Inflammatory Markers in Coronary Artery Disease

ATHEROTHROMBOSIS IS INCREASINGLY RECOGNIZED as a dynamic chronic inflammatory process of the vessel wall, in which phases of inflammatory and thrombotic activity underlie the clinical presentations of acute coronary syndromes (ACS). There is also evolving evidence that circulating monocytes and white blood cells may be involved in a proinflammatory or prothrombotic circulatory state. These 2 mechanisms— inflammatory involvement of the vessel wall and of the circulating blood—are not mutually exclusive, and both could occur within an individual patient. Two reports in this issue of THE JOURNAL draw attention to the inflammatory basis of coronary atherothrombotic disease. Zhang et al examined the relationship between levels of myeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of lipoproteins in the atheroma, and the prevalence of coronary artery disease (CAD). In a carefully constructed case-control study performed among patients recruited from an outpatient clinic and a cardiac catheterization laboratory, the investigators found that MPO levels strongly correlate with prevalence of CAD (adjusted odds ratios of 11.9 and 20.4 for CAD prevalence between the highest vs lowest quartiles of leukocyte MPO levels and blood MPO levels, respectively). The authors speculate that these striking results may indicate that MPO plays a direct causal role in the development of atherosclerosis and may serve as a marker of inflammation. Although other conventional markers of CAD risk were assessed in this study, these investigators did not compare MPO levels with other markers of inflammation such as Creactive protein (CRP). The authors are appropriately cautious about recommending measurements of MPO levels in routine clinical practice on the basis of this report, particularly since the assay used to determine MPO levels does not appear to be available outside the context of research investigations. Perhaps the most intriguing implication of this observation about MPO, an enzyme principally associated with host defense mechanisms, is whether additional research ultimately may help elucidate the role of infectious agents such as Chlamydia pneumoniae in the pathogenesis of atherosclerosis. In the second report, Lindmark et al measured circulating levels of interleukin 6 (IL-6) among patients enrolled in the prospective Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II (FRISC II) trial comparing invasive vs conservative management of patients with acute coronary syndromes. Elevated IL-6 levels were a strong and independent predictor of mortality for patients treated in both the invasive and conservative arms. Among patients with elevated IL-6 levels, assignment to the early invasive strategy strongly reduced mortality at 12 months (5.1% absolute risk reduction). Although IL-6 levels correlated with mortality, high levels of IL-6 were not predictive of the composite end point of both death and myocardial infarction at 6 to 12 months. The automated assay used in this study may facilitate measurement of IL-6 levels in routine clinical practice. However, on the basis of this report, it would seem premature to recommend such a strategy until several additional practical questions are resolved: first, the authors used a single, crude cutoff of IL-6 levels higher than 5 ng/mL to denote elevated IL-6 concentration. Perhaps a more sophisticated assay would permit more accurate risk stratification by tertiles or quartiles of IL-6 levels. Additional trials may be necessary to establish the predictive value of IL-6 after adjustment for other risk factors. For example, increased weight is associated with higher IL-6 and CRP levels. In the predominantly Scandinavian population enrolled in FRISC II, median body mass index (BMI) was approximately 26 kg/m and was identical among those with normal and elevated IL-6 levels. Surveillance data continue to document the relentless progression of obesity in the United States: 56% of the population is overweight