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Title: Endothelial function and endogenous fibrinolysis in inflammation and ischaemic heart disease
Author: Chia, Stanley
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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In a series of studies, we explored the effects of inflammation on endothelial vasomotion and fibrinolytic capacity using an in vivo forearm model of systemic and local inflammation. Systemic inflammation stimulated by typhoid vaccination had no major effect on vasomotor tone. However, tumour necrosis factor-α induced local vascular inflammation was associated with impaired resistance vessel endothelium-dependent vasodilatation, possibly through the development of acute arterial injury. Both systemic and local inflammation were found to augment the acute release of endothelial tissue plasminogen activator. In addition, intra-arterial tumour necrosis factor-α administration resulted in a unique profile of substantial and sustained local increase in endogenous tissue plasminogen activator. We extended these investigations and assessed the role of endogenous fibrinolysis and endothelial dysfunction in the pathogenesis of prothrombotic conditions such as hyperhomocysteinaemia and coronary stent thrombosis or in-stent restenosis using this forearm model of endothelial function assessment. In patients with recent myocardial infarction, elevation of plasma homocysteine concentration was associated with impaired endothelium-dependent vasodilatation but not endogenous fibrinolysis. This vasomotor dysfunction was not rectified by vitamin supplementation. We also assessed three critical aspects of vascular function in patients who have undergone percutaneous coronary intervention and found no evidence that endothelial vasomotor, fibrinolytic or platelet function play a major role in the pathogenesis of acute stent thrombosis or in-stent restenosis. We conclude that there is complex interaction between inflammation, endothelial endogenous fibrinolysis. Modulating cytokine actions and their interaction with fibrinolysis may be critical in the prevention of thrombotic coronary occlusion and myocardial ischaemia as well as in the future development of anti-thrombotic therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available