Periadventitial Rapamycin-Eluting Microbeads Promote Vein Graft Disease in Long-Term Pig Vein-Into-Artery Interposition Grafts

Abstract

Neointima formation and atherosclerosis compromise long-term graft patency in aortocoronary and peripheral vein bypass grafts. We investigated the short- and long-term effects of periadventitial application of a sustained-release formulation of rapamycin on experimental pig vein grafts with similar dimensions and kinetics to human saphenous vein bypass grafts. Periadventitial application of rapamycin-eluting polyvinyl alcohol microspheres (60 microg . cm(-2)) to porcine saphenous vein-to-carotid artery interposition grafts inhibited vein graft positive and vascular smooth muscle cell proliferation in 1-week grafts. It also decreased neointima formation and wall thickening in 4-week vein grafts compared with controls. The inhibition of vein graft thickening was not sustained; however, a catch-up phenomenon was observed, and there was no therapeutic benefit evident in 12-week grafts. Increasing the dose of rapamycin to 120 microg . cm(-2) was associated with significant local toxicity manifest by high rates of graft rupture (25%), inhibition of adventitial neoangiogenesis, and a paradoxical acceleration of vein graft disease as evidenced by increased vascular smooth muscle cell proliferation. Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease.