载脂蛋白E基因敲除小鼠用于动脉粥样硬化研究的进展

载脂蛋白（apolipoprotein,ApoE）基因敲除小鼠是目前研究动脉粥样硬化发生发展机制的最为理想的动物模型之一,尤其是近年来,又成为易损斑块动物模型研究的热点。有关apoE^-I-小鼠动脉粥样硬化斑块病理特点、炎症在斑块破裂中的作用及对其干预治疗等研究,近来又有了许多新的发现。     

新的易损斑块血清标志物妊娠相关蛋白A研究进展

冠状动脉易损斑块破裂或腐蚀继发血栓形成是急性冠脉事件发生的病理基础,寻找易损斑块新血清标记物对于早期识别和干预高危患者至关重要。新近发现妊娠相关蛋白A(PAPP-A)参与动脉粥样硬化的发生发展,并且与斑块的不稳定性关系密切,是冠心病患者不良事件的预测因子。本综述主要介绍妊娠相关蛋白-A的生物学特性及其与心血管疾病以及易损斑块关系的研究进展,为临床诊断和治疗带来新的思路。     

基质金属蛋白酶在动脉粥样硬化易损斑块中的分子影像学研究

大量研究表明,依赖Ca2+、Zn2+等金属离子的基质金属蛋白酶在动脉粥样硬化斑块处的表达与斑块的稳定性密切相关,易损斑块处基质金属蛋白酶表达水平增高.单光子发射体层成像、近红外荧光成像、磁共振成像等分子影像学的方法,能够动态无创地检测动物模型动脉斑块或人颈动脉斑块切除后标本中基质金属蛋白酶的表达水平,不仅可以提示疾病的...     

动脉粥样硬化不稳定斑块的药物治疗进展

动脉粥样硬化(As)不稳定斑块也称易损斑块.不稳定斑块表面溃疡形成、破裂及继发血栓形成,是引起急性心脑血管事件的闹饕±砘?药物治疗对防治不稳定斑块破裂的发生,降低急性心脑血管事件的发病率具有重要意义.治疗不稳定斑块的药物主要有他汀、抗氧化荆等,其主要药理学机制是抗炎、抗氧化、调节细胞因子、抑制MMPs活性等作用.本文对不稳定斑块有治疗作用的药物研究与应用进展做一综述,为急性心脑血管事件的治疗提供理论依据及线索.     

巨噬细胞能量代谢与动脉粥样硬化

巨噬细胞通过细胞表型转换与内环境的变化相适应。M1型巨噬细胞具有促炎作用,而M2型巨噬细胞具有抗炎和促纤维化作用。进展的易损动脉粥样硬化斑块内以M1型巨噬细胞为主。糖酵解是M1型巨噬细胞主要的供能途径,伴随细胞内大量活性氧的生成和炎性细胞因子的分泌。而稳定动脉粥样硬化斑块内以M2型巨噬细胞为主,M2型巨噬细胞以氧化磷酸化为主要供能途径,通过抑制巨噬细胞糖酵解,促进巨噬细胞氧化磷酸化,能够减轻动脉粥样硬化病变。本文综述了与巨噬细胞表型转换相适应的细胞能量代谢变化及其对动脉粥样硬化斑块进展和斑块稳定性的影响及其作用机制。     

小型猪动脉粥样硬化斑块稳定性模型研究

目前已有的动物模型在研究动脉粥样硬化斑块破裂、破裂的可控性及量化研究方面均不能满足研究的需要.为了建立类似于人类动脉粥样硬化病变的斑块模型,体外研究斑块稳定性,应用传统的高脂高胆固醇膳食诱导建立了小型猪动脉粥样硬化模型,并从血脂水平和斑块病理形态学特征方面加以了证实.该模型中斑块与人类成熟斑块的高度相似性使其成为研究斑块稳定性和斑块破裂的较好模型.从量化比较这一出发点着手,建立了一个体外可控可量化诱导斑块破裂模型,方法简单易行,是一个较好的量化研究斑块破裂和破裂相关因素间关系的实验模型.     

冠状动脉易损斑块影像学最新研究进展

冠心病(CAD)是世界上致死率最高的疾病之一,其中,以急性冠状动脉综合征(ACS)病情最为凶险,而近70%的急性冠脉事件并不是由显著地冠状动脉狭窄引起,而是由冠状动脉易损斑块(vulnerable plaque)破裂造成的急性狭窄,以及其后血栓形成所致,因此冠状动脉易损斑块是导致急性冠状动脉综合征的主要元凶,因此需要早期发现易损斑块并积极进行干预。近两年来,CT、MRI、血管内超声(IVUS)和光学相干断层成像(OCT)广泛应用于易损斑块的评估并取得显著进展,而分子影像学能从分子层面揭示易损斑块形成机制以及更加早期识别斑块进行。本文简要总结近两年影像学方法对易损斑块的最新研究进展及热点。     

基因修饰小鼠在脂代谢紊乱与动脉粥样硬化研究中的新进展

近十余年来,载脂蛋白(ApoE)与低密度脂蛋白(LDL)受体 (LDLr)基因敲除小鼠已成为研究脂代谢和动脉粥样硬化最为常用的模型.在这两种小鼠模型基础上,通过与不同的转基因、基因敲除小鼠杂交,产生了多种脂代谢紊乱和动脉粥样硬化小鼠模型,为发现调控血浆脂蛋白以及动脉粥样硬化发生的机制,创造了有利条件.此外,新的严重高甘油三酯血症小鼠模型也制备成功,本文笔者研究组研究了其中的脂蛋白脂酶缺陷模型与代谢性疾病的关系,得到了许多有意义的结果.而利用不同转基因和去基因小鼠作为供体, 以及ApoE或LDL受体缺陷小鼠作为接受体的骨髓移植技术,则大大丰富了人们对于巨噬细胞中不同基因在动脉粥样硬化发生、发展和消退过程中作用的认识.动脉粥样硬化的易损斑块形成是近年来的一个研究热点,应用小鼠模型进行模拟也取得了一定的成功.然而,小鼠与人类在脂代谢和动脉粥样硬化中存在很大的种系差异,本文对此也予以评述.     

动脉粥样硬化斑块钙化机制的研究进展

心血管疾病中动脉粥样硬化斑块的钙化是动脉粥样硬化的临床标志之一,主要发生在动脉血管的内膜.动脉粥样硬化斑块核心的钙化不会增加斑块的易损性,而粥样斑块纤维帽上的微钙化会加强纤维帽的周向应力,致使斑块的易损性增加.动脉粥样硬化斑块的钙化机制包括被动钙化和主动钙化,被动钙化受激素和局部信号的调节,主动钙化机制涉及复杂的细胞生命过程,基质囊泡、细胞凋亡、外泌体、氧化应激反应和细胞自噬等均参与了钙化过程.本文对动脉粥样硬化斑块的钙化机制的进展进行综述.     

S-炔丙基半胱氨酸延缓动脉粥样硬化进展并上调内皮细胞中内皮型一氧化氮合酶磷酸化（英文）

本研究旨在探究炔丙基半胱氨酸(S-propargyl-cysteine, SPRC)对延缓小鼠动脉粥样硬化进展的保护作用。用ApoE-/-小鼠通过右侧颈动脉串联双狭窄(tandem stenosis, TS)联合西方饮食构建动脉粥样硬化易损斑块小鼠模型，测定血管损伤面积、血脂和炎症水平来评估SPRC的抗动脉粥样硬化作用，组织病理学分析以评估斑块稳定性。为探究SPRC的保护机制，体外培养人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs)并用氧化型低密度脂蛋白(oxidized low-density lipoprotein,ox-LDL)刺激，用细胞活力测定试剂盒测定细胞活力，用Western blot和RT-qPCR分别检测磷酸化内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)蛋白和mRNA表达。结果表明，每天80 mg/kg SPRC组小鼠主动脉弓和颈动脉病变面积显著减少，血浆胆固醇和低密度脂蛋白胆固醇水平显著降低，斑块中的胶原水平增加，且斑块中基质金属蛋白9(matri...     

Imaging of coronary atherosclerosis and identification of the vulnerable plaque

Identification of the vulnerable plaque responsible for the occurrence of acute coronary syndromes and acute coronary death is a prerequisite for the stabilisation of this vulnerable plaque. Comprehensive coronary atherosclerosis imaging in clinical practice should involve visualisation of the entire coronary artery tree and characterisation of the plaque, including the three-dimensional morphology of the plaque, encroachment of the plaque on the vessel lumen, the major tissue components of the plaque, remodelling of the vessel and presence of inflammation.Obviously, no single diagnostic modality is available that provides such comprehensive imaging and unfortunately no diagnostic tool is available that unequivocally identifies the vulnerable plaque.The objective of this article is to discuss experience with currently available diagnostic modalities for coronary atherosclerosis imaging. In addition, a number of evolving techniques will be briefly discussed.     

动脉粥样硬化易损斑块的核医学和磁共振分子影像学研究进展

动脉粥样硬化分子影像学通过使用具有敏感性和特异性影像对比的分子探针针对动脉粥样硬化斑块相关的特定分子进行分子成像.该方法会极大地提高对动脉粥样硬化病变特性的检测水平和增强对该病变特征,尤其对斑块的组成成份的识别能力.斑块的组成成份和斑块的破裂、斑块的易损性以及斑块破裂后导致的结果密切相关.因此了解斑块组成成份的在体无创性检测将对动脉粥样硬化病人的治疗和判断预后产生非常重要的临床应用价值.     

IVUS-based computational modeling and planar biaxial artery material properties for human coronary plaque vulnerability assessment

Image-based computational modeling has been introduced for vulnerable atherosclerotic plaques to identify critical mechanical conditions which may be used for better plaque assessment and rupture predictions. In vivo patient-specific coronary plaque models are lagging due to limitations on non-invasive image resolution, flow data, and vessel material properties. A framework is proposed to combine intravascular ultrasound (IVUS) imaging, biaxial mechanical testing and computational modeling with fluid-structure interactions and anisotropic material properties to acquire better and more complete plaque data and make more accurate plaque vulnerability assessment and predictions. Impact of pre-shrink-stretch process, vessel curvature and high blood pressure on stress, strain, flow velocity and flow maximum principal shear stress was investigated.     

Imagerie moléculaire de la plaque d’athérome vulnérable. Évaluation préclinique et clinique de traceurs radioactifs

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for greater than 19.10⁶ deaths annually. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerosis in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could potentially allow the identification of vulnerable patients by non-invasive scintigraphic imaging following administration of a radiolabeled tracer. The development of radiolabeled probes that specifically bind to and allow the in vivo imaging of vulnerable atherosclerotic plaques is therefore the subject of intense ongoing experimental and clinical research. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET imaging. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable atherosclerotic plaques in the carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of the coronary arteries remains a challenging issue because of the small size of atherosclerotic lesions and of their vicinity with blood and the circulating tracer activity.     

Stress analysis of carotid plaque rupture based on in vivo high resolution MRI

Atheromatous carotid plaque rupture is responsible for the majority of ischaemic strokes in the developed world. Plaque rupture has been associated with plaque morphology, plaque components' properties, inflammation and local stress concentration. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in vivo. This study combined the recent advances in finite element analysis (FEA) and MRI, and performed stress analysis of five vulnerable carotid plaques based on the geometry derived from in vivo MRI. Image segmentation was based on multi-spectral MRI and co-registered with histology for plaque characterization. Plaque fibrous cap, lipid pool and vessel wall were modelled as isotropic, incompressible hyperelastic materials undergoing large deformation under pulse pressure loading. High stress concentrations were predicted at the shoulders and the thinnest fibrous cap regions of the plaque, and the mean maximal stresses were found to be higher in the ruptured plaques (683.3 kPa) than those in the unruptured plaques (226.9 kPa). The effect of the relative stiffness of fibrous cap to lipid pool on the stress within the cap itself was studied. It was shown that larger relative stiffness of fibrous cap to lipid pool resulted in higher stress within the cap. Thus, it is likely that high stress concentrations in vulnerable plaque may cause plaque rupture and lead to acute ischaemic sequelae. A combination of in vivo high resolution MRI and FEA could potentially act as a useful tool to assess plaque vulnerability and risk stratify patients with carotid atheroma.     

Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent

Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Plaque burden and progression have been shown to be independent predictors for future cardiac events by intravascular ultrasound. Routine prospective imaging is hampered by the invasive nature of intravascular ultrasound. A noninvasive technique would therefore be more suitable for screening of atherosclerosis in large populations. Here we introduce an elastin-specific magnetic resonance contrast agent (ESMA) for noninvasive quantification of plaque burden in a mouse model of atherosclerosis. The strong signal provided by ESMA allows for imaging with high spatial resolution, resulting in accurate assessment of plaque burden. Additionally, plaque characterization by quantifying intraplaque elastin content using signal intensity measurements is possible. Changes in elastin content and the high abundance of elastin during plaque development, in combination with the imaging properties of ESMA, provide potential for noninvasive assessment of plaque burden by molecular magnetic resonance imaging (MRI).     

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

Atherosclerosis is the main pathophysiological process underlying coronary artery disease (CAD). Acute complications of atherosclerosis, such as myocardial infarction, are caused by the rupture of vulnerable atherosclerotic plaques, which are characterized by thin, highly inflamed, and collagen-poor fibrous caps. Several lines of evidence mechanistically link the heme peroxidase myeloperoxidase (MPO), inflammation as well as acute and chronic manifestations of atherosclerosis. MPO and MPO-derived oxidants have been shown to contribute to the formation of foam cells, endothelial dysfunction and apoptosis, the activation of latent matrix metalloproteinases, and the expression of tissue factor that can promote the development of vulnerable plaque. As such, detection, quantification and imaging of MPO mass and activity have become useful in cardiac risk stratification, both for disease assessment and in the identification of patients at risk of plaque rupture. This review summarizes the current knowledge about the role of MPO in CAD with a focus on its possible roles in plaque rupture and recent advances to quantify and image MPO in plasma and atherosclerotic plaques.     

Higher critical plaque wall stress in patients who died of coronary artery disease compared with those who died of other causes: A 3D FSI study based on ex vivo MRI of coronary plaques

Mechanical forces play an important role in the rupture of vulnerable plaques. This process is often associated with cardiovascular syndromes, such as heart attack and stroke. In this study, magnetic resonance imaging (MRI)-based models were used to investigate the association between plaque wall stress (PWS) and coronary artery disease (CAD).