From the National Institutes of Neurological Disorders and Stroke/Stroke
Branch (T.J.D., L.P., R.M.M., S.S., J.M.H.), National Institutes of Health,
Bethesda, Md; the Uniform Services University of the Health Sciences (T.J.D.,
A.-L.S.), Bethesda; the National Naval Medical Center, Department of
Neurosurgery (T.J.D., L.P., R.H.), Bethesda; and the National Institute of
Mental Health (K.D.P.), National Institutes of Health, Bethesda, Md.
Correspondence to Thomas J. DeGraba, MD, Stroke Branch, NINDS, NIH, 36 Convent Dr MSC 4128, Bldg 36 Room 4A03, Bethesda, MD 20892-4128. E-mail tjd{at}helix.nih.gov
Methods—Carotid plaques from symptomatic (n=25) and
asymptomatic (n=17) patients undergoing carotid
endarterectomy with lesions involving >60%
stenosis were snap-frozen at the time of surgery.
Immunofluorescence studies were performed to
measure the percentage of luminal endothelial surface
that expressed ICAM-1. The relationships of stroke risk factors, white
blood cell count, percent stenosis, and soluble ICAM-1
(sICAM-1) plasma levels to endothelial ICAM-1
expression were investigated.
Results—An increased expression of ICAM-1 was found in the
high-grade regions of symptomatic (29.5%±2.4%,
mean±SEM) versus asymptomatic (15.7%±2.7%, mean±SEM)
plaques (P=0.002) and in the high-grade versus the
low-grade region of symptomatic plaques (29.5±2.4,
mean±SEM, versus 8.9±1.6; P<0.001). Plasma sICAM-1
levels were not predictive of symptomatic disease, and no
significant correlation between risk factor exposure and
endothelial ICAM-1 expression was found.
Conclusions—An elevation in ICAM-1 expression in
symptomatic versus asymptomatic plaque suggests
that mediators of inflammation are involved in the conversion of
carotid plaque to a symptomatic state. The data also
suggest a differential expression of ICAM-1, with a greater expression
found in the high-grade region than in the low-grade region of the
plaque specimen.
Recent studies have focused on the role of immune mediators and
inflammation in the destabilization of atherosclerotic
plaque.9 10 11 Adhesion molecule expression, found
preferentially on the endothelium and smooth muscle of
atherosclerotic plaque,12 13 14 15 is an essential
step for initiation, maturation,1 2 16 and
destabilization9 10 11 of plaques and is mediated
by inflammatory cytokines such as IL-1, TNF-
In an effort to find a common mechanism for both plaque rupture and
intraluminal thrombosis without fissuring or intraplaque
hemorrhage, we hypothesized that the increased expression of
adhesion molecules on the vessel luminal endothelial
surface and the subsequent intensified interaction between perivascular
monocytes/macrophages and the local endothelium
are pivotal to multiple processes that predispose the atherosclerotic
plaque to convert from an asymptomatic to a
symptomatic state. In addition to a strong association with
intraplaque hemorrhage, inflammatory cells lead to the
increased local production of platelet-activating
factor,18 IL-1, and TNF-
The specific aim of our study was to determine whether ICAM-1,
reportedly a key component of the inflammatory pathway by causing
endothelial/leukocyte interaction and subsequent
luminal thrombosis, is preferentially expressed on the
endothelium of carotid plaques of
symptomatic versus asymptomatic patients. The
current practice of performing CEA in symptomatic and
asymptomatic patients to reduce the risk of stroke allows
us a unique opportunity to examine and compare vascular specimens
between the 2 clinical states.
Carotid plaque specimens were collected in the operating room (with
care to remove the plaque in a single piece if possible). The methods
used to divide the plaque into "high-grade" and "low-grade"
regions are as follows. The distance from the carotid bifurcation to
the point of maximal stenosis was measured on the angiogram.
The corresponding region on the plaque specimen was identified, and
a 7- to 12-mm block surrounding the estimated point of maximal
stenosis was recovered. The lumen was filled with Tissue-Tek
optimal cutting temperature compound (Laboratory-Tek Products), and
the specimens were snap-frozen in liquid nitrogen and stored at
–70°C until sectioning. Cryostat sections of 16-µm thickness were
obtained, and multiple slides from the highest region of
stenosis by visual inspection were used for analysis.
The low-grade region was obtained from the distal edge of the internal
carotid artery plaque where the specimen tapered to a near
normal–appearing vessel. These regions corresponded to <30%
stenosis by angiogram and generally had the visual
characteristics of near normal vascular endothelial
tissue. ICAM-1 expression was identified in each sample by incubating
with a mouse anti-human ICAM-1 monoclonal antibody, subclass IgG1 (R&D
Systems, 1:1000 dilution) for 48 hours at 4°C and then washed 3 times
(10 minutes each). A FITC–labeled second antibody (goat anti-mouse IgG
F(ab')2; Jackson ImmunoResearch Laboratories, Inc), 30 minutes of
incubation, was used to visualize ICAM-1. To measure
endothelial cell surface area, sections were then
incubated in rabbit anti-human factor VIII–related antigen antibodies
(1:1000) at 4°C for 24 hours and washed 3 times (10 minutes each) in
0.2% Triton X–PBS. The factor VIII antibodies were visualized by
incubating for 30 minutes with a rhodamine-labeled second antibody,
goat anti-rabbit IgG F(ab')2 (Jackson ImmunoResearch Laboratories, Inc,
1:100) to reveal endothelial surface area.
Immunohistochemical staining of all specimens was performed at the same
time to avoid variations in primary and secondary antibody
concentrations and incubation conditions. Preabsorption studies were
performed in the initial evaluation of the anti–ICAM-1 antibody to
rule out nonspecific binding. Sections were processed on an image
analyzer (Image-1 version 4.0, Universal Imaging) by an
investigator who was not aware of the group origin of the specimens.
Eight pairs of images per high-grade region and 8 pairs of images from
the low-grade region were acquired and analyzed from each
plaque at 25x magnification. The degree of ICAM-1 expression (FITC
fluorescence) was measured as a percentage of the total
endothelial cell surface area as demonstrated by
anti–von Willebrand factor immunoreactivity (Figure 1
Preoperative blood was drawn from all patients for the measurement of
sICAM-1 to determine whether plasma levels were
representative of focal or systemic vascular
upregulation of adhesion molecule expression. Plasma sICAM-1 levels
were also compared with levels obtained from volunteer risk
factor–free, age-matched control subjects without carotid
arteriosclerosis recruited at the National Naval
Medical Center. Levels of sICAM-1 were determined using an ELISA kit
(R&D Systems).
Statistical Analysis
An investigation performed to measure potential relationships between
the risk factors for stroke (as listed in Table 1
In logistic regression analyses, none of the risk factor
variables contributed significantly to the logistic model
prediction, with or without the inclusion of percent ICAM-1. The only
variable that contributed significantly to a logistic model was
percent ICAM-1 in high-grade symptomatic plaque, both
singularly and in conjunction with the other variables.
Finally, analysis of the plasma sICAM-1 levels showed the
symptomatic, asymptomatic, and control groups
to be statistically significant, P<0.02 (Table 2
Findings from the NASCET revealed evidence that high-grade
stenotic symptomatic lesions (70% to 99%)
resulted in a high incidence of recurrent strokes in the medically
treated group.21 However, degree of
stenosis alone does not explain the stroke risk, since patients
on aspirin in the Asymptomatic Carotid
Atherosclerosis Study (with 60% to 99%
stenosis) had a significantly lower yearly stroke
rate.23 Although there are differences between
how these 2 studies were performed, it is not inappropriate to conclude
that atherosclerotic plaque with a given degree of stenosis
imparts a greater risk of recurrent stroke in a patient who has become
symptomatic than in one who has not.
Various studies have analyzed the potential role of
atherosclerotic plaque components in the development of patient
symptoms. Avril et al6 reported that "soft
plaques" containing atheromatous debris or
intraplaque hemorrhage were more commonly seen in
symptomatic carotid lesions than "hard plaques"
composed primarily of collagen or calcium. These findings were echoed
by O'Holleran et al24 who reached similar
conclusions via ultrasound analysis of carotid plaques. Lusby
et al5 found acute or recent plaque
hemorrhage in 49 of 53 (92.5%) symptomatic
patients undergoing CEA compared with only 7 of 26 (27%) in
asymptomatic patients. However, more recent studies by
Hatsukami et al3 and Bassiouny et
al4 revealed no correlation between the
preoperative ischemic symptom status and the presence and
quantity of fibrous intimal tissue, lipid core/total
cholesterol, fibrinogen, necrotic plaque core,
calcification, or intraplaque hemorrhage.
Intuitively, intraplaque hemorrhage and the potential for
plaque rupture and ulceration would seem to be associated with a
luminal surface ripe for focal thrombosis. However, even the data
presented by Lusby et al5 revealed that
90% of asymptomatic patients had evidence of remote
intraplaque hemorrhage, suggesting that the severity of
hemorrhage represents a spectrum that most likely
serves as an interrelated contributing factor to plaque activation but
not the single element that institutes focal
endothelial thrombosis. In addition, evidence for
plaque ulceration was found to be absent on the intimal lining of the
symptomatic plaque in greater than 40% of the first 500
patients examined in the NASCET,7 suggesting
again that other elements can play a role in the formation of
thrombosis in the absence of overt disruption in plaque
morphology.25
Accumulation of data from numerous sources has permitted an emerging
characterization of the role of inflammatory mediators in the process
of atherosclerosis. Proinflammatory cytokines,
such as TNF-
Previously, we demonstrated a relationship between risk factor exposure
and intensification of an interaction between perivascular monocytes
and the cerebral endothelium mediated by inflammatory
cytokines.15 28 29 30 We hypothesize that
prolonged exposure to risk factors can prepare segments of the vascular
bed for focal thrombosis and hemorrhage on exposure to TNF-
To accumulate the data presented here we used
immunostaining techniques to best localize the adhesion
molecule expression to the endothelial cell surface in
an effort to characterize the interactive surface of the plaque with
the blood interface. The findings demonstrate that the greatest
percentage of ICAM-1 expression was observed in the high-grade regions
of the symptomatic plaque. These findings strongly suggest
that components of the inflammatory pathway are directly involved in
the conversion of the atherosclerotic plaque to the
symptomatic or prothrombotic state. They also reveal that
ICAM-1 expression favors the high-grade region and not the entire
endothelial surface of the symptomatic
plaque, which implies a dynamic interaction at the plaque site.
Analysis showed no significant relationship of ICAM-1
expression with the risk factor profile that would explain the
difference in adhesion molecule expression. It is of particular
interest that asymptomatic patients with very similar
degrees of high-grade stenosis had a significantly lower
percentage of ICAM-1 expression, supporting the opinion that
stenosis alone does not determine the transition to a
symptomatic state. Despite the focal elevation of ICAM-1
expression, the soluble form of ICAM-1 in the plasma was not
significantly different in symptomatic compared with
asymptomatic patients. However, when compared with a risk
factor–free, age-matched control group, sICAM-1 was significantly
elevated in patients with symptomatic
atherosclerosis.
Limitations of this study are related to the quantification techniques
by which the expression of ICAM-1 was determined.
Immunostaining techniques were specifically used to
best localize the adhesion molecule expression to the
endothelial cell surface in an effort to characterize
the interactive surface of the plaque with the blood interface.
However, nonreactive or shielded epitopes of ICAM-1 may lead to an
underestimation of protein expression. Analysis was targeted at
the endothelial expression of ICAM-1, which
represents tissue that has direct contact with blood flow in
all patients and does not demonstrate autofluorescence seen in
the body of the plaque.
Numerous mechanisms could be invoked to explain our findings. First, it
should be recognized that our results are a "snapshot" in time. The
findings could represent a periodic event measurable at the
times the plaque is most active or a sustained condition that adds to
the overall potential of a positive thrombogenic event. One possible
explanation for the findings would be the presence of a focal infection
that could trigger already "prepared" (susceptible)
atheromatous tissue and push it toward a transiently
uncompensated prothrombotic state. This may explain why 2 comparably
sized bilateral carotid plaques in the same patients exhibit very
different symptom profiles. Along the same line, even systemic
infection without direct invasion of the vessel wall may trigger a
previously upregulated plaque to advance to a more prothrombotic state
in accordance with the localized Shwartzman
paradigm.31 Another possibility is that the
underlying genetic makeup of the patient may predispose to a more
proinflammatory plaque. It is known that shear stress forces and
oxidative stress regulate gene expression through
transcription-regulating proteins, such as nuclear factor–
It must be considered that adhesion molecule expression is an
epiphenomenon of the luminal thrombosis that caused the
ischemic event in the symptomatic patient. Though
possible, it is felt to be less likely given the preponderance of
evidence that inflammatory endothelial changes
generally precede thrombogenesis in atherosclerosis and
are felt to significantly contribute to the maturation of
atherosclerotic plaque.12 16
The mechanisms that lead to these findings need further
characterization, but our results are consistent with the
notion that inflammation is a pivotal factor in carotid plaque symptom
status. Inflammatory mediators may participate in thrombus formation
either in the hemorrhagic/ulcerative state or in the circumstance of
intact but modified endothelial lining.
In summary, the data from this study suggest that a local increase of
endothelial inflammatory mediator expression correlates
with the symptoms of thromboembolic ischemia and may play a
role in the conversion of atheromatous plaque to a
prothrombotic state. The data also support the fact that this line of
investigation may be useful in identifying new mechanisms in patients
at risk for stroke, which may suggest novel strategies for intervention
and prevention. This important possibility deserves further
exploration.
Received November 7, 1997;
revision received April 13, 1998;
accepted April 13, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Increased Endothelial Expression of Intercellular Adhesion Molecule-1 in Symptomatic Versus Asymptomatic Human Carotid Atherosclerotic Plaque
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—The
mechanisms that cause carotid atherosclerotic plaque to become
symptomatic remain unclear. Evidence suggests that
mediators of inflammation are not only instrumental in the formation of
plaque but may also be involved in the rapid progression of
atheromatous lesions leading to plaque fissuring,
endothelial injury, and intraluminal thrombosis. Our
goal is to determine whether intercellular adhesion molecule-1
(ICAM-1), a known component of the inflammatory pathway, is
preferentially expressed on symptomatic versus
asymptomatic carotid plaques.
Key Words: atherosclerosis • carotid endarterectomy • endothelium • intercellular adhesion molecule-1 • inflammation
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The mechanisms
involved in the initiation, progression, and maturation of
atherosclerotic plaques have been well described
previously,1 2 and are characterized by
endothelial injury, followed by lipid deposition,
macrophage migration, vascular smooth muscle proliferation, and
deposition of extracellular matrix proteins in the intimal region
between the endothelial lining and the media. Processes
within the plaque lead to further disruption of the
endothelial lining, predisposing the vessel to
intraluminal thrombogenesis that culminates in myocardial infarction,
stroke, and peripheral vascular disease. In an attempt to
isolate key factors that characterize the
pathophysiological mechanism that ultimately
results in an ischemic event, numerous studies have carefully
reported the cellular composition3 4 5 6 and
radiographic patterns7 8 found in
symptomatic and asymptomatic carotid plaques.
Lipid content, calcification, fibrous cap thickness, and intraplaque
hemorrhage have been examined as possible harbingers of plaque
activation. To date, however, overall morphological differences have
been inconsistent indices for predicting plaque conversion to a
symptomatic or prothrombotic
state.3 4 
, and
interferon-
. The expression of ICAM-1, vascular cell adhesion
molecule-1, and E-selectin is thought to modulate
leukocyte/endothelial interaction, resulting in the
emigration of leukocytes and enhancement of the potential for plaque
rupture. However, plaque rupture and intraplaque hemorrhage,
although likely to be strong contributing
factors,5 6 17 are not essential for the
formation of intraluminal thrombosis, and their presence does not
guarantee symptoms.3 4 5 , which transforms the
endothelium from an anticoagulant to a prothrombotic
state.19 20
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Forty-two carotid plaques were obtained from 40 consecutive
patients (37 men and 5 women) undergoing CEA at the National Naval
Medical Center in Bethesda, Maryland, with stenotic
atheromatous lesions of 
60%, as measured by NASCET
criteria.21 All patients gave consent for use of
their plaque and blood samples for research analysis as per the
hospital's Institutional Review Board. Twenty-five patients were
symptomatic (stroke, transient ischemic attack,
amaurosis fugax), and 17 were asymptomatic (Table 1
). Extensive history and neurological
examination were obtained by a neurologist from the National Institute
of Neurological Disorders and Stroke Stroke Branch before surgery in
all patients to determine symptomatic and
asymptomatic group selection. Stroke risk factors of
hypertension (blood pressure >140/90 for 1 or more years), past
history of smoking (at least a 5 pack-year history), diabetes (oral
agent or insulin dependent for >1 year), and
hypercholesterolemia (low-density lipoprotein
>160 untreated, fasting triglycerides >200, or on
cholesterol-lowering medication for >1 year), current
medications including use of antiplatelet agents, and time from
last ischemic event were recorded. Patients with atrial
fibrillation were excluded from the symptomatic group to
avoid the possible confusion between a cardiac and a carotid source of
ischemic events. A screening fasting blood glucose and lipid
profile was performed on all patients without known history of diabetes
or hypercholesterolemia. A CT scan of the head
was obtained for all patients and used as supporting evidence of the
history and physical in the asymptomatic population to rule
out silent infarction.
View this table:
[in a new window]
Table 1. Demographics and Distribution of Risk Factors ). Only the areas of the luminal surface
demarcated as endothelium by intense factor VIII–von
Willebrand factor staining were used for analysis of
endothelial ICAM-1 expression to avoid measuring areas
of artifactual denudation. The investigator acquiring images was also
unaware of the clinical history related to each plaque to avoid the
introduction of bias into data collection. This investigation reports
final data evolving from and using techniques from an initial
preliminary study.22
View larger version (130K):
[in a new window]
Figure 1. Panels A and B are representative
samples from a high-grade symptomatic plaque. Rhodamine
(red) fluorescence identifies the endothelium
(arrow) in panel A. FITC (green) fluorescence identifies ICAM-1
expression on the endothelial surface (arrow) in panel
B. Panels C and D are representative samples from a
high-grade asymptomatic plaque. As above, FITC
fluorescence identifies the ICAM-1 expression on the
endothelium represented by the rhodamine
fluorescence in panel C. ICAM-1 expression is measured as the
area of FITC stain as a percentage of the area of
rhodamine/endothelial surface.
Repeated measures ANOVA was used to compare the 2 patient
groups, symptomatic and asymptomatic, on ICAM-1
expression in both high- and low-grade regions of the CEA plaque. In
the analysis the group
(symptomatic/asymptomatic) x grade (high/low)
interaction was tested. Paired and independent group t tests
with Bonferroni correction were applied to determine the difference
between high-grade symptomatic and high-grade
asymptomatic regions (interplaque differences) and between
the high- and low-grade regions of the same plaques (intraplaque
differences). Pearson product moment correlations were used to
investigate the relationship of percent high-grade ICAM-1 expression
with sICAM-1, white blood cell count, and percent stenosis. The
correlations were considered for symptomatic and
asymptomatic groups combined and separately.
Point–bi-serial correlations were used to investigate the relationship
of high-grade ICAM-1 expression to the dichotomous variables of
hypertension, diabetes, hypercholesterolemia,
and smoking. A 1-way ANOVA with Welch approximation was used to compare
sICAM-1 levels among the symptomatic,
asymptomatic, and control groups. A stepwise logistic
regression analysis was performed to determine the contribution
on the occurrence of patient symptoms of the potential risk
variables of percent ICAM expression, age, percent
stenosis, and presence of stroke risk factors.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Repeated measures ANOVA on ICAM-1 expression resulted in a highly
significant group-grade interaction, demonstrating a propensity for
increased percent ICAM-1 expression in the symptomatic
patients, P=0.0003 (Figure 2).
Pair-wise comparisons of the individual group means with Bonferroni
corrected t tests demonstrated that the percentage of the
carotid endothelial surface showing positive ICAM-1
reactivity is significantly (P=0.002) higher in the
high-grade regions of symptomatic patients (29.6%±2.3%,
mean±SEM) versus the high-grade regions of asymptomatic
patients (15.7% ± 2.7%, mean±SEM). In addition, intraplaque
comparison reveals a significantly (P<0.001) increased
percentage of endothelial cell surface expressing
ICAM-1 in the high-grade regions of the symptomatic plaques
(29.6%±2.3%, mean±SEM) compared with the low-grade regions of
symptomatic plaque (8.9% ± 1.6%, mean±SEM). There was
no notable difference between the high- and low-grade regions of the
asymptomatic plaque or between the low-grade regions of the
symptomatic and asymptomatic plaques.
View larger version (20K):
[in a new window]
Figure 2. Group
(symptomatic/asymptomatic) x Grade (high/low)
interaction shows a highly significant propensity for increased ICAM-1
expression in symptomatic patients
(P=0.0003). Pair-wise comparison with Bonferroni
corrected t tests reveals significantly increased ICAM-1
expression in the symptomatic high grade versus
asymptomatic high grade (*P=0.002) and in
the symptomatic high grade versus symptomatic
low grade (**P<0.001). There was no difference in
expression between the high- and low-grade regions of the
asymptomatic plaques. 
, including
hypertension, diabetes, hypercholesterolemia,
smoking, and percent plaque stenosis, and leukocyte count) with
the degree of adhesion molecule expression showed no correlation. ). Pair-wise group t tests
revealed no difference between the symptomatic (255±81,
mean±SD, pg/mL) and asymptomatic patients (224±78,
mean±SD, pg/mL). Although the sICAM-1 level was an unreliable marker
for distinguishing elevated levels of focal expression of the adhesion
molecule on carotid plaques, there was a significant difference between
the symptomatic patients and the risk factor–free,
age-matched control population (194±41, mean±SD,,
P=0.05).
View this table:
[in a new window]
Table 2. Analysis of Plasma sICAM Levels by Group
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The processes instrumental in the initiation, progression, and
activation of atherosclerotic plaques are a complex concert of events
involving vessel conformation, hemodynamic forces,
multiple risk factor exposure, cellular composition, and
physiological mechanisms that include upregulation
of inflammatory mediators and plaque destabilization. Attempts to
reduce the incidence of strokes that result from carotid
atherosclerotic thromboemboli require a clearer understanding of the
mediators associated with the conversion of plaques from an
asymptomatic to a symptomatic state. Our data
show a strong correlation between a major mediator of local
inflammation, the expression of the adhesion molecule ICAM-1, with the
symptomatic state, which potentially represents the
next piece of the puzzle for predicting and understanding plaque
activation. ,11 26 and adhesion molecule
expression12 13 16 have been well localized to
the atherosclerotic vessel wall, and there is evidence that this
profile shifts the endothelium toward a prothrombotic
state.19 20 A strong association between the
presence of angina/myocardial infarction and plaque rupture/ulceration,
luminal thrombus, and inflammation has been noted in coronary
vessels.10 27 Luminal thrombus has been
identified in the presence of inflammation alone, although the majority
of thrombus formation in coronary arteries has been associated
with ulceration.27 Milei et
al9 has shown a correlation between
macrophage infiltration and carotid artery plaque rupture.
and IL-1, which may be released in response to a local or systemic
stimulus29 according to the localized Shwartzman
paradigm.31 
B, and
shear stress response element, thus affecting genes that regulate
adhesion molecule expression.32 33 34 35 36 In addition,
genes that control the expression of families of cytokines,
which regulate inflammation, are known to be polymorphic in nature.
Finally, periodicity to the release of mediators of inflammation such
as cytokines and chemokines may result in transient or episodic
elevations in the overall potential for a plaque to become
symptomatic.
Selected Abbreviations and Acronyms
CEA
=
carotid endarterectomy
FITC
=
fluorescein isothiocyanate
IL-1
=
interleukin-1
ICAM-1
=
intercellular adhesion molecule-1
NASCET
=
North American Symptomatic Carotid
Endarterectomy Trial
sICAM-1
=
soluble ICAM-1
TNF-
=
tumor necrosis factor-
Acknowledgments
This study was supported by the intramural Stroke Branch of the
National Institute of Neurological Disorders and Stroke. The chief,
Navy Bureau of Medicine and Surgery, Washington, DC, Clinical
Investigation Program, supported study #B93–047. We are grateful for
the support of the National Naval Medical Center's departments of
neurology, neurosurgery, and vascular surgery for their support in
patient recruitment. We also thank Paula Oberlander, RN, for her help
with data collection, subject recruitment, and patient care.
Footnotes
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
This article has been cited by other articles:
 |
|
 |
|
  M. Caprio, B. G. Newfell, A. la Sala, W. Baur, A. Fabbri, G. Rosano, M. E. Mendelsohn, and I. Z. Jaffe Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion Circ. Res., June 6, 2008; 102(11): 1359 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. L. Volger, J. O. Fledderus, N. Kisters, R. D. Fontijn, P. D. Moerland, J. Kuiper, T. J. van Berkel, A.-P. J.J. Bijnens, M. J.A.P. Daemen, H. Pannekoek, et al. Distinctive Expression of Chemokines and Transforming Growth Factor-{beta} Signaling in Human Arterial Endothelium during Atherosclerosis Am. J. Pathol., July 1, 2007; 171(1): 326 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Stoll and M. Bendszus Inflammation and Atherosclerosis: Novel Insights Into Plaque Formation and Destabilization Stroke, July 1, 2006; 37(7): 1923 - 1932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Circulation, June 20, 2006; 113(24): e873 - e923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke, June 1, 2006; 37(6): 1583 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Yoon, J. Hur, I.-Y. Oh, K.-W. Park, T.-Y. Kim, J.-H. Shin, J.-H. Kim, C.-S. Lee, J.-K. Chung, Y.-B. Park, et al. Intercellular Adhesion Molecule-1 Is Upregulated in Ischemic Muscle, Which Mediates Trafficking of Endothelial Progenitor Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1066 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Slevin, A. B. Elasbali, M. Miguel Turu, J. Krupinski, L. Badimon, and J. Gaffney Identification of Differential Protein Expression Associated with Development of Unstable Human Carotid Plaques Am. J. Pathol., March 1, 2006; 168(3): 1004 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nighoghossian, L. Derex, and P. Douek The Vulnerable Carotid Artery Plaque: Current Imaging Methods and New Perspectives Stroke, December 1, 2005; 36(12): 2764 - 2772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Ameriso, A. R. Villamil, C. Zedda, J. C. Parodi, S. Garrido, M. I. Sarchi, M. Schultz, J. Boczkowski, and G. E. Sevlever Heme Oxygenase-1 Is Expressed in Carotid Atherosclerotic Plaques Infected by Helicobacter pylori and Is More Prevalent in Asymptomatic Subjects Stroke, September 1, 2005; 36(9): 1896 - 1900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fisher, A. Paganini-Hill, A. Martin, M. Cosgrove, J. F. Toole, H. J.M. Barnett, and J. Norris Carotid Plaque Pathology: Thrombosis, Ulceration, and Stroke Pathogenesis Stroke, February 1, 2005; 36(2): 253 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. DeGraba Immunogenetic Susceptibility of Atherosclerotic Stroke: Implications on Current and Future Treatment of Vascular Inflammation Stroke, November 1, 2004; 35(11_suppl_1): 2712 - 2719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Cao, C. Thach, T. A. Manolio, B. M. Psaty, L. H. Kuller, P. H.M. Chaves, J. F. Polak, K. Sutton-Tyrrell, D. M. Herrington, T. R. Price, et al. C-Reactive Protein, Carotid Intima-Media Thickness, and Incidence of Ischemic Stroke in the Elderly: The Cardiovascular Health Study Circulation, July 15, 2003; 108(2): 166 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tsong Tan and A. D. Blann To stroke or not to stroke: Is ICAM-1 or CRP the answer? Neurology, June 24, 2003; 60(12): 1884 - 1885. [Full Text] [PDF]
|
|
|
|
|
|
K. Nuotio, P. J. Lindsberg, O. Carpen, L. Soinne, E. M.P. Lehtonen-Smeds, E. Saimanen, R. Lassila, T. Sairanen, S. Sarna, O. Salonen, et al. Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis Neurology, June 24, 2003; 60(12): 1890 - 1899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rezaie-Majd, G. W. Prager, R. A. Bucek, G. H. Schernthaner, T. Maca, H.-G. Kress, P. Valent, B. R. Binder, E. Minar, and M. Baghestanian Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F-E. de LEEUW, M. de KLEINE, C. J. M. FRIJNS, R. FIJNHEER, J. van GIJN, and L. J. KAPPELLE Endothelial Cell Activation Is Associated with Cerebral White Matter Lesions in Patients with Cerebrovascular Disease Ann. N.Y. Acad. Sci., November 1, 2002; 977(1): 306 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tanne, M. Haim, V. Boyko, U. Goldbourt, T. Reshef, S. Matetzky, Y. Adler, Y. A. Mekori, and S. Behar Soluble Intercellular Adhesion Molecule-1 and Risk of Future Ischemic Stroke: A Nested Case-Control Study From the Bezafibrate Infarction Prevention (BIP) Study Cohort Stroke, September 1, 2002; 33(9): 2182 - 2186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. G. Nadareishvili, D. E. Koziol, B. Szekely, C. Ruetzler, R. LaBiche, R. McCarron, T. J. DeGraba, and S. Jander Increased CD8+ T Cells Associated With Chlamydia pneumoniae in Symptomatic Carotid Plaque Editorial Comment Stroke, September 1, 2001; 32(9): 1966 - 1972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jander, M. Sitzer, A. Wendt, M. Schroeter, M. Buchkremer, M. Siebler, W. Muller, W. Sandmann, and G. Stoll Expression of Tissue Factor in High-Grade Carotid Artery Stenosis : Association With Plaque Destabilization Stroke, April 1, 2001; 32(4): 850 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Ameriso, E. A. Fridman, R. C. Leiguarda, G. E. Sevlever, and J. D. Spence Detection of Helicobacter pylori in Human Carotid Atherosclerotic Plaques Editorial Comment Stroke, February 1, 2001; 32(2): 385 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Circulation, January 2, 2001; 103(1): 163 - 182. [Full Text] [PDF]
|
|
|