斑块侵蚀在急性冠状动脉综合征中的作用及机制研究进展

急性冠状动脉综合征是世界范围内发病率和死亡率较高的一组临床综合征。目前,越来越多的证据表明,带有完整纤维帽的斑块侵蚀是导致急性冠状动脉综合征的主要原因之一。基础实验已经揭示了斑块侵蚀的独特分子特征,已有研究表明,血流紊乱会引起内皮细胞损伤,从而导致基底膜丧失其完整性以及内皮细胞脱落,继而形成中性粒细胞胞外陷阱和血栓,导致斑块侵蚀。文章将讨论动脉粥样硬化斑块侵蚀的分子特征以及对斑块侵蚀患者未来精准医疗所需的转化研究。     

细胞水平胰岛素抵抗导致动脉粥样硬化斑块进展的研究

近期提出细胞水平胰岛素抵抗包括内皮细胞、平滑肌细胞和巨噬细胞,即粥样硬化斑块病变内细胞自身存在胰岛素信号通路的缺陷导致细胞生物学性能的改变,在动脉粥样硬化斑块进展中起关键作用.如斑块内细胞自身胰岛素抵抗可降低内皮细胞的舒张功能、平滑肌细胞的增殖、迁移并增加巨噬细胞凋亡和吞噬缺陷,导致粥样硬化斑块坏死核心的扩大.因此,深入了解细胞水平胰岛素抵抗参与动脉粥样硬化疾病发生、发展的机制为未来研发新型药物开辟新方向.     

炎症反应在易损斑块中的作用及其机制研究进展

炎症反应在易损斑块的形成和进展中发挥重要作用,同时调控血管局部病变及全身炎症状态。一些促炎性细胞和炎症因子使斑块纤维帽的抗张强度降低,坏死脂质内核增大,血管机械稳定性丧失和斑块破裂;另一方面,炎症反应的激活和代谢紊乱也会引起内皮功能不全、斑块侵蚀进而导致血栓形成。该过程主要由巨噬细胞和淋巴细胞等多种炎症细胞参与,并受到多种因素调控,包括胆固醇结晶和脂质递质、血管剪切力、血管新生及斑块内出血等。此外,机体还存在一些抑炎性分子,能避免易损斑块向破裂或侵蚀进展。促炎和抗炎反应的平衡影响急性冠状动脉事件的发生。因此,以炎症反应为靶点,筛选出有易损斑块的患者并干预,或可减少急性冠状动脉事件的发生和改善预后,具有重要临床价值。     

动脉粥样硬化病变组织中PAI—1和uPA抗原表达的变化

目的了解动脉粥样硬化（ＡＳ）病变组织中Ｉ型组织型纤溶酶原激活剂抑制物（ＰＡＩ－１）与尿激酶型纤溶酶原激活剂（ｕＰＡ）抗原表达的变化。方法采用免疫组织化学染色检测了８例ＡＳ病变动脉，并以３例非血管性疾病死亡的新鲜尸检动脉为对照。结果对照动脉中，ＰＡＩ－１在内皮细胞和中膜平滑肌细胞表达；ＡＳ病变中，ＰＡＩ－１在病变表面的内皮细胞中表达增强，粥样斑块中的泡沫细胞呈阳性，病灶的细胞外基质中有广泛的ＰＡＩ－１分布，陈旧性病灶形成的肉芽组织中的毛细血管壁ＰＡＩ－１呈阳性反应。对照动脉内皮细胞中ｕＰＡ呈弱表达；ＡＳ病变中，纤维斑块病变的结缔组织帽下可见数层泡沫细胞ｕＰＡ表达呈强阳性，粥样斑块中新生毛细血管壁呈阳性，新生毛细血管周围有散在的阳性反应细胞。结论ＡＳ病变血管组织中，ＰＡＩ－１和ｕＰＡ抗原的分布和表达强度不一致，可能与它们参与ＡＳ过程的作用机理有关。     

单核细胞与高密度脂蛋白胆固醇比值与缺血性心脑血管病预后研究进展

2017年全球疾病负担数据显示,脑卒中和缺血性心脏病是我国人口减寿年数(years of life lost)以及全年龄伤残调整生命年(disability-adjusted life-years)增加的前两大原因[1]。血管病变是缺血性心脑血管病发病机制的主要特征。血管内皮细胞在危险因素作用下发生损伤,导致血小板激活,炎性反应诱发,引发血管病理性重构,继而动脉粥样斑块形成、破裂和侵蚀,以及血栓形成、血管痉挛和血管栓塞,导致缺血性心脑血管病发生。     

不要低估血管平滑肌细胞在动脉粥样硬化斑块形成中的作用

血管内皮细胞、平滑肌细胞(SMC)和巨噬细胞共同参与动脉粥样硬化(As)斑块形成。近年研究表明,SMC来源的细胞占As斑块中细胞总数的70%以上。As斑块中的SMC通过自分泌细胞因子促进自身的增殖、迁移和炎症反应,通过旁分泌激活单核/巨噬细胞并将其募集到As损伤部位,同时通过其细胞膜表面表达的脂蛋白受体摄取脂质形成泡沫细胞。SMC在As斑块形成中扮演十分重要的角色,应进一步深化对SMC在As发生发展中的作用及作用机制的研究。     

细胞调亡与动脉粥样硬化

平滑肌细胞、内皮细胞和巨噬细胞与动脉粥样硬化的发生发展密切相关。在动脉粥样硬化斑块中，巨噬细胞、平滑肌细胞与内皮细胞都经历着凋亡与坏死，调亡占主导地位，参与了粥样硬化的形成过程。氧自由基、某些生长因子、一氧化氮、内毒素以及氧化型低密度脂蛋白等可诱导细胞调亡。细胞调亡具有复杂的分子调控机制，多种基因参与了凋亡的发生。     

细胞调亡与动脉粥样硬化

平滑肌细胞、内皮细胞和巨噬细胞与动脉粥样硬化的发生发展密切相关。在动脉粥样硬化斑块中，巨噬细胞、平滑肌细胞与内皮细胞都经历着凋亡与坏死，凋亡占主导地位，参与了粥样硬化的形成过程。氧自由基基、某些生长因子、一氧化氮、内毒素以及氧化型低密度脂蛋白等可诱导细胞凋亡。细胞凋亡具有复杂的分子调探机制，多种基因参与了凋亡的发生。     

动脉粥样硬化与易损斑块

动脉血栓栓塞性疾病的共同病理基础是动脉粥样硬化，血栓的形成基本上都是动脉粥样斑块破裂的结果。动脉粥样硬化的发展与内皮细胞功能损伤直接相关，在动脉粥样硬化的整个病变过程中，直到最后形成动脉粥样硬化斑块，均伴随着内皮细胞的损伤。按照动脉粥样硬化发展的病理过程一般分为脂质条纹、粥样斑块和纤维斑块期（图1）。     

肥大细胞在动脉粥样硬化斑块形成和破裂中的意义

肥大细胞,作为炎症细胞参与了人类动脉粥样硬化病变的早期和后期机制。体外研究表明,活化的即有免疫学活性的肥大细胞既可以水解低密度脂蛋白3使胆固醇在细胞内积累,又可以水解高密度脂蛋白使细胞内胆固醇流出减少,从而促进巨噬细胞和平滑肌细胞转成泡沫细胞;它能够激活基质金属蛋白酶、降解细胞外基质,还能抑制平滑肌细胞增生、诱导平滑肌细胞凋亡、抑制胶原合成和促进新血管形成而使斑块倾向破裂。以上这些作用使它在斑块形成和斑块破裂中起着重要作用。     

Myeloperoxidase may help to differentiate coronary plaque erosion from plaque rupture in patients with acute coronary syndromes

Coronary thrombosis is the most frequent final event leading to an acute coronary syndrome. In approximately two-thirds of cases, the thrombus overlies a ruptured plaque, whereas in one-third of cases it overlies an intact plaque with superficial endothelial erosion, a finding showed initially by histopathological postmortem studies and more recently confirmed by in vivo optical coherence tomography imaging. Interestingly, recent observations suggest that mechanisms leading to plaque rupture or erosion are different. In fact, in a recent study, we showed that myeloperoxidase levels in peripheral blood and expression within thrombi overlying the culprit plaque are much higher in patients with plaque erosion than in those with plaque rupture. These observations suggest that innate immunity activation is likely to play a key role, in particular, in plaque erosion and might become a therapeutic target in this subset of patients.     

Thrombosis formation on atherosclerotic lesions and plaque rupture

Atherosclerosis is a silent chronic vascular pathology that is the cause of the majority of cardiovascular ischaemic events. The evolution of vascular disease involves a combination of endothelial dysfunction, extensive lipid deposition in the intima, exacerbated innate and adaptive immune responses, proliferation of vascular smooth muscle cells and remodelling of the extracellular matrix, resulting in the formation of an atherosclerotic plaque. High‐risk plaques have a large acellular lipid‐rich necrotic core with an overlying thin fibrous cap infiltrated by inflammatory cells and diffuse calcification. The formation of new fragile and leaky vessels that invade the expanding intima contributes to enlarge the necrotic core increasing the vulnerability of the plaque. In addition, biomechanical, haemodynamic and physical factors contribute to plaque destabilization. Upon erosion or rupture, these high‐risk lipid‐rich vulnerable plaques expose vascular structures or necrotic core components to the circulation, which causes the activation of tissue factor and the subsequent formation of a fibrin monolayer (coagulation cascade) and, concomitantly, the recruitment of circulating platelets and inflammatory cells. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors eventually leads to platelet activation, aggregation and the subsequent formation of a superimposed thrombus (i.e. atherothrombosis) which may compromise the arterial lumen leading to the presentation of acute ischaemic syndromes. In this review, we will describe the progression of the atherosclerotic lesion along with the main morphological characteristics that predispose to plaque rupture, and discuss the multifaceted mechanisms that drive platelet activation and subsequent thrombus formation. Finally, we will consider the current scientific challenges and future research directions.     

Proteolysis of the pericellular matrix: a novel element determining cell survival and death in the pathogenesis of plaque erosion and rupture

The 2 major general concepts about the cell biology of atherogenesis, growth of smooth muscle cells, and lipid accumulation in macrophages, ie, foam cell formation, have not been able to satisfactorily explain the genesis of acute coronary syndromes. Rather, the basic pathology behind the acute atherothrombotic events relates to erosion and rupture of unstable coronary plaques. At the cellular level, we now understand that a switch from cellular growth to cellular death, notably apoptosis, could be involved in turning at least some types of atherosclerotic plaques unstable. Because intimal cells require a proper matrix environment for normal function and survival, the vulnerability of an atherosclerotic plaque may critically depend on the integrity of the pericellular matrix of the plaque cells. In vitro studies have revealed that plaque-infiltrating inflammatory cells, such as macrophages, T-lymphocytes, and mast cells, by secreting a variety of proteases capable of degrading pericellular matrix components, induce death of endothelial cells and smooth muscle cells, and so provide a mechanistic explanation for inflammation-dependent plaque erosion and rupture. Thus, a novel link between inflammation and acute coronary syndromes is emerging. For a more explicit understanding of the role of proteases released by inflammatory cells in the conversion of a clinically silent plaque into a dangerous and potentially killing plaque, animal models of plaque erosion and rupture need to be established.     

Inflammation and atherosclerosis

Atherosclerosis is a vascular pathology in which inflammation plays a major role at every stage of the disease. The inflammatory process develops in response to abnormal cholesterol deposits in the intima of large arteries. The inflammatory reaction is initiated by a phase of endothelial activation induced by cytokines, oxidized low density lipoprotein (LDL) and/or changes in endothelial shear stress. This leads to the primary expression of endothelial adhesion molecules and chemokines followed by the recruitment and activation of circulating monocytes and lymphocytes. The clinical manifestations of atherosclerosis, including acute coronary syndromes, are the consequences of atherosclerotic plaque rupture/erosion that triggers thrombus formation leading to the occlusion of the vessel lumen. The local inflammatory process at the level of the atherosclerotic plaque might influence the stability of the plaque through its potential effects on the extracellular matrix, and on the plaque thrombogenicity. In humans, systemic inflammation has been recognized as a major risk factor of occurrence of acute coronary syndromes.     

内皮祖细胞与动脉粥样硬化蚀损斑块合并血栓形成

动脉粥样硬化易损斑块是急性冠脉综合征和心脏缺血性猝死的重要病理基础。蚀损斑块是易损斑块的重要病理类型之一,其主要特点:斑块表面大面积内皮细胞脱落和血栓形成。目前有关蚀损斑块合并血栓形成机制的研究罕见。近年的研究认为,内皮祖细胞参与血管内皮损伤后的修复。因此,内皮祖细胞可能参与蚀损斑块合并血栓形成,或对其有治疗作用,此方面研究国内外未见,值得探讨。     

内皮祖细胞在动脉粥样硬化易损斑块中的作用

目的 动脉粥样硬化易损斑块是急性冠状动脉综合征和心脏缺血性猝死的重要病理基础.研究证实易损斑块表面大面积内皮细胞受损和血栓形成,内皮受损后可引起炎症因子瀑布样反应、单核细胞浸润和血管平滑肌细胞增生,进而促发动脉粥样硬化易损班块形成,故修复受损血管内皮、促使血管重新内皮化已经成为防止动脉粥样硬化的重要课题.近年研究认为,...     

Effects of Abciximab as adjunctive therapy in primary percutaneous coronary intervention patients (results from the DANAMI‐2 trial)

Atherosclerosis is a progressive process with potentially devastating consequences and has been identified as the leading cause of morbidity and mortality, especially in the industrial countries. The underlying mechanisms include endothelial dysfunction, lipid accumulation and enhanced inflammatory involvement resulting in plaque disruption or plaque erosion and subsequent thrombosis. However, it has been made evident, that the majority of rupture prone plaques that produce acute coronary syndromes are not severely stenotic. Conversely, lipid‐rich plaques with thin fibrous cap, heavily infiltrated by inflammatory cells have been shown to predispose to rupture and thrombosis, independently of the degree of stenosis. Therefore, given the importance of plaque composition, a continuously growing interest in the development and improvement of diagnostic modalities will promptly and most importantly, accurately detect and characterize the high‐risk atheromatous plaque. Use of these techniques may help risk stratification and allow the selection of the most appropriate therapeutic approach.     

Inflammation and plaque vulnerability

Atherosclerosis is a maladaptive, nonresolving chronic inflammatory disease that occurs at sites of blood flow disturbance. The disease usually remains silent until a breakdown of integrity at the arterial surface triggers the formation of a thrombus. By occluding the lumen, the thrombus or emboli detaching from it elicits ischaemic symptoms that may be life‐threatening. Two types of surface damage can cause atherothrombosis: plaque rupture and endothelial erosion. Plaque rupture is thought to be caused by loss of mechanical stability, often due to reduced tensile strength of the collagen cap surrounding the plaque. Therefore, plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap. Endothelial erosion, on the other hand, may occur after injurious insults to the endothelium instigated by metabolic disturbance or immune insults. This review discusses the molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis.     

内皮祖细胞在动脉粥样硬化过程中所起作用的研究进展

动脉粥样硬化性疾病的发病率和病死率很高。以往的观点认为,内皮损伤引发炎症反应,导致动脉粥样硬化性病变。如今对于动脉粥样硬化的研究已经不局限于血管壁受损,它与内皮祖细胞的改变也存在很大的相关性。现就影响内皮祖细胞的危险因素,到内皮祖细胞减少及功能障碍的机制,再到斑块的形成,最后到临床症状的出现,综述了内皮祖细胞在动脉粥样硬化形成、发展过程中所起的作用。