SELECTIVE ETA RECEPTOR ANTAGONISM REDUCES NEOINTIMAL HYPERPLASIA IN APORCINE CORONARY STENT MODEL

Background-As endothelin binds to ETA receptors, it stimulates vascula r 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 ETA antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model. Methods and Result s-Fifty-five pigs were randomized to receive placebo or the oral ETA-s elective 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 e picardial coronary arteries. Three animals (5.5%) died as a consequenc e of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until pre determined euthanasia at 28 days. In the placebo group, mean injury sc ore was 1.73 +/- 0.80, with a mean neointimal response of 0.45 +/- 0.2 4 mm. By comparison, the low-dose group had a similar mean injury scor e 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 neointi mal 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 al so significantly greater than in the placebo arm (1.93 +/- 0.73; P<0.0 5). Despite this, neointimal response was also significantly less (0.3 7 +/- 0.37 mm; P<0.01). Conclusions-Oral, selective ETA receptor antag onism significantly reduced neointimal hyperplasia forming over porcin e coronary stented injuries in the first 28 days. This strategy may ha ve clinical potential for the limitation and treatment of coronary res tenosis after percutaneous revascularization.