Initial evidence suggested that IL‐6 may be a better predictor of coronary artery disease than CRP,w9 w10 while its effect on the risk for stroke was particularly strong (relative risk (RR) 3.7, 95% confidence interval (CI) 1.67 to 8.21). However, it seems that IL‐6 is also elevated in the presence of subclinical atherosclerosis, and it is hard to distinguish between patients with advanced and subclinical atherosclerosis.w11 The association between subclinical disease and IL‐6 is consistent with data from the Health ABC Study, which showed that both IL‐6 and TNFα are higher in older adults with subclinical cardiovascular disease.w12
Furthermore, in a study by Ridker et alw13 it was found that apparently healthy subjects with IL‐6 at the highest quartile had relative risk for future myocardial infarction, in a 6 year follow up period, 2.3 times higher than those in the lowest quartile (95% CI 1.3 to 4.3), with an increase of risk by 38% for each quartile increase in IL‐6.
Although TNFα is directly implicated in atherogenesis, it has not been frequently measured in epidemiologic studies. In the Health ABC Study, it was moderately correlated with IL‐6 and weakly correlated with CRP,w12 while a stronger relationship between TNFα and coronary heart disease (CHD) than with either IL‐6 or CRP has been reported.w9 Additionally, in a nested case–control study, Ridker et alw14 reported a multivariable‐adjusted relative risk of recurrent coronary events of 2.5 (95% CI 1.3 to 5.1) among men whose TNFα levels exceeded the 95th centile, as compared with men with lower levels. However, TNFα has a limited half‐life and is difficult to measure in large‐scale epidemiologic studies,w15 and this is the main reason for the observed lack of data from prospective studies about the predictive role of TNFα in clinical practice.
Alternatively, the soluble forms of TNF receptors 1 (sTNF‐R1
) and 2 (sTNF‐R2
) levels can be measured; they may be of greater significance than direct measurement of TNFα, and they can be measured with greater sensitivity and reliability.w15
The soluble TNF receptors may attenuate the bioactivity of TNFα but may also serve as slow‐release reservoirs and promote inflammation in the absence of free TNF ligand.w16
Only a few studies have examined the relationship between levels of sTNF‐R1
and the risk of CHD.2 w9 w17
However, recent evidence suggested that measurement of these receptors is a rather weak approach to predicting cardiovascular risk compared to classic inflammatory markers, such as CRP or IL‐6.w18
Another cytokine with a potential interest for future clinical research, but with limited clinical data currently available, is IL‐10. IL‐10 is an anti‐inflammatory cytokine that inhibits the production of a variety of inflammatory cytokines such as IL‐2, TNFα and IFNγ, and it is strongly associated with better prognosis in patients with ACS.w10 w20 However, IL‐10 has not been evaluated in any epidemiologic study, and its clinical use is still obscure.