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the Department of Neurology, Christian-Doppler-Klinik (B.I., G.L.)
the First Department of Internal Medicine, St. Johanns Hospital (P.C., L.M., B.P.), Landeskliniken, and Paracelsus Private Medical University, Salzburg, Austria.
Abstract
Background and Purpose— The metabolic syndrome (MetS) is associated with an increased risk for subsequent development of type 2 diabetes mellitus, cardiovascular disease, and stroke. Type 2 diabetes increases the risk of stroke and coronary heart disease in women to a greater extent than in men, and thus the question arises whether there are sex differences in the association of early atherosclerosis and MetS.
Methods— 1588 middle-aged Austrian subjects (1001 males, 587 females) were included in the present study. MetS was defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Early atherosclerosis was assessed by intima-media thickness (IMT) and extent of plaques (B-score) of the carotid arteries.
Results— B-score and carotid artery IMT parameters were significantly higher in subjects with the MetS. After adjustment for established risk factors, the difference in B-score remained significant only in women. Computed common carotid artery IMT values using general linear model equations with age, body mass index, and low-density lipoprotein cholesterol as covariates displayed the highest values for men with MetS (811.8±9.5 μm). Women with MetS (797.6±15 μm) and men without the syndrome (788.8±5 μm) showed similar IMTs, whereas women without the MetS presented significantly lower values (735.6±7 μm). Among the subcomponents of the MetS, high-density lipoprotein cholesterol showed the strongest impact on IMT in men, whereas blood glucose ranked first in women.
Conclusions— The effect of MetS on early atherosclerosis is more pronounced in females. The impact of the components of MetS on carotid IMT differs between men and women.
Key Words: atherosclerosis carotid intima-media thickness metabolic syndrome sex
Introduction
Aconcurrence of several metabolic and nonmetabolic abnormalities within the single individual was described repeatedly over the past decades1–3 and designated "syndrome X,"4 "metabolic syndrome," (MetS)5 or "insulin resistance syndrome."3 The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III proposed a definition of the MetS,6 which is easy to use in clinical practice and epidemiological studies. Recent data demonstrate an association of MetS with an increased cardiovascular risk.7 In a multi-ethnic cohort prospective study, an increased stroke risk was observed in women with MetS.8 Several observational studies suggest that type 2 diabetes increases the risk of coronary heart disease in women to a greater extent than in men,9–11 but to our knowledge there are no data demonstrating sex differences for the association of MetS and subclinical atherosclerosis. Because there is a strong relationship of type 2 diabetes and MetS,4 the question arises whether there are sex differences concerning its impact on atherosclerosis at an early stage.
Subjects and Methods
Subjects
The cohort of 1588 white subjects consisted of 1001 males (aged 40 to 55 years) and 587 females (50 to 65 years) who were participants of the Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR), a prospective study to investigate genetic and metabolic factors for progression of atherosclerosis. The study objectives, its recruitment procedures, and population characteristics have been detailed.12 In sum, unrelated healthy subjects of the greater Salzburg region who responded to invitations by their workplace or family physicians were included. Subjects with established coronary heart disease, cerebrovascular or peripheral arterial disease, congestive heart failure, valvular heart disease, chronic alcohol (>3 drinks per day) or drug abuse, and/or morbid obesity (body mass index >40 kg/m2) were excluded to reduce possible confounding resulting from therapeutic interventions. The sample included 57 diabetic subjects (42 men, 15 women) defined by a fasting glucose level of 7mmol/L or antidiabetic treatment. At baseline, all participants were subjected to a screening program including a questionnaire on personal and family history, physical examination, and determination of anthropometric and biochemical parameters, including carotid artery ultrasound. Informed consent was obtained from all participants.
Laboratory Data
Venous blood was collected after an overnight fast. Total serum cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), apolipoprotein B, high-sensitive C-reactive protein, and fasting glucose were determined using commercially available kits (Roche Diagnostics). LDL size was measured by gradient gel electrophoresis (LFS Lipogel; Zaxis), fasting insulin was assessed using the IMX insulin kit (Abbot Diagnostic Division), insulin sensitivity was estimated using the short insulin tolerance test (k-ITT),13 and homeostasis model assessment indices were calculated.14
Definition of MetS
According to NCEP-ATPIII criteria,6 MetS is present when 3 or more of the following determinants are met: fasting blood glucose level 6.1 mmol/L, blood pressure 130/85 mm Hg (either value) or antihypertensive treatment, plasma triglycerides 1.7mmol/L, plasma HDL <1 mmol/L in men and <1.3 mmol/L in women, and waist circumference >1020 mm in men and >880 mm in women.
Blood Pressure
The 24-hour ambulatory blood pressure measurement was performed in all participants (TM 2430 PC system; Bosch + Sohn, Jungingen, Germany). Only daytime values were used for analysis because of a higher rate of missing values overnight.
Ultrasonography
At baseline, carotid atherosclerosis was determined by B-mode ultrasound (ATL HDI 3000 CV; Philips Medical Systems) according to the ACAPS protocol.15 Measurements were performed and read by a single experienced ultrasound operator, blinded to all clinical and laboratory characteristics. The protocol included multiple longitudinal and transverse imaging planes of the common carotid artery (CCA) (8 mm proximal to the bifurcation) at height of the flow divider and within the proximal 8 mm of the internal carotid artery (ICA). Intima-media thickness (IMT) was measured end-diastolic as the distance from the leading edge of the first bright line of the far wall (lumen–intima interface) to the leading edge of the second bright line (media–adventitia interface).16 As described, the intraobserver variability of this method is rather low (<3% or <25 μm).17 Mean IMT values of near and far walls of both the right and left arteries, taken for the CCAs and ICAs separately and as an average value of all selected sites, respectively, were used for statistical analyses. Number and diameter of plaques, if present, were measured to obtain an atherosclerosis score (B-score).18
Statistics
Analyses were performed using SPSS 10.0 statistical package (SPSS Inc). Characteristics of subjects are described as means and SDs if nothing else is indicated. Unpaired Student t tests were used for comparison of continuous variables, 2 tests for nominal parameters, respectively. General linear model analysis was used to assess intergroup differences of B-score and IMT between subjects with and without MetS after adjustment for relevant covariates. Because of significant interactions of sex with age, BMI, and LDL, separate models were fitted for males and females. To assess the fitted linear models, the following parameters were calculated for CCA-IMT and B-score, respectively: mean difference between subjects with MetS and controls, the standard error of this difference, the probability value for testing whether this difference is unequal from zero and a 95% confidence interval. Furthermore, R2, adjusted R2 of the model as a whole, and the effect size Eta2 of MetS were calculated. To compare males and females, fitted linear models were used to estimate the expected carotid IMT at mean age, BMI, and LDL. Logistic regression was used for analyzing the association of sonographic phenotypes of carotid atherosclerosis with the MetS. Assessment was conducted before and after adjustment for established risk factors. The effect size Eta2 was used to analyze individual associations of the components of MetS with CCA-IMT.
Results
MetS was present in 179 of 1001 men (17.9%) and 90 of 587 women (15.3%). Table 1 presents clinical and biochemical characteristics of the study participants. Significant differences (P<0.0005) between subjects with MetS and controls were found for the components of the MetS, as well as for other risk factors: BMI, fasting insulin, homeostasis model assessment index, k-ITT, LDL size, and high-sensitive C-reactive protein. Cigarette smoking was slightly more frequent in individuals with MetS, and the number of smokers was significantly higher in men (P<0.0005).
No statistically significant difference for the clustering of traits of the MetS between men and women was demonstrated: 131 (13.1%) men presented with 3 components of the MetS, 42 (4.2%) with 4 components, and 6 (0.6%) with 5 features. In females, corresponding numbers were 64 (10.9%), 23 (3.9%), and 3 (0.5%). Significantly more females fulfilled criteria for hypertriglyceridemia and increased waist circumference (P<0.0005), whereas the differences for blood glucose (P=0.021) and HDL (P=0.030) were less pronounced. Blood pressure difference between males and females with the MetS was just below significance (P=0.057). Remarkable is the small proportion of subjects with low HDL.
Significantly higher carotid IMT values were observed in subjects with the MetS (Table 2). In the following, only statistical analyses using CCA-IMT are presented, because the number of missing values because of imaging problems was higher for the ICAs and analyses including IMT of the ICAs were essentially consistent. Results of a detailed analysis of CCA-IMT are summarized in Table 3. R2, adjusted R2, and the effect size Eta2 of the MetS variable demonstrate a stronger impact of the MetS in females after adjustment for established risk factors. Unadjusted analysis of the disparity in mean B-score demonstrated significantly higher values for subjects with the MetS in both sexes (P=0.01), whereas after adjustment for the aforementioned risk factors the difference persisted on significant level only in females (P=0.02).
Furthermore we computed IMT values assuming an age of 53 years, a BMI of 27 kg/m2, and a serum LDL level of 3.8 mmol/L; these values for BMI and LDL correspond to the observed means in both sexes and the age of 53 is midway between the mean age of males (49.2 years) and females (56.2 years). The highest CCA-IMT values were obtained for men with the MetS (811.8±9.5 μm), whereas women with (797.6±15 μm) and men without (788.8±5 μm) MetS presented similar results. Women without MetS (735.6±7 μm), however, displayed significantly lower IMT (Figure 1).
Logistic regression was performed after dichotomization at the median (C50=750 μm) and the 90th percentile (C90=925 μm) of CCA-IMT, respectively, which turned out to be identical in males and females. In unadjusted models, in both sexes the MetS was significantly associated with IMT values beyond the 50th and 90th percentile, respectively (P<0.0005). After adjustment for age, BMI, LDL, and current cigarette smoking, the odds ratio for IMT values >750 μm remained significant in women (OR, 2.26; 95%, CI 1.31 to 3.89; P=0.003), but not in males (OR, 1.16; 95% CI, 0.77 to 1.15). Presence of MetS conferred higher odds for having IMT values >925 μm in women (OR, 3.90; 95% CI, 1.86 to 8.23; P<0.0005) than in men (OR, 2.05; 95% CI, 1.12 to 3.78; P=0.021). In unadjusted logistic regression models, MetS was significantly associated with presence of atherosclerotic plaques (males: OR, 1.47; 95% CI, 1.01 to 2.14; P=0.042; females: OR, 2.08; 95% CI, 1.29 to 3.33; P=0.002). After adjustment for age, BMI, LDL, and cigarette smoking, a significant correlation was observed only in women (females: OR, 2.05; 95% CI, 1.17 to 3.59; P=0.012; males: OR, 1.11; 95% CI, 0.72 to 1.73). Figure 2 outlines crude and adjusted ORs and 95%CIs.
Adjustment for k-ITT, homeostasis model assessment index, LDL size, high-sensitive C-reactive protein, or antihypertensive and antilipemic agents did not influence these findings.
Analysis of the association between CCA-IMT and the components of the MetS revealed noticeable sex differences. After adjustment for age, BMI, and LDL, in men CCA-IMT was most strongly associated with HDL (Eta2=0.016), whereas associations with blood glucose and triglycerides were extremely weak (Eta2=0.003 and 0.000, respectively). In contrast, for women the strongest associations were found with blood glucose and triglycerides (Eta2=0.014), whereas the association with HDL was very weak (Eta2=0.004).
Discussion
To our best knowledge, the present study provides the first information on sex differences in the association of the MetS with early atherosclerosis. NCEP-III criteria were chosen for their easy applicability to clinical practice and epidemiological studies, because they do not require insulin and microalbuminuria assessment or an oral glucose tolerance test, as needed for the diagnostic criteria suggested by the World Health Organization (WHO),19 which were modified for better practicality in most studies.7 Assessment by WHO criteria defines a higher number of subjects with the MetS, but none of the 2 criteria seems superior to the other in the definition of cardiovascular risk.7 Modest to moderate associations of IMT with various cerebrovascular and cardiovascular endpoints have established IMT as a surrogate parameter of clinical endpoints.20–22 Growing insight suggests that phenotypes of carotid atherosclerosis established by ultrasound may represent different stages of disease as well as distinct and common determinants.23 Our results are consistent with different sonographic phenotypes of atherosclerosis, thus suggesting that atheroprotection of females is lost in the presence of MetS. Support for the presence of genetic mechanisms is provided by the identification of sex-specific and sex-independent quantitative trait loci for components of the MetS in animal models.24 Furthermore, an influence of sex on several of the components of the MetS was reported from investigations among male and female twins.25 This concept of a sex difference in the impact of the traits of the MetS is supported by our results. In females, blood glucose and triglyceride levels showed the strongest association with IMT, whereas in males HDL ranks first. The strong association with blood glucose in females is of interest because of the close relationship between the MetS and type 2 diabetes. Several studies reported that type 2 diabetes increases the risk for stroke8,26 and coronary heart disease 9–11 in women to a greater extent than in men. Nondiabetic women, particularly in the premenopausal state, have lower levels of blood pressure, fibrinogen, and visceral fat, as well as a less atherogenic lipoprotein profile than nondiabetic men.9 These data may be explained to some extent by the presence of estrogen, which raises HDL and lowers LDL, abdominal obesity, and blood pressure.27,28 Insulin resistance, which is a key feature of the MetS, has been linked to lower estrogen concentrations and hyperandrogenicity,29 thus reversing the usually favorable risk profile of women. Similar levels of insulin resistance in males and females of our study are not conflicting in this background, because the majority of women in our population were in the postmenopausal state.
The finding of identical values for the 50th and 90th percentiles of CCA-IMT strongly suggests an equal development of atherosclerosis in both sexes. Relating to this background, our finding of higher odds for having CCA–IMTs beyond the 50th and 90th percentiles, respectively, in females with the MetS compared with men with the syndrome is a strong argument for a sex-specific effect. Because we found no significant differences for socioeconomic background, pharmacological treatment of risk factors, and the severity of the MetS, as defined by the number of traits, we conclude that there is a stronger impact of the MetS on atherosclerosis in women, despite the cross-sectional study design warrants cautious interpretation of the results.
Our observation is reminiscent of results obtained in subjects with type 2 diabetes and consistent with the concept of a close association between these disorders. Sex differences cannot be explained sufficiently by available data, thus implicating the need for further investigations on this topic.
Acknowledgments
All statistical analyses were performed by Mynda Schreuer, PhD. The Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR) is supported by grants from the Medizinische Forschungsgesellschaft Salzburg and the Kamillo Eisner Foundation.
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