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The idea that inflammatory processes are involved in the pathogenesis of atherosclerotic coronary artery disease is not new,1 but it has attracted renewed focus recently because of combined clinical, epidemiological, pharmacological, and histological observations. Case–control studies have established consistent associations between circulating inflammatory markers, in particular C reactive protein (CRP), and the subsequent risk of cardiovascular events in healthy people2 3 and in patients with established coronary heart disease.4 5 CRP concentrations are often increased during acute coronary syndromes and higher concentrations predict a worse outcome in patients with unstable angina.6 Indeed, the protective effects of aspirin3 and pravastatin5 are greatest in patients with the highest baseline CRP concentrations, in keeping with the anti-inflammatory properties of both drug classes,7 while angiotensin converting enzyme (ACE) inhibitors also prevent coronary events, probably through anti-inflammatory activity.8 The pivotal roles of monocyte derived macrophages and T lymphocytes as the regulators of matrix degradation, apoptosis, cell replication, and recruitment of circulating cells within the atherosclerotic plaque continue to be elucidated.9
Marker of coronary plaque inflammation
Interleukin 6 (IL-6) has gradually and quietly moved into the spotlight as a local and circulating marker of coronary plaque inflammation. Familiar to rheumatologists, endocrinologists, oncologists, and immunologists, this versatile cytokine is found in large quantities in human atherosclerotic plaques,10typically in macrophage rich areas.8 Raised circulating concentrations are found in patients with unstable angina11 and in patients at risk of future cardiovascular events.12 It can be produced by many vascular cells including endothelial cells, smooth muscle cells, lymphocytes and macrophages13 and, being the principal regulator of CRP release from the liver, it plausibly accounts for the link between coronary events and raised circulating CRP concentrations. Interestingly, based on its pleiotropic in vitro behaviour, the net biological effect of IL-6 at the plaque may either be to upregulate or to pacify the inflammatory response,13 although the balance of opinion favours the former.
In this issue of Heart, Hojo and colleagues explore links between IL-6 and restenosis in patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) for stable angina.14 Coronary sinus blood was drawn before and after PTCA and the concentrations of four inflammatory cytokines measured. Of these four, two (monocyte chemoattractant protein 1 and macrophage colony stimulating factor) did not change, one (platelet derived growth factor subtype AB) was rarely measurable, but coronary sinus IL-6 concentrations were significantly raised postprocedure. This release was specific to PTCA rather than diagnostic catheterisation, so common elements of both techniques (peripheral arterial instrumentation, coronary arterial and coronary sinus catheterisation, administration of contrast agents) were unlikely to be the stimulants of IL-6 release. It also arose from the heart in that IL-6 concentrations were not raised in peripheral arterial blood samples taken at the same time. The authors performed six month follow up coronary angiography and found that the late loss index (an angiographic measure of restenosis) correlated with the increase in IL-6 concentration after PTCA. The strength of the relation is not strong: between a one- and twofold increase (most patients) no clear correlation is visible, although all patients who had more than a twofold rise had a high late loss index, and patients who had no or minimal IL-6 increases had minimal late loss at follow up. Patients who fulfilled binary criteria for restenosis had more post-PTCA IL-6 release than those who did not.
Novel features of this study
Previous workers have measured IL-6 concentrations after PTCA, but one of the novel features of the present study is that IL-6 release was consistently detected in patients after PTCA of clinically stable lesions. Post-PTCA IL-6 release has been demonstrated in patients with unstable angina15 and acute myocardial infarction,16 although in neither study could it be detected in patients with stable angina. The use of a more sensitive IL-6 assay in the present study (stated lower limit of detection 0.1 pg/ml as compared with 3.0 pg/ml15 and 2.0 pg/ml16) accounts for these disparities, and the authors have maximised their capacity to detect subtle cardiac IL-6 release by sampling coronary sinus blood. We do not know whether the source of this IL-6 is predominantly circulating leucocytes, adherent leucocytes or cells contained within the plaque, although the nature of PTCA associated trauma suggests that it is likely to be the latter.
That the magnitude of inflammatory marker release may also predict restenosis after PTCA and stenting is an attractive theory that is raised but not proven by the present study. It is supported by observations that serum amyloid A release is common post-PTCA and that it predicts restenosis in patients with unstable angina,17and that raised plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) predict restenosis after PTCA for acute myocardial infarction.18 The failure of a long list of anti-inflammatory drugs to prevent restenosis may indicate that inflammation is a marker rather than a cause of restenosis, that the agents tested have not been sufficiently specific or that inappropriate components of the inflammatory system were targeted. Exciting recent animal studies suggest that inhibition of leucocyte adhesion via the Mac-1 integrin receptor substantially attenuates post-PTCA and post-stenting restenosis,19 paving the way for clinical trials of Mac-1 receptor blockers to prevent restenosis.
The designation of atherosclerosis as a chronic inflammatory or autoimmune process, much like rheumatoid arthritis or pulmonary fibrosis, represents an exciting and logical paradigm shift for cardiologists. Plasma concentrations of IL-6 and its hepatic byproduct CRP appear to reflect the intensity of occult plaque inflammation and by inference may grade vulnerability to rupture,20 a concept supported by the fact that the population risk of acute cardiovascular events is predicted by their ambient circulating concentrations.2-5 12 Potential consequences include population screening for circulating inflammatory markers, recommendation of anti-inflammatory treatment (aspirin, HMG-CoA reductase inhibitors or ACE inhibitors) for those thought to be at higher risk, and the use of CRP rather than low density lipoprotein assays to guide dosing of HMG-CoA reductase inhibitor treatment.21 If fibrinolytic agents dominated the 1980s and platelet directed drugs ruled the 1990s, the next decade may well see effective leucocyte modulating therapy as a new cornerstone of cardiovascular treatment.