Abstract 10070: Long-term Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy
Introduction: Resulting from intimal thickening, saphenous vein graft occlusion is a significant clinical problem with approximately 50% of vein grafts failing within 10 years after coronary artery bypass grafting. Intimal thickening is caused by migration of vascular smooth muscle cells (VSMCs) from the media to the intima where they proliferate and form a neointima. Therapeutic interventions using gene transfer to inhibit VSMC proliferation and migration (and increase the patency of coronary artery vein grafts) are attractive since ex vivo genetic modification of the graft is possible.
Methods: The involvement of matrix-degrading metalloproteinases (MMPs) in intimal thickening is well established and we have previously shown that adenoviral delivered overexpression of an endogenous inhibitor, the tissue inhibitor of metalloproteinases-3 (TIMP-3), significantly retards intimal thickening in short-term autologous porcine arteriovenous interposition grafts (28days). However, whether this approach will provide long-term benefits was unknown. We assessed whether a replication-defective recombinant adenovirus that overexpresses TIMP-3 (RAdTIMP-3) affects vein graft intimal thickening in the longer term (at 3 months). Porcine saphenous veins were subjected to lumenal infection with 2.5x1010pfu/ml RAdTIMP-3 or RAd60 (control virus) or vehicle control, for 30 minutes prior to implantation into the carotid artery (n=11, 15 and 16 grafts, respectively).
Results: Analysis of grafts harvested 3 months post-delivery revealed that RAdTIMP-3-infected grafts had significantly reduced intimal areas compared to both controls (3.0±0.4mm2 vs 5.6±0.6mm2 and 5.8±0.5mm2, RAdTIMP-3, RAd60 and PBS, respectively). Medial areas were also significantly decreased by TIMP-3 (3.8±0.4mm2 vs 6.5±0.9mm2 and 5.3±0.5mm2, RAdTIMP-3, RAd60 and PBS, respectively).
Conclusion: Our data demonstrates that overexpression of TIMP-3 provides a sustained retardation of vein graft intimal thickening and highlights the translational potential for ex vivo TIMP-3 gene therapy to reduce vein graft failure in the clinic setting.
Acknowledgement: The work was supported by the British Heart Foundation and the Hong Kong Research Grant Council Earmarked Grants.
- © 2010 by American Heart Association, Inc.