Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene significantly influences circulating ACE levels and plays a role in the development of target organ damage, that is, left ventricular hypertrophy in essential hypertension (EH), and microalbuminuria in diabetes mellitus. We have examined the role of the I/D polymorphism in essential hypertensive patients with renal involvement. The study was divided in two independent protocols. In protocol 1, we retrospectively analyzed the ACE genotypes in 37 essential hypertensive patients with a clinical and histopathological diagnosis of nephroangiosclerosis. In protocol 2, ACE genotypes as well as microalbuminuria and renal hemodynamic parameters were investigated in 75 patients with EH with normal renal function and a strong family history of hypertension. As control group, 75 healthy subjects with BP < 130/85 mm Hg and no family history of cardiovascular diseases were studied. The ACE variants were determined by PCR and the genotypes were classified as DD, DI and II. In protocol 1, patients with nephroangiosclerosis displayed a significant difference in the genotype distribution (57% DD, 27% DI, 16% II) when compared to the control population (25% DD, 64% DI, 11% II; P < 0.001). There was no significant difference in genotype distribution between hypertensive patients with normal renal function (protocol 2; 33% DD, 59% DI, 8% II) and the control group. There were no differences in age, blood pressure, microalbuminuria and duration of the disease among the three genotypes in the EH group from protocol 2. Taken together, these findings suggest that the DD genotype of ACE is associated with histopathologic-proven kidney involvement in patients with EH and that this polymorphism could be a potential genetic marker in hypertensives at risk of renal complications.     

The deletion polymorphism of the angiotensin I-converting enzyme gene is associated with target organ damage in essential hypertension

The activity of the renin-angiotensin-aldosterone system is thought to play a significant role in the development of target organ damage in essential hypertension. An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has recently been associated with increased risk for left ventricular hypertrophy and coronary heart disease in the general population. The D allele is associated with higher levels of circulating ACE and therefore may predispose to cardiovascular damage. The study presented here was performed to investigate the association between the ACE genotype, microalbuminuria, retinopathy, and left ventricular hypertrophy in 106 patients with essential hypertension. ACE gene polymorphism was determined by polymerase chain reaction technique. Microalbuminuria was evaluated as albumin-to-creatinine ratio (A/C) in three nonconsecutive first morning urine samples (negative urine culture) after a 4-wk washout period. Microalbuminuria was defined as A/C between 2.38 to 19 (men) and 2.96 to 20 (women). Hypertensive retinopathy was evaluated by direct funduscopic examination (keith-Wagener-Barker classification) and left ventricular hypertrophy by M-B mode echocardiography. The distribution of the DD, ID, and II genotypes was 27, 50, and 23%, respectively. The prevalence of microalbuminuria, retinopathy, and left ventricular hypertrophy was 19, 74, and 72% respectively. There were no differences among the three genotypes for age, known duration of disease, body mass index, blood pressure, serum glucose, uric acid, and lipid profile. DD and ID genotypes were significantly associated with the presence of microalbuminuria (odds ratio, 8.51; 95% confidence interval, 1.07 to 67.85; P = 0.019), retinopathy (odds ratio, 5.19; 95% confidence interval, 1.71 to 15.75; P = 0.005) and left ventricular hypertrophy (odds ratio, 5.22; 95% confidence interval, 1.52 to 17.94; P = 0.016). Furthermore, patients with DD and ID genotypes showed higher levels of A/C (3.6 +/- 0.9, DD; 2.6 +/- 0.7, ID; 0.9 +/- 0.2 mg/mmol, II; P = 0.0015 by analysis of variance) and increased left ventricular mass index (152 +/- 4.7, DD + ID versus 133 +/- 5.7 g/m2, II; P = 0.01) compared with II patients. The D allele was significantly more frequent in patients with microalbuminuria (odds ratio, 2.59; 95% confidence interval, 1.24 to 5.41; P = 0.013) and in those with retinopathy (odds ratio, 2.44; 95% confidence interval, 1.21 to 4.90; P = 0.015). Multiple regression analyses performed among the entire cohort of patients demonstrated that ACE genotype significantly and independently influences the presence of retinopathy, left ventricular hypertrophy, and microalbuminuria. In conclusion, the D allele of the ACE gene is associated with microalbuminuria as well as with retinopathy and left ventricular hypertrophy, and seems to be an independent risk factor for target organ damage in essential hypertension.     

Angiotensin I-converting enzyme gene polymorphism in a low-risk European population for coronary artery disease

PURPOSE: Physiologic and non-physiologic tumor motion complicates the use of tight margins in three-dimensional (3D) conformal radiotherapy. Setup reproducibility is an important non-physiologic cause of tumor motion. The objective of this study is to evaluate and compare patient setup reproducibility using the reusable T-bar and the disposable expanded foam immobilization device (EFID) in radiation therapy for lung cancer. METHODS AND MATERIALS: Two hundred forty-four portal films were taken from 16 prospectively accrued patients treated for lung cancer. Patients were treated with either a pair of anterior and posterior parallel opposing fields (POF), or a combination of POF and a three-field isocentric technique. Each patient was treated in a supine position using either the T-bar setup or EFID. Six patients were treated in both devices over their treatment courses. Field placement analysis was used to evaluate 3D setup reproducibility, by comparing positions of bony landmarks relative to the radiation field edges in digitized simulator and portal images. Anterior-posterior, lateral, and longitudinal displacements, as well as field rotations along coronal and sagittal planes were measured. Statistical analyses of variance were applied to the deviations among portal films of all patients and the subgroup treated with both immobilization methods. RESULTS: For the T-bar immobilization device, standard deviations of the setup reproducibility were 5.1, 3.7, and 5.1 mm in the anterior-posterior, lateral, and longitudinal dimensions, respectively. Rotations in the coronal plane and the sagittal plane were 0.9 degrees and 1.0 degrees, respectively. For the EFID, corresponding standard deviations of set up reproducibility were 3.6 mm, 5.3 mm, 5.4 mm, 0.7 degrees and 1.4 degrees, respectively. There was no statistically significant difference (p = 0.22) in the 3D setup reproducibility between T-bar and EFID. Subgroup analysis for the patients who were treated with both immobilization devices did not reveal a difference either. There was no consistent systematic error from simulator to treatment unit identified for either immobilization device. CONCLUSION: Although the optimal immobilization technique and patient positioning for thoracic radiotherapy have yet to be determined, this study indicates that T-bar is comparable with EFID in its setup reproducibility. In view of the inherent advantages of T-bar, it has become a standard immobilization device at our institution. The observed range of displacements in field positioning with either immobilization device implies that one cm (two standard deviations [SD] of setup error) will be a more appropriate margin to allow for setup variability in radiation therapy for lung cancer.     

Angiotensin I-converting enzyme insertion/deletion polymorphism: clinical implications

Since the identification of an Insertion/Deletion polymorphism in the ACE gene, numerous studies have evaluated the potential risk of the DD genotype in cardiovascular disease and hypertension. The report of many conflicting publications reveals a strong need for reviewing the most important data. There is evidence of the absence of an association between the ACE polymorphism and hypertension in Caucasians. In blacks a positive association between the D allele and high blood pressure was seen, Japanese studies show discrepant results. Several studies showed no association between the ACE polymorphism and the risk of myocardial infarction. However, in certain subpopulations, such as low risk patients or coronary care unit patients, an increased risk of myocardial infarction in DD type is present, and a meta-analysis supports this proposition. Because of conflicting data, the potential association between the ACE polymorphism and coronary artery disease, cerebrovascular disease, left ventricular hypertrophy, hypertrophic and idiopathic dilated cardiomyopathy, carotid artery disease and diabetic and immunoglobin A nephropathy, remains inconclusive.     

Angiotensin converting enzyme inhibitors for hypertension

The review paper presents modern opinions upon angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension. It describes their hypotensive properties and therapeutic efficacy. The review discusses also using of ACE inhibitors for disorders often coexisting with hypertension, likewise it presents ACE inhibitors in combination with other hypotensive drugs. The paper discusses also side effects of ACE inhibitors as well as diseases, in which ACE inhibitors are contraindicated.     

Evaluation of the angiotensinogen locus in human essential hypertension: a European study

Adult male Wistar rats were implanted bilateraly with bipolar electrodes in substantia nigra-ventral tegmental area (SN-VTA) to experience intracranial self-stimulation (ICSS) for 15 min per day over a period of 10 days. These rats were then assessed for the acquisition and performance of the operant and the spatial learning tasks. ICSS experienced rats showed rapid acquisition of both the operant and the spatial learning tasks. Both the lever press performance for 7 sessions in the operant learning task and mean number of alternations per session in the spatial learning task were significantly higher (p < .001) in ICSS experienced rats compared with controls. The results suggest that prior ICSS experience facilitates the acquisition and performance in both the operant and the spatial learning tasks, which may be due to the structural and neurochemical alterations in the hippocampus induced by ICSS experience.     

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms and heart rate variability in twins

Decreased heart rate variability (HRV) is associated with congestive heart failure, post-myocardial infarction, ventricular arrhythmias, sudden cardiac death, and advancing age. A deletion/insertion polymorphism in the angiotensin-converting enzyme (ACE) gene and a substitution (M235T) in the angiotensinogen gene have been associated with risk for heart disease. The aim of this study was to determine the heritability of HRV and related parameters in monozygotic and dizygotic twins and to assess the influence of ACE and angiotensinogen polymorphisms. We studied 95 MZ pairs and 46 DZ pairs. We measured HRV and related parameters, ACE and angiotensinogen levels, plasma norepinephrine, ACE, and angiotensinogen genotypes. We found that HRV and related parameters were significantly influenced by genetic variability, although nonshared genetic effects were also important. Angiotensinogen and plasma norepinephrine were generally correlated with decreased HRV, whereas ACE was correlated with perturbances of normal rhythmic HRV. Nevertheless, the DD ACE genotype was associated with increased HRV (p <0.05), whereas angiotensinogen polymorphisms had no effect. We conclude that HRV and related parameters are in part heritable. Interestingly, the DD ACE genotype is associated with increased HRV.     

M235T polymorphism of the angiotensinogen gene and hypertension in Chinese

OBJECTIVES: To compare the distributions of the genotypes and alleles of the M235T polymorphism of the angiotensinogen gene for hypertensive patients and normotensive controls. DESIGN: A study of association of genetic polymorphisms. SETTING: An outpatient clinic run by a university department handling referrals from primary care. PATIENTS: Two hundred and four subjects, 103 normal controls and 101 patients with newly diagnosed or documented hypertension. METHOD: Genomic DNA was extracted from peripheral blood leucocytes, amplified by polymerase chain reaction and digested with the restriction enzyme Tth 111 I. Methionine (M) and threonine (T) alleles were identified after electrophoresis. MAIN OUTCOME MEASURES: Prevalences of angiotensinogen genotypes and alleles for hypertensive patients and controls. Results: MM, TM and TT genotypes occurred in 3, 24 and 73% of controls and 1, 22 and 77% of hypertensive patients, respectively. The prevalences of the M and T alleles were 0.15 and 0.85 among controls and 0.12 and 0.88 among hypertensive patients. The prevalences of the angiotensinogen genotypes and alleles for controls and hypertensive patients did not differ significantly. CONCLUSIONS: Our findings differed from previous reports and suggested that this polymorphism is not associated with hypertension in this population.     

Angiotensin I-converting enzyme (ACE): estimation of DNA haplotypes in unrelated individuals using denaturing gradient gel blots

The Reticuloendothelial System (RES) consists of cells descending from the monocytes which are able to perform phagocytosis of foreign materials and particles. 90% of the RES are located in the liver. The most important function of the RES ist phagocytosis, but it also takes part in cytotoxicity against tumor cells and has a function in the regulation of the immune system. The importance of the RES is obvious in diseases of the bile ducts. An obstruction can lead to a decrease in the function of the RES. Beside a mathematical model there are also a few experimental methods to measure the phagocytic capacity and thus the efficiency of the RES. They are based on a clearance study of the amount of particles absorbed by the RES. This study can e.g. be done with Nanocoll which has been marked with 99mTc. But instead of the bloody clearance, a scintigraphic study using a gamma camera can be performed. With that, the increase time, the liver extraction fraction and the steepness of increase can be determined. Such a test could be of clinical relevance as a parameter for the prognosis of patients with trauma, sepsis or shock. The function of the RES in the pathogenesis of the biliary pancreatitis could also be examined closer with the help of such a test. The requirements a test of the RES should meet are reproducibility, repeatability and practicability.     

M235-->T polymorphism of the angiotensinogen gene predicts hypertension in the elderly

OBJECTIVE: To determine whether the M235-->T polymorphism (exon 2) of the angiotensinogen gene is associated with hypertension in elderly patients with isolated systolic hypertension [ISH: systolic blood pressure (SBP) > or = 160 mmHg, diastolic blood pressure (DBP) < 90 mmHg) or systolic-diastolic hypertension (SDH: DBP > or = 90 mmHg, SBP > or = 160 mmHg) compared with normotensive controls (SBP < 160 mmHg, DBP < 90 mmHg). DESIGN: A case-control study in 769 non-institutionalized, elderly (aged > or = 60 years; female:male ratio 0.85) residents of Dubbo, New South Wales. METHODS: Individuals were classified as having ISH (n = 171), having SDH (n = 218) and being normotensive controls (n = 366) with age and sex matching. MM, TT and MT genotypes were determined by a nested polymerase chain reaction strategy using DNA extracted from serum. The prediction of ISH or SDH by genotype or allele was examined in a multiple-logistic regression model that controlled for various confounders. RESULTS: SBP (mean +/- SD, mmHg)/DBP (mean +/- SD, mmHg) was 176 +/- 16/79 +/- 8 in the ISH group, 167 +/- 23/97 +/- 7 in the SDH group and 134 +/- 14/74 +/- 9 in the normotensive control group. The frequencies of M and T alleles in the normal population (0.69 and 0.31, respectively) were altered significantly in the ISH group (0.61 and 0.39, respectively; chi 2 = 6.0, P < 0.02) and the SDH group (0.62 and 0.38, respectively; chi 2 = 6.0, P < 0.02). The presence of the TT genotype predicted both ISH (odds ratio 1.9, 95% confidence interval 1.1-3.3) and SDH (1.7, 1.0-3.0) as did that of the T allele (ISH: 1.3, 1.0-1.7; SDH: 1.3, 1.0-1.7). CONCLUSIONS: The M235-->T polymorphism may be a marker for both forms of hypertension in the elderly. Whether the TT genotype represents a genetic risk factor for the development of hypertension in later life requires confirmation.     

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with hypertension, non-insulin-dependent diabetes mellitus, and coronary heart disease in Taiwan

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been identified that determines most of the plasma ACE activity genetically. Association of the D allele with insulin sensitivity and of the D/D genotype with coronary heart disease (CHD) has been reported in various ethnic populations. To study the role of this genetic polymorphism in patients with hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and NIDDM with CHD in a Taiwanese population, we used a polymerase chain reaction (PCR)-based genotyping technique with an insertion-specific primer for confirmation of the I allele. One hundred ninety-seven unrelated normal controls, 67 subjects with hypertension, 107 subjects with NIDDM, and 70 subjects with NIDDM and CHD were recruited for this study; all were Han Chinese. Subjects without a history of diabetes were studied by a standard 75-g oral glucose tolerance test. Hypertension was diagnosed according to the Fifth Joint National Committee criteria, and CHD was confirmed by a history of acute myocardial infarction and coronary angiographic intervention. The frequency of the I allele of the ACE gene in the normal population was 64.2%, which was higher than reported in white populations. The prevalence of the I allele of the ACE gene was not significantly increased in subjects with hypertension (73.1%), NIDDM (62.1%), and NIDDM with CHD (65%) compared with healthy controls. The I allele of the ACE gene did not correlate with demographic and metabolic variables. I/D polymorphism of the ACE gene is not a marker for hypertension, NIDDM, or CHD in this Taiwanese population.     

Electron paramagnetic resonance studies of cobalt-substituted angiotensin I-converting enzyme

The traditional treatment of high-flow vascular malformations consists of selective embolization, surgical removal, or a combination of both. Recurrence of the lesion and bleeding control are still the main problems, and the result of treatment is sometimes disappointing. We suggest treatment of these lesions with surgical ligation of the distal major feeding arteries followed by intravascular injection of a sclerosing agent (3% tetradecyl sulfate), and surgical excision and reconstruction when indicated. We have found this to be an effective treatment regimen. We present 14 cases of high-flow vascular malformations of the head and neck area treated with this approach, of which 4 cases developed skin necrosis. Three of these 4 cases of skin necrosis were later treated with skin grafting and, in 1 case, an upper arm skin tube flap was used for nasal tip reconstruction. Three cases underwent delayed reconstruction using tissue expanders. From a symptomatic and aesthetic point of view, preliminary satisfactory results were obtained. We feel that this approach is a good option for treating difficult, high-flow vascular malformations.     

Serum angiotensin converting enzyme activity in patients with untreated essential arterial hypertension

The serum angiotensin converting enzyme (ACE) in 30 patients with untreated essential arterial hypertension, 30 patients with chronic renal failure accompanied with arterial hypertension and 30 healthy individuals was measured. The subjects of both sexes have been old 35-60 years. The serum ACE activity was determined by the spectrophotometric method, using Hip-Gly-Gly as a substrate. The serum ACE activity significantly increased in patients with arterial hypertension (32.48 +/- 2.02; X +/- SEM) and patients with chronical renal failure accompanied with arterial hypertension (37.10 +/- 1.45) when compared to the healthy individuals (20.83 +/- 1.33). Possible mechanisms of increasing ACE activity with the patients suffering of arterial hypertension are discussed.     

Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells

OBJECTIVE: To study the determinants of early and late outcome after coronary artery bypass grafting (CABG) for evolving myocardial infarction. METHOD: 269 consecutive patients underwent isolated primary or repeat CABG from 1971 to 1992 for evolving myocardial infarction. By institutional policy, these were patients, strictly diagnosed, infarcting either in the cardiac cateterization laboratory, shortly after a previous CABG, or on cardiac intervention waiting lists. At operation, 125 patients were hemodynamically stable, 89 patients in cardiogenic shock 55 patients in cardiopulmonary resuscitation (CPR). Interval between infarct onset and surgical reperfusion ranged from 53 min to 15 h (median, 135 min; 90% between 75 and 360). An internal mammary artery graft (IMA) was used in 81 patients. Cross-sectional follow-up was 100% complete and multivariable analysis was conducted in the hazard function domain. RESULT: One-month, 1-year and 10-year survival was 86, 84 and 66%, respectively. The 1-year and 10-year survival, stratified by hemodynamic class, was respectively 98 and 77% for the stable patients, 77 and 60% for the patients in shock and 62 and 49% for those undergoing CPR. Shock and CPR were incremental risk factors for early but not late risk. Use of an IMA graft was not a risk factor early or late in either stable or unstable patients. CONCLUSION: CABG can be performed with acceptable early and long-term risk in selected patients with evolving myocardial infarction, whatever their hemodynamic state. Outcome as regards survival is neither adversely or advantageously affected by choice of bypassing conduit. An evolving myocardial infarction with stable hemodynamics carries a lesser risk than an unstable anginal state with changing ST-segment.     

Angiotensin-converting enzyme gene polymorphism in essential hypertensive patients in Japanese population

Association between angiotensin-converting enzyme (ACE) gene polymorphism and essential hypertension in a Japanese population with the same socioeconomic background was investigated. Insertion-deletion (I/D) polymorphism of the ACE gene located on intron 16 was detected by polymerase chain reaction. Association between ACE gene polymorphism and family history of essential hypertension as well as the development of vascular damage in eye fundi were also investigated. Variation at ACE loci did not contribute to essential hypertension and the vascular damages in eye fundi. These results suggest that the ACE gene was not directly responsible for essential hypertension in this particular Japanese population with the same socioeconomic background.     

Polymorphism of the angiotensin I converting enzyme gene in essential hypertensive patients

In order to study the relationship between plasma and platelet von Willebrand factor (vWF), we used an experimental model of crossed bone marrow transplantation (BMT) between SLA immunocompatible normal and homozygous von Willebrand (vWD) pigs. A normal pig received bone marrow from a vWD pig and a second pig with vWD was engrafted with marrow from a normal pig. Each recipient, after total irradiation of 10 Grays, received by a central catheter 10(10) monocellular bone marrow cells without immunosuppression. The animals were followed for 50 d and no graft rejection or graft-versus-host disease was observed. After aplasia occurring 3 weeks after BMT, white blood cells and platelets returned to normal. Before transplantation, in the vWD pig, vWFAg and vWF activity were not detected in plasma and in platelet and megakaryocyte alpha-granules. After transplantation with normal marrow, platelet vWFAg and platelet vWF activity wer normal and high molecular weight multimers and numerous tubular structures were present in alpha-granules. Before transplantation, the normal pig had normal plasma and platelet vWFAg-vWF activity, normal multimeric pattern, and the platelet and megakaryocyte alpha-granules displayed many tubular structures, eccentrically located in one of their poles, coinciding with immunogold staining vWFAg. After transplantation with homozygous vWD marrow, platelet and megakaryocyte alpha-granules lacked tubular structures. Alpha-granule immunogold staining for vWF was consistently negative, although plasma vWF was at a normal level. In conclusion, this study shows that, unlike other plasma proteins such as fibrinogen. vWF endocytosis does not occur from plasma to the platelet alpha-granules. Platelet and megakaryocyte vWF solely originates from megakaryocyte endogenous synthesis and is independent of plasma vWF.