雷帕霉素-巴曲酶复合药物涂层支架预防支架内再狭窄的实验研究

目的评价雷帕霉素-巴曲酶复合药物涂层支架对再狭窄和支架内血栓的防治作用及安全性,减少术后抗血小板药物的应用及并发症的发生率。方法采用随机、双盲试验在16头微型猪的冠状动脉前降支或左旋支分别置入支架1枚,其中雷帕霉素涂层支架（每枚支架药物剂量1.2μg/mm2）共8枚,为对照组;雷帕霉素-巴曲酶复合药物涂层支架（每枚支架含雷帕霉素1.2μg/mm2、巴曲酶0.3μg/mm2）共8枚,为实验组。对照组术前3 d起每天口服氯吡格雷75 mg和阿司匹林0.3 g直至28 d处死;实验组术前3 d至术后7 d每天口服氯吡格雷75 mg和阿司匹林0.3 g,此后改为每天口服阿司匹林0.3 g,直至28 d处死。28 d时进行冠状动脉造影随访,术后处死动物,取出支架血管,进行组织学分析。结果再狭窄率:对照组为0,实验组为0。管腔丢失率:对照组为（7±5）%,实验组为（4±3）%。新生内膜面积:对照组为（1.0±0.8）mm2,实验组为（0.9±0.7）mm2。结论雷帕霉素-巴曲酶复合药物涂层支架与单纯雷帕霉素涂层支架比较可以减少支架置入术后的口服氯吡格雷总量及用药时间。     

Mytrolimus药物洗脱支架预防支架内再狭窄的实验研究

目的评价新型聚烯烃类高分子化合物涂层携载雷帕霉素衍生物-Mytrolimus(CCI-779)洗脱支架在小型猪冠状动脉模型预防再狭窄的疗效。方法小型猪冠状动脉分别置入裸支架、单纯聚烯烃类高分子化合物涂层支架和Mytrolimus洗脱支架(160μg/18mm)。术后4周重复冠状动脉造影后处死动物,测定3组支架血管段的损伤指数、冠状动脉横截面积、管腔面积、支架上平均内膜厚度、支架间平均内膜厚度、新生内膜面积、面积再狭窄百分比,并作比较。结果裸支架组(置入支架数n=10)、单纯聚烯烃类高分子化合物涂层支架组(n=10)和Mytrolimus洗脱支架组(n=8)3组冠状动脉大小和血管损伤程度基本相同,术后4周,单纯聚烯烃类高分子化合物涂层组与裸支架比较多项参数差异均无统计学意义。Mytrolimus药物洗脱支架组和裸支架组的支架上内膜厚度分别为(0.18±0.08)mm和(0.33±0.25)mm(P<0.05);支架间内膜厚度分别为(0.14±0.05)mm和(0.28±0.23)mm(P<0.05);新生内膜面积分别为(1.09±0.24)mm2和(2.44±1.59)mm2(P<0.05)。上述多项参数在Mytroliums洗脱支架组均显著少于裸支架组。Mytrolimus组新生内膜面积比裸支架组少了55.33%,且Mytrolimus组无一例再狭窄。结论Mytrolimus洗脱支架在置入小型猪冠状动脉4周时可有效抑制内膜增生、预防冠状动脉实验性支架内再狭窄。     

雷帕霉素与紫杉醇药物洗脱支架对小型猪早期冠状动脉炎症性狭窄治疗的定量冠状动脉造影研究

目的:制作小型猪冠状动脉炎症型支架再狭窄模型,用定量冠状动脉造影、测定支架处血管壁内膜增生程度及炎症因子表达等方法探讨雷帕霉素及紫杉醇涂层支架对炎症性冠状动脉狭窄的抑制作用。方法:小型雄性家猪14头,开胸法将冠状动脉外膜包裹吸附白介素-1β(IL-1β)琼脂糖微粒悬液的纸巾。2周后,用定量冠状动脉造影观察管腔狭窄程度及随机分为雷帕霉素支架组(n=7)、紫杉醇支架组(n=9)及裸支架组(n=8)。1个月后进行随访定量冠状动脉造影测定各组冠状动脉支架节段内和支架内的最小管腔直径(MDL),参照管腔直径(RLD),管腔狭窄百分比(DS),计算出晚期管腔丢失(LLL)进行对比分析。塑料包埋法进行支架血管切片,测定管腔增生面积及血管壁单核细胞趋化因子-1(MCP-1)、肿瘤坏死因子-α(TNF-α)、P-选择素、血管细胞间黏附因子-1(VCAM-1)的表达。结果:冠状动脉外膜包裹IL-1β血管段局限性狭窄平均达到70％以上。裸支架组中冠状动脉支架节段内和支架内的LLL明显高于雷帕霉素支架组和紫杉醇支架组,且再狭窄(DS)率高。雷帕霉素支架组及紫杉醇支架组冠状动脉支架节段内和支架内LLL均低于裸支架组,且明显抑制内膜增生(P<0．01)。但只有雷帕霉素支架组明显下调MCP-1,TNF-α,P-选择素和VCAM-1的表达。结论:雷帕霉素和紫杉醇药物洗脱支架对IL-1β诱发的小型猪冠状动脉炎症性狭窄均有较好的抗内膜增殖作用,但在LLL指标及抑制内膜增生方面雷帕霉素优于紫杉醇药物洗脱支架,有可能是通过直接或间接抗炎机制达到的。     

雷公藤甲素涂层支架在兔髂动脉再狭窄模型中抑制新生内膜增殖的作用

目的研究雷公藤甲素涂层支架抑制血管新生内膜增殖的有效性、量效关系,并研究该支架的安全性。方法采用兔髂动脉再狭窄模型,实验支架分4组,每组10个支架。具体分为裸支架组、西罗莫司(雷帕霉素)涂层支架组,5.6μg和56μg雷公藤甲素涂层支架组。每只兔两侧髂动脉各放一支架,共置入40枚支架。比较支架置入后28天各组的形态测量学、组织病理学及血生化结果。结果5.6μg雷公藤甲素涂层支架内的新生内膜面积与裸支架组相似,但大于西罗莫司支架组。56μg雷公藤甲素涂层支架内的新生内膜面积小于裸支架组,与西罗莫司支架组相似。各组支架两端内膜增生不明显。血生化检查未发现雷公藤甲素涂层支架对受试动物产生明显的毒害作用。结论雷公藤甲素涂层支架能够抑制内膜增殖,其效应具有剂量依赖性。56μg雷公藤甲素涂层支架能抑制内膜增殖且无毒副作用。这些结果提示雷公藤甲素涂层支架在置入后4周内能防止再狭窄。     

雷帕霉素-缬沙坦复方药物洗释支架预防支架内再狭窄的实验研究

目的　探讨雷帕霉素 -缬纱坦复方药物洗释支架 (复方药物洗释支架 )对支架植入术后再狭窄的预防作用。方法　对 2 2只雄性新西兰白兔进行腹主动脉拉伤后分别植入复方药物洗释支架 (复方组 )和普通支架 (裸支架组 )各 11只。两组均在术后 8周行血管内超声检查和腹主动脉行造影检查。结果　支架部位血管腔面积裸支架组小于复方组 (P <0 0 1)、支架内增生内膜面积及内膜增生程度裸支架组大于复方组 (P <0 0 0 1)。结论　复方药物洗释支架在动物实验中具有明显预防支架内再狭窄的作用     

雷帕霉素涂层支架对支架内早期再狭窄的预防

目的 :评价乳酸和乙醇酸聚合物携带雷帕霉素并以支架为载体抑制血管新生内膜的作用和预防支架内再狭窄的有效性。方法 :采用随机、双盲试验 ,在 2 0头微型猪的冠状动脉前降支或左旋支分别置入支架 1枚 ,其中金属裸支架 8枚 ;雷帕霉素涂层支架 12枚。涂层材料选用乳酸和乙醇酸聚合物 ,根据两种材料比例将涂层支架分为雷帕霉素缓慢释放涂层支架 (药物剂量 6 5～ 90 μg/支架 ,5枚 )和雷帕霉素快速释放涂层支架 (药物剂量 6 8～ 96 μg/支架 ,7枚 )。2 8d后进行冠状动脉造影 ,术后处死动物 ,取出支架血管 ,进行组织学分析。 结果 :对照组的再狭窄率为 2 5 .0 % (2 /8) ;两组雷帕霉素涂层支架均为 0 %。平均狭窄程度 :对照组为 (31± 2 2 ) % ,雷帕霉素缓慢释放涂层支架组减少了 2 8% (P <0 .0 5 ) ;雷帕霉素快速释放涂层支架组减少了 2 3% (P <0 .0 5 ) ;新生内膜面积 :对照组 (2 .18± 1.0 3)mm2 ;雷帕霉素缓慢释放涂层支架组减少了 1.0 9mm2 (P <0 .0 5 ) ;雷帕霉素快速释放涂层支架组减少了 1.2 4mm2 (P <0 .0 5 )。结论 :乳酸和乙醇酸聚合物携带雷帕霉素涂层支架可以降低支架内的狭窄程度 ,有效地减少血管内新生内膜面积 ,预防支架内的狭窄     

雷帕霉素-替罗非班复合药物涂层支架预防支架内血栓和再狭窄的实验研究

目的探讨雷帕霉素-替罗非班复合药物涂层支架预防支架内血栓和再狭窄的疗效及机制。方法8只小型猪随机分为单纯雷帕霉素涂层支架（RES）组和雷帕霉素-替罗非班复合药物涂层支架（RTES）组,每只动物于冠状动脉中置入支架2枚。术后RES组服用阿司匹林300 mg/d和氯吡格雷75 mg/d,3个月;RTES组服用阿司匹林300 mg/d,3个月,氯吡格雷75 mg/d,1个月。实验期间对动物行为学和出凝血障碍等并发症进行观察。3月后复查冠状动脉造影,处死动物,取出支架血管段,行组织病理学分析。结果①两组均未发现急性、亚急性和远期血栓,无出凝血等并发症发生。②支架部位血管腔面积:雷帕霉素涂层支架组为（4.89±0.46）mm2,雷帕霉素-替罗非班复合涂层支架组为（4.96±0.35）mm2;新生内膜面积:雷帕霉素涂层支架组为（1.05±0.09）mm2,雷帕霉素-替罗非班复合涂层支架组为（1.12±0.10）mm2;管腔面积丢失率:雷帕霉素涂层支架组为（21±7）%,雷帕霉素-替罗非班复合药物涂层支架组为（19±9）%。结论①雷帕霉素-替罗非班复合药物涂层支架可有效预防PC I术后支架内血栓形成。②雷帕霉素-替罗非班复合药物涂层支架防治支架内再狭窄的疗效与单纯雷帕霉素支架无差异。     

雷公藤内酯醇洗脱支架对冠状动脉支架内再狭窄的影响

目的研究雷公藤内酯醇洗脱支架预防冠状动脉支架植入术后再狭窄的有效性及安全性。方法杂种幼猪20只,分别植入雷公藤内酯醇洗脱支架和普通裸金属支架各10枚。术后28d比较两组的冠状动脉造影形态、组织病理及血生化结果。结果支架部位血管腔面积裸支架组小于雷公藤内酯醇组(P<0.05)、支架内增生内膜面积及内膜增生程度裸支架组大于雷公藤内酯醇组(P<0.05)。未发现明显毒副作用。结论雷公藤内酯醇洗脱支架能抑制新生内膜的形成,在支架植入后4周能预防再狭窄的形成。     

雷帕霉素洗脱支架治疗冠脉左前降支近中段病变的临床疗效评价

目的评价雷帕霉素洗脱支架治疗冠脉左前降支近中段病变的临床疗效。方法以冠脉造影显示左前降支近中段狭窄病变并分别置入雷帕霉素洗脱支架(SES组)或裸金属支架(BMS组)的患者各100例为研究对象。记录患者的一般情况、临床和冠脉病变特征,术后1年临床随访和冠脉造影复查。结果两组患者匹配良好,仅SES组置入支架的长度显著长于BMS组(21.07±7.45mmvs18.25±6.82mm,P=0.0057)。在随访中,无心源性死亡,SES组1例因支架内再狭窄发生急性心肌梗死。冠脉造影复查显示SES组再狭窄率较BMS组显著降低(7.4%vs25.9%,P=0.002),并直接导致不良事件发生率的下降。结论药物洗脱支架显著降低左前降支近中段狭窄病变介入治疗后再狭窄发生率,可作为血运重建的一种有效策略。     

冠状动脉支架置入后局部内膜增生模式的探讨

目的探讨冠状动脉支架置入局部血管内膜的增生模式。方法建立冠状动脉支架置入的广西种的微型猪模型。分别于支架置入后3,7,28,90和180 d截取支架段血管连同临近的近端正常血管段,进行病理组织学检查和聚合酶链反应检测支架局部血管内膜增生情况。结果正常血管段表达增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)mRNA在各个时间段没有显著性差异。支架置入后3 d局部血管壁PCNA mRNA的表达明显增高。并在术后7 d达到高峰。术后90 d PCNA mRNA的表达呈现下降的趋势,但仍显著高于正常血管段,并且差异一直持续到术后180 d。术后7～180 d支架段内膜及中膜面积明显大于正常血管段。结论冠状动脉支架置入后局部内膜呈现了一种持续过度的增生反应。     

雷帕霉素药物洗脱支架对糖尿病小型猪冠状动脉支架置入后内膜增生的影响

目的:评估雷帕霉素药物洗脱支架(SES)对糖尿病小型猪冠状动脉支架置入后内膜增生的作用.方法:建立链脲菌素诱导的糖尿病小型猪模型(糖尿病组,n=12),随机选取2支冠状动脉置入SES,共计置入24枚支架,术后饲养6个月,与非糖尿病置入SES支架的小型猪模型(对照组,n=12)比较冠状动脉造影、血管内超声及组织切片检查结果.结果:两组动物支架置入冠状动脉分布,术前参照血管直径[糖尿病组:(2.78±0.35)mm,对照组:(2.81±0.29)mm]及术后即刻最小管腔内径[糖尿病组:(2.90±0.42)mm,对照组:(2.89±0.33)mm]均相似(P均>0.05).术后6个月糖尿病组支架内狭窄程度[(35.6±9.2)%和(7.9±3.1)%,P<0.001]、支架内晚期管腔丢失[(0.32±0.09)mm和(0.09±0.04)mm,P<0.001]、新生内膜厚度[血管内超声:(0.35±0.12)mm和(0.11±0.08)mm,P<0.05]及新生内膜面积[血管内超声:(1.29±0.51)mm~2和(0.26±0.11)mm~2,P<0.001;组织切片:(1.24±0.76)mm~2和(0.19±0.08)mm~2,P<0.05]均显著高于对照组.结论:糖尿病小型猪冠状动脉置入SES后内膜增生程度显著高于无糖尿病模型.     

OCT对于DES术后晚期或晚晚期血栓治疗的指导作用

目的 观察光学相干断层成像（OCT）技术对于药物洗脱支架（DES）术后发生晚期或晚晚期血栓治疗对策的指导作用.方法 选取2010年7月至2013年11月本院收治的行DES支架置入术后发生晚期或晚晚期支架内血栓患者22例,对患者行OCT检查,根据OCT结果采取进一步治疗措施.结果 DES术后晚期或晚晚期血栓的OCT表现为：支架内皮化不全6例、贴壁不良12例、支架内新生动脉粥样硬化斑块形成8例,支架内纤维过度增生较为少见2例,有些患者上述情况同时存在.治疗对策：单纯支架内皮化不全及支架贴壁不良者采取单纯球囊扩张术12例,新生动脉粥样硬化斑块形成或纤维过度增生者采取球囊扩张加支架置入术10例.结论 OCT可以准确了解DES术后晚期或晚晚期血栓的原因,提供更为合适的治疗方案.     

雷帕霉素洗脱支架与紫杉醇涂层支架治疗冠状动脉复杂病变

目的评价雷帕霉素洗脱支架(CypherTM)与紫杉醇涂层支架(Taxus ExpressTM)治疗冠状动脉复杂病变(B2／C型病变)的近期和远期疗效。方法入选本研究267例,男性占68％,糖尿病占38．5％。雷帕霉素洗脱支架组169例,共植入雷帕霉素洗脱支架172条;紫杉醇涂层支架组98例,植入紫杉醇涂层支架165条。观察6个月的主要心血管事件。结果两组的临床特征相似。支架植入成功率100％,95％的病人完成6个月的随访。主要心血管事件发生率:雷帕霉素洗脱支架组5．9％(10／169),紫杉醇涂层支架组9．2％(9／98),两组差异无统计学意义(X2=1．001,P=0．317)。结论雷帕霉素洗脱支架治疗冠状动脉复杂病变疗效和安全性与紫杉醇涂层支架相似。     

Incomplete arterial healing 8 years after the implantation of sirolimus‐eluting stent. In vivo visualization by optical coherence tomography

The time course of complete arterial healing after drug eluting stent implantation is unknown. We present a case of incomplete endothelialization and late stent malapposition identified by optical coherence tomography 8 years after a sirolimus‐eluting stent implantation, which was not related with any adverse clinical event. © 2011 Wiley Periodicals, Inc.     

Vascular responses to drug eluting stents: importance of delayed healing

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI). Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis. Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined.     

Acute thrombosis of drug eluting stent following protamine: a case report

Reversal of anticoagulant effect of heparin to treat coronary perforation after bare metal stent implantation is an accepted practice. However this practice may not be safe following drug eluting stent implantation. We report a case of acute stent thrombosis following protamine administration for coronary perforation after drug eluting stent implantation.     

Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model.

An advanced six-ring morpholino backbone c-myc antisense (AVI-4126) was shown to inhibit c-myc expression and intimal hyperplasia after local catheter delivery in a porcine balloon injury model. The purpose of this study was to investigate the effects of an AVI-4126-eluting phosphorylcholine-coated (PC) stent on c-myc expression restenosis and vascular healing after stent implantation in porcine coronary arteries. PC stents were loaded with AVI-4126 using soak trap. Nine pigs underwent AVI-4126 PC coronary stent implantation (two stents/animal). Two to six hours postprocedure, three pigs were sacrificed and stented segments were analyzed by Western blot for c-myc expression. In chronic experiments, six pigs (12 stent sites) were sacrificed at 28 days following intervention and vessels were perfusion-fixed. High-performance liquid chromatography analysis of plasma samples showed minimal presence of the antisense. Western blot analysis of the stented vessels demonstrated inhibition of c-myc expression at 2 and 6 hr after procedure. Quantitative histologic morphometry showed that the neointimal area was significantly reduced (by 40%) in the antisense-coated group compared with control (2.3 +/- 0.7 vs. 3.9 +/- 0.8 mm(2), respectively; P = 0.0077). Immunostaining and electron microscopy demonstrated complete endothelialization, without fibrin deposition, thrombosis, or necrosis in all implanted stents. In the porcine coronary model, an advanced c-myc-eluting PC stent blocked c-myc expression and significantly inhibited myointimal hyperplasia and allowed complete reendothelialization and healing response.     

Rapamycin in cardiovascular medicine

Abstract
The cellular action of rapamycin (sirolimus), a natural fermentation product produced by Strepto­myces hygroscopicus , is mediated by binding to the FK506 binding protein. By inhibiting a kinase known as the target of rapamycin, it restricts the proliferation of smooth-muscle cells by blocking cell-cycle progression at the G1/S transition.
The finding that rapamycin possesses both anti­proliferative and antimigratory activity suggests that it could contribute to the control of arterial re-­narrowing after percutaneous intervention and control the vascular manifestations of chronic rejection in transplanted hearts.
The first clinical trials of implantation of rapamycin-coated stents in obstructive coronary artery lesions have been reported and, in selected patient groups, it appears that the restenosis process has been abolished. Studies are underway to establish the benefits of rapamycin-coated stents in day-to-day interventional practice, including small vessels, long lesions and patients with multivessel disease. With the addition of novel antiplatelet agents and delivery systems, it is possible that the two major limitations of percutaneous coronary intervention − restenosis and stent thrombosis − will be overcome.
Cardiac graft loss due to intimal hyperplasia and accelerated atherosclerosis remains the major limit­ation to long-term survival following cardiac transplantation. Animal studies of rapamycin have suggested that this process can be reduced or abolished. Human studies of the efficacy of rapamycin in preventing both acute rejection and allograft arterial disease are in progress.
Concerns regarding toxicity, carcinogenicity, delayed healing and endothelialization remain. As with any new agent or technology, we must remain vigilant to late adverse side-effects. (Intern Med J 2003; 33: 103−109)