Soluble receptors for advanced glycation end products as predictors of restenosis following percutaneous coronary intervention

Abstract

The principal cause of non-ST-segment myocardial infarction (NSTEMI), a subclass of acute coronary syndrome (ACS), is thrombosis and the underlying cause is atherosclerosis. Percutaneous coronary intervention (PCI) is one of the treatments to attenuate the ischemic effects of severe coronary artery stenosis. However, restenosis following PCI (post-PCI) is a major problem for the long-term success of the procedure. Recently, the interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the development of atherosclerosis in animal models. Interaction of AGE with RAGE results in activation of nuclear factor kappa-B (NF-êB), release of cytokines including tumor necrosis factor-alpha (TNF-á), the expression of adhesion molecules including soluble vascular adhesion molecule-1 (sVCAM-1) and induction of oxidative stress all of which have been implicated in the development of atherosclerosis. The soluble receptor for advanced glycation end products (sRAGE) acts as a decoy for RAGE ligands (AGEs) and this occurs by competing with RAGE. In animal models, balloon inflation and de-endothelialization of the carotid artery increase the concentration of AGE and RAGE in the arterial wall and induces neointimal hyperplasia and stenosis. Treatment with sRAGE in animal models reduces neointimal growth and decreases smooth muscle cell migration and proliferation and expression of extracellular matrix.

It is hypothesized that NSTEMI and post-PCI restenosis may be due to low levels of serum sRAGE resulting in increased AGE and RAGE interactions. Low levels of sRAGE would also increase the levels of serum TNF-á and sVCAM-1.

The objectives of this study were to determine whether: (1) the levels of serum sRAGE are lower and the levels of AGE, TNF-á and sVCAM-1 are higher in NSTEMI patients compared to control; (2) the levels of serum sRAGE are lower and the levels of AGE, TNF-á and sVCAM-1 are higher in NSTEMI patients with restenosis compared to those without restenosis; and (3) sRAGE or AGE/sRAGE ratio may serve as a biomarker/ predictor of NSTEMI and post-PCI restenosis.

The study objectives include 46 consecutive NSTEMI patients undergoing elective PCI and 28 healthy age-matched male controls. Pre-PCI and 6 month post-PCI angiography were performed in all NSTEMI patients. Blood samples were collected at designated intervals for the measurement of sRAGE, AGE, TNF-á, and sVCAM-1 using commercially available enzyme-linked immunosorbent assay (ELISA) kits.

The levels of serum sRAGE were lower and those of TNF-á, sVCAM-1, AGE and AGE/sRAGE were higher in NSTEMI patients compared to control subjects. (sRAGE, 884.55 ± 50 vs. 1287 ± 41.5 pg/mL{p