Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis

Kaptoge S, Seshasai SR, Gao P et al.
Eur Heart J 2014 35: 578-589

Background

Inflammatory processes may play an important role in the pathogenesis of vascular disease. In particular ‘upstream’ markers of inflammation, such as pro-inflammatory cytokines, may be directly related to the development of coronary heart disease (CHD), because they govern inflammation pathways [1].
Epidemiological evidence suggests that long-term levels of soluble interleukin-6 (IL-6) are associated with CHD risk, to a similar extent as some major established risk factors [2]. Human genetic studies support a causal role for IL-6 signalling in CHD [3,4]. Other upstream markers of inflammation are less well studied, for example IL-18 and matrix metalloproteinase-9 (MMP-9) (both produced by the innate immune system), and soluble CD40 ligand (sCD40L) and TNF-α (also produced by cells of the adaptive immune system). Also, there is little information about the normal fluctuations of these analytes in individuals over time, which is important for the interpretation of epidemiological studies with an aetiological motivation.
This study examined the associations of these five inflammatory markers with incident CHD outcomes in a population-based prospective cohort of the Danish Research Centre for Prevention and Health (RCPH) [5]. Data of 1514 participants aged 30-70 at baseline, and followed-up for on average 12 years, were used. Data from two other prospective studies (BRHS and Reykjavik studies) were used to assess long-term within-person variability. Furthermore, an update meta-analysis was performed into the association of these cytokines with non-fatal myocardial infarction (MI) or CHD death.

Main results

• Four cytokines showed a log-linear relationship with incident CHD risk (age- and sex-adjusted), with for each 1-SD higher log-transformed levels, HR being 1.37 (95%CI: 1.21-1.54) for IL-6, 1.26 (95%CI: 1.11-1.44) for IL-18, 1.30 (95%CI: 1.16-1.46) for MMP-9, and 1.13 (95%CI: 1.01-1.27) for TNF-a. Additional adjustment of HRs for potential confounders modestly attenuated the HRs.
• An analysis restricted to a subset of patients with information on CRP showed a somewhat stronger dose-response association for baseline log(e) CRP than for the other cytokines. Further adjustment of the associations for log(e) CRP further attenuated them, which may reflect mediation rather than confounding since CRP is downstream of IL-6 in the inflammation pathway.
• The meta-analysis, including the current analysis, revealed pooled RRs for non-fatal MI or CHD death per 1-SD higher baseline cytokine levels (adjusted for conventional CHD risk factors) of 1.25 (95%CI: 1.19-1.32) for IL-6, 1.13 (95%CI: 1.05-1.20) for IL-18, 1.07 (95%CI: 0.97-1.19) for MMP-9, 1.09 (95%CI: 0.97-1.19) for sCD40L, and 1.17 (95%CI: 1.09-1.25) for TNF-α.
• The extent of long-term within-person variability in cytokine levels appears to be substantial (low regression dilution ratios) in published studies. This may imply a potential underestimation of the true magnitude of the associations with non-fatal MI or CHD death. Comparison of the observed associations of estimated baseline levels with those inferred for long-term average levels BRHS and Reykjavik studies also indicated this.

Conclusion

Circulating levels of several pro-inflammatory cytokines in initially healthy people are associated with risk of CHD outcomes in an approximately log-linear manner, and largely independent of many conventional and emerging cardiovascular risk factors. This finding was underscored by an updated meta-analysis, which suggests that a 1-SD higher baseline level of IL-6, IL-18 and TNF-α is associated with about 10-25% higher risk of non-fatal MI or CHD death. If individual fluctuation of these cytokines over time would be taken into account, the estimated strength of the associations may be higher.
These data support the inflammation hypothesis in vascular disease, but causal roles for these cytokines in CHD remain to be established.

Editorial comment [6]

Since C-reactive protein (CRP) was linked to future CV events in otherwise healthy individuals, no other biomarker of vascular inflammation has been revealed that better predicts CV risk. This study confirms this, as the studied cytokines were associated with CHD risk, but to a lesser extent than the downstream marker CRP.
What’s more interesting about this study, is that it addresses how epidemiological evidence can help to better understand potential causal pathways. The observation that both upstream and downstream biomarkers of inflammation associate with vascular risk, suggest that a therapeutic approach that targets a casual pathway, rather than a single biomarker, might be more promising.
The CANTOS trial addresses this question, by directly testing the inflammation hypothesis, by inhibiting IL-1β with the antibody canakinumab. It evaluates whether reduction of upstream pro-inflammatory cytokines (IL-1, TNF-α and IL-6) and downstream biomarkers (CRP) will safely reduce CV events. The CIRT trial follows a similar logic, with low-dose methotrexate that inhibits upstream cytokines and downstream production of hepatic acute phase proteins.These and other approaches to inhibit vascular inflammation will give insight into whether CRP and other inflammatory markers is more than a clinical biomarker indicative of higher risk patients.
The possible negative consequences of a potential need for long-term immunosuppression in the case of a chronic condition like atherosclerosis need to be carefully considered. Post-trial registries will help establish long-term safety, with respect to opportunistic infections, potential for reactivation of tuberculosis and cancer.

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