Strong and Significant Relationships Between Aggregation of Major Coronary
Risk Factors and the Acceleration of Carotid Atherosclerosis in the General
Population of a Japanese City
The Suita Study
Toshifumi Mannami, MD; Shunroku Baba, MD; Jun Ogata, MD
Background Carotid arterial intimal-medial thickness (IMT) measured by high-resolution
B-mode ultrasonography has come to be used as a noninvasive surrogate end
point to measure progression of atherosclerosis. However, there are no detailed
data on the relationship between aggregation of coronary risk factors and
carotid atherogenesis.
Methods Cross-sectional assessment of the relationship between carotid atherosclerosis
detected by high-resolution ultrasonography and integration of major coronary
risk factors by age and sex. Subjects aged 30 to 86 years were randomly selected
from Suita, located in Osaka, the second largest urban area of Japan, including
1896 men and 2102 women. Carotid atherosclerosis was evaluated by using our
atherosclerotic indexes of IMT, plaque number, plaque score, and percentage
of stenosis of the carotid artery assessed using ultrasonography by sex and
age group classified by number of major coronary risk factors (ie, hypertension
[diastolic blood pressure 90 mm Hg and/or systolic blood pressure 140
mm Hg or receiving medication], smoking [current smoker], and hypercholesterolemia
[serum total cholesterol level 5.68 mmol/L [220 mg/dL] or receiving medication]).
Results The mean carotid atherosclerotic index value, especially the mean IMT
value, of the subjects with 1 major coronary risk factor was on average 0.028
mm (3.2%) higher for men and 0.025 mm (2.9%) higher for women than that of
the subjects without major coronary risk factors; for subjects with 2 risk
factors, 0.054 mm (6.3%) higher for men and 0.053 mm (6.2%) higher for women;
and for high-risk subjects with 3 major risk factors, 0.135 mm (15.8%) higher
for men and 0.137 mm (15.4%) higher for women. The percentage of the subjects
with severe stenosis of at least 50% increased stepwise with increases in
the number of coronary risk factors and showed a significant difference (P<.05) between men and women, ie, 2.4% vs 0.6% (P = .01) among the subjects with no risk factors; 6.7%
vs 1.5% (P<.001), subjects with 1 risk factor;
10.7% vs 2.7% (P<.001), subjects with 2 risk factors;
and 18.6% vs 5.0% (P = .01), high-risk subjects.
Conclusions Aggregation of established major coronary risk factors strongly influenced
carotid atherogenesis in both sexes. There were significant differences between
sexes in the acceleration or progression of carotid atherosclerosis.
Arch Intern Med. 2000;160:2297-2303
WITH THE aid of high-resolution B-mode ultrasonography, we can evaluate
early carotid atherosclerosis precisely and noninvasively. There is growing
evidence that carotid arterial intimal-medial thickness (IMT) measured by
B-mode ultrasonography has come to be used as a noninvasive end point in epidemiological
studies and clinical trials to gauge progression and regression of atherosclerosis.1-8
Futhermore, its IMT has been used recently not only as a surrogate end point
for atherosclerosis of the coronary artery but also as a good indicator of
the presence and extent of coronary artery disease.9, 10
A close histological relationship between carotid and coronary atherosclerosis
has been seen in an autopsy study,11 and both
arterial beds share major coronary risk factors that contribute to the progression
of atherosclerosis.12, 13
The effect of major coronary risk factors such as high levels of serum
cholesterol and high-density lipoprotein (HDL) cholesterol, high blood pressure,
and cigarette smoking on the incidence of coronary disease in middle-aged
people has been well described and well known.14-16
In addition, it is well known that there is a strong relationship between
the incidence of coronary events and the aggregation of major coronary risk
factors, as shown in the Framingham Study.17
However, to our knowledge there have been no data exploring the relationship
between aggregation of major coronary risk factors and acceleration of carotid
atherosclerosis based on a general population study.
The Suita Study is a cohort study based on sample subjects randomly
selected from the residents of Suita, a city located in Osaka, the second
largest urban area in Japan. They represent an urban general population of
a Japanese city strongly influenced by Westernization. As a first step, a
strong relationship between major coronary risk factors and carotid atherosclerosis
has been reported by our laboratory.18 Our
present study is the second step toward the final goal of establishing a noninvasive
method for evaluation of coronary atherosclerosis based on the extent of carotid
atherosclerosis. The third step will be a longitudinal follow-up study of
these subjects, with the recording of morbid and fatal events such as stroke
or myocardial infarction for several years.
Our present aim was to investigate, through a cross-sectional analysis,
whether aggregation of major coronary risk factors (ie, hypertension, smoking,
and hypercholesterolemia) may affect carotid atherogenesis and to obtain the
fundamental data for the third step.
SUBJECTS AND METHODS
SUBJECT POPULATION
The population for our present study is based on a random sample selected
from the residents of Suita. The sample consisted of 12,200 men and women
aged 30 to 79 years, although 3000 men and woman were added randomly in the
same way in 1996 and 1997. The basic sampling of the population started in
1989 with a cohort study base.
The subjects have been visiting the National Cardiovascular Center every
2 years since then for regular health checkups. In addition to performing
a routine blood examination that included total serum cholesterol, HDL cholesterol,
triglyceride, and glucose levels and blood pressure and anthropometric measurements,
a physician or nurse administered questionnaires covering personal and family
history of cardiovascular and other diseases and smoking and drinking habits.
The carotid ultrasonic examinations were begun in April 1994 and performed
by a single physician (T.M.). The subjects in our present study included 1896
men and 2102 women, aged 30 to 86 years, who attended regular health checkups
from April 1, 1994, through October 31, 1998.
STUDY VARIABLES
The definitions of major coronary risk factors (ie, hypertension, smoking,
and hypercholesterolemia) were as follows. Subjects were classified as current
smokers if they smoked at least 1 cigarette per day, nonsmokers if they had
never smoked, and past smokers if they had quit smoking for more than 1 year.
Subjects were defined as hypertensive if diastolic blood pressure (DBP) was
at least 90 mm Hg and/or systolic blood pressure (SBP) was at least 140 mm
Hg or if they were taking antihypertensive medication. Those subjects whose
serum total cholesterol levels were at least 5.68 mmol/L (220 mg/dL) or
who were taking antihypercholesterolemic medication were defined as having
hypercholesterolemia. Those subjects whose fasting blood glucose levels were
at least 7.00 mmol/L (126 mg/dL) based on the new criteria or who were
taking antidiabetic medication were defined as diabetic. Subjects who had
a history of coronary heart disease or cerebrovascular disease were excluded
from this study (122 men and 60 women). Blood samples were obtained after
overnight fasting, resulting in 85 men and 104 women being excluded because
they did not meet this condition. Altogether, 207 men and 164 women among
the total of 3998 subjects were excluded from this analysis.
The details of the method of carotid ultrasonic examination have been
published elsewhere.18 The method used in our
present study was the same. We used a high-resolution B-mode ultrasonic machine
with 7.5-MHz transducers yielding an axial resolution of 0.2 mm. The regions
between 30 mm proximal from the beginning of the dilation of the bifurcation
bulb and 15 mm distal from the flow divider of both common carotid arteries
(CCAs) were scanned. All measurements were made at the time of scanning using
the instrument's electronic caliper and were recorded as photocopies. The
IMT was measured on a longitudinal scan of the CCAs at a point 10 mm proximal
from the beginning of the dilation of the bulb. We defined the IMT as the mean of the IMT of the near and far walls at the point of
measurement. We defined a plaque as an area where
IMT was at least 1.10 mm and calculated the plaque number (PN) by counting the number of plaques in the bilateral carotid arteries
in the scanning area. We also calculated the plaque score (PS) by totaling the maximum thickness of all the plaques in the same
area. Finally, we defined stenosis as a condition
in which a plaque occupied more than half of the luminal circumference of
an artery on a cross-sectional scan, and the degree of stenosis was calculated as a percentage ratio of the area of the plaque to
that of the lumen, using the following formula:
(Lumen Area -Residual Lumen)/Lumen Area 
100.
Both areas were measured automatically by the system on a frozen transverse
section at the maximal narrowing site. If there was at least 50% stenosis,
another skilled ultrasonographer performed color flow Doppler examination
to confirm the stenosis.
Blood samples drawn from the subjects after a fast of 12 hours or more
were collected in EDTA-containing tubes. Total cholesterol and triglyceride
levels were assayed enzymatically with a biochemical discrete analyzer (Toshiba
TBA-80M; Toshiba, Tokyo, Japan). Glucose level was assayed enzymatically,
and HDL cholestrol level was measured after precipitation with heparin and
calcium ions with a different biochemical discrete analyzer (Toshiba TBA-20R;
Toshiba). The measurements of total cholesterol, HDL cholesterol, and triglyceride
levels were standardized in accordance with the protocol of the Centers for
Disease Control and Prevention, Atlanta, Ga.
STATISTICAL METHODS
We used the Statistical Package for the Social Sciences (SPSS Inc, Chicago,
Ill) for the analysis. The mean levels of all numerical values were tested
using the t test, and those of all the categorical
values were tested by means of the 
2 test. Mean levels of
the 3 indexes of carotid atherosclerosis (IMT, PN, and PS) in each age group
by sex and the number of major coronary risk factors were obtained and tested
by means of 1-way analysis of variance. Values of P<.05
were considered significant.
RESULTS
Table 1 shows the characteristics
of the subjects by age group and sex. In all age groups, the percentage of
men with diabetes mellitus was significantly higher than that of women, and
the smoking rate for men was also much higher than that for women (P<.05). Also, the percentage of both sexes with hypertension, except
for the group aged 30 to 44 years, was high because of our definition of hypertension.
On the other hand, in all the other age groups, the mean total and HDL cholesterol
levels for women were significantly higher than those for men (P<.05).
Figure 1 shows the mean IMT
values of both sexes divided into 4 classes by the number of major coronary
risk factors, which were hypertension, smoking, and hypercholesterolemia,
in each age group. The IMT values of subjects of either sex with 3 risk factors
was significantly higher in all age groups (P<.05),
and the values of the highest-risk subjects were almost equal to those of
the lowest-risk subjects 20 years older. Furthermore, the IMT value increased
with the increase in number of coronary risk factors in each age group for
both sexes. There were no female subjects with 3 risk factors in the group
aged 30 to 44 years. As shown in Figure 2, the mean IMT value of the subjects with 1 risk factor was on average
0.028 mm (3.2%) higher for men and 0.025 mm (2.9%) higher for women than that
of the subjects with no risk factors. Similarly, that of the subjects with
2 risk factors was on average 0.054 mm (6.3%) higher for men and 0.053 mm
(6.2%) higher for women, and that of the high-risk subjects with 3 risk factors
was on average 0.135 mm (15.8%) higher for men and 0.137 mm (15.4%) higher
for women. The mean IMT value of the healthy subjects without risk factors
increased on average 0.0075 mm/y for men and 0.0069 mm/y for women. In other
words, these findings suggest that the aggregation of major coronary risk
factors accelerated the carotid atherosclerosis, and that the presence of
1 major coronary risk factor advances the carotid atherosclerosis about 3
to 4 years, the presence of 2 risk factors advances the disease about 7 to
8 years, and the presence of a higher number of major coronary risk factors
advances the disease about 17 to 20 years.
Figure 3 shows the mean PN
values of both sexes divided into 4 classes by the number of major coronary
risk factors in each age group. The results were roughly similar to those
shown in Figure 1.
Figure 4 shows the mean PS
values of both sexes divided into 4 classes by the number of major coronary
risk factors in each age group. These results were also roughly similar to
those shown in Figure 1, Figure 2 and Figure 3.
Figure 5 shows the percentage
of subjects with 2 grades of stenosis divided by the number of coronary risk
factors. The percentages of the 2 grades of stenosis increased as the number
of risk factors increased for both sexes.
COMMENT
To our knowledge, this is the first report showing that there are strong
relationships between the aggregation of major coronary risk factors and differences
of carotid atherosclerosis based on a large general population of both sexes.
As shown in Figure 1, Figure 2, Figure 3, Figure 4, and Figure 5, carotid atherosclerotic indexes became higher with increasing
numbers of coronary risk factors. Our results suggest that the carotid atherosclerosis
of a high-risk person who has all major coronary risk factors progresses roughly
20 years ahead of that of a person with no major coronary risk factors. There
are uncertainties when we compare the IMT of CCAs because there are several
differences (ie, the apparatus, the techniques, the method of measuring carotid
IMT, and the background of the population). However, if the findings in the
Atherosclerosis Risk in Communities cohort (a US study) that the IMT of CCAs
increases approximately 0.011 mm/y in men and 0.009 mm/y in women19 are applied to our present data, the IMT of a person
with a single major coronary risk factor will advance about 2 to 3 years,
that of a person with 2 risk factors will advance about 5 to 6 years, and
that of a high-risk person with 3 major coronary risk factors will advance
about 12 to 16 years. These results are similar to our present results, which
indicates that our data seem to be reasonable.
Futhermore, our present data showed that there was a strong and significant
sex difference in the genesis of carotid atherosclerosis, as we had expected,
and that the atherosclerotic process in men seemed to be about 10 years ahead
of that in women. There have been few data published so far on this subject
based on a general population study, and our data seem to provide fundamental
and valuable information on carotid atherosclerosis. Also, there have been
few data or analyses published so far on these aspects of carotid atherosclerosis,
although it has been reported that there were strong relationships between
each coronary risk factor, including aging, and carotid atherosclerosis.20-26
In fact, a similar analysis has been reported in a previous study.18 Some authors have reported recently that IMT of the
carotid artery is a reliable and powerful predictor of incident coronary events,27 although its index differs slightly among the studies.
An autopsy study also has shown that there was a histologically close relationship
between the carotid and coronary arteries.11
Furthermore, it is well known, as shown in the Framingham Study, that there
is a strong relationship between the integration of major coronary risk factors
and the incidence of coronary events.17 Taking
these findings into consideration, our data suggest that it is possible to
infer noninvasively and correctly the extent of coronary atherosclerosis on
the basis of evaluation of the extent of carotid atherosclerosis.
In fact, Salonen and Salonen24 reported
that a 1-time measurement of the maximal common arterial IMT of greater than
1.0 mm on the basis of a categorical system describing carotid artery structural
changes was a predictive index for acute myocardial infarction during a period
of 1 month to 3 years (relative risk, 2.2 [confidence interval, 0.7-6.7]).
Belcaro and colleagues28 also reported that
a 1-time IMT measurement of greater than 1.0 mm in asymptomatic patients was
predictive of a cardiovascular event during a 6-year period using a categorical
system describing the severity of atherosclerosis at the carotid and femoral
artery bifurcations. Certainly, our atherosclerotic indexes are a little different
from those of both studies because our indexes are not categorical, but our
definition of a plaque as an abnormal condition of IMT is similar because
early-phase atherosclerosis IMT values of less than 1.0 mm were considered
the referent category in these studies. Futhermore, a previous report has
found that there were strong and significant relationships between cardiovascular
risk factors and our carotid atherosclerotic indexes (ie, IMT, PN, and PS).18 In addition, carotid artery wall thickness measured
by ultrasonography has been documented as a good measure for evaluating regression
or progression of atherosclerosis in clinical trials.1-8
A study has recently shown that for each 0.03-mm increase per year in common
carotid arterial IMT, the relative risk for nonfatal myocardial infarction
or coronary death was 2.2, and the relative risk for nonfatal myocardial infarction,
coronary death, or a revascularization procedure was 3.1, although the participants
of this study were limited to those who had previously had coronary artery
bypass graft surgery.29 Our present results
suggest that aggregation of coronary risk factors may accelerate or progress
IMT, and that ultrasonographic monitoring and data of early-phase carotid
atherosclerosis may sufficiently incorporate independent information leading
to the prediction of coronary events. Furthermore, our present data suggest
that the addition of direct ultrasonographic information on carotid atherosclerosis
to the data of traditional risk factors derived from blood samples may make
it possible to indentify subjects at high risk for the development of symptoms
of cardiovascular disease. However, a longitudinal study is necessary as a
third step because previous studies from our laboratory and our present study
had a cross-sectional design to obtain basic data.
CONCLUSIONS
Our present data showed that there is a strong relationship between
the aggregation of major coronary risk factors (ie, hypertension, smoking,
and hypercholesterolemia) and acceleration or progression of carotid atherosclerosis
in both sexes. Also, our data seem to be helpful in progressing toward our
final goal, establishment of a noninvasive screening and prevention system
for cardiovascular diseases (ie, stroke or myocardial infarction) using carotid
atherosclerotic indexes.
Author/Article Information
From the Department of Preventive Cardiology, National Cardiovascular
Center, Suita, Japan.
Reprints: Toshifumi Mannami, MD, Department of Preventive Cardiology,
National Cardiovascular Center, Fujishirodai 5-7-1, Suita, Osaka, 565-8565
Japan (e-mail: mtoshi@hsp.ncvc.go.jp).
Accepted for publication March 2, 2000.
REFERENCES
1.
Blankenhorn DH, Hodis HN.
George Lyman Duff Memorial Lecture: arterial imaging and atherosclerosis
reversal.
Arterioscler Thromb.
1994;14:177-192.
MEDLINE
2.
Hodis HN, Mack WJ.
Risk factor assessment, treatment strategy and prevention of coronary
artery disease: the need for a more rational approach [editorial].
J Intern Med.
1994;236:111-113.
MEDLINE
3.
Mack WJ, Selzer RH, Hodis HN, et al.
One-year reduction and longitudinal analysis of carotid intima-media
thickness associated with colestipol/niacin therapy.
Stroke.
1993;24:1779-1783.
MEDLINE
4.
Furberg CD, Byington RP, Borhani NA, for the MIDAS Research Group.
Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS).
Am J Med.
1989;86:37-39.
MEDLINE
5.
Margiti SE, Bond MG, Crouse JR, Furberg CD, Probstfield JL.
Progression and regression of carotid atherosclerosis in clinical trials.
Arteriosclerosis.
1991;11:443-451.
6.
ACAPS Group.
Rationale and design for the Asymptomatic Carotid Artery Plaque Study.
Control Clin Trials.
1992;13:293-314.
MEDLINE
7.
Crouse JR, Byington RP, Bond MG, et al.
Pravastatin, lipids, and atherosclerosis in the carotid arteries: design
features of a clinical trial with carotid atherosclerosis outcome.
Control Clin Trials.
1992;13:495-506.
MEDLINE
8.
Crouse JR, Byington RP, Bond MG, et al.
Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II).
Am J Cardiol.
1995;75:455-459.
MEDLINE
9.
Geroulakos G, O'Gorman DJ, Kalodiki E, Sheridan DJ, Nicolaides AN.
The carotid intima-media thickness as a marker of the presence of severe
symptomatic coronary artery disease.
Eur Heart J.
1994;15:781-785.
MEDLINE
10.
Crouse JR, Craven TE, Hagaman AP, Bond MG.
Association of coronary disease with segment-specific intima-medial
thickening of the extracranial carotid artery.
Circulation.
1995;92:1141-1147.
MEDLINE
11.
Mitchell JR, Schwartz CJ.
Relationship between arterial disease at different sites.
BMJ.
1962;1:1293-1301.
12.
Persson J, Formgren J, Israelsson B, Berglund G.
Ultrasound-determined intima-media thickness and atherosclerosis: direct
and indirect validation.
Arterioscler Thromb.
1994;14:261-264.
MEDLINE
13.
Geroulakos G, O'Gorman D, Nicolaides A, Sheridan D, Elkeles R, Shaper AG.
Carotid intima-media thickness: correlation with the British Regional
Heart Study risk score.
J Intern Med.
1994;235:431-433.
MEDLINE
14.
Stamler J, Wentworth DN, Neaton JD.
Is the relationship between serum cholesterol and risk of death from
coronary heart disease continuous and graded? findings on the 356,222 primary
screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
JAMA.
1986;256:2823-2828.
MEDLINE
15.
Anderson KM, Wilson PWF, Odell PM, Kannel WB.
An updated coronary risk profile: a statement for health professionals.
Circulation.
1991;83:357-362.
16.
Stamler J, Neaton JD, Wentworth DN.
Blood pressure (systolic and diastolic) and risk of fatal coronary
heart disease.
Hypertension.
1989;13:I2-I12.
MEDLINE
17.
Kannel WB.
CHD risk factors: a Framingham Study update.
Hosp Pract (Off Ed).
1990;25:119-127.
MEDLINE
18.
Mannami T, Konishi M, Baba S, Nishi N, Terao A.
Prevalence of asymptomatic carotid atherosclerotic lesions detected
by high-resolution ultrasonography and its relation to cardiovascular risk
factors in the general population of a Japanese city: the Suita Study.
Stroke.
1997;28:518-525.
MEDLINE
19.
Howard G, Sharrett AR, Heiss G, et al, for the ARIC Investigators.
Carotid artery intimal-medial thickness distribution in general populations
as evaluated by B-mode ultrasound.
Stroke.
1993;24:1297-1304.
MEDLINE
20.
Craven TE, Ryu JE, Espeland MA, et al.
Evaluation of the association between carotid artery atherosclerosis
and coronary artery stenosis.
Circulation.
1990;82:1230-1242.
MEDLINE
21.
Bouithon-Kopp C, Scarabin PY, Taquet A, Touboul PJ, Malmejac A, Guize L.
Risk factors for early carotid atherosclerosis in middle-aged French
women.
Arterioscler Thromb.
1991;11:966-972.
MEDLINE
22.
Fabris F, Zanocchi M, Bo M, et al.
Carotid plaque, aging, and risk factors: a study of 457 subjects.
Stroke.
1994;25:1133-1140.
MEDLINE
23.
Solberg LA, Strong JP.
Risk factors and atherosclerotic lesions: a review of autopsy studies.
Arteriosclerosis.
1983;3:187-198.
MEDLINE
24.
Salonen JT, Salonen R.
Ultrasonographically assessed carotid morphology and the risk of the
coronary heart disease.
Arterioscler Thromb.
1991;11:1245-1249.
MEDLINE
25.
Crouse JR, Toole JF, McKinney WM, et al.
Risk factors for extracranial carotid artery atherosclerosis.
Stroke.
1987;18:990-996.
MEDLINE
26.
Salonen JT, Seppanen K, Ranramaa R, Salonen R.
Risk factors for carotid atherosclerosis: the Kuopio Ischemic Heart
Risk Factor Study.
Ann Med.
1989;21:227-229.
MEDLINE
27.
Chambless LE, Heiss G, Folsom AR, et al.
Association of coronary heart disease incidence with carotid arterial
wall thickness and major risk factors: the Atherosclerosis Risk in Communities
(ARIC) Study, 1987-1993.
Am J Epidemiol.
1997;146:483-494.
MEDLINE
28.
Belcaro G, Nicolaides AN, Laurora G, et al.
Ultrasound morphology classification of the arterial wall and cardiovascular
events in a 6-year follow-up study.
Arterioscler Thromb Vasc Biol.
1996;16:851-856.
MEDLINE
29.
Hodis HN, Mack WJ, LaBree L, et al.
The role of carotid arterial intima-media thickness in predicting clinical
coronary events.
Ann Intern Med.
1998;128:262-269.
MEDLINE
