Intimal hyperplasia in human long saphenous vein: The effects of statins

Ruiz, Maria-Carmen (2007) Intimal hyperplasia in human long saphenous vein: The effects of statins. MD thesis, University of Glasgow.

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Abstract

The overall aims of the study were: to establish whether long saphenous veins from ischaemic limbs were more susceptible to developing intimal hyperplasia in organ culture compared with veins from non-ischaemic limbs; to investigate the effect of simvastatin on this process; to compare the proliferation and migration of vascular smooth muscle cells explanted from ischaemic and non- ischaemic veins and the effect of simvastatin on these processes; and to audit the outcomes of all infrainguinal vein bypass grafts performed at Glasgow Royal Infirmary between 1993-2003, correlating graft occlusion with statin use. Veins were obtained from two patient groups: those undergoing lower limb amputation due to severe ischaemia- ischaemic veins; and those undergoing coronary artery bypass grafting using the long saphenous vein- non-ischaemic veins. These were placed in organ culture for 14 days in either culture medium with growth factors alone or culture medium with growth factors and simvastatin. At the end of this period, vein rings were fixed and processed for histological analysis and the area of Tunica Intima was calculated using Image Analysis software. Vascular smooth muscle cells were explanted from the vein rings and grown on for use in proliferation and migration assays. Cell proliferation was assayed using a 3H labelled Thymidine incorporation technique. Cell migration was assayed using a modified Boyden chamber technique. Veins from both ischaemic and non-ischaemic limbs had the same amount of vessel area as Tunica Intima in the fresh fixed state. Veins from both groups showed significant growth of the intimal layer following 14 days in culture. Veins from the ischaemic limbs developed significantly more intimal growth compared with the veins from non-ischaemic limbs. Simvastatin abolished the growth of intima in the veins from ischaemic limbs and reduced the growth of intima in veins from non-ischaemic limbs. The proliferation of vascular smooth muscle cells from both ischaemic and non-ischaemic veins was inhibited in a dose-dependent manner by simvastatin. There was no difference in the mean 50% inhibitory concentration of simvastatin for the two groups of vein cells. Vascular smooth muscle cell migration in response to platelet-derived growth factor was enhanced in cells from the ischaemic veins compared with cells from the non-ischaemic veins. Simvastatin appeared to inhibit vascular smooth muscle cell migration. Between 1993-2003, 207 infrainguinal vein bypass grafts were created in Glasgow Royal Infirmary. Data was available for 133 of these grafts. The graft patency in patients taking a statin at 1,3 and 5 years was 97%, 91% and 83% compared with 88%, 72% and 56% for patients not taking a statin. The median survival of grafts was 9.8 years for those taking a statin and 6.7 years for those not taking a statin. These differences approach statistical significance. Additionally, female gender was associated with increased risk of graft occlusion. In conclusion, ischaemia predisposes the long saphenous vein to develop intimal hyperplasia in organ culture and simvastatin abolishes this process. This tendency to develop intimal hyperplasia may be partly explained by the finding that vascular smooth muscle cells from ischaemic veins have an accelerated migration response in cell culture compared with cells from non-ischaemic veins. Simvastatin inhibits vascular smooth muscle cell proliferation and migration in vitro and this can explain the effect of simvastatin in organ culture. These findings raise the possibility of using simvastatin to prevent intimal hyperplasia in infrainguinal vein grafts. The concentration of simvastatin used in these experiments, however, was much higher than can be attained with normal oral doses and, as such, may lead to the development of novel drug delivery techniques such as drug eluting sutures. Clinically, simvastatin has been associated with improved infrainguinal graft patency. How this relates to the in vitro findings here is not clear but is likely to involve more than the known anti-proliferative and anti-migratory effects of statins.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine
Date of Award: 2007
Depositing User: Enlighten Team
Unique ID: glathesis:2007-71019
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 May 2019 14:28
Last Modified: 09 May 2019 14:28
URI: http://theses.gla.ac.uk/id/eprint/71019

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