大鼠冠状动脉自体微血栓栓塞形成无复流及地尔硫卓治疗作用的研究
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摘要
第一部分大鼠冠状动脉自体微血栓栓塞模型的构建
目的：采用自体微血栓创建一种稳定性好且模拟临床病理生理过过程的大鼠冠脉微栓塞模型。
方法：采用健康雄性SD大鼠72只,体重280-320g。随机分为假手术组(SHAM, sham operation group,n=36)、冠脉微栓塞组(CME, Coronary microembolization group,n=36); CME组依注射的血栓剂量为5mg,并根据不同取材时间点再分为术后3小时、24小时和4周3个亚组,每亚组12只。术前尾静脉取血0.5ml,于37℃温箱内形成血凝块,匀浆器研碎血凝块后从主动脉根部内注射注入微血栓制成的混悬液,而微栓塞组注入等量生理盐水。另外96只大鼠(SHAM=48, CME=48)用来进行评价c-TNI水平以及vWF含量以及炎症细胞炎症因子表的的检查,分别于6小时,24小时,1周,4周取材,采用HE、HBFP、CARSTAIRS及Masson染色及电镜观察CME术后3h,4w心肌组织病理学改变；血液动力学、超声心动图检测大鼠心功能变化。
结果：与假手术组相比,CME组血浆cTNI以及vWF水平升高,HE、HBFP染色显示CME各组可见不均一的,多个中心小片状心肌缺血、坏死伴炎症细胞浸润增加。CARSTAIRS染色进一步证实心肌微小动脉内(<100μm)有散在的血栓形成。CME各组微梗死面积显著增加,Masson染色显示CME后心肌微小纤维灶形成,且多分布于心内膜区,纤维化增加。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。
结论：经主动脉根部注射自体微血栓5mg、同时短暂主动脉夹闭可建立稳定、重复性好且模拟人体病变的大鼠冠状动脉微栓塞模型。
第二部分大鼠冠状动脉自体微血栓栓塞后微循环障碍及其形成无复流现象的机制研究
目的
通过构建大鼠自体微栓塞模型探讨微血栓塞后微循环障碍及其形成无复流现象的机制。
方法
将SD大鼠随机分成自体微栓塞组(CME)和假手术组(SHAM),在血管夹火闭升主动脉时10秒钟从主动脉根部注射0.2ml自体微血栓颗粒,造成冠脉微栓塞模型,假手术组用等量生理盐水注射。模型成功后分别于不同的时间点取大鼠心脏标本。通过注射硫磺素S来评价大鼠心肌的无复流面积,取大鼠血浆测定cTNI以及假性血友病因子(von Willebrand Factor)水平,病理学分析微栓塞后不同直径范围微动脉血管密度的变化,免疫组织化学染色以及免疫印法测定术后炎症因子(IL-6, TNF-a)表达；超声心动图、血液动力学检测大鼠心功能变化。
结果
与假手术组相比,CME组血浆cTNI以及vWF水平升高,大鼠心肌无复流面积明显增加,免疫组织化学染色提示CME组大鼠直径在10～50μm之间的,尤其是直径在20-50μm之间的的小动脉血管较SHAM组大鼠的数量明显减少,免疫组织化学染色以及免疫印法测定术后炎症因子(IL-6,TNF-a)表达明显增加,且心肌炎症反应不仅局限于微梗灶及周围,同时在许多非梗塞血管也出现炎症细胞明显激活。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。
结论
通过建立大鼠自体冠状动脉微栓塞模型,可以进行冠状动脉微栓塞后微循环障碍及其形成无复流现象的病理生理机制研究。
第三部分静脉应用地尔硫卓对大鼠冠状动脉自体微血栓栓塞的治疗作用及其机制的探讨
目的：探讨静脉注射地尔硫卓对大鼠冠状动脉自体微血栓栓塞的治疗作用以及可能的机制。
材料和方法：在血管夹夹闭大鼠升主动脉10秒钟的同时从主动脉根部用28g的细针注射0.2m1自体微血栓颗粒,造成大鼠的冠状动脉微栓塞模型。造模成功并存活的大鼠被随机分成模型组(CME组,n=38)和地尔硫卓治疗组(CME+DIL组,n=38).地尔硫卓治疗组的大鼠在注射微血栓颗粒5分钟后从尾静脉持续泵入地尔硫卓针剂(1mg/ml,50μg/min/Kg)持续175分钟。血浆cTNI以及vWF水平,血流动力学测定,心脏彩超以及心肌的病理学检查在不同的时间点进行(术后3小时,24小时,7天和28天)。
结果：CME组血浆cTNI以及vWF水平升高,HE、HBFP染色显示CME各组可见多中心小灶性心肌缺血、坏死伴白细胞浸润以及炎症因子的表达增加。CARSTAIRS染色进一步证实心肌微小动脉内(<100gm)有散在的血栓形成。CME各组微梗死面积显著增加,无复流面积明显增加,MassFn染色显示CME后心肌微小纤维灶形成,纤维化增加。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。与CME组相比,CME+DIL组大鼠在病理学检查上提示心肌损伤以及炎性浸润明显减轻,心功能有所恢复。
结论：这种大鼠冠状动脉自体微血栓栓塞模型适合评价静脉注射地尔硫卓的治疗作用,地尔硫卓通过减轻冠状动脉微栓塞以及栓塞后的炎症反应改善了心肌重构和心功能。
Part I Establishment and characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats
Objective:To establish a model of coronary thrombotic microembolism in rats.
Methods:5mg dried auto-microthrombotic particulates dissolved in0.2ml saline (CM E group) or0.2ml saline (SHAM group) was injected into temporarily clamped aorta of male Sprague-Dawley rats. After auto-microthrombotic particulates injection, serum c-troponin I was measured by electrochemistry and immunofluorescence method and von Willebrand factor (3hours,24hours,1days,28days) was determined by antibody in antigen-based sandwich enzyme-linked immunosorbent assay, myocardial leukocyte infiltration (24hours and7days,28days), percent of arterioles obstructed by thrombosis, early myocardial ischemia or infarct area (3hours),myocardial fibrosis (28days) were observed by HE, CARSTAIRS,HBFP and Masson staining in Light Microscopic Analysis. Cardiac function was evaluated by transthoracic echocardiography and hemodynamic measurements.
Results:After automicrothrombotic particulate injection, serum c-troponin I and von Willebrand factor levels, myocardial leukocyte infiltration levels, the percentage of arterioles obstructed by thrombosis, and myocardial fibrosis were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the SHAM group.
Conclusions:Injection of5mg homologous microthrombotic particle suspension into aorta when clamping the ascending aorta is an effective method to produce coronary microembolism in small animals.
Part II The study on microcirculatory disturbance and no-reflow phenomenon mechanism after coronary artery autologous micro thromboembolism in rats
Objective:To research microcirculatory disturbance and no-reflow phenomenon mechanism in the model of coronary thrombotic microembolism in rats.
Methods:5mg dried auto-microthrombotic particulates dissolved in0.2ml saline (CME group) was injected into temporarily clamped aorta of male Sprague-Dawley rats. After auto-microthrombotic particulates injection, serum c-troponin I a, von Willebrand factor and ET-level (3hours,24hours,1days,28days) was determined, no-flow area was evaluated by Thioflavin-S (3hours), myocardial leukocyte infiltration (24hours and7days,28days), myocardial expressions of TNFa and IL-6(24hours,1and28days) were measured by Immunohistochemical Analysis and Western Blot Analysis, Arteriole density (AD) was calculated by immunohistochemical analysis. Cardiac function was evaluated by transthoracic echocardiography and hemodynamic measurements
Results:After automicrothrombotic parti cul ate injection, serum c-troponin I and von Willebrand factor levels, the no-flow area as evaluated by Thioflavin S, myocardial leukocyte infiltration levels, myocardial expressions of tumor necrosis factor and interleukin-6, were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the SHAM group. Number of arterioles with diameter between10-50μm, especially for arterioles with diameter between20-50μm was significantly lower in CME group at3hours post injection.
Conclusion:aortic automicrothrombotic particulate injection could induce coronary microembolism in rats, and this model could be of value in improving the understanding of pathophysiology of no-reflow phenomenon mechanism.
Part III Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism
Objective:The objective of this study was to evaluate the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic microembolism (CME).
Methods:CME was induced by injecting0.199ml saline containing5mg automicrothrombotic particulates (around10μm) into the aorta of Sprague-Dawley rats over10seconds using a tuberculin syringe with a28-gauge needle. CME rats were randomized to untreated (CME, n=38) group and diltiazem-treated (CME+DIL, n=38) group. Diltiazem (1mg/ml,50μg/min/Kg) was intravenously injected with an infusion pump through tail vein for175minutes at5minutes after automicrothrombotic particulates injection. Hemodynamic measurements, echocardiographic and pathohistogical examinations were performed at various time points (3hours,24hours,7days and28days) post operation.
Results:Arteriole thrombosis, multi-focal myocardial necrosis, inflammatory cell infiltration with remarkably increased myocardial TNF-a, IL-6expression and reduced LV systolic function as well as increased plasma vWF, ET-1and c-TNI levels (indicating vascular endothelial injury and myocardial necrosis) were evidenced in CME rats. These pathologic responses in CME rats could be partly attenuated by intravenous diltiazem treatment.
Conclusion:This CME model is suitable to evaluate the therapeutic effects of intravenous diltiazem and intravenous diltiazem treatment significantly improves cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat CME model.
目的：采用自体微血栓创建一种稳定性好且模拟临床病理生理过过程的大鼠冠脉微栓塞模型。
方法：采用健康雄性SD大鼠72只,体重280-320g。随机分为假手术组(SHAM, sham operation group,n=36)、冠脉微栓塞组(CME, Coronary microembolization group,n=36); CME组依注射的血栓剂量为5mg,并根据不同取材时间点再分为术后3小时、24小时和4周3个亚组,每亚组12只。术前尾静脉取血0.5ml,于37℃温箱内形成血凝块,匀浆器研碎血凝块后从主动脉根部内注射注入微血栓制成的混悬液,而微栓塞组注入等量生理盐水。另外96只大鼠(SHAM=48, CME=48)用来进行评价c-TNI水平以及vWF含量以及炎症细胞炎症因子表的的检查,分别于6小时,24小时,1周,4周取材,采用HE、HBFP、CARSTAIRS及Masson染色及电镜观察CME术后3h,4w心肌组织病理学改变；血液动力学、超声心动图检测大鼠心功能变化。
结果：与假手术组相比,CME组血浆cTNI以及vWF水平升高,HE、HBFP染色显示CME各组可见不均一的,多个中心小片状心肌缺血、坏死伴炎症细胞浸润增加。CARSTAIRS染色进一步证实心肌微小动脉内(<100μm)有散在的血栓形成。CME各组微梗死面积显著增加,Masson染色显示CME后心肌微小纤维灶形成,且多分布于心内膜区,纤维化增加。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。
结论：经主动脉根部注射自体微血栓5mg、同时短暂主动脉夹闭可建立稳定、重复性好且模拟人体病变的大鼠冠状动脉微栓塞模型。
第二部分大鼠冠状动脉自体微血栓栓塞后微循环障碍及其形成无复流现象的机制研究
目的
通过构建大鼠自体微栓塞模型探讨微血栓塞后微循环障碍及其形成无复流现象的机制。
方法
将SD大鼠随机分成自体微栓塞组(CME)和假手术组(SHAM),在血管夹火闭升主动脉时10秒钟从主动脉根部注射0.2ml自体微血栓颗粒,造成冠脉微栓塞模型,假手术组用等量生理盐水注射。模型成功后分别于不同的时间点取大鼠心脏标本。通过注射硫磺素S来评价大鼠心肌的无复流面积,取大鼠血浆测定cTNI以及假性血友病因子(von Willebrand Factor)水平,病理学分析微栓塞后不同直径范围微动脉血管密度的变化,免疫组织化学染色以及免疫印法测定术后炎症因子(IL-6, TNF-a)表达；超声心动图、血液动力学检测大鼠心功能变化。
结果
与假手术组相比,CME组血浆cTNI以及vWF水平升高,大鼠心肌无复流面积明显增加,免疫组织化学染色提示CME组大鼠直径在10～50μm之间的,尤其是直径在20-50μm之间的的小动脉血管较SHAM组大鼠的数量明显减少,免疫组织化学染色以及免疫印法测定术后炎症因子(IL-6,TNF-a)表达明显增加,且心肌炎症反应不仅局限于微梗灶及周围,同时在许多非梗塞血管也出现炎症细胞明显激活。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。
结论
通过建立大鼠自体冠状动脉微栓塞模型,可以进行冠状动脉微栓塞后微循环障碍及其形成无复流现象的病理生理机制研究。
第三部分静脉应用地尔硫卓对大鼠冠状动脉自体微血栓栓塞的治疗作用及其机制的探讨
目的：探讨静脉注射地尔硫卓对大鼠冠状动脉自体微血栓栓塞的治疗作用以及可能的机制。
材料和方法：在血管夹夹闭大鼠升主动脉10秒钟的同时从主动脉根部用28g的细针注射0.2m1自体微血栓颗粒,造成大鼠的冠状动脉微栓塞模型。造模成功并存活的大鼠被随机分成模型组(CME组,n=38)和地尔硫卓治疗组(CME+DIL组,n=38).地尔硫卓治疗组的大鼠在注射微血栓颗粒5分钟后从尾静脉持续泵入地尔硫卓针剂(1mg/ml,50μg/min/Kg)持续175分钟。血浆cTNI以及vWF水平,血流动力学测定,心脏彩超以及心肌的病理学检查在不同的时间点进行(术后3小时,24小时,7天和28天)。
结果：CME组血浆cTNI以及vWF水平升高,HE、HBFP染色显示CME各组可见多中心小灶性心肌缺血、坏死伴白细胞浸润以及炎症因子的表达增加。CARSTAIRS染色进一步证实心肌微小动脉内(<100gm)有散在的血栓形成。CME各组微梗死面积显著增加,无复流面积明显增加,MassFn染色显示CME后心肌微小纤维灶形成,纤维化增加。超声心动图以及血流动力学监测提示CME组左室收缩功能明显降低。与CME组相比,CME+DIL组大鼠在病理学检查上提示心肌损伤以及炎性浸润明显减轻,心功能有所恢复。
结论：这种大鼠冠状动脉自体微血栓栓塞模型适合评价静脉注射地尔硫卓的治疗作用,地尔硫卓通过减轻冠状动脉微栓塞以及栓塞后的炎症反应改善了心肌重构和心功能。
Part I Establishment and characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats
Objective:To establish a model of coronary thrombotic microembolism in rats.
Methods:5mg dried auto-microthrombotic particulates dissolved in0.2ml saline (CM E group) or0.2ml saline (SHAM group) was injected into temporarily clamped aorta of male Sprague-Dawley rats. After auto-microthrombotic particulates injection, serum c-troponin I was measured by electrochemistry and immunofluorescence method and von Willebrand factor (3hours,24hours,1days,28days) was determined by antibody in antigen-based sandwich enzyme-linked immunosorbent assay, myocardial leukocyte infiltration (24hours and7days,28days), percent of arterioles obstructed by thrombosis, early myocardial ischemia or infarct area (3hours),myocardial fibrosis (28days) were observed by HE, CARSTAIRS,HBFP and Masson staining in Light Microscopic Analysis. Cardiac function was evaluated by transthoracic echocardiography and hemodynamic measurements.
Results:After automicrothrombotic particulate injection, serum c-troponin I and von Willebrand factor levels, myocardial leukocyte infiltration levels, the percentage of arterioles obstructed by thrombosis, and myocardial fibrosis were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the SHAM group.
Conclusions:Injection of5mg homologous microthrombotic particle suspension into aorta when clamping the ascending aorta is an effective method to produce coronary microembolism in small animals.
Part II The study on microcirculatory disturbance and no-reflow phenomenon mechanism after coronary artery autologous micro thromboembolism in rats
Objective:To research microcirculatory disturbance and no-reflow phenomenon mechanism in the model of coronary thrombotic microembolism in rats.
Methods:5mg dried auto-microthrombotic particulates dissolved in0.2ml saline (CME group) was injected into temporarily clamped aorta of male Sprague-Dawley rats. After auto-microthrombotic particulates injection, serum c-troponin I a, von Willebrand factor and ET-level (3hours,24hours,1days,28days) was determined, no-flow area was evaluated by Thioflavin-S (3hours), myocardial leukocyte infiltration (24hours and7days,28days), myocardial expressions of TNFa and IL-6(24hours,1and28days) were measured by Immunohistochemical Analysis and Western Blot Analysis, Arteriole density (AD) was calculated by immunohistochemical analysis. Cardiac function was evaluated by transthoracic echocardiography and hemodynamic measurements
Results:After automicrothrombotic parti cul ate injection, serum c-troponin I and von Willebrand factor levels, the no-flow area as evaluated by Thioflavin S, myocardial leukocyte infiltration levels, myocardial expressions of tumor necrosis factor and interleukin-6, were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the SHAM group. Number of arterioles with diameter between10-50μm, especially for arterioles with diameter between20-50μm was significantly lower in CME group at3hours post injection.
Conclusion:aortic automicrothrombotic particulate injection could induce coronary microembolism in rats, and this model could be of value in improving the understanding of pathophysiology of no-reflow phenomenon mechanism.
Part III Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism
Objective:The objective of this study was to evaluate the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic microembolism (CME).
Methods:CME was induced by injecting0.199ml saline containing5mg automicrothrombotic particulates (around10μm) into the aorta of Sprague-Dawley rats over10seconds using a tuberculin syringe with a28-gauge needle. CME rats were randomized to untreated (CME, n=38) group and diltiazem-treated (CME+DIL, n=38) group. Diltiazem (1mg/ml,50μg/min/Kg) was intravenously injected with an infusion pump through tail vein for175minutes at5minutes after automicrothrombotic particulates injection. Hemodynamic measurements, echocardiographic and pathohistogical examinations were performed at various time points (3hours,24hours,7days and28days) post operation.
Results:Arteriole thrombosis, multi-focal myocardial necrosis, inflammatory cell infiltration with remarkably increased myocardial TNF-a, IL-6expression and reduced LV systolic function as well as increased plasma vWF, ET-1and c-TNI levels (indicating vascular endothelial injury and myocardial necrosis) were evidenced in CME rats. These pathologic responses in CME rats could be partly attenuated by intravenous diltiazem treatment.
Conclusion:This CME model is suitable to evaluate the therapeutic effects of intravenous diltiazem and intravenous diltiazem treatment significantly improves cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat CME model.
引文
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1. Huang Y, Hunyor SN, Jiang L, et al. Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization:functional, energetic, structural, and cellular responses. Am J Physiol Heart Circ Physiol 2004; 286(6): H2141-50.
2. Heusch G, Schulz R, Haude M, et al. Coronary microembolization. J Mol Cell Cardiol 2004; 37(1):23-31.
3. Weber KT, Malinin TI, Dennison BH, et al. Experimental myocardial ischemia and infarction:Production of diffuse myocardial lesions in unanesthetized calves. Am J Cardiol 1972; 29(6):793-802
4. Monroe RG, LaFarge CG, Gamble WJ, et al. Left ventricular performance and coronary flow after coronary cmbolization with plastic microsphercs. J Clin Invest 1971; 50(8):1656-1665.
5. Brown C:Blood collection from the tail of a rat. Lab Anim (NY) 2006,35:24-25
6. Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A,Shaffer-Hartman J, Shayman JA:Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 2003,14:298-302
7. Fujita M, Fujioka Y, Ommura Y:Histopathological diagnosis of early stages of myocardial infarction:applications of the improved hematoxylin basic fuchsin picric acid (HBFP) staining method to human autopsy hearts. Hokkaido Igaku Zasshi 1985, 60:313-320
8. Goldner J:A modification of the Masson trichrome technique for routine laboratory purposes. Am J Pathol 1938,14:237-243
9. Grossman W:Pressure measurement. Cardiac Catheterization, Angiography,and Intervention. Edited by Grossman W, Baim DS,2000,pp.139-141
10. Blann AD:Plasma von Willebrand factor, thrombosis, and the endothelium:the first 30 years. Thromb Haemost 2006,95:49-55
11. With Not(?) AT, Bogeberg Mathiesen E, Amiral J, Vissac AM, Hansen JB: Endothelial dysfunction and systemic inflammation in persons with echolucent carotid plaques. Thromb Haemost 2006,96:53-59
12. Skyschally A, Erbel R, Heusch G. Coronary microembolization. Circ J 2003; 67(4):279-286.
13. Frink RJ, Rooney PA, Trowbridge JO, et al. Coronary thrombosis and platelet/fibrin microembolic in death associated with acute myocardial infarction.Br Heart J 1988; 59(2):196-200.
14. Dorge H, Neumann T, Behrends M, etal. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation. Am J Physiol Heart Circ Physiol 2000; 279(6):H2587-92.
15.沈成兴,梁春,陈良龙等。经冠状动脉内注射月桂酸钠构建大鼠冠状动脉微栓塞模型。中国动脉硬化杂志2005；13(4)：447-450
16. Ruggeri ZM:Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003,1:1335-1342
17. Davis MR, Fitzpatrick CM, Dixon PM, Kashyap VS:Thrombus-induced endothelial dysfunction:hemoglobin and fibrin decrease nitric oxide bioactivity without altering eNOS. J Surg Res 2004,122:121-129
1. Reffelmann T, Kloner RA. The "no-reflow" phenomenon:basic science and clinical correlates. Heart,2002,87:162-168.
2. Heusch G, Kleinbongard P, Bose D, Levkau B, Haude M, et al. Coronary microembolization:from bedside to bench and back to bedside. Circulation.2009; 120:1822-1836.
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6. Pasceri V, Patti G, Di Sciascio G. Prevention of myocardial damage during coronary intervention. Cardiovasc Hematol Disord Drug Targets.2006; 6:77-83.
7. Valero SJ, Moreno R, Reyes RM, Recalde AS, Galeote G, et al.Pharmacological approach of no-reflow phenomenon related with percutaneous coronary interventions. Cardiovasc Hematol Agents Med Chem.2008; 6:125-129.
8. Kleinbongard P, Konorza T, Bose D, et al.Lessons from human coronary aspirate. J Mol Cell Cardiol.2012; 52:890-896.
9. Giampaolo Niccoli, Francesco Burzotta, Leonarda Galiuto, et al. Myocardial No-Reflow in Humans. J. Am. Coll. Cardiol.2009;54;281-292.
10. Erbel R, Heusch G. Brief review:coronary microembolization. J Am Coll Cardiol 2000; 36:22-4.
11. Genda S, Miura T, Miki T, Ichikawa Y, Shimamoto K:K(ATP) Channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia.J Am Coll Cardiol 2002, 40:1339-1346
12.骆景光,陈韵岱,吕媛等。硫磺素S染色对实验性无复流的诊断价值。药物研究。2010；19(15)：11-12。
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16. Deten A, Volz HC, Briest W, Zimmer HG:Cardiac cytokine expression is upregulated in the acute phase after myocardial infarction:experimental studies in rats Cardiovasc Res 2002,55:329-340
17. Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG,Smith CW, Michael LH, Entman ML:Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions.Circulation 1999,99:546-551
18. Skyschally A, Schulz R, Haude M, Erbel R, Heusch G:Coronary microembolization: perfusion-contraction mismatch secondary to myocardial inflammation. Herz 2004, 29:777-781
19. Do"rge H, Neumann T, Behrends M, Skyschally A, Schulz R, Kasper C,Erbel R, Heusch G:Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol HeartCirc Physiol 2000,279:H2587-H592
20. Do"rge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I, Frede S, Hartung T, Vinten-Johansen J, Youker KA, Entman ML,Erbel R, Heusch G: Coronary microembolization:the role of TNFalpha in contractile dysfunction. J Mol Cell Cardiol 2002,34:51-62
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1. Huang Y, Hunyor SN, Jiang L, et al. Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization:functional, energetic, structural, and cellular responses. Am J Physiol Heart Circ Physiol 2004; 286(6): H2141-50.
2. Heusch G, Schulz R, Haude M, et al. Coronary microembolization. J Mol Cell Cardiol 2004; 37(1):23-31.
3. Weber KT, Malinin TI, Dennison BH, et al. Experimental myocardial ischemia and infarction:Production of diffuse myocardial lesions in unanesthetized calves. Am J Cardiol 1972; 29(6):793-802
4. Monroe RG, LaFarge CG, Gamble WJ, et al. Left ventricular performance and coronary flow after coronary cmbolization with plastic microsphercs. J Clin Invest 1971; 50(8):1656-1665.
5. Brown C:Blood collection from the tail of a rat. Lab Anim (NY) 2006,35:24-25
6. Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A,Shaffer-Hartman J, Shayman JA:Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 2003,14:298-302
7. Fujita M, Fujioka Y, Ommura Y:Histopathological diagnosis of early stages of myocardial infarction:applications of the improved hematoxylin basic fuchsin picric acid (HBFP) staining method to human autopsy hearts. Hokkaido Igaku Zasshi 1985, 60:313-320
8. Goldner J:A modification of the Masson trichrome technique for routine laboratory purposes. Am J Pathol 1938,14:237-243
9. Grossman W:Pressure measurement. Cardiac Catheterization, Angiography,and Intervention. Edited by Grossman W, Baim DS,2000,pp.139-141
10. Blann AD:Plasma von Willebrand factor, thrombosis, and the endothelium:the first 30 years. Thromb Haemost 2006,95:49-55
11. With Not(?) AT, Bogeberg Mathiesen E, Amiral J, Vissac AM, Hansen JB: Endothelial dysfunction and systemic inflammation in persons with echolucent carotid plaques. Thromb Haemost 2006,96:53-59
12. Skyschally A, Erbel R, Heusch G. Coronary microembolization. Circ J 2003; 67(4):279-286.
13. Frink RJ, Rooney PA, Trowbridge JO, et al. Coronary thrombosis and platelet/fibrin microembolic in death associated with acute myocardial infarction.Br Heart J 1988; 59(2):196-200.
14. Dorge H, Neumann T, Behrends M, etal. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation. Am J Physiol Heart Circ Physiol 2000; 279(6):H2587-92.
15.沈成兴,梁春,陈良龙等。经冠状动脉内注射月桂酸钠构建大鼠冠状动脉微栓塞模型。中国动脉硬化杂志2005；13(4)：447-450
16. Ruggeri ZM:Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003,1:1335-1342
17. Davis MR, Fitzpatrick CM, Dixon PM, Kashyap VS:Thrombus-induced endothelial dysfunction:hemoglobin and fibrin decrease nitric oxide bioactivity without altering eNOS. J Surg Res 2004,122:121-129
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