心脏移植后冠状动脉血管病变

心脏移植后冠状动脉血管病变是影响受体远期存活的主要因素之一,表现为心外膜下及心肌内冠状动脉弥漫性、同心圆状的纤维性内膜增厚,管腔狭窄,伴有大量炎性细胞浸润。免疫因素和非免疫因素均参与该病变过程。冠状动脉造影和血管内超声是主要检查手段。临床表现与冠状动脉狭窄的范围和程度有关。新型免疫抑制剂、他汀类药物等可以延缓病变进程,但不能从根本上防治血管病变的发生。     

心脏移植后同种异体血管病的预防和治疗的研究

心脏移植后冠状血管病变(cardiac allograftvasculopathy,CAV)是心脏移植术后远期的重要并发症,是限制心脏移植患者术后长期存活率的主要因素之一。它的5年发生率高达20%～40%。主要病理表现是在心脏移植后的早期出现弥漫性血管内膜增厚,与血管炎症相似,随着时间发展,脂质沉积,粥样斑形成、钙化,最后管腔狭窄、闭塞,心肌内小血管较心表大的冠状动脉更早闭塞,发生微小的星状的心肌梗死[1]。CAV的发病机制尚不清楚,研究结果表明,免疫学和非免疫学因素对其发病及病变的程度均有影响。免疫学因素包括:HLA抗原匹配程度、急性及亚急性排斥反应…     

小肠移植中急性抗体介导排斥反应的病理学

目的:观察重度急性抗体介导排斥反应(antibody-mediated rejection,AMR)的病理形态学改变,回顾分析相关文献,为小肠移植急性AMR的诊断总结经验.方法:切除的失功能移植肠经10%中性福尔马林固定,石蜡包埋,4?m切片并行HE染色.详细观察移植物中肠壁各层及肠系膜内组织中主要的病理形态学改变,分级评价急性排斥反应及血管病变,并进行C4d免疫组织化学染色.结果:移植物内各级血管广泛受累,包括肠壁及肠系膜内各级血管.受累血管的改变以肠壁浆膜下层内的小血管及动静脉的滋养血管最为显著,主要表现为小血管壁的纤维素性坏死和/或血管内血栓形成,受累血管周围组织中性粒细胞浸润,红细胞漏出,组织水肿,部分病变血管周围伴有纤维素性坏死.免疫组织化学染色可见病变血管内膜C4d沉积.小肠黏膜固有层内血管显著扩张伴淤血,偶见血栓形成,肠黏膜隐窝上皮细胞正常,未见急性排斥反应.结论:血管壁的纤维素性坏死及血管内血栓形成是重度急性AMR的主要病理学改变.病变可以广泛累及移植物内各级血管;小肠黏膜内血管的病变可能不代表最严重的病变;临床早期确诊AMR的发生不能单纯依赖小肠黏膜活检.     

小鼠心脏移植后穿孔素及颗粒酶B表达水平与急性排斥反应的关系

目的:研究穿孔素和颗粒酶B蛋白在心脏移植后表达水平变化与心脏移植急性排斥反应的关系.方法:采用小鼠腹部心脏移植模型,分为移植排斥组、实验处理组和同系移植组,每组20对.观察移植物存活时间、供心病理改变.采用Western blot法检测受鼠脾脏淋巴细胞穿孔素及颗粒酶B蛋白表达水平,免疫荧光方法观察心脏移植物内穿孔素及颗粒酶B的表达情况.结果:移植排斥组及实验处理组移植物平均存活时间分别为7.8±0.77 d、14.80±1.01d,同系移植组移植物存活均超过28 d,三组差异有显著性.移植排斥组与实验组及同系移植组相比较,移植物内心肌细胞变性坏死严重并有大量炎性细胞浸润.移植术后7 d,移植排斥组与实验处理组和同系移植组相比,受鼠脾脏淋巴细胞穿孔素蛋白表达分别增加3.02倍、4.13倍.颗粒酶B蛋白表达分别增加3.44倍、2.50倍,差异有显著性.与另外两组相比,移植排斥组心脏移植物冠状动脉分支内充填大量穿孔素与颗粒酶B阳性细胞,组织间隙内也有较多双阳性细胞浸润.结论:穿孔素与颗粒酶B蛋白表达增加与急性排斥反应相关,可作为急性排斥反应的早期诊断指标.     

铁离子在小鼠心脏移植急性排斥反应中的作用

目的:探讨铁离子在心脏移植急性排斥反应中的作用。方法:建立小鼠颈部异位心脏移植模型,实验分为同系移植组(C57BL/6→C57BL/6)和同种异体移植组(BALB/c→C57BL/6),普鲁士兰染色观察铁离子在心肌组织的沉积情况,免疫组化法观察血红素加氧酶-1(HO-1)在心肌组织的表达。结果:铁离子在浸润的巨噬细胞中沉积。HO-1主要在浸润的炎性细胞中表达,二者随急性排斥反应的加重表达上调。结论:铁离子参与了心脏移植急性排斥反应的病理过程,铁离子在心肌组织的沉积可作为心脏移植急性排斥反应的监测指标。     

外膜炎症诱发载脂蛋白E基因敲除鼠冠状动脉粥样硬化病灶

研究载脂蛋白E基因敲除(载脂蛋白E°)小鼠冠状动脉内粥样硬化病灶的分布、组成与动脉外膜炎症的关系.取载脂蛋白E°小鼠心脏作连续切片,Movat法染色,追踪冠状动脉主干及其心肌内的小分支;寻找病灶,观察病灶内组成,分析其分布规律.复制小鼠股动脉外膜无菌性炎症模型,用免疫组织化学方法检查内膜粘附分子的表达.结果发现,冠状动脉主干内有延伸病灶,在主干以下分支(包括心肌内小分支)内有在原位生成的病灶,在两类病灶相邻的外膜有炎性细胞浸润,外膜炎症面积大于动脉粥样硬化病灶累及的内膜面积,亦发现一些部位血管外有炎性细胞浸润,而尚无病灶形成.原位病灶均发生于心室壁,大的原位病灶多发生在左室壁心肌内、血管分支处和乳头肌附近的冠状动脉分支内.股动脉外膜炎症可诱发内膜表达细胞间粘附分子1和血管细胞粘附分子1,同时伴白细胞的附壁.以上提示血管外膜炎症是小鼠冠状动脉内病灶的一个始动环节.     

同种移植大鼠心脏Ⅱ类主要组织相容性抗原表达及其机制探讨

目的　探讨同种移植心脏术后Ⅱ类主要组织相容性 (MHC)抗原表达及其影响机制。方法　建立大鼠颈部心脏移植模型 ,以同基因移植和无移植动物作为对照 ,采用免疫组化、逆转录PCR等技术测定异基因大鼠移植心脏Ⅱ类MHC抗原表达和心肌IL 2、IL 4mRNA的水平变化。结果移植心脏Ⅱ类MHC抗原表达与心肌急性免疫排斥病理学改变明显相关 (P <0 0 1 ) ,排斥早期其阳性表达细胞位于小血管内皮及周围 ,随着急性免疫排斥病变发展心肌IL 2、IL 4mRNA水平与Ⅱ类MHC抗原表达存在相关变化 (P <0 0 1 )。结论　移植心脏Ⅱ类MHC抗原表达是术后急性免疫排斥识别和效应时相的重要环节 ,急性免疫排斥早期移植心脏功能改变可能与微血管内皮损伤有关 ,受体细胞因子网络对供体Ⅱ类MHC抗原表达有调节作用     

同种异体骨髓基质细胞心肌移植的研究

目的 :研究大鼠同种异体骨髓基质细胞 (BMSCs)移植到心肌梗死区后能否存活 ,并进一步增殖、分化以及对宿主心脏的影响。方法 :结扎大鼠冠状动脉左前降支制作急性心肌梗死模型。 4周后 ,取传两代的体外培养的同种异体BMSCs ,注射到大鼠心肌梗死区 ,为移植组 ;同时设置注射培养基的对照组。移植 4周后检测受体心脏的血流动力学指标 ,然后取标本 ,检测移植细胞存活、分化和组织的血管新生状况。结果 :移植组大鼠心脏血流动力学指标较对照组明显改善 ;同种异体BMSCs移植入心肌梗死区后能够度过急性炎症期 ,而且不引起明显移植排斥反应 ;位于梗死区的移植细胞主要分化为成纤维细胞 ,部分位于心肌梗死区周围的细胞分化为血管内皮细胞 ,并促进了血管新生 ;移植组心肌梗死区及其周围新生血管数目较对照组明显增加。结论 :同种异体BM SCs移植促进心肌梗死后血管新生、改善心功能 ,是用于心肌移植可供选择的种子细胞。     

雷帕霉素对大鼠移植心脏血管平滑肌细胞表型及内膜增生的影响

目的 探讨雷帕霉素对大鼠移植心脏血管平滑肌细胞表型及内膜增生的影响.方法 建立大鼠腹腔内心脏移植模型.实验分为4组,每组8只,正常心脏组:取未经任何处理的Wistar大鼠心脏作为空白对照;同系移植组:供体、受体均为Wistar大鼠,以标准鼠食喂养.异系移植取Wistar大鼠作供体,SD大鼠作受体,分为以下两组,环孢霉素组:术后给予环孢霉素A 10 mg/(kg·d),皮下注射;雷帕霉素组:术后用雷帕霉素1.25 mg/(kg·d)灌胃.移植60天后取移植心脏进行电镜观察、形态学观察和用免疫组织化学法分析移植心脏冠状血管平滑肌激动蛋白α的表达情况.结果 正常心脏组和同系移植组移植心脏未见明显冠状血管狭窄.环孢霉素组管腔狭窄程度最明显,雷帕霉素组血管狭窄程度最轻.正常心脏组和同系移植组血管内膜、心肌细胞及心肌间质均未见血管平滑肌激动蛋白α表达.心脏移植60天后,环孢霉素组移植心脏血管内膜大量血管平滑肌激动蛋白α表达,心肌细胞亦有血管平滑肌激动蛋白α表达.雷帕霉素组移植心脏血管内膜血管平滑肌激动蛋白α表达较少.很少有血管平滑肌激动蛋白α表达于心肌间质.各组之间移植心脏血管内膜组织中血管平滑肌激动蛋白α表达差异有显著性.正常心脏组及同系移植组电镜下血管平滑肌细胞呈收缩表型,环孢霉素组可见血管平滑肌细胞呈合成表型,雷帕霉素组见大部分血管平滑肌细胞呈收缩表型.结论 雷帕霉素可以抑制大鼠移植心脏血管病变过程中血管平滑肌细胞表型的变化,减轻新生内膜的增生程度.     

大鼠心脏移植后冠状血管病模型的建立

目的 :为研究心脏移植后冠状血管病提供良好的实验模型。　　方法 :Lewis大鼠心脏移植于F344大鼠腹腔 ,取移植心脏行病理学检查 ,半定量方法统计冠状动脉内膜增生程度。　　结果 :存活 4周以上的移植心脏 ,冠状动脉内膜增生明显 ,管腔面积减少 ( 54± 2 1 ) % ,受体自身心脏冠状动脉正常 ,两者比较 ,有显著性差异 (P <0 0 5)。　　结论 :选择合适大鼠种属 ,可复制出移植后冠状血管病模型 ,用于研究移植后冠状血管病的发病机制和预防。     

The role of vitronectin receptor (alphavbeta3) and tissue factor in the pathogenesis of transplant coronary vasculopathy

OBJECTIVES: This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin alphavbeta3. BACKGROUND: The vitronectin receptor (integrin alphavbeta3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury. METHODS: A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n = 35) or with acute rejection (grade >1A, n = 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and alphavbeta3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis. RESULTS: Patients with CV (n = 24) had increased expression of alphavbeta3 (2.7-fold, p = 0.003) and TF (7.9-fold, p = 0.04) compared with patients without evidence of vasculopathy (n = 8). In the absence of myocardial fibrosis, alphavbeta3 expression correlated significantly with the cellular rejection score (r = 0.58, p = 0.02). CONCLUSIONS: Transplant vasculopathy is associated with increased expression of both TF and alphavbeta3. The significant correlation of alphavbeta3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy.     

Obstruction of the proximal right coronary artery with acute inferior infarction due to blunt chest trauma.

Two patients developed an acute transmural myocardial infarction due to severe obstruction of the proximal right coronary artery after blunt chest trauma. Neither had a history of ischemic heart disease, and both had an arteriographically normal left coronary artery. In one patient significant resolution of the subtotal obstruction occurred within 3 months. An intimal tear or subintimal hemorrhage with luminal thrombosis, or both, are the suggested mechanism of coronary arterial occlusion. Spasm and platelet aggregates may contribute. Despite a large number of automobile accidents, obstruction of the right coronary artery due to blunt chest trauma has not been previously described. This suggests it has been overlooked and should be especially suspected in persons with injury to the sternum and an acute inferior myocardial infarction.     

Thrombolytic effects of intracoronary streptokinase on canine coronary artery thrombosis

Summary The thrombolytic and hemodynamic properties of intracoronary streptokinase (SK) application were studied in anin-vivo canine model with left circumflex coronary artery thrombosis, initiated by electrical stimulation (150 A, DC for 6 h) of the artery's intima via an implanted silver wire. In pentobarbitalanesthetized, open-chest dogs acute myocardial ischemia was determined by a dehydrogenase-dependent staining of the coronary artery perfusion area. Thrombus weight was determinedpost-mortem.Saline-treated control animals developed coronary thrombosis after 3.1±0.4 h of stimulation. Thrombus weight was 64±3.1 mg. Acute infarct volume was 32±3.1% of total left ventricle, and 53±6.2% of the coronary artery risk region for infarction. At occlusive thrombosis, blood pressure, ventricular pressure and the LV dP/dt_max fell significantly, whereas heart rate and the end-diastolic filling pressure increased. Severe ST-segment elevation and loss of R wave voltage indicated myocardial ischemia. At 20 min into thrombotic vessel occlusion, 2,000 IU/min SK were infused by way of a Sonescatheter advanced to the thrombus. Coronary thrombosis consistently lysed after 12±0.7 min of SK infusion, and coronary blood flow as well as hemodynamics were restored. Only minor acute infarction was found indicating viability of ischemic jcopardized myocardium. In another group, the continuous SK-infusion (20 IU/kg/min) concomitant with electrical vessel stimulation prevented coronary thrombosis and acute ischemia, and no significant hemodynamic alterations were noted.These results indicate that intracoronary SK-infusion can lyse acute thrombosis as sequel of electrical stimulation. This prevents development of acute myocardial infarction. Continuous SK-infusion can completely prevent coronary thrombosis in response to intimal injury.Professor Dr. Otto Bayer in memoriam     

Plaque rupture possibly induced by coronary spasm--an autopsy case of acute myocardial infarction

The histological picture of sites of coronary spasms has not yet been made sufficiently clear. A histopathological examination was performed on the coronary artery of a patient who died of acute myocardial infarction after a refractory coronary spasm was identified by coronary arteriography. In the site of the coronary spasm, intimal bleeding as well as infiltration by lymphocytes and plasma cells in the adventitia were seen. In the same region, fracture of intimal collagen fibers and rupture of atheromatous plaque were observed. Although it is very difficult to prove in individual cases of acute myocardial infarction that spasms played a part, some cases involving spasms may possibly exist among the cases of acute myocardial infarction showing atheromatous plaque rupture--thrombus formation.     

Immunoexpression of perforin and granzyme B on infiltrating lymphocytes in human renal acute allograft rejection

Graft destruction can be effected by direct cell-to-cell contact between activated effector T cell and a target graft resulting in delivery of cytotoxic molecules. Perforin and granzyme B can be used as activation markers for cytotoxic cells in allograft tissue. The aim of the study was to determine the immunoexpression of perforin and granzyme B by immune cells infiltrating renal tissue during acute allograft rejection and to evaluate any correlation between the phenotype of infiltrating lymphocytes and cells expressing cytotoxic granules as well as the severity of graft damage as defined by Banff 97 criteria. Immunoperoxidase staining was carried out using monoclonal antibodies anti-perforin, -granzyme B, -CD3 and -CD8 on renal allograft biopsy specimens from twenty one patients with acute renal transplant rejection: Banff 97 IA (n = 11) and Banff 97 IB (n = 10). As a control 11 biopsy specimens of renal transplant patient without any signs of rejection were used. All allograft biopsy specimens with acute renal transplant rejection contained a high number of CD3+ T cells (Banff IA: 437.4 +/- 154.4 and Banff IB: 825 +/- 339.9 vs 123.4 +/- 52.5 in controls) and CD8+ T lymphocytes (Banff 97 IA: 177.6 +/- 89.2 and Banff IB: 293.2 +/- 112.4 vs 64.2 +/- 37.1 in controls). Immunostaining for granzyme B and perforin was negative in controls. The immunopositivity for perforin was similar in Banff IA and Banff IB acute allograft rejection (1.5 +/- 0.6 vs 1.8 +/- 0.8, respectively). Granzyme B+ cell count was significantly higher in severe rejection group Banff IB (128.3 +/- 74.3) than in Banff IA group (48.2 +/- 18.3). Moreover, in acute allograft rejection Banff IB the number of granzyme B+ cells and perforin+ cells was correlated with the number of CD8+ T cells. In conclusion, our results suggest that in acute tubulointerstitial allograft rejection activated cytotoxic T lymphocytes play a major role. The strong immunopositivity for granzyme B on infiltrating cells in renal transplant tissue is suggested as a marker of severity of graft damage.     

急性心肌梗死的分子成像研究进展

心血管疾病尤其是冠状动脉粥样硬化性心脏病,在中国乃至世界范围内都是造成死亡的重要原因。冠状动脉粥样硬化的发生、斑块破裂和血栓形成,以及心肌梗死后心肌损伤和修复过程受到诸多复杂的细胞和分子信号网络的调控。当前临床使用的影像学手段可评估冠状动脉及心脏的解剖、灌注等,但无法准确体现病变的病理生理过程和病变的进展。近年来,分子成像技术使心血管疾病病理过程可视化和定量化成为可能,因而,对心血管疾病的精准诊断和预后判断具有重要的临床价值。文章综述了目前急性心肌梗死的分子成像研究最新进展。     

Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy

PURPOSE OF REVIEW: As the frequency of cellular rejection after heart transplantation is decreasing, biopsy-negative episodes of rejection are being recognized more often. This article reviews the features of humoral rejection, which we believe is responsible for most episodes of biopsy-negative rejection. Hemodynamic compromise, in the absence of acute cellular rejection, called biopsy-negative rejection occurs in 10 to 20% of cardiac allograft recipients. These episodes of rejection are often more severe, and more difficult to treat, than classical acute cellular rejection. Histologic, immunofluorescence, and immunoperoxidase studies of endomyocardial biopsies from such patients often reveal intravascular macrophages, and immunoglobulin and complement deposition in capillaries, in the absence of lymphoid infiltrates, suggesting an antibody-mediated or humoral form of rejection. RECENT FINDINGS: Humoral rejection is associated with increased graft loss, accelerated transplant coronary artery disease, and increased mortality. Severely ill patients require intense therapy, which includes high-dose corticosteroids, cytolytic agents, intravenous heparin, intravenous gamma globulin, plasmapheresis, and/or antiproliferative agents. SUMMARY: Currently, our knowledge of the pathogenesis, diagnostic criteria, and optimal therapy for biopsy-negative rejection is incomplete, and evolving.     

结节性多动脉炎合并心肌梗死8例临床分析

目的总结结节性多动脉炎累及冠状动脉导致心肌梗死患者的临床表现及冠状动脉受累特点。方法对北京协和医院有病案记录的结节性多动脉炎合并心肌梗死的8例患者的临床症状、系统受累、实验室检查、冠状动脉及其他血管造影、超声心动图和病理检查等进行回顾性分析。结果 8例患者中男性5例,女性3例,年龄21～52岁,平均(37.6±11.7)岁。胸痛6例,心力衰竭1例。心电图缺血性ST-T改变5例,除窦性心动过速、房性期前收缩外,未见其他恶性心律失常。左心室射血分数降低(≤50%)3例,节段性室壁运动异常6例,室壁瘤形成2例,心肌病变2例,肺高压1例。4例有冠状动脉影像学检查资料,均累及右冠状动脉,3例为三支病变,1例为两支病变,其造影结果描述为冠状动脉弥漫性病变、冠状动脉扩张、多发动脉瘤以及节段性狭窄、闭塞。这些患者均有其他多部位血管受累的表现和动脉造影检查的异常。结论结节性多动脉炎可累及冠状动脉导致心肌梗死,其冠状动脉受累常为多支病变、多有右冠状动脉受累,动脉瘤伴血栓形成和节段性狭窄。对冠心病低危心肌梗死的患者,需要完善血管检查,警惕结节性多动脉炎累及冠状动脉的情况。     

Assessment of medications in patients with tako-tsubo cardiomyopathy

In heart transplant recipients, the aetiology of coronary vasospasm is largely unknown but it has been reported to be related to coronary vasculopathy or allograft rejection. We report a case of acute, reversible coronary vasospasm which caused malignant arrhythmias in a cardiac transplant recipient one month after transplantation without evidence of coronary vasculopathy or allograft rejection. The patient had a normal post-operative course with no other complications; this case supports the hypothesis that coronary vasospasm is not necessarily related to epicardial coronary artery disease or allograft rejection, but rather may be due to an abnormal reversible vasoreactivity.     

Thrombosis of epicardial coronary veins in acute myocardial infarction.

Thrombosis of epicardial coronary veins was demonstrated in 16 of 50 cases of left ventricular acute myocardial infarction and/or recent coronary arterial thrombosis. All patients with valvular heart disease had venous thrombosis. In cases without valvular heart disease, venous thrombosis was seen in infarctions involving more than 30% of the left ventricular myocardial mass with a post-attack survival time of at least 24 hours. The veins thrombosed were in all cases those draining the infarcted myocardium. Coronary vein thrombosis seems not to be prevented by anticoagulant medication.