Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
Circ Cardiovasc Interv. 2010 Dec;3(6):543-8. doi: 10.1161/CIRCINTERVENTIONS.110.953885. Epub 2010 Nov 9.
Vascular inflammation can lead to plaque instability and acute coronary syndromes (ACS). Viruses produce potent immunomodulating proteins that regulate key inflammatory pathways. A myxoma virus-derived serpin Serp-1 reduces inflammatory cell invasion and plaque growth in vascular injury models. Our objective was to evaluate the safety and efficacy of Serp-1 in patients with ACS undergoing percutaneous coronary intervention.
This double-blind pilot trial included 48 ACS patients undergoing percutaneous coronary intervention randomly assigned to Serp-1 at doses of 5 μg/kg (n=19) or 15 μg/kg (n=17) or to placebo (n=12). Serp-1 was given by intravenous bolus immediately before intervention and 24 and 48 hours later. Patients were assessed for safety (primary objective) and efficacy outcomes, including biomarker analysis. In-stent neointimal hyperplasia was evaluated by intravascular ultrasound at 6 months. Key safety outcomes including coagulation parameters and adverse events did not differ between Serp-1 and placebo groups. A dose-dependent reduction in troponin I levels was observed with Serp-1 at 8, 16, 24, and 54 hours (P<0.05) and in creatine kinase-MB levels at 8, 16, and 24 hours after dose (P<0.05). The composite of death, myocardial infarction, or coronary revascularization occurred in 2 of 12 patients with placebo, 5 of 19 in the low-dose group, and none of 17 patients with the high-dose (P=0.058). Intravascular ultrasound did not detect changes in neointimal hyperplasia among groups.
This is the first study of a viral serpin demonstrating its safety in ACS patients. The significant reduction in myocardial damage biomarkers supports further assessment of Serp-1 in ACS patients undergoing stent deployment.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243308.
血管炎症可导致斑块不稳定和急性冠脉综合征（ACS）。病毒产生强效的免疫调节蛋白，调节关键的炎症途径。一种源自粘液瘤病毒的丝氨酸蛋白酶抑制剂 Serp-1 可减少血管损伤模型中的炎症细胞浸润和斑块生长。我们的目的是评估 Serp-1 在接受经皮冠状动脉介入治疗的 ACS 患者中的安全性和疗效。
这项双盲试验纳入了 48 例接受经皮冠状动脉介入治疗的 ACS 患者，随机分为 Serp-1 低剂量组（5μg/kg，n=19）、高剂量组（15μg/kg，n=17）和安慰剂组（n=12）。Serp-1 在介入治疗前即刻、24 小时和 48 小时时通过静脉推注给药。评估患者的安全性（主要终点）和疗效结局，包括生物标志物分析。6 个月时通过血管内超声评估支架内新生内膜增生。Serp-1 组和安慰剂组之间关键的安全性结局（包括凝血参数和不良事件）无差异。Serp-1 可剂量依赖性地降低肌钙蛋白 I 水平，在 8、16、24 和 54 小时时（P<0.05）和肌酸激酶同工酶-MB 水平在给药后 8、16 和 24 小时时（P<0.05）。安慰剂组有 2 例（2/12）、低剂量组有 5 例（5/19）、高剂量组无 1 例（0/17）发生死亡、心肌梗死或冠状动脉血运重建（P=0.058）。血管内超声未检测到各组间新生内膜增生的变化。
这是首例研究病毒丝氨酸蛋白酶抑制剂 Serp-1 的安全性的研究，该研究显示其可显著降低心肌损伤生物标志物，支持进一步评估 Serp-1 在接受支架植入术的 ACS 患者中的疗效。
