无复流现象的预防与治疗

急性心肌梗死（AMI）治疗的关键是尽早给予冠状动脉（冠脉）血管重建，包括药物溶栓、经皮冠状动脉腔内成形术（PTCA）、支架及冠状动脉搭桥等，使梗死相关动脉再通，恢复心肌灌注。然而在临床实践中，某些心外膜血管在再灌注治疗期间已解除机械性梗阻，但相应心肌组织并没有完全有效地恢复血流灌注，即无复流现象。Abbo指出无复流作为一种并发症，使住院死亡和MI发生率增加5～10倍。无复流本身虽不是危险区心肌梗死（MI）的最初原因，但无复流是继续缺血、梗死延展、心室重构、心功能恢复障碍及MI急性期高死亡率的预测指标，也是严重心肌和微血管损伤的标记。无复流是评估现代再灌注治疗成功与否的主要指标之一，因此成为近年来研究的焦点。     

冠状动脉无复流机制及评估方法研究进展

冠状动脉无复流现象在急性心肌梗死罪犯血管血运重建发生率较高。其主要病理生理机制包括心肌缺血损伤、心肌再灌注损伤、冠状动脉远端栓塞和微循环损伤等。无复流可加重心肌缺血,引起梗死面积扩大,加快心室重构及心力衰竭的发生,阻滞心脏传导系统,甚至引发心源性猝死。目前无复流的评估方法主要以心脏核磁共振成像、心肌声学造影、TIMI血流分级等为主。     

移植肾缺血-再灌注损伤与炎症和微血管病变

移植肾早期不可避免地存在缺血再灌注损伤(IRI),对移植肾的早期恢复和远期预后均有重要影响.缺血-再灌注除损伤肾小管上皮细胞外,还导致间质炎症和徽血管病变;而后者是IRI引起肾功能障碍的关键.缺血后微血管病变以内皮细胞肿胀和随之而来的微血管闭塞为特征,导致再灌注不能顺利进行(无复流现象).阐明内皮细胞功能障碍机制,为移植肾IRI的治疗提供新思路.     

阿托伐他汀对大鼠急性心肌缺血再灌注无复流现象的影响及其机制

目的探讨阿托伐他汀预处理对大鼠急性心肌缺血再灌注后无复流现象和前炎症因子白介素17(IL-17)表达的影响、相关机制及IL-17在其中的作用。方法健康雄性Wistar大鼠18只,按体质量从大到小排序,然后采用随机数字表法将大鼠分成3组:假手术组、损伤组、预处理组,每组6只。预处理组给予阿托伐他汀2mg·kg~(-1)·d~(-1),另外两组给予等量生理盐水,每天1次,共7 d。损伤组和预处理组予冠状动脉结扎60 min、再灌注15min,建立大鼠急性心肌缺血再灌注模型,假手术组只穿线不结扎。大鼠冠状动脉结扎前,结扎后15、30min和45min、再灌注15min时查心电图。再灌注15min后取血及心脏。形态学方法观察建模后是否存在无复流现象以及他汀类药物对无复流现象的影响。用酶联免疫吸附法(ELISA)测血清IL-17、IL-6水平。结果大鼠急性心肌缺血再灌注后存在无复流现象。与损伤组相比,预处理组无复流面积明显减小[(21.37%±3.35%)比(48.96%±6.94%),P<0.01],血清IL-17[(90.45±11.63)ng/L比(151.67±11.19)ng/L,P<0.05]和IL-6[(112.47±10.40)ng/L比(167.89±5.13)ng/L,P<0.05]显著降低。结论他汀类药物可减少无复流心肌范围,并且可减轻IL-17和炎症因子IL-6的表达,这可能是其减轻炎症、减少大鼠急性心肌缺血再灌注后无复流的机制之一。     

冠心病的微血管损伤研究进展

微血管损伤在冠心病发病机制中起到一定的作用 ,本文从心肌缺血—再灌注期间微血管损伤、微血管性心绞痛心肌血流量的异常分布、减少白细胞数量和组织型纤维蛋白溶酶原激活剂、去铁铵对损伤的微血管中血栓形成的影响、急性心肌梗死后微血管完整性与钠积蓄时间过程和血管紧张素转换酶抑制剂等冠状动脉系统微血管功能与调节和冠心病微血管损伤防治方面进行了最新研究综述     

热休克蛋白A12B对缺血/再灌注损伤心肌微血管内皮完整性的保护作用

目的探讨热休克蛋白A12B(heat shock protein A12B,HSPA12B)对心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤后微血管无复流现象、血管通透性及其微血管内皮结构完整性的影响。方法实验选用同窝、8~10周龄雄性HSPA12B转基因鼠(HSPA12B Transgenic,Tg)和野生型鼠(wild type,WT)。所有小鼠均接受手术,即结扎冠状动脉左前降支诱导心肌缺血(45 min),松开结扎为I/R开始。I/R 30 min后,采用番茄血凝素免疫荧光标记检测心肌微血管血流灌注情况,伊文斯兰染料检测心肌微血管渗透性。I/R 4 h后取小鼠心脏组织,电子显微镜观察心肌微血管内皮细胞超微结构变化。结果 I/R损伤后,与WT鼠相比,Tg鼠心肌无复流面积显著减少,血管通透性明显降低,微血管内皮细胞损伤减少且细胞间连接更加完整。结论高表达HSPA12B显著减轻心肌I/R诱导的心肌微血管内皮细胞结构和功能损伤,从而保护心肌I/R损害,提示HSPA12B可能为治疗心肌I/R损伤的新靶点。     

内皮细胞损伤与心肌无复流现象

内皮系统是一个动态的平衡系统,对于维持局部内环境的稳定十分重要.已经证实内皮细胞结构完整及功能正常对血管壁通透性屏障、免疫防御、抗凝、抗血栓及炎性反应均有重要作用.血管内皮细胞损伤与心肌无复流密切相关,可显著降低急性心肌梗死病人的生存率,防治血管内皮细胞损伤是临床工作的重要难题.研究显示:心肌缺血-再灌注易导致内皮细胞结构及功能损伤,促进无复流的发生发展;相应的临床干预措施在一定程度上可修复损伤内皮细胞,改善心肌无复流.本文主要针对缺血-再灌注时内皮细胞损伤的最新发生机制及临床处理做一综述,以期为防治心肌无复流提供理论依据.     

冠脉无复流现象发生机制的研究进展

冠脉无复流是指血管造影无血管机械性阻塞的证据 ,而冠脉循环所支配的节段心肌灌注不足的一种现象。本文对无复流的概念、分类及可能的机制进行探讨。目前认为冠脉无复流的发生是包括血管内皮损伤、微血管阻塞、白细胞和氧自由基等多因素作用所致     

心肌缺血再灌注损伤进展

缺血-再灌注损伤指的是在组织器官缺血恢复血流后,不仅没使组织器官功能恢复,反而使缺血所致的功能和代谢障碍及结构破坏进一步加重,甚至出现不可逆损伤的现象。研究最多的就是心肌缺血-再灌注损伤。随着溶栓、冠状动脉搭桥术、经皮冠状动脉内成形术等血管再灌注疗法通过恢复缺血组织的供血有效挽救濒死心肌。但是再灌注受缺血组织血管再通时间限制并存在再灌注损伤等问题,因此随着新的再灌注技术在临床广泛应用,防治心肌缺血-再灌注损伤成为冠心病治疗亟待解决的关键问题之一。     

核因子-κB与心肌缺血再灌注后无复流

冠状动脉介入或溶栓治疗后无复流的发生严重影响了急性心肌梗死患者的预后,其分子机制已经成为目前研究的热点.核因子-κB介导参与缺血再灌注损伤、远端血管栓塞/微血栓形成和冠状动脉微循环障碍的个体易患性、细胞凋亡及自噬等可能是无复流发生的机制.     

Donor simvastatin treatment and cardiac allograft ischemia/reperfusion injury

Ischemia/reperfusion injury of a transplanted heart may result in serious early and late adverse effects such as primary graft dysfunction, increased allograft immunogenicity, and initiation of fibroproliferative cascades that compromise the survival of the recipient. Microvascular dysfunction has a central role in ischemia/reperfusion injury through increased vascular permeability, leukocyte adhesion and extravasation, thrombosis, vasoconstriction, and the no-reflow phenomenon. Here we review the involvement of microvascular endothelial cells and their surrounding pericytes in ischemia/reperfusion injury, and the pleiotropic, cholesterol-independent effects of statins on microvascular dysfunction. In addition, we delineate how the rapid vasculoprotective effects of statins could be used to protect cardiac allografts against ischemia/reperfusion injury by administering statins to the organ donor before graft removal and transplantation.     

The effect of ischemia and reperfusion on microvascular function: a human in vivo comparative study with conduit arteries

Although microvascular dysfunction is of critical importance in the pathophysiology of myocardial ischemic syndromes, no study has investigated whether there are differences in the sensitivity to ischemia and reperfusion injury between microvessels and conduit arteries. Ten healthy young nonsmoking male volunteers (age range 24-45) were enrolled. Parameters measured included radial (conduit) artery (endothelium-dependent) flow-mediated dilation, microvascular cutaneous reactive hyperemia (using laser Doppler) and acetylcholine-induced microvascular vasodilation (laser Doppler iontophoresis). Data were acquired before and after ischemic injury (15 minutes of ischemia of the brachial artery followed by 15 minutes reperfusion) and analyzed in a randomized, blinded fashion. Conduit artery FMD was significantly blunted after ischemia (before: 7.5 +/- 1.1%; after: 2.9 +/- 1.0%, P < 0.05). Conversely, ischemia had no effect on microvascular reactive hyperemia (P = ns) and acetylcholine-induced vasodilation (P = ns). Using a human in vivo model, we demonstrate that microvessels are more resistant to ischemic injury as compared to conduit arteries.     

Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion

Although morphological studies suggest that coronary vascular injury is a result of prolonged ischemia and subsequent reperfusion, whether functional coronary microvascular injury develops during brief in vivo ischemia is unclear. In other organs, permeability is a sensitive indicator of functional vascular injury. Therefore, a new double-indicator method of assessing vascular protein permeability, a method that is both sensitive and specific for vascular injury, was used to investigate the effects of ischemia of graded duration followed by reperfusion on coronary microvascular function. To help confirm functional coronary vascular injury, endothelium-dependent vasodilation of isolated coronary vascular rings also was examined. Microvascular permeability was quantitatively assessed as a protein leak index by measuring the rate of extravascular accumulation of radiolabeled protein (indium 113m transferrin) normalized for vascular surface area (technetium 99m erythrocytes). Anesthetized dogs underwent 0 (control), 15, 30, or 60 minutes of left anterior descending coronary artery occlusion followed by 60 minutes of reperfusion. Even 15 minutes of ischemia increased the protein leak index by 50% (3.16 +/- 0.30 ischemic vs. 2.09 +/- 0.11 control). Longer periods of ischemia increased the protein leak index in proportion to the duration of ischemia. The protein leak index increased threefold (6.51 +/- 0.60) after 60 minutes of ischemia. At each duration of ischemia, there was significant regional variation in the protein leak index that correlated with the severity of ischemic blood flow to that region measured with microspheres. Endothelial injury also was evident after 15 and 30 minutes of ischemia as impaired vasodilation of isolated coronary rings in response to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Electron microscopy and in vitro direct immunofluorescence revealed evidence of vascular injury after 60 minutes but not after 15 minutes of ischemia. We conclude that even brief ischemia and reperfusion cause functional coronary vascular injury evident as increased microvascular permeability and impaired endothelium-dependent vasodilation and that regional differences in the degree of microvascular injury correlate with differences in the severity of ischemia.     

Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear.

Tissue injury resulting from ischemia and reperfusion forms the basis of several important disorders including myocardial infarction, stroke, and circulatory shock. To examine the role of neutrophils in this process and to determine the extent to which injury is a consequence of reperfusion, we utilized the monoclonal antibody 60.3, directed to CD18, the human leukocyte adherence glycoprotein, to block intravascular neutrophil aggregation and neutrophil adherence to endothelium in a rabbit model of tissue ischemia and reperfusion. Antibody treatment either before ischemia or after ischemia, but prior to reperfusion, resulted in the same degree of significant protection against endothelial, microvascular, and tissue injury. We conclude that neutrophils and increased neutrophil adhesiveness are important in the development of microvascular and tissue injury after ischemia and reperfusion and that under these circumstances, injury is primarily a consequence of reperfusion.     

Ischemic preconditioning prevents postischemic arteriolar, capillary, and postcapillary venular dysfunction: signaling pathways mediating the adaptive metamorphosis to a protected phenotype in preconditioned endothelium

Prolonged ischemia followed by reperfusion (I/R) results in impaired endothelial cell function in all segments of the microvasculature. Moreover, endothelial dysfunction plays a major role in the genesis of the reperfusion component of total tissue injury in I/R. Thus, preservation of endothelial function is an important therapeutic goal for ameliorating injury in tissues subjected to I/R. An accumulating body of evidence indicates that both microvascular endothelium and parenchymal cells can be rendered resistant to the pathological effects of I/R by antecedent exposure to brief periods of ischemia, a phenomenon referred to as ischemic preconditioning (IPC). Although the mechanisms underlying the microvascular effects of preconditioning have been far less extensively studied, work conducted to date indicates that there are fundamental differences in the signaling pathways that underlie the adaptive transformation to a protected or defensive phenotype in the endothelium compared to those that contribute to the development of a preconditioned state in parenchymal cells. Thus, the purposes of this review are to summarize our current understanding of the mechanisms whereby IPC induces the adaptive transformation to a protected or defensive phenotype in parenchymal cells and to compare and contrast this with the signaling pathways that invoke a preconditioned state in arteriolar, capillary, and venular endothelium. In addition, we highlight understudied areas with regard to microvascular protection afforded by antecedent ischemia in the hopes that this will stimulate investigation of the underlying mechanisms. Understanding these signaling pathways may provide a mechanistic rationale for the development of novel treatment interventions that target both the microcirculatory and parenchymal sequelae to I/R, thereby maximizing the therapeutic potential of the protected phenotypes produced by pharmacological preconditioning.     

Myocardial reperfusion injury

Myocardial reperfusion injury is defined as the adverse effects that ensue upon restoration of the circulation, which allows blood and nutrients to reach cells previously subjected to ischemia. Restoration of blood flow can be accompanied by the release of oxygen free radicals, the appearance of intracellular calcium overload, and alterations in cell metabolism -all situations that can give rise to functional or structural myocardial injury. Clinical signs of injury may appear after circulation is restored or after the use of extracorporeal circulation during heart surgery, and are manifested as stunned or hibernating myocardium after acute coronary syndromes, as the no-reflow phenomenon (microvascular injury) after blood flow is restored during angioplasty or after , and especially after surgical revascularization. This review examines the pathophysiological substrates, clinical manifestations and current approaches to treatment for each of these entities.     

心脏微血管内皮屏障功能和心肌缺血/再灌注损伤：转化医学意义探寻

微血管内皮屏障是氧、养分和代谢产物进行选择性交换的场所,对于维持心肌微环境稳态起核心作用.微血管通透性增加可促进白细胞跨内皮迁移、组织水肿和炎症反应.微血管通透性增加与心肌再灌注损伤程度不仅存在显著的正相关,还有生物学机制上的密切关联.虽然现有的再灌注治疗和公认的辅助治疗措施能够有效降低急性心肌梗死患者的病死率,但该部分患者仍存在再灌注损伤的剩余风险,调节微血管通透性的转化医学研究成果有望进一步改善患者预后.     

急性心肌梗死的治疗进展--从再通到再灌注

对于急性心肌梗死患者冠状动脉的再灌注治疗已得到广泛开展。然而,由于微循环无复流现象的存在,使得梗死相关血管的再通并不完全意味着心肌水平再灌注的实现。几项研究发现,超过 25%的急性心肌梗死患者经成功的溶栓或经皮冠脉介入术后都存在无复流现象,即未达到充分的心肌再灌注。所以,我们应把更多的注意力和研究重点转移到对心肌微循环再灌注的实现,而非冠状动脉的再通。     

Assessment of “microvascular no-reflow phenomenon” using technetium-99m macroaggregated albumin scintigraphy in patients with acute myocardial infarction

Objectives. The aim of this study was the scintigraphic evaluation of clinical no-reflow phenomenon.Background. In patients with acute myocardial infarction, the relationship of the severity of reduction of microvascular reflow to the ischemia time or to the secondary extension of myocardial necrosis is poorly understood, and we accordingly conducted a scintigraphic evaluation of clinical no-reflow phenomenon.Methods. The group studied consisted of 25 consecutive patients with their first acute myocardial infarction. After recanalization, each patient received intracoronary injections of technetium-99m macroaggregated albumin (MAA).Results. Eight patients (32%) had absent tracer uptake (scintigraphic no-reflow phenomenon). Fourteen patients showed absent or moderately reduced MAA uptake (group 1) and 11 showed slightly reduced or normal uptake (group 2). The time to recanalization was significantly longer in group 1 than in group 2 (290.4 ± 130.6 min vs. 177.3 ± 93.5 min; p = 0.0238). In chronic phase, the thallium-201 (Tl-201) defect score index was significantly larger (p < 0.01) and regional ejection fraction was significantly lower (p < 0.01) in group 1 compared with corresponding values in group 2. No significant deterioration from acute phase to chronic phase in either Tl-201 defect score index or regional ejection fraction was found in either group (two-way repeated measures analysis of variance).Conclusions. These findings suggest that scintigraphic no-reflow phenomenon occurs in a subgroup of patients without angiographic no-reflow phenomenon, that the myocardial damage depends on the severity of microvascular damage and that prolonged ischemia time may increase the likelihood of “microvascular no-reflow phenomenon.”     

远隔器官缺血预处理心脏保护作用的研究进展

心肌缺血预处理现象的发现,为心肌缺血再灌注损伤的预防开拓了一个新的研究领域。近年来,随着预处理研究的不断深入,其方法学也有一些新的进展。研究发现,心外组织如肾脏、小肠及骨骼肌短暂缺血不仅能减轻局部组织的再灌注损伤,对远隔的心脏也有保护作用,并将这种现象称为远隔预处理。现就远隔器官缺血预处理对心脏的保护作用及其机制作一简要综述。