Renovascular hypertension (RVH) caused by

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1 AJH 2000;13: Angiotensin-Converting Enzyme Gene I/D Polymorphism and Carotid Artery Disease in Renovascular Hypertension Attilio Losito, Antonio Selvi, Steve Jeffery, Ali R. Afzal, Basso Parente, and Pier Giorgio Cao There is evidence linking the activation of the renin-angiotensin system (RAS) with target organ damage in renovascular hypertension (RVH). A genetic association of the DD genotype of the angiotensin-converting enzyme (ACE) gene with cardiovascular complications has been found in various clinical conditions. The aim of our study was to determine whether the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the high prevalence of target organ damage reported in RVH. A total of 65 atherosclerotic patients (age years) with RVH and 49 atherosclerotic patients (age years) with essential hypertension (EH) were sequentially enrolled when attending the outpatient clinic for specialist assessment of their vascular disorder. Cardiac, renal, and vascular involvement were assessed in both groups and blood was taken for genetic analysis. Patients with RVH had a higher prevalence of left ventricular hypertrophy (LVH), carotid artery disease, and albuminuria than those with EH. In RVH, but not in EH, the DD genotype was significantly associated with severe arterial disease. In RVH, carotid disease (lumen narrowing >60%) was present in 62% of DD patients versus 25% of the other genotypes (OR 4.90, 95% CI: ). Such an association was also present in peripheral vascular disease: 72.4% in DD patients versus 41.6% in the other genotypes (OR 3.67, 95% CI ). Logistic regression analysis showed that the DD genotype was the strongest predictor of risk of severe carotid disease. We conclude that, in atherosclerotic RVH, there is an association of the severity of vascular disease with the DD genotype of the ACE gene. Am J Hypertens 2000;13: American Journal of Hypertension, Ltd. KEY WORDS: Angiotensin converting enzyme gene, renovascular hypertension, carotid artery disease. Renovascular hypertension (RVH) caused by atherosclerotic lesions of renal arteries is now being detected more often, because of an aging population and the availability of more sensitive techniques. 1 In RVH, the prevalence of Received December 9, Accepted June 7, From Unità Operativa Nefrologia e Dialisi Policlinico (AL, AS), Perugia, Italy; Medical Genetics Unit (SJ, ARA), St George s Hospital Medical School, London, England; and Unità Operativa Chirurgia Vascolare (BP, PGC), Policlinico, Perugia, Italy. Address correspondence and reprint requests to Dr Attilio Losito, Unità Operativa Nefrologia e Dialisi, Policlinico Monteluce, Perugia, Italy; atlosito@tin.it cardiovascular complications is significantly higher than in essential hypertension (EH). 2 Consequently the mortality rate is remarkably high, mainly because of cerebrovascular and cardiovascular events. 3 The activation of the renin-angiotensin system (RAS), induced by a hemodynamically significant renal artery stenosis, has been suggested as one of the main factors responsible for the vascular lesions. 4 Indirect support for this mechanism comes from the blockade of this system by angiotensin-converting enzyme inhibitor drugs (ACEi), which prevent vascular injury in animal models 5 and heart enlargement and coronary ischemic events in man. 6 Angiotensin-converting enzyme is a key enzyme in 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 AJH FEBRUARY 2000 VOL. 13, NO. 2 ACE GENE IN RENOVASCULAR HYPERTENSION 129 TABLE 1. CLINICAL CHARACTERISTICS OF PATIENTS STUDIED RVH EH Number Age (years) Sex (men/women) 57/8 45/4 Smokers Diabetic 7 7 Systolic blood pressure mm Hg mm Hg Diastolic blood pressure mm Hg mm Hg Duration of hypertension (years) Creatinine clearance (ml/min) EH, essential hypertension. RVH, renovascular hypertension. * Mean SD. t P.001. the production of angiotensin II; its gene has been cloned, and an insertion (I)-deletion (D) polymorphism in intron 16 has been identified. 7 The ACE I/D polymorphism appears to be a major determinant of circulating and tissue ACE, with serum levels of ACE being higher in subjects homozygous for the D allele. 8 Clinical studies of genetic association have shown that the DD genotype is associated with an elevated risk for LVH 9 and myocardial infarction. 10 Data based on linkage analysis have confirmed these reports and have shown an influence of the D allele on left ventricular size. 11 Furthermore, in patients with EH the D allele is an independent risk factor for microalbuminuria, retinopathy, and LVH. 12 In the present study we assessed heart and vascular disease and monitored the renal function in atherosclerotic RVH patients. We also tested the ACE genotype to investigate a possible association between an insertion-deletion (I-D) polymorphism of the ACE gene and cardiovascular abnormalities, both in RVH patients and in an EH control group. PATIENTS AND METHODS This study was performed on 65 consecutive atherosclerotic patients with RVH. The diagnosis of RVH was based on clinical suspicion raised by selected clues 13 and was confirmed by renal angiography and captopril renography with 99m technetium diethylenetriamine pentacetic acid ( 99m Tc-DTPA). The criteria of Setaro et al were followed in the interpretation of the test. 14 Renal artery stenosis was of atherosclerotic origin in all patients, with an average lumen narrowing of % for each artery studied. Stenosis was bilateral in 10 patients and unilateral in the remaining patients. The group of essential hypertensive (EH) subjects comprised 49 consecutive atherosclerotic hypertensive patients, of similar age and sex distribution, who attended the vascular surgery clinic during the same period. These individuals had EH, diffuse atherosclerotic vascular disease, and aortic abdominal aneurysm; the renal angiogram, obtained during the diagnostic procedure, was negative. The diagnosis of EH was made on the basis of medical history, physical examination, a negative renal angiogram, and laboratory tests aimed at ruling out primary renal disorders. Table 1 shows the most relevant characteristics of both groups of patients. All subjects studied were on antihypertensive treatment with one or more drugs when admitted to the hospital. The RVH patients had been treated for high blood pressure for years and EH for years. The number of antihypertensive drugs, per patient, that was necessary to keep BP under control was in RVH and in EH (t 2.71; P.006). The agents employed were calcium channel antagonists, diuretics, adrenoceptor antagonists, clonidine, peripheral vasodilators, and ACEi. These drugs were employed in 36% of RVH patients and in 24% of those with EH. Treatment with lipid-lowering drugs was given to 10 patients with RVH and seven with EH. Renal function was assessed by serum creatinine and creatinine clearance. Cardiovascular Evaluation A thorough evaluation of blood lipids was made in all subjects (Table 2). Routine electrocardiography was associated with echocardiography, which was particularly aimed at obtaining left ventricular dimensions and performed according to the recommendations of the American Society of Echocardiography. 15 Left ventricular hypertrophy (LVH) was considered to be present when the left ventricular mass index was 110 and 134 g/m 2 in female and male patients, respectively. The sonographic examination of extracranial carotid arteries was carried out in all patients by the same operator (B.P.), by color flow echo-doppler (color duplex scanner Aloka SSD 680, Aloka, Co., Ltd, Mitaka-shi, Tokyo, Japan, with a linear probe of 7.5 MHz). The common carotid artery, internal carotid artery, and external

3 130 LOSITO ET AL AJH FEBRUARY 2000 VOL. 13, NO. 2 TABLE 2. CLINICAL FINDINGS IN RVH AND EH PATIENTS RVH (n 65) EH (n 49) Odds Ratio (95% CI) Left ventricular hypertrophy 29 (44.6%) 8 (16.3%) 4.12 ( ) Carotid stenosis ( 60%) 24 (36.9%) 6 (12.2%) 4.19 ( ) Peripheral vascular disease 40 (61.5%) 13 (26.5%) 4.43 ( ) Urinary protein excretion ( 300 mg 24 h) 43 (66.1%) 12 (24.4%) 6.02 ( ) carotid artery were evaluated by analysis of the B- mode imaging, Doppler signal, and color code signal. The B-mode was employed for the study of the arterial wall, and was particularly aimed at the plaque assessment (ie, low acoustic density plaque or echo translucent; high acoustic density plaque, or echogenic, homogeneous plaque, ulcerous plaque, etc). The sonographic study included the vertebral-subclavian district. Carotid artery lesions were classified into five degrees of involvement by applying a slight modification to a previously reported classification. 16 Classes 1 and 2 were absent and minimal stenosis was of no hemodynamical consequence. Classes 3, 4, and 5 indicated lesions with lumen narrowing between 60% and 100%. On the basis of this classification, carotid involvement was scored from 1 to 5. The sonographic examinations of carotid arteries were performed before the renal angiography; therefore, the operators had no knowledge of the final diagnosis. Atherosclerotic peripheral vascular disease was assessed by color flow echo-doppler or by angiography. Arterial involvement was scored on an arbitrary scale (from 0 to 3), taking into account the number of involved vessels and the degree of narrowing. 2 Angiotensin-Converting Enzyme Gene Polymorphism Genetic analysis was performed blind (by S.J. and A.R.A.) on coded blood samples. Blood samples were drawn from 42 healthy subjects (hospital personnel), 29 female and 13 male, age years. The RVH and EH patients and healthy controls were white. DNA extraction and ACE polymorphism detection were carried out exactly as previously described. 24 After the first determination, all DD genotypes were checked with insertion-specific primers; 24 only one mistyping was detected. Statistical Analysis Statistical analysis was performed on a computer using the BMDP package (BMDP Statistical software, Cork, Ireland). For normally distributed data, mean and standard deviation were calculated; the comparisons were made with the Student t test. Ordinal data and proportions were compared with nonparametric tests ( 2, Fisher s exact test, Mann-Whitney U test, and odds ratio). The results obtained with this type of test ( 2 ) were integrated by logistic multiple regression analysis. To determine the respective roles played by the genotype and by other relevant comorbid conditions in carotid artery disease, we employed a logistic regression analysis in RVH and EH patients separately. Severe carotid disease (stenosis 60%) was chosen as a dependent variable. The following variables were entered into the analysis as covariates: age, sex, diabetes, smoking habit, blood pressure, duration of hypertension, serum cholesterol, urinary protein, and ACE gene polymorphism. The stepwise forward selection was implemented to build the model, with the score statistics used to assess the significance of each variable. The likelihood ratio statistics were employed to test the model after the removal of the single variables. Once checked for goodness-of-fit for the model, the final significance was given by the 2 value. The same procedure was repeated using peripheral vascular disease as a dependent variable. RESULTS Clinical Data The main findings of renal and cardiac involvement in RVH and EH are summarized in Table 2. Atherosclerotic Vascular Disease Widespread atherosclerotic vascular disease was a criterion for admission to the study; therefore, it was present in both groups. A more detailed breakdown of the lesions showed that the peripheral vascular disease of the limbs was more severe in RVH patients (score ) than in EH (score ), (U test: P.002). The assessment of carotid lesions based on the scoring system also showed a significant difference: in RVH versus in EH (U test: P.0169). Serum values of lipids and lipoproteins were comparable between RVH and EH (Table 3). Genetic Analysis The distribution of DD, ID, and II genotypes in RVH patients, EH patients, and healthy controls is shown in Table 4. We found no significant differences among the three groups, either in the distribution of genotypes or in the frequency of the D and I alleles.

4 AJH FEBRUARY 2000 VOL. 13, NO. 2 ACE GENE IN RENOVASCULAR HYPERTENSION 131 TABLE 3. LIPID TESTS IN THE TWO GROUPS Genetic Association Study We tested the presence and the severity of damage in target organs in association with the different polymorphisms of the ACE gene. In RVH, 51% of DD patients had LVH compared to 35% of the other genotypes. In EH, LVH was found in 35% of the DD genotype and in 20% of the others. The difference in prevalence was not statistically significant (Table 5). The association of genotypes and vascular disease was as follows. In RVH patients the average lumen narrowing of the renal arteries in DD genotype was 80.3% 13.2% compared to 74.4% 18.4% in the remaining patients (NS). The prevalence of peripheral vascular disease in patients with RVH with the DD genotype was 72.4% compared to 41.1% with the other genotypes (OR 3.67; 95% CI: ); in patients with EH, such an association was absent. Extracranial carotid disease was associated with the DD genotype in RVH: 62% of patients with DD genotype had carotid stenosis of 60%, compared with 22.5% of the other genotypes (OR 4.90; 95% CI: ). The comparison based on the scoring of carotid lesions showed that DD genotype was associated with a more severe disease; the average score was in the DD and in the ID-II group (U test: P.007). Patients treated with ACEi did not differ from the others in the severity of carotid disease. Systolic blood pressure was mm Hg in TABLE 4. ANGIOTENSIN-CONVERTING ENZYME GENE INSERTION DELETION (I/D) POLYMORPHISM IN THE TWO GROUPS OF PATIENTS AND IN HEALTHY CONTROL SUBJECTS Group DD ID II Number (%) Number (%) Number (%) RVH 29 (44.6%) 32 (49.2%) 4 (6.1%) EH 17 (34.6%) 24 (48.9%) 8 (16.3%) Control 19 (45.2%) 21 (50%) 2 (4.7%) RVH EH Cholesterol mmol/l mmol/l HDL cholesterol mmol/l mmol/l LDL cholesterol mmol/l mmol/l Apolipoprotein A g/l g/l Apolipoprotein B g/l g/l Triglycerides mmol/l mmol/l Values are expressed as mean SD. RVH patients with less severe carotid disease and was mm Hg in those with a severe degree of stenosis (NS). In patients with EH, a significant carotid artery stenosis was present in 12.5% of carriers of DD genotype and in 13.3% of those with ID and II. With the scoring assessment no association was found between the degree of carotid arteries disease and genotypes. The logistic regression analysis, applied to severe carotid disease, showed that the DD genotype had the higher partial correlation coefficient between the variables entered into the model (R 0.471; P.0007). At the end of the model selection procedure, the DD genotype was the only indicator selected with a significance of P The same procedure applied to peripheral vascular disease did not produce significant results. In EH patients the logistic regression analysis, implemented with the same dependent variables and the same covariates entered in RVH, did not result in significant results. Renal Function Serum creatinine 133 mol/l was present in 44.8% of RVH patients with DD genotype and in 28% with ID; the respective values in EH were 25% and 18% (NS). In RVH, a 24-h urinary protein excretion 300 mg was present in 37.9% of DD and 33.2% of other genotypes (NS). In EH, the respective prevalence was 15.3% (DD) and 13%. DISCUSSION The main finding of this study is that the ACE DD genotype is associated with severe vascular disease (particularly of the extracranial carotid arteries) in patients with RVH of atherosclerotic origin. This was not the case for EH patients. The fact that substantial improvement in blood pressure with the removal of the obstruction was not demonstrated presents a limitation on the diagnosis of RVH, 17 but a positive captopril renography is known to have a predictive value for blood pressure cure after revascularization of 86%. 18 Furthermore, in the presence of an angiographically demonstrated renal artery stenosis 50%, this value attains 95%. 19 Systolic blood pressure was higher in RVH than in EH, and it is known that over a long term systolic blood pressure is a risk factor for carotid disease. 20 However, in our study, SBP was comparable between patients with severe carotid disease and those with a lesser degree of involvement. Patients with EH had a longer duration of hypertension. We have failed to confirm the recently reported association of the D allele with microalbinuria and LVH in hypertensive subjects. 12 There is also disagreement in the literature regarding arterial thickening and ACE I/D association, with two studies giving negative results, 21,22 whereas another found the DD

5 132 LOSITO ET AL AJH FEBRUARY 2000 VOL. 13, NO. 2 TABLE 5. PREVALENCE OF TARGET ORGAN DAMAGE IN RVH AND EH PATIENTS WITH THE DD GENOTYPE RVH (n 29) EH (n 17) Odds Ratio 95% CI Statistical Significance LVH 51.7% 35.2% NS Carotid disease stenosis 60% 62.0% 17.5% P.01 Peripheral artery disease 72.4% 41.1% P.02 Serum creatinine 133 mol/l 44.8% 25% NS Urinary protein excretion 300 mg/24 h 37.9% 15.3% NS genotype to be associated with increased carotid thickness. 23 Carotid plaques were found to be associated with the D allele in Japanese subjects, 24 and the possibility of error due to ethnic admixture must be considered in polymorphism association studies. 25 In the present study, all subjects were white. RVH induced renal artery stenosis is an interesting model for studying the link between the ACE gene polymorphism and vascular disease, as a characteristic of this condition is the activation of the reninangiotensin system at an early stage of the disease. A recent article has shown an increased genetic risk for atherosclerotic stenosis of renal arteries that is related to the D allele of the ACE genotype. 26 In our study, a higher degree of renal artery stenosis was present in patients with the DD genotype, but the difference was not significant. It appears that the RAS can have an effect on the local remodeling of the vascular wall, 27 as well as acting systemically. 28 Our RVH patients are an excellent model to examine the possible vasculotoxic action of the DD genotype, as all of the essential cofactors were present. The atherosclerotic vascular disease, the activation of the renin-angiotensin system by renal artery stenosis and arterial hypertension are all risk factors for severe vascular disease. A confirmation that this kind of multifactoriality operates in RVH comes from the EH group, in which (despite the presence of high blood pressure for a longer time, and widespread atherosclerosis) carotid and limb artery disease was less severe and the association with the DD genotype was absent. The lack of the activation of the reninangiotensin system could well be the discriminating factor. In our RVH patients, we have only indirect evidence of the activation of the RAS, which comes from the response of the renal hemodynamics to the administration of captopril shown by the DTPA renography. 29 Repeated measurements of circulating renin and angiotensin would have offered a stronger support to our hypothesis. The DD genotype may act in an autocrine or paracrine manner in as much as, locally, ACE is the ratelimiting step of the renin-angiotensin enzyme cascade. 30 The problem of small sample size and type 1 error have to be considered very seriously in this study, bearing in mind the lack of association of the D allele with cardiovascular events in the American Physicians Study. 31 However, the fact that the only factor selected by the statistical model was the DD genotype suggests that the findings are valid. With present knowledge, the finding of a genetic association of the DD genotype with severe carotid disease offers a possible clue to the reported high prevalence of carotid artery disease in RVH. Therefore, we believe that the determination of the ACE gene polymorphism could help in singling out patients who are at greatest risk for cerebrovascular morbidity and mortality. ACKNOWLEDGMENTS We thank Mrs C. Covarelli for technical assistance. REFERENCES 1. National High Blood Pressure Education Program Working Group: 1995 Update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med 1996;156: Losito A, Fagugli RM, Zampi I, Parente B, De Rango P, Giordano G, Cao PG: Comparison of target organ damage in renovascular and essential hypertension. Am J Hypertens 1996;9: Isles C, Main J, O Connell J, Brown I, Findlay J, Stewart R, Wilkinson R: Survival associated with renovascular disease in Glasgow and Newcastle: a collaborative study. Scot Med J 1993;35: Rossi GP, Rossi A, Zanin L, Calabrò A, Feltrin GP, Pessina AC, Crepaldi G, Dal Palù C: Excess prevalence of extracranial carotid artery lesions in renovascular hypertension. Am J Hypertens 1992;5: Kakinuma Y, Kawamura T, Bills T, Yoshioka T, Ichikawa I, Fogo A: Blood pressure independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Kidney Int 1992;42: Pfeffer M, Braunwal E, Boye L, the SAVE Investigators: Effect of captopril on mortality and mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992;327: Soubrier F, Alhenc-Gelas F, Hubert C, Allegrini G, John M, Tregear G, Corvol P: Two putative active centers in human angiotensin I-converting enzyme revealed by

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