Angiotensin-converting enzyme gene polymorphism in Kuwaiti patients with systemic lupus erythematosus

OBJECTIVE: To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in patients with systemic lupus erythematosus (SLE), and to study the correlation between I/D polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement, lupus nephritis and disease severity. METHODS: The frequency of ACE gene I/D polymorphism genotypes was determined in 92 patients with SLE from Kuwait, and compared to that in 100 ethnically matched healthy controls using the polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in SLE patients was not significantly different from controls. Further analyses of SLE patients showed that there was a significant association between DD genotype and Raynaud's phenomenon (p=0.008, odd ratio=5.4, 95% confidence interval: 1.6-18.6). However, there was no significant association between the ACE genotype and lupus nephritis or disease severity. CONCLUSION: No difference was found between the distribution of the ACE genotype in SLE patients and the general pop-ulation in Kuwait. However, the presence of the DD genotype may confer susceptibility to the development of vascular morbidity.     

Association of angiotensin-converting enzyme DD genotype with 24-h blood pressure abnormalities in normoalbuminuric children and adolescents with Type 1 diabetes.

AIMS: To assess the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in children and adolescents with Type 1 diabetes and to evaluate the association between ACE genotype and blood pressure (BP). METHODS: ACE genotypes were assessed in 124 normoalbuminuric, clinically normotensive Type 1 diabetic children and adolescents and 120 non-diabetic controls using polymerase chain reaction. Twenty-four-hour ambulatory BP monitoring was undertaken in all patients. RESULTS: ACE genotypes distributed in patients as follows: 34 (27%) DD, 57 (46%) ID, 33 (27%) II. The distribution was similar in the control group: DD in 28% (33), ID in 45% (54), and II in 27% (33). Patients with DD genotype had higher mean 24-h diastolic BP (73.8 +/- 6.2 vs. 70.2 +/- 5.0 and 69.7 +/- 6.3 mmHg; P = 0.005) and lower diurnal variation in BP (11.8 +/- 4.6 vs. 14.2 +/- 4.2 and 14.8 +/- 4.3%; P = 0.011) compared with ID and II groups. Four patients in the DD group proved to be non-dipper compared with one in the ID and none in the II group (P = 0.026). Twenty-four-hour diastolic blood pressure was independently predictive for AER as dependent variable in the DD genotype patient group (r(2) = 0.12, P = 0.03). CONCLUSIONS: Children and adolescents with Type 1 diabetes do not differ from the non-diabetic population regarding the I/D polymorphism of the ACE gene. ACE gene polymorphism is associated with BP abnormalities in normotensive and normoalbuminuric children and adolescents with Type 1 diabetes.     

Association of the angiotensin-converting enzyme gene polymorphism with chronic heart failure in Chinese Han patients

BACKGROUND: An insertion/deletion (I/D) polymorphism is present in the 16th intron of the angiotensin-converting enzyme (ACE) gene and is associated with serum and tissue ACE level. Some studies have shown that the DD genotype is associated with some cardiovascular diseases; while ACE polymorphism's effect on chronic heart failure (CHF) remains uncertain. AIM: To investigate the association of the ACE gene I/D polymorphism with CHF in the Chinese Han population. METHODS: The genotype was determined by polymerase chain reaction in 102 normal controls and in 79 patients with CHF. Plasma angiotensin (Ang) levels were assessed by radio-immunity assay. Left ventricular end-diastolic diameters (LVDD) and left ventricular ejection fractions were assessed by echocardiography. RESULTS: The ACE gene polymorphism distribution was similar in patients and control subjects. However, ACE gene DD polymorphism was associated with a more severe condition, greater LVDD [mm: DD: 71+/-7, ID: 62+/-5, II: 60+/-5, P<0.001 DD vs. ID, P<0.001 DD vs. II] and higher plasma Ang II level [pg/ml DD: 92+/-19, ID: 79+/-21, II: 65+/-17 P<0.05 DD vs. ID, P<0.001 DD vs. II]. CONCLUSION: In Chinese Han patients with CHF, ACE gene DD polymorphism might be a marker of a more severe condition, and a higher level of activation of the renin-angiotensin system.     

Relationship between polymorphism of the angiotensin-converting enzyme gene and the response to angiotensin-converting enzyme inhibition in hypertensive patients.

The aim of this study was to investigate the relationship between polymorphism of the anglotensin-converting enzyme (ACE) gene and the blood pressure response to ACE inhibition in a hypertensive cohort. Imidapril (5-10 mg/day) or benazepril (10-20 mg/day) was administered for 6 weeks to 517 essential hypertensives. ACE gene polymorphism was examined by the polymerase chain reaction (PCR) method and the patients were classified as having the 190-bp deletion homozygous (DD) genotype, the 490-bp insertion homozygous (II) genotype, or the 490-bp insertion, 190-bp deletion heterozygous (ID) genotype. The achieved change in systolic and diastolic blood pressure (SBP and DBP) was analyzed for association with genotypes at the ACE gene locus. The DD genotype was observed in 132 patients (25.5%), the ID genotype in 255 patients (49.3%), and the II genotype in 130 patients (25.2%). The SBP reductions in the patients with the DD genotype, II genotype, and ID genotype were -14.5 +/- 12.7 mmHg, -14.3 +/- 13.1 mmHg and -14.0 +/- 12.2 mmHg, respectively (p = 0.94). The DBP reductions in the patients with the DD genotype, II genotype, and ID genotype were -8.7 +/- 7.4 mmHg, -8.7 +/- 7.7 mmHg and -8.5 +/- 6.7 mmHg, respectively (p = 0.96). There was no significant association between the ACE gene polymorphisms and the response to ACE inhibition. These results suggest that ACE genotype does not predict the blood pressure-lowering response to antihypertensive treatment with ACE inhibition.     

Polymorphisms of the renin-angiotensin system genes in Brazilian patients with lupus nephropathy

Genetic polymorphisms of the renin-angiotensin system (RAS) has been associated with cardiovascular events and the progression of nephropathy in several diseases. The objective of this study was to evaluate a possible association of the genetic polymorphisms of RAS with the development and/or progression of lupus nephritis in a Brazilian population. Seventy-five SLE patients with lupus nephropathy (LN group) were compared to 72 SLE patients without LN (SLE group) and 65 healthy individuals (CONTROL group), of sex and ethnic matched, in a Brazilian population sample. Mean global follow-up was 9 +/- 6 years for lupus without nephropathy and 11 +/- 7 years for lupus nephropathy. Following the extraction of genomic DNA from the leukocytes in the peripheral blood, angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT M(235)T) and angiotensin II type 1 receptor (AGTR1 A(1166)C) genotypes were determined by the polymerase chain reaction. No significant difference of ACE, AGT and AGTR1 genotypes distribution between groups was observed in this study. There was no significant association between the variables of the RAS genotypes and the presence of hypertension in SLE. However, an increased frequency ofDD genotype (ACE I/D) was observed in SLE patients with LN who progressed to CRF compared to healthy controls (DD 60%, DI 26.7%, II 13.3% versus 27.7%, 60% and 12.3%, respectively; chi2 = 6.299, P = 0.0429). In the population studied, there was no influence of the RAS genetic polymorphisms in the development of lupus nephropathy, but the progression to CRF was associated with ACE DD polymorphism.     

Angiotensin converting enzyme genotype influences the response to the angiotensin II receptor antagonist losartan in patients with hypertension.

To examine whether the response to the angiotensin II receptor antagonist losartan varies depending on the angiotensin converting enzyme (ACE) genotype, we prospectively studied the effect of losartan in 42 hypertensive patients (20 men, 22 women; mean age: 60.4 years). After a 4-week observation period, losartan was administered at 50 mg/day and blood pressure was measured every 2 to 4 weeks for 12 weeks. Among the 42 patients, 19, 11, and 12, respectively, had the II, ID, and DD ACE genotypes. The baseline plasma ACE activity in patients with the ID or DD genotype was significantly higher than that in patients with the II genotype (13.8 +/- 4.2 vs. 9.6 +/- 2.3 IU/l; p = 0.0002). However, age, gender, baseline systolic and diastolic blood pressure (SBP/DBP), and body mass index (BMI) were not different among the groups. After 12 weeks of treatment with losartan alone, DBP in the ID+DD group was significantly higher than that in the II group (85.0 +/- 9.0 vs. 77.8 +/- 9.6 mmHg, p = 0.018), while the percent reduction in DBP in the ID+DD group was significantly smaller than that in the II group (7.9 +/- 8.8 vs. 14.3 +/- 10.1%, p = 0.035). Multiple regression analysis showed that the significant predictors of the DBP at 12 weeks were age (p = 0.030), ACE genotype (p = 0.029) and baseline DBP (p = 0.0001). The ACE genotype may be a determinant of the response to losartan in hypertensive patients.     

Association of left ventricular systolic performance and cavity size with angiotensin-converting enzyme genotype in idiopathic dilated cardiomyopathy

The insertion-deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene is a marker linked to differences in plasma and cardiac ACE activity as well as to an increased mortality in patients with idiopathic heart failure. We examined the possibility that ACE gene ID variants are associated with differences in left ventricular (LV) systolic performance or internal LV dimensions in a high-risk cohort of patients with idiopathic dilated cardiomyopathy (IDC). The ACE genotype was determined in 171 patients selected with IDC in New York Heart Association functional class II to III heart failure and with a LV ejection fraction of < or = 40%. Left ventricular performance and dimensions were assessed using echocardiography (n = 161) and radionuclide ventriculography (n = 169). The frequency of ACE gene ID alleles was not different in the study versus non-age-matched (n = 171; odds ratio 0.94) and age-matched (n = 106, odds ratio 0.88) control groups. Ejection fraction was found to be worse in patients with the DD genotype (echocardiography, DD = 23.5 +/- 0.70, ID + II = 26.8 +/- 0.8, p = 0.009; ventriculography, DD = 21.7 +/- 0.9, ID + II = 25.3 +/- 0.8, p = 0.003). LV end-systolic and end-diastolic diameters were increased in patients with the DD genotype. Multifactor regression analysis showed the ACE genotype to be an independent predictor of both ejection fraction (echocardiography, p <0.02; ventriculography, p <0.03) and end-diastolic diameter (p <0.02). In conclusion, the results of this study indicate that the DD genotype of the ACE gene is independently associated with both a reduced LV systolic performance and an increased LV cavity size in patients with IDC.     

Serum angiotensin I-converting enzyme is reduced in Crohn's disease and ulcerative colitis irrespective of genotype

OBJECTIVES: Crohn's disease (CD) is recognized to be a vascular endothelial-associated disease. Angiotensin I-converting enzyme (ACE) exists mainly in endothelial cells. There are some reports on serum ACE levels in patients with CD, but the ACE level is still controversial. Recently, genetic control of serum ACE levels by ACE gene polymorphisms (classified as II, ID, and DD) has been suggested. Although we must consider such polymorphisms to elucidate ACE levels in patients with CD, there is no report about this. METHODS: We studied 341 healthy controls (male/female = 178/162), 39 patients with CD (31/8), 43 patients with ulcerative colitis (UC) (22/21) and 19 patients with infectious enterocolitis (8/11). The polymorphism in intron 16 of the ACE gene was examined by PCR. Serum ACE levels were measured by the method of Kasahara. RESULTS: Serum ACE levels in patients with CD and UC were significantly lower than in healthy controls, irrespective of the genotype of ACE (genotype II: CD 7.0+/-2.5 [mean +/- SD], UC 7.1+/-3.3, controls 11.8+/-2.9, genotype ID: CD 9.7+/-4.1, UC 11.4+/-4.6, controls 15.2+/-3.6, genotype DD: CD 13.9+/-5.8, UC 10.7+/-3.6, controls 19.3+/-3.9 IU/L, controls vs CD, UC; p < 0.01, 0.05). However, there was no significant difference in serum ACE levels between CD and UC. CONCLUSIONS: Considering ACE gene polymorphism, serum ACE levels in patients with inflammatory bowel disease are lower than in controls. Serum ACE levels reflect a part of the pathogenesis of inflammatory bowel disease.     

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity

OBJECTIVES: We investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function. BACKGROUND: The deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene. METHODS: In 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine. RESULTS: Compared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 +/- 26% vs. 121 +/- 11%, p = 0.003, and diameter increase 21.9 +/- 2% vs. 17 +/- 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow -10 +/- 4% vs. 11 +/- 5%, p = 0.003, ACE DD vs. II and diameter constriction -6.3 +/- 1.2% vs. -1.9 +/- 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH. CONCLUSIONS: Patients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis.     

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.     

The ACE/DD genotype is associated with the extent of exercise-induced left ventricular growth in endurance athletes

OBJECTIVES: We studied the impact of the angiotensin-converting enzyme (ACE)/DD genotype on morphologic and functional cardiac changes in adult endurance athletes. BACKGROUND: Trained athletes usually develop adaptive left ventricular hypertrophy (LVH), and ACE gene polymorphisms may regulate myocardial growth. However, little is known about the impact of the ACE/DD genotype and D allele dose on the cardiac changes in adult endurance athletes. METHODS; Echocardiographic studies (including tissue Doppler) were performed in 61 male endurance athletes ranging in age from 25 to 40 years, with a similar period of training (15.6 +/- 4 h/week for 12.6 +/- 5.7 years). The ACE genotype (insertion [I] or deletion [D] alleles) was ascertained by polymerase chain reaction (DD = 27, ID = 31, and II = 3). Athletes with the DD genotype were compared with their ID counterparts. RESULTS: The DD genotype was associated with a higher left ventricular mass index (LVMI) than the ID genotype (162.6 +/- 36.5 g/m(2) vs. 141.6 +/- 34 g/m(2), p = 0.031), regardless of other confounder variables. As a result, 70.4% of DD athletes and only 42% of ID athletes met the criteria for LVH (p = 0.037). Although systolic and early diastolic myocardial velocities were similar in DD and ID subjects, a more prolonged E-wave deceleration time (DT) was observed in DD as compared with ID athletes, after adjusting for other biologic variables (210 +/- 48 ms vs. 174 +/- 36 ms, respectively; p = 0.008). Finally, a positive association between DT and myocardial systolic peak velocity (medial and lateral peak S(m)) was only observed in DD athletes (p = 0.013, r = 0.481). CONCLUSIONS: The ACE/DD genotype is associated with the extent of exercise-induced LVH in endurance athletes, regardless of other known biologic factors.     

Angiotensin-converting enzyme insertion/deletion polymorphism and systemic lupus erythematosus: a metaanalysis

OBJECTIVE: To explore whether insertion (I) and deletion (D) polymorphisms within intron 16 of the angiotensin-converting enzyme (ACE) gene confer susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN). METHODS: We surveyed studies of ACE I/D polymorphism and SLE using Medline and manual searches. We conducted a metaanalysis of the DD genotype (recessive effect), DD and DI genotype (dominant effect), and D allele of the ACE overall and in each ethnic population. We performed a metaanalysis of ACE I/D polymorphism in SLE and LN. RESULTS: Thirteen comparison studies were included in our metaanalysis consisting of 1411 patients with SLE and 1551 controls. We found no association of ACE I/D polymorphism with SLE in the total sample and by ethnic groups. There was a trend for association of the DD genotype (OR 1.212, 95% CI 0.966-1.520, p = 0.097) and the D allele with SLE in Caucasian patients (OR 1.157, 95% CI 0.991-1.349, p = 0.064); however, this was not statistically significant. The metaanalysis also showed no association of the ACE I/D polymorphisms with LN. CONCLUSION: This metaanalysis of 2962 subjects showed there is a lack of association of the ACE I/D polymorphism with SLE and LN.     

Association between angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in patients treated with angiotensin-converting enzyme inhibitors.

PURPOSE: An insertion/deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with left ventricular hypertrophy. The present study examined polymorphisms of the ACE gene in patients with essential hypertension and left ventricular hypertrophy who were participants in a long-term trial of therapy with an ACE inhibitor. PATIENTS AND METHODS: ACE inhibitor therapy was administered for >2 years to 54 patients with hypertension who had moderate or severe left ventricular hypertrophy. Cardiac dimensions were monitored by echocardiography before the initiation of therapy and after 1 and 2 years of treatment. Serum ACE activity and plasma concentrations of brain natriuretic peptide, a marker for left ventricular hypertrophy, were also monitored. RESULTS: Eighteen patients had the II genotype for the angiotensin-converting enzyme gene, 19 had the ID genotype, and 17 had the DD genotype. Baseline (mean +/- SD) serum ACE activity was significantly greater (P <0.05) in the DD (18 +/- 7 IU/L) group than in the II (7 +/- 4 IU/L) or ID (12 +/- 6 IU/L) groups. ACE inhibitor therapy was effective in controlling blood pressure, and it reduced posterior and septal wall thickness, left ventricular mass index, and plasma brain natriuretic peptide concentration in all three groups. Despite similar blood pressure reductions, after 2 years, mean (+/- SD) regression in posterior wall thickness was significantly less (P <0.05) in the DD group (-9% +/- 5%) than in the ID (-21% +/- 7%) and II (-21% +/- 9%) groups. Similar results were seen for the reductions in brain natriuretic peptide levels. The magnitudes of regression of septal wall thickness and left ventricular mass index during therapy were less in the DD group than the II group (P <0.05). CONCLUSION: Hypertensive patients with the DD genotype are less likely to have regression of left ventricular hypertrophy when treated with ACE inhibitors than are patients with other ACE genotypes.     

Effects of angiotensin-converting enzyme gene polymorphism on the left-ventricular function and mass in patients with acromegaly

In this study we have investigated the contribution of the ACE genotype to the development of left-ventricular hypertrophy (LVH) and systolic and diastolic dysfunctions in acromegalic patients. The study group consisted of 30 acromegalic patients (21 women and 9 men, age: 37.9 +/- 10.8 years, disease duration: 9.0 +/- 6.9 years). The distribution of the DD, ID and II genotypes was 40.0 (n = 12), 46.6 (n = 14) and 13.3% (n = 4), respectively, being similar to frequencies observed in a healthy population. Plasma ACE levels were 55.0 +/- 12.0 (45-84), 28.7 +/- 15.7 (8-58) and 24.5 +/- 12.0 (16-33) U/I in patients with the DD, ID and II genotype, respectively. The mean serum ACE activity in the DD genotype was significantly higher than in the heterozygous group (p < 0.0001). Serum ACE activity showed a significant negative association with the mean growth hormone level (r = -0.52, p = 0.007). The LV early diastolic flow velocity/LV presystolic flow velocity (E/A) ratios were 1.2 +/- 0.4 for the DD genotype, 1.3 +/- 0.3 for the ID genotype and 0.7 +/- 0.1 for the II genotype. The E/A ratio was considerably lower in acromegalic patients with the II genotype compared to the other genotypes (p = 0.03). The LV mass index (LVMI) values were 131.5 +/- 4.2 g/m2 for the DD genotype, 141.7 +/- 50.3 g/m2 for the ID genotype and 159.6 +/- 48.2 g/m2 for the II genotype. However, there was no significant difference in LVMI among allelic groups. All other indices of systolic and diastolic function were not statistically different in the acromegalic patients. The present data fail to support a role of ACE gene polymorphism in determining LVH in acromegalic patients. However, the I allele may prove as a useful marker predicting the development of diastolic dysfunction in acromegalic patients.     

Angiotensin-converting enzyme gene polymorphism influences degree of left ventricular hypertrophy and its regression in patients undergoing operation for aortic stenosis.

Insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with increased left ventricular hypertrophy (LVH) in patients with cardiomyopathy and congestive heart failure. Patients with aortic stenosis (AS) have varying degrees of LVH at a given valve area. The aim of this study was to examine the relation between ACE gene polymorphism and the degree of LVH in patients undergoing operation for AS. Eighty-two patients who underwent operation for AS with a stentless valve were followed prospectively with echocardiographic assessments of left ventricular mass index (LVMI). ACE gene polymorphism was determined by polymerase chain reaction. The genotype (DD, ID, and II) frequency was the same as in healthy controls. The pressure difference across the aortic valve did not differ between genotypes. Patients with the DD genotype of the ACE gene had a higher LVMI (197 +/- 47 g/m2) preoperatively than those with ID (175 +/- 41 g/m2) or II (155 +/- 43 g/m2) genotypes (p = 0.01). LVMI decreased significantly in DD (p <0.001) and ID (p <0.001) genotypes but not in the II genotype during follow-up (mean 15 months). There was a significant difference in regression of LVMI over time between genotypes (p = 0.0056), with no significant difference between genotypes at follow-up. The DD genotype of the ACE gene is associated with increased preoperative LVH in patients treated surgically for AS. The DD genotype appears to be an important factor which increases hypertrophic myocardial reactivity to pressure overload.     

Association between the angiotensin-converting enzyme gene polymorphisms and tissue oxygenation during exercise in patients with COPD

STUDY OBJECTIVES: We have recently determined that the angiotensin-converting enzyme (ACE) DD genotype might be associated with pulmonary hypertension during exercise in patients with COPD. Therefore, this study was designed to determine whether ACE gene polymorphisms adversely affect tissue oxygenation during exercise in patients with COPD. DESIGN: Cross-sectional analysis. SETTING: University hospital. PATIENTS: Thirty-nine patients (14 patients with II genotype, 12 patients with ID genotype, and 13 patients with DD genotype). INTERVENTIONS: All patients underwent right-heart catheterization and constant-load exercise testing for 5 min on an ergometer. Measurements and results: The ratio of the change in oxygen delivery (DO(2)) to the increase in oxygen consumption (O(2)) during exercise (DeltaDO(2)/DeltaO(2)) was significantly lower in patients with the DD genotype (1.5 +/- 0.2) than in those with the II genotype (1.9 +/- 0.3, p = 0.0006) and the ID genotype (1.7 +/- 0.2, p = 0.037). Mixed venous oxygen tension (PO(2)) after exercise in patients with the DD genotype (23.5 +/- 1.5 mm Hg) was also significantly lower than in patients with the II genotype (26.7 +/- 1.6 mm Hg, p = 0.0002) and the ID genotype (25.0 plus minus 2.0 mm Hg, p = 0.045). In addition, the change in plasma concentration of lactate during exercise (DeltaLactate) was significantly higher in patients with DD genotype (33.3 +/- 4.3 mmol/L) than in those with the II genotype (25.5 +/- 3.6 mmol/L, p = 0.0002) and the ID genotype (28.8 +/- 4.0 mmol/L, p = 0.029). The mean pulmonary arterial pressure after exercise was significantly correlated with DeltaDO(2)/DeltaO(2) (r = - 0.423, p = 0.0076) but not with PvO(2) after exercise and with DeltaLactate. CONCLUSIONS: The ACE DD genotype may be associated with an impairment in peripheral tissue oxygenation during exercise in patients with COPD.     

DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans.

A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial function of the 3 genotypes (II: n=25; ID: n=31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (II), 25+/-6 (ID), and 25+/-6 (DD) years. We assessed the impact of the genotypes on endothelial function and found that the DD genotype was associated with a significant blunting in endothelial-dependent vasodilatation (forearm blood flow data are presented as mean+/-SD ratio of blood flow in response to 3 incrementally increasing doses of each vasoactive agent in the test arm to blood flow in the control arm; the comparison is between DD versus ID versus II; the P value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison between genotypes): acetylcholine, 2.88+/-1.45 versus 3.81+/-1.93 versus 4.23+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91; 95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There was also a significant difference with the endothelial-independent vasodilator sodium nitroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/-1.18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0.03 to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -independent vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investigating the effects of cigarette smoking on each genotype demonstrated that for II and DD genotypes, acetylcholine responses were further blunted if subjects smoked. These data demonstrate that the DD ACE genotype in a young population is associated with a blunting of stimulated endothelial NO and donated NO responses but not to non-NO vasodilators or vasoconstrictors.     

The deletion genotype of the angiotensin I-converting enzyme is associated with an increased vascular reactivity in vivo and in vitro.

OBJECTIVES: To define a link between the deletion genotype (DD) and vascular reactivity, we studied in vivo and in vitro phenylephrine (PE)-induced tone and the effect of angiotensin II (AII) at physiological (subthreshold) concentrations on PE-induced tone. BACKGROUND: The deletion allele (D) of the angiotensin I-converting enzyme (ACE) has been associated with a higher circulating and cellular ACE activity and possibly with some cardiovascular diseases. METHODS: During cardiac surgery PE-induced contraction was studied in patients with excessive hypotension. In parallel, excess material of internal mammary artery, isolated from patients operated for bypass surgery, was mounted in an organ chamber, in vitro, for isometric vascular wall force measurement. RESULTS: In patients under extracorporeal circulation, PE (25 to 150 microg) induced higher contractions in patients with the DD genotype (e.g., with PE 75 microg: 20.3 +/- 2.9 vs. 11.5 +/- 2.5 mm Hg/ml per min, DD vs. II/ID, n = 15 vs. 30, p < 0.03). In the mammary artery, in vitro, contractions to PE (0.1 to 100 micromol/liter) or AII (1 or 100 nmol/liter) were not affected by the genotype. Angiotensin II (10 pmol/liter) significantly potentiated PE (1 micromol/liter)-induced contraction in both groups. Potentiation of PE-induced tone by AII was significantly higher in the DD than in the II/ID group. CONCLUSIONS: The DD genotype was associated with an increased reactivity to PE in vivo and potentiating effect of exogenous AII in vitro. The higher response to PE in vivo might reflect a higher potentiation by endogenous AII. These data should be considered to understand possible link(s) between cardiovascular disorders and the ACE gene polymorphism.     

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.