Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women
The British Regional Heart Study
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.
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.
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
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.
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.
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=(9×age)+(2.85×SBP)+(70 if subject indicates angina)+(90 if smokes 1 to 20 cigarettes per day)+(130 if smokes >20 cigarettes per day). BRHS Score=(5×years of smoking)+(3×SBP)+(51×cholesterol 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).
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.
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.
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.
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.
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⇓).
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, 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⇓).
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.
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 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.
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.
- Copyright © 1999 by American Heart Association
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