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External stenting reduces long-term medial and neointimal thickening and platelet derived growth factor expression in a pig model of arteriovenous bypass grafting

Abstract

Bypass of stenotic coronary arteries with autologous saphenous vein is an established treatment for ischemic heart disease. However, its long-term clinical success is limited1,2. Late vein graft failure is the result of medial and intimal thickening consequent upon medial vascular smooth muscle cell migration, proliferation and extracellular matrix deposition, followed later by superimposed atherosclerosis3. These changes directly compromise graft blood flow and provoke thrombosis. Vein graft wall thickening may represent an adaptation imposed by arterial hemodynamic factors4–6, and these factors have been shown to promote vascular smooth muscle cell migration and proliferation through activation of key mediators including platelet-derived growth factor (PDGF)7. Many pharmacological interventions aimed at preventing these long-term changes have proven unsuccessful in clinical evaluation8. We recently demonstrated in a pig saphenous vein graft model that application of an external polyester stent to the outside of carotid interposition vein grafts reduced intimal hyperplasia and total wall thickness 1 month after implantation9. However, it is not known whether the benefits of the stent are maintained in the longer term or what mechanisms underlie its effect. The present study therefore compared morphological changes and PDGF expression in stented grafts and contralateral unstented grafts in the same pigs, 6 months after graft implantation. Reduced medial thickening, neointima formation, and cell proliferation were sustained in externally stented grafts, and these effects were associated with a significant reduction in PDGF expression.

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References

  1. Campeau, L., et al. Atherosclerosis and late closure of saphenous vein grafts: Sequential angiographic studies 2 weeks, 1 year, 5 to 7 years and 10 to 12 years after surgery. Circulation 68 (Suppl. II), II.1–II.7 (1983).

    Google Scholar 

  2. Lytle, B., et al. Long term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts. J. Thorac. Cardiovasc. Surg. 89, 248–258 (1985).

    CAS  PubMed  Google Scholar 

  3. Angelini, G. & Newby, A. The future of saphenous vein as a coronary artery bypass conduit. Eur. Heart J. 10, 273–280 (1989).

    Article  CAS  Google Scholar 

  4. Zwolak, R., Adams, M. & Clowes, A. Kinetics of vein graft hyperplasia: Association with tangential stress. J. Vase. Surg. 5, 126–136 (1987).

    Article  CAS  Google Scholar 

  5. Morinaga, K., Okadome, K., Kuroki, M., Muto, Y. & Inokuchi, K. Effect of wall shear stress on intimal thickening of arterially transplanted autogenous veins in dogs. J. Vase. Surg. 2, 430–433 (1985).

    Article  CAS  Google Scholar 

  6. Dobrin, P., Littooy, F. & Endean, E. Mechanical factors predisposing to intimal hyperplasia and medial thickening in autologous vein grafts. Surgery 105, 393–400 (1989).

    CAS  PubMed  Google Scholar 

  7. Francis, S. et al. Release of platelet derived growth factor activity from arteriovenous bypass grafts. J. Thorac. Cardiovasc. Surg. 108, 540–548 (1994).

    CAS  PubMed  Google Scholar 

  8. Bryan, A. & Angelini, G. The biology of saphenous vein graft occlusion: Etiology and strategies for prevention. Curr. Opin. Cardiol. 9, 641–649 (1994).

    Article  CAS  Google Scholar 

  9. Angelini, G., Izzat, M. Bryan, A. & Newby, A. External stenting reduces wall thickening in arteriovenous bypass grafts. J. Thorac. Cardiovasc. Surg. 112, 79–84 (1996).

    Article  CAS  Google Scholar 

  10. Angelini, G., et al. Time course of medial and intimal thickening in pig venous arterial grafts: Relationship to endothelial injury and cholesterol accumulation. J. Thorac. Cardiovasc. Surg. 103, 1093–1103 (1992).

    CAS  PubMed  Google Scholar 

  11. Izzat, M., et al. The influence of external stent size on early medial and neointimal thickening in a pig model of saphenous vein bypass grafting. Circulation 94, 1741–1745 (1996).

    Article  CAS  Google Scholar 

  12. Roussel, F. & Dalion, J. Lectins as markers of endothelial cells: Comparative study between human and animal cells. Lab Animal 22, 135–140 (1988).

    Article  CAS  Google Scholar 

  13. George, S., Williams, A. & Newby, A. An essential role for platelet-derived growth factor in neointima formation in human saphenous vein in vitro. Atherosclerosis 120, 227–240 (1996).

    Article  Google Scholar 

  14. Newby, A. & George, S. Proposed roles for growth factors in mediating smooth muscle proliferation in vascular pathologies. Cardiovasc. Res. 27, 1173–1183 (1993).

    Article  CAS  Google Scholar 

  15. Ross, R., Raines, E. & Bowen-Pope, D. The biology of platelet-derived growth factor. Cell 46, 155–169 (1986).

    Article  CAS  Google Scholar 

  16. Jawien, A., Bowen-Pope, D., Lindner, V., Schwartz, S. & Clowes, A. Platelet derived growth factor promotes smooth muscle cell migration and intimal thickening in a rat model of balloon angioplasty. J. Clin. Invest. 89, 507–511 (1992).

    Article  CAS  Google Scholar 

  17. Nabel, E., et al. Recombinant platelet derived growth factor B gene expression in porcine arteries induces intimal hyperplasia in vivo. J. Clin. Invest 91, 1822–1829 (1993).

    Article  CAS  Google Scholar 

  18. Ferns, C., et al. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 253, 1129–1132 (1991).

    Article  CAS  Google Scholar 

  19. Francis, S., et al. Release of platelet derived growth factor activity from arteriovenous bypass grafts. J. Thorac. Cardiovasc. Surg. 108, 540–548 (1994).

    CAS  PubMed  Google Scholar 

  20. Hoch, J.R., Stark, V.K., Hullett, D.A. & Turnipseed, W.D. Vein graft intimal hyperplasia - leukocytes and cytokine gene- expression. Surgery 116, 463–471 (1994).

    CAS  PubMed  Google Scholar 

  21. Hoch, J.R., Stark, V.K. & Turnipseed, W.D. The temporal relationship between the development of vein graft intimal hyperplasia and growth-factor gene-expression. J. Vase. Surg 22, 51–58 (1995).

    Article  CAS  Google Scholar 

  22. Barker, S., et al. The adventitia and atherogenesis: Removal initiates intimal proliferation in the rabbit which regresses on generation of a ‘neoadventitia’. Atherosclerosis 105, 131–144 (1994).

    Article  CAS  Google Scholar 

  23. Barker, S., Talbert, A., Cottam, S., Baskerville, P. & Martin, J. Arterial intimal hyperplasia after occlusion of the adventitial vasa vasorum in the pig. Arterioscler. Thromb. 13, 70–77 (1993).

    CAS  Google Scholar 

  24. Goldman, S., et al. Long term graft patency (3 years) after coronary artery surgery: Effects of aspirin. Results of a VA Cooperative Study. Circulation 89, 1138–1143 (1994).

    Article  CAS  Google Scholar 

  25. Zilla, P., von Oppell, U. & Deutsch, M. The endothelium: A key to the future. J. Cardiac Surg. 8, 32–60 (1993).

    Article  CAS  Google Scholar 

  26. Kohler, T., Kirkman, T. & Clowes, A. The effect of rigid external support on vein graft adaptation to the arterial circulation. J. Vase. Surg. 9, 277–285 (1989).

    Article  CAS  Google Scholar 

  27. Violaris, A., Newby, A. & Angelini, G. Effects of external stenting on wall thickening in arteriovenous bypass grafts. Ann. Thorac. Surg. 55, 667–671 (1993).

    Article  CAS  Google Scholar 

  28. Karayannacos, P. et al. Late failure in vein grafts: Mediating factors in subendothelial fibromuscular hyperplasia. Ann. Surg. 187, 183–188 (1978).

    Article  CAS  Google Scholar 

  29. Home Office Animals (Scientific Procedures) Act 1986. Guidance on the operation on animals. (HMSO, London, 1990).

  30. Galand, P. & Degraef, C. Cyclin/PCNA immunostaining as an alternative to tritiated thymidine pulse labelling for marking S-phase cells in paraffin sections from animal and human tissues. Cell Tissue Kinet. 22, 383–392 (1989).

    CAS  PubMed  Google Scholar 

  31. Soyombo, A., Angelini, G., Bryan, A., Jasani, B. & Newby, A. Intimal proliferation in an organ culture of human saphenous vein. Am. J. Pathol. 137, 1401–1410 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

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Mehta, D., George, S., Jeremy, J. et al. External stenting reduces long-term medial and neointimal thickening and platelet derived growth factor expression in a pig model of arteriovenous bypass grafting. Nat Med 4, 235–239 (1998). https://doi.org/10.1038/nm0298-235

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