(Stroke. 2000;31:774.)
© 2000 American Heart Association, Inc.
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Comments, Opinions, and Reviews |
The Symptomatic Carotid Plaque
Jonathan Golledge, MChir;
Roger M. Greenhalgh, MD
Alun H. Davies, DM
From the Department of Vascular Surgery, Imperial College School of
Medicine, Charing Cross Hospital, London, UK.
Correspondence to J. Golledge, Department of Vascular Surgery, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. E-mail J.Golledge{at}tesco.net
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Abstract
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BackgroundThe natural histories
of equally severe symptomatic
and asymptomatic
carotid stenoses are very different, which
suggests dichotomy
in plaque behavior. The vascular biology
of the symptomatic
carotid plaque is presented in this review.
Summary of ReviewHistology studies comparing
asymptomatic and symptomatic plaques were
identified from MEDLINE. Reports in which stenosis severity was
not stated or not similar for symptomatic and
asymptomatic patients were excluded. In vitro studies and
reports from the coronary circulation were reviewed with regard
to the vascular biology of the plaque. Histology studies comparing
carotid plaques removed from symptomatic and
asymptomatic patients reveal characteristic features of
unstable plaques: surface ulceration and plaque rupture (48% of
symptomatic compared with 31% of asymptomatic,
P<0.001), thinning of the fibrous cap, and infiltration
of the cap by greater numbers of macrophages and T cells. In
vitro studies suggest that macrophages and T cells release
cytokines and proteinase, which stimulate breakdown of cap
collagen and smooth muscle cell apoptosis and thereby promote
plaque rupture.
ConclusionsInfiltration of inflammatory cells to the surface of
carotid plaques may be a critical step in promoting plaque rupture and
resultant embolization or carotid occlusion. Further understanding of
cell recruitment and behavior in carotid
atherosclerosis may allow better detection of unstable
plaques and therapeutic methods of plaque stabilization.
Key Words: atherosclerosis carotid artery diseases leukocytes
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Introduction
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Stroke is the second most common cause of death
worldwide, with
an incidence in theUnited Kingdom of approximately
400/100 000.
1 The neurological deficits that follow
stroke have been used
to classify the stroke and provide some
information about the
prognosis and pathophysiology.
2 3 4
The frequency of related
carotid artery disease varies with the type of
stroke
4 (Table
1

).
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Mechanism of Stroke in Carotid Artery Disease: Embolization
Versus Ischemia
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While it is likely that some strokes associated with carotid
artery
disease result from hypoperfusion,
6 the majority of
such strokes
appear to result from embolization from an atherosclerotic
plaque
or acute occlusion of the carotid artery and propagation of
thrombus
distally. In support of embolization as the etiology of most
strokes,
few infarcts are in watershed areas,
7 microemboli
can be detected
in the middle cerebral artery,
8 9 and
stenosis or restenosis
of similar
hemodynamic severity are much less likely to be
associated
with stroke when asymptomatic
10 11 12 13 14
(Figure 1

). The
frequency of embolization
on transcranial Doppler (TCD) is greater
in patients
with recent symptoms such as transient ischemic
attack (TIA)
compared with patients with similarly severe asymptomatic
disease.
8 9 A high frequency of microemboli (

2 per hour)
correlates with
risk of subsequent ipsilateral ischemic
symptoms, although no
relationship has been demonstrated between
microemboli and subsequent
stroke alone.
15 Because many of
the microemboli are asymptomatic,
other factors, such as
the size of emboli and the collateral
blood supply, must be important
in determining the effect of
any one emboli.

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Figure 1. Freedom from stroke ipsilateral to a
symptomatic and asymptomatic severely stenosed
carotid artery. Data are taken from the medical arm of NASCET, ECST,
and ACAS trials.11 12 13 Also included is the rate for
stroke ipsilateral to a symptomless stenosis that is
contralateral to a symptomatic stenosis, from the
medical arm of ECST.14 Symptomatic patients
had experienced 1 or more carotid territory ischemic events
that were either transient or nondisabling in the last 4 (NASCET) or 6
(ECST) months. The severity of carotid artery disease is roughly
equivalent for the 2 groups of symptomatic patients
(allowing for the different methods of stenosis measurement),
ie, 70% to 99% stenosis by the NASCET method; however, the
patients with asymptomatic disease have 60% to 99%
stenosis measured by the NASCET method.
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Relationship Between Presenting Symptom and Stroke
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While there are many risk factors for ischemic
stroke,
16 , transient
ischemic events in patients
with significant carotid stenosis
are powerful predictors of
subsequent stroke.
11 12 Figure 1
compares the incidence of
stroke ipsilateral to a severely stenosed
carotid artery in patients
with and without recent transient
ischemic symptoms, using data
from the North American Symptomatic
Carotid
Endarterectomy Trial (NASCET), the European Carotid
Surgery
Trial (ECST), and the Asymptomatic Carotid
Atherosclerosis Study
(ACAS).
11 12 13 14
Clearly, the stroke risk associated with
a symptomatic
stenosis is much greater. Table 2

illustrates
the stroke rates from the 3 trials related to the severity
of
stenosis.
11 12 13 14 17 For symptomatic
stenoses there is a
clearly increasing stroke risk with
severity of stenosis. Interestingly,
in ACAS there was no
association between the stroke rate and
the severity of
stenosis, although the number of patients with
80% to 99%
stenosis was only 88. The low risk of stroke associated
with
asymptomatic severe carotid stenosis has been
confirmed
by other studies.
18 19 20 These data, therefore,
suggest 2
types of carotid artery disease: one form stable and unlikely
to
produce symptomatic embolization or carotid occlusion
and a
second form, while not necessarily being any more
stenotic,
unstable and at high risk of producing
symptomatic embolization
or carotid occlusion.
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Methods
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To investigate the biology underlying the differences in plaque
behavior,
we have assessed studies that compare the histology of
plaques
removed from symptomatic and
asymptomatic patients. Using PUBMED,
MEDLINE, and
hand-searching of journals, we identified 21 studies
that compared
carotid plaque histology.
8 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Carotid plaque
characteristics,
such as surface ulceration, intraplaque
hemorrhage, and lumen
thrombosis, have been shown to vary with
stenosis severity.
25 32 Therefore, studies that
did not state severity of carotid
stenosis or in which the
degree of stenosis was not comparable
were excluded. Reports
that stated only macroscopic findings
or did not compare
symptomatic and asymptomatic patients were
also
not included. Most studies did not state whether plaque
histology was
analyzed in a blinded fashion. A total of 11 studies
were
thereby excluded.
21 22 23 24 25 26 27 28 29 30 31 In addition,
basic science reports
describing the vascular biology of the
unstable atherosclerotic plaque
were also studied.
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The Vascular Biology of the Unstable Plaque
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Studies From the Carotid Circulation
The Atherosclerotic Plaque
The atherosclerotic plaque at the carotid bifurcation is an
example
of the advanced fibrous plaque found at sites of predilection
throughout
the arterial system. It is composed of a dense
cap of connective
tissue embedded with smooth muscle cells, overlying a
core of
lipid and necrotic debris
41 (Figure 2

). The plaque contains
monocyte-derived
macrophages, smooth muscle cells, and T lymphocytes
(Figure 2

). Interaction between these cells types and the connective
tissue
appears to determine the development of the plaque, including
important
complications, such as plaque rupture.
41

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Figure 2. Features of symptomatic and
asymptomatic plaques. The unstable plaque has a thin,
fibrous cap that contains large numbers of macrophages and T
lymphocytes but small numbers of smooth muscle cells (SMC; bottom
panel). The stable plaque has a thicker cap with larger numbers of
smooth muscle cells and less inflammation (top).
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Comparison of Carotid Plaque Histology From Symptomatic
and Asymptomatic Patients
A large number of studies have compared carotid plaques
removed from symptomatic and asymptomatic
patients in an attempt to understand the mechanisms underlying plaque
"activation."8 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Comparisons have been
principally restricted to plaques taken from patients with any focal
symptoms, such as TIA, amaurosis fugax, or stroke with minimal
disability, and from those with no symptoms. No studies have isolated
plaque features peculiar to patients with 1 symptom type. The studies
comparing plaque histology in asymptomatic and
symptomatic patients with similar stenosis severity
are summarized in Tables 3
and 4
.8 32 33 34 35 36 37 38 39 40 Table 3
includes the 3 plaque features for which summary analysis is
possible, because common methods of assessment have been used, while
Table 4
includes the 3 plaque features for which disparate
methods of analysis have been made. There is some variation in
the findings of different studies, possibly related to variation in
time between onset in symptoms and assessment of plaque, in addition to
differences in method of plaque removal and analysis.
Unfortunately, little information is given on the reproducibility of
the different plaque assessments.
The summation analysis demonstrates that plaque rupture or
ulceration is much more common in symptomatic patients
(48% versus 31%, P<0.001), but lumen thrombus (40%
versus 35%) and intraplaque hemorrhage (48% versus 50%) are
equally common in symptomatic and asymptomatic
patients (Table 3
). Although the methods of assessment have been
different, most studies have shown that the fibrous cap of
symptomatic plaques is thinner34 35 36 37 38 and
inflammation is more common, with greater number of macrophage
and T cells detected in the cap of symptomatic
plaques36 37 39 (Table 4
). The core of the plaques
would appear to be similar in symptomatic and
asymptomatic patients, with no significant difference in
frequency or size of necrotic core in most studies in which similarly
severe stenoses have been compared8 32 33 34 35 36 37 38 (Table 4
). The quantity of extractable lipid has been found to be
greater in symptomatic plaques in 1 study.35
This histology finding equates with results from ultrasound studies
that demonstrate echolucent, lipid-rich plaques are more often
associated with symptoms.42
Detailed histological examinations have demonstrated
there are subtle differences in the characteristics of the
atherosclerotic plaque removed from symptomatic patients.
In symptomatic patients the necrotic core is placed nearer
to the fibrous cap and the minimum cap thickness is less37
(Table 3
, Figure 2
). Thus, while the volume of fibrous
cap and lipid core may be similar in symptomatic and
asymptomatic plaques, the position of the core and local
thinning of the cap may predispose to rupture.36 37 An
interesting study by Sitzer and colleagues8 relates plaque
histology to frequency of embolization on TCD. The authors discovered
an association between plaque ulceration, lumen thrombus, and the
frequency of TCD microemboli, which suggests the importance of plaque
rupture in the pathogenesis of stroke.8
Studies From the Coronary Circulation and Experimental
Models
Plaque Features and Risk of Rupture
To date, more detailed studies have been performed in
atherosclerotic plaques removed from patients with unstable angina in
comparison to those with symptomatic carotid artery
disease.43 44 45 46 47 48 49 Because the hemodynamic
environment of the coronary circulation is very different from
that of the carotid arteries, care should be taken in relating findings
from one vascular bed to another. Postmortem and atherectomy studies
have demonstrated that plaques removed from patients with unstable
coronary symptoms have larger lipid-filled cores and thinner
fibrous caps, which contain larger numbers of activated
macrophages and T lymphocytes but smaller numbers of smooth
muscle cells and less collagen content than plaques from patients with
stable angina.43 44 45 46 47 The likelihood of plaque rupture is a
balance between the tensile strength of the plaque and the stress
exerted on it. The plaque features demonstrated in patients with
unstable angina have been shown in vitro to confer low tensile
strength.48 Interestingly, decreasing fibrous cap
thickness drastically increases the circumferential stress on the
plaque, whereas increasing stenosis severity actually decreases
circumferential stress.49
Cellular Biology of the Plaque and Rupture
Invitro studies have suggested the pathogenic mechanisms
underlying the unstable plaque. Smooth muscle cells lay down collagen,
the principal connective tissue component of the fibrous cap. Collagen
breakdown is dependent on the balance between the proteolytic enzymes
metalloproteinases (MMPs) and their inhibitors, tissue
inhibitors of metalloproteinase (TIMPs). High levels of
MMPs have been demonstrated at the site of the inflammatory infiltrate
in the fibrous cap.50 While smooth muscle cell
apoptosis has also been demonstrated in unstable
plaques,51 studies in cultured cells suggest that the T
lymphocytes may be central to plaque instability.52 53 T
cells can induce macrophages to secrete MMPs via stimulation of
CD40, and in addition, through production of interleukin-1, can
promote SMC apoptosis (Figure 3
).52 53 Accumulation of T
cells and macrophages in the fibrous cap has been correlated
with plaque ulceration, lumen thrombosis, TCD emboli frequency, and
cortical symptoms in the carotid circulation.8 39

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Figure 3. Vascular biology of the unstable plaque. T
lymphocytes, by stimulating macrophages and inducing
apoptosis of smooth muscle cells, may be central to plaque
destabilization. Release of MMPs from macrophages promotes
collagen breakdown.
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Cellular Recruitment to the Plaque
Leukocyte recruitment is dependent on the expression of adhesion
molecules on the intimal surface, plus the release of soluble factors
favoring leukocyte attraction and activation. In vitro
studies54 have demonstrated that leukocyte adhesion and
transmigration is an orderly process requiring initially rolling along
the endothelium promoted by interaction between
endothelial selectins and leukocyte ligands. Further
leukocyte infiltration is promoted by attractants such as monocyte
chemotactic protein (MCP-1), while firm adhesion requires
binding of leukocyte CD18 and endothelial adhesion
molecules such as intercellular adhesion molecule-1 (ICAM-1) and
vascular cellular adhesion molecule-1 (VCAM-1). Expression of these
adhesion molecules has been studied in coronary plaques, and
increased expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 has
been correlated with high density of macrophages and T
lymphocytes in the fibrous cap (Table 5
).56 58 One
study40 has demonstrated increased ICAM-1 expression in
the stenotic region of symptomatic plaques (Table 4
). It is uncertain by which route leukocytes enter the plaque.
Three possibilities exist: first, via the intima lining the lumen;
second, via the vasa vasorum; and third, via the new vessels often
demonstrated within the intima of complex plaques
(neovasculature).58 OBrien et al,58 in
studying coronary plaques, have demonstrated that the
expression of E-selectin, ICAM-1, and VCAM-1 was twice as common in the
neovasculature of the plaque as the arterial lumen and
correlated this with density of macrophages and T cells. The
authors suggest that these immature vessels may be the most important
source of the inflammatory focus.
Plaque Thrombogenicity
On plaque rupture, exposure of the necrotic core to the
circulation promotes thrombosis. This appears to be an important
mechanism of plaque progression, in addition to embolization.
Postmortem studies59 suggest that plaque rupture is often
asymptomatic. Clearly, symptoms are more likely to develop
if the developing thrombus is larger. Increased expression of tissue
factor, the most important stimulant of the clotting cascade, has been
demonstrated in plaques from patients with unstable angina or
myocardial infarction.60 Interestingly, in an animal
model, plaque rupture is associated with increased tissue factor
production from circulating monocytes, which is reduced by
treatment with a nitric oxide precursor.61 As yet, no data
have been published on the thrombogenicity of the
symptomatic carotid plaque.
Triggers to Plaque Rupture
Because plaque rupture depends on a balance between the
tensile strength of the plaque and stress exerted on it, rupture is
likely triggered by a sudden increase in stress on the plaque or, less
likely, by a sudden reduction in plaque strength. Possible causes
include sudden increases in blood pressure or pulse rate (eg, during
exercise or sympathetic system stimulation),62 vasospasm
forcing plaque contents through a weakened plaque cap,63
and hemorrhage into the plaque.64 There are
presently no data to support triggers of plaque rupture in the
carotid circulation.
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Potential Therapeutic Measures to Stabilize the Unstable
Carotid Plaque
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Statins
There is now good evidence that treatment with statins lowers
stroke
risk by approximately 30%.
65 This effect is likely
to be multifactorial.
Lowering cholesterol will reduce
ischemic heart disease as well
as carotid and
intracerebral atherosclerosis. Thus,
some of
the benefit from statins likely result from decreased incidence
of
cardiac embolization. Interestingly, as in the coronary
circulation,
the reduction in carotid intimal thickening is very small
as
a result of statin therapy,
66 and therefore the
important effect
of therapy is likely to be plaque stabilization.
Experimental
studies in a rabbit model of
atherosclerosis have demonstrated
that lowering
cholesterol leads to stabilization of atherosclerotic
plaques
over a period of 8 to 16 months. There is increased collagen
and
decreased inflammatory cells, MMPs, and proteolytic activity
in the
fibrous cap.
67 Statins also have a range of other
potential
benefits, including improved endothelial
function,
68 reduction
in
hypercoagulability,
69 and beneficial modulation of immune
function,
70 which likely contributes to their effect in
stroke reduction.
ß-Blockers
These drugs have been shown to reduce reinfarction and sudden
death following myocardial infarction71 and therefore have
been suggested to have a role in plaque stabilization or blunting of
triggers to plaque rupture.72
Anticoagulants and Antiplatelet Agents
The principal effect of these agents is to reduce the complication
of plaque rupture rather than stabilize plaques, although the
anti-inflammatory effect of aspirin might have a stabilizing
effect.
Tetracyclines
In animal models of aortic aneurysms, doxycycline reduces
aneurysm growth by inhibiting MMP activity.73 The
similar effect of tetracyclines in carotid plaques may reduce the risk
of plaque rupture.
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Identification of the Unstable Carotid Plaque
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Ultrasound
Ultrasound studies
74 have demonstrated an association
between
echolucent plaques, surface ulceration, and symptoms.
Echolucent
plaques are lipid rich
75 and have also been
shown to herald
an increased risk of subsequent development of TIA or
stroke
76 ; unfortunately, clear prediction of stroke
without warning
has not been demonstrated. Improved determination of
plaque
morphology with computer-guided assessment of gray-scale median
may
better predict stroke risk.
42
Angiography
Although ulceration demonstrated on angiography has been
associated with increased risk of stroke,77 in general it
does not appear possible to detect unstable plaques from
angiography.78
Thermography
Studies on carotid endarterectomy
samples79 have related increased temperature to
inflammatory cell density and demonstrated cellular areas through
infrared thermography.
Radiolabeled Imaging
Radiolabeled antibodies to macrophages or adhesion
molecules could potentially identify unstable
plaques.80
Conclusions and Further Research
Comparisons of plaques from symptomatic and
asymptomatic patients have revealed characteristic features
of unstable carotid plaques. These studies, along with in vitro work,
suggest that infiltration of inflammatory cells into the fibrous cap of
a carotid plaque is a key step. Subsequent release of
collagen-digesting enzymes and cytokines that promote smooth
muscle cell apoptosis can weaken the surface of the plaque,
thus promoting thrombosis, embolization, and arterial
occlusion. Future studies investigating the recruitment of inflammatory
cells and release of mediators may lead to strategies of plaque
stabilization. Uniformity in reporting and analyzing carotid plaques
will be an important consideration in these studies.
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Acknowledgments
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The BUPA Foundation provided financial support for this
work.
Received August 25, 1999;
revision received December 2, 1999;
accepted December 2, 1999.
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