Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 1995;92:2066-2071

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by van Bockxmeer, F. M.
Right arrow Articles by Taylor, R. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van Bockxmeer, F. M.
Right arrow Articles by Taylor, R. R.

(Circulation. 1995;92:2066-2071.)
© 1995 American Heart Association, Inc.

Articles

Angiotensin-Converting Enzyme and Apolipoprotein E Genotypes and Restenosis After Coronary Angioplasty

Frank M. van Bockxmeer, BSc, PhD; Cyril D. S. Mamotte, BSc, MAACB; Frances A. Gibbons, MIR; Valerie Burke, MD, FRACP; Roger R. Taylor, MB, FRACP

From the Department of Biochemistry (F.M. van B., C.D.S.M.), Department of Cardiology (F.A.G., R.R.T.), and University Department of Medicine (R.R.T., V.B.), Royal Perth (Australia) Hospital.

Correspondence to Frank M. van Bockxmeer, PhD, Department of Biochemistry, Royal Perth Hospital, Wellington Street, Perth, Western Australia 6000.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) has been associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene was postulated to be a candidate gene affecting the important clinical problem of restenosis after percutaneous transluminal balloon coronary angioplasty (PTCA). Because restenosis is influenced by the apolipoprotein E (apoE) genotype, the possibility of a relation between ACE and apoE genotypes and restenosis was also sought.

Methods and Results Subjects (<70 years of age) were prospectively followed and had coronary angiography 6 months after PTCA to determine the presence or absence of restenosis. Those who had angiography earlier and did not have restenosis (>=50% loss of gain at PTCA plus >=50% luminal diameter stenosis) also had angiography at 6 months. The whole group (n=207) had a higher DD genotype frequency than did 136 population control subjects (38% versus 26%, P<.02); in PTCA patients, the frequency was the same in those with and without prior myocardial infarction. The distribution of ACE genotypes was not different in the 88 patients with and 119 patients without restenosis, while the {epsilon}4/4 genotype was more frequent in those with restenosis (8 of 88 versus 3 of 118, P<.05). There was no effect of the ACE genotype in noncarriers of the {epsilon}4 allele, but there was a significant effect in {epsilon}4 carriers (P<.005). The combined D and {epsilon}4 carrier state showed a 16-fold increase in the odds ratio for restenosis (P<.02). Multiple linear regression examining the loss of lumen as a continuous variable showed significant independent effects of the ACE and apoE genotypes.

Conclusions Overall, the ACE genotype had no clear influence on restenosis, but there was an interaction between ACE and apoE genotypes. The combined carrier state for the D and apoE {epsilon}4 alleles substantially increased restenosis. For loss of lumen as a continuous variable, there were significant effects of both ACE and apoE genotypes. While the observations may not affect current management, they no doubt have implications in pathophysiology.


Key Words: genes • restenosis • apolipoproteins • angiotensin


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
An insertion/deletion (I/D) polymorphism of intron 16 of the gene for angiotensin-converting enzyme (ACE) has been related to a variation in the plasma level of the enzyme1 ; subsequently, homozygosity for the deletion (D) allele was reported to be associated with myocardial infarction, especially in low-risk subjects.2 While the literature contains discrepant or even contrary reports,3 additional evidence, on balance, supports the latter association,4 5 and an interrelation between this polymorphism and one in the gene for the angiotensin II type 1 receptor and myocardial infarction has been described.6 Other studies have found relations between the D allele and left ventricular hypertrophy,7 ischemic and idiopathic cardiomyopathy,8 and the expression of hypertrophic cardiomyopathy.9

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) is an important clinical problem and is a response to injury of the vessel wall, platelet aggregation, thrombus formation, liberation of growth factors, cellular hyperplasia involving predominantly smooth muscle proliferation and migration, and intercellular matrix formation.10 11 12 13 14 Angiotensin II variably stimulates smooth muscle cell division and growth, depending on the interplay between the enhanced expression of growth factors, including platelet-derived growth factor, transforming growth factor (TGF-ß), and fibroblast growth factor.13 15 16 17 18 Infusion of angiotensin II induces smooth muscle proliferation in the rat arterial wall, more marked in arteries damaged by balloon inflation.17 ACE and other components of the renin-angiotensin system are present in vessel walls, and ACE is increased in vessel walls, associated primarily with myocytes, after injury.13 19 Hence, evidence has suggested that the renin-angiotensin system might be involved in the process of restenosis, a concept initially supported by results with ACE inhibition in animals.11

About half of the individual variation in plasma ACE depends on the I/D polymorphism of the ACE gene; average levels in DD, ID, and II genotypes are found to be approximately 5:4:3.1 The polymorphism also influences ACE levels in human T lymphocytes,20 and when an effect at the local vessel wall level was postulated, an impact on restenosis was proposed.

The primary aim of this study was to examine the possibility of a relation between polymorphism of the ACE gene and restenosis after coronary balloon angioplasty. The subjects were those previously involved in a prospective 6-month angiographic study of restenosis.21 In the subjects of that study, we later found that restenosis was more frequent in patients homozygous for the E4 variant of apolipoprotein E (apoE),22 a polymorphism associated with atherosclerotic coronary artery disease.23 24 25 26 27 Therefore, the second aim of this study was to explore a relation between ACE and apoE genotypes and restenosis. We also compared the ACE genotypes of the patients of the study with those of a community control group of healthy subjects.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Subjects and Protocol
The patient group comprised 207 (170 men, 37 women) who completed follow-up in a prospective 6-month angiographic study of restenosis after PTCA.21 The original aim of the study was to evaluate the effect of low-dose aspirin on restenosis; the study design and protocol were reported previously.21 Aspirin (Cardiprin) and a calcium antagonist were started before the PTCA procedure, and the medication was continued in patients taking ß-adrenoceptor–blocking drugs. After PTCA, patients were discharged on aspirin 100 mg/d and calcium antagonists. ß-Blocking drugs were continued only if indicated. Calcium antagonists were discontinued at the discretion of the referring cardiologist at the scheduled 2-week review. At that review, subjects were assessed for inclusion in the aspirin/placebo study or for the same follow-up without randomization. Of the 207 patients in this report, 143 were randomized subjects and 64 were nonrandomized. They were all patients who had fasting blood taken at the time of initial angioplasty and had DNA available for ACE genotyping. ApoE genotyping was carried out in all but 1 patient.

The study was restricted to those having elective PTCA of a previously untreated native coronary artery, ie, without previous PTCA or coronary artery bypass grafting, outside the setting of acute myocardial infarction, who were <70 years of age, who gave informed consent, who were referred by the cardiologists of the one hospital, and in whom primary angioplasty success was achieved. The latter was defined as >=20% increase in luminal diameter and a postdilatation lumen >50%. This was determined from the mean of electronic caliper measurements in multiple projections that adequately demonstrated the lesion, including projections with craniocaudal and caudocranial tilt. Angiograms were assessed independently by two observers, and the average of measurements was taken. The 207 patients had 296 successfully dilated lesions.

Angiographic restenosis was prospectively defined as loss of >=50% of the gain attained at PTCA together with stenosis of >=50% of luminal diameter; both criteria had to be satisfied as previously described.21 Subjects who had clinically indicated coronary angiography before 6 months and who had restenosis were considered to have reached an end point. Those who did not have restenosis when studied were restudied at 6 months to define their status. Patients were considered to have restenosis when any previously dilated lesion satisfied the above criteria. Results in the 88 subjects who had restenosis are compared with those in the 119 who did not. As outlined previously,21 because restenosis is not an all-or-none phenomenon, the percentage loss of lumen from immediately after PTCA to angiographic follow-up was also examined in relation to the genotypes.

In addition to the main study of restenosis, ACE genotypes in the 207 patients are compared with those of 136 population control subjects 28±4 (mean±SD) years of age (range, 20 to 34 years) recruited from electoral rolls. All subjects in the study were residents of the Perth area of Western Australia; the great majority were Caucasian.

The study protocol was approved by the Royal Perth Hospital Ethics Committee.

Genotyping
Genomic DNA was extracted from EDTA or clotted blood by a standard Triton X-100 procedure and genotyped for the ACE I/D polymorphism by a modification of the method of Rigat et al.28 Conditions for the polymerase chain reaction (PCR) included 1 U Tth polymerase (Biotech International) in 25 µL of a reaction mixture supplied by the manufacturer and containing 3 mmol MgCl2/L amplified on a HYBAID thermocycler (Cambridge Instruments) by initial denaturation at 95°C for 240 seconds followed by 30 cycles of 70 seconds of denaturing at 94°C, 70 seconds of annealing at 63°C, and 120 seconds of extension at 72°C. Taq polymerase from another supplier (Amersham) gave identical results under these conditions. We analyzed 15 µL of the final reaction mix by polyacrylamide gel electrophoresis (PAGE; 12% T, 3.3% C) using pGEM Mr standards (Promega Corp). Initial attempts with 58°C as the annealing temperature as originally described28 gave inconsistent results, particularly in heterozygotes in whom variably low product levels of the I allele compared with the D allele were observed, leading to possible misclassification of ID genotypes as DD. Others have recognized this problem,29 30 but we found that use of the appropriate temperature resolved the problem without the addition of dimethyl sulfoxide.30 Even so, the intensity of ethidium bromide staining of the I allele product was lower than expected on the basis of its size compared with the D allele product in heterozygotes. This phenomenon has been attributed to a lower amplification efficiency of long compared with short DNA segments during PCR.29 Additionally, nonspecific amplification products were found at an annealing temperature of 58°C that could be resolved from the true I allele product by PAGE but not by electrophoresis on agarose gels. Such material could be erroneously classified as I allele product on agarose electrophoresis.

ApoE genotyping was performed by the method of Hixson and Vernier.31 Briefly, genotypes were determined by Hhal digestion of a 244–base pair PCR-amplified fragment spanning the two polymorphic sites with resolution of restriction enzyme fragments on polyacrylamide gel (18% T, 3.3% C) using pGEM Mr standards as previously described.25

Statistical Analysis
Differences between the means of the two groups were evaluated with a Student's two-tailed t test. Differences in the distribution of ACE and apoE genotypes individually between the groups with and without restenosis were tested with the normal approximation of the binomial distribution. Logistic regression was used to examine the relations between ACE and apoE genotypes and restenosis as a binary variable. The effects of ACE and apoE genotypes individually on the percentage loss of lumen in follow-up were tested by ANOVA with the Bonferroni correction applied for multiple comparisons. Their contributions to variation in loss of lumen were examined by use of linear regression models. A value of P<.05 was considered significant.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Table 1Down compares the ACE genotypes in the 207 patients of this study with those in 136 population control subjects. The DD genotype was significantly more frequent in the group with coronary artery disease (79 of 207 versus 35 of 136, P<.02). The odds ratio (OR) for coronary artery disease for the DD genotype was 1.8 (95% CI, 1.1 to 2.9), whereas the comparable OR for survivors of myocardial infarction and population control subjects in the original ECTIM study2 averaged 1.3 and ranged from 1.1 to 2.1 in several centers. In our patients, genotype distribution did not differ between the 66 patients with previous myocardial infarction and the 141 without; the DD genotype was present in 25 (38%) and the II genotype in 14 (21%) of those with prior infarction compared with 54 (38%) and 28 (20%), respectively, in those without prior infarction.


View this table:
[in this window]
[in a new window]
  		Table 1. ACE Genotypes in Angioplasty and Healthy Control Groups

Table 2Down presents the clinical features and therapy at the beginning of follow-up 2 weeks after PTCA in the 207 patients of the study, 88 (42.5%) of whom developed angiographic restenosis. There were no significant differences in any of the features tested, including fasting serum cholesterol, between those who developed restenosis and those who did not. An insubstantial number of patients were on lipid-lowering medication (3 of those developed restenosis; 4 did not) or ACE inhibitors (the initial study was carried out from 1986 through 1988, when such therapy was infrequent). Table 2Down does not include aspirin treatment because not all patients were randomized to aspirin or placebo at 2 weeks. Of the 143 randomized patients, 25 of 70 (36%) randomized to aspirin developed restenosis; 34 of 73 (47%) receiving placebo did also (P=NS).


View this table:
[in this window]
[in a new window]
  		Table 2. Characteristics of Patient Groups

Table 3Down presents the ACE genotypes in the patients with and without restenosis. Although there was a tendency for patients without restenosis to have more II genotypes, the distribution of genotypes was not significantly different between the two groups. For example, the OR for the DD compared with the II genotype was 1.8 (95% CI, 0.8 to 3.9); the OR for the DD genotype was 1.1 (CI, 0.6 to 2.0). The power of this test, however, was only 60%.


View this table:
[in this window]
[in a new window]
  		Table 3. ACE Genotypes in Angioplasty Subjects With and Without Restenosis

ApoE genotypes were available in all but 1 patient. Eight of 88 (9%) with restenosis and 3 of 118 without restenosis were {epsilon}4/4 genotype (P<.05). A relation between ACE and apoE genotypes was then sought. Table 4Down gives the numbers in each ACE genotype group who were {epsilon}4 homozygotes, {epsilon}4 heterozygotes, and noncarriers of {epsilon}4, with and without restenosis. The numbers are relatively small and may be open to interpretation, but a clear interrelation between genotypes and restenosis is revealed. Among carriers of {epsilon}4, homozygotes and heterozygotes, 27 had restenosis and 26 did not. Twenty-six of the 27 with restenosis were carriers of the D allele, whereas 16 of the 26 without restenosis were D carriers (P<.005). Conversely, there was no influence of the ACE genotype in noncarriers of the {epsilon}4 allele (Table 4Down). Similarly, from the viewpoint of carriers of D, restenosis was related to apoE genotype. In carriers of the D allele, 26 of 42 (62%) who carried {epsilon}4 developed restenosis; 49 of 123 (40%) noncarriers of {epsilon}4 did also (P<.02). These results were confirmed by logistic regression analysis, which indicated a significant interaction between the D allele carrier and the {epsilon}4 allele carrier states: carriers of both the D and the {epsilon}4 alleles had a 16-fold increase in the OR for restenosis (P<.02). Logistic regression examining {epsilon}4 carriers and DD and ID genotypes separately showed an OR of 21 for the ID genotype and an OR of 12 for the DD genotype.


View this table:
[in this window]
[in a new window]
  		Table 4. ACE and ApoE Genotypes in Angioplasty Subjects With and Without Restenosis

Restenosis is, of course, not an all-or-none phenomenon, and it was of interest to examine the ACE genotype in relation to the extent of loss of lumen from the time of dilatation of the coronary stenoses to angiographic follow-up.21 Table 5Down presents these data for all angiographic follow-up of the 296 lesions dilated and separately for the 254 lesions in subjects who came to the planned 6-month assessment. Because only those subjects who prematurely satisfied the criteria for restenosis did not have the 6-month angiographic assessment, the losses of lumen presented in Table 5Down are greater for all follow-up than for planned follow-up only; ie, the latter figures exclude those with premature restenosis. Therefore, the most appropriate results to analyze are those of all follow-up. Results have not been analyzed according to the size or site of the artery dilated,32 but the proportion of left anterior descending (LAD) to non-LAD lesions was similar in each ACE genotype group—DD, 45 of 112 (40%); ID, 54 of 72 (43%); and II, 26 of 58 (45%)—as in apoE genotype groups.


View this table:
[in this window]
[in a new window]
  		Table 5. Changes in Lesions From After Dilatation to Angiographic Follow-up

Table 5Up indicates that the average loss of lumen was similar for DD and ID and less for II genotypes. The groups were tested with ANOVA with Bonferroni's correction for multiple comparisons. No two groups were significantly different (P=.09), although the II group was significantly different from all carriers of D, ie, from the DD and ID groups combined (P=.03). Examination of the apoE genotype groups similarly shows a significant difference between {epsilon}4 homozygotes, {epsilon}4 heterozygotes, and noncarriers of {epsilon}4, the loss of lumen being 35.2±7.9% (n=13), 19.5±3.3% (n=65), and 17.6±1.7% (n=217), respectively (mean±SEM, P<.05); the {epsilon}4/4 group was the significantly different group. Multiple regression with logarithmic transformation of the loss of lumen as the dependent variable showed significant independent association between the ACE and apoE genotypes (P<.001). The contribution to variance for ID (11%) and DD (10%) genotypes (P<.01) was similar, whereas that attributable to {epsilon}4 heterozygosity was 14% (P<.05) and that to {epsilon}4 homozygosity was 3% (P=NS). The lack of significance of the {epsilon}4/4 contribution to variance is attributable to the relative small number (13) involved.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The primary outcomes of this study concern the influence of the I/D polymorphism of the ACE gene and of polymorphism in the apoE gene on restenosis after PTCA. The role of the renin-angiotensin system in pathophysiology suggested that the ACE gene could affect restenosis,10 11 12 13 14 15 16 17 18 19 and a report in a Japanese population indicated an increase in the DD genotype in those developing restenosis after PTCA in the setting of acute myocardial infarction.33 Overall, we did not find a significant effect of the DD genotype or the D allele, but multivariate analysis revealed such an effect when the effect of the apoE genotype was taken into account. There was also an interaction between the ACE and apoE genotypes and restenosis, so there was a substantial effect of the ACE genotype in carriers of the {epsilon}4 allele but no effect in noncarriers. The effect seemed to be similar for the DD and ID genotypes; therefore, the II genotype might alternatively be regarded as protective.

There were several additional findings of the study. In the total PTCA patient group, ie, a group with significant obstructive coronary artery disease, there was an enrichment of the DD genotype similar to that found in survivors of myocardial infarction in the original ECTIM multicenter European study.2 The difference between our patient and control groups was slightly greater than the average in that study but fell between the results from their several centers. The frequency rate of the DD genotype in our control population (26%) was similar to the 27% frequency rate in control subjects in the ECTIM study. Our control group was younger than our patient group, but all subjects were younger than 70 years of age. The age difference could hardly have produced a misleading result in the comparison of patients with control subjects. Any loss of DD genotypes from coronary artery disease in the middle years would have reduced the difference between the two groups. At the same time, it may be that the DD genotype contributes in some way to survival into extreme old age; this genotype has been reported to be overrepresented in centenarians.34 35

The other new finding in the present study concerns the relation between the ACE genotype and coronary artery disease and the fact that only approximately one third of our patient group had evidence of previous myocardial infarction. The frequency rate of the DD genotype was 38% in those with and without previous myocardial infarction. This strongly suggests that the D allele is related to the occurrence of atheromatous coronary artery disease rather than specifically to myocardial infarction. This is perhaps not surprising in view of the pathophysiologies of the renin-angiotensin system, atherosclerosis, and myocardial infarction, the last usually being secondary to thrombosis after atheromatous plaque rupture,36 although it must be conceded that the precise mechanisms for the ACE genotype effect are unclear.

Correct genotyping was obviously essential to this study and, as mentioned, there are pitfalls in ACE genotyping.29 30 Documentation of the nature of the study group and full angiographic follow-up are also essential in any study on restenosis. When restenosis is described as a binary variable, it is rational to incorporate a measure of the loss of the gain attained by PTCA or the loss of lumen from the time of PTCA into a discrete criterion21 rather than using 50% of lumen diameter as a single criterion. We examined both discrete restenosis and loss of lumen as a continuous variable in relation to genotypes, with substantially the same results.

The report from Japan, which found an increase in the DD genotype in subjects with restenosis, concerned direct PTCA in the setting of acute myocardial infarction.33 Our study excluded such patients. The Japanese study included 82 subjects; 21 of 32 patients who developed restenosis within 6 months were of the DD genotype compared with 16 of 50 without restenosis. The 45% frequency rate of the DD genotypes in their patient group is similar to the 38% rate in ours, but the frequency of DD genotypes in their Japanese control population is apparently 16% (16 of 102 subjects), which is substantially lower than in our study or the ECTIM multicenter European study.2 It would be interesting to know the apoE genotype of the subjects in the Japanese study, especially in light of our findings and the knowledge that the frequency of the {epsilon}4 allele is rather low in healthy Japanese people. Therefore, there might also be important racial differences. Because we found the ACE genotype to be a significant determinant of restenosis under one set of conditions (in carriers of the {epsilon}4 allele) and not under another, the nature of the population studied could be of great relevance to the occurrence of restenosis.

Early animal studies suggested that ACE inhibitor drugs could reduce intimal hyperplasia and arterial stenosis after balloon injury in the rat, in which, interestingly, apoE is similar to apoE4, but subsequent studies in pigs produced disparate results.11 Clinical studies of two different ACE inhibitors have been negative.37 38 Our study indicates clear involvement of the ACE genotype only in a subgroup of patients, those who are {epsilon}4 carriers, which could be one of numerous factors leading to the difficulty in demonstrating a general effect of ACE inhibitors on restenosis. It has also been proposed that the doses of the ACE inhibitors used clinically might not have been adequate to inhibit tissue ACE. There is support for this in rats in which the dose of the ACE inhibitor quinapril required to suppress ACE in the damaged carotid wall was greater than that required to inhibit serum ACE. Inhibition of neointimal proliferation was more closely related to tissue ACE levels.19 The negative clinical trials, therefore, do not constitute good evidence against an involvement of the renin-angiotensin system in clinical restenosis, and our study suggests that a future approach to inhibiting the system at a tissue level, at least in certain subgroups, might be productive.

In our previous study encompassing many of the patients in this study, the effect of the apo {epsilon}4 allele in potentiating restenosis did not appear to be mediated through serum cholesterol or apo(a) levels,22 and further evidence against an important role for serum cholesterol continues to accrue.39 The mechanism of the apoE4 effect might be related to the intriguing interaction between the ACE and apoE genes. As already outlined, angiotensin II stimulates cellular hyperplasia and production of intercellular matrix through a number of interrelated mechanisms and induction of growth factors.10 13 15 16 17 18 Among the latter is TGF-ß, which is increased in clinical restenotic lesions12 and is a major stimulant for production of some of the proteoglycans.10 12 13 40 Not only does matrix constitute a large proportion of neointimal material,14 but, importantly, the substantial proteoglycan components are physiologically active compounds. They influence the phenotype of smooth muscle cells, which probably helps retain them in the synthetic form,40 41 bind and modulate the activity of the various growth factors,13 40 and bind lipids, increasing their cellular uptake.40 42 Indeed, lipid binding through membrane-related proteoglycans and receptor binding may be intimately related.42 The apoE-augmented proteoglycan binding of lipids is dependent on the apoE isoform; the available direct evidence indicates reduced binding by apoE2 compared with apoE3.43 The important apoE4 polymorphism has been studied surprisingly little; some indirect evidence, such as the more rapid disappearance of apoE4 than apoE3 from the circulation after intravenous injection,44 suggests that the apoE4 isoform might accentuate binding. How these processes are related remains to be unraveled, but it is hoped that our findings stimulate further thought on these complex mechanisms and contribute to the relatively small body of knowledge on the determinants of restenosis.


*    Acknowledgments
 
This study was supported by grants from the Royal Perth Hospital Medical Research Foundation, the Medical Research Fund of Western Australia, the Faculty of Medicine, the University of Western Australia, and Len Buckeridge. We are grateful to Valerie Hall for technical assistance and to Dr Konrad Jamrozik, Department of Public Health University of Western Australia, for recruiting the healthy subjects.

Received December 8, 1994; revision received March 8, 1995; accepted March 13, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343-1346.
  2. Cambien F, Poirier O, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Bard J-M, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641-644. [Medline] [Order article via Infotrieve]
  3. Bohn M, Berge KE, Bakken A, Erikssen J, Berg K. Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and myocardial infarction. Clin Genet. 1993;44:292-297.[Medline] [Order article via Infotrieve]
  4. Tiret L, Kee F, Poirier O, Nicaud V, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Amouyel P, Cambien F. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet. 1993;341:991-992. [Medline] [Order article via Infotrieve]
  5. Evans AE, Poirier O, Kee F, Lecerf L, McCrum E, Falconer T, Crane J, O'Rourke DF, Cambien F. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. Q J Med. 1994;87:211-214. [Abstract/Free Full Text]
  6. Tiret L, Bonnardeaux A, Poirier O, Ricard S, Marques-Vidal P, Evans A, Arveiler D, Luc G, Kee F, Ducimetière P, Soubrier F, Cambien F. Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet. 1994;344:910-913. [Medline] [Order article via Infotrieve]
  7. Schunkert H, Hense H-W, Holmer SR, Stender M, Perz S, Keil U, Lorell BH, Riegger GAJ. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med. 1994;330:1634-1638. [Abstract/Free Full Text]
  8. Raynolds MV, Bristow MR, Bush EW, Abraham WT, Lowes BD, Zisman LS, Taft CS, Perryman MB. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet. 1993;342:1073-1075. [Medline] [Order article via Infotrieve]
  9. Marian AJ, Yu Q-T, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993;342:1085-1086. [Medline] [Order article via Infotrieve]
  10. Forrester JS, Fishbein M, Helfant R, Fagin J. A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol. 1991;17:758-769. [Abstract]
  11. Ferrell M, Fuster V, Gold HK, Chesebro JH. A dilemma for the 1990s: choosing appropriate experimental animal model for the prevention of restenosis. Circulation. 1992;85:1630-1631. [Free Full Text]
  12. Nikol S, Isner JM, Pickering G, Kearney M, Leclerc G, Weir L. Expression of transforming growth factor-ß1 is increased in human vascular restenosis lesions. J Clin Invest. 1992;90:1582-1592.
  13. Berk BC, Corson MA. Autocrine and paracrine growth mechanisms in vascular smooth muscle. Curr Opin Cardiol. 1992;7:739-744.
  14. Strauss BH, Chisholm RJ, Keeley FW, Gotlieb AI, Logan RA, Armstrong PW. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res. 1994;75:650-658. [Abstract/Free Full Text]
  15. Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993;87:1816-1828. [Free Full Text]
  16. Sadoshima J-I, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res. 1993;73:413-423. [Abstract/Free Full Text]
  17. Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991;68:450-456. [Abstract/Free Full Text]
  18. Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. 1993;91:2268-2274.
  19. Rakugi H, Wang DS, Dzau VJ, Pratt RE. Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation. Circulation. 1994;90:449-455. [Abstract/Free Full Text]
  20. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J. 1993;290:33-40.
  21. Taylor RR, Gibbons FA, Cope GD, Cumpston GN, Mews GC, Luke P. Effects of low-dose aspirin on restenosis after coronary angioplasty. Am J Cardiol. 1991;68:874-878. [Medline] [Order article via Infotrieve]
  22. van Bockxmeer FM, Mamotte CDS, Gibbons FR, Taylor RR. Apolipoprotein M4 homozygosity: a determinant of restenosis after coronary angioplasty. Atherosclerosis. 1994;110:195-202. [Medline] [Order article via Infotrieve]
  23. Cumming AM, Robertson FW. Polymorphism at the apolipoprotein-E locus in relation to risk of coronary disease. Clin Genet. 1984;25:310-313. [Medline] [Order article via Infotrieve]
  24. Davignon J, Greg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8:1-21. [Abstract/Free Full Text]
  25. van Bockxmeer FM, Mamotte CDS. Apolipoprotein M4 homozygosity in young men with coronary heart disease. Lancet. 1992;340:879-880. [Medline] [Order article via Infotrieve]
  26. Katzel LI, Fleg JL, Paidi M, Ragoobarsignh N, Goldberg AP. ApoE4 polymorphism increases the risk for exercise-induced silent myocardial ischemia in older men. Arterioscler Thromb. 1993;13:1495-1500. [Abstract/Free Full Text]
  27. Luc G, Bard J-M, Arveiler D, Evans A, Cambou J-P, Bingham A, Amouyel P, Schaffer P, Ruidavets J-B, Cambien F, Fruchart J-C, Ducimetiere P. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction: the ECTIM Study. Arterioscler Thromb. 1994;14:1412-1419. [Abstract/Free Full Text]
  28. Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism in the human angiotensin 1-converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase l). Nucleic Acids Res. 1992;20:1433. [Free Full Text]
  29. Shanmugan V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993;3:120-121. [Medline] [Order article via Infotrieve]
  30. Fogarty DG, Maxwell AP, Doherty CC, Hughes AE, Nevin NC. ACE gene typing. Lancet. 1994;343:851. [Medline] [Order article via Infotrieve]
  31. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by E gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545-548. [Abstract]
  32. Foley DP, Melkert R, Serruys PW. Influence of coronary vessel size on renarrowing process and late angiographic outcome after successful balloon angioplasty. Circulation. 1994;90:1239-1251. [Abstract/Free Full Text]
  33. Ohishi M, Fujii K, Minamino T, Higaki J, Kamitani A, Rakugi H, Zhao, Y, Mikami H, Miki T, Ogihara T. A potent genetic risk factor for restenosis. Nat Genet. 1993;5:324-325. [Medline] [Order article via Infotrieve]
  34. Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994;6:29-32. [Medline] [Order article via Infotrieve]
  35. van Bockxmeer FM. ApoE and ACE genes: impact on human longevity. Nat Genet. 1994;6:4-5. [Medline] [Order article via Infotrieve]
  36. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (first of two parts). N Engl J Med. 1992;326:242-250. [Medline] [Order article via Infotrieve]
  37. The Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR Study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation. 1992;86:100-110. [Abstract/Free Full Text]
  38. Desmet W, Vrolix M, De Scheerder I, Van Lierde J, Willems JL, Piessens J. Angiotensin-converting enzyme inhibition with fosinopril sodium in the prevention of restenosis after coronary angioplasty. Circulation. 1994;89:385-392. [Abstract/Free Full Text]
  39. Violaris AG, Melkert R, Serruys PW. Influence of serum cholesterol and cholesterol subfractions on restenosis after successful coronary angioplasty: a quantitative angiographic analysis of 3336 lesions. Circulation. 1994;90:2267-2279. [Abstract/Free Full Text]
  40. Camejo G, Hurt-Cambejo E, Olsson U, Bondjers G. Proteoglycans and lipoproteins in atherosclerosis. Curr Opin Lipidol. 1993;4:385-391.
  41. Campbell J, Campbell G. The biological path to atherosclerosis. Today's Life Sci. 1994;6:12-16.
  42. Ji Z-S, Brecht WJ, Miranda RD, Hussain MM, Innerarity TL, Mahley RW. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem. 1993;268:10160-10167. [Abstract/Free Full Text]
  43. Mann A, Meyer N, Weber W, Rinninger F, Greten H, Beisiegel U. Coordinate effect of apolipoprotein E and lipoprotein lipase on binding of lipoproteins to cells. Circulation. 1993;88:(suppl I):I-321. Abstract.
  44. Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB Jr. Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest. 1986;78:815-821.



This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
E. Milne, F. M. van Bockxmeer, L. Robertson, J. M. Brisbane, L. J. Ashton, R. J. Scott, and B. K. Armstrong
Buccal DNA collection: comparison of buccal swabs with FTA cards.
Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 816 - 819.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Singh, B. J. Gersh, R. L. McClelland, K. K.L. Ho, J. T. Willerson, W. F. Penny, and D. R. Holmes Jr
Predictive factors for ischemic target vessel revascularization in the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial
J. Am. Coll. Cardiol., January 18, 2005; 45(2): 198 - 203.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
W. Koch, J. Mehilli, A. Pfeufer, A. Schomig, and A. Kastrati
Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting
J. Lipid Res., December 1, 2004; 45(12): 2221 - 2226.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. Hara, T. Matsushima, H. Satoh, N. Iso-o, H. Noto, M. Togo, S. Kimura, Y. Hashimoto, and K. Tsukamoto
Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans
Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 269 - 274.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
G. Kolovou, D. Daskalova, and D. P. Mikhailidis
Apolipoprotein E Polymorphism and Atherosclerosis
Angiology, January 1, 2003; 54(1): 59 - 71.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
D. E. Cutlip, M. S. Chauhan, D. S. Baim, K. K. L. Ho, J. J. Popma, J. P. Carrozza, D. J. Cohen, and R. E. Kuntz
Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials
J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2082 - 2089.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
F. Bonnici, B. Keavney, R. Collins, and J. Danesh
Angiotensin converting enzyme insertion or deletion polymorphism and coronary restenosis: meta-analysis of 16 studies
BMJ, September 7, 2002; 325(7363): 517 - 520.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
J. E. Eichner, S. T. Dunn, G. Perveen, D. M. Thompson, K. E. Stewart, and B. C. Stroehla
Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review
Am. J. Epidemiol., March 15, 2002; 155(6): 487 - 495.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
W. R. P. Agema, J. W. Jukema, S. N. Pimstone, and J. J. P. Kastelein
Genetic aspects of restenosis after percutaneous coronary interventions;towards more tailored therapy
Eur. Heart J., November 2, 2001; 22(22): 2058 - 2074.
[PDF]

Home page
 AM J ALZHEIMERS DIS OTHER DEMENHome page
T. Isbir, B. Agachan, H. Yilmaz, M. Aydin, I. Kara, D. Eker, and E. Eker
Interaction between apolipoprotein-E and angiotensin-converting enzyme genotype in Alzheimer's disease
American Journal of Alzheimer's Disease and Other Dementias, July 1, 2001; 16(4): 205 - 210.
[Abstract] [PDF]

Home page
 CirculationHome page
T. Kosokabe, K. Okumura, T. Sone, J. Kondo, H. Tsuboi, H. Mukawa, T. Tomida, T. Suzuki, H. Kamiya, H. Matsui, et al.
Relation of a Common Methylenetetrahydrofolate Reductase Mutation and Plasma Homocysteine With Intimal Hyperplasia After Coronary Stenting
Circulation, April 24, 2001; 103(16): 2048 - 2054.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
M. F. Newman, D. T. Laskowitz, W. D. White, J. L. Kirchner, H. P. Grocott, M. Stafford-Smith, M. H. Sketch, R. H. Jones, J. G. Reves, and A. M. Saunders
Apolipoprotein E Polymorphisms and Age at First Coronary Artery Bypass Graft
Anesth. Analg., April 1, 2001; 92(4): 824 - 829.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
R. Y. L. Zee, A. Fernandez-Ortiz, C. Macaya, E. Pintor, K. Lindpaintner, and A. Fernandez-Cruz
ACE D/I Polymorphism and Incidence of Post-PTCA Restenosis : A Prospective, Angiography-Based Evaluation
Hypertension, March 1, 2001; 37(3): 851 - 855.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
B. Zhu, D. G. Kuhel, D. P. Witte, and D. Y. Hui
Apolipoprotein E Inhibits Neointimal Hyperplasia after Arterial Injury in Mice
Am. J. Pathol., December 1, 2000; 157(6): 1839 - 1848.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
L. U. Gerdes, C. Gerdes, K. Kervinen, M. Savolainen, I. C. Klausen, P. S. Hansen, Y. A. Kesaniemi, and O. Fargeman
The Apolipoprotein {epsilon}4 Allele Determines Prognosis and the Effect on Prognosis of Simvastatin in Survivors of Myocardial Infarction : A Substudy of the Scandinavian Simvastatin Survival Study
Circulation, March 28, 2000; 101(12): 1366 - 1371.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
A. Okamura, M. Ohishi, H. Rakugi, T. Katsuya, Y. Yanagitani, S. Takiuchi, Y. Taniyama, K. Moriguchi, H. Ito, Y. Higashino, et al.
Pharmacogenetic Analysis of the Effect of Angiotensin-Converting Enzyme Inhibitor on Restenosis After Percutaneous Transluminal Coronary Angioplasty
Angiology, October 1, 1999; 50(10): 811 - 822.
[Abstract] [PDF]

Home page
 J. Appl. Physiol.Home page
R. R. Taylor, C. D. S. Mamotte, K. Fallon, and F. M. van Bockxmeer
Elite athletes and the gene for angiotensin-converting enzyme
J Appl Physiol, September 1, 1999; 87(3): 1035 - 1037.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
A. Kastrati, A. Schomig, S. Elezi, H. Schuhlen, M. Wilhelm, and J. Dirschinger
Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions
Circulation, June 23, 1998; 97(24): 2396 - 2401.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
F. Ribichini, G. Steffenino, A. Dellavalle, G. Matullo, E. Colajanni, T. Camilla, A. Vado, G. Benetton, E. Uslenghi, and A. Piazza
Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme : A Major Risk Factor and a Marker of Risk for Coronary Stent Restenosis
Circulation, January 20, 1998; 97(2): 147 - 154.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
L. Ferrucci, J. M. Guralnik, M. Pahor, T. Harris, M.-C. Corti, M.-C. MHS, B. T. Hyman, R. B. Wallace, and R. J. Havlik
Apolipoprotein E {epsilon}2 Allele and Risk of Stroke in the Older Population
Stroke, December 1, 1997; 28(12): 2410 - 2416.
[Abstract] [Full Text]

Home page
 CirculationHome page
F. M. van Bockxmeer, C. D.S. Mamotte, S. D. Vasikaran, and R. R. Taylor
Methylenetetrahydrofolate Reductase Gene and Coronary Artery Disease
Circulation, January 7, 1997; 95(1): 21 - 23.
[Abstract] [Full Text]