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Ann Thorac Surg 2004;77:1580-1585
© 2004 The Society of Thoracic Surgeons
a Departments of Cardiac Surgery and Pathology, Innsbruck University, Innsbruck, Austria
Accepted for publication October 2, 2003.
* Address reprint requests to Dr Schachner, Innsbruck University Hospital, Department of Cardiac Surgery, Anichstrasse 35, A-6020 Innsbruck, Austria
e-mail: thomas.schachner{at}uibk.ac.at
BACKGROUND: Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. Rapamycin coated stents have been demonstrated to suppress restenosis in experimental and clinical studies of percutaneous coronary catheter intervention. We investigated whether rapamycin can reduce neointima formation in a mouse model of vein graft disease.
METHODS: C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 100 µg or 200 µg of rapamycin was applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 6 weeks and underwent morphometric analysis as well as immunohistochemical analysis.
RESULTS: In grafted veins without treatment (controls), median intimal thickness was 9.6 (6.4 to 29)µm, 11.9 (7.9 to 39.9)µm, 46.6 (12.4 to 57.7)µm, and 57.5 (32.5 to 71.1)µm after 1, 2, 4, and 6 weeks, respectively. Treatment with 100 µg or 200 µg rapamycin showed a dose dependant reduction of intimal thickness. In the 200 µg rapamycin treatment group the intimal thickness was 4.3 (3.4 to 5.6)µm, 3.8 (3.2 to 6.3)µm, 17.1 (4.8 to 63)µm, and 33.9 (11.3 to 80.3)µm after 1, 2, 4, and 6 weeks, respectively. This difference of intimal thickness of 200 µg treated animals compared with controls was statistically significant at 1 and 2 weeks. Immunohistochemically the reduction of intimal thickness was associated with a decreased amount of infiltration of CD-8 positive cells and a decreased amount of metallothionein positive cells in the rapamycin treated grafts.
CONCLUSIONS: We conclude that perivascular application of rapamycin inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that rapamycin may have a therapeutic potential for the treatment of vein graft disease.
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