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(Stroke. 1999;30:841-850.)
© 1999 American Heart Association, Inc.
Original Contributions |
Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women
The British Regional Heart Study
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.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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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 (r=0.36) and women (r=0.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very common, affecting 57% (n=239) of men and 58% (n=211) 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.
Key Words: atherosclerosis • cardiovascular diseases • carotid arteries • risk factors • ultrasonography
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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B-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 intima-media 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 7 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 10 11 12 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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 Score=(9xage)+(2.85xSBP)+(70 if subject indicates
angina)+(90 if smokes 1 to 20 cigarettes per day)+(130 if smokes >20
cigarettes per day). BRHS Score=(5xyears of
smoking)+(3xSBP)+(51xcholesterol value)+(170 if subject
recalls diagnosis of ischemic heart disease)+(100 if diagnosed
with angina)+(50 if parental history of heart trouble)-(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 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 between-technologist coefficients of variation for IMT measurements
were assessed in pilot studies and were between 3% and 5%, which was
consistent with previous reproducibility estimates from this
laboratory. The mean difference between technicians showed no evidence
of bias and was -0.005 mm, with 95% limits of agreement of
-0.12 to +0.11 mm.
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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.
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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 (r=0.36) and women (r=0.38). There
were no differences in either IMT measure between the 2 towns.
Carotid plaques were very common, affecting 57% (n=239) of men and
58% (n=211) 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 prevalence of plaques, and age-adjusted relative odds are
shown for each of the lifestyle risk factors.
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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 cholesterol, 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 (OR=1.83; 95% CI, 1.1 to 3.2; and
OR=1.92; 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
age-adjusted 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).
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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).
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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, diagnosis 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).
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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 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 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.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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
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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 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 previously 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.
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.
Fibrinogen is an important risk predictor for CVD, which may reflect
its contribution to atherogenesis, thrombosis, or blood
viscosity.26 35 42 43 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.
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Acknowledgments |
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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.
Received June 4, 1998; revision received December 21, 1998; accepted January 8, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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 S. Y. Chan, G. B. J. Mancini, L. Kuramoto, M. Schulzer, J. Frohlich, and A. Ignaszewski The prognostic importance of endothelial dysfunction and carotid atheromaburden in patients with coronary artery disease J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1037 - 1043. [Abstract] [Full Text] [PDF]
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 S. A. R. Hernandez, A. A. Kroon, M. P.J. van Boxtel, W. H. Mess, J. Lodder, J. Jolles, and P. W. de Leeuw Is There a Side Predilection for Cerebrovascular Disease? Hypertension, July 1, 2003; 42(1): 56 - 60. [Abstract] [Full Text] [PDF]
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D A Lawlor, G Davey Smith, P Whincup, G Wannamethee, O Papacosta, S Dhanjil, M Griffin, A N Nicolaides, and S Ebrahim Association between offspring birth weight and atherosclerosis in middle aged men and women: British Regional Heart Study J Epidemiol Community Health, June 1, 2003; 57(6): 462 - 463. [Full Text]
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 P. Prandoni, F. Bilora, A. Marchiori, E. Bernardi, F. Petrobelli, A. W.A. Lensing, M. H. Prins, and A. Girolami An Association between Atherosclerosis and Venous Thrombosis N. Engl. J. Med., April 10, 2003; 348(15): 1435 - 1441. [Abstract] [Full Text] [PDF]
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P. Risley, P. Jerrard-Dunne, M. Sitzer, A. Buehler, S. von Kegler, and H. S. Markus Promoter Polymorphism in the Endotoxin Receptor (CD14) Is Associated With Increased Carotid Atherosclerosis Only in Smokers: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, March 1, 2003; 34(3): 600 - 604. [Abstract] [Full Text] [PDF]
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T. C. Wascher, B. Paulweber, L. Malaimare, A. Stadlmayr, B. Iglseder, I. Schmoelzer, and W. Renner Associations of a Human G Protein {beta}3 Subunit Dimorphism With Insulin Resistance and Carotid Atherosclerosis Stroke, March 1, 2003; 34(3): 605 - 609. [Abstract] [Full Text] [PDF]
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M. T. Magyar, Z. Szikszai, J. Balla, A. Valikovics, J. Kappelmayer, S. Imre, G. Balla, V. Jeney, L. Csiba, and D. Bereczki Early-Onset Carotid Atherosclerosis Is Associated With Increased Intima-Media Thickness and Elevated Serum Levels of Inflammatory Markers Stroke, January 1, 2003; 34(1): 58 - 63. [Abstract] [Full Text] [PDF]
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 M. Sandrock, D.-C. Cheng, D. Schmitz, and A. Schmidt-Trucksass Quantification of the Wall Inhomogeneity in B-mode Sonographic Images of the Carotid Artery J. Ultrasound Med., December 1, 2002; 21(12): 1395 - 1404. [Abstract] [Full Text] [PDF]
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J. D. Spence, M. Eliasziw, M. DiCicco, D. G. Hackam, R. Galil, and T. Lohmann Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy Stroke, December 1, 2002; 33(12): 2916 - 2922. [Abstract] [Full Text] [PDF]
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J. Luedemann, U. Schminke, K. Berger, M. Piek, S. N. Willich, A. Doring, U. John, and C. Kessler Association Between Behavior-Dependent Cardiovascular Risk Factors and Asymptomatic Carotid Atherosclerosis in a General Population Stroke, December 1, 2002; 33(12): 2929 - 2935. [Abstract] [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, P. W.F. Wilson, P. A. Wolf, D. Levy, J. F. Polak, R. B. D'Agostino, and C. J. O'Donnell Association of C-Reactive Protein With Carotid Atherosclerosis in Men and Women: The Framingham Heart Study Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1662 - 1667. [Abstract] [Full Text] [PDF]
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M. Silvestrini, B. Rizzato, F. Placidi, R. Baruffaldi, A. Bianconi, and M. Diomedi Carotid Artery Wall Thickness in Patients With Obstructive Sleep Apnea Syndrome Stroke, July 1, 2002; 33(7): 1782 - 1785. [Abstract] [Full Text] [PDF]
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 B. Ariff, A. Stanton, D. Barratt, A. Augst, F. Glor, N. Poulter, P. Sever, Yun Xu, A. Hughes, and S. A. Thom Comparison of the effects of antihypertensive treatment with angiotensin II blockade and beta-blockade on carotid wall structure and haemodynamics: protocol and baseline demographics Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 116 - 122. [Abstract] [PDF]
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L.M. Cupini, P. Pasqualetti, M. Diomedi, F. Vernieri, M. Silvestrini, B. Rizzato, F. Ferrante, and G. Bernardi Carotid Artery Intima-Media Thickness and Lacunar Versus Nonlacunar Infarcts Stroke, March 1, 2002; 33(3): 689 - 694. [Abstract] [Full Text] [PDF]
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T.-C. Su, J.-S. Jeng, K.-L. Chien, F.-C. Sung, H.-C. Hsu, and Y.-T. Lee Hypertension Status Is the Major Determinant of Carotid Atherosclerosis: A Community-Based Study in Taiwan Stroke, October 1, 2001; 32(10): 2265 - 2271. [Abstract] [Full Text] [PDF]
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Y. Nagai, K. Kitagawa, M. Sakaguchi, Y. Shimizu, H. Hashimoto, H. Yamagami, M. Narita, T. Ohtsuki, M. Hori, and M. Matsumoto Significance of Earlier Carotid Atherosclerosis for Stroke Subtypes Stroke, August 1, 2001; 32(8): 1780 - 1785. [Abstract] [Full Text] [PDF]
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 M. Zureik, F. Kauffmann, P.-J. Touboul, D. Courbon, and P. Ducimetiere Association Between Peak Expiratory Flow and the Development of Carotid Atherosclerotic Plaques Arch Intern Med, July 9, 2001; 161(13): 1669 - 1676. [Abstract] [Full Text] [PDF]
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S. Homma, N. Hirose, H. Ishida, T. Ishii, G. Araki, and J. H. Halsey Jr Carotid Plaque and Intima-Media Thickness Assessed by B-Mode Ultrasonography in Subjects Ranging From Young Adults to Centenarians Editorial Comment Stroke, April 1, 2001; 32(4): 830 - 835. [Abstract] [Full Text] [PDF]
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B. Frauchiger, H. P. Schmid, C. Roedel, P. Moosmann, and D. Staub Comparison of Carotid Arterial Resistive Indices With Intima-Media Thickness as Sonographic Markers of Atherosclerosis Stroke, April 1, 2001; 32(4): 836 - 841. [Abstract] [Full Text] [PDF]
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 H. Matsunaga, Y. Tanaka, M. Tanaka, J.-S. Gong, J. Zhang, T. Nomiyama, O. Ogawa, T. Ogihara, Y. Yamada, K. Yagi, et al. Antiatherogenic Mitochondrial Genotype in Patients With Type 2 Diabetes Diabetes Care, March 1, 2001; 24(3): 500 - 503. [Abstract] [Full Text]
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L. Dow and S. Ebrahim Commentary: Lung function and risk of fatal and non-fatal stroke--The Copenhagen City Heart Study Int. J. Epidemiol., February 1, 2001; 30(1): 152 - 153. [Full Text] [PDF]
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Y. Agmon, B. K. Khandheria, I. Meissner, G. L. Schwartz, T. M. Petterson, W. M. O'Fallon, F. Gentile, J. P. Whisnant, D. O. Wiebers, and J. B. Seward Independent Association of High Blood Pressure and Aortic Atherosclerosis : A Population-Based Study Circulation, October 24, 2000; 102(17): 2087 - 2093. [Abstract] [Full Text] [PDF]
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Y. Jiang, K. Kohara, and K. Hiwada Association Between Risk Factors for Atherosclerosis and Mechanical Forces in Carotid Artery Stroke, October 1, 2000; 31(10): 2319 - 2324. [Abstract] [Full Text] [PDF]
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D. Baldassarre, M. Amato, A. Bondioli, C. R. Sirtori, and E. Tremoli Carotid Artery Intima-Media Thickness Measured by Ultrasonography in Normal Clinical Practice Correlates Well With Atherosclerosis Risk Factors Stroke, October 1, 2000; 31(10): 2426 - 2430. [Abstract] [Full Text] [PDF]
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S. Takiuchi, H. Rakugi, K. Honda, T. Masuyama, N. Hirata, H. Ito, K. Sugimoto, Y. Yanagitani, K. Moriguchi, A. Okamura, et al. Quantitative Ultrasonic Tissue Characterization Can Identify High-Risk Atherosclerotic Alteration in Human Carotid Arteries Circulation, August 15, 2000; 102(7): 766 - 770. [Abstract] [Full Text] [PDF]
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M. Zureik, P. Ducimetiere, P.-J. Touboul, D. Courbon, C. Bonithon-Kopp, C. Berr, and C. Magne Common Carotid Intima-Media Thickness Predicts Occurrence of Carotid Atherosclerotic Plaques : Longitudinal Results From the Aging Vascular Study (EVA) Study Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1622 - 1629. [Abstract] [Full Text] [PDF]
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E. Stensland-Bugge, K. H. Bonaa, O. Joakimsen, and I. Njolstad Sex Differences in the Relationship of Risk Factors to Subclinical Carotid Atherosclerosis Measured 15 Years Later : The Tromso Study Stroke, March 1, 2000; 31(3): 574 - 581. [Abstract] [Full Text] [PDF]
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