From the Cardiac Catheterization Unit (F.R., G.S., A.D.), Division of
Cardiology (A.V., E.V.), and Laboratory for Clinical Biochemistry (T.C.),
Ospedale Santa Croce, Cuneo, Italy, and Dipartimento di Genetica (G.M., E.C.,
G.B., A.P.), Biologia e Biochimica e Centro CNR–CIOS, Universita'
di Torino, Italy.
Correspondence to Giuseppe Steffenino, MD, Laboratorio di Emodinamica, Ospedale Santa Croce, Via M Coppino, 26, 12100 Cuneo, Italy. E-mail emodinam{at}www.lrcser.it
Methods and Results—One hundred seventy-six consecutive patients
with successful, high-pressure, elective stenting of de novo lesions in
the native coronary vessels were considered. At follow-up
angiography, recurrence was observed in 35 patients (19.9%).
Baseline clinical and demographic variables, plasma glucose and
serum fibrinogen levels, lipid profile, descriptive and quantitative
angiographic data, and procedural variables were not significantly
different in patients with and without restenosis; mean plasma
ACE levels (±SEM) were 40.8±3.5 and 20.7±1.0 U/L, respectively
(P<.0001). Diameter stenosis percentage and
minimum luminal diameter at 6 months showed statistically significant
correlation with plasma ACE level (r=.352 and -.387,
respectively P<.001). Twenty-one of 62 patients
(33.9%) with D/D genotype, 13 of 80 (16.3%)
with I/D genotype, and 1 of 34 (2.9%) with
I/I genotype showed recurrence; the
restenosis rate for each genotype is consistent
with a codominant expression of the allele D.
Conclusions—In a selected cohort of patients, both the
D/D genotype of the ACE gene, and high plasma
activity of the enzyme are significantly associated with in-stent
restenosis. Continued study with clinically different subsets
of patients and various stent designs is warranted.
In this prospective angiographic study of restenosis after
elective CS, plasma ACE level and the I/D polymorphism
were assessed, along with factors currently implicated in
restenosis after balloon angioplasty.
Angioplasty and Stenting Technique
Definitions
Angiographic Assessment and QCA
Conventional clinical and laboratory risk factors determined for all
patients were age, sex, body mass index, family history of
coronary artery disease (occurrence of unambiguous acute
myocardial infarction, death from coronary artery disease,
coronary artery bypass surgery, or PTCA), current smoking
habits (>10 cigarettes/d), hypertension (diastolic blood
pressure >90 mm Hg or systolic blood pressure >160
mm Hg), and non–insulin-dependent diabetes mellitus.
Biochemical Measurements
Genotyping of the ACE Gene I/D
Polymorphism
Statistical Analysis
Acute and follow-up QCA parameters were correlated with
plasma ACE levels and tested. QCA parameters were
transformed to avoid possible skewedness in their distribution.
Log-transformation has been used for all variables, but %DS, which
is a percentage, was transformed in arcsin %DS, the angular
transformation that makes constant the sampling error of a percentage
regardless of its value. Kruskal-Wallis nonparametric
one-way ANOVA was used to evaluate differences within ACE
genotypes, and the Least-Significant Difference
multiple-comparison test (at a significance level of .05) was used to
detect statistically significant differences of continuous
parameters between genotypes (SPSS statistical
package, release 5.01 for Windows).
This survey was approved by the ethical review committee of the
relevant hospital division, and all patients gave informed consent to
their inclusion in the study.
Follow-up coronary angiography for the whole cohort was
performed at a mean of 6.17±2.3 months after the procedure (range,
2.74 to 10.24 months). Angiographic restenosis (R group) was
present in 35 patients (19.9%) and absent (NR group) in 141; the
mean time of follow-up was not statistically different for each
genotype: 6.2±1.8 for the D/D, 6.4±1.8 for the
I/D, and 6.3±1.1 months for the I/I group. QCA
analysis did not show differences in the D-Ref between R and NR
patients. Differences in MLD, %DS, late loss, and net gain are shown
in Table 2
Univariate Analysis
Multivariate Analysis
The association between restenosis after PTCA and the
D/D genotype of the ACE gene was first
observed by Ohishi et al.18 Three studies,
however, failed to confirm these findings19 20 21 ;
similar negative conclusions were reached by van Bockxmeer et
al,22 who found a strong interaction between
ACE and
To our knowledge, there was no other research aimed at evaluating the
association between the I/D genotype and the plasma
ACE level in patients treated with CS. To avoid the confounding effects
of other variables, we used very strict criteria for patient
selection: (1) only de novo lesions in native vessels and one type of
prosthesis with high-pressure deployment were considered, and
(2) subjects using ACE inhibitors throughout the follow-up
period were excluded for two reasons: first, the possible effect of the
drug on patients with high basal level of ACE, even though an
inhibitory effect on endothelial vascular
proliferation seems unlikely at conventional oral
doses,24 and second, our intention to estimate
the physiological basal levels of ACE for each
genotype and, therefore, the fraction of the ACE level variance
explained by the I/D polymorphism.
Allele and genotype frequencies in our cohort are identical
to those found in previous studies on European
populations,17 and mean plasma ACE levels for
each of the three genotypes are in agreement with that reported
in other studies.9 25
Baseline clinical and angiographic variables were not significantly
different in our R and NR groups. Unstable
angina,26 lipid levels,27
and elevated plasma fibrinogen28 have been
proposed as risk factors for restenosis after balloon PTCA;
their roles, however, in the recurrence of lesions after
elective, high-pressure CS are unclear. Diabetes was identified as one
predictor of recurrence after balloon
PTCA,29 and there is emerging evidence that it
may also predict restenosis after CS30 ;
many of the mechanisms promoting restenosis in diabetics are
related to higher glucose or insulin levels or both; glycemic control
may generally reverse the process and reduce the restenosis
rate in diabetic patients.31 In our study,
non–insulin-dependent diabetes mellitus seems not to be associated
with restenosis, but the exclusion of patients with
insulin-dependent diabetes mellitus did not allow us to draw similar
conclusions for insulin-dependent diabetes mellitus.
Although the role of other patient-related or lesion-related factors
cannot be excluded, our study shows that both the I/D
polymorphism of the ACE gene and high plasma ACE level
are correlated with late luminal narrowing after CS.
Restenosis after balloon PTCA is a complex and partially
understood phenomenon: early events after balloon injury include
elastic recoil, platelet deposition, and thrombus formation,
followed by subsequent smooth muscle cell proliferation and matrix
formation.3 Restenosis occurs less
frequently after CS than after balloon PTCA,1 2
and recent observations with intravascular ultrasound have partially
explained this difference. After metallic scaffolding of the vessel
wall, late recoil of Palmaz-Schatz stents rarely
occurs.7 Stents inhibit negative
arterial remodeling (a decrease in arterial or
external elastic membrane cross-sectional area), with
neointimal hyperplasia being the predominant responsible
for in-stent restenosis. A different mechanism of
restenosis is observed in nonstented lesions, in which 73% of
late lumen loss is due to arterial remodeling and 27% is
due to actual tissue growth.5 Two major
mechanisms leading to restenosis after CS or PTCA appear not to
be equally balanced, and in-stent proliferation seems to be the
predominant one in restenosis after stent implantation. ACE may
play a key role by inducing in-stent cell growth secondary to the
production of angiotensin II and inhibition of
bradykinin.24 32
If ACE activity is involved in the proliferative response causing
recurrence of lesions after CS, plasma ACE level itself may be
a more direct marker of this process than the ACE
genotype. In fact, although plasma and cellular ACE level
appear to be tightly controlled by a genetic polymorphism, the
ACE I/D polymorphism is a genetic marker
probably in strong linkage disequilibrium with a functional mutation
(ACE S/s) located within or near the ACE
gene.9 In previous studies, the S/s
functional polymorphism and the I/D polymorphism
accounted for 44% to 47% and 28%, respectively, of the
interindividual variance of plasma ACE level9 33 ;
the latter figure is identical to that calculated in our study. Mean
plasma ACE level in our D/D patients was more than twice as
high as that in the I/I patients and intermediate to that in
the I/D patients. High (as defined above) concentrations of
plasma ACE were found in 46.7% of D/D patients, 10% of
I/D patients, and none of I/I patients. Different
rates of restenosis were observed among the D/D,
I/D, and I/I genotypes (33.9%, 16.3%,
and 2.9%), this is consistent with recently published
data.23 When restenosis rates are
calculated only in patients with high plasma ACE levels, we found rates
of 62%, 75%, and 0%, respectively. This suggests that plasma ACE
level determination may be more predictive than ACE
I/D genotyping for risk of restenosis after CS and
possibly for other cardiovascular disorders as
well.16 17 34 35 Plasma ACE level and %DS at
follow-up are correlated, depending, as expected, on the ACE
genotypes (Fig 3A
A statistically significant, albeit not high, correlation between
restenosis and plasma ACE level is also expected (Table 4
As stated in a recent meta-analysis published in
Circulation,36 the identification of
the genetic effect of the D allele in
cardiovascular disorders remains an important
unresolved issue; our results are consistent with this
statement and point out that (1) restenosis is the effect of a
complex mechanism in which neointimal proliferation is a
predominant factor; (2) the ACE-related mechanism plays an important,
but not exclusive, role in in-stent restenosis, which could be
even more significant than in myocardial infarction; (3) subjects
without the D allele seem to be protected from
restenosis, but I/D subjects behave more as
D/D than it is expected on the basis of their heterozygous
genotype (codominance effect); (4) the I/D
polymorphism is probably a marker for a functional variant that
controls ACE level and, presumably, restenosis—its linkage
disequilibrium with the letter one is unknown; and (5) plasma ACE level
may be a more informative marker for this process.
Our results are not necessarily in conflict with those from the
MERCATOR37 and MARCATOR38
trials. These studies have shown that oral therapy with ACE
inhibitors does not reduce the incidence of
restenosis after PTCA. Vessel wall remodeling seems to be the
major factor of recurrence after balloon dilatation, and the
effects of these drugs on vascular wall remodeling are still poorly
known. The use of ACE inhibitors to antagonize tissue
proliferation might be beneficial in some patients who are predisposed
to proliferation after balloon PTCA. If a high plasma ACE level is
taken to mark this predisposition, benefit from these drugs is likely
to be observed in
We agree with the conclusions of a recent editorial by Singer et
al39 that further studies are needed to shed more
light on the significance of positive associations between ACE
D allele and disease and to search for alternative genetic
models of restenosis, such as the mostly proliferative model
described for CS.40 Although our findings await
confirmation in studies with larger sample sizes, clinically different
subsamples of patients, various types of coronary stents, and
perhaps different implantation techniques, we suggest that elective CS
in addition to PTCA can dramatically reduce restenosis rates to
<8% in patients with a low proliferative risk, as identified by a low
plasma ACE level or lack of the D allele. On the
contrary, it can be speculated that high-pressure CS after PTCA may
favor the recurrence of lesions in patients with high
proliferative risk: for these cases, plain balloon PTCA or other forms
of coronary revascularization may prove
more beneficial.
Preliminary data from this study were presented in part at the 68th Scientific Sessions of the American Heart Association, November 1995, Anaheim, Calif, and the 45th Scientific Sessions of the American College of Cardiology, March 1996, Orlando, Fla.
Received July 16, 1997;
revision received September 9, 1997;
accepted September 25, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme
A Major Risk Factor and a Marker of Risk for Coronary Stent Restenosis
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Tissue proliferation is
almost invariably observed in recurrent lesions within stents, and ACE,
a factor of smooth muscle cell proliferation, may play an important
role. Plasma ACE level is largely controlled by the insertion/deletion
(I/D) polymorphism of the enzyme gene. The
association among restenosis within coronary stents,
plasma ACE level, and the I/D polymorphism is
analyzed in the present prospective study.
Key Words: stents • genes • angiotensin • follow-up studies • coronary disease
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Recurrence of lesions
after CS occurs in 22% to 32% of patients.1 2
Compared with restenosis after balloon angioplasty, less is
known about the mechanisms of restenosis after
intracoronary stent placement; it is likely due to a
predominant proliferative model of
restenosis3 4 because stent diameter
remains constant after placement and arterial remodeling
cannot occur. In fact, analyses with ultrasounds have shown
that restenoses after CS and after balloon PTCA
differ5 in the amount of tissue proliferation,
which is almost invariably observed within
stents.6 7 ACE may play an important role in the
proliferation of vascular smooth muscle cells through activation of
angiotensin II (an inducer of cell proliferation) and
inhibition of bradykinin (an inhibitor of
growth).8 Plasma ACE activity is under genetic
control: a functional mutation located within, or close to, the
ACE locus, in almost complete linkage disequilibrium with
the ACE I/D polymorphism, has been suggested
to account for half of the ACE level variance.9
Therefore, both ACE level and I/D genotypes can be
predictive risk markers for in-stent restenosis.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Design
Between December 1993 and October 1996, 196 consecutive patients
were enrolled. Each of them had a de novo lesion in a native
coronary artery successfully treated with elective placement of
one or more Palmaz-Schatz stents and they had received no medication
with ACE inhibitors in the week before the procedure or
during the follow-up period because even minimal doses of these drugs
may interfere with basal plasma ACE level.10
Clinical and angiographic criteria for exclusion of patients were
primary and rescue PTCA, PTCA within 2 days of acute myocardial
infarction, insulin-dependent diabetes mellitus, a severe comorbid
status, ostial lesions of the right coronary or left main stem
artery, total coronary occlusions older than 2 weeks, lesions
longer than 30 mm, and angiographic follow-up beyond 12 months.
Twenty patients initially included in the study were excluded for the
following reasons: (1) 11 patients received treatment with ACE
inhibitors after the procedure, (2) 2 patients had
subacute stent thrombosis, and (3) 7 patients (5 for personal
reasons and 2 for medical reasons) did not undergo angiographic
control. Therefore, we analyzed a total of 176 subjects with
successful stent implantation, no treatment with ACE
inhibitors, and angiographic follow-up at 6 months (or
earlier when restenosis was suspected on clinical
grounds).
Treatment with 250 mg ticlopidine BID started 2 days before the
procedure and continued for 2 months. Balloon dilatation was performed
according to the conventional technique. Palmaz-Schatz stents were
hand-crimped onto undersized compliant balloons and deployed at nominal
pressures; all the prostheses were then expanded with a noncompliant
balloon of the same diameter as the reference vessel segment, with
inflations in the range of 14 to 20 atm for 60 to 90 sec.
"Multiple Palmaz-Schatz stenting" was used for long lesions
or dissections (>15 mm), with angiographic overlapping of the
stent edges. "Stenting" was "elective" in all cases: it did not
obviate an acute or impending vessel occlusion after balloon
dilatation. "Immediate angiographic success" was considered the
deployment of the stent or stents in the target lesion, with a
Thrombolysis in Myocardial Infarction grade 3
coronary flow11 and a residual
stenosis of <20%.
The American College of Cardiology/American
Heart Association classification as modified by Ellis et
al12 was used to evaluate the morphology of
coronary lesions. QCA was performed before balloon angioplasty,
after high-pressure CS, and at follow-up coronary angiography
using an online system (Philips DCI). Images of lesions were displayed
in at least two orthogonal projections with the 13-cm image
intensifier field after the administration of 0.5 mg
intracoronary nitroglycerin. Measurements were
made with the DCI Host Automated Coronary Analysis
package (release 1.1.2).13 The D-Ref, MLD, and
%DS were calculated as the mean of values obtained in two orthogonal
views. Follow-up angiography used the same projections as the
original procedure. "Acute gain" was defined as the increase in MLD
achieved immediately after high-pressure CS. "Late loss" was
defined as the decrease in MLD of the same segment observed on the
follow-up angiogram. The "net gain" was the difference between the
acute gain and the late loss. The definition of restenosis was
%DS of 
50% at the site of the lesion treated with the stent or
stents observed in at least one of two orthogonal projections, one
of which always including the "worst view" of the segment being
analyzed (ie, in-stent restenosis). QCA of follow-up
angiograms was performed by one of the cardiologists of our unit with
experience in QCA who had no knowledge of other clinical, biochemical,
and genetic data for the patient).
Blood samples collected in the morning of the procedure after
12-hour fasting were tested for levels of plasma glucose, total
cholesterol, HDL cholesterol, and
triglycerides with the use of
enzymatic-colorimetric methods. Fibrinogen levels were
measured with a fibrometer, and apolipoprotein B was measured with a
nephelometric method. Plasma ACE activity was measured through
quantitative kinetic determination at 340 nm with the use of FAPGG
substrate (Sigma Diagnostics). Fasting blood samples were
drawn from the femoral sheath immediately after the end of the CS
procedure. In 40 consecutive patients, five blood samples were
sequentially collected before PTCA, immediately after PTCA, and then
12, 24, and 48 hours later. The enzyme curves thus obtained were used
to investigate possible deviations from basal level, as consequences of
ACE release from injured vessel walls or ruptured plaques. ACE
determinations were performed at the time of angiographic follow-up in
84 patients.
Genomic DNA was extracted from 200 µL of whole blood with a
QUIAmp Blood Kit (QUIAGEN). The I/D polymorphism of the
ACE gene was determined according to the method of Rigat et
al,14 with slight modifications. The sequences of
the sense and antisense primers were 5'-CTG GAG ACC ACT CCC ATC CTT
TCT-3' and 5'-GAT GTG GCC ATC ACA TTC GTC AGA T-3', respectively. PCR
was performed in a final volume of 50 µL that contained 
500 ng
genomic DNA, 12.5 pmol of each primer, 500 µM dNTP, 1.5 mmol/L
MgCl2, 50 mmol/L KCl, 10 mmol/L
Tris-HCl (pH 8.3), 5% DMSO, and 1 U AmpliTaq DNA Polymerase
(Perkin-Elmer Cetus). Amplification was performed with a 9600 Perkin
Elmer Thermal Cycler. Samples were denatured for 1 minute at 94°C and
then cycled 30 times through the following steps: 45 seconds at 94°C,
1 minute at 62°C, and 1 minute at 72°C. PCR products were
electrophoresed in 1.6% agarose gel and visualized directly with
ethidium bromide staining. The insertion allele (I) was
detected as a 490-bp band, and the deletion allele (D)
was detected as a 190-bp band. DMSO was included in the PCR to prevent
underestimation of heterozygotes and overestimation of D/D
genotype15 ; moreover, each D/D
type was subjected to a second, independent PCR amplification with a
primer pair that recognizes an insertion-specific sequence (5'-TGG GAC
CAC AGC GCC CGC CAC TAC-3'; 5'-TCG CCA GCC CTC CCA TGC CCA TAA-3'),
with identical PCR conditions except for an annealing temperature of
67°C and the absence of 5% DMSO.16
Student's t test, and one-way ANOVA with
Bonferroni's correction for pairwise comparisons were used to test
differences between mean values of continuous variables. The
2 statistic with Yates' correction, or
Fisher's exact test when appropriate, was used to test associations of
noncontinuous variables. Potential associations among clinical,
angiographic, biochemical variables, I/D
genotypes, and restenosis were first tested by
univariate methods (Student's or
2 tests).
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Baseline Values
The cohort of the study included 151 men and 25 women aged 34 to
80 years old (mean age, 60±9.1 years). The I/D
polymorphism genotype proportions fit the Hardy-Weinberg
equilibrium law with allele frequencies p (D)=.58 and q
(I)=.42, which was very similar to those from surveys with
larger sample sizes.17 The genotype
distribution and the corresponding mean plasma ACE level are shown in
Table 1
. No significant difference was
found among plasma ACE level at 12, 24, and 48 hours after CS and in
basal determinations in 40 consecutive patients receiving single
stenting (21.5±9, 19.7±10, 20.3±11, and 19.9±9 U/L, respectively).
Fig 1 shows that in 84 patients at
6-month angiography, plasma ACE levels were highly and significantly
correlated with basal levels (r=.872, P<.001).
With the only exception of mean plasma ACE level, no significant basal
clinical, angiographic, or biochemical difference was found among
patients with D/D, I/D, and I/I
genotypes.
View this table:
[in a new window]
Table 1. Mean Plasma ACE Level Distributed by ACE
Genotypes and ANOVA
View larger version (24K):
[in a new window]
Figure 1. Correlation between basal and follow-up ACE plasma
levels (U/L) in 84 patients (r=.872,
P<.001) .
Cardiovascular medication used during the follow-up
period did not differ in the two groups.
View this table:
[in a new window]
Table 2. QCA at Follow-up
Patients with and without restenosis showed no significant
difference in age, sex, clinical, angiographic, and procedural
parameters; QCA data before angioplasty and after CS were
also similar in R and NR patients (Table 3). Mean plasma ACE level was 40.8±3.5
U/L in the R group versus 20.7±1.0 in the NR group
(P<.0001); their distribution is shown in Fig 2. Correlation between ACE plasma level
and %DS (after angular transformation) gives a value of
r=.352, which is statistically different from zero (Table 4). Similar values were obtained when ACE
level is correlated with MLD (r=-.387) and late loss at
angiographic follow-up (r=0.280). Fig 3A through 3C shows how basal plasma ACE
level correlates with 6-month %DS for each genotype. The
relationships among follow-up QCA results, plasma ACE level, and
I/D genotypes are shown in Table 4. Twenty-one of 62
patients (33.9%) with D/D genotype, 13 of 80
patients (16.3%) with I/D genotype, and 1 of 34
patients (2.9%) with I/I genotype showed
restenosis. The D/D genotype was
significantly more prevalent in the R group (21 of 35 [60%] versus
41 of 141 [29%], P=.026). An optimal cutoff value for
plasma ACE level was calculated by maximizing the specificity for
predicting restenosis: the resulting value of 34 U/L predicts
occurrence and no occurrence of restenosis in 65% and 92% of
the cases. Restenosis occurred in 11 of 139 patients (7.9%)
with "low" (<34 U/L) ACE level and 24 patients of 37 patients
(64.9%) with "high" (34 U/L) ACE levels (P<.00001),
with the angiographic follow-up mean time between the two groups not
statistically different (6.42±1.55 versus 6.10±1.37 months,
respectively; P=NS). In 62 patients with D/D
genotype, high and low plasma ACE levels were observed in 29
(46.8%) and 33 (53.2%) cases, respectively; restenosis
occurred in 18 (62%) of the former and in 3 (9.1%) of the latter
(P=.0001).
View this table:
[in a new window]
Table 3. Baseline Parameters of Patients at
Recruitment
View larger version (19K):
[in a new window]
Figure 2. ACE plasma levels (U/L) observed in patients with
or without restenosis represented by a box plot.
The box bounds the first and the third quartiles (interquartile range);
encompasses 50% of the data, and includes the median (line within the
box). Dispersion of the data above and below this range is marked by
"whiskers" that extend to the most extreme values within a
"fence" at 1.5 times the interquartile range. Mild outliers (*)
are found within three times the interquartile range, and extreme
outliers (open circles) are found outside of this boundary.
View this table:
[in a new window]
Table 4. Acute and Follow-up QCA Results According to Plasma
ACE Level and ACE Genotype
View larger version (12K):
[in a new window]
Figure 3. Correlation between basal ACE plasma level (U/L)
(in ordinate) and angular-transformed (arcsin p) percentage of
diameter stenosis (%DS) at follow-up (in abscissa) for the
three genotypes (A through C); 68.3% confidence interval
ellipsoids are displayed. Correlation coefficients: r
(DD)=.308 (P=.015), r
(ID)=.307 (P=.006), r
(II)=.214 (P=.224). Regression
coefficients of the lines: b (DD)=20.99, b
(ID)=14.70, and b (II)=7.97.
Stepwise logistic multiple regression analysis identified
plasma ACE level and I/D polymorphism as the only
significant predictors of restenosis. The relative risk of
angiographic restenosis was 8.2 in the group of patients with
high plasma ACE level (95% CI, 4.43 to 15.15). The relative risks for
restenosis among patients carrying the I/I,
I/D, and D/D genotype were 0.12, 0.71,
and 2.75, respectively (95% CI, 0.02 to 0.86, 0.38 to 1.32, and 1.51
to 5.03). The I/D polymorphism, however, when considered
together with the plasma ACE level, was no longer a significant
predictive risk factor because of the correlation between the two
variables.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Many variables have been associated with restenosis in
balloon angioplasty, and a number of these are suspected to contribute
to restenosis after stent implantation. The role of plasma
level of ACE and ACE genotypes in the susceptibility
to restenosis after elective coronary stent placement
have been analyzed in 176 consecutive patients: our follow-up
angiographic results showed a 19.9% global restenosis
rate. 
4 apoE genotypes with
restenosis, an observation that supports a multifactorial basis
for the etiology of restenosis. A report recently published in
Circulation shows that the D allele of the
ACE gene is associated with an increased restenosis
rate after CS.23 
through 3C). ). The
latter is the phenotypic expression of a major gene that is clearly
codominant because of an additive effect. Data in Table 1 show the
codominant effect of the D allele on the
phenotype (ACE level). Even if restenosis rates differ
among I/D genotypes, when D/D and
I/I are contrasted with I/D genotypes the
codominant expression of the D allele as risk factor for
restenosis is suggested, but it does not reach statistical
significance. 20% of European patients (ie, nearly one half of
the patients carrying the D/D genotype). Last, but
not least, drug dosages being used in these trials, albeit effective in
reducing blood pressure, may not be high enough to affect
neointima formation. In fact, animal studies
show24 that neointimal proliferation
may be affected by ACE inhibitors only if treatment is
started before balloon injury and at much higher doses than required
for the inhibition of circulating ACE.
Selected Abbreviations and Acronyms
CA
=
coronary stenting
CI
=
confidence interval
D/D
=
deletion/deletion
D-Ref
=
reference diameter
DMSO
=
dimethylsulfoxide
%DS
=
percent diameter stenosis
I/D
=
insertion/deletion
I/I
=
insertion/insertion
MLD
=
minimum luminal diameter
NR
=
no restenosis
PCR
=
polymerase chain reaction
PTCA
=
percutaneous transluminal coronary angioplasty
QCA
=
quantitative coronary analysis
R
=
restenosis
Acknowledgments
This work was supported in part by a grant from the Istituto
Superiore della Sanita', Roma, Italy, and grant MURST 60% given by
the University of Torino, Italy. We wish to thank Dr Ian Penn
(Vancouver General Hospital) for his valuable comments and Maria
Stefania Dutto, RN, and Marilena Tomatis, RN, for their help in data
collection.
Footnotes
Reprint requests to Flavio Ribichini, MD, Laboratorio di Emodinamica, Ospedale Santa Croce, Via M Coppino, 26, 12100 Cuneo, Italy.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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W. Koch, J. Mehilli, N. von Beckerath, C. Bottiger, A. Schomig, and A. Kastrati Angiotensin I-converting enzyme (ACE) inhibitors and restenosis after coronary artery stenting in patients with the DD genotype of the ACE gene J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1957 - 1961. [Abstract] [Full Text] [PDF]
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B. Schieffer and H. Drexler The race for ACE: A simple answer to the controversial puzzle of angiotensin-converting enzyme (ACE) polymorphisms J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1962 - 1963. [Full Text] [PDF]
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 G. Mello, E. Parretti, F. Gensini, E. Sticchi, F. Mecacci, G. Scarselli, M. Genuardi, R. Abbate, and C. Fatini Maternal-Fetal Flow, Negative Events, and Preeclampsia: Role of ACE I/D Polymorphism Hypertension, April 1, 2003; 41(4): 932 - 937. [Abstract] [Full Text] [PDF]
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 S. Nordfeldt and U. Samuelsson Serum ACE Predicts Severe Hypoglycemia in Children and Adolescents With Type 1 Diabetes Diabetes Care, February 1, 2003; 26(2): 274 - 278. [Abstract] [Full Text] [PDF]
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 A.H. Gomma, M.A. Elrayess, C.J. Knight, E. Hawe, K.M. Fox, and S.E. Humphries The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis Eur. Heart J., December 2, 2002; 23(24): 1955 - 1962. [Abstract] [PDF]
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K. Kohlstedt, F. Shoghi, W. Muller-Esterl, R. Busse, and I. Fleming CK2 Phosphorylates the Angiotensin-Converting Enzyme and Regulates Its Retention in the Endothelial Cell Plasma Membrane Circ. Res., October 18, 2002; 91(8): 749 - 756. [Abstract] [Full Text] [PDF]
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F. Ribichini, V. Ferrero, W. Wijns, G. Matullo, A. Piazza, E. Uslenghi, J. L. Zhuo, F. A.O. Mendelsohn, and M. Ohishi Can ACE Inhibitors Promote Detrimental Vascular Effects After Percutaneous Injury? * Response Hypertension, October 1, 2002; e6(4): . [Full Text] [PDF]
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 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]
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H. Montgomery, S. Humphries, and S. Danilov Is genotype or phenotype the better tool for investigating the role of ACE in human cardiovascular disease? Eur. Heart J., July 2, 2002; 23(14): 1083 - 1086. [Full Text] [PDF]
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