Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia

Jason A. Petrofski, Jonathan A. Hata, Thomas R. Gehrig, Steven I. Hanish, Matthew L. Williams, Richard B. Thompson, Cyrus J. Parsa, Walter J. Koch, Carmelo A. Milano, Frank W. Sellke, Aftab R. Kherani, Paul A. Kurlansky

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24 Scopus citations

Abstract

Objective: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is an initial, critical step in the progression toward occlusion. To date, no clinically relevant large animal models of aortocoronary saphenous vein graft intimal hyperplasia have been fully characterized. Gene therapy holds promise as a novel treatment for aortocoronary saphenous vein graft intimal hyperplasia. The 2 objectives of this study are to characterize a canine model of aortocoronary saphenous vein graft intimal hyperplasia and to demonstrate that ex vivo gene delivery is possible in these grafts using adenoviral vectors. Methods: Ten dogs underwent aortocoronary bypass grafting using saphenous veins. Six dogs underwent serial arteriograms to monitor graft patency. On post-operative day 90, the dogs were killed and their grafted and nongrafted saphenous veins were studied histologically. Four dogs underwent the same procedure, but their saphenous veins were treated with 1 × 1012 total viral particles of a replication-deficient, recombinant adenovirus containing β-galactosidase (n = 2) or the β-adrenergic receptor kinase carboxyl terminus (n = 2). These animals were killed on postoperative day 7 for determination of transgene expression. Results: All grafts were demonstrated patent by arteriogram before the animals were killed. The mean intimal area of the saphenous vein grafts was increased when compared with that of the nongrafted saphenous veins (2.83 mm2 vs 0.09 mm2, P < .0008). Adenoviral-treated saphenous vein grafts demonstrated positive transgene expression either by X-gal staining (β-galactosidase) or Northern analysis (β-adrenergic receptor kinase carboxyl terminus). Conclusion: This study characterizes a clinically relevant canine model of aortocoronary saphenous vein graft intimal hyperplasia. In addition, it demonstrates that adenoviral vectors can be delivered ex vivo to the saphenous vein graft vessel wall at subphysiologic distension pressures. This model may be used in future studies to manipulate molecular targets critical in aortocoronary saphenous vein graft intimal hyperplasia.

Original languageEnglish (US)
Pages (from-to)27-33
Number of pages7
JournalJournal of Thoracic and Cardiovascular Surgery
Volume127
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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    Petrofski, J. A., Hata, J. A., Gehrig, T. R., Hanish, S. I., Williams, M. L., Thompson, R. B., Parsa, C. J., Koch, W. J., Milano, C. A., Sellke, F. W., Kherani, A. R., & Kurlansky, P. A. (2004). Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia. Journal of Thoracic and Cardiovascular Surgery, 127(1), 27-33. https://doi.org/10.1016/j.jtcvs.2003.07.032