Camrud, Ladonna J.

Background —As endothelin binds to ET A receptors, it stimulates vascular smooth muscle cell proliferation and may thus be pivotally involved in the pathogenesis of restenosis. This study assessed the ability of a potent and selective ET A antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model. Methods and Results —Fifty-five pigs were randomized to receive placebo or the oral ET A -selective antagonist ABT147627 twice daily for 28 days in one of three doses: 0.75 mg/kg (low), 3.75 mg/kg (mid), and 10.0 mg/kg (high). Each underwent oversized stent deployment in two randomly assigned major epicardial coronary arteries. Three animals (5.5%) died as a consequence of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until predetermined euthanasia at 28 days. In the placebo group, mean injury score was 1.73±0.80, with a mean neointimal response of 0.45±0.24 mm. By comparison, the low-dose group had a similar mean injury score of 1.79±0.75 with reduced neointimal response, 0.36±0.22 mm ( P <0.01). Mean injury score in the mid-dose animals was significantly greater than in the placebo group (1.94±0.92; P <0.05). The neointimal hyperplasia associated with this injury was less than with placebo, although the difference did not reach statistical significance (0.40±0.25 mm; P =0.05). In the high-dose pigs, mean injury score was also significantly greater than in the placebo arm (1.93±0.73; P <0.05). Despite this, neointimal response was also significantly less (0.37±0.37 mm; P <0.01). Conclusions —Oral, selective ET A receptor antagonism significantly reduced neointimal hyperplasia forming over porcine coronary stented injuries in the first 28 days. This strategy may have clinical potential for the limitation and treatment of coronary restenosis after percutaneous revascularization.

Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury–induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10 12 viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus–treated vessels. The average intimal area of the AV-W9–treated group 10 days after balloon injury and treatment was 0.42±0.36 mm 2 , whereas the AV-null group demonstrated an intimal area of 0.70±0.52 mm 2 . At day 10 the average intimal thickness of the AV-W9–treated vessels was 9.1 μm (n=5, ×20 magnification) compared with 21.2 μm (n=5, ×20 magnification) in control virus–treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9–treated vessels demonstrated an average intimal thickness of 4.7 μm (n=8, ×20 magnification) compared with 13.3 μm (n=3, ×20 magnification) in control virus–treated vessels and 7.3 μm (n=5, ×20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty–induced intimal hyperplasia in the coronary artery.