The role of novel cytokines in inflammation: Defining peripheral artery disease among patients with coronary artery disease

Abstract

Coronary artery disease (CAD) patients with concomitant peripheral artery disease (PAD) experience more extensive and calcified atherosclerosis, greater lesion progression and more common coronary events compared to patients with CAD only. To characterize the distinct features of this aggressive atherosclerotic disease, we studied novel cytokines that code different stages of atherogenesis. One hundred and eighty consecutive subjects (60 patients into each group of CAD+PAD, CAD and controls) were recruited among patients with stable angina pectoris scheduled for coronary angiography. An ankle-brachial index (ABI) 0.9 was determined as occlusive PAD. Fasting serum tumor necrosis factor (TNF)-like antigen 1A (TL1A) and its receptor death receptor 3 (DR3), NOGO-B (reticulon 4B) and its receptor NUS1, high-sensitivity C-reactive protein (hsCRP), A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1, 4, 5 and interleukin (IL) 6 levels were determined. Serum hsCRP and DR3/TL1A concentrations were similar and higher than controls in the CAD and CAD+PAD groups. Levels of NOGO-B and its receptor NUS1 were increased and ADAMTS-5 was decreased in patients with CAD+PAD. Independent predictors of ABI in multivariate analysis were smoking (B = -0.13, p = 0.04), NUS1 (B = -0.88, p < 0.001), ADAMTS-5 (B = 0.63, p < 0.001) and SYNTAX score (B = -0.26, p < 0.001). Similarly, smoking (OR = 5.5, p = 0.019), SYNTAX score (OR = 1.2, p < 0.001), NUS1 (OR = 14.4, p < 0.001), ADAMTS-5 (OR = 1.1, p < 0.001) and age (OR = 1.1, p = 0.042) independently predicted the involvement of peripheral vasculature in logistic regression. The diagnostic performance of these cytokines to discriminate CAD+PAD were AUC 0.79 (p < 0.001) for NUS1 and 0.37 (p = 0.013) for ADAMTS-5. We report herein that circulating cytokines can give clues to the ongoing atherosclerotic process and the extent of vascular involvement in which distinct features of ADAMTS-5 and NUS1 make them promising cytokines for future research.