Perivascular Treatment with Azathioprine Reduces Neointimal Hyperplasia in Experimental Vein Grafts

Abstract

Azathioprine is an immunosuppressive and anti-inflammatory drug, and it has been shown to induce apoptosis in human T-lymphocytes. We investigated whether local treatment with azathioprine can inhibit neointimal hyperplasia in experimental vein grafts. C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group azathioprine was perivascularly applied. The control group did not receive local treatment. Vein grafts were harvested at 1 and 2 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL). In grafted veins without treatment (controls), neointimal thickness was 10 microm (range, 6-29 microm), and 12 microm (range, 8-40 microm) at 1 and 2 weeks postoperatively, respectively. In azathioprine-treated grafts, the neointimal thickness was 2 microm (range, 1-5 microm) and 4 microm (range, 3-11 microm) at 1 and 2 weeks postoperatively, respectively. This reduction of neointimal thickness was significant at 1 week (P = .001) and 2 weeks (P = .016) postoperatively. Azathioprine-treated vein grafts showed an increased rate of apoptosis in the vascular wall as compared with controls (593 [range, 26-783] versus 45 [range, 0-106] apoptotic cells/mm(2) at 1 week, P = .063; and 656 [range, 327-1270] versus 19 [range, 0-79] apoptotic cells/mm(2) at 2 weeks, P = .016). We conclude that treatment of experimental vein grafts with azathioprine is associated with a reduction of neointimal hyperplasia and an increased apoptosis rate in the vascular wall. These results suggest that azathioprine may be useful for the prevention of vein graft disease after coronary artery bypass grafting.