Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:256-261
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:256-261.)
© 1996 American Heart Association, Inc.
In Hypercholesterolemia, Lower Peripheral Monocyte Count Is Unique Among the Major Predictors of Atherosclerosis
Zei-Shung Huang;
Chiu-Hwa Wang;
Ping-Keung Yip;
Chi-Yu Yang;
Ti-Kai Lee
From the Departments of Internal Medicine (Z.-S.H., C.-Y.Y., T.-K.L.),
Clinical Pathology (C.-H.W.), and Neurology (P.-K.Y.), College of Medicine,
National Taiwan University, Taipei, Taiwan, ROC.
 |
Abstract
|
|---|
Abstract Many studies have shown that enhanced monocyte
adherence
is an important factor in the initiation of
atherosclerosis.
Because the relationships between
circulating monocyte count
and atherosclerosis or its
major predictors have received little
attention, we conducted this
study with the aim of clarifying
these relationships. The study
included 409 men and women who
underwent a carotid artery duplex study
and white blood cell
analysis (Sysmex Cell Counter) during a
2-day health check at
our hospital in 1994. We found no correlation
between preexisting
carotid atherosclerosis and
monocyte count. After adjustment
for age and sex,
hypercholesterolemia, among the major
predictors
of atherosclerosis, showed a unique
correlation with both lower
monocyte count and percentage
(
P<.001,
P<.0001, respectively),
whereas
smoking was correlated with a higher monocyte count
(
P<.001).
There was a slight but nonsignificant increase in
monocyte count
in hypertension, diabetes, and
hypertriglyceridemia. Our results
imply
that: (1) hypercholesterolemia has a strong,
peripheral
monocyte–reducing effect, probably due to
direct enhancement
of monocyte adhesion to the
endothelium, which subsequently
initiates the
atherosclerotic process, and (2) the mechanisms
of other
predictor(s)-induced atherosclerosis may be quite
different
from that of hypercholesterolemia.
Another possible explanation
for the inverse correlation between
monocyte count and serum
cholesterol level is that
decreased monocyte levels might lead
to
hypercholesterolemia because of decreased
uptake of cholesterol
from the plasma by less
monocyte-derived macrophages. The reasons
why preexisting
carotid atherosclerosis did not correlate with
monocyte
count are also discussed.
Key Words: monocytes • hypercholesterolemia • atherosclerosis • predictors • risk factors
|
Introduction
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Monocytes and
monocyte-derived macrophages play major roles
in
atherosclerosis.
1 2 3 Many studies have
shown that an increase
in monocyte adhesion to the
endothelium is an important factor
in the initiation of
atherosclerosis.
1 2 3 4 5
Some studies
have also
noted that enhanced monocyte adherence is associated
with the major
predictors for atherosclerosis, such as
hypertension,
6 diabetes mellitus,
7
hyperlipidemia,
2 4 8 9 10 11
and
smoking.
4 12 The influence of the number of
circulating
monocytes on
atherosclerosis and the relationships
between monocyte count
and the aforementioned
atherosclerosis predictors have received
less attention
and are poorly understood.
13 14 We conducted
this
study
with the aim of clarifying these relationships.
|
Methods
|
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Subjects
The study subjects were 409 men and women who
underwent a 2-day
health
check program at our hospital in 1994. They were selected and
included
in the study because they had undergone both a carotid artery
duplex
study and peripheral WBC analysis (Sysmex
Cell Counter NE-8000,
TOA Medical Electronics Co, Ltd). There was no
other condition
for case enrollment. The carotid artery duplex study
was undertaken
voluntarily after the procedure and its clinical
significance
had been explained by the ward staff. Consent was obtained
from
the study subjects, and the study protocol conformed to ethics
committee
guidelines regarding studies of human subjects.
Clinical and Laboratory Data
The following data were
collected retrospectively from the
health check records: (1) age, sex, and history of hypertension,
diabetes mellitus, hyperlipidemia, and smoking habits;
(2) blood pressure of the right arm, measured (in mm Hg) while the
subject was seated; (3) biochemical data, including FBG, 2-h BG, serum
TC, and TGs; (4) results of peripheral WBC
analysis; and (5) results of the carotid artery duplex study,
which were grouped as those with or without evidence of atherosclerotic
plaque. A Diasonics DRF 400 or an Aloka SSD 3000 duplex ultrasound
system was used for carotid artery evaluation. The examination included
longitudinal and transverse views of the common carotid artery, carotid
bulb bifurcation area, and bilateral internal and external carotid
arteries. Detection and measurement of atherosclerotic plaque were
performed by a modified method of Sutton-Tyrrell et
al.15 16 A plaque was defined as a focal or segmental
intimal lesion >1.1 mm thick.
Diagnosis of Diseases
Hypertension was diagnosed if at least
one of the following
conditions was found: (1) positive history of and treatment for
hypertension; (2) both SBP and DBP higher than upper-normal limits
(
160 and 95 mm Hg, respectively); (3) SBP 180 mm Hg with a normal
DBP; or (4) DBP 105 mm Hg with a normal SBP. A diagnosis of
normotension was made when SBP and DBP were both within normal limits
and there was no history of hypertension. A "suspicious"
diagnosis was made when criteria for either hypertension or
normotension did not fit.
Diabetes was diagnosed if at least one of the
following conditions was
found: (1) positive history of and treatment for diabetes, (2) FBG
>7.77 mmol/L, or (3) 2-h BG >11.1 mmol/L. The diagnosis of
nondiabetes was made when FBG and 2-h BG were both within normal limits
(
6.66 and 7.77 mmol/L, respectively) and there was no history of
diabetes. A "suspicious" diagnosis was made when criteria for
either diabetes or nondiabetes did not fit.
Hypercholesterolemia was
diagnosed if at least
one of the following conditions was found: (1) positive history of and
treatment for hypercholesterolemia or (2) serum
TC 6.47 mmol/L. The diagnosis of
nonhypercholesterolemia was made when serum TC
was <5.69 mmol/L and there was no history of
hyperlipidemia. A "suspicious" diagnosis was made
for those participants whose serum TC level ranged from 5.68 to 6.47
mmol/L.
Hypertriglyceridemia was diagnosed if at
least one of the following conditions was found: (1) positive history
of and treatment for hypertriglyceridemia
or (2) serum TGs 1.81 mmol/L. The diagnosis of
nonhypertriglyceridemia was made when
the serum TG level was <1.47 mmol/L and there was no history of
hyperlipidemia. A "suspicious" diagnosis was made
for those participants whose serum TG level ranged from 1.46 to 1.81
mmol/L.
Definition of Smoker
Those who had smoked 10 cigarettes
per day for >5 years were
defined as smokers. Nonsmokers were defined as those who had never
smoked. Those participants who did not fit either set of criteria for
smoking or nonsmoking were classified as "suspected
smokers."
Statistical Methods
Correlations between peripheral monocyte
counts and
the clinical and laboratory variables mentioned above were
analyzed by the SAS statistical program.
|
Results
|
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Correlations between preexisting CA and major atherosclerotic
predictors
are presented in Table 1
. The overall
rate of CA was 18.6%,
much lower than that in our acute stroke
patients (61.9%). Hypercholesterolemia
and
hypertension were the two predictors related to CA in our
subjects
(
P<.0001 and
P<.01, respectively). Older age
was
also significantly correlated with preexisting CA
(
P<.0001).
Table 2 compares relative (percent) and absolute (count)
monocyte content by age, sex, and the presence of major
atherosclerosis predictors.
Hypercholesterolemia was unique among the major
predictors studied in its correlation with lower monocyte
percentage (P<.0001) and lower monocyte count
(P<.001). Smoking and
hypertriglyceridemia were associated with a
higher monocyte count (P<.001 and P<.05,
respectively). There was a slight but nonsignificant increase in
monocyte count for hypertension and diabetes. Both age and sex
significantly affected monocyte count: those who were older and female
had fewer monocytes. The Figure shows the relationship
between monocyte count and serum TC by sex and age separately. An
inverse trend of correlation between monocyte count and serum TC was
observed for both sexes and age groups but was statistically
nonsignificant in men and younger subjects.
View larger version (34K):
[in this window]
[in a new window]
|
Figure 1. Linear correlations between monocyte count
(x axis) and serum TC (y axis) in
men (A), women (B), older subjects (55 years; C), and younger
subjects (D). The correlation coefficient for all subjects was
-.17497 (n=409, P<.001).
|
|
Results of multivariate analysis of monocyte
percentage and count by age, sex, SBP, FBG, serum TC, serum TG, and
smoking habit are shown in Table 3. This age- and
sex-adjusted analysis revealed that: (1) among the
variables analyzed, serum TC was the main determinant for
monocyte percentage (P<.0001); (2) serum TC and smoking
habit were significantly correlated with monocyte count, and as in
Table 2
, serum TC was inversely correlated whereas smoking was
positively correlated with monocyte count; and (3) there was no
significant correlation between monocyte count and SBP, FBG, or serum
TG.
View this table:
[in this window]
[in a new window]
|
Table 3. Multivariate Analysis of
Monocyte Percentage and Count by Age, Sex, SBP, FBG, Serum TC, Serum
TGs, and Smoking Habit
|
|
We also compared monocyte percentage and count by the presence of CA
and its related predictors (eg,
hypercholesterolemia and hypertension; see
Table 1). The results showed that monocyte percentage and count
were
not significantly different between those with and without CA for all
subjects as well as for those with
hypercholesterolemia or hypertension.
Differential WBC counts were compared by the presence of CA and the
major atherosclerosis predictors (Table 4). Additional findings
included the following: (1)
there was no difference in differential WBC counts between persons with
and those without CA; (2) hypercholesterolemic
subjects had a higher lymphocyte count (P<.05) and an
insignificant increase in total WBCs and neutrophils; (3) smokers had a
higher total WBC count (P<.001) and higher differential
counts except basophils; (4) subjects with hypertension, diabetes, or
hypertriglyceridemia all had higher total
WBC counts (P<.05, P<.001, and
P<.0001, respectively), mainly due to increases in
neutrophils and lymphocytes; and (5) lymphocytes were the only WBC type
that increased significantly with all major predictors of
atherosclerosis.
|
Discussion
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Our study found no correlation between peripheral
monocyte count
and preexisting CA. After adjustment for age and sex,
hypercholesterolemia,
among the major
predictors of atherosclerosis, showed a unique
correlation
with a lower monocyte count and percentage, whereas smoking
was
associated with a higher monocyte count. There was a slight
but
nonsignificant increase in monocytes in subjects with hypertension,
diabetes,
and hypertriglyceridemia.
Why is it that preexisting CA was not correlated with
peripheral monocyte count4 if monocytes are so
important in atherogenesis?1 2 3 A simple
explanation may be
that monocyte adherence or activity, rather than count, is of major
importance.1 2 3 4 5
However, from our results, several other
reasons may also be considered. The first possibility is that the
causes or predictors of atherosclerosis are
multiple17 and may have different or even opposing
influences on the peripheral monocyte count. Our results
showed that hypercholesterolemic subjects had low
monocyte counts, whereas smokers had high monocyte counts. In
hypercholesterolemic nonsmokers with CA, the
monocyte count
(0.256±0.017x103/mm3, n=14;
data not shown) was (1) obviously lower than that of
hypercholesterolemic nonsmokers without CA
(0.301±0.021x103/mm3, n=27),
but not statistically different because of the small number of cases
and high SEs and (2) significantly lower than that of
hypercholesterolemic smokers with CA
(0.395±0.050x103/mm3, n=5,
P<.005). Second, these data also indicated that the small
number of hypercholesterolemic subjects with CA (21
of 68 cases with hypercholesterolemia) may be
another reason for the lack of correlation between monocyte count and
CA, because hypercholesterolemia was found to
be the main determinant for monocyte count in this study. The third
possible reason is that atherosclerosis is a very
chronic and late consequence of its predictor(s) but that alterations
in circulating monocyte character or count may be induced more quickly
by these predictors.18 19 Therefore, as the monocyte
count
may fluctuate following changes in the status of disease predictor(s),
it would then be difficult to correlate with an already formed
atherosclerotic plaque. The fourth possibility is that monocytes are
important in the formation of early atherosclerotic lesions, as cited
in several animal
studies,1 2 8 10 but not so
in the more
advanced plaques that can be easily detected by carotid
ultrasonography. In other words, monocyte count may be more reflective
of early atherogenesis than of clinically advanced atherosclerotic
disease.
Hypercholesterolemia has a strong, circulating
monocyte–reducing effect that is probably directly related to its
proatherogenicity in humans. Several animal studies have investigated
the role of circulating monocyte counts in
hypercholesterolemia.18 19 20 21
One of
those studies found marked monocytosis 20 weeks after initiation of a
high-cholesterol diet in swine,18 whereas
in their rabbit study, Inoue et al19 noted an abrupt
reduction in circulating monocyte count after 
12 weeks of a
high-cholesterol diet, which was accompanied by an
obvious progression of atherosclerosis.
Significant changes in monocyte count were not found in two
other rabbit studies 45 days or 30 weeks after initiation of a
high-cholesterol diet.20 21 To our
knowledge, clinical information on monocyte count in human
hypercholesterolemia is unavailable. In view of
the abundant convincing evidence for the enhanced monocyte
adherence in
hypercholesterolemia,1 2 4 8 9 10 11 22 23
the findings of several studies that monocyte adhesion to the
endothelium is a key factor in the initiation of early
atherosclerotic lesions,2 8 23 the
results of Inoue et
al,19 and our present study, we speculate that the
primary mechanism of
hypercholesterolemia-induced
atherosclerosis may be a direct potentiation of
monocyte adherence to the endothelium and subsequent
migration into the intima. On the other hand, our data could also imply
that a decreased monocyte level leads to
hypercholesterolemia, a notion indirectly
supported by reports that serum cholesterol level decreases
after injection of macrophage colony-stimulating
factor.24 25 It is possible that a lower monocyte
level
leads to a lower level of tissue macrophages, which then
results in less uptake of cholesterol from plasma.
The mechanism of smoking-induced atherosclerosis
may be quite different from that of
hypercholesterolemia, as suggested by the
higher monocyte counts in smokers in our and other
studies.26 27 Numerous mechanisms have been
hypothesized
for smoking-induced atherosclerosis, including
endothelial injury,28 29 30 enhanced
platelet reactivity and
platelet-endothelium
interactions,28 31 increased fibrinogen
levels,28 32 enhanced monocyte
adherence,4 12
modifications of lipid metabolism,29 32 and
enhanced neutrophil activity.33 Although the main
mechanism has not yet been defined, endothelial injury
from several diverse routes appears to be important. Direct
potentiation of monocyte adherence caused by smoking remains
controversial4 12 26 but is unlikely to
be a major cause.
A higher monocyte count in smokers does not necessarily indicate that
smoking does not increase monocyte adhesion to the
endothelium, as smoking may also stimulate the
production of monocytes and other WBCs at the same
time.13 26 27
In this study age and sex also affected monocyte percentage or count,
but the mechanisms for this effect and their significance are unknown.
After adjustment for age and sex, SBP, FBG, and serum TGs were not
significantly correlated with monocyte count (Table 3). It
seems likely
that hypertension, diabetes, and
hypertriglyceridemia have no direct
influence on circulating monocytes. Although the pathogenesis of
hypertension-induced atherosclerosis has been
extensively studied, so far there is little evidence that hypertension
directly potentiates monocyte
adherence.6 34 35 It is
generally thought that hypertension triggers
atherosclerosis mainly via mechanical insults to
the arterial wall that injure the
endothelium, stimulate smooth muscle cell growth, and
induce other structural and functional
alterations.34 35 36
Increased monocyte adhesion to the endothelium in
hypertensives is probably secondary to endothelial
changes.37 The mechanisms of diabetes-induced
atherosclerosis are multifactorial38 and
include nonenzymatic protein glycosylation of the
endothelium by hyperglycemia,38 39
increased platelet reactivity,40 changes in lipid
metabolism,41
hyperinsulinemia,38 and
immune-inflammatory disorders.38 There is no
definitive evidence that diabetes directly enhances monocyte
adherence.7 38 In fact, some studies have noted that
monocyte adherence, or chemotaxis, is reduced in
diabetes.42 43 Therefore, increased monocyte adhesion
to
the endothelium in diabetes is probably secondary to,
for example, advanced protein glycosylation of the
endothelium.44 Frequently seen in diabetes
or dyslipidemia,
hypertriglyceridemia is an equivocal
independent predictor of
atherosclerosis.45 Reports on enhanced
monocyte adherence in hypertriglyceridemia
are rare.46 Our finding that
hypertriglyceridemia was correlated with a
higher monocyte count on univariate analysis but
not on multivariate analysis suggests an
indirect or unremarkable influence of
hypertriglyceridemia on monocytes.
Circulating lymphocytes may also play an important role in the early
stages of atherosclerosis. In our study, lymphocytes
were the only WBC type that increased significantly with all major
predictors of atherosclerosis. Many studies have found
lymphocytes, mostly T lymphocytes, in the arterial intima
and accompanied by monocytes and macrophages in the early
atherosclerotic
plaque.2 37 47 48 49
Our results provide
additional evidence of the importance and involvement of circulating
lymphocytes in the early atherosclerotic process.
A high total WBC count is commonly found with the major predictors of
atherosclerosis.13 50 51 In our study,
the
higher total WBC count was mainly due to an increase in the number of
neutrophils and lymphocytes. It is possible that increases in these
types of circulating WBCs reflects an ongoing atherosclerotic process
induced by related predictor(s). Their interrelationships and causal
factors are not well known and require further
investigation.51
In conclusion, peripheral monocyte count was not correlated
with preexisting CA but was affected significantly by two major
predictors of atherosclerosis, ie,
hypercholesterolemia and smoking. Age and sex
also influenced monocyte count. The unique lower monocyte count and
percentage in hypercholesterolemia among the
major predictors of atherosclerosis suggest that
hypercholesterolemia may trigger the
atherosclerotic process via direct potentiation of monocyte adherence.
This in turn causes a great shift in the monocytes, from the
circulation to the endothelium. The mechanisms of other
predictor(s)-induced atherosclerosis may be quite
different from that of hypercholesterolemia.
The lymphocyte count was significantly higher with all major predictors
of atherosclerosis, indicating that a common and
important role is played by lymphocytes in the early stages of
atherosclerosis.
|
Selected Abbreviations and Acronyms
|
|---|
| 2-h BG |
= |
2-hour blood glucose |
| CA |
= |
carotid atherosclerosis |
| FBG |
= |
fasting blood glucose |
| TC |
= |
total cholesterol |
| TG(s) |
= |
triglyceride(s) |
| WBC(s) |
= |
white blood cell(s) |
|
|
Footnotes
|
|---|
Reprint requests to Z.-S. Huang, Department of Internal Medicine,
National
Taiwan University Hospital, No. 7 Chung-Shan S Rd, Taipei, Taiwan,
ROC
(10016).
Received July 18, 1995;
accepted October 20, 1995.
|
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Abstract
Introduction