Neopterin: still a forgotten biomarker.

To the Editor: We read with interest the recent authoritative review article by Apple et al. (1) regarding biomarkers and acute coronary syndromes (ACS). Although the article is both exhaustive and clinically relevant, we felt that the authors failed to recognize the potential value of neopterin as a marker of cardiovascular risk. Neopterin, a pteridine derivative produced by activated macrophages in response to stimulation by inter-feron-␥, is a marker of both immune activation and coronary artery disease (CAD) activity (2). Several studies have shown that circulating neop-terin concentrations are higher in patients with ACS than in patients with chronic stable angina pectoris (CSA) and in apparently healthy persons. Increased neopterin is associated with the presence of vulnerable or disrupted atheromatous plaques (3) and represents a marker of increased risk of further events in patients with ACS (4). Moreover, recent studies from our group have shown that increased serum neopterin predicts rapid CAD progression (5) and the development of major adverse coronary events in patients with CSA (6, 7) and in hypertensive persons without obstructive CAD (8). Neopterin has been also suggested to play a pathogenic role in CAD, and studies in recent years support the notion that neopterin may provide information complementary to that of C-reactive protein (CRP) regarding cardiovascular risk. Despite the wealth of evidence that CRP is a potentially useful marker of risk in the clinical setting, no head-to-head comparisons between CRP and other inflammatory markers such as neop-terin have been carried out in large clinical trials. A recent study from our group (6), however, showed that CRP was not a significant predictor of risk in patients with CSA. In contrast , patients in the highest neop-terin tertile (Ͼ7 nmol/L) had a 3-fold higher risk of developing adverse cardiovascular events (odds ratio ϭ 3; 95% confidence interval, 1.25–7.2; P ϭ 0.015) compared with those in the lowest tertile (Ͻ4.5 nmol/L), even after adjustment for potential confounders in multivariate analysis. In one relatively small study in patients with non-Q-wave myocardial infarction (4), combined measurements of CRP and neopterin were found to have a stronger predictive value than neopterin measurements alone. Recent studies from our group suggest that neopterin may provide more comprehensive information regarding risk of cardiovascular events than do CRP measurements, particularly when macrophage activation is implicated, as seen in rapid CAD progression (5) and atheromatous plaque disruption (3). The numbers of patients in these studies, however, were …