. We performed this study to evaluate the rheologic status in 239 RTRs at least 12 months after transplantation with stable and normal renal function compared with 90 control subjects. In RTRs, a significantly higher hematocrit-adjusted, but not native, whole blood viscosity was found (P < .0001). Moreover, plasma viscosity and red blood cell deformability were significantly higher in patients than in control subjects (P < .0001), whereas no difference in erythrocyte aggregation between patients and control subjects was observed (P = .5). Fibrinogen, but not hematocrit, significantly increased in RTRs (P = .001). This preliminary study provides evidence of an altered hemorheologic profile in RTRs.

The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis.

OBJECTIVE: To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc). METHODS: 350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA. RESULTS: A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS-670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS-670A allele was found in dcSSc. The FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS-670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS-670AA genotype compared with those carrying the FAS-670GG genotype (p = 0.003 in SSc, p = 0.004 in controls). CONCLUSION: The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.

Association between a stromal cell-derived factor 1 (SDF-1/CXCL12) gene polymorphism and microvascular disease in systemic sclerosis.

OBJECTIVE: To investigate the possible implication of SDF1-3' polymorphism in systemic sclerosis (SSc) susceptibility or clinical phenotype, or both. METHODS: 150 patients with SSc and 150 controls were enrolled. Skin involvement, autoantibodies, interstitial lung disease, pulmonary arterial hypertension (PAH), scleroderma renal crisis, past and/or current skin ulcers were assessed. Genotyping was performed by PCR-RFLP. RESULTS: Genotype distribution and allele frequency were similar in SSc and controls. SDF1-3'A allele and SDF1-3'GA/AA genotype frequencies were significantly higher in SSc-PAH than in SSc-non-PAH (33.3% vs 18.3%, p = 0.01) and in SSc with skin ulcers than in SSc without ulcers (27.3% vs 16.9%, p = 0.03). The SDF1-3'A allele influenced the predisposition to SSc-related PAH (OR = 2.52, 95% CI 1.11 to 5.69, p = 0.02) and skin ulcers (OR = 2.31, 95% CI 1.18 to 4.52, p = 0.01). After adjustment for age and gender, the SDF1-3'A allele remained a susceptibility factor for the SSc-related vascular manifestations (PAH: OR = 2.37, 95% CI 1.04 to 5.42, p = 0.04; ulcers: OR = 2.33, 95% CI 1.78 to 4.62, p = 0.01). CONCLUSION: The SDF1-3'A allele is significantly associated with microvascular involvement in SSc.

Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients. METHODS: According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited. RESULTS: SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P < 0.03). No significant differences (P > 0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P < 0.04). ABPI was not different among ACE gene genotypes. CONCLUSION: Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.

Etrurians vs Greeks: May ACE I/D polymorphism still be considered as a marker of susceptibility to SSc?

OBJECTIVE: SSc is characterized by immune dysfunction and microvascular involvement. A different genetic background may determine a different polymorphic allele frequency between different populations, and data from literature reported conflicting results about the role of genetic components in predisposing to the disease. We carried out this study in order to compare the ACE I/D polymorphism genotype distribution and alleles frequency in two different populations from the Mediterranean area. METHODS: Forty-eight Italian and 41 Greek SSc patients compared with 112 Italian and 93 Greek controls, have been studied. The ACE I/D polymorphism has been analysed. RESULTS: The genotype distribution and allele frequency were in Hardy-Weinberg equilibrium for Italian and Greek SSc patients and controls. Among the Italian patients a significantly higher ACE D allele frequency than in the controls was found, whereas among the Greeks a higher prevalence was observed in the healthy subjects. A significant difference in ACE D allele frequency between Italian and Greek controls was observed (p = 0.04). ACE D allele was associated to the predisposition to SSc in Italians, but not in Greeks. CONCLUSION: We confirm that Italian SSc patients have a higher ACE D allele frequency that is not present in the Greek patients. Thus, the two populations living in different Mediterranean areas and resulting from the Mediterranean civilization, do not show the same ACE-gene related allele frequencies. Other populations of the Mediterranean area must be investigated by using unlinked genetic markers to verify the homogeneity of the genetic background, and to test for a "true" difference in their ethnic origin.

Protein Z plasma levels in different phases of activity of coronary atherosclerosis.

We previously reported that low protein Z plasma levels are associated with acute coronary syndromes (ACS). Aim of the present study was to evaluate protein Z levels in different phases of activity of coronary atherosclerosis. Protein Z plasma levels were measured in 166 (131 male and 35 female) patients consecutively admitted to the University of Florence with a diagnosis of ACS (group A), 166 (131 male and 35 female) patients selected by age and gender in relation to group A from those with a clinical history of ACS who remained symptom- and/or event-free over the last year before the investigation (group B); and 332 (262 male and 70 female) controls comparable for age and gender with the other two groups. None had liver or renal dysfunction nor showed a positivity for antiphospholipid antibodies or for factor V Leiden mutation. Patients under warfarin therapy were excluded. Mean protein Z plasma levels were found to be significantly (P < 0.0001) lower in group A (1475 +/- 684.1 ng mL(-1)) and group B (1327.6 +/- 690.7 ng mL(-1)) as compared with control group (1650.1 +/- 634.5 ng mL(-1)), while no significant differences existed between the two groups of patients (P = 0.06). A logistic regression analysis, performed after the division of the study population into quartiles of protein Z levels and adjusted for all possible confounders, showed a significant increased risk of ACS for the lowest (<1213 ng mL(-1)) as compared with the highest quartile of protein Z in both groups of patients [group A odds ratio (OR): 2.7, 95% CI 1.3-5.5, P = 0.007; group B OR: 3.2, 95% CI 1.1-8.9, P = 0.02). In conclusion, these results strengthen our previous data on low protein Z plasma levels in ACS and indicate a possible dose-response effect of decreasing protein Z plasma levels on the coronary atherosclerotic disease.

The fibrinolytic system components are increased in systemic sclerosis and modulated by Alprostadil (alpha1 ciclodestryn).

OBJECTIVES: To evaluate urokinase plasminogen activator (u-PA), urokinase plasminogen activator soluble receptor (su-PAR), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) plasma levels in SSc patients (pts) versus healthy controls and their modulation by intravenous alphacyclodestrine (Alprostadil). METHODS: Plasma levels of u-PA, su-PAR, PAI-1 and t-PA were measured in 40 SSc (34 lSSc and 6 dSSc) pts and in 30 healthy controls. In SSc, blood was drawn before and after 3 consecutive daily of Alprostadil infusion (60 mg in 250 cc NaCl 0.9%). RESULTS: In SSc su-PAR basal levels were higher than controls (7.48 +/- 2.5 vs 4.69 +/- 0.4 ng/ml; p = 0.001) and were significantly reduced by Alprostadil (5.93 +/- 1.7; p = 0.002), but remain higher than controls (p = 0.03). u-PA basal levels were higher than controls (3.78 +/- 1.5 vs 1.29 +/- 0.3 ng/ml; p < 0.001) and were reduced by Alprostadil (2.39 +/- 1.7; p < 0.001) to control levels. SSc PAI-1 basal levels were lower than controls (31.60 +/- 7.7 vs 48.30 +/- 6.8 ng/ml; p < 0.001) and increased by Alprostadil (34.66 +/- 5.4; p = 0.04), but lower than controls (p < 0.001). SSc t-PA basal levels were higher in respect to controls (1645.81 +/- 792.7 vs 571.95 +/- 75.5 pg/ml; p < 0.0001) and reduced by Alprostadil (1318.06 +/- 603.5; p = 0.04), but still higher than controls (p = 0.001). CONCLUSION: Fibrinolysis were increased in SSc. Infusions of Alprostadil modulate u-PA, su-PAR, PAI-1 and t-PA, restoring near normal levels. In SSc, fibrinolysis system may become a potential target for new therapies.

ACE DD genotype: a predisposing factor for abdominal aortic aneurysm.

OBJECTIVE: To examine the role of polymorphisms in angiotensin converting enzyme (ACE, I/D) and angiotensin II receptor (AT1R, A1166C) in the development of abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: We investigated 250 consecutive patients, 217 males and 33 females (median age 72, range 50-83), undergone AAA elective repair and 250 healthy controls, comparable for sex and age. ACE and AT1R polymorphisms were studied by PCR-RFLP analysis. The genotype distribution was in Hardy-Weinberg equilibrium for all polymorphisms. RESULTS: The genotype distribution and allele frequency of ACE I/D, but not AT1R A1166C polymorphism were significantly different between patients and controls (ACE I/D: p=0.0002 and p<0.0001, respectively, and AT1R A1166C: p=0.6 and p=0.4, respectively). An association between the ACE DD genotype and the predisposition to AAA was found (OR DD vs. ID+II=1.9 95% CI 1.3-2.9, p<0.0001). Multivariate analysis adjusted for age, sex, traditional vascular risk factors and other atherosclerotic localizations, showed ACE DD genotype to be independently related to the disease (OR DD vs. ID+II=2.4, 95% CI 1.3-4.2 p=0.003). CONCLUSIONS: Our findings document that ACE DD genotype represents a susceptibility factor for AAA.

Influence of eNOS gene polymorphisms on carotid atherosclerosis.

INTRODUCTION: Nitric oxide (NO) is an endothelium-derived relaxing factor which plays a role in atherogenetic events. Polymorphisms in the endothelial NO synthase gene (eNOS) influences the functional activity of the enzyme and affect the susceptibility to atherogenesis. In this study we determined whether T-786C, G894T and 4a/4b eNOS genetic variants may increase the susceptibility to carotid atherosclerosis. METHODS: The study groups included 304 consecutive patients with severe carotid stenosis (>/=70%) and 544 control subjects. The eNOS polymorphisms were analysed by molecular biology techniques. RESULTS: The genotype distribution and allele frequency of eNOS 4a/4b, but not T-786C and G894T, polymorphism was significantly different between patients and controls. Using logistic regression with adjustment for other risk factors, the 4a allele and the combined genotype 4a4a+4a4b/894TT+GT and -786CC+TC/894TT+GT were associated with carotid stenosis (OR=1.5, p=0.02; OR=1.8, p=0.01; OR=1.5, p=0.04, respectively). In a subset of patients (30 of 304) with no traditional risk factors for atherosclerosis, a relatively high incidence of the 4a allele and 4a4a+4a4b/-786CC+TC combined genotype was noted. DISCUSSION: Our findings suggest that the 4a allele and the eNOS combined genotypes are independent predisposing factors to carotid atherosclerosis.

ACE DD genotype: an independent predisposition factor to venous thromboembolism.

BACKGROUND: The renin angiotensin system affects haemostasis through different mechanisms; data on the possible role of angiotensin-converting enzyme I/D polymorphism in the pathogenesis of deep venous thrombosis are conflicting, and no information is available regarding the A1166C polymorphism of the angiotensin type 1 receptor gene. In order to investigate this issue, angiotensin-converting enzyme and AT1R polymorphisms were genotyped in 336 consecutive venous thromboembolism patients and 378 controls. MATERIALS AND METHODS: Haemostasis-related risk factors have been evaluated by routine tests. Factor V Leiden, Factor II (G20210A), angiotensin-converting enzyme (I/D), and angiotensin type 1 receptor (A1166C) polymorphisms have been identified by molecular analysis. RESULTS: We documented a significant association between angiotensin-converting enzyme DD genotype and venous thromboembolism (OR=2.19 95%CI 1.51-3.17 adjusted for acquired and haemostasis-related risk factors, P<0.0001); in patients with haemostasis-related risk factors, angiotensin-converting enzyme DD genotype modified the risk of venous thromboembolism in hyperhomocysteinaemic and Factor V Leiden patients and was associated with the risk of recurrent venous thromboembolism (OR=1.83 95%CI 1.06-3.17 P=0.03). In patients without haemostasis-related risk factors the angiotensin-converting enzyme DD genotype was still an independent predictor of venous thromboembolism (OR=3.29 95%CI 2.17-4.98 adjusted for acquired risk factors, P<0.0001). No significant association between the angiotensin type 1 receptor CC genotype and venous thromboembolism was found. CONCLUSIONS: This study shows that angiotensin-converting enzyme DD genotype represents a susceptibility marker of thrombosis in subjects apparently without predisposing factors and traditional thrombophilic alterations, and increases the risk of venous thromboembolism in subjects in whom a thrombogenic condition occurs. Moreover, angiotensin-converting enzyme DD genotype may be considered a new predisposing factor to venous thromboembolism recurrence.

Thrombophilias as risk factors for disorders of pregnancy and fetal damage.

Inherited thrombophilias have been suggested as a possible condition of increased susceptibility to adverse pregnancy outcomes. Although there is no consensus on the association between the factor V Leiden mutation and early (less than 10 weeks) pregnancy loss, the evidence suggests an association between the mutation and second-, and third-trimester fetal loss and severe preeclampsia. At present the relationship between the prothrombin G20210A mutation and inherited thrombophilias and adverse pregnancy outcomes remains controversial. Due to the low prevalence, AT and PC deficiencies have been rarely found as the cause of complicated pregnancy, whereas increased risk for preeclampsia and fetal losses has been found in relation to PS deficiency. Concerning the association between pathological pregnancies and PAI-1 4G/5G deletion/insertion polymorphism, only few controversial data are available. A meta-analysis of ten case-control studies suggested an association between hyperhomocysteinemia, MTHFR C677T mutation and repeated pregnancy losses before 16 weeks. Recently a role for Angiotensin Converting Enzyme I/D polymorphism in obstetrical complications has been suggested.

RAS genes influence exercise-induced left ventricular hypertrophy: an elite athletes study.

PURPOSE: The association of ACE I/D polymorphism with changes in LV mass in response to physical training has been observed, but no association has been found with AT1R A1166C polymorphism. We investigated the ACE I/D, AT1R A1166C, and AT1R CA microsatellite polymorphisms genotype distribution in elite athletes and whether the presence of AT1R C1166 variant, in addition to ACE D allele affects the training-induced LV mass alterations in elite trained athletes. METHODS: The study population comprised 28 healthy players recruited from an Italian elite male soccer team and 155 healthy male subjects. LV mass, LV mass adjusted for body surface area, septal thickness, posterior wall, end-diastolic and end-systolic ventricular dimension, and ejection fraction were determined by echocardiography in pretrained period, at rest and 7 months later during the training. All subjects were genotyped for ACE I/D, AT1R A1166C, and CA microsatellite polymorphisms. RESULTS: Training induced an LV mass increase in all but six athletes. The percentage of athletes in whom an increase of LV mass was found after training was statistically different in relation to the ACE D allele: no increase was observed in three of 24 D allele carriers and in three of four II genotype players (Fisher's exact test, P = 0.02). As AT1R is concerned, no increase was observed in 4 of 15 C allele carriers and in 2 of 13 AA genotype athletes (Fisher's exact test, P > 0.05). The contemporary presence of ACE D and AT1R C allele did not affect the changes after training. No difference has been observed in the CA microsatellite marker allele frequencies between athletes and controls (P = 0.46). CONCLUSION: In this study, we provide the evidence that soccer play does not select athletes on genotype basis. Training-induced LV mass changes in male elite athletes are significantly associated with the presence of ACE D allele, but not of AT1R C allele.

Angiotensin-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetal-loss susceptibility.

Complications of pregnancy have been found to be related with thrombophilic polymorphisms that explain about 30% of obstetric complications. We evaluated the angiotensin converting enzyme (ACE) and the angiotensin type 1 receptor (AT1R) gene polymorphisms in the renin-angiotensin system (RAS) as possible risk factors for fetal loss. Fifty-nine women with a history of three or more first-trimester fetal losses and 70 healthy women with a history of normal pregnancies were enrolled in this study. Thrombophilic factors, ACE insertion/deletion (I/D) and AT1R A1166C polymorphisms, prothrombin G20210A and factor V Leiden mutations were analyzed. At univariate and multivariate analysis, a significant association between ACE DD and AT1R CC genotype and fetal loss was observed. The effect of the ACE DD genotype on the risk of fetal loss was higher in AT1R C allele carriers. The prevalence of hyperhomocysteinemia (Hcy) (defined as baseline plasma levels higher than the 95% percentile; cut-off, 10.5 micromol/l per l) was significantly higher in women with fetal loss, and an association between Hcy and fetal loss was detected. All patients showed normal antithrombin, protein C, protein S, and plasminogen activator inhibitor-1 (PAI-1) values. The presence of one risk factor not associated with others was found in 33 out of 59 patients (56%); ACE DD genotype was the most prevalent risk factor. Our results identify new possible predictive markers for fetal loss in RAS polymorphisms and Hcy. Large-scale studies are warranted to attribute clinical relevance to these polymorphisms as risk factors for complicated pregnancies.

Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms.

BACKGROUND: Polymorphisms within renin angiotensin system genes have been investigated as risk factors for coronary artery disease in different populations with contradicting results. The aim of this study was to investigate the genotype distribution and the allele frequencies of ACE, AT1R and AGT gene polymorphisms as coronary artery disease factors and their synergistic effects on coronary risk in an Italian population. METHODS AND RESULTDS: In this study ACE, AT1R and AGT gene polymorphisms were investigated in 205 consecutive coronary artery disease patients and in 209 controls. These polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The ACE D and AGT 235T allele, but not AT1R C allele, frequency was statistically significant in patients. An association between coronary artery disease and ACE DD, AT1R CC and AGT TT genotype, was found by univariate analysis (OR 2.06 P=0.0007, OR 2.49 P=0.009, OR 1.87 P=0. 019, respectively). At multivariate analysis ACE DD and AT1R CC genotype (OR 1.81 P=0.011, OR 2.61 P=0.011, respectively) remained associated with coronary heart disease. Subjects carrying the ACE DD genotype and AT1R C allele showed a stronger association with myocardial infarction (OR=4.02, P<0.0001). CONCLUSION: Our report indicates the increased risk of coronary artery disease in the presence of ACE DD and AT1R CC genotypes independent of other risk factors, in Italian patients. The present study stresses the relevance of screening for genetic risk factors.

Angiotensin converting enzyme DD genotype affects the changes of plasma plasminogen activator inhibitor-1 activity after primary percutaneous transluminal coronary angioplasty in acute myocardial infarction patients.

Angiotensin converting enzyme (ACE) DD genotype, and plasminogen activator inhibitor (PAI-1) 4G/4G genotype have been reported to affect PAI-1 activity in control subjects and atherosclerotic patients, but no data are available on the influence of angiotensin II type 1 receptor (AT1R) A1166C polymorphism on the inhibitor levels. The degree of fibrinolytic activation after percutaneous transluminal coronary angioplasty (PTCA) has been found to affect the risk of restenosis. The aim of this study was to investigate the possible influence of ACE I/D, AT1R A1166C, and PAI-1 4G/5G polymorphisms on the changes of PAI-1 activity after primary successful percutaneous transluminal angioplasty. In 29 consecutive acute myocardial infarction patients, undergoing primary successful angioplasty, genotyping of ACE I/D, AT1R A1166C, and PAI-1 4G/5G polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism analysis, and PAI-1 plasma activity (chromogenic method) was assessed before and after angioplasty. Following angioplasty, PAI-1 activity increased in 10 of 29 patients and decreased or remained unchanged in 19 of 29. ACE DD genotype was significantly (P = 0.04) associated with an increase of PAI-1 activity post angioplasty (OR DD/ID+II = 6.5, CI 95% 4.83-8.22). Whereas no effect of PAI-1 4G/5G and AT1R A1166C polymorphisms on PAI-1 response to angioplasty was demonstrated, these data suggest that renin-angiotensin system genes are involved in the regulation of the fibrinolytic response to balloon injury, possibly affecting angiotensin converting enzyme activity. This interaction between the renin-angiotensin system and hemostasis may be a mechanism by which ACE DD genotype affects the risk of restenosis after percutaneous transluminal angioplasty.