Carotid Plaque, Intima Media Thickness, Cardiovascular
Risk Factors, and Prevalent Cardiovascular Disease in
Men and Women
The British Regional Heart Study
Shah Ebrahim, DM; Olia Papacosta, MSc; Peter Whincup, MB, PhD; Goya Wannamethee, PhD;
Mary Walker, MFPHM[Hon]; Andrew N. Nicolaides, FRCS; Surinder Dhanjil, MSc;
Maura Griffin, MSc; Gianni Belcaro, MD; Ann Rumley, PhD; Gordon D.O. Lowe, MD
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Background and Purpose—B-mode ultrasound is a noninvasive method of examining the walls of peripheral arteries and
provides measures of the intima-media thickness (IMT) at various sites (common carotid artery, bifurcation, internal
carotid artery) and of plaques that may indicate early presymptomatic disease. The reported associations between
cardiovascular risk factors, clinical disease, IMT, and plaques are inconsistent. We sought to clarify these relationships
in a large, representative sample of men and women living in 2 British towns.
Methods—The study was performed during 1996 in 2 towns (Dewsbury and Maidstone) of the British Regional Heart Study that
have an '2-fold difference in coronary heart disease risk. The male participants were drawn from the British Regional Heart
Study and were recruited in 1978–1980 and form part of a national cohort study of 7735 men. A random sample of women
of similar age to the men (55 to 77 years) was also selected from the age-sex register of the general practices used in the
original survey. A wide range of data on social, lifestyle, and physiological factors, cardiovascular disease symptoms, and
diagnoses was collected. Measures of right and left common carotid IMT (IMTcca) and bifurcation IMT (IMTbif) were made,
and the arteries were examined for plaques 1.5 cm above and below the flow divider.
Results—Totals of 425 men and 375 women were surveyed (mean age, 66 years; range, 56 to 77 years). The mean (SD) IMTcca
observed were 0.84 (0.21) and 0.75 (0.16) mm for men and women, respectively. The mean (SD) IMTbif were 1.69 (0.61) and
1.50 (0.77) mm for men and women, respectively. The correlation between IMTcca and IMTbif was similar in men (r50.36)
and women (r50.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very
common, affecting 57% (n5239) of men and 58% (n5211) of women. Severe carotid plaques with flow disturbance were
rare, affecting 9 men (2%) and 6 women (1.6%). Plaques increased in prevalence with age, affecting 49% men and 39% of
women aged ,60 years and 65% and 75% of men and women, respectively, aged .70 years. Plaques were most common
among men in Dewsbury (79% affected) and least common among men in Maidstone (34% affected). IMTcca showed a
different pattern of association with cardiovascular risk factors from IMTbif and was associated with age, SBP, and FEV1 but
not with social, lifestyle, or other physiological risk factors. IMTbif and carotid plaques were associated with smoking, manual
social class, and plasma fibrinogen. IMTbif and carotid plaques were associated with symptoms and diagnoses of
cardiovascular diseases. IMTbif associations with cardiovascular risk factors and prevalent cardiovascular disease appeared to
be explained by the presence of plaques in regression models and in analyses stratified by plaque status.
Conclusions—IMTcca, IMTbif, and plaque are correlated with each other but show differing patterns of association with risk factors and
prevalent disease. IMTcca is strongly associated with risk factors for stroke and with prevalent stroke, whereas IMTbif and plaque are
more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Our analyses suggest that
presence of plaque, rather than the thickness of IMTbif, appears to be the major criterion of high risk of disease, but confirmation of
these findings in other populations and in prospective studies is required. The association of fibrinogen with plaque appears to be
similar to its association with incident cardiovascular disease. Further work elucidating the composition of plaques using ultrasound
imaging would be helpful, and more data, analyzed to distinguish plaque from IMTbif and IMTcca, are required to understand the
significance of thicker IMT in the absence of plaque. (Stroke. 1999;30:841-850.)
Key Words: atherosclerosis n cardiovascular diseases n carotid arteries n risk factors n ultrasonography
Received June 4, 1998; revision received December 21, 1998; accepted January 8, 1999.
From the Department of Social Medicine, University of Bristol (UK) (S.E.); Department of Primary Care and Population Sciences, Royal Free Hospital
School of Medicine, London (UK) (O.P., P.W., G.W., M.W.); Irvine Laboratory for Cardiovascular Investigation and Research, Department of Vascular
Surgery, Imperial College School of Medicine, St Mary’s Hospital, London (UK) (A.N.N., S.D., M.G., G.B.); and University Department of Medicine,
Royal Infirmary, Glasgow, Scotland (A.R., G.D.O.L.).
Correspondence to Professor Shah Ebrahim, Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.
© 1999 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
841
842
Carotid Ultrasound and Cardiovascular Disease
B
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-mode ultrasound is a noninvasive method of examining
the walls of peripheral arteries and provides measures of
intima-media thickness (IMT), presence of stenosis, and
presence of plaques.1,2 The IMT corresponds to the intimamedia complex, which comprises endothelial cells, connective tissue, and smooth muscle and is the site of lipid
deposition in plaque formation.3
In healthy adults, IMT ranges from 0.25 to 1.5 mm,2,4 and
values .1.0 mm are often regarded as abnormal.3 IMT has
been proposed as a quantitative index of atherosclerosis of
value in monitoring disease progression and the effects of
treatment and as a surrogate end point in clinical trials.5 The
validity of IMT for these purposes has been assessed by
making comparisons of mean IMT in people with and without
clinical evidence of CVD6 – 8 and discriminatory ability has
been demonstrated.
Epidemiological studies, which are less prone to bias
inherent in clinical case series, have reported associations
between a range of cardiovascular risk factors (smoking,
blood pressure, elevated blood cholesterol) and IMT.4,9 –13
Age is one of the most powerful determinants of IMT, with
increases of from 0.01 to 0.02 mm per year,2,9 and consequently may confound comparisons of IMT made between
groups if appropriate age adjustment is not made.
Reported findings have demonstrated inconsistent associations between IMT, risk factors, and clinical disease4,14,15
and have also highlighted the importance of the presence and
severity of arterial wall plaque as determinants of clinical
events.16 Some of this variation in findings is likely to be due
to the method of measuring IMT: mean bifurcation, mean
bulb origin, mean common carotid, mean internal carotid, and
combinations of these. Correlations between these different
approaches are reported to be high. It has been suggested that
measurement of IMT at the “common carotid artery alone,
particularly for studies of association of risk factors with
carotid arterial disease, cohort studies, or clinical trials, in that
it, too, is associated with the status of coronary atherosclerosis” is a reasonable alternative to more detailed and technically difficult measurement at other sites.17 However, plaque
formation is not common in the common carotid artery. Since
thicker IMT bifurcation and bulb origin values tend to occur
in people who also have plaques,18 it is possible that presence
or absence of plaque, and not IMT at either the common
carotid or bifurcation sites, is the more relevant indicator of
early atherosclerosis.
Therefore, we sought to clarify the relationship between a
wide range of cardiovascular disease (CVD) risk factors,
prevalent CVDs, common carotid IMT (IMTcca), bifurcation
IMT (IMTbif), and plaques in a large and representative
sample of men and women in 2 British towns.
Subjects and Methods
The study was performed during 1996 in 2 towns (Dewsbury and
Maidstone) of the British Regional Heart Study that have an '2-fold
difference in coronary heart disease risk.19
Participants
The male participants were drawn from the British Regional Heart
Study. They were recruited in 1978 –1980 and form part of a national
cohort study of 7735 men who have been followed up for mortality
and nonfatal CVD events.19 A random sample of women of similar
age to the men (56 to 77 years) was also selected from the age-sex
register of the general practices used in the original survey.
Measurements
Lifestyle Factors
A self-administered questionnaire was used to obtain information on
smoking behavior, alcohol consumption, physical activity, and social
class. Subjects were classified into never, former, and current
smokers. In women there was an additional group who were
currently nonsmokers but who could not be classified into never
smokers or ex-smokers because of inconsistent responses on the
questionnaire; they were excluded from the analysis related to
smoking. Alcohol consumption was classified as none, occasional,
and “weekend or daily” drinking. Sporting activity was classified as
none, occasional, or frequent, as indicated by the subjects on the
questionnaire. Occupation was coded in accordance with the Registrar General’s occupation classification. Social class was derived on
the basis of the longest held occupation of each man or of each
husband in the case of married women. In the case of a single
woman, her own occupation was used. In the analysis, social class is
presented as manual or nonmanual occupations.
Biological Factors
Subjects had measurements of height, weight, waist-hip ratio, standing and sitting blood pressure, spirometry, and a 12-lead ECG
performed. Body mass index was calculated as an index of relative
weight and is presented in tertiles. The values of forced expiratory
volume in 1 second (FEV1) used in the analysis were height
standardized to a height of 1.73 m in men and 1.59 m in women,
which were the sample mean values. Blood was taken for lipids,
glucose, insulin, hematocrit, fibrinogen, and coagulation factor VII20
and for DNA extraction, with samples being separated and, when
appropriate, snap-frozen on dry ice in the field before transport to
central laboratories.
Symptoms, Preexisting Disease, and
Regular Medication
Information on chest pain, leg pain, and breathlessness was obtained
from the self- administered questionnaire. Subjects were also asked
to recall a physician’s diagnosis of stroke, high blood pressure, or
ischemic heart disease and details of current regular medication,
including antihypertensive drugs and aspirin.
Stroke Score and British Regional Heart Study Score
Two scores were computed from risk factor data. The Stroke Score
comprises data on systolic blood pressure (SBP), smoking, presence
of CVD, and age; scores in the top quintile predict a greatly
increased risk of suffering a stroke over the next 5 years.21 The
British Regional Heart Study Score (BRHS Score) for detection of
major coronary heart disease events comprises smoking-years, SBP,
cholesterol, diagnoses of ischemic heart disease and diabetes, angina,
and parental death from heart trouble.22 Scores in the top quintile
identified predict 59% of those who subsequently suffered from
coronary heart disease over 5 years. These scores were computed as
follows: Stroke Score5(93age)1(2.853SBP)1(70 if subject indicates angina)1(90 if smokes 1 to 20 cigarettes per day)1(130 if
smokes .20 cigarettes per day). BRHS Score5(53years of
smoking)1(33SBP)1(513cholesterol value)1(170 if subject recalls diagnosis of ischemic heart disease)1(100 if diagnosed with
angina)1(50 if parental history of heart trouble)2(95 if diabetic).
Ultrasound Measurements
Measurements were made with an Advanced Technology Laboratories HDI (high-definition imaging) 3000 triplex system with a
high-resolution broadband width linear array transducer L 7– 4 MHz.
Ultrasound parameters were preset with the use of a special IMT
program that kept constant the postprocessing map, dynamic range,
persistence, frame rate, and power output, and transmit gain control
was altered to obtain optimal quality images. Magnification and
Ebrahim et al
April 1999
843
consistent with previous reproducibility estimates from this laboratory. The mean difference between technicians showed no evidence
of bias and was 20.005 mm, with 95% limits of agreement of 20.12
to 10.11 mm.
Intima-Media Thickness
For each subject, the IMTcca was calculated to be the average of the
left and right IMTcca. IMTbif was calculated as the average of the
thickest point, including plaque, of the left and right carotid bulb
origin measurements.
Carotid Plaques
An artery was classified as being affected by plaque if there was a
localized thickening .1.2 mm that did not uniformly involve the
whole left or right common carotid bifurcation with or without flow
disturbance.1,24 Plaques were identified by the vascular technologist
at the time of ultrasound measurement.
Figure 1. Normal carotid bifurcation showing the sites of measurements of IMT at the origin of the bulb (O) and IMTcc (I).
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depth were also preset but could be adjusted depending on patient
anatomy and size. Regular use of an RMI (model 415) phantom
ensured system accuracy in sensitivity, distance measurements, and
axial and lateral resolution measurements.
All ultrasound measurements were made by 2 experienced vascular technologists, and images were recorded on magneto-optical
discs and VHS videotape for further analyses using previously
described methods.1,23,24 Measurements were made of both right and
left carotid arteries. After the artery bifurcations were localized by a
transverse scan, the probe was rotated 90° to obtain and record a
longitudinal image of both the anterior and posterior artery walls.
The carotid bifurcation was examined over a length of 3 cm (1.5 cm
proximal and distal to the flow divider) for plaques. The IMTcca was
measured at its thickest point on the distal (far) wall of the common
carotid artery, '1.5 cm proximal to the flow divider. IMT was also
measured at the origin of the bulb, which was defined as the point at
which the arterial wall diverges to form the bulb (Figure 1, site
shown as O). In the presence of a plaque, the maximum thickness of
the plaque was measured (Figure 2), and this was taken as the
bifurcation IMT (IMTbif). In the absence of a plaque, the IMT
measured at the bulb origin was the thickest part of the intima-media
complex and was defined as IMTbif. The within- and betweentechnologist coefficients of variation for IMT measurements were
assessed in pilot studies and were between 3% and 5%, which was
Figure 2. Common carotid artery and bulb (which contains a
plaque) showing the sites of measurements of IMTcc (I), IMT at
the origin of the bulb (O), and plaque thickness (P). In the presence of plaque, IMTbif was given the value of maximum plaque
thickness. In the absence of plaque, IMTbif was given the value
of IMT at the origin of the bulb.
Analyses and Statistical Methods
Relationships between cardiovascular risk factors and IMTcca, IMTbif,
and carotid plaques were examined. Femoral ultrasound data were
not considered in these analyses. Comparisons were expressed as
odds ratios (ORs) for plaques, and mean (SE) values were used for
both IMT measures when the means of the right and left carotid
artery estimates were used. All statistical analyses were performed
with the SAS package. ANCOVA was used to obtain age-adjusted
means (SE) for IMTcca and IMTbif. Logistic regression was used to
derive age-adjusted ORs and their CIs for the presence of plaques in
all the risk factors considered in the analyses. Continuous variables
were grouped in tertiles or quintiles and analyzed as categorical
variables.
Results
Totals of 425 men and 375 women were surveyed (mean age,
66 years; range, 56 to 77 years). The response rates for men
and women were 83% and 69%, respectively. Of these
subjects, adequate ultrasound images were obtained on 418
men and 367 women.
Distribution of IMT and Plaques
IMTcca was normally distributed with means (SD) of 0.84
(0.21) and 0.75 (0.16) mm for men and women, respectively.
IMTbif was also normally distributed with means (SD) of 1.69
(0.61) and 1.50 (0.77) mm for men and women, respectively.
The correlations between IMTcca and IMTbif were similar in
men (r50.36) and women (r50.38). There were no differences in either IMT measure between the 2 towns.
Carotid plaques were very common, affecting 57%
(n5239) of men and 58% (n5211) of women. Severe carotid
plaques with flow disturbance were rare, affecting 9 men
(2%) and 6 women (1.6%). Plaques increased in prevalence
with age, affecting 49% of men and 39% of women aged ,60
years and 65% and 75% of men and women, respectively,
aged .70 years. Plaques affected 79% of men and 53% of
women in Dewsbury and 34% of men and 62% of women in
Maidstone. On average, IMTcca was '0.1 mm greater among
those with plaques than among those without. Among those
with no evidence of plaques, 1 of 4 men and 1 of 16 women
had an IMTcca $1.0 mm, indicating IMT thickening.
Social and Lifestyle Factors
Results on the associations between social and lifestyle risk
factors, mean IMT, and presence of plaques are presented in
Table 1. Age-adjusted mean IMTcca and IMTbif, unadjusted
844
Carotid Ultrasound and Cardiovascular Disease
TABLE 1. Lifestyle Risk Factors and Age-Adjusted Mean Common Carotid and Bifurcation IMT and Odds Ratios for Presence of
Carotid Plaques
Men
Women
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
% With
Plaques
Age-Adjusted
OR (95% CI)
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
% With
Plaques
Age-Adjusted
OR (95% CI)
Never*
115
0.82 (0.02)
1.56 (0.07)
46.1
Ex-smoker
213
0.84 (0.01)
1.71 (0.05)
59.2
1.6 (1.0, 2.5)
1.0
162
0.74 (0.01)
1.37 (0.05)
48.8
91
0.77 (0.02)
1.54 (0.07)†
57.1
1.3 (0.8, 2.3)
83
0.87 (0.02)
1.86 (0.08)‡
67.5
2.4 (1.3, 4.3)‡§
62
0.77 (0.02)
1.72 (0.08)‡
74.2
3.7 (1.9, 7.2)‡§
None
54
0.85 (0.03)
1.65 (0.10)
51.9
Occasional
82
0.81 (0.02)
1.66 (0.08)
51.2
1.2 (0.6, 2.3)
1.0
128
0.77 (0.01)
1.51 (0.06)
64.8
90
0.74 (0.02)
1.54 (0.07)
56.7
0.8 (0.5, 1.5)
270
0.85 (0.01)
1.71 (0.04)
60.4
1.6 (0.9, 2.9)
126
0.73 (0.01)
1.41 (0.06)
50.0
0.7 (0.4, 1.1)
265
0.83 (0.01)
1.72 (0.04)
59.6
223
0.75 (0.01)
1.51 (0.04)
60.1
31
0.84 (0.04)
1.60 (0.12)
54.8
0.9 (0.4, 1.1)
32
0.71 (0.03)
1.32 (0.11)
40.6
0.6 (0.3, 1.3)
106
0.86 (0.02)
1.61 (0.07)
49.1
0.7 (0.4, 1.1)
72
0.74 (0.02)
1.42 (0.07)
51.4
0.7 (0.4, 1.3)
1
139
0.82 (0.02)
1.65 (0.06)
56.1
122
0.74 (0.01)
1.45 (0.06)
56.6
2
139
0.85 (0.02)
1.68 (0.06)
57.6
1.2 (0.7, 1.9)
122
0.76 (0.01)
1.55 (0.06)
59.8
1.1 (0.6, 1.8)
3
138
0.86 (0.02)
1.76 (0.06)
58.0
1.1 (0.7, 1.8)
122
0.74 (0.01)
1.47 (0.06)
55.7
0.9 (0.5, 1.5)
Non-manual
173
0.83 (0.02)
1.61 (0.05)
52.0
154
0.73 (0.01)
1.42 (0.05)
47.4
1.0
Manual
245
0.85 (0.01)
1.76 (0.05)†
60.8
158
0.76 (0.01)
1.54 (0.05)
65.2
2.1 (1.3, 3.4)‡
Smoking
Current
1.0
Alcohol
Weekend and daily
drinkers
1.0
Exercise
None
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Occasional
Frequent
1.0
1.0
BMI (tertiles)
1.0
1.0
Social class
1.0
1.4 (0.9, 2.0)
Mean IMTcca, IMTbif, and OR for presence of plaques are age adjusted; % with carotid plaques is unadjusted.
*46 currently nonsmoking women could not be classified into never smokers or ex-smokers and were therefore excluded.
†P,0.05.
‡P,0.01.
§Test for linear trend significant at P,0.01.
prevalence of plaques, and age-adjusted relative odds are
shown for each of the lifestyle risk factors.
There were no significant relationships between IMTcca and
smoking habits, alcohol intake, physical exercise, body mass
index, or social class in men or women. By contrast, both
IMTbif and the presence of carotid plaques showed similar
strong associations with smoking. Social class associations
did not show consistent statistically significant associations
between men and women, but the trends were similar. IMTbif
was associated with manual social class in men, whereas
plaques were not; in women, plaque was associated with
manual social class, but IMTbif was not. Neither IMTcca,
IMTbif, nor plaques showed any relationship with parental
death from heart trouble.
Physiological Risk Factors
Right IMTbif showed a stronger relationship with age than
IMTcca, with a 0.3-mm (men) to 0.4-mm (women) increase
per decade of age for IMTbif compared with increases for
IMTcca of 0.1 mm (men) and 0.09 mm (women). IMTcca was
positively associated with SBP and inversely related to FEV1
in men and women. There was no association between IMTcca
and height, total cholesterol, HDL cholesterol, hematocrit,
fibrinogen, or factor VII. By contrast, in men, IMTbif was
significantly associated with blood cholesterol, HDL choles-
terol, hematocrit, and fibrinogen and showed a trend with
SBP. Similar associations were found in women.
In men there was a significant inverse trend in plaque
prevalence in tertiles of HDL. Women whose SBP was in the
top tertile (ie, SBP .168 mm Hg) and those whose cholesterol levels were in the top tertile (ie, cholesterol
.6.3 mmol/L) were more likely to have a plaque (OR51.83;
95% CI, 1.1 to 3.2; and OR51.92; 95% CI, 1.1 to 3.3 for SBP
and cholesterol, respectively). In men, fibrinogen and factor
VII were associated with plaques; in women, only fibrinogen
showed an association. In women, time since menopause was
associated with a graded relationship with plaque prevalence,
with those $20 years after menopause having an ageadjusted OR of 3.0 (95% CI, 1.5 to 6.1). There were no other
associations between plaques and the other biological factors
(ie, height, FEV1, HDL, hematocrit). Associations between
IMTcca, age, SBP, and FEV1 were similar in those with and
without carotid plaques. With the exceptions of body mass
index in men and smoking in women, there were no significant associations between IMTbif and lifestyle or physiological risk factors in those men and women without plaques.
This suggests that the associations found with IMTbif among
those with and without plaques are explained by the presence
of plaque, rather than a graded association with IMTbif
throughout its whole distribution (Table 2).
Ebrahim et al
April 1999
845
TABLE 2. Biological Factors (in Tertiles) and Age-Adjusted Mean Common Carotid and Bifurcation IMT and Odds Ratios for Presence
of Carotid Plaques
Men
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
Women
% With
Plaques
Age-Adjusted OR
(95% CI)
n
1.0
Mean (SE)
IMTcca
Mean (SE)
IMTbif
% With
Plaques
Age-Adjusted
OR (95% CI)
SBP
1
136
0.82 (0.02)
1.65 (0.06)
51.5
122
0.72 (0.01)
1.33 (0.06)
45.1
2
143
0.84 (0.02)
1.65 (0.06)
56.6
1.18 (0.7, 1.9)
123
0.75 (0.01)
1.51 (0.06)*
59.4
1.51 (0.9, 2.6)
1.0
3
138
0.88 (0.02)†§
1.80 (0.06)
63.8
1.48 (0.9, 2.4)
122
0.77 (0.01)*‡
1.63 (0.06)†§
68.0
1.83 (1.1, 3.2)*‡
1
141
0.84 (0.02)
1.61 (0.06)
53.2
117
0.74 (0.01)
1.36 (0.06)
47.0
2
129
0.84 (0.02)
1.69 (0.06)
54.3
1.05 (0.6, 1.7)
126
0.76 (0.01)
1.55 (0.06)*
58.7
1.61 (0.9, 2.8)
3
138
0.85 (0.02)
1.79 (0.06)*‡
63.8
1.61 (1.0, 2.6)
118
0.74 (0.01)
1.52 (0.06)*
64.4
1.92 (1.1, 3.3)*§
1
119
0.86 (0.02)
1.81 (0.07)
63.0
108
0.76 (0.01)
1.55 (0.06)
59.3
2
157
0.86 (0.02)
1.69 (0.06)
59.2
0.85 (0.5, 1.4)
118
0.75 (0.01)
1.51 (0.06)
57.6
0.87 (0.5, 1.5)
3
129
0.82 (0.02)
1.61 (0.06)†‡
50.4
0.58 (0.3, 0.96)*‡
123
0.73 (0.01)
1.38 (0.06)*‡
53.7
0.80 (0.5, 1.4)
1
136
0.87 (0.02)*‡
1.79 (0.06)
65.4
1.0
122
0.77 (0.01)*‡
1.48 (0.06)
65.6
2
136
0.86 (0.02)*
1.66 (0.06)
52.9
0.67 (0.4, 1.1)
122
0.75 (0.01)
1.51 (0.06)
58.2
0.97 (0.6, 1.7)
3
136
0.80 (0.02)
1.61 (0.06)
52.2
0.72 (0.4, 1.2)
122
0.73 (0.02)
1.48 (0.06)
48.4
0.97 (0.5, 1.7)
1
131
0.86 (0.02)
1.80 (0.06)
65.7
122
0.76 (0.01)
1.51 (0.06)
67.2
2
136
0.83 (0.02)
1.69 (0.06)
57.4
0.72 (0.4, 1.2)
116
0.73 (0.01)
1.41 (0.06)
50.9
0.59 (0.3, 1.0)
3
130
0.84 (0.02)
1.62 (0.06)*‡
51.5
0.61 (0.4, 1.0)
122
0.76 (0.01)
1.52 (0.06)
52.5
0.63 (0.4, 1.1)
1
133
0.83 (0.02)
1.55 (0.06)
47.4
121
0.73 (0.01)
1.40 (0.06)
50.0
2
137
0.82 (0.02)*
1.70 (0.06)
54.7
1.32 (0.8, 2.1)
116
0.76 (0.01)
1.47 (0.06)
54.3
1.03 (0.6, 1.8)
3
135
0.88 (0.02)‡
1.81 (0.06)†§
68.2
2.29 (1.4, 3.8)†§
123
0.75 (0.01)
1.57 (0.06)*‡
65.9
1.71 (1.0, 2.9)
1
137
0.83 (0.02)
1.62 (0.06)
48.2
1.0
121
0.76 (0.01)
1.51 (0.06)
56.2
2
136
0.85 (0.02)
1.74 (0.06)
64.0
1.91 (1.2, 3.1)†
119
0.76 (0.01)
1.47 (0.06)
54.6
1.01 (0.6, 1.7)
3
135
0.85 (0.02)
1.72 (0.06)
59.3
1.56 (0.99, 2.6)§
119
0.72 (0.01)
1.47 (0.06)
60.5
1.13 (0.7, 1.9)
Cholesterol
1.0
1.0
HDL
1.0
1.0
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FEV1
1.0
Hematocrit
1.0
1.0
Fibrinogen
1.0
1.0
Factor VII
1.0
Mean IMTcca, IMTbif, and OR for presence of plaques are age adjusted; % with carotid plaques is unadjusted.
*P,0.05.
†P,0.01.
‡Test for linear trend significant at P,0.05.
§Test for linear trend significant at P,0.01.
Associations With Cardiovascular Symptoms
and Disease
In men, IMTcca was associated with exertional leg pain
suggesting intermittent claudication, as well as with breathlessness on exertion, stroke, hypertension, treatment with
antihypertensives, and use of aspirin. IMTbif and carotid
plaques showed similar relationships, but the associations
with exertional chest pain and diagnosis of ischemic heart
disease were more pronounced, and the associations with
stroke and hypertension, while in the expected direction, were
not statistically significant (Table 3).
Among women, relationships between IMTcca and symptoms were not apparent, but associations with diagnosed
ischemic heart disease, hypertension, and use of antihypertensives and aspirin were found. IMTbif and carotid plaques
showed similar associations with chest pain, leg pain, diag-
nosis of ischemic heart disease, hypertension, and use of
antihypertensive medication.
Risk Factor Scores
In both men and women, IMTcca and IMTbif showed strong
and graded relationships with the Stroke Score. In women the
Stroke Score was more strongly associated with prevalence of
carotid plaques than in men. Women in the top Stroke Score
quintile had an OR of 7.44 (95% CI, 2.8 to 20.0) (Table 4).
The BRHS Score showed strong relationships with IMTcca,
IMTbif, and carotid plaques in men and women. Seventy-six
percent of the men in the top quintile had a plaque present
compared with 34.9% in the bottom quintile. IMTcca, IMTbif,
and prevalence of plaques showed a significant positive linear
trend in quintiles of the BRHS Score. Men in the top quintile
of the BRHS Score had an age-adjusted OR for the presence
846
Carotid Ultrasound and Cardiovascular Disease
TABLE 3. Indicators of Disease and Age-Adjusted Mean Common Carotid and Bifurcation IMT and Odds Ratios for Presence of
Carotid Plaques
Men
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
Women
% With Age-Adjusted OR
Plaques
(95% CI)
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
% With
Plaques
Age-Adjusted
OR (95% CI)
Chest pain
None
294
0.84 (0.01)
1.63 (0.04)
53.1
252
0.74 (0.01)
1.46 (0.04)
56.0
1.0
Not on exertion
54
0.85 (0.03)
1.77 (0.10)
63.0
1.57 (0.9, 2.9)
1.0
42
0.75 (0.02)
1.50 (0.10)
61.9
1.32 (0.7, 2.7)
Possible/definite
angina
55
0.88 (0.03)
1.96 (0.10)†‡
72.7
2.29 (1.2, 4.4)*‡
47
0.78 (0.02)
1.69 (0.09)*‡
70.2
1.94 (1.0, 3.9)
Leg pain
No
313
0.83 (0.01)
1.62 (0.04)
52.4
1.0
276
0.74 (0.01)
1.43 (0.04)
54.7
1.0
Yes
75
0.90 (0.02)*
2.06 (0.08)†
76.0
2.70 (1.5, 4.8)†
56
0.78 (0.02)
1.76 (0.06)†
73.2
2.16 (1.1, 4.2)*
Breathlessness
No
299
0.83 (0.01)
1.60 (0.04)
52.5
1.0
224
0.74 (0.01)
1.46 (0.04)
55.4
1.0
Yes
99
0.88 (0.02)*
1.97 (0.07)†
70.7
2.13 (1.3, 3.4)†
122
0.75 (0.01)
1.56 (0.06)
62.3
1.30 (0.8, 2.1)
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IHD
No
346
0.84 (0.01)
1.64 (0.04)
52.6
1.0
327
0.74 (0.01)
1.46 (0.03)
55.1
1.0
Yes
66
0.86 (0.02)
1.97 (0.09)†
78.8
3.11 (1.7, 5.8)†
36
0.80 (0.03)*
1.79 (0.10)†
80.6
2.8 (1.1, 6.6)*
No
378
0.83 (0.01)
1.67 (0.04)
55.6
1.0
338
0.74 (0.01)
1.47 (0.03)
55.9
1.0
Yes
26
0.96 (0.04)†
1.85 (0.14)
69.2
9
0.80 (0.05)
1.92 (0.21)*
77.8
1.9 (0.4, 10.2)
Stroke
1.55 (0.6, 3.7)
High blood pressure
No
305
0.83 (0.01)
1.66 (0.04)
54.8
Yes
107
0.89 (0.02)†
1.78 (0.07)
62.6
1.0
1.33 (0.8, 2.1)
247
0.73 (0.01)
1.40 (0.04)
51.8
1.0
116
0.78 (0.01)†
1.69 (0.06)†
69.8
2.3 (1.4, 3.7)†
Aspirin
No
315
0.83 (0.01)
1.65 (0.04)
54.0
1.0
306
0.74 (0.01)
1.46 (0.04)
56.5
1.0
Yes
83
0.90 (0.02)†
1.86 (0.08)*
69.9
1.86 (1.1, 3.1)†
37
0.81 (0.03)†
1.73 (0.10)*
64.9
1.1 (0.5, 2.4)
Antihypertensive drugs
No
282
0.83 (0.01)
1.64 (0.04)
53.9
Yes
118
0.88 (0.02)*
1.79 (0.07)
65.3
1.0
1.52 (1.0, 2.4)
231
0.73 (0.01)
1.39 (0.04)
50.2
1.0
125
0.77 (0.01)*
1.70 (0.05)†
75.2
2.8 (1.7, 4.7)†
IHD indicates ischemic heart disease. Mean IMTcca, IMTbif and OR for presence of plaques are age adjusted; % with carotid plaques is unadjusted.
*P,0.05.
†P,0.01.
‡Test for linear trend significant at P,0.01.
of plaque of 5.51 (95% CI, 2.6 to 11.9). There was a marked
increase in mean IMTcca (but not IMTbif) from the 4th to the
5th quintile of BRHS Score in both men and women. The
relationship between BRHS Score measured at baseline in
men showed very similar relationships with plaque, but the
IMTcca relationship was less marked than that for IMTbif. At
baseline, only SBP (but not total cholesterol, LDL cholesterol, FEV1, sporting activity, or smoking) was associated with
IMTcca at follow-up 16 to 18 years later. By contrast, baseline
SBP, total and LDL cholesterol, FEV1, smoking, and alcohol
consumption were all associated with presence of plaques at
follow-up.
Independence of IMT and Plaque Associations
With Risk Factors
To test whether the associations with risk factors found
between both IMT measures and plaques were independent of
each other, regression analyses, with each risk factor and
symptom or diagnosis in turn used as the dependent variable,
were performed. These analyses attempted to examine
whether risk factor associations remained significant after
including the presence or absence of plaque into the regression model with additional control for age. For IMTcca,
associations with SBP, FEV1, stroke, and diagnosed hypertension appeared to be independent of presence or absence of
plaque. By contrast, IMTbif associations with cholesterol,
hematocrit, fibrinogen, chest pain, diagnosed ischemic heart
disease, and stroke (women only) were no longer significant
when plaque was included in the models. The associations
with leg pain and breathlessness remained significant but
were markedly attenuated by the addition of plaque to the
models.
Using the BRHS and Stroke scores as dependent variables
summarizing major risk factors, we examined the r2 obtained
using age together with IMTcca, IMTbif, or plaque as independent variables. For the baseline BRHS Score in men, IMTcca,
IMTbif, and plaque gave r2 values of 13%, 18%, and 15%,
respectively. For the Stroke Score in men, IMTcca, IMTbif, and
Ebrahim et al
April 1999
847
TABLE 4. The British Regional Heart Study and Stroke Scores and Age-Adjusted Mean Common Carotid and Bifurcation IMT and
Odds Ratios for Presence of Carotid Plaques
Men
n
Mean (SE)
IMTcca
Mean (SE)
IMTbif
Women
% With
Plaques
Age-Adjusted OR
(95% CI)
n
1.0
Mean (SE)
IMTcca
Mean (SE)
IMTbif
% With
Plaques
Age-Adjusted
OR (95% CI)
Stroke score
1
80
0.80 (0.03)
1.60 (0.09)
47.4
67
0.71 (0.02)
1.20 (0.08)
30.0
2
81
0.80 (0.02)
1.66 (0.08)
51.9
1.14 (0.6, 2.1)
68
0.71 (0.02)
1.34 (0.08)‡
48.5
1.98 (1.0, 4.1)
1.0
3
81
0.81 (0.02)
1.52 (0.08)
49.4
0.92 (0.5, 1.8)
67
0.74 (0.02)
1.52 (0.07)‡
62.7
3.19 (1.5, 6.8)
4
81
0.89 (0.02)†
1.77 (0.08)
68.4
2.03 (1.0, 4.2)
68
0.77 (0.02)†
1.54 (0.08)‡
66.2
3.18 (1.4, 7.4)
5
80
0.92 (0.02)‡t1
1.93 (0.08)†t1
69.6
1.97 (0.9, 4.4)t1
67
0.79 (0.02)†t1
1.88 (0.08)‡t1
83.6
7.44 (2.8, 20)t1
1
68
0.79 (0.02)
1.42 (0.08)
34.9
55
0.73 (0.02)
1.25 (0.09)
27.3
2
69
0.84 (0.02)
1.55 (0.08)
44.1
55
0.73 (0.02)
1.34 (0.08)
50.1
3
69
0.80 (0.02)
1.48 (0.08)
53.7
2.10 (1.04, 4.3)†
55
0.72 (0.02)
1.38 (0.08)
47.3
0.81 (0.4, 1.6)
4
69
0.85 (0.02)
1.80 (0.08)‡
62.3
2.96 (1.5, 6.0)‡
55
0.73 (0.02)
1.62 (0.08)‡
61.8
1.34 (0.7, 2.7)
5
68
0.96 (0.03)‡t1
2.07 (0.08)‡t1
76.1
5.51 (2.6, 11.9)‡t1
55
0.79 (0.02)‡t
1.82 (0.08)‡t1
87.3
5.92 (2.5, 14.2)‡t1
1
82
0.81 (0.02)
1.44 (0.08)
34.2
2
85
0.80 (0.02)
1.62 (0.08)
50.6
3
82
0.84 (0.02)
1.57 (0.08)
58.5
2.58 (1.4, 4.9)‡
4
82
0.90 (0.02)‡
1.82 (0.08)‡
67.1
3.73 (1.9, 7.2)‡
5
84
0.87 (0.02)t1
2.01 (0.08)‡t1
75.0
5.15 (2.6, 10.4)‡t1
BRHS score
1.0
1.51 (0.8, 3.0)
1.0
0.90 (0.5, 1.7)
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BRHS score
at baseline
1.0
1.94 (1.04, 3.6)†
Mean common carotid IMT (IMTcca), bifurcation IMT (IMTbif) and OR for presence of plaques are age adjusted; % with carotid plaques is unadjusted. BRHS score
for women assumes all women started smoking at age 20.
†P,0.05, ‡P,0.01, t test for linear trend significant at P,0.05, t1 test for linear trend significant at P,0.01.
plaques gave very similar r2 values of 38%, 37%, and 38%,
respectively. In women, Stroke Score r2 values were somewhat greater, with IMTcca, IMTbif, and plaques giving r2 values
of 47%, 49%, and 48%, respectively.
Discussion
The distribution and size of IMTcca in our study were broadly
comparable to those in reports from other population-based
studies. We have examined a wider and more comprehensive
range of risk factors for their associations with IMTcca, IMTbif,
and carotid plaque than any previous population-based study
(Table 5). IMTcca was associated with SBP (which may
promote smooth muscle hypertrophy), with age, and with
FEV1. This latter finding has not been reported previously,
but FEV1 is an important independent risk factor for stroke.25
IMTbif values were higher than IMTs measured at the
bifurcation in other populations (Table 5). This probably
represents the high prevalence of plaques in our population.
IMTbif showed a different pattern of risk factor associations
from IMTcca, which broadly mirrored the pattern seen for
associations we found with plaque. Our attempts to “control”
for the presence or absence of plaque in regression analyses
of risk factors and symptoms or diagnoses is open to criticism
because both IMT measures and plaque are not truly independent of each other. Nonetheless, the risk factor and
disease associations of IMTcca remained significantly associated in these analyses, whereas the associations with IMTbif
did not. In addition, a stratified analysis examining those
participants without plaque demonstrated similar findings:
IMTcca associations remained significant, but IMTbif associations did not. Furthermore, the variation in BRHS and Stroke
scores “explained” by IMTbif and plaque were very similar.
Taken together, these findings suggest that IMTbif associations are due to the presence of plaque. Consequently, the
notion that IMTbif measurements can be considered to be a
continuous variable associated with risk factors and CVD
throughout the full range of measurement is not supported by
our findings. IMTcca associations were with risk factors that
are specifically linked with stroke (ie, blood pressure and
FEV1) and also with prevalent stroke and treatment for
hypertension. IMTcca also “explained” a large proportion of
the variation in Stroke Score, suggesting that IMTcca may be
a better predictor of stroke than ischemic heart disease risk.
We defined plaques nonarbitrarily as a localized area of
thickening of .1.2 mm because we believe that plaque
should be considered to be qualitatively different from
general increases in wall thickness. Plaques were very common in both men and women, and, in contrast to IMT, the
presence of plaques was strongly associated both with cardiovascular risk factors and with prevalent cardiovascular
symptoms and diagnosed disease. Surprisingly, plaques were
no more common in the north than in the south of England,
but this may be due to chance or the age of our participants.
Family studies using heritability analyses suggest that up to
two thirds of the variation in IMTcca may be genetically
848
TABLE 5.
Carotid Ultrasound and Cardiovascular Disease
Summary of Population-Based Studies of B-Mode Ultrasound Screening of Carotid Arteries
Study
Protocol
Findings
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Edinburgh Artery Study (1992)
Allan, 199712,26
ATL Ultramark 9, 10-MHz probe, 4 observers. Single
measurement of far wall R1L CCA 2 cm proximal to
bifurcation. IMT measured to nearest 0.1 mm.
Maximum IMT used and dichotomized .1.05 mm in
some analyses, quartiles of IMT in other analyses.
N51156; age range 60–79 y. IMTcca F50.79 mm,
M50.85 mm. Associations with IMTcca in men:
fibrinogen, blood viscosity. No significant associations
in women.
Vascular Aging (EVA) Study (1991)
Bonithon-Kopp, 199627
Aloka SSD-650, 4 observers, 7.5-MHz probe. CCA, ICA,
and bifurcation scanned for plaques. Far wall CCA
using automated edge-detection algorithm. Mean of 2
R1L CCA measures used. Plaque extent and severity
were graded.
N51271; mean age 65 (59–71) y. Plaque prevalence:
F516.5%, M525.6%. IMTcca F50.65 mm,
M50.69 mm. Associations with IMTcca and plaque:
age, SBP, cholesterol, diabetes.
Bruneck Study, Italy (1990)
Bonora, 199728
ATL Ultramark 8, single observer. Multiple sites CCA
and ICA. Plaque thickness summed into a score.
Repeat at 5 years.
N5888; mean age 59 (40–79) y. Plaque prevalence:
F536%, M548%. Associations with plaque: age, SBP,
DBP, LDL cholesterol, U-shaped insulin.
Rotterdam Study, Netherlands (1990)
Bots, 19934
ATL Ultramark IV, 7.5-MHz transducer, single observer.
Mean far wall IMT (L1R/2) used. Beginning of distal
CCA for 10 mm scanned. Plaques classified as present
or absent.
N510001; mean age 69 y. IMTcca; F50.76 mm,
M50.81 mm. Associations with IMTcca: age, SBP, BMI
(men only), smoking (men only).
Suita Study, Japan (1989)
Mannami, 199729
Toshiba SSA-250A, 7.5-MHz transducer, single
observer. 30 mm proximal to bulb and 15 mm distal to
flow divider scanned. IMT at 10 mm proximal to
beginning of CCA bulb. Mean near1far wall IMT used.
Plaque5IMT.1.1 mm, plaque thickness summed into
a score.
N51445; mean age 63 (50–79) y. Plaque prevalence
(age 60–69): F545%, M557%. IMTcca: F50.89 mm,
M50.92 mm. Associations with IMTcca and plaque:
age, SBP, smoking (men only), cholesterol, glucose.
San Daniele Project, Italy (1989)
Prati, 199213
Angioview 600, 7.5-MHz transducer, single observer.
IMT far wall site not defined. 30 mm proximal to flow
divider and 15 mm distal examined for plaque
mineralization or protrusion into lumen.
N51348 aged 18–99, N5569 aged 50–79 y. Plaque
prevalence: age 50–79: F526%, M535%. No mean
IMT reported (treated as categorical variable).
Associations with IMTcca and plaque: age, SBP,
smoking, alcohol, HDL.
Cardiovascular Health Study (1988)
O’Leary, 199615
Toshiba SSA-270A, 6.7-MHz probe. Mean of maximum
near and far wall or R1L CCA and ICA. Multiple
machines and observers.
N55176; age range 651 y. IMTcca: F50.96 mm,
M51.04 mm. IMTica: F51.35 mm, M51.57 mm.
Associations with IMTcca: age, SBP, smoking,
cholesterol, diabetes.
Atherosclerosis Risk in Communities
(ARIC) Study, USA (1987)
Heiss, 199130
Li, 199431
Device and probe not stated in primary publications.
Multiple observers, near and far wall at CCA, ICA,
bifurcation at multiple sites. IMT treated as a
dichotomized variable using maximum IMT.1.6 mm.
N5772 (1991), 12 841 (1997); mean age 57 (45–64)
y. Plaque prevalence: 34%. Disease-free IMTcca:
F50.60 mm, M50.66 mm. Associations with IMTcca
and plaque: age, SBP, DBP, BMI, smoking, cholesterol,
income, education.
Koupio Ischaemic Heart Disease Risk
Factor Study, Finland (1987)
Salonen, 199110
ATL Ultramark IV, 10-MHz probe. Single observer. 33
of far wall R1L CCA, bifurcation, mean IMT recorded,
plaque included if not mineralized.
N51224; age range 42–60 y, men only. Mean IMT not
reported, range IMTmax 0.48–4.09 mm. Associations
with IMTmax and plaque: age, SBP, smoking, LDL,
diabetes, history of IHD, serum copper, education,
income, manual occupation.
MONICA Project, Augsburg, Germany
(1984)
Gostomzyk, 198832
Biosound, 8-MHz probe. CCA, ICA, ECA examined. No
other details. Only detected plaques.
N51338; age range 25–65 y. Plaque prevalence:
23.8%. Associations with plaque in men: age,
cholesterol, diabetes, history of IHD. No association
with SBP or smoking. In women, no associations
found.
Seven Countries Study, Finland (1989)
Salonen, 199433
ATL Ultramark V, 7.5-MHz probe. Protocol as in Koupio
Study. Mean maximum IMT in L1R CCA measured
from 3 readings.
N5182; age range 70–89 y. Plaque prevalence: 93%.
Mean IMTcca: 1.5 mm. Associations with plaque:
smoking and cholesterol.
R indicates right; L, left; CCA, common carotid artery; ICA, internal carotid artery; ECA, external carotid artery; F, female; M, male; DBP, diastolic blood pressure;
BMI, body mass index; IHD, ischemic heart disease; and IMTmax, maximum IMT measured from any site.
determined.34 We did not find any association between IMTcca
or plaque and family history of ischemic heart disease.
The strong relationships observed between plaque prevalence
and Stroke and BRHS scores, which both predict clinical
events,21,22 suggest that the presence of any plaque on ultrasound
increases the likelihood of clinical disease in the future. The
relationships seen with IMTcca were less clear than those previ-
ously reported from a clinical case series.7 Baseline measurements (conducted between 16 and 18 years earlier) of most
cardiovascular risk factors were associated with plaque prevalence and, with the exception of SBP, not with IMTcca. However,
the strong associations of IMTcca, IMTbif, and plaque with BRHS
and Stroke scores, which are themselves predictive of future
disease, suggest that there may be little to choose between them.
Ebrahim et al
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Other population studies have reported strong age-adjusted
correlations between IMT and a wide range of cardiovascular
risk factors (Table 5). Many of these studies used an ultrasound scanning protocol that included plaque in the measurement of the maximum IMT.10,12,30,33 Some investigators
dichotomized the IMT measurement above and below a
threshold level of IMT,12,26,30 which has the effect of pooling
those subjects with plaques into the higher IMT group since
plaques tend to be more common in those with a thicker
IMT.27 Inclusion of plaque thickness in IMT measurement
may be confounding 2 qualitatively different pathological
processes: smooth muscle hypertrophy and plaque formation.
The association between myocardial infarction and presence of plaques was confirmed in a study of 2322 asymptomatic individuals followed up for 6 years. Clinical events
and deaths occurred only in those with evidence of plaque
and showed a graded relationship with the severity of the
plaque as assessed by morphology.1 In the Atherosclerosis
Risk in Communities (ARIC) Study, during 4 to 7 years of
follow-up, a strong association between clinical events and
IMTbif was reported, but after adjustment for other CVD risk
factors, the association was markedly attenuated and was only
apparent among those in the top third of the IMTbif distribution.35 In the Rotterdam Study, a nested case-control design
was used to examine the role of IMTcca in stroke and acute
myocardial infarction. Significant relationships were found
between disease events and IMTcca, but after adjustment for
other risk factors, these fell to insignificant levels in myocardial infarction and were of only borderline significance for
stroke.36
Intervention studies have reported changes in IMTcca and
IMTbif as surrogate end points for trials of antihypertensives
and cholesterol-lowering drugs.5,37 Reductions in IMTbif and
IMTcca have been reported after cholesterol-lowering treatment with statins38,39 and colestipol and niacin40 but not after
antihypertensive treatment. In these studies, the patients have
typically already suffered a clinical event and are at high risk
of recurrence. In these circumstances, the maximum IMTbif
measured is very likely to include plaque. Measurement of
changes in plaque area or volume may be of greater value in
assessing progression or regression of disease in the carotid
arteries.
Separate characterization of plaque and IMTcca may provide better information to determine disease risk. The Ultrasonic Score,1 which grades the information obtained from
ultrasound from a normal IMT to large plaque with flow
disturbance, is one method of enabling the relationships
between different manifestations of carotid artery pathology
and clinical disease to be identified.
IMTcca appears to be primarily determined by age and
blood pressure, as indicated by both the risk factor measurements made at baseline and concurrently. Therefore, changes
in IMTcca thickness may be adaptive rather than indicative of
atherosclerosis.41 However, the close association between
thicker IMTcca and increased prevalence of plaques supports
the hypothesis that IMTcca is related to atherosclerosis. Prospective studies are needed to determine which of the
ultrasound measures are most strongly associated with
disease.
April 1999
849
Fibrinogen is an important risk predictor for CVD, which
may reflect its contribution to atherogenesis, thrombosis, or
blood viscosity.26,35,42– 44 The present study is the first to
separate associations of fibrinogen with IMTcca, IMTbif, and
plaque, showing a stronger association with plaque than
IMTcca. A significant association of fibrinogen with IMTbif
was explained by the presence of plaque in the regression
model. The association with plaque was observed in men and
women, and the strength of relationship ('2-fold increase in
OR between upper and lower thirds of the fibrinogen distribution) was similar to that seen in an meta-analysis of
fibrinogen and incident CVD.42 The association of fibrinogen
with plaque rather than IMTcca suggests either a role for
fibrinogen in plaque development (eg, mural thrombi) or a
role for plaque in elevating fibrinogen (eg, inflammation).
Factor VII also showed an association with plaque in men,
although it is not associated with stroke.44
In our study population, IMTbif and plaque show very
similar patterns of association with cardiovascular risk factors
and disease, whereas IMTcca appears to be more strongly
associated with stroke risk factors. Separating the independent effects of IMT from plaque is difficult because these
factors are highly correlated. Further examination of these
relationships in other study populations and prospective
follow-up will help to determine which of these ultrasound
measures are most useful in predicting clinical events. Our
findings suggest that ultrasound protocols should make explicit distinctions between those with and without localized
plaque at the bifurcation and should clarify where IMT has
been measured. Further work elucidating the composition of
plaques using ultrasound textural analysis would be helpful,
and more data are required to determine the significance of
plaque and IMT measured at various sites and, in particular,
the significance of thicker IMT in the absence of plaque.
Confirmation of our findings would indicate that the presence
of plaque, together with other major cardiovascular risk
factors, could be used to define people at high risk of
suffering clinical events. It is possible that knowledge of the
presence of a presymptomatic plaque may provide added
motivation for people to modify lifestyle risk factors and to
adhere to any necessary medication.
Acknowledgments
We thank the Stroke Association for funding this study and the
Department of Health and British Heart Foundation for program
grant funding of the British Regional Heart Study. We also thank
CDER Trust for funding the ultrasound equipment funding. We are
grateful to the 2 general practices who collaborated in the field work,
to our field team (Stella Barlow, RGN, Annaliese Hamilton, RGN,
and Lucy Lennon, BSc) who carried out the field work, and to all the
participants of the British Regional Heart Study.
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Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent
Cardiovascular Disease in Men and Women: The British Regional Heart Study
Shah Ebrahim, Olia Papacosta, Peter Whincup, Goya Wannamethee, Mary Walker, Andrew N.
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Stroke. 1999;30:841-850
doi: 10.1161/01.STR.30.4.841
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