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American Journal of Epidemiology Advance Access originally published online on June 12, 2007
American Journal of Epidemiology 2007 166(4):403-412; doi:10.1093/aje/kwm115
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

The Female Advantage in Cardiovascular Disease: Do Vascular Beds Contribute Equally?

Isabella Kardys1, Rozemarijn Vliegenthart1,2, Matthijs Oudkerk2, Albert Hofman1 and Jacqueline C. M. Witteman1

1 Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
2 Department of Radiology, University Medical Center Groningen, Groningen, the Netherlands

Correspondence to Dr. J. C. M. Witteman, Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands (e-mail: j.witteman{at}erasmusmc.nl).

Received for publication December 18, 2006. Accepted for publication February 28, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The female advantage in coronary heart disease occurrence is not completely understood. To characterize gender differences in cardiovascular disease by vascular site, the authors compared degrees of coronary, carotid, peripheral, and aortic atherosclerosis in men and women aged ≥55 years from the population-based Rotterdam Study (Rotterdam, the Netherlands). Data were collected between 1997 and 2000. A subset of 2,013 participants had data on both coronary calcification and one or more measures of extracoronary atherosclerosis, including intima-media thickness (IMT), carotid plaques, ankle-arm index (AAI), and aortic calcification. The multivariable-adjusted male:female odds ratios for calcium score > 1,000 were 7.8 (95% confidence interval (CI): 3.2, 19.3), 5.4 (95% CI: 2.8, 10.2), and 3.0 (95% CI: 1.7, 5.2) in the lowest, middle, and highest age tertiles, respectively. For IMT > 1.0 mm, severe carotid plaques, AAI < 0.90, and severe aortic calcification, ratios did not decline with age. Overall multivariable-adjusted male:female odds ratios for these measures were 2.9 (95% CI: 2.0, 4.1), 2.0 (95% CI: 1.4, 2.8), 0.9 (95% CI: 0.7, 1.3), and 1.0 (95% CI: 0.8, 1.5), respectively. The authors conclude that the gender difference in atherosclerosis is larger in the coronary vessels than in other vascular beds. Remarkably, it is absent in the aorta and the lower-extremity vessels. Factors causing this site-specific gender difference require further investigation.

atherosclerosis; cardiovascular diseases; coronary disease; coronary vessels; risk factors; sex

Abbreviations: AAI, ankle-arm index; CI, confidence interval; HDL, high density lipoprotein; IMT, intima-media thickness


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
After two decennia of rigorous research, the remarkable gender difference in coronary heart disease occurrence is still not completely understood. It cannot be fully explained by risk factors such as lifestyle, lipid profile, and blood pressure (1). The hypothesis that estrogen carries a cardioprotective effect is still being debated and could not be proven in large randomized controlled trials on estrogen therapy (2, 3). Although the gender difference is also present to a much smaller extent for stroke and peripheral arterial disease, it is most prominent for coronary heart disease (4–9). This suggests that gender differences in cardiovascular disease may differ according to vascular site. Autopsy studies support such a differential gender effect (10–13).

Although studies have been performed in living populations to examine gender differences in atherosclerosis at single vascular sites (14–17), to our knowledge, no studies have been performed in living populations to compare gender differences in atherosclerosis at different sites of the vascular tree. To further characterize gender differences in cardiovascular disease according to various vascular sites, we compared degrees of coronary, carotid, aortic, and peripheral atherosclerosis between male and female participants aged 55 years or more in a population-based cohort study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
This study was embedded in the Rotterdam Study, a population-based study aimed at addressing the occurrence of and risk factors for chronic diseases in the elderly. The rationale and design of the Rotterdam Study have been described elsewhere (18). The study started with a baseline examination conducted between 1990 and 1993, which included 7,983 men and women aged 55 years or more (78 percent of the eligible population) living in a well-defined suburb of the city of Rotterdam, the Netherlands. Follow-up visits took place in 1993–1994 and 1997–1999. From 1997 onwards, participants through 85 years of age who completed the third phase of the Rotterdam Study were invited to participate in the Rotterdam Coronary Calcification Study and to undergo electron-beam computed tomography for assessment of coronary calcification in the epicardial coronary arteries (19). The medical ethics committee of Erasmus Medical Center, Rotterdam, approved the study. Participants gave written informed consent and permission to retrieve information from treating physicians.

Coronary calcification
Imaging was performed with a C-150 Imatron scanner (Imatron, South San Francisco, California) and has been described in detail previously (19). Briefly, quantification of coronary calcification was performed with AccuImage software (AccuImage Diagnostics Corporation, South San Francisco, California) displaying all pixels with a density of over 130 Hounsfield Units. A calcium score was obtained as proposed by Agatston et al. (20). We added the scores for individual calcifications, resulting in a calcium score for the entire epicardial coronary system. A calcium score above 1,000 was considered the outcome measure. Interobserver reliability for calcium scoring has been found to be excellent, with correlation coefficients for calcium scores obtained by different observers being greater than 0.99 and only small differences in absolute calcium scores being observed (21).

Measures of extracoronary atherosclerosis
During the third phase of the Rotterdam Study (1997–1999), several noninvasive measurements of atherosclerosis were conducted. A detailed description of the procedures used has been given previously (22). Ultrasonography of both carotid arteries was performed according to the protocol of the Rotterdam Study. Measurements of common carotid intima-media thickness (IMT) involved regions of the common carotid arteries proximal to the carotid bulb, starting at a distance of 1 cm from the bulb. IMT was determined as the average of mean near- and far-wall measurements, computing the average of left and right common carotid IMT. We considered carotid IMT above 1.0 mm to be high carotid IMT. In a reproducibility study of IMT measurements carried out among 80 participants of the Rotterdam Study, intraclass correlation coefficients between ultrasonographers, readers, and visits to the study center were 0.63, 0.88, and 0.74, respectively (23).

The left and right common carotid arteries, bifurcations, and internal carotid arteries were evaluated for the presence of atherosclerotic lesions (plaques). A plaque was defined as a focal widening relative to adjacent segments, with protrusion into the lumen. The anterior and posterior walls were evaluated and the number of affected locations counted. This resulted in a plaque score between 0 and 6. Carotid plaque scores of 4 or greater were considered severe. A reproducibility study among 166 Rotterdam Study participants on the assessment of plaques in the carotid bifurcation revealed kappa values of 0.59 for the left carotid artery, 0.65 for the right carotid artery, and 0.60 for plaques in either side (24). These findings were statistically significant (p < 0.001) and indicated moderate agreement.

Using a random-zero sphygmomanometer, sitting blood pressure was measured at the right upper arm, and systolic blood pressure at both ankles (posterior tibial artery) was measured in the supine position. We computed the ratio of systolic blood pressure at the ankles to systolic blood pressure at the arm to obtain the ankle-arm index (AAI). For the current analyses, we used the lowest measurement. Because of possible measurement artifacts reflecting the presence of rigid or calcified walls, participants with AAIs greater than 1.5 were excluded. AAIs smaller than 0.90 were considered anomalous.

Aortic calcification was diagnosed by radiographic detection of calcified deposits in the abdominal aorta. Lateral abdominal radiographs were made from a fixed distance with the participant seated. Calcifications in the abdominal aorta were classified as present when linear densities were seen in an area parallel and anterior to the lumbar spine. The extent of aortic calcification was scored according to the length of the involved area of the posterior wall, with scores 0–5 corresponding to 0, <1.0, 1.0–2.4, 2.5–4.9, 5.0–9.9, and ≥10.0 cm. Severe aortic calcification was considered present when the length of the area was 5 cm or more. A comparison study conducted in our department involving computed tomography among 56 subjects showed that abdominal calcification could be detected radiographically in 32 subjects; in all but one of these subjects, calcification was located in the aorta on the corresponding computed tomography images (25).

Assessment of covariates
A trained interviewer visited all participants at home and collected information using a computerized questionnaire. Information obtained included current health status, medical history, smoking, and medication use, including use of hormone replacement therapy. Clinical measurements were obtained during a visit to the research center. Height and weight were measured, and body mass index (weight (kg)/height (m)2) was calculated. Blood pressure was measured at the right brachial artery using a random-zero sphygmomanometer with the participant in a sitting position. Blood samples were obtained after overnight fasting. Serum total cholesterol level was determined by an enzymatic procedure, and high density lipoprotein (HDL) cholesterol was measured similarly after precipitation of the non-HDL fraction (26). Glucose was determined enzymatically by the hexokinase method. Diabetes was defined as the use of antidiabetic medication and/or a fasting glucose level ≥7.0 mmol/liter and/or a nonfasting glucose level ≥11.1 mmol/liter (27). Using a nephelometric method (Immage; Beckman Coulter, Inc., Fullerton, California), C-reactive protein was measured in serum samples, which were kept frozen at –80°C.

Population for analysis
Of the 3,371 participants who completed the third phase of the Rotterdam Study and were eligible for electron-beam computed tomography scanning, scans were obtained for 2,063 participants (a response of 61 percent). For several reasons (i.e., metal clips from cardiac surgery, severe artifacts, and registration errors (electrocardiogram, acquisition)), image acquisition data could not be reconstructed or analyzed for 50 participants. Thus, calcium scores were available for 2,013 participants. The present study was conducted in these participants. In this group, IMT, carotid plaque scores, AAI, and aortic calcification measurements were available for 1,859, 1,736, 1,926, and 1,753 participants, respectively. The analysis was repeated excluding participants with prevalent cardiovascular disease; prevalent myocardial infarction, stroke, heart failure, and angina pectoris and claudicatio intermittens, both diagnosed by Rose questionnaire (28), were present in 255, 71, 74, 138, and 64 of the 2,013 participants, respectively. Their exclusion resulted in exclusion of 468 participants, leaving 1,545 participants for whom calcium scores were available. In this group, IMT, carotid plaque scores, AAI, and aortic calcification measurements were available for 1,432, 1,341, 1,490, and 1,347 participants, respectively.

Statistical analysis
In the statistical analysis, we first tested for differences in baseline characteristics between men and women. For this purpose, we used t tests for continuous variables and chi-squared tests for categorical variables. A Mann-Whitney U test was used for C-reactive protein because of the skewed data distribution. Second, we examined the associations of baseline characteristics with measures of atherosclerosis in men and women using linear regression, adjusting for age.

Subsequently, participants were stratified according to gender and age. Age, ranging from 61 to 85 years, was divided into tertiles (61–67, 68–73, and 74–85 years). Mean values were computed for IMT and AAI, and median values were computed for coronary calcium score, carotid plaque score, and aortic calcification score because of their skewed distributions, for men and women in strata of age. Using logistic regression, male:female odds ratios were calculated for having coronary calcification > 1,000, IMT > 1.0 mm, severe carotid plaques, AAI < 0.90, or severe aortic calcification in different age tertiles. In model 1, we adjusted for age. In model 2, we additionally adjusted for body mass index, systolic and diastolic blood pressure, total and HDL cholesterol, smoking, diabetes mellitus, C-reactive protein, hormone replacement therapy in women, and use of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering drugs (defined as those with World Health Organization Anatomical-Therapeutic-Chemical (ATC) code C10; www.whocc.no/atcddd). Analyses were repeated after excluding participants with prevalent myocardial infarction, stroke, heart failure, angina pectoris, and claudicatio intermittens.

Values for cardiovascular covariates were missing in less than 4 percent of participants, except for the presence of diabetes mellitus, for which 6.8 percent of values were missing. These missing values were handled by single imputation using an expectation-maximization algorithm. Analyses were performed using SPSS 11.0 for Windows (SPSS, Inc., Chicago, Illinois).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 shows baseline characteristics of the study population. Mean age was 71.3 years, and the population consisted of 46 percent men and 54 percent women. Men had a significantly lower body mass index, significantly higher systolic and diastolic blood pressures, significantly lower total and HDL cholesterol levels, and significantly higher prevalences of smoking and diabetes mellitus than did women. Age and C-reactive protein level were similar in men and women. Associations of baseline characteristics with coronary calcium score, IMT, and AAI showed similar patterns in men and women (see Web table 1, which is posted on the Journal's website (www.aje.oxfordjournals.org)). For carotid plaques, current smoking and diabetes were significant risk factors in men, whereas in women, they did not reach statistical significance (Web table 2). For aortic calcification, systolic blood pressure was a significant risk factor in men but did not reach statistical significance in women (Web table 3).


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  		TABLE 1. Baseline characteristics of the study population, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000

 

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  		TABLE 2. Male:female odds ratios for atherosclerosis among all participants and by age tertile, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000

 

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  		TABLE 3. Male:female odds ratios for atherosclerosis in participants without prevalent myocardial infarction, cerebrovascular accident, heart failure, angina pectoris,* or claudicatio intermittens,* among all participants and by age tertile, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000

 
Figure 1 shows median coronary calcium score, mean IMT, median carotid plaque score, mean AAI, and median aortic calcification score according to age and gender. Median coronary calcium score was higher in men than in women in all age categories. A similar, though less pronounced, pattern was seen for IMT and carotid plaque score. For AAI and aortic calcification score, the pattern was more heterogeneous, with less obvious differences between men and women.


Figure 1
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  		FIGURE 1. Measures of atherosclerosis according to gender (stripes, men; dots, women) and age tertile, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000. Mean values and standard deviations (bars) are displayed for ankle-arm index and intima-media thickness, and median values and interquartile ranges (bars) are displayed for coronary calcium score, carotid plaque score, and aortic calcification score, because of their skewed distributions. For coronary calcium score, the 75th percentiles are shown in parentheses.

 
Crude percentages of participants with atherosclerosis, according to gender and age, are shown in figure 2 for each of the vascular locations. For all four measures of atherosclerosis, percentages of participants with high degrees of atherosclerosis increased with increasing age. Percentages with severe coronary calcification, IMT > 1.0 mm, and severe carotid plaques were notably higher in men than in women.


Figure 2
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  		FIGURE 2. Crude percentages of participants with severe atherosclerosis at various vascular locations, according to gender (stripes, men; dots, women) and age tertile, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000. IMT, intima-media thickness; AAI, ankle-arm index.

 
Table 2 shows numbers of cases and participants in gender and age categories and male:female odds ratios as computed by logistic regression. Coronary calcification showed the highest male:female odds ratios as compared with the other measures of atherosclerosis. The age-adjusted male:female odds ratios for having a calcium score above 1,000 in the two lowest age tertiles were 6.9 (95 percent confidence interval (CI): 3.4, 13.9) and 7.4 (95 percent CI: 4.3, 12.7), showing that the men had a substantially higher degree of coronary calcification than the women. In the highest age tertile, the odds ratio declined to 2.7 (95 percent CI: 1.8, 4.0). The odds ratios for IMT, carotid plaques, AAI, and aortic calcification did not show an evident decline with increasing age, and the overall age-adjusted odds ratios for these measures were 2.6 (95 percent CI: 2.0, 3.4), 2.7 (95 percent CI: 2.0, 3.5), 1.3 (95 percent CI: 1.0, 1.7), and 1.3 (95 percent CI: 1.0, 1.6), respectively.

Adjustment for established cardiovascular disease risk factors, C-reactive protein level, hormone replacement therapy, and use of cardiac medication changed the estimates slightly. Multivariable-adjusted odds ratios are displayed in figure 3. This figure emphasizes that the gender difference in severe coronary calcification is particularly present at lower ages; at higher ages, the difference is less marked as compared with other measures of atherosclerosis.


Figure 3
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  		FIGURE 3. Male:female odds ratios for different measures of atherosclerosis according to age tertile, Rotterdam Study (Rotterdam, the Netherlands), 1997–2000. Odds ratios were adjusted for age, body mass index, systolic and diastolic blood pressure, total and high density lipoprotein cholesterol, smoking, diabetes mellitus, C-reactive protein, hormone replacement therapy, and use of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering drugs. Bars, 95% confidence interval.

 
When we repeated the analysis after excluding participants with prevalent myocardial infarction, stroke, heart failure, angina pectoris, and claudicatio intermittens, the pattern of the risk estimates did not materially change (table 3).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
This study demonstrates that the gender difference in atherosclerosis in the coronary vessels is large, that it is particularly high in younger participants, and that it remains present at older ages. The gender difference in the coronary vessels is strikingly larger than in the other studied vascular beds. The gender difference in carotid atherosclerosis is also substantial, yet smaller and less consistent. Remarkably, differences in the aorta and the lower extremity vessels are virtually absent. The difference in gender ratio between sites is not explained by differences in cardiovascular disease risk factors.

Strengths of the present study include its population-based nature, its large size, the availability of several noninvasive measures of extracoronary atherosclerosis in combination with a noninvasive measure of coronary atherosclerosis, and standardized assessment of risk factors. Nevertheless, some issues warrant consideration.

First, in the assessment of coronary calcium, 61 percent of the invited population participated. In general, slight differences were present between responders and nonresponders, such as the younger age of the scanned population (mean age difference, 1.7 years) and the relatively higher proportion of men in the scanned population (46.3 percent vs. 37.8 percent) (19). Female participants in electron-beam computed tomography scanning more frequently were former smokers (38.9 percent vs. 33.4 percent) than nonparticipants. Male participants in electron-beam computed tomography scanning were also more frequently former smokers (72.2 percent vs. 66.9 percent) than nonparticipants. Furthermore, they had a somewhat higher body mass index (26.5 vs. 26.1) and a somewhat higher diastolic blood pressure (77 mmHg vs. 76 mmHg). Additional missing values for the other measures of atherosclerosis in the scanned population were missing for logistic reasons, and therefore were considered to be missing at random. Any differences in cardiovascular disease risk factors between participants and nonparticipants in these measurements were also of very small magnitude. Although we think it is unlikely that selection bias occurred, we cannot fully exclude the possibility of a slight underestimation or overestimation of the studied associations.

Second, although interobserver reproducibility of coronary calcium scoring has been found to be excellent (14), when interpreting our results, it must be noted that the measures of extracoronary atherosclerosis have lower reproducibility. Still, it has been shown that measurement of IMT is highly reproducible (23) and measurement of carotid plaques is moderately reproducible (24). Radiographic detection of aortic calcification has been validated (25). Reproducibility of AAI measurements is dependent on the standardization of the technique and the experience of the personnel (29, 30); both were optimized in the Rotterdam Study.

Finally, the definition of peripheral arterial disease is conventionally stated as an AAI < 0.90 (31–33). However, using the cutpoint of 0.90 in both men and women assumes equal sensitivity for arterial obstruction, whereas in truth it may differ between the genders. It was not possible for us to examine the association of AAI with true arterial obstruction in our population empirically. The disadvantage of choosing a gender-specific cutpoint in an attempt to approximate equal sensitivity in men and women is that this may potentially introduce a new bias into the gender estimates. Therefore, we used the cutpoint of 0.90 in the analysis. In line with this thinking, we applied the frequently used absolute cutpoint of 1.0 mm for IMT in the analyses (34, 35). Furthermore, the meaning of mean AAI (figure 1) in a population may be questioned; while the interpretation of a low AAI as indicative of arterial obstruction has been validated, the meaning of the mean AAI is less clear. However, AAI has been suggested to have an association with cardiovascular disease across its entire range (36–38), which supports the possibility that AAI may be used as a continuous variable.

The differential gender effect for vascular sites was demonstrated in autopsy studies several decades ago (10–13). Present studies demonstrate the prominence of the gender difference in coronary heart disease (4). The gender difference in diseases which originate in other vascular beds, such as stroke and peripheral arterial disease, is not nearly as large (5–9). In the present study, we found that the male:female odds ratio for severe coronary calcification was almost 8 in the lowest age tertile and diminished with increasing age. The large male:female ratio is in accordance with prior data (39); the incidence of hospitalization for a first myocardial infarction in the Netherlands results in a male:female ratio of 4.2 in the age category 50–59 years, diminishing to 1.2 in persons aged 90 years or older. Furthermore, in the present study, the overall male:female odds ratio was somewhat lower for IMT > 1.0 mm and severe carotid plaques, with values of approximately 3 and 2, respectively. Prior data have demonstrated that the male:female ratio for cerebral infarction ranges from 1.6 in persons aged 55–64 years to 1.0 in persons aged 85 years or older (40). Note that the contribution of atherothromboembolism to ischemic stroke is limited to 50 percent (41); however, this should not influence the gender ratio, unless this percentage differs highly between men and women. With regard to peripheral arterial disease, research performed previously within the Rotterdam Study has demonstrated that the prevalences in 5-year age categories are similar for men and women (7). Gender differences in cardiovascular events such as myocardial infarction may be attributable to differences in exposure to risk factors, differences in the development of atherosclerosis, differences in "trigger" factors given equal severity of atherosclerosis, or a combination of these processes. The present findings underscore the role of the development of atherosclerosis in gender differences in the occurrence of coronary events.

To explain the differential gender effects across vascular sites, we should search for risk factors that have different effects on atherosclerosis in men and women but also have varying effects on atherosclerosis in different vascular beds. As demonstrated by our study, traditional cardiovascular disease risk factors do not seem to provide an explanation. Cardiovascular risk factors are considered to be generally the same for both genders, with the exception of diabetes mellitus, HDL cholesterol, and triglycerides, which have been found to have stronger effects among women (42). Furthermore, low density lipoprotein particle size may be of particular importance for coronary heart disease in men (43). In general, risk factors for atherosclerosis in different vascular beds are the same as those that predispose to disease in each individual vascular bed (44–47). The impact of these risk factors may vary according to vascular site; for instance, smoking and diabetes have a larger impact on peripheral arterial disease than the other risk factors (48). Although the risk factors are generally the same, differences in vascular anatomy, leading to regional disturbances of blood flow, and local changes in the arterial wall that affect interaction with blood components may still cause differences between the vascular sites. Not much is known about risk factors for atherosclerosis that simultaneously differ between men and women and between vascular sites. Finding these factors may provide clues as to why men have substantially more atherosclerosis than women in the coronary arteries but not in the aorta and peripheral vessels. This may help to elucidate the reason for the gender gap in coronary heart disease.

In conclusion, our study illustrates that the gender difference in coronary calcification is impressive, that it is particularly high in younger participants, and that it remains present at older ages. In younger participants, the multivariable-adjusted male:female odds ratio in the coronary arteries was close to 8. In the carotid arteries, the gender difference was also substantial, reaching 3 overall, but in the aorta and the peripheral vessels the male:female odds ratio remained close to the null value of 1. Presently known risk factors do not fully explain why the gender difference in cardiovascular disease varies in the different vascular beds. We believe that investigation of the causes of the site-specific gender differences may shed more light on the gender gap in coronary heart disease.


   ACKNOWLEDGMENTS
 
Dr. Isabella Kardys is supported by grant 948-00-016 from the Research Institute for Diseases in the Elderly (RIDE) of the Netherlands Organization for Health Research and Development (ZonMw).

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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