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.<p>
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.<p>
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.<p>
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.<p>
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<0.001}; TNF-á, 23.1 ± 2.3 vs. 10.3 ± 0.8 pg/mL {p<0.002}; sVCAM-1, 1059.62 ± 70.8 vs. 651 ± 35.5 ng/mL {p<0.0003}, AGE, 1192.50 ± 82.6 vs. 669.40 ± 47.9 ng/mL {p<0.001}; and AGE/sRAGE, 1.75 ± 0.17 vs. 0.52 ± 0.06 {p<0.001}).<p>
The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the sRAGE biomarker test were 59%, 100%, 100%, 100% and 74% respectively, while those of the AGE/sRAGE test were 85%, 91%, 97%, 67% and 86%, respectively, in the diagnosis of patients with NSTEMI acute coronary syndrome.
The pre-PCI levels of serum sRAGE in patients with restenosis were significantly lower (p<0.001) than in patients without restenosis (610.6 ± 24.1 vs. 1143.8 ± 52.5 pg/mL). The post-PCI levels of serum sRAGE were significantly lower (p<0.0001) in patients with restenosis compared to those without restenosis (477 ± 18.6 vs. 1106.7 ± 41.9 pg/mL). The pre-PCI levels of serum TNF-á and sVCAM-1 were significantly higher (p<0.001 and p<0.001) in patients with restenosis compared to those without restenosis (TNF-á, 37.9 ± 2.5 vs. 11.6 ± 0.41 pg/mL; sVCAM-1, 1381.8 ± 63.5 vs. 811.37 ± 26.5 ng/mL). The post PCI levels of serum TNF-á and sVCAM-1 were also significantly higher (p<0.0001 and p<0.0001) in patients with restenosis than in patients without restenosis (TNF-á, 48.4 ± 1.4 vs. 12.5 ± 0.44 pg/mL; sVCAM-1, 1381.8 ± 63.5 vs. 762.2 ± 26.4 ng/mL). The post-PCI levels sRAGE were lower while those of TNF-á and sVCAM-1 were higher compared to the pre-PCI levels in patients with restenosis. However, the pre- and post-PCI levels of serum sRAGE, TNF-á and sVCAM-1 were similar in patients without restenosis. The pre-PCI levels of serum AGE and AGE/sRAGE were significantly higher (p<0.001 and p<0.001) in patients with restenosis compared to those without restenosis (AGE, 1512.1 ± 84.53 vs. 891.7 ± 92.4 ng/mL; 2.39 ± 0.20 vs. 1.03 ± 0.17).<p>
The sensitivity, specificity, PPV, NPV, and accuracy of the pre-PCI sRAGE tests were 73%, 100%, 100%, 80%, and 87%, respectively while those of the AGE/sRAGE tests were 81%, 94%, 93%, 84% and 88%, respectively in identifying patients with post-PCI restenosis.<p>
In conclusion the results suggest that: (1) the levels of serum sRAGE are lower while those of TNF-á, sVCAM-1, AGE and AGE/sRAGE are higher in NSTEMI patients compared to control subjects; (2) serum levels of sRAGE are negatively correlated with the number of diseased vessels; (3) Both low sRAGE and high AGE/sRAGE may serve as a biomarker/predictor of NSTEMI, but AGE/sRAGE has a greater sensitivity compared to sRAGE; (4) the pre-PCI levels of serum sRAGE are lower while those of AGE/sRAGE are higher in patients with restenosis compared to those without restenosis; and (5) both low sRAGE and high AGE/sRAGE may serve as a predictor/ biomarker of post-PCI restenosis; however, AGE/sRAGE has a greater sensitivity than sRAGE.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-08242009-151257 |
| Date | 11 September 2009 |
| Creators | McNair, Erick Donnell |
| Contributors | Lopez, Jose, Wells, Calvin, Hiebert, Linda, Godin, David, Krahn, John, Prasad, Kailash, Qureshi, Mabood |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-08242009-151257/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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