Ali M N, Mazur W, Kleiman N S, Rodgers G P, Abukhalil J M, French B A, Raizner A E
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Coron Artery Dis. 1996 Nov;7(11):851-61. doi: 10.1097/00019501-199611000-00010.
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.
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 approximately 1.2) and balloon injury (circumflex; balloon artery ratio approximately 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.
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 < or = 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 < or = 0.06). The PAS for the balloon injured vessels was 30 +/- 12% in the heparin group versus 19 +/- 14 in the ATIII group (P < or = 0.06). In stented vessels the PAS was 45 +/- 16% in the heparin group versus 38 +/- 16% in the ATIII group (P < or = 0.1).
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.
凝血酶介导的血管平滑肌细胞增殖与冠状动脉再狭窄有关。抑制这种促有丝分裂活性的尝试最近集中在非生理性直接凝血酶抑制剂上，而内源性凝血酶抑制剂如抗凝血酶III（ATIII）却很少受到关注。ATIII是凝血酶的主要生理性抑制剂，因此可能是预防再狭窄的一种潜在治疗药物。
在通过使用超大支架（左前降支和右冠状动脉；支架与动脉比例约为1.2）和球囊损伤（回旋支；球囊与动脉比例约为1.2）诱导再狭窄前30分钟，给12只动脉粥样硬化猪注射人ATIII（125 U/kg）和肝素（200 U/kg）。11只对照猪每6小时仅接受肝素治疗，共24小时，并接受类似的支架和球囊损伤。4周后进行定量冠状动脉造影[最小管腔直径变化（ΔMLD）]和形态计量分析[狭窄面积百分比（PAS）]。
治疗猪的ATIII活性（平均值±标准差）从基线的103±10%增加到峰值的266±48%，而通过每6小时输注药物，谷值水平在72小时内维持在259±55%。在球囊损伤血管中，主要血管造影终点ΔMLD在肝素组为-0.57±0.33 mm，而在ATIII组为-0.26±0.27 mm（P≤0.03）。对于植入支架的血管，肝素组的ΔMLD为-0.61±0.33 mm，而ATIII组为-0.41±0.37 mm（P≤0.06）。球囊损伤血管的PAS在肝素组为30±12%，而在ATIII组为19±14%（P≤0.06）。在植入支架的血管中，肝素组的PAS为45±16%，而ATIII组为38±16%（P≤0.1）。
超生理水平的ATIII与肝素联合使用可抑制受到超大球囊损伤的冠状动脉中MLD的降低，并在受到超大支架损伤的动脉中显示出有益趋势。这些数据为进一步研究ATIII预防冠状动脉再狭窄提供了谨慎的乐观态度。
