Prospective epidemiological studies have shown associations of circulating inflammatory markers with risk of CHD (coronary heart disease); however, these associations are modest after adjustment for confounding by established risk factors, and do not add significantly to the predictive value of current clinical risk scores. In contrast, experimental human studies of local arterial inflammation, such as the brachial artery infusion of TNF-α (tumour necrosis factor-α) model reported in this issue of Clinical Science by Robinson and co-workers, are of value in elucidating the pathophysiology of atherothrombosis.
There is increasing interest in the epidemiological associations between circulating markers of inflammation and risk of CHD (coronary heart disease), stroke and peripheral arterial disease . Although recent attention has focussed on CRP (C-reactive protein), meta-analyses of prospective studies have shown that several other circulating inflammatory markers show similar associations with risk of CHD. These include other reactant proteins synthesized in the liver [e.g. serum amyloid A, albumin (which is a negative reactant protein), coagulation factors (including fibrinogen and factor VIII) and the fibrinolytic inhibitor PAI-1 (plasminogen activator inhibitor type 1)] or endothelial cells [e.g. t-PA (tissue plasminogen activator), PAI-1 and vWF (von Willebrand factor)]; traditional clinical tests of disease activity, which reflect plasma protein changes [plasma viscosity and ESR (erythrocyte sedimentation rate)]; and white cell count. The strengths of these associations are modest: typically, an increase in relative risk of CHD of approx. 50% in persons in the highest third of the population distribution compared with those in the lowest third, after adjustment for major cardiovascular risk factors . Hence their measurement is of no clinical value, because they do not add significantly to current clinical risk scores (e.g. those based on the Framingham study) in predicting CHD risk in healthy persons [1–3]. Their utility in prediction of outcome in acute coronary syndromes or stroke, and in prediction of recurrent cardiovascular events, remains to be established in further meta-analyses of relevant prospective studies .
Although therefore of no current proven clinical relevance, inflammatory markers are of considerable pathophysiological interest, because they can help to elucidate biological mechanisms through which environmental risk factors (such as tobacco smoking and obesity) promote the continuing global epidemic of cardiovascular disease. Such studies can be performed at the epidemiological level , or at the experimental level in humans, other mammals or mammalian cell cultures . In this issue of Clinical Science, Robinson and co-workers  report an elegant model of acute local arterial inflammation [brachial artery infusion of the primary pro-inflammatory cytokine TNF-α (tumour necrosis factor-α)] in which they studied the effects of TNF-α on endothelial cell release of t-PA and its inhibitor PAI-1, as well as endothelial function (acetylcholine- and nitroprusside-induced vasodilation, and bradykinin-induced release of t-PA). In a saline-controlled randomized double-blind crossover study in 12 males with stable CHD, they observed that intra-arterial TNF-α caused a rise in t-PA activity and antigen levels in the infused arm, but not the non-infused arm. TNF-α pre-treatment impaired acetylcholine- and nitroprusside-induced vasodilation, and augmented bradykinin-induced release of t-PA.
The value of this local model of acute inflammation, as pointed out by the authors , is that it avoids the induction of systemic inflammation, which has many biological actions and could be confounded by indirect or extravascular effects. In epidemiological studies, circulating levels of inflammatory markers may be strongly influenced by such effects (e.g. the effects of cigarette smoking on the respiratory tract, as well as the circulation), which may explain why they are associated with not only cardiovascular, but also non-cardiovascular mortality . Although previous studies in healthy volunteers have shown that acute systemic inflammation is associated with a transient impairment in vasomotor function , Robinson et al.  have shown that such an impairment in vasomotor function can also be mediated by local inflammation.
Robinson et al.  have also shown that local infusion of TNF-α increases both basal and bradykinin-induced local release of t-PA. Although blood flow affects endothelial cell t-PA release by altering shear stress , TNF-α infusion did not affect blood flow nor did it affect PAI-1 concentrations. The authors  discuss other possible mechanisms for this effect, and speculate that endothelial dysfunction, induced by inflammation, may be one of several mechanisms underlying the association of increased circulating t-PA antigen levels with risk of CHD . It is possible that increased local t-PA activity in arterial plaques may potentiate degradation of extracellular matrix and aggravate plaque instability [9,10]. The authors  suggest that this adverse effect may at times outweigh the beneficial effect of local t-PA release in lysing intravascular fibrin.
The model reported by Robinson et al.  merits further evaluation in illuminating the role of local arterial inflammation in pathogenesis of CHD. Possible future studies include: (i) the effects of the other primary pro-inflammatory cytokine [IL (interleukin)-1], as well as the ‘messenger’ pro-inflammatory cytokine IL-6, whose local levels were increased by TNF-α infusion ; (ii) the measurement of endothelial cell products other than t-PA and PAI-1, which are involved in thrombosis (e.g. vWF and tissue factor); and (iii) the infusion of pro-inflammatory cytokines into arteries which (unlike the brachial artery) are affected by atherosclerosis, such as the coronary arteries. Studies of inflammation and arterial disease should focus on local effects in arteries, rather than the associations of circulating levels of inflammatory markers with risk of arterial events in epidemiological studies that are highly confounded by the effects of multiple adverse environmental factors (such as smoking, obesity and low socio-economic position), which also increase risks of non-cardiovascular morbidity and mortality .