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Association of Multiple Inflammatory Markers with Carotid Intimal Medial Thickness and Stenosis (from the Framingham Heart Study)

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Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of ≥25% carotid stenosis by ultrasonography. Circulating inflammatory markers assessed from an examination 4 years later included CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoattractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory markers were significantly associated with ICA-IMT (p = 0.01), marginally with carotid stenosis (p = 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75th percentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (for ICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p = 0.0004; for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p = 0.007) after adjustment for age, gender, and established risk factors for atherosclerosis. There was a similar significant multivariate-adjusted association of CRP with ICA-IMT but not with carotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p = 0.009) and with IL-6 (p = 0.006); the association was more pronounced in current (vs former or never) smokers. In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers.

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Participants and covariates

The selection criteria and design of the Framingham Heart Study have been detailed.11 Participants attending the sixth (1996 to 1998) and seventh (1998 to 2001) examination cycles were eligible for this investigation. There were 3,532 participants in the Offspring Cohort study at examination cycle 6, of whom 3,407 (96%) underwent B-mode carotid ultrasonography. Among those with carotid ultrasonography, 2,885 men and women also had serum inflammatory markers (CRP, interleukin-6 [IL-6],

Results

The mean age of the 2,885 eligible participants (53% women) was 59 years at examination cycle 6, when the carotid measures were assessed. Additional clinical characteristics as well as distributions of carotid measures and inflammatory markers are listed in Table 1.

In the multimarker model, we found that the 6 inflammatory markers as a group were significantly associated with ICA-IMT (p = 0.01; Table 2), although they accounted only for an additional 0.5% of the variability in ICA-IMT. The 6

Discussion

In our large community-based cohort, we examined the relations of a panel of 6 inflammatory markers with measures of carotid atherosclerosis. In the multivariate-adjusted multimarker model, inflammatory markers as a group were found to be associated with ICA-IMT. Further examination of individual markers revealed that CRP and IL-6 were positively related to ICA-IMT, and IL-6 was positively associated with carotid stenosis.

Our findings confirm and extend our previous report of a significant

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    This study was supported by Contract N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Benjamin was supported by Grants HL64753 and 1 RO1 HL076784, Dr. Keaney by Grants DK55656 and HL60886, Dr. Vasan by Grant HL70139, and Dr. Wang by Grant HL074077 from the National Institutes of Health, Bethesda, Maryland. Dr. Vasan is the recipient of Research Career Award HL04334 from the National Institutes of Health.

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