(Circulation. 1996;93:1334-1338.)
© 1996 American Heart Association, Inc.
Articles |
From the Sections of Atherosclerosis and Leukocyte Biology, Department of Medicine, Baylor College of Medicine, Houston, Tex.
Correspondence to Christie M. Ballantyne, MD, Department of Internal Medicine, 6565 Fannin St, MS A-601, Houston, TX 77030.
| Abstract |
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Methods and Results To determine whether
dyslipidemia is associated with increased expression of
CAMs, we examined the levels of soluble intercellular adhesion molecule
1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and
soluble E-selectin (sE-selectin) in individuals with either
hypercholesterolemia or
hypertriglyceridemia and in control
subjects matched for age and sex. Patients with
hypertriglyceridemia had significantly
higher levels of sVCAM-1 (739±69 ng/mL) compared with patients with
hypercholesterolemia (552±63 ng/mL) and
control subjects (480±56 ng/mL). Levels of sICAM-1 were significantly
increased in both the hypercholesterolemic and
hypertriglyceridemic groups (298±29 and
342±31 ng/mL, respectively) compared with the control group (198±14
ng/mL). Levels of sE-selectin were significantly increased in
hypercholesterolemic patients (74±9 ng/mL)
compared with control subjects (48±5 ng/mL). Ten
hypercholesterolemic patients were treated
aggressively with atorvastatin alone or a combination of colestipol and
either atorvastatin or simvastatin for a mean of 42 weeks
and had an average LDL cholesterol reduction of 51%.
Comparison of soluble CAMs before and after treatment showed a
significant reduction only in sE-selectin (77±11 versus 56±6 ng/mL,
P
.03) but not for sVCAM-1 or sICAM-1.
Conclusions Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.
Key Words: lipids arteriosclerosis adhesion molecules
| Introduction |
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4ß1 and
4ß7 present on monocytes and lymphocytes, whereas ICAM-1
interacts with the ß2-integrins CD11a, CD11b, and
CD11c.3 The expression of CAMs is stimulated in vitro by
cytokines such as interleukin-1, tumor necrosis factor, and
interferon-
,4 and pathological studies of human
atherosclerosis have shown increased expression of
VCAM-1 and ICAM-1 on endothelial cells, smooth muscle
cells, and macrophages in human atherosclerotic plaques and in
the endothelium of adventitial vessels adjacent to
plaques.5 6 7 E-selectin expression is also increased in
atherosclerosis but is confined to the vascular
endothelium. Animal studies of
hyperlipidemia and diabetes mellitus have demonstrated
increased expression of VCAM-1 and E-selectin associated with
atherosclerosis.8 Lysophosphatidylcholine,
a component of modified LDL, has been shown to upregulate VCAM-1
expression,9 and recent reports suggest that fatty acids
may also modulate expression of VCAM-1.10 11
Unfortunately, determining whether dyslipidemia leads to
increased expression of endothelial CAMs has been
difficult because of the inability to assess the level of adhesion
molecule expression of the vascular endothelium in
vivo. Soluble forms of these adhesion molecules (sVCAM-1, sICAM-1, and sE-selectin) can be detected in the serum and are increased in conditions with an inflammatory component, such as pulmonary fibrosis, vasculitis, melanoma, and heart transplantation.12 13 The mechanism by which levels of soluble CAMs are increased is unknown, but the soluble levels are increased in conditions in which expression on the cell membrane has also been shown to be increased, such as after heart or liver transplantation.13 14 The purpose of this study was twofold. First, we wanted to determine whether patients with severe dyslipidemia due to defects in either LDL or TG metabolism had increased levels of soluble CAMs, and second, we wanted to determine whether aggressive lowering of LDL-C by drug therapy in a subset of patients would lead to a reduction in the levels of soluble CAMs.
| Methods |
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Treatment of Hypercholesterolemic
Subjects
Of the 14 HC subjects, 10 received aggressive treatment for
their hypercholesterolemia for a period of 37
to 46 weeks (mean, 41.6±1.1 weeks). Four patients received
atorvastatin, an experimental 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitor, as monotherapy at a dosage
of 80 mg/d. Three patients were treated for 16 weeks with colestipol 20
g/d, then with a combination of colestipol 20 g/d and atorvastatin 40
mg/d for an additional 21 to 30 weeks (mean, 25.7±2.6 weeks). One of
these 3 patients discontinued the colestipol after 17 weeks because of
gastrointestinal complaints and remained on atorvastatin 40 mg/d. The
final 3 patients received colestipol 20 g/d for 16 weeks followed by a
combination of colestipol 20 g/d and simvastatin 40 mg/d
for an additional 21 to 30 weeks (mean, 26±2.6 weeks).
Measurements
Blood samples were obtained by standard venipuncture
after a 12-hour fast from all subjects at baseline. Plasma TC was
measured with either a Hitachi 747 or Cobas-Fara II analyzer
according to CDC reference procedures.15 The same
technique was used to measure HDL-C in control and HC subjects after
precipitation of apo Bcontaining lipoproteins from samples by the use
of dextran sulfate and magnesium.16 In the HTG subjects,
HDL particles were separated by ultracentrifugation
at a density of 1.125 g/mL, and cholesterol concentration
then was determined by the same methods as described for TC. Plasma TG
was measured after preparation with lipase, glycerol phosphate oxidase,
and peroxidase.17 LDL-C was calculated in the HC patients
and control subjects by the Friedewald equation.18 In the
HTG patients, LDL-C was measured directly after fractionation of the
lipoproteins by differential ultracentrifugation at
density 1.006 g/mL. In the 10 HC subjects who received drug therapy, a
second 20-mL blood sample was collected after treatment, and values for
TC, HDL-C, TG, and LDL-C were obtained by the same techniques described
above. Levels of sICAM-1, sVCAM-1, and sE-selectin were determined by
the use of monoclonal antibody-based ELISA assays (R and D Systems)
on frozen serum collected at baseline from all subjects and after
treatment from the patients who received medication. All samples and
controls were performed in duplicate, and concentrations of samples
were determined by analyzing standards with known concentrations of
recombinant adhesion molecules coincident with samples and plotting a
curve of signal versus concentration.
Statistics
ANOVA with the Bonferroni-Dunn comparison19 was
performed to determine the differences among the three subject groups
in age, baseline lipid levels, and baseline levels of sICAM-1, sVCAM-1,
and sE-selectin. Nonparametric tests (ie, ANOVA on the
ranks rather than on the raw data20 ) were used for TG,
HDL-C, and sICAM-1 because of the large difference in variability among
the groups in these parameters. Simple regression
analysis was used to examine the relation among sICAM-1,
sVCAM-1, and sE-selectin levels. ANOVA on ranked data (Kruskal-Wallis
test) was used to determine if the levels of sICAM-1, sVCAM-1, and
sE-selectin differed among the risk factor categories of the subjects.
For all ANOVAs, pairs of groups were compared only if the overall
comparison was significant (P<.05). Soluble CAM levels in
subjects with atherosclerosis were compared with those
in hyperlipidemic (HC and HTG) subjects without
clinical atherosclerosis using the unpaired Student's
t test. The paired Student's t test was used to
compare lipid levels, sICAM-1, sVCAM-1, and sE-selectin before and
after treatment in the subjects who received drug treatment for
elevated LDL-C. Results are presented as mean±SE.
| Results |
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The level of sVCAM-1 was significantly increased in the HTG group
(739±69 ng/mL) compared with the HC (552±63 ng/mL) and control
(480±56 ng/mL) groups (Fig 1
, top). Levels of sICAM-1
were increased in both the HC and HTG groups (289±29 and 342±31
ng/mL, respectively) compared with the control group (198±14 ng/mL).
Level of sE-selectin was increased in the HC group (74±9 ng/mL)
compared with the control group (48±5 ng/mL). More patients in the HTG
group had other risk factors or clinical evidence of
atherosclerosis; therefore, a second analysis
that considered the presence of these factors was performed to compare
levels of soluble CAMs in the control subjects, subjects with
hyperlipidemia alone (either elevated LDL-C or TG,
n=19), and subjects with hyperlipidemia plus any other
risk factor (n=8). Patients with hyperlipidemia and at
least one other risk factor had significantly higher levels of both
sVCAM-1 and sICAM-1 than the other groups, as shown in the bottom of
Fig 1
. The 5 patients with hyperlipidemia and
atherosclerosis had significantly increased
sVCAM-1 compared with the other 22 patients with
hyperlipidemia (977±143 versus 566±37 ng/mL,
P
.0004). In the overall study population, there was a
significant correlation between levels of sICAM-1 and sVCAM-1
(r=.56, P
.001) and between levels of
sICAM-1 and sE-selectin (r=.61,
P
.0001) but not between sVCAM-1 and sE-selectin
(r=.19, P=.25). Because of the small sample size
of this study, we did not perform separate analyses to examine
the role of additional risk factors in patients with
hypercholesterolemia versus
hypertriglyceridemia, nor did we examine
the relative impact of specific risk factors such as diabetes versus
hypertension.
|
Lipid-lowering drug treatment effects in the HC patients evaluated
by comparing pretreatment and posttreatment lipid levels showed
reductions of TC (327±15 versus 200±17 mg/dL [39%]) and LDL-C
(252±14 versus 124±17 mg/dL [51%]) without significant changes in
TG (139±19 versus 113±13 mg/dL) or HDL-C (47±3 versus 53±4 mg/dL).
Comparison of soluble CAMs before and after treatment showed a
significant reduction in sE-selectin (77±11 versus 56±6 ng/mL,
P
.03) but no significant change in sVCAM-1 (626±76 versus
672±51 ng/mL) or sICAM-1 (314±36 versus 342±36 ng/mL) (Fig 2
).
|
| Discussion |
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Although treatment of hyperlipidemia in patients with documented atherosclerosis is believed to be cost-effective, considerable controversy exists about the cost-effectiveness of drug treatment for lipids in primary prevention, particularly in women. Noninvasive tests that would help to identify individuals with atherosclerosis who would be at high risk for cardiovascular events would improve the cost-effectiveness of lipid-lowering therapy. Studies are in progress using sera from individual in the Atherosclerosis Risk in Communities study27 to determine whether levels of soluble CAMs can be used as biochemical markers in conjunction with traditional risk factors to identify asymptomatic individuals at high risk for developing cardiovascular events because of atherosclerosis.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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| Footnotes |
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Received August 14, 1995; revision received February 5, 1996; accepted February 5, 1996.
| References |
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