The aetiology and prevention of infrainguinal vein bypass graft stenosis.

Stenoses occur in 20-30% of infrainguinal vein bypass grafts, and are the commonest cause of graft failure in the medium term (1 month to 1 year). The aim of this thesis was to investigate the aetiology and prevention of these stenoses. In the first two chapters the literature regarding peripheral vascular disease and vein graft stenoses are reviewed. In Chapter 3 a retrospective study of 81 infragenicular vein grafts performed in Leicester revealed that small diameter grafts and the distal section of in-situ grafts were more prone to stenoses. This suggested that some inherent abnormality of the graft itself may play a role in the development of these stenoses. The structure of the long saphenous vein in patients with arterial disease was therefore studied in Chapter 4. A process causing intimal thickening was identified in the majority of veins, possibly in response to haemodynamic stresses. The pre or intraoperative detection of these changes in the vein using duplex and intravascular ultrasound was limited however. These techniques do not therefore reliably identify "at risk" grafts. In order to study the vascular biology of vein graft intimal hyperplasia, the underlying cause of graft stenoses, a vein culture model was established. The methods used to validate this model are detailed in Chapters 5 and 6. In Chapter 7 the influence of injury on neointimal proliferation was studied. The endothelium was found to act as a promoter of neointimal proliferation but no response to direct smooth muscle cell injury was detected, In Chapter 8 the inhibition of neointimal proliferation by low molecular weight heparin was studied. This was effective, but only at high doses. Non anticoagulant derivatives or alternative drug delivery systems are therefore required before heparin could be safely used in the clinical setting. Blockade of the angiotensin II AT1-receptor with Losartan was studied in Chapter 9. This reduced neointimal thickness and proliferation by approximately 33%. This agent may prove to be of therapeutic value, particularly as part of a combination therapy regime.