Chia, Stanley

2018-03-29T12:15:36Z

2018-03-29T12:15:36Z

2006

The vascular endothelium plays a vital role in the control of blood flow, haemostasis, fibrinolysis and inflammation. Impairment of endothelial vasomotor and fibrinolytic function is implicated in the pathogenesis of ischaemic heart disease. Atherosclerosis is now widely recognised to be an inflammatory disease process, but the mechanistic links between inflammation, endothelial dysfunction and endogenous fibrinolysis remain poorly understood.

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-a induced local vascular inflammation was associated with impaired resistance vessel endotheliumdependent 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-a 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 function and endogenous fibrinolysis. We have identified the unique role of systemic inflammation and specifically, tumour necrosis factor-a. Furthermore, our studies indicated that there were no significant associations between fibrinolysis and hyperhomocysteinaemia or coronary stent complications. Therefore 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.

http://hdl.handle.net/1842/29061

The University of Edinburgh

Annexe Thesis Digitisation Project 2018 Block 17

Already catalogued

Endothelial function and endogenous fibrinolysis in inflammation and ischaemic heart disease

Thesis or Dissertation

Doctoral

MD Doctor of Medicine