Inflammatory Markers and Cardiovascular Disease

Abstract

Background: Inflammation is now recognised to play a central part in the initiation, progression and clinical manifestation of atherosclerotic cardiovascular disease. Correspondingly, on a population level, circulating levels of a wide range of inflammatory markers have been shown to be predictive of future cardiovascular events, regardless of whether they are measured in asymptomatic people, patients with stable angina, or patients with acute coronary syndromes. These include both systemic markers of inflammation such as the white blood cell count (WBC), fibrinogen, and C-reactive protein (CRP), and locally produced mediators of inflammation such as the cellular adhesion molecule soluble intercellular adhesion molecule 1 (sICAM-1), the cell-surface protein soluble CD40 ligand (sCD40L), and the metalloproteinase pregnancy associated plasma protein-A (PAPP-A). Investigation of these inflammatory markers has given many useful insights into the mechanisms that underlie the development of atherosclerosis and atherosclerotic clinical events. However, although the association (on a population level) of raised inflammatory markers with increased atherosclerotic events is widely accepted, the clinical utility of these markers (their ability to provide meaningful additional information that will help individualise treatment strategies and lead to better clinical outcomes) remains a subject of vigorous debate. Consequently, the research presented in this thesis has two broad purposes: to determine the value of inflammatory markers in a particular clinical situation (the prediction of restenosis following percutaneous coronary intervention), and to examine whether vascular inflammation is a modifiable risk factor (whether marker levels can be lowered by health interventions such as drug therapy, exercise, or smoking cessation). Methods and results: a. Inflammatory markers and restenosis To investigate whether inflammatory markers are predictive of restenosis following PCI, inflammatory markers (CRP, sICAM-1, sCD40L and PAPP-A) were measured prior to and 48 hours, 1 week and 1 month after elective PCI, and angiographic follow-up was performed at 6 months, in 133 stable angina patients. PCI led to a significant rise in CRP, sCD40L and PAPP-A levels 48 hours post-procedure, but neither pre-PCI nor post-PCI inflammatory marker levels were predictive of restenosis. This lack of association could not be attributed to concurrent use of medications such as statins, thienopyridines or glycoprotein IIb/IIIa inhibitors, since 50% of patients were not on statins and no patients received thienopyridines or glycoprotein IIb/IIIa inhibitors during the study. b. The effects of lipid lowering agents on inflammatory marker levels The effects of lipid-modifying agents on inflammatory marker levels were tested in 215 participants with stable angina randomised to simvastatin or placebo, and a further 100 participants randomised to simvastatin or bezafibrate, over a treatment period of at least 2 years. In addition, the effect of statins on the inflammatory response to PCI was assessed in a subset of 92 patients by comparing inflammatory marker levels before and 48 hours, 1week, and 1 month after PCI in those randomised to simvastatin versus those randomised to placebo. Although simvastatin led to a reduction in CRP levels with long-term therapy, the effect was modest and variable compared to the predictable effect on cholesterol levels. Average CRP levels fell ~5%, compared to a 40% reduction in LDL cholesterol, and CRP levels increased in nearly a quarter of patients on simvastatin. In addition, simvastatin did not lower levels of any other inflammatory marker, and had no appreciable effect on the inflammatory response to PCI. Similarly, bezafibrate therapy did not lower levels of any inflammatory marker. c. The effect of exercise training on inflammatory marker levels. The effects of exercise training on inflammatory markers were assessed in two separate randomised controlled trials. The first trial involved CRP measurement in 63 healthy elderly participants randomised to either 6 months’ exercise training or to a control group. The second trial involved measurement of several inflammatory markers (WBC, fibrinogen, CRP, sCD40L, sICAM-1) in 152 healthy female smokers randomised to either 12 weeks’ exercise training or to a health education (control) group as part of a smoking cessation program. In both trials, exercise led to a significant improvement in fitness but had no effect on inflammatory marker levels. d. The effect of smoking cessation on inflammatory marker levels The smoking cessation trial also investigated the effect of abstinence from smoking on inflammatory marker levels. Forty-eight individuals (35%) achieved 6 weeks verified abstinence from smoking. Abstinence caused a significant decrease in WBC and fibrinogen levels but had no effect on other inflammatory markers (CRP, sICAM-1, and sCD40L). Conclusions: There are several important findings from this research. Firstly, inflammatory markers are not useful in the prediction of restenosis following PCI in stable angina. Secondly, neither simvastatin nor bezafibrate have major antiinflammatory effects in vivo. This brings into question the mechanism(s) by which statins lower CRP, and has implications for recent proposals in the literature advocating the clinical use of CRP to titrate statin therapy. Thirdly, smoking cessation leads to a reduction in WBC and fibrinogen levels (which may reflect changes in pulmonary inflammation), but neither exercise nor smoking cessation are associated with a broad reduction in inflammatory markers linked to cardiovascular risk. It is therefore unlikely the appreciable cardiovascular benefits of these interventions are due in any substantial part to antiinflammatory effects. It remains to be demonstrated whether there are interventions which can reliably lower inflammatory marker levels, whether this decreases cardiovascular risk, and whether measurement of inflammatory markers improves upon current management of cardiovascular disease and leads to actual clinical benefit.