Prevalence and Determinants of Carotid Atherosclerosis in Healthy Postmenopausal Women
Background and Purpose Subclinical atherosclerosis in the carotid arteries can be assessed noninvasively with B-mode ultrasound. Few studies have included enough younger postmenopausal women to examine risk factors specific to this group that were related to subclinical carotid atherosclerosis.
Methods A subgroup of 200 participants of the Healthy Women Study underwent B-mode ultrasound of the carotid arteries. Intima-media thickness (IMT) and focal plaque were assessed in each carotid artery. Data regarding risk factors, including blood pressure parameters, lipid values, body mass index, smoking history, and hormone status, were collected at three separate time points ( before menopause, 1 year after menopause, and 5 or 8 years after menopause).
Results The mean IMT was 0.76±0.11 mm, and 50% of the population had at least one focal plaque. Smoking had the strongest association with the presence of plaque. Women who smoked at the time of the ultrasound evaluation had five times the odds of having at least one focal plaque compared with women who had never smoked (95% confidence interval, 2.0 to 13.0; P≤.01). After we controlled for age and years after menopause, premenopausal values of pulse pressure (P≤.05), LDL cholesterol (P≤.05), and a history of smoking (P≤.01) were independently predictive of plaque. Premenopausal values of triglycerides, pulse pressure, and ever smoking were independently related to average IMT after we controlled for age and years after menopause.
Conclusions This study has provided valuable information about the prevalence of carotid atherosclerosis and the risk factors related to carotid atherosclerosis in a group of healthy postmenopausal women.
Research has suggested that atherosclerosis in the carotid arteries is a marker of generalized atherosclerosis throughout the body, including the large coronary arteries. Individuals with subclinical cardiovascular disease compared with those without subclinical disease have a significantly higher risk of death and cardiovascular events.1 2 The assessment of subclinical atherosclerosis in the carotid arteries can be accomplished noninvasively by means of B-mode ultrasound. This technique allows detection and measurement of carotid artery IMT and the degree of plaque.
The extent of carotid atherosclerosis is associated with cardiovascular risk factors such as increased age, increased systolic blood pressure, smoking, increased LDL cholesterol, history of coronary heart disease, and diabetes.3 4 5 6 7 8 9 Most studies have included elderly individuals or highly selected populations.4 6 7 Few have included enough younger postmenopausal women to examine risk factors specific to this group.5 8 10 11
The prevalence of subclinical carotid atherosclerosis was examined in 200 healthy postmenopausal women aged 52 to 60 years and compared with prevalence in existing literature. The relationship of disease to cardiovascular risk factors measured before and after menopause was also evaluated.
Subjects and Methods
The HWS is a prospective investigation of the biological and behavioral risk factor changes in healthy women as they undergo menopause. Beginning in 1983, 541 premenopausal women aged 42 to 50 years, living in Pittsburgh, Pa, were recruited.12 Eligible women had diastolic blood pressures <100 mm Hg, were free from chronic disease requiring medication (including blood pressure medication), were not taking hormone replacement therapy, and were menstruating within 3 months of the baseline examination.12 Women were evaluated at baseline (before menopause) and at 1, 2, 5, and 8 years after menopause. Menopause was defined as cessation of menses for 12 months and/or the use of hormone replacement therapy for 12 months. Beginning in 1993, carotid ultrasound examinations were performed on women who had experienced menopause ≥5 years previously.
The clinic evaluations included the collection of blood samples for the measurement of serum lipoproteins and apolipoproteins, a 2-hour glucose tolerance test, measurement of height and weight, and questions regarding gynecologic and medical history and health-related behavior. Blood pressures were measured twice with the use of a random-zero sphygmomanometer, and the results were averaged.
Lipids were measured at a central laboratory located at the University of Pittsburgh Graduate School of Public Health. Standards of the Centers for Disease Control were used to measure total serum cholesterol,13 total HDL cholesterol,14 HDL2 and HDL3, and triglycerides. The Friedewald equation was used to estimate LDL cholesterol. Plasma glucose was determined by enzymatic assay, and plasma insulin concentration was measured by radioimmunoassay.15 16
Carotid ultrasound was performed at the University of Pittsburgh Epidemiology Ultrasound Research Laboratory. A Toshiba SSA-270A scanner (Toshiba American Medical Systems) equipped with a 5-MHz linear array imaging probe was used. Scans were performed by trained sonographers and recorded on Super VHS tape for later scoring. The right and left CCA, carotid bulb, and the first 1.5 cm of the ICA and external carotid artery were evaluated. For each location, the sonographer imaged the vessel in multiple planes and then focused on the interfaces required to measure IMT and also on the largest area of focal plaque. Frames representing the best images of the near wall of the CCA and the far walls of the CCA, carotid bulb, and ICA were digitized. Peak blood flow velocity measures were taken at mid-CCA (2 cm proximal to the bifurcation) and ICA (1 to 2 cm distal to the flow divider).
Scans were read by trained readers. The reading protocol resulted in two measures of carotid atherosclerosis: mean IMT and the plaque index (a measurement of extent of focal plaque). IMT was measured with the aid of a reading program developed by the Cardiovascular Health Study17 and modified in Pittsburgh. IMT was measured at eight sites: the near and far walls of the distal CCA, the far wall of the carotid bulb, and the far wall of the ICA on both right and left sides. For each location, digitized images were displayed on the computer screen, and the medial-adventitial and intima-lumen interfaces were traced across a 1-cm segment with a mouse-controlled cursor. The computer then made 110 to 140 individual IMT measures of the distance between the lines across the 1-cm segment. The minimum, maximum, and mean of these measures were recorded. An overall mean IMT was calculated by averaging measurements from the eight locations across the right and left sides of the carotid artery.
To assess the overall degree of plaque, the carotid system was divided into five segments: proximal CCA, distal CCA, carotid bulb, ICA, and external carotid. Plaque was defined as a distinct area identified with either a focal area of hyperechogenicity and/or a focal protrusion into the lumen of the vessel. For each segment, the degree of plaque was graded according to the following criteria: grade 0, no observable plaque; grade 1, one small plaque (<30% of the vessel diameter); grade 2, one medium plaque (between 30% and 50% of the vessel diameter) or multiple small plaques; grade 3, one large plaque (>50% of the vessel diameter) or multiple plaques with at least one medium plaque. The grades were summed, creating a variable called the plaque index, which is a measure of eccentric plaque.17 The study protocol was approved by our institutional review committee, and all participants gave written informed consent.
Reproducibility of study measures was evaluated in five women who underwent two ultrasound evaluations separated by 1 week. Women were scanned by two separate sonographers on each occasion. When we accounted for both sonographer and reader variation, the Pearson correlation coefficient was .84 for mean IMT. The plaque index, determined by the sonographer at the time of the scan, was found to be highly reproducible. The intraclass correlation coefficient between sonographers was .96.
Descriptive statistics, including measures of central tendency (means, medians, percentiles) and dispersion (standard deviations, ranges), were computed for continuous variables. The distribution of mean IMT was markedly skewed. Thus, Spearman correlations were used to describe the relationship between continuous risk factors and mean IMT. An inverse exponential transformation was performed to normalize the distribution of mean IMT, and stepwise linear regression techniques were used to evaluate factors independently associated with mean IMT.
The plaque index was dichotomized into two groups: those without plaque (plaque index=0) and those with plaque (plaque index ≥1). We used t tests to evaluate continuous risk factors associated with the presence of plaque. Stepwise logistic regression was used to evaluate independent risk factors that predicted plaque development.
The subgroup of women who underwent carotid ultrasound evaluation was very similar to the total cohort with the exception of smoking history (Table 1⇓). Women in the subgroup were more likely to have ever smoked compared with the full sample (64% versus 59%).
The mean age of the women at the time of the carotid evaluation was 57 years, and the mean length of time after menopause was 5.7 years (range, 3.9 to 10.2 years; median, 5 years). Ten percent of women reported having had a hysterectomy.
Half of the population had at least one focal plaque in either the right or left carotid artery (Figure⇓). The mean plaque index was 1 (range, 0 to 8). Six percent of women had a plaque index of ≥4, and the majority of the focal plaque occurred in the carotid bulb. None of the subjects had evidence of an elevated blood flow velocity in the ICA, defined as an ICA-to-CCA ratio of ≥1.4. Thus, there was no evidence for a clinically significant stenosis.
The mean IMT in this population was 0.76±0.11 mm, with a range of 0.69 to 1.21 mm (median, 0.73 mm). Mean IMT was thickest in the far wall of the bulb (0.85±0.24 mm).
Because reports in the literature describe carotid atherosclerosis in a number of different ways, we also calculated the prevalence of atherosclerosis using a number of other definitions (Table 2⇓). The definition of increased IMT used by Bonithon-Kopp et al5 was an IMT ≥0.75 mm measured in the mid-CCA. Forty-one percent of the HWS population had a mean IMT ≥0.75 mm measured across eight sites of the carotid artery. The San Daniele Project defined an increased IMT as ≥1 mm across the CCA, the bifurcation, or the ICA.8 Ten percent of women in this population aged 50 to 59 years had an IMT ≥1 mm compared with 3.5% of the HWS participants. The Cardiovascular Health Study reported carotid stenosis as mild, moderate, and severe defined by maximum ICA lumen reduction and based on B-mode and Doppler data.18 In the HWS, 17% had a 1% to 29% ICA lumen reduction, 1% had a 30% to 50% ICA lumen reduction, and none had a severe stenosis, defined as a 75% to 100% ICA lumen reduction.
Mean values of cardiovascular risk factors measured before menopause, 1 year after menopause, and at the time of the carotid scan for women with and without plaque were compared (Table 3⇓). Total cholesterol and LDL cholesterol were significantly higher in women with plaque, regardless of the time when they were measured. Premenopausal values of systolic blood pressure, pulse pressure, and triglycerides were significantly elevated in women with at least one focal plaque. Smoking history was significantly related to the presence of plaque at all time points (not shown). Women who currently smoked at the time of the ultrasound evaluation had five times the odds of having at least one plaque compared with those who had never smoked (95% confidence interval, 2.0 to 13.0; P≤.01).
After we controlled for age and years after menopause, premenopausal values of pulse pressure (P≤.05), LDL cholesterol (P≤.05), and a history of smoking (P≤.01) were independently predictive of plaque. The models were similar for risk factors measured at 1 year and 5 or 8 years after menopause with the exception of the blood pressure parameter. Systolic blood pressure measured at both 1 year and 5 or 8 years after menopause was moderately associated with plaque, but this did not reach statistical significance.
Continuous risk factors measured at all time points were correlated with mean IMT (Table 4⇓). Systolic blood pressure, pulse pressure, and BMI measured at all time points were significantly and positively associated with mean IMT. Triglycerides measured before menopause and LDL measured at 1 year and 5 or 8 years after menopause were also significantly positively associated with mean IMT. In addition, HDL measured before menopause and at 5 or 8 years after menopause was significantly negatively associated with mean IMT.
Independent risk factor associations with mean IMT differed depending on when the risk factors were measured (ie, before menopause, 1 year after menopause, or at the time of the scan) (Table 5⇓). For risk factors measured before menopause, independent associations with IMT were found for triglycerides, pulse pressure, and ever smoking. At 1 year, postmenopausal LDL cholesterol, pulse pressure, BMI, and ever smoking were independently associated with mean IMT. For risk factors measured at 5 or 8 years after menopause, systolic blood pressure, glucose, LDL cholesterol, and ever smoking were significantly associated with IMT. All models controlled for age and years after menopause.
Our investigation found half of our healthy women participants to have at least one focal plaque, with most of the plaque primarily restricted to the bulb area. The ARIC Study also found the prevalence of plaque to be greatest in the bifurcation.10 The prevalence rate for plaque was 8.7% in the study of healthy French women.5 A similar prevalence was observed in the San Danielle population. Eight percent of women aged 50 to 59 years had nonstenotic plaque.8 This is markedly lower than our findings in the HWS population, despite the fact that the definition for plaque was similar and similar locations in the carotid system were evaluated. One reason might be that the women we studied experienced menopause ≥5 years previously, and since menopause occurs at a mean age of 51 years, a substantial percentage of the French population may have been premenopausal or perimenopausal. In addition, even though we defined plaque as an area of hyperechogenicity and/or a focal protrusion into the lumen of the vessel, these areas were not directly measured unless they were included in the 1-cm segment where IMT was measured. If a focal area of hyperechogenicity or protrusion was noted on the back, far, or near wall of a segment of the artery, it was counted as a plaque. Bonithon-Kopp et al5 included only focal protrusions that could be measured.
Women with at least one focal plaque tended to have a more atherogenic risk factor profile. The strongest independent predictor at all time points after we controlled for age and years after menopause was current or former smoking. Total cholesterol and LDL cholesterol levels were related to plaque at all time points, and blood pressure parameters (ie, systolic blood pressure or pulse pressure) were most predictive of plaque at the premenopausal time point. Similar results were found in a study of 1189 members of the Framingham cohort. Increased total cholesterol measured 8 years before carotid evaluation showed a strong positive correlation with the occurrence of stenosis in women.9
Other studies have shown lipid levels and blood pressure parameters to be associated with carotid atherosclerosis in both men and women.3 4 5 7 19 Specifically for women, in the Cardiovascular Health Study, subclinical disease was positively associated with LDL cholesterol, systolic blood pressure, blood glucose, and smoking and negatively correlated with HDL cholesterol.20 Bonithon-Kopp et al5 observed increased age, smoking history, increased LDL cholesterol, decreased HDL cholesterol, and blood pressure parameters to be independently related to the severity of carotid atherosclerosis.
Many of the risk factors predicting plaque were also correlated with increased mean IMT. Smoking was again independently predictive of mean IMT, as was a blood pressure parameter. However, blood pressure parameters (either systolic blood pressure or pulse pressure) were independently predictive of wall thickening at all time points, unlike observations for plaque. Premenopausal triglyceride levels were independently associated with increased wall thickness, but this association disappeared at 1 year and 5 or 8 years after menopause. LDL cholesterol was an important predictor of increased wall thickness after menopause. This is consistent with the fact that LDL levels increase from premenopausal to postmenopausal periods. The HWS data also suggest that increased BMI measured 1 year after menopause and increased glucose measured at 5 or 8 years after menopause are predictive of increased mean IMT. Investigators of the ARIC Study observed that women with an increased BMI and a history of diabetes had thicker carotid walls. Increased BMI and glucose both tend to be associated with a higher blood pressure, which in turn may cause injury to the endothelium.3
These data provide evidence that the risk factors measured near the menopause affect the atherosclerotic process, and this can be evaluated with the use of B-mode ultrasound techniques. Because we studied apparently healthy women at a time of rapid change in risk factors, our findings were not confounded by the presence of clinical disease. If women at risk for atherosclerosis can be identified early, aggressive risk factor modification can be implemented.
Selected Abbreviations and Acronyms
|ARIC||=||Atherosclerosis Risk in Communities|
|BMI||=||body mass index|
|CCA||=||common carotid artery|
|HWS||=||Healthy Women Study|
|ICA||=||internal carotid artery|
This study was supported by National Institutes of Health grants HL-28266 and 5PO1 HL-40962.
- Received September 19, 1996.
- Revision received December 4, 1996.
- Accepted December 13, 1996.
- Copyright © 1997 by American Heart Association
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