Inflammatory Cytokines and Risk of Coronary Heart Disease

New Prospective Study and Updated Meta-analysis

Stephen Kaptoge; Sreenivasa Rao Kondapally Seshasai; Pei Gao; Daniel F. Freitag; Adam S. Butterworth; Anders Borglykke; Emanuele Di Angelantonio; Vilmundur Gudnason; Ann Rumley; Gordon D.O. Lowe; Torben Jørgensen; John Danesh


Eur Heart J. 2014;35(9):578-589. 

In This Article

Abstract and Introduction


Aims Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies.

Methods and results Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21–1.54) for IL-6, 1.26 (1.11–1.44) for IL-18, 1.30 (1.16–1.46) for MMP-9, 1.01 (0.89–1.15) for sCD40L, and 1.13 (1.01–1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08–1.46) for IL-6, 1.12 (0.95–1.31) for IL-18, 1.21 (1.05–1.39) for MMP-9, 0.93 (0.78–1.11) for sCD40L, and 1.14 (1.00–1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19–1.32) for IL-6; 1.13 (1.05–1.20) for IL-18; 1.07 (0.97–1.19) for MMP-9; 1.07 (0.95–1.21) for sCD40L; and 1.17 (1.09–1.25) for TNF-α.

Conclusions Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.


As inflammatory processes may play an important role in the pathogenesis of vascular disease,[1,2] there is interest in the relevance of circulating markers of inflammation to coronary heart disease (CHD). Previous epidemiological studies have mainly reported on associations between 'downstream' markers of inflammation [e.g. C-reactive protein (CRP) and fibrinogen] with the risk of incident CHD.[3,4] However, human genetic evidence has reduced the likelihood that these liver-derived factors are causally relevant.[5–7] In contrast, 'upstream' markers of inflammation, such as pro-inflammatory cytokines, may be more likely to be directly aetiologically relevant to CHD because they govern inflammation cascades.[8] Most epidemiological evidence on the relevance of such markers has been obtained for interleukin-6 (IL-6).[9] Previous work has suggested that long-term soluble IL-6 levels are associated with CHD risk about as strongly as some major established risk factors,[9] and a causal role for IL-6 signalling in CHD has been supported by human genetic evidence.[10,11] These findings have intensified interest in recently launched large-scale phase 3 clinical trials of various anti-inflammatory agents in the secondary prevention of cardiovascular disease (CVD).[12,13]

However, in contrast with IL-6, other further upstream markers of the inflammatory response have been less well studied (Supplementary material online, Table S1). These include factors which are involved in vascular inflammation and which are produced mainly by cells of the innate immune system, such as IL-18[14] and matrix metalloproteinase-9 (MMP-9),[15] and factors that are also produced by cells of the adaptive immune system, such as soluble CD40 ligand (sCD40L),[16] and tumour necrosis factor-α (TNF-α).[17] So far, direct comparison between the markers has been difficult, because the individual markers have not been measured in the same studies or participants. Furthermore, there is little information about the extent to which these analytes fluctuate within individuals over time, as such data are essential to the interpretation of epidemiological studies with an aetiological motivation.

We report new findings on the association of the above five inflammatory markers and incident CHD outcomes based on data from population-based prospective cohorts at the Danish Research Centre for Prevention and Health (RCPH),[18] comprising a total of 1514 participants aged 30–70 years at baseline and an average of follow-up of 12 years. Furthermore, we used data from serial measurements of these cytokines from two other prospective studies [Reykjavik[9] and British Regional Heart Study (BRHS)[16,17,19,20]] to assess long-term within person variability. Finally, to contextualize our findings, we also report an updated systematic review and meta-analyses of the association of these cytokines and non-fatal myocardial infarction (MI) or CHD death in population-based prospective studies.