INFLAMMATORY MARKERS AS NOVEL PREDICTORS OF CARDIOVASCULAR DISEASE

Inflammation is widely considered to be an important contributing factor in atherogenesis and the risk of atherothrombotic complications. Baseline measurements of some inflammatory markers are known to be predictive risk factors for future cardiovascular disease (CVD) events in prospective epidemiological studies. Inflammatory markers dominant in the literature are acute phase response (APR)-associated and include fibrinogen, C-reactive protein (CRP) and, more recently, interleukin- (IL-) 6. This thesis reviews the literature and suggests the need for further research into novel inflammatory markers of CVD risk. The broad aim was to expand on limited existing data and ascertain if circulating levels of four novel inflammatory markers (tumour necrosis factor alpha [TNF alpha], IL-18, soluble CD40 ligand [sCD40L], and matrix metalloproteinase-9 [MMP-9]) are associated with classical cardiovascular risk factors, and with future CVD events in several epidemiological studies. In studies of pre-analytical variables, all four markers had commercially available assays acceptable for epidemiological use, but only IL-18 and TNF alpha displayed assay stability and the ability to be measured in plasma or serum. Due to limited serum samples, MMP-9 and sCD40L were less extensively measured. Results suggest a moderate positive association of MMP-9 with coronary heart disease (CHD) risk (although confounded by smoking and markers of general inflammation), while serum sCD40L may be moderately inversely related to CHD risk. More data is required for these markers. IL-18 and TNF alpha displayed similar degrees of short-term biological variability and regression dilution as CRP. Population distributions of both cytokines were consistent with limited previous reports. Both displayed associations with conventional vascular risk factors (such as age, gender, HDL cholesterol, and smoking), although interestingly, associations with epidemiological measures of obesity were poor. Both cytokines demonstrated moderate associations with vascular disease in a retrospective CHD study. In 3 prospective CHD or CVD studies, IL-18 demonstrated consistent but moderate associations with risk of vascular events in age- and sex-adjusted models (Odds ratio [OR]~1.6 in the top versus bottom third of the population). The association became borderline significant after adjustment for conventional risk markers. Associations of TNF alpha with risk of CHD in these studies were inconsistent, and more data are needed. In 3 prospective stroke studies, TNF alpha demonstrated some moderate associations with acute stroke outcome and recurrent stroke risk, but not with incident stroke in the elderly with vascular disease. IL-18 demonstrated no association with risk or outcome in any stroke study. Meta-analysis in 4 suitable prospective studies showed (in full adjustment models) that IL-18 (OR 1.18 [95% CI 0.95-1.48] comparing extreme thirds) and TNF alpha OR 1.05 [0.67-1.64]) have at best weak independent associations with CVD risk. Therefore these markers are unlikely to add significantly to clinical vascular risk prediction models, although these cytokines may still be of biological significance and potential therapeutic targets. More data is required for these markers. In conclusion IL-18, TNF alpha, MMP-9 and sCD40L may show weak associations with CVD. However, despite animal and tissue models indicating that they may play pivotal roles in atherogenesis, circulating concentrations of these inflammatory markers have limited independent vascular risk associations. Elevated circulating levels of APR-associated markers may sensitively reflect exposure to a wide range of adverse pro-inflammatory stimuli including lifestyle exposures, whereas some other inflammatory markers may not.