Histological Features of Symptomatic Carotid Plaques in
Relation to Age and Smoking
The Oxford Plaque Study
Jessica N.E. Redgrave, MRCP; Joanne K. Lovett, DPhil; Peter M. Rothwell, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Background and Purpose—Rates of incident and recurrent cardiovascular events rise steadily with age, due partly to more
extensive atherosclerotic burden. However, in patients with similarly severe symptomatic carotid stenosis, increasing
age is associated with a greater risk of ipsilateral ischemic stroke. This effect may be due to age-related differences in
the pathology of symptomatic carotid plaques. However, previous studies of plaque pathology in relation to age have
not accounted for potential confounders, particularly smoking, which is often less prevalent in the elderly population
undergoing endarterectomy.
Method—We related patient age (⬍55, 55 to 64, 65 to 74, 75⫹ years) and smoking habit (never, exsmoker, recent smoker,
and current smoker; and number of cigarettes smoked per day) to detailed histological assessments of 526 carotid
plaques from consecutive patients undergoing carotid endarterectomy for symptomatic carotid stenosis.
Results—Three hundred seventy-nine (72.1%) patients were male (mean/SD age 66.6/8.7). Current/recent smokers were
on average 7 years younger at carotid endarterectomy than ex-/never smokers (P⬍0.001), and age at carotid
endarterectomy decreased with increasing number of cigarettes smoked per day (P trend⫽0.005). Plaques from
current/recent smokers had a lower prevalence of intraplaque hemorrhage (P -trend⫽0.01), but histology was otherwise
similar to that in ex-/never smokers, and both groups showed similar changes with age. With increasing age, plaque
calcification and large lipid core increased (P⬍0.001 and P⫽0.01, respectively) and fibrous tissue (P⫽0.01) decreased,
but lymphocyte infiltration of the plaque (P⫽0.03) and cap (P⫽0.002) and overall plaque inflammation (P⫽0.03) also
decreased such that overall plaque instability was unrelated to age.
Conclusion—Smoking is associated with a lower age at carotid endarterectomy suggesting that it may accelerate the
development and/or progression of atherosclerosis. However, the mechanisms of plaque instability seem largely
unrelated to smoking. Plaques from younger patients had greater inflammatory cell infiltration, whereas those from older
patients had a larger lipid core, but there were no age trends in overall plaque instability suggesting the increased risk
of stroke in the elderly with symptomatic carotid stenosis is due to other factors. (Stroke. 2010;41:2288-2294.)
Key Words: atherosclerosis 䡲 endarterectomy 䡲 risk factors 䡲 smoking
T
he incidence of stroke and of acute ischemic events in
other vascular territories increases steeply with age.1
These age trends are due partly to an increased prevalence
with age of intermediate phenotypes such as atherosclerosis,
but it is also possible that the characteristics of these
phenotypes change with age. For example, age ⱖ75 years is
an independent predictor of increased risk of ipsilateral
ischemic stroke on medical treatment (and hence benefit from
carotid endarterectomy [CEA]) in patients with similarly
severe symptomatic carotid stenosis,2 and older patients have
been found to have an unexpectedly high periprocedural risk
of stroke and death due to carotid stenting.3,4 One possible
explanation for these observations is that carotid plaque
instability changes with age.
Two previous histology studies of CEA specimens in
relation to patient age have reported conflicting results. The
first used a multivariate discriminant analysis in 180 symptomatic plaques and found that older patients tended to have
plaques with a high fibrous tissue content.5 A more recent
study found that plaque lipid content increased with age but
that there was no change in calcification or macrophage
content.6 However, in that study, asymptomatic and symptomatic plaques were combined in the analyses and no
adjustment was made for potentially confounding vascular
risk factors such as smoking or hypertension. Because the
prevalence of carotid plaques increases with smoking, male
sex and adverse lipid profile as well as age, and the effects of
these other risk factors are particularly strong at younger
Received April 9, 2010; final revision received May 16, 2010; accepted June 1, 2010.
From the Stroke Prevention Research Unit, University Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
Correspondence to Peter M. Rothwell, PhD, Stroke Prevention Research Unit, Department of Clinical Neurology, University of Oxford, Level 6, West
Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail [email protected]
© 2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.587006
2288
Redgrave et al
Table 1.
Carotid Plaques, Age, and Smoking
2289
Baseline Clinical Characteristics in Relation to Age Group
Age Group, Years
⬍55 (n⫽54)
55– 64 (n⫽151)
65–74 (n⫽231)
ⱖ75 (n⫽90)
P for Heterogeneity
Male sex
36 (66.7)
110 (72.8)
172 (74.5)
61 (67.8)
0.51
Median/interquartile ipsilateral stenosis
85 (70–90)
83 (70–90)
85 (75–90)
85 (75–91)
9 (16.7)
27 (17.9)
70 (30.3)
34 (37.8)
⬍0.001
Most recent event⫽stroke
17 (31.5)
44 (29.1)
68 (29.4)
30 (33.3)
0.90
Median/interquartile range days since event
67 (30–133)
86 (32–134)
82 (41–155)
93 (36–163)
0.79
Smoked in last 6 months
34 (63.0)
92 (60.9)
69 (29.9)
14 (15.6)
Treated hypertension
26 (48.1)
78 (51.7)
132 (57.1)
64 (71.1)
0.01
14 (25.9)
52 (34.4)
51 (22.1)
29 (32.2)
0.05
5 (9.3)
18 (11.9)
48 (20.8)
15 (16.7)
0.06
Contralateral ⱖ50% stenosis
␤-blocker
Angiotensin-converting enzyme inhibitor
Diuretic
Calcium channel blocker
Other antihypertensive
0.14
⬍0.001
9 (16.7)
38 (25.2)
71 (30.7)
36 (40.0)
0.01
10 (18.5)
37 (24.5)
62 (26.8)
27 (30.0)
0.46
4 (7.4)
12 (7.9)
11 (4.8)
11 (12.2)
0.14
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Mean (SD) systolic blood pressure
149.8 (18.2)
155.3 (22.2)
160.4 (21.1)
163.4 (22.4)
0.001
Mean (SD) diastolic blood pressure
87.2 (9.6)
0.65
85.9 (13.2)
86.6 (12.2)
84.8 (14.0)
19 (36.5)
36 (24.5)
43 (19.0)
22 (24.4)
0.06
On dual antiplatelet agents
8 (14.8)
21 (13.9)
20 (8.7)
18 (20.0)
0.04
Diabetes
3 (5.6)
16 (10.6)
25 (10.8)
9 (10.0)
0.70
Previous myocardial infarction
3 (5.6)
21 (13.9)
30 (13.0)
9 (10.0)
0.36
Peripheral vascular disease
9 (16.7)
24 (15.9)
42 (18.2)
19 (21.1)
0.77
Treated hyperlipidemia
ages,7 any study of plaque pathology in relation to age should
consider these as possible interactions. We therefore studied
carotid plaque histology in relation to age, smoking, and other
vascular risk factors in symptomatic patients undergoing
CEA.
Method
We studied consecutive carotid plaques from 526 patients undergoing CEA for symptomatic stenosis in Oxford, UK (the Oxford Plaque
Study). The degree of stenosis had been measured using carotid
Doppler ultrasound by experienced technicians before surgery.
Plaques were considered “symptomatic” if the patient had experienced either an ocular or hemispheric transient ischemic attack or
stroke on the side ipsilateral to the carotid stenosis. At the time of the
study, it was policy to operate on patients with symptomatic carotid
stenosis of ⱖ70% according to the European Carotid Surgery Trial
criteria.8 Patients undergoing CEA for restenosis or radiotherapyinduced carotid stenosis were excluded.
Our methods for plaque processing and histological assessments
have been described elsewhere,9 –11 but briefly, the excised plaque
was fixed in formalin immediately after removal and the portion of
carotid bifurcation showing maximum disease was cut transversely.
Further divisions were made at 3-mm intervals along the length of
the plaque and all sections were embedded in paraffin wax. At the
same time in 2003, all 526 plaques were taken and 5-␮m transverse
sections from each wax block were stained with hematoxylin and
eosin and Elastin van Gieson and CD68 and CD3 antibody to stain
for macrophages and lymphocytes, respectively. A second researcher
experienced in vascular pathology examined all the histology sections blind to the clinical details. The following features were graded
on simple, reproducible semiquantitative scales as published previously;9 –11 cap rupture, lipid core size, foam cells, vascularity, plaque
and cap infiltration with macrophages and lymphocytes, proportion
of fibrous tissue, calcification, intraplaque hemorrhage, and surface
thrombus. Briefly, lipid core was defined as amorphous material
containing cholesterol crystals and was considered “large” if it
occupied ⬎50% of the thickness of the plaque or ⬎25% of the total
cross-sectional area. Intraplaque hemorrhage was recorded if there
was an area of erythrocytes within the plaque causing disruption of
plaque architecture or when there was clear evidence of organized
hemorrhage with the accumulation of hemosiderin-laden macrophages or iron deposition on plaque connective tissue.12 Calcification was defined as stippling or calcified nodules. Marked inflammation in the plaque or cap was defined as ⬎1 group of 20
lymphocytes or 50 macrophages.9 Cap rupture was recorded if there
was clear communication between the lipid core and the lumen with
a break in the fibrous cap, which did not appear to have been created
during surgery. Surface thrombus was defined as an organized
collection of fibrin and red blood cells in the lumen.13 A plaque with
“thin fibrous cap” was defined where the minimum cap thickness
was ⬍200 ␮m as measured using a calibrated graticule in the
microscope eyepiece.11
Plaques were also classified according to the American Heart
Association (AHA) classification of coronary atherosclerosis in
which Grade 6 represented plaques complicated by hemorrhage,
rupture, or thrombus.14 However, the AHA grade does not take into
account important determinants of plaque instability such as lipid
core size or inflammation. Thus, those nonruptured plaques with ⱖ2
other features of marked instability, for example, large hemorrhage,
marked inflammation, large lipid core, or thin fibrous cap, were
classified as “unstable” as well as all ruptured plaques.9 This
assessment of “overall instability” was based on accepted descriptions of unstable plaque in the coronary circulation.15
We have previously shown that our histological assessments are
reproducible and that there is reasonable agreement between adjacent
3-mm plaque sections.10 Furthermore, in a study of 128 plaques, we
have shown that several histology features (eg, cap rupture, intraplaque hemorrhage, large lipid core, and “unstable plaque”) are
strongly associated with plaque ulceration on angiography.9
Clinical Data Collection
All patients were reviewed before consideration of CEA by a
neurologist and the dates, nature, and duration of ipsilateral ischemic
episodes were recorded. An event was classified as a stroke if
cerebral or retinal ischemic symptoms persisted ⬎24 hours. The
2290
Stroke
October 2010
Table 2. Mean/SD Age According to No. of Cigarettes
Smoked per Day in Patients Who Had Smoked Within the 6
Months Before CEA
Results
Cigarettes per Day*
No.
Mean Age (SD)
1–9
21
65.0 (8.37)
10 –19
47
63.7 (7.11)
20–29
60
61.9 (8.99)
ⱖ30
26
58.7 (8.84)
Patients were operated a median of 85 days (interquartile
range, 34 to 150 days) after their most recent symptomatic
ischemic event, which was a stroke in 159 (30.2%) and a
transient ischemic attack in 367 (69.8%). Three hundred
seventy-nine patients (72.1%) were male (mean/SD age
66.6/8.7) and the mean/SD stenosis of the operated artery was
80.7% (16.8). Four hundred eighty-two patients (91.6%) were
on antithrombotic therapy at the time of surgery and 67
(12.7%) were on dual antiplatelet agents (Table 1). Three
hundred three (57.6%) were on treatment for hypertension,
120 (23%) were on lipid-lowering therapy, and 53 (10.1%)
were diabetic. Two hundred nine patients (39.7%) were
current or recent smokers. Only 85 patients (16.2%) had
never smoked.
Fifty-four (10.2%) patients were aged ⬍55 years, 151
(28.7%) were 55 to 64, 231 (43.9%) were 65 to 74, and 90
(17.1%) were aged ⱖ75 years. The prevalence of male sex,
diabetes, and the nature (stroke versus transient ischemic
attack) and timing of most recent ischemic symptoms before
CEA did not differ across the age subgroups (Table 1). The
prevalence of treated hypertension increased with age
(P⫽0.01) as did the use of dual antiplatelet agents (P⫽0.04),
but a history of smoking within the previous 6 months
decreased markedly with age (63.0% (age ⬍55 years) versus
60.9% (55– 64 years) versus 29.9% (65–74 years) versus
15.6% (ⱖ75 years; P trend ⬍0.001). Smokers were on
*No. of cigarettes smoked per day known for 154 (74%) smokers.
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responsible clinician at the time of admission for CEA used a
standardized data collection form to collect data on age, sex,
percentage carotid stenosis (ipsilateral and contralateral to the
ischemic event), hypertension, hyperlipidemia, smoking, medical
history, and current medication. Blood pressure readings taken at
preoperative assessment and at the time of admission for CEA were
recorded. Age of the patient at CEA was coded as ⬍55, 55 to 64, 65
to 74, and ⱖ75 years. Smoking was coded as current smoker, recent
smoker (quit within 6 months), exsmoker (quit ⬎6 months before
CEA), or never smoked.
Statistical Analyses
Baseline clinical characteristics in age subgroups were compared
using an unpaired t test or ␹2 tests as appropriate. A binary logistic
regression model was used to determine the significance of trend for
the prevalence of histology features to change with increasing age
and worsening smoking habit. We determined age-related trends in
histology features for smokers and nonsmokers separately. SPSS
(Version 14.0) was used for the analyses.
Table 3.
Prevalence of Histology Features in Relation to Smoking Status
Smoking
Never
(n⫽85)
Exsmoker
(n⫽232)
Recent
(n⫽62)
Current
(n⫽147)
P Trend*
Morphological features
Cap rupture
52 (61.2)
141 (61.8)
28 (45.9)
85 (58.2)
0.44
Large lipid core
58 (68.2)
136 (58.6)
31 (50.0)
95 (64.6)
0.61
Predominantly fibrous
25 (29.4)
75 (32.3)
27 (43.5)
45 (30.6)
0.73
Surface thrombus
28 (33.3)
70 (30.3)
20 (32.3)
52 (35.6)
0.70
Intraplaque hemorrhage
62 (72.9)
157 (67.7)
35 (56.5)
86 (58.5)
0.01
Marked vascularity
28 (32.9)
85 (37.0)
19 (30.6)
45 (30.6)
0.36
Marked calcification
46 (54.1)
113 (48.7)
29 (46.8)
65 (44.2)
0.73
Many foam cells
29 (34.1)
90 (39.0)
29 (46.8)
70 (47.6)
0.13
Thin fibrous cap†
36 (48.6)
99 (54.4)
19 (38.0)
55 (46.6)
0.32
Plaque macrophages
56 (65.9)
146 (64.0)
44 (74.6)
93 (63.3)
0.28
Plaque lymphocytes
43 (51.8)
122 (55.5)
33 (57.9)
85 (59.0)
0.91
Plaque inflammation
53 (63.1)
148 (65.2)
48 (77.4)
97 (66.9)
0.72
Cap macrophages†
58 (78.4)
128 (69.9)
32 (68.1)
91 (73.4)
0.79
Cap lymphocytes†
34 (45.9)
76 (44.2)
20 (42.6)
58 (47.2)
0.32
Cap inflammation†
57 (77.0)
130 (71.0)
32 (64.0)
88 (70.4)
0.20
AHA Grade 6
42 (50.0)
117 (50.4)
28 (45.2)
77 (52.7)
0.93
“Unstable plaque”
56 (66.7)
146 (64.0)
34 (57.6)
95 (65.5)
0.73
Marked inflammation
Composite assessments
*P value for trend across smoking categories adjusted for age and sex.
†Ninety-four plaques excluded from cap analysis as insufficient cap was visible for reliable assessment (60 关19%兴
never/exsmokers and 34 关16%兴 current/recent smokers).
Redgrave et al
Carotid Plaques, Age, and Smoking
2291
Table 4. Carotid Plaque Histology Features According to Age (Values Are No. [%] Unless
Otherwise Stated)
Age Group, Years
⬍55
(n⫽54)
55– 64
(n⫽151)
65–74
(n⫽231)
ⱖ75
(n⫽90)
P*
Morphological features
Cap rupture
28 (51.9)
86 (57.3)
138 (60.3)
54 (62.1)
0.39
Large lipid core
26 (48.1)
93 (61.6)
141 (61.0)
60 (66.7)
0.01
Predominantly fibrous
26 (48.1)
48 (31.8)
72 (31.2)
26 (28.9)
0.01
Surface thrombus
16 (29.6)
58 (38.4)
69 (30.3)
27 (30.0)
0.61
Intraplaque hemorrhage
31 (57.4)
100 (66.2)
149 (64.5)
60 (66.7)
0.88
Marked vascularity
15 (27.8)
53 (35.1)
79 (34.5)
30 (33.3)
0.59
Marked calcification
15 (27.8)
63 (41.7)
120 (51.9)
55 (61.1)
⬍0.001
Many foam cells
29 (53.7)
70 (46.7)
89 (38.5)
30 (33.3)
0.07
Thin fibrous cap†
21 (50.0)
53 (43.1)
98 (51.9)
37 (52.9)
0.49
Plaque macrophages
37 (68.5)
103 (69.1)
151 (66.2)
48 (54.5)
0.09
Plaque lymphocytes
34 (63.0)
86 (60.6)
123 (55.9)
40 (45.5)
0.03
Plaque inflammation
37 (68.5)
109 (73.6)
154 (67.2)
46 (52.9)
0.03
Cap macrophages†
30 (68.2)
86 (70.5)
144 (74.6)
49 (71.0)
0.54
Cap lymphocytes†
25 (56.8)
63 (52.9)
78 (42.2)
22 (32.4)
0.002
Cap inflammation†
33 (75.0)
90 (72.0)
135 (69.6)
49 (71.0)
0.51
AHA Grade 6
24 (44.4)
85 (56.3)
109 (47.4)
46 (51.7)
0.87
“Unstable plaque”
32 (59.3)
98 (66.2)
141 (62.4)
60 (68.2)
0.67
Marked inflammation
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Composite assessments
*P values for trend with age as a continuous variable adjusted for sex, smoking and hypertension.
†Ninety-four plaques excluded from cap analysis as insufficient cap was visible for reliable assessment.
average 7 years younger at CEA than nonsmokers (mean age
62.6 versus 69.2 years, P⬍0.001). Furthermore, mean age at
CEA decreased with rising daily cigarette consumption in the
smokers (P trend⫽0.005; Table 2).
With increased smoking, the prevalence of intraplaque
hemorrhage decreased (P trend⫽0.01). However, other histology features, for example, plaque inflammation (P⫽0.72),
large lipid core (P⫽0.61), and unstable plaque (P⫽0.73),
were not associated with smoking habit (Table 3). Furthermore, in patients who were current/recent smokers and for
whom data on cigarettes smoked/day were available
(n⫽154), there were no associations between any of the
histology features and increasing daily cigarette consumption,
for example, intraplaque hemorrhage (P trend⫽0.97), large
lipid core (P⫽0.14), and “unstable plaque” (P⫽0.96).
As age of the patients at CEA increased, the prevalence of
marked calcification (P⬍0.001) and large lipid core
(P⫽0.01) increased, whereas marked lymphocyte infiltration
of the cap and plaque (P⫽0.002 and 0.03, respectively),
marked overall plaque inflammation (P⫽0.03), and fibrous
tissue (P⫽0.01) decreased (Table 4). In contrast, there was no
association between the prevalence of marked macrophage
infiltration of the plaque (P⫽0.09) and cap (P⫽0.54), AHA
Grade 6 (P⫽0.87) or “unstable plaque” (P⫽0.67), and age.
The direction of these age-associated trends in the prevalence
of histology features was similar in current/recent smokers
and ex-/never smokers, but was particularly marked in
current/recent smokers (Table 5).
Discussion
Previous histology studies of CEA specimens in relation to
age have had conflicting results but did not fully account for
other vascular risk factors.5,6 In the largest carotid plaque
histology study to date, we have found that smoking was
associated with a lower age at CEA and was therefore a
potentially important confounding factor but that the mechanisms of plaque instability appeared to be largely unrelated to
smoking. Plaques from younger patients had greater inflammatory cell infiltration, whereas those from older patients had
a larger lipid core, but the lack of age trends in overall
instability suggests that the increased risk of stroke on
medical treatment alone in older patients with symptomatic
carotid stenosis is due to other factors.
The negative association between smoking and age at CEA
in our study is consistent with evidence that smoking accelerates the development and/or progression of atherosclerosis.
The exact mechanisms of this effect are unclear but may
involve granulocyte activation,16 increased levels of fibrinogen,17 and free-radical induced endothelial injury,18,19 all of
which have been associated with cigarette smoking. Furthermore, cigarette smoke contains bacterial endotoxin, a potent
mediator of inflammation.20 In our study, smoking was not
associated with increased plaque inflammation, but there was
a negative association with intraplaque hemorrhage, which
may reflect a hypercoagulable state.17 Nevertheless, the broad
similarities between plaques from smokers and nonsmokers
2292
Stroke
October 2010
Table 5. Plaque Histology Features With Age According to Whether Patients Had Smoked Within
the Preceding 6 Months (Values Are No. [%] Plaques With Feature)
Age Subgroup, Years
⬍55
(n⫽54)
55– 64
(n⫽151)
65–74
(n⫽231)
ⱖ75
(n⫽90)
P*
Yes (n⫽209)
16 (47.1)
47 (51.6)
No (n⫽317)
12 (60.0)
39 (66.1)
43 (63.2)
7 (50.0)
0.45
95 (59.0)
47 (64.4)
0.66
Morphology
Smoked in last 6 months
Cap rupture
Large lipid core
Yes
15 (44.1)
55 (59.8)
44 (63.8)
12 (85.7)
0.006
No
11 (55.0)
38 (64.4)
97 (59.9)
48 (63.2)
0.38
Predominantly fibrous
Yes
18 (52.9)
31 (33.7)
21 (30.4)
2 (14.3)
0.006
No
8 (40.0)
17 (28.8)
51 (31.5)
24 (31.6)
0.33
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Surface thrombus
Yes
10 (29.4)
35 (38.0)
22 (32.4)
5 (35.7)
0.92
No
6 (30.0)
23 (39.0)
47 (29.4)
22 (28.9)
0.50
Intraplaque hemorrhage
Yes
17 (50.0)
56 (60.9)
40 (58.0)
8 (57.1)
0.59
No
14 (70.0)
44 (74.6)
109 (67.3)
52 (68.4)
0.67
Marked vascularity
Yes
10 (29.4)
29 (31.5)
17 (24.6)
8 (57.1)
0.67
No
5 (25.0)
24 (40.7)
62 (38.8)
22 (28.9)
0.37
Yes
10 (29.4)
38 (41.3)
38 (55.1)
8 (57.1)
0.03
No
5 (25.0)
25 (42.4)
82 (50.6)
47 (61.8)
0.001
Marked calcification
Many foam cells
Yes
19 (55.9)
46 (50.0)
29 (42.0)
5 (35.7)
0.12
No
10 (50.0)
24 (41.4)
60 (37.0)
25 (32.9)
0.39
Thin fibrous cap†
Yes
11 (47.8)
29 (37.7)
28 (50.0)
6 (50.0)
0.78
No
10 (52.6)
24 (52.2)
70 (52.6)
31 (53.4)
0.61
Marked inflammation
Smoked in last 6 months
Plaque macrophages
Yes
24 (70.6)
62 (68.9)
45 (66.2)
6 (42.9)
0.06
No
13 (65.0)
41 (69.5)
106 (66.3)
42 (56.8)
0.47
Yes
25 (73.5)
51 (58.6)
35 (53.0)
7 (50.0)
0.05
No
9 (45.0)
35 (63.6)
88 (57.1)
33 (44.6)
0.24
Plaque lymphocytes
Plaque inflammation
Yes
27 (79.4)
66 (72.5)
44 (63.8)
8 (61.5)
0.01
No
10 (50.0)
43 (75.4)
110 (68.8)
38 (51.4)
0.36
Cap macrophages†
Yes
18 (72.0)
55 (73.3)
44 (74.6)
6 (50.0)
0.23
No
12 (63.2)
31 (66.0)
100 (74.6)
43 (75.4)
0.06
Yes
15 (60.0)
40 (53.3)
19 (32.8)
4 (33.3)
0.001
No
10 (52.6)
23 (52.3)
59 (46.5)
18 (32.1)
Cap lymphocytes†
0.12
(Continued)
Redgrave et al
Table 5.
Carotid Plaques, Age, and Smoking
2293
Continued
Age Subgroup, Years
⬍55
(n⫽54)
55– 64
(n⫽151)
65–74
(n⫽231)
ⱖ75
(n⫽90)
P*
Yes
20 (80.0)
55 (70.5)
No
13 (68.4)
35 (74.5)
38 (63.3)
7 (58.3)
0.06
97 (72.4)
42 (73.7)
0.41
Yes
14 (41.2)
No
10 (50.0)
50 (54.3)
34 (50.0)
7 (50.0)
0.74
35 (59.3)
75 (46.3)
39 (52.0)
0.97
Yes
No
18 (52.9)
58 (65.2)
44 (65.7)
9 (64.3)
0.87
14 (70.0)
40 (67.8)
97 (61.0)
51 (68.9)
0.73
Cap inflammation†
Composite assessments
AHA Grade 6
Unstable plaque
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
*P values for trend with age as continuous variable adjusted for sex and hypertension.
†Ninety-four plaques excluded from cap analysis as insufficient cap was visible for reliable assessment (60 关19%兴
never/exsmokers and 34 关16%兴 current/recent smokers).
and the lack of association between rising daily cigarette
consumption and histology features suggest that the overall
mechanisms of plaque instability are similar in smokers and
nonsmokers.
Advancing age was associated with increased plaque calcification and a large lipid core and decreased infiltration of
the plaque and cap with lymphocytes, but the prevalence of
“unstable plaque” did not increase with age. Therefore, the
increased risk of recurrent stroke in the elderly2 may not be
due to differences in plaque pathology, but may instead be
due to other factors such as reduced collateral circulation,
impaired cerebral autoregulation,21 aspirin resistance,22 or
hypertension.23 Of note, the elderly patients in our study had
greater mean blood pressure than younger patients despite a
greater use of antihypertensive medication (Table 1).
The age-related trends in histology were more striking
when analyses were confined to current/recent smokers, but
this was probably due to relatively large numbers of patients
in the 2 youngest age categories (⬍55 and 55 to 64 years) of
smokers between which the greatest differences in the prevalence of the histology features were seen. Overall, the age
trends in histology features were similar in current/recent
smokers and ex-/never smokers.
The increase in plaque calcification with age was not
unexpected. In the coronary arteries, calcification on CT,
which is a marker of coronary plaque burden24 and future
cardiovascular events,25 has been found to increase with
age.26 In relation to the carotid bifurcation, a correlation
between severe lesion calcification and stroke after stenting
has been reported.27 Taken together with the findings from
the lead-in phase of the Carotid Revascularization Endarterectomy versus Stent Trial (CREST),3 that increased patient
age is associated with increased risk of periprocedural stroke,
it is therefore possible that age-associated plaque calcification
is partly responsible, perhaps by contributing to emboli
formation.28 Future prospective studies of plaque characteristics in relation to stent outcomes may help to clarify this
further.
There were several potential limitations to our study. First,
data on pack-years of smoking, which might have revealed
clearer associations with plaque histology,29 were not available. However, it is reasonable to assume that the older
smokers in our study had accumulated more pack-years than
young smokers. A second limitation is that only patients fit
enough to undergo CEA were included in our study and
patients with severe/fatal strokes would have been systematically excluded. Because stroke mortality increases with age,1
the effects of such selection bias may have been more marked
in the older patients. Third, although the prevalence of carotid
stenosis increases with age, the rates of diagnosis and CEA
tend to fall in clinical practice, especially in patients ⬎80
years,30 which may also have led to some selection bias.
Fourth, there was a time lapse between the most recent
ischemic symptoms and CEA and we have shown in a
previous study that certain histological features decline with
time since stroke, especially plaque infiltration with macrophages.31 However, because the proportion of patients with
stroke and the median/interquartile range number of days
since most recent ischemic event were similar across the
patient age and smoking subgroups, these factors were
unlikely to have been a source of bias in the analyses. Fifth,
because this was a study of plaque histology, it was necessarily cross-sectional and was therefore subject to potential
bias from risk factors we have not accounted for. An
alternative way of assessing how plaques change with aging
of the patient would be to perform a longitudinal study with
serial in vivo plaque imaging over many years. This would
allow subjects to act as internal controls and allow risk factor
profiles to be more easily monitored, for example, changes in
smoking habits with time. However, such a study would have
to be extremely large to capture sufficient numbers of patients
who go on to develop symptomatic carotid stenosis. Furthermore, because in vivo plaque imaging techniques currently
lack the resolution to detect some plaque features (eg, thin
fibrous cap and inflammation) reliably, plaques would ideally
still have to be harvested at endarterectomy for histological
analysis.
2294
Stroke
October 2010
In conclusion, although smoking may well accelerate the
progression of carotid atherosclerosis, the underlying mechanisms of plaque instability appear to be similar in smokers
and nonsmokers. In our patient population, plaques did not
become more unstable overall with increasing age, suggesting
the increased early risk of recurrent stroke in elderly patients
with symptomatic carotid stenosis may be due to factors other
than plaque instability.
Acknowledgments
We thank Patrick J. Gallagher for his contributions to the article.
Source of Funding
Funding provided by the Stroke Association and the NIHR Biomedical Research Centre, Oxford.
Disclosures
None.
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
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Histological Features of Symptomatic Carotid Plaques in Relation to Age and Smoking:
The Oxford Plaque Study
Jessica N.E. Redgrave, Joanne K. Lovett and Peter M. Rothwell
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Stroke. 2010;41:2288-2294; originally published online September 2, 2010;
doi: 10.1161/STROKEAHA.110.587006
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