© 1997 American Heart Association, Inc.
Articles |
The II Genotype of the Angiotensin-Converting Enzyme Gene Delays the Onset of Acute Coronary Syndromes
From the First Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city 520-21, Shiga, Japan.
Correspondence to Naoharu Iwai, MD, 1st Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city 520-21, Shiga, Japan.
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Abstract |
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Abstract The DD genotype of the angiotensin-converting enzyme (ACE) gene has been reported to be a risk factor for myocardial infarction. However, this association has not been confirmed in some populations. We hypothesized that the discrepancies between these studies may be due to their definition of ischemic heart diseases. According to the genotype of the ACE gene, we analyzed the profiles of 320 patients who underwent coronary angiography for possible ischemic heart diseases. Of these, 23 patients had no significantly diseased vessels and no acetylcholine-induced vasospasm (normal acetylcholine responder [NAR]) (II, 7; ID, 14; DD, 2), 34 patients had no significantly diseased vessels and acetylcholine-induced vasospasm (paradoxical acetylcholine responder: [PAR]) (II, 15; ID, 18; DD, 1), 80 angina pectoris (AP) patients had significantly diseased vessels (II, 41; ID, 37; DD, 2), and 183 patients demonstrated myocardial infarction (MI) (II, 67; ID, 91; DD, 25). The frequency of the DD genotype was significantly lower in PAR and AP patients than in those with MI (P=.0344). Next we analyzed the length of time between the first anginal pain and the onset of myocardial infarction in the MI group. We obtained reliable information regarding this period in 149 of the 183 patients. This period was significantly shorter in the ID and DD groups than in the II group (P=.0022). Multiple regression analyses revealed that this period was significantly determined (P=.0003, R=.324) by the genotype of the ACE gene (II=1, ID+DD=2, P=.0003) and age (P=.034). The D allele of the ACE gene and lower age were associated with a shorter period. On the other hand, the genotype of the ACE gene had no significant effect on the number of significantly diseased (>50%) lesions. The frequency of the D allele in subjects with a rapid progression of MI was significantly higher than that in subjects with a prolonged history of stable AP (P<.0001). In summary, the II genotype of the ACE gene was associated with a longer period of time between the first anginal pain and the onset of myocardial infarction than the ID and DD genotypes of the ACE gene.
Key Words: myocardial infarction • genetics • angiotensin
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a multicenter study designed to identify the genetic determinant of myocardial infarction (ECTIM study), Cambien et al. found that the frequency of the D allele of the angiotensin-converting enzyme (ACE) gene was significantly higher in patients with myocardial infarction than in control subjects, especially in patients who were otherwise classified as low risk according to their body mass index and plasma apo B.1 This finding that the DD genotype of the ACE gene is associated with an increased risk for MI is supported by several studies in various ethnic backgrounds.2 3 4 5 However, a study in Norwegian MI patients6 and a prospective case-control study in American male physicians7 have failed to demonstrate this association.
We hypothesized that the discrepancies between these studies may be due to their definition of ischemic heart diseases. Thus, according to the genotype of the ACE gene, we analyzed the profiles of 320 patients who underwent coronary angiography in our department for possible ischemic heart diseases. We found that the length of time between the first anginal pain and the onset of MI was significantly shorter in subjects with the DD or ID genotype than in subjects with the II genotype. We propose that the I allele of the ACE gene may delay the onset of acute coronary syndrome.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Subjects
All of the subjects in this study were hospitalized and studied in our department for possible ischemic heart diseases between April 1992 and April 1995. We collected blood samples for DNA analysis from almost all of the patients who underwent routine cardiac catheterization from April 1992 to April 1995. We could collect DNA from 320 subjects who underwent coronary arteriogram for the first time for possible ischemic heart diseases during this period. Subjects with valvular diseases or inherited heart malformations who underwent coronary arteriogram for preoperative evaluation were excluded from the study. Subjects diagnosed as having hypertrophic cardiomyopathy or idiopathic cardiomyopathy were also excluded. All drugs were withdrawn from patients who were suspected of having variant angina from coronary artery spasm for at least 24 hours before coronary angiography. An acetylcholine provocation test was performed only when the patient had no myocardial infarction and no stenotic coronary arteries with luminal narrowing of more than 75%. When luminal narrowing during the acetylcholine test was 50% or more, the patients were classified as paradoxical acetylcholine responders (PARs). Of the 320 subjects, 23 (II, 7; ID, 14; DD, 2) had no significantly diseased vessels and no spasm in response to the acetylcholine provocation test, and were classified as normal acetylcholine responders (NARs). Thirty-four patients had no significantly diseased vessels and PAR (II, 15; ID, 18; DD, 1), 80 angina pectoris (AP) patients had significantly diseased vessels (II, 41; ID, 37; DD, 2), and 183 patients demonstrated myocardial infarction (MI) (II, 67; ID, 91; DD, 25).
Patient Profile
Body mass index and age were recorded at the time of
coronary angiography. Patients who had smoked at least 10
cigarettes per day for more than 10 years were considered smokers.
Subjects were considered to have hypertension if they met the criteria
of the World Health Organization or if they were already being treated.
Subjects were considered to be hyperlipidemic if they
had a cholesterol level of 220 mg/dL or more or if
they were already being treated. Subjects were considered to be
diabetic if they had a fasting blood glucose level of 140 mg/dL
or more or if they were already being treated.
The severity of coronary atherosclerosis was determined by the number of significantly stenosed (>50%) lesions. Angiograms were assessed by two cardiologists who were unaware that the patients were to be included in this study.
Onset of the First Anginal Pain
We carefully determined when each patient experienced his or her
first anginal pain. Chest pain associated with exertion and chest pain
relieved by nitrate and/or calcium antagonist were
considered anginal pain. For each patient, at least two medical staff
members (one doctor and one nurse) independently recorded the
patient's history. When these two records were
inconsistent, we contacted patients through our outpatient
clinic to confirm when they experienced anginal pain. When chest pain
was atypical or not present, the patient was excluded from the
analysis. We excluded patients without chest pain who were
first identified as possibly having ischemic heart diseases
with exercise stress testing. We also excluded patients in whom the
onset of MI was not precisely determined by ECG and creatine
phosphokinase elevation.
DNA Studies
DNA was isolated from peripheral leukocytes and the
ACE genotype was determined as previously
reported.8 The DD genotype of the ACE gene was
reconfirmed by a second PCR using Taq extender (Stratagene).
Statistical Analyses
All statistical analyses were performed using the
Statview 4.0 statistical analysis package. Differences in
frequencies were analyzed by the contingency table (chi-square)
method. Differences between numerical data among the groups were
analyzed by one-way ANOVA. To predict the length of time
between the first anginal pain and the onset of myocardial infarction,
multiple regression analyses were used. When Bartlett's test
for the homogeneity of variances suggested that within-group variance
was not homogeneous among the groups, a logarithmic
transformation was performed to allow the use of ANOVA and multiple
regression analyses. We also used multiple regression
analysis to evaluate associations between the severity of
coronary atherosclerosis and the
genotype of the ACE gene.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study population consisted of 320 subjects whose clinical profiles are summarized in Table 1
. The
subjects consisted of 23 NAR, 34 PAR, 80 AP, and 183 MI patients.
Patients with NAR and PAR were younger and had a lower frequency of
hyperlipidemia. The PAR and AP groups each showed a
lower frequency of the DD genotype than the MI group
(P=.0344).
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Next, we compared patient profiles in the MI group according to the ACE
genotype (Table 2). No
significant differences were observed among the II, ID, and DD groups
with respect to age, male/female ratio, frequency of smoking,
hypertension, diabetes mellitus, hyperlipidemia, or the
severity of coronary atherosclerosis.
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Stepwise and multiple regression analyses revealed that the number of significantly diseased lesions was significantly (r=.261, P=.0018) determined by age (P=.0045) and the presence of DM (P=.0312). The genotype of the ACE gene (II=1, ID=2, DD=3, II=1, ID+DD=2, II=ID=1, and DD=2), age, sex, cholesterol, body mass index, presence of hypertension, presence of a smoking habit, presence of DM, and the length of time between the first anginal pain and the onset of MI were included as independent variables. No significant effects of the genotype of the ACE gene on the severity of coronary atherosclerosis were observed in this population (the MI group).
We obtained reliable information on the length of time between the
first anginal pain and the onset of MI for 149 of the 183 MI patients.
The length of this period (month) (logarithmic transformation) was
significantly different among the II, ID, and DD groups (Table 2
,
P=.0022, Fig 1). Stepwise and
multiple regression analyses revealed that this period
(logarithmic transformation) was significantly determined
(P=.0003, R=.324) by age (P=.034) and
the genotype of the ACE gene (II=1, ID+DD=2,
P=.0003). The II genotype was associated with a
longer period of time between the first anginal pain and the onset of
MI. Greater age was also associated with longer duration of this
period.
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We obtained reliable information on the length of time between the
first anginal pain and coronary angiography in 72 of the 80 AP
patients. In the AP and MI groups, 67 patients had a history of stable
effort angina pectoris for more than 1 year; 39, 26, and 2 patients had
the II, ID, and DD genotypes, respectively. In the MI
group, 87 patients developed MI within 30 days (1 month) after
the first anginal pain; 22, 47, and 18 patients had the II, ID, and DD
genotypes, respectively. The genotype frequencies in
the stable AP group were significantly different (P<.0001)
from those in the MI group with acute progression (Table 3). The frequency of the D allele in
subjects with a rapid progression of MI was 0.477, which is
significantly higher (P<.0001) than that (.224) in subjects
with a prolonged history of stable AP.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we demonstrated that the length of time between the first anginal pain and the onset of MI was associated with both the genotype of the ACE gene and age. This period was significantly shorter in the DD and ID groups than in the II group. Accordingly, the frequency of the II genotype was high in subjects with a long history (more than 1 year) of stable effort AP. On the other hand, the genotype of the ACE gene had no significant effect on the severity of coronary atherosclerosis.
These results suggest that the lower frequency of the DD
genotype of the ACE gene in the PAR and AP groups may be due to
the fact that in PAR or AP subjects with the DD genotype MI may
rapidly develop. The frequency of the D allele in the MI group was
0.385, which is comparable to the frequency of the D allele in
Japanese control subjects in other studies.2 3 8 9 As
confirmed by an exercise stress test, the frequency of the D allele
in 194 subjects without ischemic heart diseases (normal control
group) in our previously studied population was 0.363 (II, 82; ID, 83;
DD, 29).9 Although the frequency of the D allele in
our MI group (0.385) is comparable to that in a normal control group
(0.363), this value in subjects with MI with rapid progression (Table 3) is 0.477, which is significantly higher than that in the normal
control group (P=.011). Therefore, it is likely that
patients with PAR or AP and the DD genotype may show rapid
progression of MI; thus the DD genotype may be depleted from
these two groups. Moreover, the frequency of the D allele in the MI
group may be underestimated. Since the length of time between the first
anginal pain and the onset of MI was significantly shorter in patients
with the DD or ID genotype, we should expect them to have poor
collateral development and consequently to have a larger infarcted area
than patients with the II genotype, as suggested by our
previous studies.10 11 Therefore, patients with the DD or
ID genotype might have higher probability to experience sudden
death, and a significant proportion might not be
represented in our study population.
Since the genotype of the ACE gene is associated with the length of time between the first anginal pain and the onset of MI, classification of ischemic heart diseases into PAR, AP, and MI may not be appropriate for assessing the significance of the genotype of the ACE gene. MI may be caused by plaque rupture or coronary spasm. While some of the MI subjects had a long history of stable AP, others had no preinfarct angina. Thus the MI group itself is very heterogeneous. The ratio of MI subjects with a long history of stable AP to MI subjects without any preinfarct angina may vary with the study population. This may explain the discrepancies among studies1 2 3 4 5 6 7 on the association of MI with the genotype of the ACE gene.
It is unclear at present why the D allele of the ACE gene is associated with a shorter length of time between the first anginal pain and the onset of MI. Plaque rupture and subsequent formation of a thrombus is a critical step in the progression of coronary atherosclerosis and acute coronary syndromes.12 13 Assessment of angiograms obtained before acute MI and those obtained during the infarction has indicated that the lesions that are most likely to precipitate an infarct-provoking thrombosis often did not appear highly stenotic by angiography.14 15 16 17 A short length of time between the first anginal pain and the onset of MI may indicate an increased thrombogenicity or vulnerable plaque. On the other hand, stable effort AP for a prolonged period of time may indicate the existence of a stable and highly stenotic lesion for a prolonged period of time without precipitating thrombosis. Since angiotensin II has been reported to upregulate plasminogen activator inhibitor-1,18 19 the D allele of the ACE gene, which is associated with higher ACE activity20 and presumably with higher tissue levels of angiotensin II, may be associated with impaired fibrinolytic activity. Indeed, a significant positive correlation between serum ACE activity and plasma plasminogen activator inhibitor-1 activity has been reported.21 However, this notion is highly speculative and further careful observation of the progression of coronary atherosclerosis according to the genotype of the ACE gene, especially with regard to the morphology of plaques, will be necessary.
In summary, the II genotype of the ACE gene was associated with a longer period of time between the first anginal pain and the onset of MI than the ID and DD genotypes of the ACE gene. The II genotype may delay the onset of acute coronary syndrome.
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Selected Abbreviations and Acronyms |
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Received August 8, 1996; accepted January 8, 1997.
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