In these two nested case control studies we found that women and men with MetS had significantly higher inflammatory marker levels and a significantly increased RR of CHD compared to subjects without MetS. The RR of CHD related to MetS was significantly higher in women than in men. The association between MetS and risk of CHD was independent of the levels of most inflammatory markers, although in men the association was no longer statistically significant after adjustment for CRP levels. Most of the inflammatory markers were not predictive of CHD risk when MetS status was taken into account; only CRP and sICAM remained independently predictive of CHD and this association was limited to men.
Differences in the strength of association between MetS and CVD may be caused by heterogeneity in outcomes, MetS definitions, and study populations. A recent meta-analysis that included 11 studies found that MetS was associated with a RR of 1.74 (1.43–2.12) for CVD [23
]; however, the results were quite heterogeneous. Possible causes of the heterogeneity include the use of diverse cardiovascular endpoint definitions. Additionally, the different definitions of MetS include a broad range of disease entities. For example, some criteria used to define MetS include elevated fasting glucose levels (“pre-diabetes”) as well as manifest type 2 diabetes [2
]. Thus, in the meta-analysis the RR in studies that excluded diabetics was 1.58, while in those that included diabetics it was 2.02 [23
]. When we excluded subjects with diabetes at baseline from our analysis the RR of CHD was 2.40 in women and 1.56 in men. Differences across studies may also be related to the underlying study populations, particularly gender distribution. Only a limited number of studies have included both men and women, enabling a direct comparison between the sexes [13
]. In agreement with our results, most of these studies found higher RRs associated with MetS in women than in men [13
]. The reasons for this gender difference are unclear, but may be due, in part, to the stronger gradient in risk of CHD associated with low HDL-C and insulin resistance for women compared to men [29
]. Another reason may be that men generally have a higher absolute risk of CHD than women.
Circulating inflammatory marker levels may predict cardiovascular events years in advance [4
]. Observations from the NHS, the HPFS, and other studies suggest that among the inflammatory markers, CRP has been shown to be most consistently associated with coronary risk independent of traditional risk factors [6
]. Inflammatory markers are also closely related to obesity, insulin resistance, diabetes, hypertension, and low HDL-C levels [6
]. It is therefore not unexpected that we found significantly higher inflammatory marker levels in participants with MetS compared to those without. However, despite the close relationship of MetS with inflammation, adjustment for most inflammatory markers only modestly attenuated its association with CHD, suggesting that the effects of MetS on CHD are largely independent of inflammation. In contrast, only CRP and sICAM remained statistically significantly predictive of CHD risk after controlling for MetS, and this association was limited to men; among women, the predictive role of each of the inflammatory markers was eliminated after controlling for the presence or absence of MetS. While knowledge of inflammatory marker levels among diabetics may not influence the already aggressive medical management required for these patients we found similar results when these individuals were excluded. The reasons for the gender differences are unclear, but underline earlier speculations that mechanisms of insulin sensitivity rather than inflammation may contribute more to CHD risk in women than men [6
]. Our results are in line with previous reports [11
], suggesting that CRP predicts CVD events beyond MetS alone, but our results also suggest that the improvement in disease prediction may be small and limited to men. In the WHS, the risk of CVD was increased in women with MetS if they also had CRP levels ≥3.0 mg/L compared with <3.0 mg/L. In contrast, no such augmentation was observed among our cohorts in stratified analysis. Reasons for this dissimilarity may be related to differences in cardiovascular endpoints or in the degree of adjustment between the studies. Further, our stratified analysis may be limited by small numbers of cases within strata of MetS and CRP.
Because waist circumference measurements, blood pressure, and glucose levels were not available at baseline we used a modified definition of MetS which may limit the comparability with other studies. The prevalence of MetS among controls in our analysis using a modified NCEP definition was similar when compared to age-adjusted data published from NHANES for subjects ≥20 years using the NCEP definition (women, 23.4%; men, 24.0%) [33
], but lower than what was reported for the age-categories of 50–59 years (prevalence between 30 and 35%) and for the age-categories of 60–69 years (between 40 and 45%) [33
]. This is not unexpected given that our cohorts include health professionals. Further, our definition of MetS was based on identical criteria in the two cohorts and our primary purpose was to examine differences in the association of MetS with inflammatory markers and CHD risk between sexes. A similar definition has been used in a report from the WHS [12
]. Any potential misclassification due to the use of a modified version of MetS in our study does not sufficiently explain why the strength of the association between MetS and CHD risk was different between men and women or why CRP was significantly related to CHD risk beyond MetS in men but not in women. Our cohorts do not represent random samples of the U.S. population, which may limit the generalizability of our results. However, the biological relationship between risk factors and cardiovascular outcomes found in this study should be similar to men and women in general. Previous studies have suggested that BMI may underestimate body fat and CHD risk in elderly men [34
]. When we used a cut-off of 102 cm to define abdominal obesity based on waist circumference reported by the HPFS participants in 1996 (2 years past blood draw) in our study, the RR of CHD was 1.83 (95%-CI 1.27–2.64) in men with MetS compared to those without. We can therefore not rule out that the observed gender difference is due to the fact that BMI is less accurate to assess CHD risk in this population. We also can not completely rule out that the men and women may differ in their accuracy of describing self-reported risk factors. However, any potential inaccuracy should be minimal given that both cohorts include health professionals. Further, in a subsample of our cohorts we found correlation coefficients between self-reported weight and weight as measured by trained technicians of 0.97 for men and for women [18
], indicating a similar accuracy for both sexes, at least for anthropometric factors. About one third of the members of our cohorts provided non-fasting blood samples, which may affect TG levels; however, we accounted for fasting status and found essentially the same results when we excluded non-fasting subjects. While the RR of CHD related to MetS was higher in women than in men it should be noted that the absolute risk of CHD in our cohorts was higher in men than in women. Also, it remains to be investigated whether the gender differences observed for CHD also apply to other cardiovascular endpoints. Finally, it should be noted that use of MetS for risk assessment and its designation as a syndrome has been questioned by some authors [35
In conclusion, MetS was associated with elevated levels of inflammatory markers and was a stronger predictor of CHD in women than in men. Most inflammatory markers did not add appreciable information beyond MetS to predict CHD; only CRP and sICAM remained independently predictive of CHD and this association was limited to men. The basis for these sex-based differences warrants further study.