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.     

Angiotensin-Converting Enzyme Gene Polymorphism and Plasminogen Activator Inhibitor 1 Levels in Subjects with Cerebral Infarction

It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary artery disease, but its relation to cerebral infarction is still controversial. Plasminogen activator inhibitor 1 (PAI-1) is also a predictor of risk of atherothrombotic disease. In this study we investigated the association of the ACE gene polymorphism and plasma PAI-1 levels in subjects with cerebral infarction. We evaluated the genotype of the ACE gene in 26 subjects with and 28 subjects without a history of ischemic stroke. The ACE genotype was analyzed by the polymerase chain reaction. Plasma PAI-1 antigen levels were measured by ELISA. There were no differences in accepted risk factors between the groups with or without cerebral infarction. However, the frequency of the D allele was significantly higher in subjects with cerebral infarction (0.63) than in those without infarction (0.39) (² = 6.306, P = 0.012). The frequency of the DD genotype of the ACE gene was also significantly higher in subjects with than in those without cerebral infarction (DD: 46.2%, ID: 34.6%, II: 19.2% vs. DD: 14.3%, ID: 50.0%, II: 35.7%, ² = 6.689, P = 0.035). Plasma PAI-1 levels were not significantly different between groups with and without cerebral infarction. There was no association between the ACE genotype and PAI-1 levels. The DD genotype of the ACE gene is associated with cerebral infarction, which is independent of plasma PAI-1 level.     

Plasma adiponectin, T94G gene polymorphism and PAI-1 in patients with and without hypertension

BACKGROUND: Reduced adiponectin level has been associated with metabolic syndrome, type 2 diabetes, coronary artery disease and gene polymorphisms, but the interrelationships of T94G genotype, plasma adiponectin and plasminogen activator inhibitor-1 (PAI-1) are less understood. PATIENTS AND METHODS: The T94G genotypes and plasma levels of adiponectin, and PAI-1 were determined in 568 Chinese patients, 212 with and 356 without hypertension, to study the possible associations of T94G genotype, plasma adiponectin, PAI-1 and blood pressure. RESULTS: Hypertensive patients showed significantly lower plasma adiponectin (9.7 +/- 11.1 vs. 11.5 +/- 10.0 microg/ml, p = 0.04) and higher PAI-1 (p < 0.001) levels but not significantly greater adiponectin TT genotype percentage (38.7 vs. 33.5%) and T allele frequency (0.620 vs. 0.585) than normotensive subjects. Plasma adiponectin was inversely related to PAI-1 activity (r = -0.09, p = 0.03) and antigen (r = -0.202, p < 0.001). Furthermore, the TT genotypic group showed significantly lower plasma adiponectin level (10.4 +/- 10.5 vs. 13.4 +/- 10.8 mug/ml, p = 0.03) and higher plasma PAI-1 activity (17.0 +/- 9.7 vs. 13.5 +/- 7.6 IU/ml, p = 0.003) and antigen (32.3 +/- 22.7 vs. 25.9 +/- 14.7 ng/ml, p = 0.01) than the GG genotypic group. Multiple linear regression analysis in all study subjects, in men and in normotensives documented an impact of adiponectin T94G genotype on plasma levels of adiponectin (p = 0.007, 0.003 and 0.03) and PAI-1 activity (p = 0.02, 0.03 and 0.04) and antigen (p = 0.03, 0.007 and 0.04) after adjustment for potential confounding factors. CONCLUSIONS: The present study demonstrated a significant correlation of the TT genotype with lower plasma adiponectin and higher plasma PAI-1 levels in a Chinese population. The contribution of this genotype seemed greater in men and normotensives. It suggested the adiponectin gene T94G polymorphism might affect the regulation of circulating adiponectin and PAI-1.     

Angiotensin-converting enzyme insertion/deletion genotype is associated with the activities of plasma coagulation factor VII and X independent of triglyceride metabolism

BACKGROUND: The D allele of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and coagulation activity play important roles in cardiovascular events, however, the precise association between these two risk factors remains unclear. METHODS: We identified the ACE I/D genotype and measured the plasma coagulation factor VII and X (FVII and FX) activities and serum lipids in 172 patients (110 men and 62 women, mean age 56.7+/-13.3 years) undergoing coronary angiography. RESULTS: The frequency of the D allele was significantly higher in those with a history of myocardial infarction (MI) than in those with normal coronary arteries, but there was no significant association between FVII and FX activities and the stage of coronary disease. Plasma coagulation factor VII and FX activities were significantly lower in the DD genotype (n=42) than in the II genotype (n=67, P<0.001 and P<0.001, respectively) or the ID genotype (n=63, P<0.01 and P<0.05, respectively). The association of the ACE D allele with lower activities of FVII and FX was also seen in patients with coronary artery disease (CAD). There was a significant association between serum triglyceride levels with FVII and FX, but not with the ACE I/D genotype. CONCLUSION: We concluded that the ACE I/D polymorphism may contribute more to the onset of MI than the activities of FVII and FX and that the ACE D allele might be associated with lower plasma activities of FVII and FX. The potential link between ACE I/D polymorphism and the plasma activities of FVII and FX is probably independent of triglyceride metabolism.     

Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study.

Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.     

Plasminogen activator inhibitor-1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D gene polymorphisms and fibrinolytic activity in patients with essential hypertension and dyslipidemia

Essential arterial hypertension often predisposes patients to prothrombotic state and increased risk of vascular and organ complications. Vital role in regulation of hemostatic processes is played by genetic factors, renin-angiotensin system and disorders of lipid metabolism. Prime genetic factors involved in the process are 4G/5G polymorphism of promoter region coding tissue plasminogen activator inhibitor-1 (PAI-1) and I/D polymorphism for angiotensin converting enzyme (ACE) gene. The aim of work was the evaluation of alterations within fibrinolysis system (estimation of t-PA and PAI-1 levels), fibrinogen concentration (Fb) and ACE activity with regard to co-existent dyslipidemia and features of left ventricle hypertrophy (LVH). Moreover the analysis of influence of 4G/5G PAI and I/D ACE gene polymorphism on intensification of aforementioned alterations among hypertensive patients was performed. Research was carried out in 170 subjects under 40 years old, in two study groups, HT-- hypertensive group--125 patients with previously untreated hypertension without clinical features of ischaemic heart disease and NT--45 normotensive, healthy subjects. HT group has been further divided into four subgroups: DLP (dyslipidemic, n = 51), NLP (normolipidemic n = 74), LVH+ (with features of left ventricle hypertrophy, n = 35), LVH (-) (without features of left ventricle hypertrophy, n = 90). In a whole HT group significantly higher levels of PAI-1, t-PA and Fb were noted in comparison to NT group, considerably more pronounced within DLP rather than NLP subgroups. Moreover, pronounced increase in ACE activity was recorded in DLP and LVH+ subgroups. It has been proved that 4G/4G homozygous subjects of 4G/5G PAI-1 gene polymorphism from HT group tend to present higher levels of PAI-1 and t-PA if contrasted to 4G/4G genotype of NT group, with more distinct effect within DLP subgroup. Carriers of D allele (genotypes I/D, D/D) of I/D ACE gene polymorphism from HT group characterise with significantly higher activity of ACE in contrast to I/I genotype of HT group, with particularly marked effect in DLP and LVH+ subgroups. Basing on above mentioned results it may be concluded that essential hypertension (especially if complicated with dyslipidemia) impairs fibrinolysis, what might be related to renin-angiotensin system activation in lipid metabolism disorders. Deletion alleles of 4G/5G polymorphism (4G allele) and I/D polymorphism (D allele) in patients with hypertension independently modify fibrinolysis towards prothrombotic state with more distinct effect in dyslipidemia. Increased activity of ACE in D allele carriers may predispose to left ventricle hypertrophy.     

ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time

ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT1) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m2, or fasting serum triglyceride > or =2.8 mmol/L) hypertensive subjects (mean age, 47.9+/-2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019) pressure. Ramipril (from 133.6+/-5.1/94.5+/-2.4 to 127.0+/-3.1/91.4+/-3.3 mm Hg) or losartan (from 137.0+/-3.9/93.1+/-2.9 to 123.7+/-2.6/86.4+/-2.1 mm Hg) further reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013) but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT1 receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT1 receptor antagonism.     

Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting

BACKGROUND: Observations with intravascular ultrasound demonstrated that neointimal hyperplasia is the predominant factor responsible for in-stent restenosis. Experimental data suggest that angiotensin I converting enzyme (ACE) plays a role in the thickening of neointima after balloon denudation. Insertion/deletion (I/D) polymorphism of the ACE gene is significantly associated with plasma level of ACE and subjects with D/D genotype have significantly higher plasma levels of ACE than normal. OBJECTIVE: To investigate whether this polymorphism influences the risk of restenosis after coronary stenting. METHODS: We genotyped 158 patients who had undergone single-vessel coronary stenting for the ACE I/D polymorphism. RESULTS: Of the 158 patients, 56 (35%) had the D/D genotype, 71 (45%) had the I/D genotype and 31 (20%) had the I/I genotype. Prevalences of genotypes were compatible with Hardy-Weinberg equilibrium and distributions of ACE genotype among patients and 132 healthy controls from the same geographic area did not differ. At follow-up (after a median duration of 5.4 months), overall rates of angiographic restenosis and of revascularization of target lesion (RTL) were 32.3 and 22.8%, respectively. Of 51 patients with angiographic restenosis, 31 (60.8%) had focal and 20 (39.2%) had diffuse patterns of restenosis. Diffuse in-stent restenosis was significantly more prevalent among patients with D/D genotype (P = 0.016). Multiple stepwise logistic regression analysis identified ACE I/D polymorphism as the independent predictor of angiographic restenosis and RTL. Relative risk of angiographic restenosis was 6.29 [95% confidence interval (CI), 1.80-22.05, P = 0.0004] for D/D genotype and 3.88 (95% CI 1.11-13.12, P = 0.029) for I/D genotype, whereas relative risk of RTL was 7.44 (95% CI 1.60-34.58, P = 0.01) for D/D genotype and 3.88 (95% CI 0.083-18.15, P = 0.085) for I/D genotype. CONCLUSIONS: The ACE I/D polymorphism is significantly associated with risk of angiographic and clinical restenosis after coronary stenting. Angiographic pattern of restenosis is also significantly associated with I/D polymorphism, diffuse type being more prevalent among subjects with D/D genotype.     

Association of angiotensin converting enzyme and plasminogen activator inhibitor-1 promoter gene polymorphisms with features of the insulin resistance syndrome in patients with premature coronary heart disease.

Polymorphisms of the angiotensin-converting enzyme (ACE) (insertion/deletion (I/D) in intron 16) and of the plasminogen activator inhibitor-1 (PAI-1) (promoter 4G/5G) genes have been linked with coronary heart disease (CHD) and/or myocardial infarction (MI). We studied the association of polymorphisms in these genes with CHD with linkage and association analyses in 118 families with premature and severe CHD and in 110 healthy controls. In linkage analysis there was no evidence for a linkage of the ACE or PAI-1 loci with CHD. However, in quantitative linkage analysis the ACE locus was linked with fasting glucose (P=0. 047) and fasting free fatty acid levels (P=0.029). In association analysis the ACE genotype frequencies of probands with CHD did not differ from those of healthy controls. Normoglycemic probands with MI and with the ACE polymorphism DD genotype had characteristics of the insulin resistance syndrome. They had higher levels of 1-h glucose (P=0.008) and 2-h free fatty acids (P=0.011) in an oral glucose tolerance test and higher levels of total (P=0.005) and very-low-density lipoprotein triglycerides (P=0.006) than probands with the ID or the II genotypes. The PAI-1 gene polymorphism was not associated with any of the variables of glucose or lipid metabolism. In conclusion, the ACE and PAI-1 gene polymorphisms are not linked with early-onset CHD. However, the ACE gene polymorphism is associated with features of the insulin resistance syndrome.     

Effects of perindopril treatment on hemostatic function in patients with essential hypertension in relation to angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms

BACKGROUND AND AIM: An imbalance in the hemostatic system is a frequent finding in untreated essential hypertension (HT), and it has been shown that treatment with angiotensin converting entyme (ACE) inhibitors improves hemostatic function. In order to elucidate the role of genetic factors, we studied hemostasis in patients with untreated and treated HT and correlated the results with ACE I/D and plasminogen activator enhibitor-1 (PAI-1) 4G/5G gene polymorphisms. METHODS AND RESULTS: Forty-three males with HT (mean age 31.7 +/- 6.8 years) were compared with 34 age and gender-matched controls. All of the patients were treated with perindopril (4 mg/day) and, after one and six months of therapy, their levels of plasma fibrinogen (Fb), t-PA antigen, PAI-1 antigen, von Willebrand factor (vWF), ACE activity and blood pressure were measured. ACE and PAI-1 genotypes were identified by means of the polymerase chain reaction on DNA isolated from peripheral blood lymphocytes. Untreated patients had significantly higher levels of Fb, PAI-1 (p < 0.01) and t-PA (p < 0.05) regardless of their ACE or PAI-1 genotypes. Perindopril reduced blood pressure regardless of ACE or PAI-1 genotype (p < 0.001). ACE II homozygotes showed the greatest decrease in ACE activity (p < 0.01) and a significant reduction in Fb levels (p < 0.05) after just one month of treatment. Analysis of the group as a whole revealed an increase in t-PA antigen levels after six months of treatment, regardless of ACE or PAI-1 genotype (p < 0.01). CONCLUSIONS: Our results show that essential hypertension predisposes to the procoagulant state characterized by hyperfibrinogenemia and hypofibrinolysis. Perindopril reduced fibrinogen levels in ACE II homozygotes due to its more potent inhibitory action on the renin-angiotensin system in such patients. It improved fibrinolysis by increasing t-PA levels regardless of ACE and PAI-1 genotype.     

Genotype-corrected reference values for serum angiotensin-converting enzyme.

The deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene has the greatest impact on serum ACE level in Caucasians of any factor yet discovered. The aim of the present study was to establish new ACE genotype-corrected normal ranges for serum ACE level in a population of central European origin. After a medical examination, 159 healthy Caucasians volunteered to donate blood for the study. ACE genotypes were assessed by PCR and serum ACE levels were determined using two different kinetic tests. The distribution of the D/I polymorphism of the ACE gene was in accordance with the Hardy-Weinberg equilibrium. Serum ACE levels and ACE genotypes correlated significantly, with the highest serum ACE levels in subjects with ACE genotype D/D, and the lowest serum ACE levels in subjects with genotype I/I (mean+/-sd, assay 1: D/D 59.3+/-15.1 U x L(-1), D/I 45.5+/-15.2 U x L(-1), I/I 34.8+/-13.7 U x L(-1); assay 2: D/D 43.7+/-14.1 U x L(-1), D/I 33.7+/-12.1 U x L(-1), I/I 25.4+/-9.5 U x L(-1)). Although they gave different absolute values of serum ACE levels, the results of the two test kits correlated significantly. In conclusion, the present authors recommend the use of new, genotype-specific reference values for serum angiotensin-converting enzyme levels, especially to improve the sensitivity and specificity of tests for angiotensin-converting enzyme in the follow-up of sarcoidosis.     

Association of PAI-1 gene promoter 4g/5g polymorphism with plasma PAI-1 activity in Chinese patients with and without hypertension

BACKGROUND: The PAI-1 gene promoter 4G/5G polymorphism was found to be associated with plasma PAI-1 activity in white but not yet in Chinese patients. Hypertension might exaggerate the 4G/5G genotype effect on plasma PAI-1. METHODS: The 4G/5G genotypes and plasma PAI-1 levels were determined in 565 Chinese, 211 with and 354 without hypertension to study the genotype effect and the mode of gene-environment interaction. RESULTS: Hypertensive patients showed significantly higher plasma PAI-1 activity (18.2 +/- 10.0 v 14.6 +/- 8.8 IU/mL, P <.001) than normotensive subjects, and also higher body mass index (BMI) and plasma triglyceride (TG), but had neither significant difference in the 4G allele frequency (0.531 v 0.549) nor in the 4G/4G genotype percentage (24.6% v 26.5%). The 4G/4G genotypic group had higher plasma PAI-1 activity (17.6 +/- 10.2 v 14.5 +/- 7.3 IU/mL, P =.027) than the 5G/5G genotypic groups, but the statistic significance was present in women (18.1 +/- 10.0 v 14.8 +/- 6.9 IU/mL, P =.025) and not in men (17.2 +/- 10.5 v 14.3 +/- 7.7 IU/mL, P =.39) after log transformation. Multiple regression analysis of all cases documented the independent effect of BMI (P =.000), plasma TG (P =.000), age (P =.006), gender (P =.046), and the PAI-1 genotype (4G/4G v 5G/5G, P =.012) on plasma PAI-1 activity. However, the significant association of 4G/4G genotypes with higher plasma PAI-1 activity was present in women (P =.004) but not in men. There was a significant difference (P =.04) on the plasma TG-PAI-1 activity correlations between the 4G/4G (r = 0.521) and 5G/5G (r = 0.117) genotypic groups of hypertensive patients. CONCLUSIONS: The present study showed that the 4G/4G genotype was associated with elevated plasma PAI-1 activity in Chinese patients with and without hypertension. The contribution of the PAI-1 genotype seemed larger in women. In hypertensives carrying the 4G/4G genotype, higher TG was correlated with higher PAI-1, suggesting a possible contribution of gene-environmental interaction to their high risk for atherothrombotic disease.     

Renal changes on hyperglycemia and angiotensin-converting enzyme in type 1 diabetes

Hyperglycemia causes capillary vasodilation and high glomerular capillary hydraulic pressure, which lead to glomerulosclerosis and hypertension in type 1 diabetic subjects. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene can modulate risk of nephropathy due to hyperglycemia, and the II genotype (producing low plasma ACE concentrations and probably reduced renal angiotensin II generation and kinin inactivation) may protect against diabetic nephropathy. We tested the possible interaction between ACE I/D polymorphism and uncontrolled type 1 diabetes by measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during normoglycemia ( approximately 5 mmol/L) and hyperglycemia ( approximately 15 mmol/L) in 9 normoalbuminuric, normotensive type 1 diabetic subjects with the II genotype and 18 matched controls with the ID or DD genotype. Baseline GFR (145+/-22 mL/min per 1.73 m2) and ERPF (636+/-69 mL/min per 1.73 m2) of II subjects declined by 8+/-10% and 10+/-9%, respectively, during hyperglycemia; whereas baseline GFR (138+/-16 mL/min per 1.73 m2) and ERPF (607+/-93 mL/min per 1.73 m2) increased by 4+/-7% and 6+/-11%, respectively, in ID and DD subjects (II versus ID or DD subjects: P=0.0007 and P=0.0005, for GFR and ERPF, respectively). The changes in renal hemodynamics of subjects carrying 1 or 2 D alleles were compatible, with a mainly preglomerular vasodilation induced by hyperglycemia, proportional to plasma ACE concentration (P=0.024); this was not observed in subjects with the II genotype. Thus, type 1 diabetic individuals with the II genotype are resistant to glomerular changes induced by hyperglycemia, providing a basis for their reduced risk of nephropathy.     

血管紧张素转化酶基因多态性对血清血管紧张素转化酶水平及血脂的影响

为探讨血管紧张素转化酶基因多态性对本地人群高血压患者和正常人血清血管紧张素转化酶及血脂水平的影响,采用聚合酶链反应技术,对118例高血压患者和98例正常人的血管紧张素转化酶基因插入/缺失多态性进行分型,并检测血清血管祭张素转化酶活性及血脂含量。结果发现,高血压组血管紧张素转化酶三种基因型(缺失纯合子型、插入纯合子型和杂合子型)及插入/缺失等位基因的频率与正常对照组比较差异无统计学意义(X2=0.468,P=0.791;X2=0.379,P=0.538)。血清血管紧张素转化酶活性在三种基因型之间差异有显著性意义(F=17.107,P=0.000)。高血压组总胆固醇、低密度脂蛋白胆固醇、脂蛋白(a)高于正常对照组(P<0.05);高血压组三种基因型之间血脂各指标含量及正常对照组三种基因型之间总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和载脂蛋白B含量差异有显著性意义(P<0.05)。此结果提示,血管紧张素转化酶基因多态性与血清血管肾张素转化酶活性及血脂含量有关,缺失纯合子型高血压患者血清血管紧张素转化酶活性最高且易患高脂血症。     

Angiotensin-converting enzyme-gene polymorphism is associated with collagen I synthesis and QT dispersion in essential hypertension

AIM: This study tested the hypothesis that abnormal QT dispersion, an indicator of arrhythmogenic risk, is associated with angiotensin-converting enzyme (ACE) gene polymorphism and abnormalities of collagen metabolism. METHODS: A total of 132 patients with untreated essential hypertension (EHT) were recruited. QT dispersion corrected by heart rate (QTc) on a 12-lead electrocardiogram, ACE genotype, left ventricular mass index (LVMI) and E/A ratio using echocardiogram, plasma ACE activity and serum propeptide type I C-terminal procollagen (PICP) concentration, a marker of myocardial fibrosis, were determined. A normal control group (NC) of 200 normotensive subjects was used for comparison of QT dispersion. RESULTS: Number of EHT patients with ACE genotype I/I, I/D and D/D was 61, 52 and 19, respectively. LVMI and E/A ratio were similar in the three groups. Compared with subjects with I/I or I/D genotype, subjects with D/D showed higher plasma ACE activity (I/I: 13 +/- 0.6, I/D: 17 +/- 0.9, and D/D: 21 +/- 1.1 nmol/min per ml, mean +/- SE, P05) and serum PICP concentration (I/I: 106 +/- 5.4, I/D: 106 +/- 4.9, D/D: 140 +/- 12.1 ng/ml, P < 0.01). QTc dispersion was larger in the three hypertensive subgroups than in NC, and was the largest in EHT with D/D (NC: 0.037 +/- 0.001, I/I: 0.056 +/- 0.003, I/D: 0.055 +/- 0.002, D/D: 0.069 +/- 0.004 s, P < 0.05). CONCLUSION: ACE D/D genotype could be associated with an elevation of serum PICP concentration possibly leading to myocardial fibrosis and increased QT dispersion.     

The angiotensin-converting-enzyme insertion/deletion polymorphism is not a risk factor for peripheral arterial disease

BACKGROUND: An insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for atherosclerotic vascular disease. The aim of the present study was to analyze the role of this polymorphism for peripheral arterial disease (PAD). METHODS: The study was designed as a case-control study including 522 patients with documented PAD and 522 sex- and age-matched controls. ACE genotype was determined by size-analysis of polymerase chain reaction products. RESULTS: ACE genotype frequencies were similar between patients (II: 23.4%; ID: 44.8%; DD: 31.8%) and controls (II: 23.8%; ID: 48.3%; DD: 27.9%, P=0.37). The adjusted odds ratio of carriers of the DD genotype for PAD was 1.29 (95% confidence interval 0.95-1.75). The polymorphism was furthermore not associated with age at onset of PAD (P=0.56), Fontaine stage of the disease (P=0.68) or ankle/brachial index of patients (P=0.86). CONCLUSION: The ACE I/D polymorphism is not a significant risk factor for PAD.     

Increased plasma fibrinolysis and tissue-type plasminogen activator/tissue-type plasminogen activator inhibitor ratios after ethanol withdrawal in chronic alcoholics.

The effects of alcohol withdrawal on fibrinolysis were studied in 10 middle-aged male chronic alcoholics institutionalized for withdrawal therapy. All patients were sampled on admission [day 1 (D1)] and 21 days after alcohol withdrawal [day 22 (D22)]. The overall plasma fibrinolytic capacity (OFC) was assayed by measuring the ability of patient plasma to generate D-dimers from a standardized fibrin clot, and tissue-type plasminogen activator (t-PA) and t-PA inhibitor (PAI-1) levels were assayed together with serum cholesterol, triglyceride and cholesterol fractions. At D22, the OFC significantly increased in seven patients [D1 = 10 +/- 0.7 microg/h (mean +/- SD), D22 = 17 +/- 7.4 microg/h; P < 0.01], while t-PA and PAI-1 levels decreased in all patients but two (t-PA: D1 = 16.6 +/- 5 ng/ml, D22 = 10.2 +/- 3.8 ng/ml; P < 0.001; and PAI-1: D1 = 46 +/- 39 ng/ml, D22 = 21 +/- 28 ng/ml; P < 0.01). This study clearly demonstrates an increase in overall fibrinolytic activity after alcohol withdrawal, which is mainly due to a decrease in PAI-1 levels. These changes induced by alcohol abstinence might provide clear benefit by reducing the risk of thromboembolic events and particularly of stroke associated with elevated PAI-1 levels described in heavy drinkers.     

Risk of venous thromboembolism associated with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene.

The circulating levels of angiotensin I-converting enzyme (ACE) are linked with a 287-base pair insertion/deletion (I/D) polymorphism at intron 16 of the ACE gene. Thus, the homozygous deletion (D/D genotype) could cause chronic vasoconstriction, arterial hypertension and, possibly, coronary artery disease. Also, the increase in plasminogen activator inhibitor-1 level and impaired fibrinolysis were related with the D/D genotype. The D allele has been recently associated with venous thrombosis among African-American men as well as among patients that underwent elective total hip replacement. We assess the risk of venous thromboembolism (VTE) linked with each genotype of the I/D ACE gene polymorphism in a Caucasian population by means of a case-control study. We genotyped the ACE gene in a series of 148 patients aged 45.0 +/- 16.0 years (range, 11-80 years), objectively diagnosed in our centre of deep-vein thrombosis or pulmonary embolism, and in 240 thrombosis-free subjects (25-75 years) from the same geographic area. The observed difference in D allele frequencies between patients (0.56) and controls (0.62) was nonsignificant overall; however, statistical significance (P = 0.05) was found by considering the recessive hypothesis (D/D versus I/ D + I/I) [odds ratio (OR) = 0.64, 95% confidence interval (CI95) = 0.42-0.99]. The OR was 0.88 (CI95 = 0.51-1.53; P = 0.65) for the dominant hypothesis (D/D + I/D versus I/I genotypes). The relative risk for the D allele was close to 1 for the dominant hypothesis, both considering gender and recurrent tendency; however, it was protective in men regarding the recessive hypothesis (OR = 0.53, CI95 = 0.29-0.97, P = 0.04). The I/D ACE allele distribution was similar among the 46 thrombophilic patients (antithrombin, protein C or protein S deficiencies, factor V R506Q, factor II G20210A or lupus anticoagulant). In conclusion, among (Spanish) Caucasians, this study does not support the hypothesis that the deletion allele (D) of the ACE gene could be a significant risk factor for VTE, being protective in men.