摘要
背景及目的
支架内再狭窄是困扰冠心病支架治疗预后的主要瓶颈,损伤、炎症反应及内膜增生在支架内再狭窄的发病机制中有重要作用,新型支架涂层聚合物的研发利用是解决支架内再狭窄问题的主要思路之一。本研究利用小型猪冠状动脉支架损伤再狭窄动物模型评估新型磷酸胆碱聚合物涂层雷帕霉素药物洗脱支架对支架内再狭窄的抑制作用。
方法
健康实验用小型猪24头,雄性,体重28～38(33±2.4)kg,6-9月龄。采用随机数字法分为四组：裸支架组(6头,植入钴铬合金金属裸支架)、低剂量组(6头,植入磷酸胆碱聚合物120μg/cm2雷帕霉素洗脱支架)、高剂量组(6头,植入磷酸胆碱聚合物150μg/cm2雷帕霉素洗脱支架)和精工组(6头,植入精工处理磷酸胆碱聚合物120μg/cm2雷帕霉素洗脱支架)。各组基线资料一致。
1.小型猪支架损伤模型建立及支架组织相容性评估。动物完成术前适应后采用经皮血管穿刺的方法,经股动脉入路进行冠脉造影及支架植入。术后服用肠溶阿斯匹林100mg／天和硫酸氢氯吡格雷75mg／天,普通饲料喂养至28天时处死取材。基线与28天时取静脉血检查血常规及血生化指标。取材后血管标本固定进行扫描电镜分析评估支架表面内皮化情况。综合上述资料初步评估支架的组织相容性。
2. 28天时取支架段血管标本固定后进行塑料包埋,切片染色后用光学显微镜下进行损伤及炎症积分评估,专业图像分析软件测量支架内再狭窄相关参数。对上述数据进行相关分析及组间差异比较。评估各组支架抗再狭窄的安全性和有效性。
结果
1.组织相容性
磷酸胆碱支架植入小型猪冠脉后,无全身严重不良反应发生。病理大体观察发现各组的支架段血管壁组织均呈脂肪样改变,药物支架组更为明显,精工组表现较轻。扫描电镜观察发现各组动物的支架段血管内皮化完全,新生内膜及内皮细胞结构完整。
2.对支架内再狭窄的抑制作用
实验动物支架段血管Schwartz损伤积分、Kornowski炎症积分与支架内再狭窄主要形态学参数新生内膜厚度、内膜面积、面积再狭窄程度呈明显正相关。裸支架组、低剂量组、高剂量组、精工组的病理结果显示它们对支架段血管新生内膜的抑制程度有逐渐增加的趋势,但只有精工组的内膜厚度较裸支架组有统计差异,在内膜面积、面积狭窄程度两参数未表现出统计差异。
结论
磷酸胆碱聚合物支架植入小型猪冠状动脉后表现出较好整体相容性及支架撑杠表面的内皮化。裸支架组发生了支架内再狭窄,面积狭窄为52.73%；低剂量组和高剂量组均无再狭窄发生,面积狭窄分别为38.01%和34.17%,精工组面积狭窄在四组中最低31.62%。裸支架组、低剂量组、高剂量组、粗工组的病理结果显示它们对支架段血管新生内膜的抑制程度有逐渐增加的趋势,只有精工组的内膜厚度较裸支架组有统计差异,在内膜面积、面积狭窄程度两参数未表现出统计差异。
Background and Objective
In-stent restenosis is the main bottleneck of prognosis after percutaneous stent therapy for coronary heart disease. Factors like lesion,inflammation and neointima formation are known as the important contributing elements in restenosis mechanism. The study and utilization of new types of polymer is one of the key roads to resolve the hard nut of restenosis. Our study uses a porcine model of coronary stent lesion and restenosis to evaluate the anti in-stent restenosis performance of phosphocholine stent.
Methods
Twenty four healthy male minature pig(weight 28-38kg,aged 6-9 months) were divided at random into four groups:BMS (6, implanting bare cobalt-chromi-um stent), low dose DES(6, implanting phosphocholine stent with 120μg/cm2 sirolimus), high dose DES(6, implanting phosphocholine stent with 150μg/cm2 sirolimus)and refined DES(6, implanting rerefinedd phosphocholine stent with 120μg/cm2 sirolimus). The animals in four groups are comparable at base line.
1.The establishment of miniature pig coronary stent lesion and restenosis model and the evaluation of histocompatibility of the new stent.After the animals completed adaptative period,angiography and stents implantation were performed through femoral artery percutaneously.After the operation each pig was given aspirin(100mg/d),clopidogrel(75mg/d) and routine feed. The blood samples were taken at base line and on 28th day after operation for routine and biochemical analysis.The samples of artery with stent were fixed and proceeded to do SEM analysis for endothelialization assessment. The histocompatibility of the stent was evaluated.
2.On 28th day after operation, the samples of artery with stent were fixed and proceeded to plastic embedding, sectioning and staining. The cross sections were analyzed under optical microscope to assess the injury and inflammation score. Digital pictures were obtained and analyzed by professional image analysis software to measure and analyze parameters of restenosis.Those data were conducted correlation and difference analysis between groups to evaluate the safety and validity of the anti restenosis effect of the stent.
Results
1. Histocompatibilty
After phosphocholine stents were implanted into miniature pigs'coronary, no serious whole body adverse effect was observed. Gross pathological observation revealed that all samples of coronary arterys with stent showed fat-like change,which was more apparent in DES groups and mild in refined DES. SEM analysis indicated full endothelialization above stent struts with integrated neointima in all coronary arteries with stent.
2.Anti in-stent restenosis effect
The Schwartz injury score and Kornowski inflammation score of coronary arteries with stents are positively correlated to those morphologic parameters of restenosis.Pathological results of BMS, low dose, high dose and refined groups show their inhibition ability of neointima with an upward trend.But only the difference between refined DES and BMS group shows statistical significance in neointima thickness.There are no statistically significant differences in parameters of neointimal area and degree of area restenosis.
Conclusions
The phosphocholine stents show preferable gross histocomparability and endothelialization above stent strut. BWS group shows area restenosis of 52.73% (more than 50%).While low dose, high dose and refined DES groups show no restenosis occurrence(not more than 50%).Their area restenosis is 38.01%,34.17% and 31.62% respectively. Pathological results of BMS, low dose, high dose and refined group show their inhibition ability of neointima with an upward trend. But only the difference of neointima thickness between refined DES group and BMS group was statistically significant.There are no statistical difference in parameters of neointimal area and degree of area restenosis between defined and BMS group.
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