The DD genotype of angiotensin converting enzyme polymorphism is a risk factor for coronary artery disease and coronary stent restenosis in Japanese patients

Stent implantation has decreased the incidence of restenosis after coronary intervention, but has not eliminated it. The contribution of the angiotensin-converting enzyme (ACE) genotype to the development of coronary artery disease and restenosis after coronary stenting was investigated in 67 Japanese patients in whom 103 lesions in which stents had been successfully implanted were assessed by quantitative coronary angiography, before, immediately after coronary stenting, and during follow-up. The distribution of the patients with the DD, ID, and II genotypes was 13%, 54%, and 33%, respectively. The prevalence of multivessel disease in the DD genotype was significantly higher (DD genotype: 78%; ID genotype: 58%; II genotype: 27%, chi2=8.13, p=0.016) and the late loss in the DD genotype (1.43+/-0.96 mm) was significantly greater (ID genotype: 0.78+/-0.98 mm and II genotype: 0.79+/-0.88 mm, p<0.05 vs DD genotype). However, there was no significant difference in the restenosis rate among the 3 genotypes. The present study in Japanese patients indicates that the DD genotype is associated with more extensive coronary artery disease and progression of the inward remodeling within the stented lesion, which is primarily caused by neointimal hyperplasia.     

The relationship between angiotensin converting enzyme gene polymorphism, coronary artery disease, and stent restenosis: the role of angiotensin converting enzyme inhibitors in stent restenosis in patients with diabetes mellitus

Patients with diabetes mellitus (DM) have advanced atherosclerosis compared with nondiabetics. Restenosis after intracoronary stent implantation occurs frequently in diabetic patients. Angiotensin II is an important growth factor for the development of neointimal hyperplasia after vascular injury. The aim of our study was to evaluate the relationships between angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary artery disease (CAD) and stent restonosis in diabetic patients. One hundred and thirty consecutive patients with CAD and 47 consecutive patients (14 males, mean age, 58.0 +/- 10.0) without CAD were enrolled in the study. All patients had type 2 (noninsulin dependent) DM. The patients with CAD underwent percutaneous transluminal coronary angioplasty (PTCA) and stenting. Ninety-four (59 males, mean age, 60.3 +/- 9.8) underwent control coronary angiography at the end of the follow-up period (mean duration, 9.1 +/- 2.9 months). ACE gene I/D genotyping was identified in all patients. No significant difference was found among patients with and without CAD with respect to ACE gene I/D polymorphism (P = 0.460). In the control coronary angiography, stent restenosis and new lesion development were comparable in each genotyping subgroup. However, a significant relationship was observed between restenosis and the use of ACE inhibitors (ACEI) in patients with D allele (ACEI ratio, 43.5% in the restenosis group and 56.5% in non-restenotic group, P < 0.05). We did not find any relationship between ACE gene I/D polymorphism and CAD and stent restenosis and new lesion development in diabetic patients. On the other hand, ACEI treatment may reduce stent restenosis in type 2 diabetic patients with D allele (DD or ID).     

The effect of angiotensin converting enzyme inhibition on coronary blood flow and hemodynamics in patients without coronary artery disease

We examined the role of the renin-angiotensin system in the regulation of systemic and coronary vascular tone by studying the effect of converting enzyme inhibition by teprotide on systemic and coronary hemodynamic parameters in 14 normal patients undergoing routine cardiac catheterization. Serial hemodynamic measurements were made before and up to 30 minutes after 1 mg/kg of intravenous teprotide. A significant rise in cardiac index and stroke volume index occurred with a fall in systemic vascular resistance. The increase in cardiac index was related to the level of resting plasma renin activity. Blood pressure, pulmonary artery and left ventricular end-diastolic pressures remained unchanged. Coronary sinus thermodilution blood flow also showed no significant change; however, some patients demonstrated dramatic increase in flow. The change in blood flow was highly correlated with the resting plasma renin activity (r = 0.939 P < 0.001). The change in coronary vascular resistance and myocardial oxygen consumption were likewise related to the resting plasma renin level.Converting enzyme inhibition produces significant systemic hemodynamic changes in normal patients which implies that the renin-angiotensin system is important in normal cardiovascular homeostasis. The direct relationship between plasma renin activity and coronary blood flow suggests that the renin-angiotensin system may play an important role in coronary vasomotor regulation.     

Role of angiotensin converting enzyme genotype in sodium sensitivity in older hypertensives

BACKGROUND: Individuals differ in their blood pressure (BP) response to changes in dietary sodium (Na+) intake. It is possible that differences in BP responses to dietary Na+ are influenced by genes. METHODS: A total of 35 older (62.9 +/- 1.2 years) hypertensive subjects had their mean arterial blood pressure (MABP) determined after 8 days of low (20 mmol/day) and high (200 mmol/day) Na+ intake. The insertion/ deletion polymorphism of the angiotensin converting enzyme (ACE) gene was genotyped with standard polymerase chain reaction methods. RESULTS: Of the 35 subjects, 24 were classified as sodium-sensitive (> or = 5 mm Hg increase in MABP in response to the increase in dietary Na+) and 11 were classified as sodium-resistant (<5 mm Hg increase in MABP). Those homozygous for the insertion allele of the ACE gene (insertion/insertion [II]; n = 8) had lower (P = .04) MABP responses to the increase in dietary Na+ (0 +/- 3 mm Hg) compared to heterozygotes (insertion/deletion [ID]; n = 20) (9 +/- 2 mm Hg; P = .0001) and those homozygous for the deletion allele (deletion/deletion [DD]; n = 7) (9 +/- 3 mm Hg; P = .05). The prevalence of sodium sensitivity was higher (P = .0083) in DD (71%) and ID (83%) compared to II (25%) genotype groups. CONCLUSIONS: Based on these data in older hypertensive individuals, we conclude that the ACE gene ID and DD genotypes are associated with an increase in BP during a high Na+ diet, which is consistent with the phenotypic characteristic of sodium sensitivity.     

血管紧张素转换酶基因缺失多态性与冠状动脉病变

目的 :探讨血管紧张素转换酶 ( ACE)基因的插入 /缺失 ( insertion/deletion,I/D)多态性与冠状动脉病变的相关性。方法 :应用聚合酶链反应 ( PCR)扩增技术检测 86例行冠状动脉造影患者的 ACE基因 I/D多态性。结果 :冠状动脉异常组的 DD基因型频率 0 .41,D等位基因频率 0 .5 2 ,显著高于冠状动脉正常组的 0 .15和 0 .2 9( P <0 .0 5 ) ;DD基因型与冠状动脉病变有关 ( OR=3.97,P<0 .0 5 )。多支病变与 DD基因型的关系更为密切 ( OR=4.72 ,P<0 .0 5 )。冠状动脉正常组、单支病变组和多支病变组的 DD型频率依次为 0 .15、0 .33和 0 .46( P <0 .0 5 ) ,D等位基因频率为 0 .2 9、0 .44和 0 .5 6( P <0 .0 1)。结论 :ACE基因的 I/D多态性与冠状动脉病变及其严重程度相关 ,DD型及 D等位基因频率随冠状动脉病变及其程度的加重而逐渐升高。在冠状动脉病变患者中 DD及 ID型患者的吸烟率、甘油三酯及血压显著低于 型者 ( P <0 .0 5 ) ,说明 D等位基因及 DD基因型可能是冠心病低危人群冠状动脉病变的重要危险因素之一。     

The multifacetted role of angiotensin converting enzyme inhibitors in congestive heart failure

The angiotensin converting enzyme (ACE) inhibitors constitute a major breakthrough in the medical management of congestive heart failure. The incidence of side effects with these agents is surprisingly low when they are used in the appropriate dosage. They produce sustained beneficial hemodynamic and symptomatic improvement in most patients with congestive heart failure and may produce greater symptomatic benefit than digoxin when given as second-line therapy to patients with heart failure on diuretics. Their neurohumoral effects generally are advantageous, resulting in normalization of sodium and potassium balance and a reduction in ventricular arrhythmias. The ACE inhibitors may improve survival in patients with congestive heart failure, and recent data suggest that they may prevent or delay the development of left ventricular dilatation and overt heart failure in patients with asymptomatic left ventricular dysfunction.     

Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells

BACKGROUND AND OBJECTIVES: Our previous studies have shown that oxidized low-density lipoprotein (ox-LDL) and angiotensin II (Ang II) influence each other's action in endothelial cells. This study was designed to examine the regulation by ox-LDL of the expression of angiotensin converting enzyme (ACE) gene in human coronary artery endothelial cells (HCAECs). In addition, we studied the effect of the HMG CoA reductase inhibitor simvastatin on this interaction. METHODS AND RESULTS: Cultured HCAECs were incubated with ox-LDL (10-80 microg/ml) for 1-24 h. Ox-LDL increased the expression of ACE in a concentration- and time-dependent fashion. The upregulation of ACE expression in response to ox-LDL was mediated by its endothelial receptor LOX-1, since pretreatment of HCAECs with a blocking antibody to LOX-1 prevented the expression of ACE (P<0.01). Native-LDL had no significant effect on ACE expression. In this process, ox-LDL-induced activation of mitogen-activated protein kinase (MAPK p42/44) played an important role, since pretreatment of HCAECs with the MAPK p42/44 inhibitor (PD98059, 10 microM) inhibited MAPK activation and subsequently attenuated the expression of ACE (P<0.01 vs. ox-LDL alone). In other experiments, we pretreated HCAECs with simvastatin (10 microM) and then exposed the cells to ox-LDL. Simvastatin markedly attenuated ox-LDL-induced MAPK activation, and concurrently reduced ACE expression (P<0.01 vs. ox-LDL alone). CONCLUSIONS: Our observations provide direct evidence that ox-LDL via LOX-1 activation induces ACE gene expression in HCAECs, and MAPK activation plays a signal transduction role in this process. Simvastatin, which inhibits MAPK activation, also blocks ox-LDL-mediated upregulation of ACE.     

血管紧张素转化酶抑制剂所致咳嗽与血管紧张素转化酶基因型相关性的研究

目的　探讨老年原发性高血压患者口服血管紧张素转换酶抑制剂 (ACEI )后发生咳嗽的机制。方法　应用聚合酶链反应 (PCR) ,检测老年原发性高血压患者口服ACEI后发生咳嗽与无咳嗽者的血管紧张素转化酶 (ACE)基因多态性 ,检测并比较两组患者血清ACE水平及ACE水平预测高血压患者口服ACEI引起咳嗽的敏感性和特异性。结果　ACEI所致咳嗽组ACE基因Ⅱ型的频率为4 0 % ,显著高于无咳嗽组 (2 0 % ,P <0 0 5 ) ,Ⅰ等位基因频率为 6 0 % ,显著高于无咳嗽组 (4 1% ,P <0 0 1)。两组患者血清ACE水平在DD型、ID型、Ⅱ型依次减低。咳嗽组血清ACE水平显著低于无咳嗽组 (P <0 0 0 1) ,血清ACE水平预测ACEI引起咳嗽的敏感性和特异性分别为 81%和 78%。结论　老年高血压患者口服ACEI所致咳嗽与血清ACE水平及ACE基因多态性有关。     

Inhibition of angiotensin converting enzyme cannot prevent increases in angiotensin II production in coronary circulation

OBJECTIVE—To determine whether inhibition of angiotensin converting enzyme (ACE) can prevent angiotensin II production in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA) in patients with myocardial ischaemia.
DESIGN, PATIENTS—41 patients who underwent elective PTCA and six control subjects who received diagnostic coronary angiography were studied. Patients were divided into two groups according to the chronic administration of ACE inhibitors (group A, 15 patients treated with ACE inhibitors; group B, 26 patients without ACE inhibitors). Blood samples were drawn through catheters placed in the aorta and coronary sinus before and 24 hours after PTCA.
RESULTS—Mean levels of ACE activity in the aorta were significantly lower in patients in group A than in group B. However, mean angiotensin II concentrations in the aorta were not significantly different between the two groups. Differences in basal angiotensin II concentrations between the coronary sinus and aorta, which reflected basal angiotensin II production in the coronary circulation, were not significant among group A, group B, and control subjects. The production of angiotensin II in the coronary circulation was significantly increased 24 hours after PTCA in both group A and group B to the same extent. No significant changes were observed in control subjects 24 hours after diagnostic coronary angiography.
CONCLUSIONS—This study revealed that inhibition of ACE activity by ACE inhibitors could not prevent increases in angiotensin II production in the coronary circulation induced by PTCA.


Keywords: angiotensin converting enzyme; chymase; angioplasty     

血管紧张素转化酶-2研究进展

根据世界卫生组织预测,到2020年心血管疾病将成为导致死亡的主要原因[1]。我国高血压患病率逐年增高,严重影响了人民群众的身体健康[2]。高血压是心血管疾病最常见可转化的危险因子之一[3]。肾素-血管紧张素系统(renin-angiotensinsystem,RAS)被认为是有着强大生理功能的激素系统,对血压的调节、血液等内环境的稳定性、血管功能以及细胞生长起着重要作用,在各种心血管疾病和肾病病理生理过程中发挥着重要的功能[4]。从肾素-血管紧张素被作为一个整体的概念提出,对肾素-血管紧张素系统的研究已有30余年历史了。尽管如此,最近几年在这个原来…     

Early angiotensin converting enzyme inhibitor therapy enhances the benefits of late coronary artery reperfusion on infarct expansion

BACKGROUND: Individually, both late reperfusion and early angiotensin converting enzyme (ACE) inhibitor treatment prevent infarct expansion after acute myocardial infarction. OBJECTIVE: To examine the effect and mechanism of early post-myocardial infarction ACE inhibitor treatment, when used in combination with late coronary artery reperfusion, on infarct expansion. METHODS: Sprague-Dawley rats underwent 8 h of coronary occlusion followed by permanent reperfusion. The treatment group received enalapril, started 1 h after coronary occlusion and continued for 13 days. A control group received placebo. Two weeks after acute myocardial infarction, hemodynamic, morphometric and histologic analyses were performed. RESULTS: Hemodynamic parameters were similar in both groups (P = NS). Infarct size was similar in the ACE inhibitor and placebo treatment groups (44 +/- 4% compared with 39 +/- 4%, P = NS). Septal thickness was also similar in the two groups (2.8 +/- 0.3 mm compared with 2.7 +/- 0.3 mm, P = NS). The ACE inhibitor-treated group had thicker infarcts than those in the placebo-treated group (0.93 +/- 0.07 mm compared with 0.76 +/- 0.04 mm, P < 0.05) and these infarcts were less expanded (expansion index 1.17 +/- 0.12 compared with 1.57 +/- 0.12, P < 0.05). ACE inhibitor treatment was associated with hypertrophy of viable myocytes within the scar compared with placebo treatment (cell diameter 11.1 +/- 0.5 microns compared with 8.9 +/- 0.4 microns, P < 0.01). CONCLUSIONS: Early post-myocardial infarction ACE inhibitor treatment enhances the benefits of late coronary reperfusion on infarct expansion. The benefits may be related to hypertrophy of still-viable myocytes within the infarcted zone.     

The relationship of chronic angiotensin converting enzyme inhibitor use and coronary collateral vessel development

BACKGROUND: Angiotensin II induces various growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor, and recent studies suggest that the expression of these growth factors promotes collateral growth. We hypothesized that the blockage of angiotensin II production by ACE inhibitors might interfere with collateral development in patients with coronary occlusion. METHODS: The study group consisted of 187 patients (114 males, mean ages, 62 +/- 11 years) who had chronic (> 1 month) coronary occlusion (TIMI flow grade < or = 1) in one of 3 epicardial coronary arteries. Collaterals were graded using the Rentrop classification, and the patients were divided into 2 groups according to having good (grade 2 and 3) or poor (grade 0 and 1) collaterals (n = 127 and 60, respectively). Clinical and angiographic characteristics were compared in the 2 groups. RESULTS: ACE inhibitor use (52% versus 35%, P = 0.04) and the prevalence of diabetes mellitus (DM) (43% versus 27%, P = 0.02) was higher in patients with poor collaterals. Patients with poor collaterals had a higher frequency of circumflex artery (Cx) occlusion, worse wall motion, and lower ejection fraction. In multivariate analysis, ACE inhibitor use (OR: 2.4; 95% CI = 1.23-4.68, P = 0.01) and the occlusion of Cx (OR: 3.3, 95% CI; 1.33-8.12, P = 0.01) were found to be independent predictors for poor collateral development, whereas there was a trend for DM as a predictor for poor collaterals (OR: 1.9, 95% CI = 0.97-3.8, P = 0.06). CONCLUSION: The findings suggest that ACE inhibitor therapy may contribute to poor collateral development in patients with coronary occlusion.     

D/D genotype of the gene for angiotensin converting enzyme as a risk factor for post-stent coronary restenosis]

INTRODUCTION: Although intracoronary stenting has decreased restenosis rate compared to percutaneous balloon angioplasty, still a high number of patients develop in-stent restenosis, which is an entity primarily due to tissue proliferation. Experimental studies have indicated that the renin-angiotensin system is involved in neointimal hyperplasia. Plasma and cellular levels of ACE are associated with an I/D polymorphism in the ACE gene. Indeed, DD subjects have the higher ACE levels. The purpose of this study was to explore the possibility that the I/D polymorphism might be related with in-stent restenosis. METHODS: We studied the ACE polymorphism in 48 consecutive patients who underwent successful implantation of an elective coronary stent in native coronary vessels and had a 6 month angiographic follow up. Restenosis (50% of the reference vessel) was observed in 23/48 patients. Patients with or without restenosis did not differ in demographic or clinical variables like diabetes, plasma cholesterol levels or in quantitative angiographic parameters such as vessel reference size or minimal lumen diameter after stent implantation. RESULTS: I/D polymorphism was distributed as follows: 22.9% of the patients were D/D; 14.5% were I/I and 62.5% of the patients were heterozygous I/D. The presence of restenosis was strongly related with the I/D polymorphism: 81.8% of the patients with D/D genotype had restenosis, compared with 40.0% of I/D patients and only 14.2% of the I/I patients (chi 2 p < 0.01). CONCLUSIONS: In this limited cohort, homocygous D/D of the ACE gene was significantly associated with in-stent restenosis, whereas restenosis was infrequent in patients with the I/I genotype.     

血管紧张素转化酶基因插入/缺失多态性与冠心病发病的关系

目的 :探讨血管紧张素转化酶 (ACE)基因多态性与冠心病 (CHD)发病的关系。方法 :以人基因组DNA为模板 ,应用聚合酶链式反应 (PCR)检测 5 0例CHD组和 5 6例正常对照组ACE基因第 16内含子插入 /缺失 (I/D)多态性 ,并按性别分组计算各组基因型和等位基因频率。结果 :①在CHD组中 ,ACE基因DD基因型和D等位基因频率分别为 36 %和 6 0 % ,正常对照组分别为 16 %和 4 1% ,两者相比差异有统计学意义 (P <0 .0 1)。②男性CHD组DD基因型和D等位基因频率均显著高于对照组 (均P <0 .0 5 )。女性CHD组DD基因型频率显著高于对照组 (P <0 .0 1) ,D等位基因频率与对照组比较差异无统计学意义。结论 :CHD与ACE基因I/D多态性有显著相关性 ,不论男性和女性 ,ACE基因DD基因型均可能是CHD发生发展过程中重要的危险因素之一。     

Effect of angiotensin converting enzyme inhibitors and beta-blockers on left ventricular remodeling after coronary artery bypass graft surgery

Preventing left ventricular (LV) remodeling after coronary artery bypass graft surgery (CABG) is important to avoid long-term congestive heart failure. The present study evaluated the effects of angiotensin converting enzyme inhibitors (ACEIs) and beta-blockers on LV remodeling. Twenty-three patients with angina pectoris and 36 with old myocardial infarction underwent CABG. We assessed end diastolic volume index (EDVI), end systolic volume index (ESVI), and ejection fraction (EF) using left ventriculography before and after CABG. Changes in EDVI, ESVI, and EF were studied in the ACEI, beta-blocker, and control groups. Although EDVI was reduced in the ACEI group, ESVI and EF improved only slightly, whereas in the group given beta-blockers, ESVI was reduced, EF improved, and EDVI was minimally reduced. These results indicate that ACEIs and beta-blockers both protect against LV remodeling, although through different mechanisms.     

Serum angiotensin converting enzyme in pulmonary disease

Synthetic acylated tripeptides, which may or may not be radiolabelled, are generally used as substrates for measuring serum angiotensin converting enzyme (SACE) activity. The capillary endothelial cells are the major source of SACE in normals and certain diseased states, however Gaucher’s cells in Gaucher’s disease and epithelioid cells in granulomatous disorders, including sarcoidosis, are the major source of enzyme in these disorders. SACE is generally elevated in active sarcoidosis and is normal when the disease is dormant or resolved. Sequential measurement of SACE are helpful in monitoring activity of sarcoidosis, both off and on corticosteroids. SACE may also be elevated in certain non-granulomatous pulmonary and systemic diseases.