Controlled periadventitial administration of verapamil inhibits neointimal smooth muscle cell proliferation and ameliorates vasomotor abnormalities in experimental vein bypass grafts

Objective: Inhibition of early myointimal proliferation may improve long-term patency of vein grafts, but the clinical use of many experimental drugs is limited by systemic toxicity, To determine whether this goal can be achieved by low-dose targeted drug administration, we constructed a polymeric system delivering verapamil and evaluated the effects on local and downstream vein graft morphology, neointimal smooth muscle cell proliferation, and vasomotor function. Methods: Ethylene-vinyl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight, These are flexible, biocompatible, and nonbiodegradable matrices, delivering the drug at a rate of 10 mu g/day. The autologous external jugular vein was used to create a carotid artery bypass graft in hypercholesterolemic (n = 22) rabbits, Verapamil-containing matrices (n = 12) or plain polymers (control, n = 10) were wrapped around the proximal third of the veins after reperfusion, Graft vasomotor function was evaluated and was also compared with function of an additional group of normocholesterolemic vein grafts (n = 8), Results: Twenty-eight days after grafting, intimal index (intima/media thickness ratio) was 31% lower, neointima/original lumen surface ratio was 26% lower, and residual luminal area was 71% greater (4.00 +/- 1.2 mm(2) versus 2.34 +/- 0.9 mm(2), all p < 0.01) under verapamil matrices compared with control grafts, Neointimal smooth muscle cell content was reduced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickness was reduced by 47% (30 mu m vs 15.8 mu m, both p < 0.01), Verapamil-treated segments distal to the matrices also showed significantly lower neointimal smooth muscle cell density and increased lumen size, Sensitivity to serotonin and vasomotor responses to serotonin, norepinephrine, and sodium nitroprusside in distal segments were significantly lower ire verapamil-treated grafts than in controls, Conclusions: Periadventitial controlled administration of verapamil below 1% of the systemic dose effectively inhibits myointimal hyperplasia in vein grafts, Local polymeric drug delivery may be readily applicable to coronary revascularization operations.