Inhibition of coronary restenosis by antithrombin III in atherosclerotic swine

Background Thrombin-mediated vascular smooth muscle cell proliferation has been implicated in coronary restenosis. Attempts to inhibit this mitogenic activity have recently focused on non-physiologic direct thrombin inhibitors, whereas endogenous thrombin inhibitors such as antithrombin III (ATIII) have received little attention. ATIII is the main physiologic inhibitor of thrombin and may thus be a potential therapeutic agent for prevention of restenosis. Methods Human ATIII (125 U/kg) and heparin (200 U/kg) were administered to 12 atherosclerotic swine 30 min prior to inducing restenosis by oversized stent (left anterior descending and right coronary arteries; stent-to-artery ratio approximate to 1.2) and balloon injury (circumflex; balloon artery ratio approximate to 1.2), Eleven control swine received only heparin every 6 h for 24 h and were subjected to similar stent and balloon injury. Quantitative coronary angiography [change in minimal lumen diameter (Delta MLD)] and morphometric analysis [percentage area stenosis (PAS)] were performed 4 weeks later. Results ATIII activity (mean +/- SD) of treated swine increased from a baseline of 103 +/- 10% to a peak of 266 +/- 48%, whereas trough levels were maintained at 259 +/- 55% for 72 h by drug infusions every 6 h. The Delta MLD, the primary angiographic endpoint in the balloon injured Vessel was -0.57 +/- 0.33 mm in heparin group versus -0.26 +/- 0.27 mm in the ATIII group (P less than or equal to 0.03). For stented vessels the Delta MLD was -0.61 +/- 0.33 mm in the heparin group versus -0.41 +/- 0.37 mm in the ATIII group (P less than or equal to 0.06), The PAS for the balloon injured vessels was 30 +/- 12% in the heparin group versus 19 +/- 14 in the ATIII group (P less than or equal to 0.06). In stented vessels the PAS was 45 +/- 16% in the heparin group versus 38 +/- 16% in the ATIII group (P less than or equal to 0.1). Conclusion Supraphysiologic ATIII levels in combination with heparin inhibits the reduction in MLD in coronary arteries subjected to oversized balloon injury and demonstrates a beneficial trend in arteries subjected to oversized stent injury. These data provide cautious optimism for further investigation with ATIII to prevent coronary restenosis.