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Review
. 2014 Mar;35(9):578-89.
doi: 10.1093/eurheartj/eht367. Epub 2013 Sep 10.

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

Stephen Kaptoge  1 , 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
Affiliations
Review

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

Stephen Kaptoge et al. Eur Heart J. 2014 Mar.

Abstract

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.

Keywords: CHD; Cytokines; Inflammation; Meta-analysis; Risk factors.

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Figures

Figure 1
Figure 1
Hazard ratios for all coronary heart disease (top panel) [The cut-points defining the fifths of each cytokine were based on the distribution of values observed in the random subcohort, so as to be representative of the expected distribution in the population (i.e. avoiding potential bias due to purposeful over-sampling of cases in the case-cohort design). Assuming a log-linear relationship the age- and sex-adjusted hazard ratio (95% CI) for any coronary heart disease per 1-SD higher values were: 1.37 (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] and for non-fatal MI or coronary heart disease death (bottom panel) [Assuming a log-linear relationship the age- and sex-adjusted hazard ratio (95% CI) for non-fatal myocardial infarction or coronary heart disease death per 1-SD higher values were: 1.38 (1.21, 1.57) for IL-6, 1.27 (1.09, 1.47) for IL-18, 1.27 (1.12, 1.45) for MMP-9, 1.03 (0.88, 1.19) for sCD40L and 1.17 (1.03, 1.33) for TNF-α.] by fifths of inflammatory cytokine levels adjusted for age and sex and stratified by cohort.
Figure 2
Figure 2
Forest plot for the updated meta-analysis of association of interleukin-6 and risk of non-fatal MI or coronary heart disease death in prospective studies adjusted for conventional risk factors*. *In most studies, these included age, sex, smoking status, adiposity markers, blood pressure, and/or lipid markers. †Current study. £The study reported total number of cardiovascular disease cases and gave relative risks for coronary heart disease without stating the number of coronary heart disease cases. ARIC, Atherosclerosis Risk in Communities; BRHS, British Regional Heart Study; BWHHS, British Women's Heart and Health Study; CaPS, Caerphilly Prospective Study; FINRISK, Finnish National Risk Factor Survey; HPFUS, Health Professionals' Follow-up Study; MONICA, MONItoring of trends and determinants in Cardiovascular disease; NSHDS, Northern Sweden Health and Disease Study; NSHS95, Canadian Nova Scotia Health Survey; PRIME, Prospective Epidemiological Study of Myocardial Infarction; RCPH, Research Centre for Prevention and Health; WHIOS, Women's Health Initiative Observational Study; WOSCOPS, West of Scotland Coronary Prevention Study.
Figure 3
Figure 3
Meta-analysis of the associations of inflammatory cytokines and risk of non-fatal MI or coronary heart disease death in prospective studies adjusted for conventional risk factors*. *In most studies, these included age, sex, smoking status, adiposity markers, blood pressure, and/or lipid markers. †Current study. $The pooled estimate and heterogeneity statistics correspond to separate meta-analysis of 25 studies with IL-6 information (Figure 2). §Relative risk estimates were further adjusted for log CRP concentrations in this study in addition to conventional risk factors. A proportion of the study participants had prevalent cardiovascular disease at baseline. £The study reported total number of cardiovascular disease cases and gave RRs for coronary heart disease without stating the number of coronary heart disease cases. Abbreviations: BHS, Busselton Health Study; BRHS, British Regional Heart Study; BWHHS, British Women's Heart and Health Study; FINRISK, Finnish National Risk Factor Survey; Health ABC, Health, Aging, and Body Composition Study; PRIME, Prospective Epidemiological Study of Myocardial Infarction; RCPH, Research Centre for Prevention and Health; ULSAM, Uppsala Longitudinal Study of Adult Men; WHI-HT, Women's Health Initiative Hormone Trials.
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