Inflammation and atherosclerosis: Serum amyloid A as an inflammatory mediator in coronary artery disease, and the contribution of coronary plaque to inflammation in atherosclerosis

The relationship between inflammation and atherosclerosis is increasingly well recognised. Systemic inflammatory states, either due to auto-immune illness, or subclinical inflammation measured by inflammatory markers, are associated with increased prevalence of coronary artery disease (CAD) and acute coronary syndromes (ACS). Serum amyloid A (SAA) is an inflammatory marker associated with CAD in some studies, and in vitro work has suggested that it may induce a pro-coagulant state in leucocytes. Additionally, pathological specimens of atheroma contain large numbers of leucocytes which express pro- and anti—inflammatory mediators and contribute to the instability of plaque. There were 2 main hypotheses for these studies: the first was that SAA is an inflammatory mediator with the capacity to induce expression of cytokines from monocytic cells. The second was that, in CAD and control subjects undergoing coronary angiography, the presence of stable or unstable coronary plaque will measurably contribute to the levels of inflammatory mediators and markers in blood leaving the heart, even when systemic concentrations of the same mediators and markers do not differ. SAA potently induced expression of several pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMC), as well as IL—10 and tissue factor. Cytokines were also secreted by isolated monocytes stimulated by SAA, suggesting that signalling by lymphocytes was not required. Macrophages differentiated from these monocytes expressed higher basal and SAA-induced levels of cytokines, though patterns of induction after SAA stimulation varied according to cell type. Additionally, compared to those from control subjects, PMBC isolated from patients with CAD tended to express higher basal cytokine levels, and increased concentrations after SAA stimulation. The local production or uptake within coronary plaque of cytokines and inflammatory markers was then investigated by comparing concentrations of these substances in the aorta and coronary sinus of control and CAD subjects undergoing coronary angiography. In control subjects, no transcoronary gradient was observed for any analyte. In subjects with CAD, we observed a positive gradient for several cytokines and SAA, indicating coronary release. Additionally, we found a negative gradient of the anti-inflammatory adipokine adiponectin in non-diabetic subjects with ACS, indicating uptake of this cytokine into plaque. These studies provide evidence that SAA is a mediator of inflammation, rather than merely an inflammatory marker. They also indicate that coronary plaque produces cytokines in measurable quantities, which may contribute to the systemic inflammatory state associated with CAD