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Everolimus attenuates neointimal hyperplasia in cultured human saphenous vein grafts

^a Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria
^b Daniel Swarovski Research Laboratory, Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria
^c Core Unit for Biomedical Research, Medical University Vienna, Vienna, Austria

Received 9 June 2008; received in revised form 15 October 2008; accepted 12 November 2008.

^_* Corresponding author. Address: Department of Cardiac Surgery, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel.: +43 512 504 80812; fax: +43 512 504 22528. (Email: severin.semsroth{at}i-med.ac.at).

Objective: Neointimal hyperplasia is the first step in a cascade leading to a reduced patency rate of saphenous vein grafts in comparison to arterial grafts in coronary artery bypass grafting. Using cultured human saphenous vein grafts as a model for coronary artery bypass grafting, we investigated if the mammalian target of rapamycin inhibitor everolimus attenuates neointimal hyperplasia. Methods: Saphenous vein grafts from 10 patients undergoing coronary artery bypass grafting were processed as follows: from each patient, one segment served as baseline control at day 0. Two segments were cultured in a neointimal hyperplasia model separately. One received no treatment and the other everolimus (1 µM). All vein grafts underwent histomorphometric analysis, assessment of proliferation by Ki-67 immunostaining and quantification of phospho-S6 ribosomal protein using western blot analysis. Results: Everolimus treatment resulted in reduced neointimal hyperplasia (thickness 3.7 ± 1.2 µm) compared to untreated controls (10.1 ± 2.5 µm, p = 0.008). The intima/intima + media-ratio was reduced in the everolimus group (0.10 ± 0.02) compared to untreated controls (0.24 ± 0.07, p = 0.008). The number of Ki-67 positive proliferating cells in everolimus treated vein grafts (15 ± 7 cells/high power field) showed a tendency of reduction compared to untreated controls (36 ± 20 cells/high power field, p = 0.036). Finally, everolimus treatment resulted in downregulation of S6 ribosomal protein phosphorylation in comparison to untreated controls. Conclusion: Everolimus is able to reduce neointimal proliferation in cultured human saphenous vein grafts by inhibition of the mammalian target of rapamycin, even though different transfection methods are to be evaluated for a clinical application in coronary artery bypass grafting.

Key Words: Neointimal hyperplasia • Saphenous vein graft • mTOR inhibition • Everolimus • Coronary artery bypass grafting