【作者】 张峰；

【导师】 葛均波；

【作者基本信息】 复旦大学 ， 内科学， 2011， 博士

【摘要】 第一部分药物洗脱支架对冠状动脉血管重构影响的实验研究目的：评价金属裸支架(BMS)、雷帕霉素洗脱支架(SES)和新型壳聚糖/肝素逐层自组装(C/HLBL)涂层支架植入猪冠状动脉后,对支架及其边缘节段血管重构的影响。方法：采用小型猪为实验动物,在猪冠状动脉内随机植入BMS(BMS组)、SES(SES组)和C/HLBL涂层支架(LBL组)。分别在支架植入后即刻和3-6个月随访时对各组支架植入血管行血管内超声(IVUS)检查和定量分析测定。结果：16头小型猪32支靶血管(BMS组9支,SES组11支,LBL组12支)完成了术后即刻和随访时的血管内超声检查。三组支架的支架节段在术后即刻的各项IVUS参数在组间均没有显著性差异。术后3-6个月随访时,三组支架节段的血管面积、中层和斑块面积以及支架面积在组间仍无显著性差异,但SES组和LBL组的管腔面积显著大于BMS组(SES组6.34±0.89 mm2比BMS组4.31±1.28 mm2,P=0.001:LBL组5.43±0.88 mm2比BMS组4.31±1.28 mm2.,P=0.029)。与术后即刻相比,BMS组在随访时发现显著的内膜增生,支架内管腔面积显著减小(4.31±1.28 mm2,比6.97±0.73 mm2,P<0.001);LBL组在随访时也存在一定程度的管腔缩小(5.43±0.88 mm2比6.90±0.64 mm2,P<0.001),但其内膜增生程度显著低于BMS组(新生内膜面积1.40±0.96 mm2比2.69±1.58mm2,P=0.032):SES组在随访时支架梁表面的内膜覆盖不明显,管腔面积较术后即刻无显著变化(6.34±0.89 mm2比6.72±0.79 mm2,P:0.305),三支架组在随访时的血管面积、中层和斑块面积以及支架面积较术后即刻均未发生显著变化。各组在IVUS随访中均未发现晚期支架贴壁不良(ISA)现象。三组支架的支架近端和远端边缘5mm内血管节段在术后即刻和术后3-6个月随访时的血管面积、中层和斑块面积和管腔面积在组间和组内均没有显著性差异。结论：BMS植入猪正常冠状动脉后3-6个月随访时发生显著的内膜增生,而SES的内膜增生程度低,支架梁表面内皮覆盖不明显,C/HLBL涂层支架的内膜增生程度则介于BMS和SES之间；BMS、SES和C/HLBL涂层支架植入猪正常冠状动脉后,支架外周和支架边缘节段血管均没有出现明显的血管重构。第二部分药物洗脱支架对冠状动脉内皮功能影响的实验研究目的：评价金属裸支架(BMS)、雷帕霉素洗脱支架(SES)和新型壳聚糖/肝素逐层自组装(C/HLBL)涂层支架植入猪冠状动脉后,对支架邻近节段心外膜冠状动脉内皮功能的影响。方法：采用小型猪为实验动物,在猪冠状动脉内随机植入BMS (BMS组)、SES(SES组)和C/HLBL涂层支架(LBL组)。分别在支架植入后即刻和3-6个月随访时于支架植入靶血管内注入乙酰胆碱(先后采用6ug、60ug和600ug共3种剂量)和硝酸甘油(200ug)行内皮依赖性和非依赖性血管舒缩反应试验,通过定量冠状动脉造影分析测定支架邻近节段心外膜冠状动脉在药物注入前后的内径变化。结果：18头小型猪41支靶血管(BMS组12支,SES组13支,LBL组16支)完成了完整的内皮依赖性和非依赖性血管舒缩反应试验。在冠脉内注入乙酰胆碱后,SES组支架近端和远端无支架节段(NSRS)表现为随剂量递增而加重的血管收缩反应,且以支架远端NSRS更为显著(随乙酰胆碱剂量递增,远端直径变化百分数分别为-14.1±6.2%,-23.5±13.7%和-52.8±22.5%；近端直径变化百分数分别为-5.3±2.7%,-5.9±3.1%,-7.3±3.0%)。与BMS组(随乙酰胆碱剂量递增,远端直径变化百分数分别为-4.2±2.6%,-5.4±2.9%和-5.7±3.0%;近端直径变化百分数分别为-3.3±2.1%,-4.6±2.7%和-4.9±3.5%)相比,LBL组支架近端和远端NSRS的内皮依赖性血管舒缩功能没有显著性差异(随乙酰胆碱剂量递增,远端直径变化百分数分别为-3.2±2.1%,-3.8±1.9%和-4.4±2.9%；近端直径变化百分数分别为-2.8±2.2%,-4.9±1.9%和-5.2±2.1%)。各组支架近端和远端NSRS对硝酸甘油的非内皮依赖性血管舒张反应没有显著性差异。结论：与BMS相比,SES植入猪冠状动脉后可导致支架邻近节段NSRS的血管舒缩功能受损,且以支架远端为著,提示局部内皮功能障碍;新型C/HLBL涂层支架植入猪冠状动脉后不会影响支架邻近节段血管的内皮功能,其内皮依赖性血管舒缩反应与BMS相比没有显著性差异。第三部分药物洗脱支架植入术后晚期支架贴壁不良的血管内超声研究目的：通过血管内超声(IVUS)对药物洗脱支架(DES)植入后发生晚期支架贴壁不良(ISA)的患者进行研究,评价ISA与血管重构的关系,同时对发生晚期ISA的患者进行长期随访,探讨晚期ISA对临床预后的影响。方法：从复旦大学附属中山医院心导管室血管内超声检查数据库中,选择连续15例DES植入后发生晚期ISA的患者。同时,在IVUS数据库中根据靶血管、糖尿病、DES类型、参照血管外弹力膜(EEM)横截面面积以2：1配对的方式选择同期30例未发生晚期ISA的患者作为对照组。分别对晚期ISA组患者支架内的ISA节段和相邻无ISA节段、以及对照组无ISA患者的术后随访期的IVUS影像行定量分析测定。并对所有15例晚期ISA患者进行2年以上的临床随访。结果：15例在随访时被检出晚期ISA患者中,2例(13%)ISA位于支架的边缘节段(支架边缘的5mm内),13例(87%)位于支架的中段体部。ISA最大面积和角度分别为5.3±2.2 mm2和163±67°。与相邻的无ISA节段相比,发生晚期ISA节段的最大EEM面积和血管重构指数均显著增加(分别为24.1±3.3比20.1±3.1mm2, P=0.002和1.6±0.2比1.3±0.2,P=0.001)。而两组的支架内管腔面积、斑块和中层面积均没有显著性差异(P>0.05)。晚期ISA患者与对照组无ISA患者相比,各项基线临床和造影特征、以及IVUS随访时支架近端和远端参照节段EEM面积、管腔面积以及支架节段的支架面积均无显著性差异(P>0.05)；但晚期ISA组的最大EEM面积和血管重构指数均显著大于对照组(分别为24.1±3.3比18.8±4.2mm2, P=0.002和1.6±0.2比1.3±0.2,P=0.001)。两组的支架内管腔面积、斑块和中层面积均没有显著性差异(P>0.05)。对15例晚期ISA患者进行了2年以上的临床随访,平均随访时间为(34±5)个月,3例(20%)患者发生了急性ST段抬高型心肌梗死,其中1例抢救无效死亡。3例患者发生心肌梗死后均接受了急诊冠脉造影,证实为极晚期支架血栓形成。这3例极晚期支架血栓分别发生在支架植入术后的第29,31和32个月,即复查造影和IVUS发现晚期ISA后的第20,23和23个月。结论：DES植入后发生的晚期ISA与支架植入节段异常的扩张性血管重构有关；DES植入后随访期检出的晚期ISA可能导致DES极晚期支架内血栓的易感性增加。更多还原

【Abstract】 Part I:Experimental evaluation of coronary remodeling after drug-eluting stent implantationObjective:To evaluate the response of the coronary vessel wall to implantation of the bare metal stent (BMS), sirolimus-eluting stent (SES), and chitosan-heperin layer-by-layer self assembly (C/H LBL) coating stent by using serial intravascular ultrasound.Methods:The BMS, SES and C/H LBL stents were randomly implanted in the miniature pigs’coronary arteries. Serial intravascular ultrasound (IVUS) was performed immediately after the stent implantation and at 3-6 months follow-up. Quantitative IVUS analysis was then performed in the stent segments,5 mm coronary segments immediately proximal and distal to the stent.Results:Serial IVUS was available for 9 BMSs (BMS group),11 SESs (SES group), and 12 C/H LBL stents (LBL group). At follow-up, significantly larger lumen (SES group 6.34±0.89 mm2 vs. BMS group 4.31±1.28 mm2, P=0.001; LBL goup 5.43±0.88 mm2 vs. BMS group 4.31±1.28 mm2, P=0.029; respectively) and lower neointimal hyperplasia areas (SES group 0.28±0.35 mm2 vs. BMS group 2.69±1.58 mm2, P=0.002; LBL goup 1.40±0.96 mm2 vs. BMS group 2.69±1.58 mm2, P= 0.032; respectively) were seen in the SES group and LBL group compared with the BMS group (by ANOVA, P< 0.001). There was no significant difference between 3 groups in either the vessel area or the media& plaque behind stent area change (all P>0.05) from after the procedure to late follow-up. For both the proximal and the distal edges, the vessel and lumen areas were also comparable among 3 groups (all P>0.05). No late incomplete stent apposition was observed in all 3 groups.Conclusion:The marked reduction in neointimal hyperplasia with SES and C/H LBL stent is not associated with abnormal vascular response or edge effects at follow-up IVUS. Part II:Experimental evaluation of coronary endothelial function associated with drug-eluting stent, and chitosan-heperin layer-by-layer self assembly coating stentObjective:To evaluate the coronary endothelial function following percutatneous implantation of the bare metal stent (BMS), sirolimus-eluting stent (SES), and chitosan-heperin layer-by-layer self assembly (C/H LBL) coating stent at follow-up.Methods:The BMS, SES and C/H LBL stents were randomly implanted in the miniature pigs’coronary arteries. Endothelial function was estimated by incremental acetylcholine (Ach) (6,60,600 ug) and nitroglycerin (200 ug) infusions into the coronary ostium at 3-6 months follow-up. The vascular response was quantitatively measured in the 10-mm segments proximal and distal to the stent.Results:The coronary vasomotor response was tested for 12 BMSs (BMS group),13 SESs (SES group), and 16 C/H LBL stents (LBL group). In the SES group, more intense vasoconstriction to incremental doses of Ach was observed at follow-up compared with the BMS goup, and was more prominent in the distal segments (-14.1±6.2%,-23.5±13.7%,-52.8±22.5%, respecitively to incremental doses of Ach) than the proximal segments (-5.3±2.7%,-5.9±3.1%,-7.3±3.0%, respecitively to incremental doses of Ach). Endothelial function associated with the C/H LBL stent (distal:-3.2±2.1%,-3.8±1.9%,-4.4±2.9%; proximal:-2.8±2.2%,-4.9±1.9%,-5.2±2.1%, respecitively to incremental doses of Ach) and BMS (distal:-4.2±2.6%,-5.4±2.9%,-5.7±3.0%; proximal:-3.3±2.1%,-4.6±2.7%,-4.9±3.5%, respecitively to incremental doses of Ach) was preserved at follow-up compared with the SES. There is no significant difference in endothelium-dependent vasomothion between LBL group and BMS goup. Endothelium-independent vasodilation to nitrate did not differ significantly among the study groups.Conclusion:SES implantation may induce significant impairment of the endothelium-dependent vasomotor function in the adjacent portion of the stent segment, while the endothelial function associated with C/H LBL stent can be well preserved. Part III:Intravascular ultrasonic evaluation in patients with late incomplete stent apposition after drug-eluting stent implantationObjective:To evaluate the coronary morphological characteristics and present the clinical outcomes of a more than 2-year follow-up in patients with late incomplete stent apposition (ISA) after drug-eluting stent implantation.Methods:From the IVUS database of our institute,15 consecutive patients who underwent DES implantation into de novo lesions and had documented ISA at follow-up by IVUS were identified. The ISA group was compared with a matched control group of patients (n=30) who had no evidence of ISA at follow-up. Clinical follow-up was available up to 41 months after DES implantation and up to 33 months after identification of ISA.Results:Of the 15 documented late ISA after DES implantation, two located at the edge (within 5 mm from stent margin) while 13 in the body of the stent. The maximum area and arc of ISA measured 5.3±2.2 mm2 and 163±67°, respectively. In patients with late ISA, the maximum external elastic membrane (EEM) area of stent segment with ISA was significantly larger than the adjacent stent segment without ISA (24.1±3.3 vs.20.1±3.1 mm2, P= 0.002), while stent area, plaque plus media (P&M) area and intrastent lumen area were comparable (P>0.05). Compared to the matched control cohort without ISA at follow-up, the maximum EEM area was also significantly larger in the late ISA group (24.1±3.3 vs.18.8±4.2 mm2, P< 0.001), while the areas of reference EEM and lumen, stent, P&M behind the stent, intimal hyperplasia and intrastent lumen were all comparable between the two groups (P>0.05). Over a mean follow-up of(34±5) months (range 24-41 months),3 of the 15 patients (20.0%) suffered from ST elevated myocardial infarction with one death. Very late stent thrombosis in the area with late ISA was demonstrated by the emergency coronary angiography in all 3 patients.Conclusion:Late ISA revealed at follow-up after DES implantation was associated with significant positive vessel remodeling. With regard to the clinical sequelae, late ISA may be associated with a high incidence of very late stent thrombosis.更多还原