Clinical aspects of vein graft stenosis and the role of endothelin and its inhibitors in intimal hyperplasia

This thesis looks at clinical and biological aspects of vein graft stenoses in order to improve on existing management strategies and to explore the possibility for a new pharmacological therapy using antagonists of the endothelin system.;After an overview of peripheral vascular disease, the introductory chapters discuss vein graft surveillance, intimal hyperplasia and properties of the vasoactive peptide, endothelin.;The work described consists of clinical and laboratory based research. In the clinical chapters a retrospective study analysed the influence of patient factors on the outcome of lower limb vein grafting in the current era of postoperative vein graft surveillance. Following this, two prospective studies examined specific aspects of graft surveillance. Firstly, the predictive value of pre-discharge duplex vein graft scans was determined. The second study validated the criteria for intervention in duplex detected vein graft flow abnormalities.;The first laboratory experiments set out to determine the effect of endothelin and endothelin receptor antagonists on proliferation in isolated venous smooth muscle cells. Following this, an organ culture system, a more representative model of intimal hyperplasia, was used to demonstrate the association between endothelin production and development of intimal hyperplasia. Using the same model, a series of experiments were then performed to determine the effect of endothelin inhibition. Endothelin was inhibited at the level of its synthesis, and by none selective and then selective receptor blockade.;The final chapter summarises and concludes the main findings and discusses areas of future work that could arise from this thesis.