Johnson, Robert G.

Background Fibrin- and platelet-rich thrombus formations occur as the initial event after percutaneous transluminal coronary angioplasty. We therefore tested the hypothesis that short-term administration of the recombinant tick anticoagulant peptide (rTAP), a factor Xa inhibitor, would reduce the thickness of neointima at 28 days after injury in a porcine coronary balloon angioplasty model. Methods and Results Continuous intravenous infusion of rTAP (average dose, 194 μg·kg −1 ·min −1 ) or placebo (vehicle only) was given to the study pigs for 60 hours. The goal of anticoagulation was to maintain the activated clotting time at 200 seconds. A central venous catheter was inserted 2 days before the procedure. On the day of coronary injury, the animals were administered boluses of rTAP (6.5 mg) and then underwent injury with an oversized metallic coil by standard methods in the right, circumflex, or left anterior descending coronary artery. No significant difference in vascular injury between rTAP and vehicle control was observed after euthanasia at 28 days. Significantly less neointimal thickening occurred in the rTAP-treated animals (thickness, mean±SD: 0.30±0.08 mm) compared with the control (0.48±0.12 mm, P <.001). Conclusions The specific factor Xa inhibitor rTAP, when given in fully anticoagulant doses for a short duration after coronary artery injury in the porcine model, resulted in a long-term decrease in neointimal thickness. These results implicate thrombin generation in neointimal formation and suggest that administration of a potent antithrombotic for several days immediately after the procedure may influence the long-term outcome of the coronary injury with a decrease in neointimal formation.

Background—Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.Methods and Results—An ETA/ETBantagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [125I]ET-1 binding to porcine ETA(IC50≈0.3 nmol/L) or ETB(IC50≈20 nmol/L) receptors and inhibited ET-1–stimulated signaling in cell culture. In anesthetized pigs, big ET-1–stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (≥0.2 mg · kg−1· h−1). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg · kg−1· h−1) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329–treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13).Conclusions—Blockade of endothelin receptors for 28 days with only a mixed ETA/ETBreceptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ETAantagonist. The effects of selective or mixed ETA/ETBantagonists in diseased vessels remain to be determined in this model.