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Title: Environmental, genetic and inflammatory factors modifying endothelial function in patients with coronary heart disease
Author: Robinson, Simon David
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Outcome measures: In a well characterised cohort of patients with stable CHD: athero-thrombotic events during follow-up; t-PA genotype; inflammatory cytokines; acute t-PA release and forearm blood flow 9FBF) during intra-brachial infusion of vaso-agonists. Results: Net t-PA release was 91% lower in the patients who experienced death, MI, CVA or hospitalisation for myocardial ischaemia (p ≤ 0.02) over a median follow-up 34 months. This novel finding validates the application of the forearm model to studying the pathophysiological changes observed in coronary heart disease and suggests that the acute endogenous fibrinolytic capacity is important in determining future cardiovascular risk. Despite confirming previous reports of impaired t-PA release and reduced FBF responses in cigarette smokers (p ≤ 0.05), we found no effect of a number of t-PA genetic polymorphisms on acute t-PA release. In subjects with established CHD, inter-individual differences in t-PA release appear to predominantly reflect the presence of environment factors such as cigarette smoking. Intra-brachial infusion of tumour necrosis factor-α impaired NO-dependent vasodilation (p < 0.001), increased basal t-PA concentrations and doubled bradykinin induced t-PA release (p=0.006). This suggests a pathosphysiological mechanism whereby circulating levels of inflammatory cytokines are directly related to plasma t-PA concentrations and the risk of future cardiovascular events.  Pharmacological interventions with anti-cytokine therapies may have a therapeutic role in subjects at risk of acute coronary syndromes. Despite augmenting the effects of basal nitric oxide release and a direct NO donor (p<0.05), a bolus and intravenous infusion of sildenafil did not affect either endothelium-dependent vasodilation or acute t-PA release. Sildenafil does not modify acute t-PA release and phosphodiesterase type 5 inhibitors are unlikely to reverse the generalised vascular dysfunction seen in patients with coronary heart disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available