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Better bypass with gene therapy?

How can bypass grafting be made even more effective? Almost half of the veins transplanted to restore blood flow in the heart become clogged again within ten years after surgery. Gene therapy pre-treatment of the vein fragments that prevents the muscle cells from entering the vascular wall, might decrease the risk of this happening.

A group of researchers led by Dr. Klaus Kallenbach, chief physician at the Department of Cardiac Surgery at the University Hospital of Heidelberg, received the Robert Stich Award of 5,000 euros from the German Society for Thoracic and Cardiovascular Surgery for its outstanding research findings.

Patients with clogged heart or leg arteries are usually transplanted with parts of their own thigh veins to make the blood divert. However, in many cases, smooth vascular muscle cells migrate through the internal elastic lamina and transform from contractile-type to secretory-type cells. This leads to the formation of a thick layer of neointima, which reduces the internal diameter of the implanted blood vessel, as well as possibly leading to arteriosclerosis in the bypass.
Professor Dr. Axel Haverich (left), Medical Director of the Department of Thoaracic and Cardiovascular Surgery at the Hanover Medical School, and Dr. Klaus Kallenbach (rright) at the prize award ceremony (Photo: private)
Professor Dr. Axel Haverich (left), Medical Director of the Department of Thoaracic and Cardiovascular Surgery at the Hanover Medical School, and Dr. Klaus Kallenbach (rright) at the prize award ceremony (Photo: private)

Gene therapy causes the muscle cells to migrate more slowly

The group of researchers carried out laboratory experiments and found that smooth muscle cells migrated much slower if they produced very high quantities of the enzyme matrix metalloproteinase-3 (MMP-3). The researchers used a virus to transfer an MMP-3 gene into the muscle cells and found that the motility of the genetically modified cells was up to 20 times lower than that of a control group.

Dr. Kallenbach and his colleagues substantiated this finding in animal experiments, in which rabbits were given a high cholesterol diet. The animals underwent autologous jugularis vein bypass grafting into carotid arteries. The walls of veins that were previously engineered to produce large quantities of MMP-3 did not become as thick as those in animals that were transplanted with untreated vein fragments.

MMP-3 enzyme protects the vascular wall

“The results are very surprising,” said Klaus Kallenbach. “The enzyme MMP-3 has generally been regarded as a promoter of the reconstruction and thickening of the vascular walls.” Like a machete cutting its way through the jungle, the aggressive protein-cleaving MMP-3 enzyme normally cuts the smooth muscle cells a way through the thick collagen fibre and protein network. “However, it seems that high MMP-3 concentrations have a protective effect on the vascular walls,” commented Kallenbach on his award-winning work. “We will now focus on the clarification of the mechanism that leads to the overexpression of MMP-3 genes and hence to the long-term success of bypass surgery.”

Literature:
Kallenbach K., Salcher R, Bog A, Geveke S, Mörike C, Heim A, Cebotari S, Haverich A. Reduction of Neointima Formation in Autologous Vein Grafts in vivo by Overexpression of Matrix Metalloproteinase-3 (Stromeylsin-1). Circulation 2006; Suppl. II, Vol. 114,18:794


Source: University Hospital Heidelberg - 15.4.2008
Further informaiton:
Priv. Doz. Dr. Klaus Kallenbach
University Hospital Heidelberg
Surgical Hospital, Department of Cardiac Surgery
Im Neuenheimer Feld 110
69120 Heidelberg
Tel.: +49 (0)6221 / 56 37982
Fax: +49 (0)6221 / 56 5585
E-mail: klaus.kallenbach@med.uni-heidelberg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/better-bypass-with-gene-therapy