Background Thrombin-rnediated 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 (1 25 U/kg) and heparin (200 U/kg) were administered to 1 2 atherosclerotic swine 30 mm prior to inducing restenosis by oversized stent (left anterior descending and right coronary arteries; stent-to-artery ratio =1.2) and balloon injury (circumflex; balloon artery ratio = 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 (AMLD)] 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 AMLD, 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 < 0.03). For stented vessels the AMLD was −0.61 ± 0.33 mm in the heparin group versus −0.41 ± 0.37 mm in the ATIII group (P ≤ 0.06). The PAS for the balloon injured vessels was 30 ± 1 2% in the heparin group versus 19 ± 14 in the ATIII group (P < 0.06). In stented vessels the PAS was 45 ± 16% in the heparin group versus 38 ± 16% in the ATIII group (P < 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.
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