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J Thorac Cardiovasc Surg 1997;114:53-63
© 1997 Mosby, Inc.
SURGERY FOR ACQUIRED HEART DISEASE |
Presented at the Sixty-ninth Scientific Sessions of the American Heart Association, New Orleans, La., November 1996.
Received for publication Dec. 23, 1996 revisions requested Jan. 23, 1997; revisions received Feb. 13, 1997 accepted for publication Feb. 21, 1997. Address for reprints: Hillel Laks, MD, Division of Cardiothoracic Surgery, UCLA Medical Center, 62-182A Center for the Health Sciences, 10833 Le Conte Ave., Los Angeles, CA 90095.
Abstract
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 µg/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 mm2 versus 2.34 ± 0.9 mm2, 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 µm vs 15.8 µm, 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 in 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
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