The main findings of this large population-based study of men and women from four ethnic groups were modest associations of inflammatory markers, CRP, IL-6 and fibrinogen, with CAC presence and burden. Combining the three markers, representing inflammatory burden, showed a stronger association than any single marker, but the combined effect was still relatively small. Prevalence and quantity of CAC and levels of inflammatory markers varied by sex and ethnicity; however, associations of biomarkers with CAC were similar in men and women and across ethnic groups.
This is the first study to directly compare associations of inflammatory markers with CAC in a population-based sample of men and women. Elevated levels of CRP, IL-6 and fibrinogen were associated with CAC presence in minimally adjusted models (age, sex and ethnicity). Adding CHD risk factors (smoking, diabetes, systolic blood pressure, dyslipidemia and BMI) attenuated associations. Associations of biomarkers with CAC burden were limited; only IL-6 was weakly associated with CAC burden. Overall, our results parallel those of previous studies in apparently healthy individuals. Comparing those with no detectable CAC to those with high levels, fibrinogen has been reported to be weakly associated with CAC in men and an age-dependent association was reported for women[6
]. Unlike MESA, these participants were selected based on results of CAC assessment. While other studies also found no association of CRP with CAC after adjustment for risk factors[3
], elevated CRP was associated with CAC in men and women in the Framingham Heart Study[5
]. However, CRP was measured 4 to 8 years prior to CAC assessment and the association may have been modified by CAC progression[5
]. Although IL-6 has been associated with other measures of subclinical atherosclerosis in older and middle-aged men and women[8
], we found only a weak association of IL-6 with CAC in MESA.
Atherosclerotic calcification is likely an organized, regulated process similar to bone formation[14
]. A variety of inflammatory mediators such as interleukins 1β, -4, -6, -10 and -12, tumor necrosis factor-α and interferon-γ play key roles in bone formation and likely calcification as well. Plaque morphology changes over time and general inflammatory markers like CRP may be more strongly associated with or influenced by plaque progression processes other than calcification; processes such as plaque rupture and thrombosis[15
]. Our data and previous studies support the hypothesis that inflammatory markers and CAC provide distinct information and may therefore be complementary in CHD risk prediction.
There are several limitations to this study. We selected several commonly measured biomarkers of generalized inflammation and found a modest association of inflammation with CAC. It is possible that biomarkers representing other facets of bone formation/calcification, such as osteoprotegerin, or markers of vascular inflammation, such as pentraxin 3, would have shown stronger associations with CAC. The study was cross-sectional and we cannot infer causality. In addition, participants in MESA were volunteers from six geographic areas in the United States and not a truly random population sample. However, MESA participants were free of clinical cardiovascular disease at baseline and not referred for CAC assessment. Men and women from four ethnic groups were also represented.
In summary, in this population-based cohort of men and women from four ethnic groups, CRP, IL-6 and fibrinogen were modestly associated with both CAC presence and burden regardless of sex or ethnicity. Our results support the hypothesis that inflammatory biomarkers and CAC may provide integrative information about CHD risk and supports the use of biomarkers to better estimate risk in individuals with established CHD burden as outlined recently by Hamirani at al[15
]. MESA, an ongoing, prospective cohort study, and other current and future studies will determine the utility of combining measurement of CAC and circulating biomarkers in risk stratification and prediction of cardiovascular events.