Suppression of Neointimal Hyperplasia by External Application of Cilostazol-Eluting Film at Anastomotic Sites in a Canine Model

Abstract

Neointimal hyperplasia is the principal mechanism of graft failure in coronary artery bypass surgery. Systemic administration of cilostazol has been reported to suppress neointimal hyperplasia in some vascular injury models. We sought to deliver cilostazol locally in an attempt to augment its beneficial effect to inhibit neointimal hyperplasia at an anastomotic site. We examined whether the external application of a novel cilostazol-eluting film can inhibit neointimal hyperplasia in a vascular anastomosis model. Canine femoral artery graft interposition was performed in 20 beagle dogs, assigned to 4 groups of 5 dogs each : a graft interposition without copolymer of L-lactide and ε-caprolactone (P (LA/CL) ) film (control group) and groups with P (LA/CL) film containing cilostazol of either 10 mg, 40 mg, or 80 mg doses. All the cilostazol-eluting film with 10 mg, 40 mg, and 80 mg dose groups had a reduced intima/media ratio compared to the control group (0.15±0.03, 0.11±0.03, and 0.12±0.03, vs. 0.31±0.03, p<0.05). Immunohistochemical analyses for proliferating cell nuclear antigens revealed reduced cellular proliferating activity associated with decreased α-actin positive cells in the cilostazol-eluting film groups compared to the control group. External application of cilostazol-eluting film can inhibit neointimal hyperplasia, at least in part, by inhibiting smooth muscle cell proliferation in the intima.