© 1996 American Heart Association, Inc.
Articles |
In Hypercholesterolemia, Lower Peripheral Monocyte Count Is Unique Among the Major Predictors of Atherosclerosis
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.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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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
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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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).
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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.
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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.
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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.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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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.
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Selected Abbreviations and Acronyms |
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Footnotes |
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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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