peripheral arterial disease (PAD), a limiting factor in the success of percutaneous transluminal angioplasty (PTA) is the development of restenosis secondary to vascular smooth muscle cell (SMC) proliferation. The aim of this study was to determine the effect of combination antiplatelet therapy on the ability of plasma, from patients undergoing PTA, to stimulate SMCs in vitro. We aimed to investigate the effect of combination treatment on levels of circulating adhesion molecules and factors which mediate SMC proliferation in experimental models. We also sought to demonstrate any association between changes in measured markers and the development of restenosis or vascular events. Methods Fifty patients were randomised to receive clopidogrel or placebo, for thirty days, in addition to their daily 75mg aspirin. To measure proliferative capacity, diluted plasma was incubated with 24h-growth-arrested rat vascular SMCs, and Extracellular-regulated-kinase (ERK)1/2 activation was analysed by Western blotting at baseline, 1-hour pre-PTA, and at 1-hour, 24-hours and 30-days post-PTA. Plasma platelet-derived growth factor (PDGF-BB), soluble (s)E-selectin, sICAM-1 (intracellular adhesion molecule-1) and von Willebrand factor (vWF) were measured by ELISA (Enzyme-linked immunosorbent assay), at the same time-points. Platelet activation was measured by flow cytometry of ADP-stimulated platelet fibrinogen binding at baseline and 1-hour post-PTA. Patients’ notes and all investigations were reviewed for 2 years post-PTA to record restenosis or vascular events. Results Samples were available for all 50 patients at baseline, 1-hour pre-PTA and 1-hour post-PTA timepoints. In this cohort ERK1/2 activation was significantly increased post-PTA in both the aspirin/clopidogrel and aspirin/placebo groups. Those who developed a symptomatic restenosis had a significantly higher level of SMC activation at the 1-hour post-PTA time-point. There was a statistically significant decrease in PDGF-BB, and increase in vWF, following loading with clopidogrel. sICAM-1 levels significantly decreased in the aspirin/placebo group following PTA. ADP-stimulated platelet fibrinogen binding was significantly inhibited by clopidogrel therapy post-PTA. Conclusions This is the first study to show in-vitro ERK1/2 activation (a marker of SMC proliferation) increases post-PTA. Patients developing a symptomatic restenosis had a significantly higher level of SMC activation at the 1-hour post-PTA time-point. Clopidogrel therapy had no significant effect on ERK1/2 activation, although it did reduce PDGF-BB in the larger cohort of patients. Further work is required to evaluate potential therapeutic treatments which may reduce peripheral PTA-induced smooth muscle cell activation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:540431 |
| Date | January 2010 |
| Creators | Wilson, Alasdair |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=165239 |
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