糖化清蛋白、高敏C反应蛋白与冠心病临界病变患者冠脉斑块形态学特征的关系及对功能性心肌缺血的预测研究

摘要 目的：分析糖化清蛋白、高敏C反应蛋白与冠心病临界病变患者冠脉斑块形态学特征的关系及对功能性心肌缺血的预测价值。方法：选择自2020年1月至2022年6月我院经冠脉造影确诊的165例冠心病临界病变患者作为研究对象,分为不稳定型心绞痛组和稳定型心绞痛组。检测两组血清糖化清蛋白、高敏C反应蛋白表达水平,使用靶血管造影检测冠脉斑块形态学指标,Pearson相关性分析血清糖化清蛋白、高敏C反应蛋白与冠脉斑块形态学指标的关系,通过ROC曲线下面积（AUC）评价血清糖化清蛋白联合高敏C反应蛋白对功能性心肌缺血的预测价值。结果：不稳定型心绞痛组血清糖化清蛋白、高敏C反应蛋白表达水平均高于稳定型心绞痛组（P＜0.05）;不稳定型心绞痛组最小管腔直径、最小管腔面积均小于稳定型心绞痛组,直径狭窄率、管腔面积狭窄率、斑块面积均大于稳定型心绞痛组（P＜0.05）;在165例冠心病临界病变患者中,发生冠脉易损斑块53例;易损斑块组血清糖化清蛋白、高敏C反应蛋白表达水平均高于非易损斑块组（P＜0.05）;经Pearson相关性分析,冠心病临界病变患者血清糖化清蛋白、高敏C反应蛋白表达水平均与最小管腔直径、最小管腔面积呈负相关,与直径狭窄率、管腔面积狭窄率、斑块面积呈正相关（P＜0.05）;经ROC曲线分析,血清糖化清蛋白联合高敏C反应蛋白预测冠心病临界病变患者发生功能性心肌缺血的AUC为0.910。结论：糖化清蛋白、高敏C反应蛋白与冠心病临界病变患者冠脉斑块形态学特征密切相关,有助于评估冠脉斑块易损性,联合预测功能性心肌缺血的效能较好,值得临床予以重视应用。     

rs25754G/A多态性与颈动脉斑块稳定性的关系

为了探讨一种具有玉型血小板反应蛋白的去整合素和金属蛋白酶12 (ADAMTS-12)基因rs25754G/A单核苷酸多态性(SNPs)与颈动脉斑块稳定性的关系,本研究选择78例颈动脉易损斑块患者和101例颈动脉稳定斑块患者作为本次实验的受试对象,应用荧光标记-限制性内切酶酶切法对ADAMTS-12基因rs25754G/A位点进行SNPs基因型检测,运用SPSS16.0统计学软件进行等位基因和基因型频数分布的分析。研究结果显示,颈动脉易损斑块组ADAMTS-12基因rs25754G/A多态位点G+AA基因型和A等位基因频率(98.72%和87.82%)明显高于颈动脉稳定斑块组(90.10%和62.38%)(p0.05)。本研究初步结论表明,ADAMTS-12基因rs25754G/A多态位点与颈动脉易损斑块的发生有相关性。     

急性脑梗死患者颈动脉斑块内新生血管超声造影评价及其与血脂指标和超敏C反应蛋白水平的关系研究

目的:探讨急性脑梗死患者颈动脉斑块内新生血管超声造影评价及其与血脂指标和超敏C反应蛋白水平的关系。方法:选取2018年6月到2019年6月期间我院收治的ACI患者186例,根据患者的颈动脉内中膜厚度(IMT)数值以及颈动脉斑块内新生血管超声造影情况将其分为无斑块组、稳定斑块组和易损斑块组。对比各组患者的总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、美国国立卫生研究院卒中量表(NIHSS)评分、改良的Rankin评分(m RS)、超敏C反应蛋白(hs-CRP)水平。结果:易损斑块组和稳定斑块组患者的TC、LDL-C、TG、hs-CRP水平均明显高于无斑块组(P<0.05),易损斑块组患者的LDL-C、hs-CRP水平均明显高于稳定斑块组(P<0.05),易损斑块组和稳定斑块组患者的NIHSS评分和m RS评分均明显高于无斑块组(P<0.05),易损斑块组患者的NIHSS评分和m RS评分均明显高于稳定斑块组(P<0.05),经Pearson分析显示,LDL-C、hs-CRP、NIHSS评分和m RS评分与斑块分级均呈正相关(P<0.05)。结论:颈动脉斑块内新生血管超声造影技术可有效评估ACI患者的斑块稳定性,ACI患者的斑块分级与脂代谢紊乱、机体的炎症反应以及患者病情严重程度和预后均存在一定的相关性。     

hs-CRP、D-二聚体和Lp-PLA2与冠心病患者冠状动脉粥样硬化易损斑块的相关性

目的:研究超敏C反应蛋白(hs-CRP)、D-二聚体和脂蛋白相关磷脂酶A2(Lp-PLA2)与冠心病患者冠状动脉粥样硬化易损斑块的相关性。方法:选择2014年1月~2016年12月在我院进行冠状动脉造影和血管内超声检查的患者106例,按照检查结果分为易损斑块组、稳定斑块组和对照组。检测和比较三组患者的血清hs-CRP、D-二聚体和Lp-PLA2水平,并采用Pearson相关分析探讨其与纤维帽厚度、斑块偏心指数和血管重构指数的相关性。结果:易损斑块组和稳定斑块组的血清hs-CRP、D-二聚体和Lp-PLA2水平明显高于对照组(P0.05),且易损斑块组的血清hs-CRP、D-二聚体和Lp-PLA2水平明显高于稳定斑块组(P0.05)。hs-CRP与纤维帽厚度呈负相关(r=-0.712,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.813,0.756,P0.05);D-二聚体与纤维帽厚度呈负相关(r=-0.654,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.912,0.853,P0.05);Lp-PLA2与纤维帽厚度呈负相关(r=-0.796,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.836,0.729,P0.05)。结论:hs-CRP、D-二聚体和Lp-PLA2与冠心病患者冠状动脉粥样硬化易损斑块具有较高的相关性,可作为评估冠状动脉粥样斑块不稳定性的参考指标。     

老年急性脑梗死患者外周血EMMPRIN表达与颈动脉易损斑块的相关性

目的:分析老年急性脑梗死(acute cerebral infarction,ACI)患者外周血血小板表面细胞外基质金属蛋白酶诱导因子(EMMPRIN)表达与颈动脉易损斑块的相关性。方法:收集2017年3月至2019年3月于我院收治的老年ACI患者作为研究对象,按照超声下颈动脉斑块的分类标准,将颈动脉斑块呈高回声受检者纳入稳定斑块组(n=41),斑块呈低回声或等回声的受检者则纳入易损斑块组(n=52)。应用logisitc回归模型,分析ACI患者颈动脉易损斑块的影响因素;采用Pearson相关分析,研究外周血单个核细胞EMMPRIN与各临床指标的相关性;采用受试者工作特征(ROC)曲线评价EMMPRIN诊断颈动脉易损斑块的准确性。结果:易损斑块组高脂血症、高血压病、2型糖尿病比例以及FPG、IL-6、IL-1β、MMP-9、MCP-1、TNF-α、LDL、EMMPRIN水平均高于稳定斑块组,组间差异显著(P0.05);易损斑块组HDL水平均低于稳定斑块组,组间差异显著(P0.05)。person相关分析结果显示,EMMPRIN与IL-6、IL-1β、MMP-9、TNF-α均呈正相关(r=0.348,0.374,0.418,0.427,P0.05)。logistic多因素回归分析显示,结果显示,高血压病、2型糖尿病、IL-1β、MMP-9、EMMPRIN均为颈动脉易损斑块的危险因素。EMMPRIN的AUC优于MMP-9、IL-1β(P=0.016,0.039,均P0.05)。结论:外周血血小板表面EMMPRIN水平可能与老年ACI患者颈动脉斑块稳定性有关,可作为辅助临床诊断颈动脉易损斑块的预警指标,对于ACI的发生、发展均具有重要的临床意义。     

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。     

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.     

不稳定动脉粥样硬化斑块的研究进展

不稳定斑块破裂及继发血栓形成是导致急性心血管事件发生的主要病理基础。不稳定斑块的形成与炎症反应、细胞凋亡等有密切联系,新近研究表明,组织蛋白酶-S、生长相关基因蛋白-α和内质网应激在动脉粥样硬化斑块趋向不稳定的过程中发挥至关重要的作用。本文就相关研究进展进行综述,为深入了解不稳定斑块的形成机制提供依据。     

脑梗死患者内脂素和基质金属蛋白酶-9 与颈动脉粥样硬化 斑块易损性的关系

目的：探讨血清内脂素（Visfatin）及基质金属蛋白酶-9（MMP-9）水平与脑梗死患者颈动脉粥样硬化斑块稳定性的关系和血 清visfatin 和MMP-9 的相关性。方法：选择脑梗死患者70 例,根据颈动脉粥样硬化斑块性质分为易损性斑块组(n=43)和非易损 性斑块组(n=27),选取健康体检者30 例作为对照组。测定血清Visfatin 和MMP-9 水平,并对二者间关系进行相关分析。结果：脑 梗死伴颈动脉硬化组血清Visfatin、MMP-9 水平高于正常对照组(P＜0.01);易损性斑块组血清Visfatin 和MMP-9 水平高于非易 损性斑块组,差异有统计学意义（P＜0.017）。外周血中的Visfatin水平与MMP-9 呈正相关关系（r=0.643,P=0.000）。结论：在脑梗 死患者中,血清Visfatin和MMP-9 参与了颈动脉粥样硬化的病理生理过程,Visfatin 和MMP-9升高可能与颈动脉粥样硬化斑块 不稳定性的形成相关,Visfatin 可通过调控MMP-9 的分泌和活性从而改变斑块的易损性。     

应用多普勒检测糖尿病患者颈动脉粥样硬化斑块并分析其与hs-CRP、HCY的关系

目的:探讨糖尿病患者血C反应蛋白(hs-CRP)、同型半胱氨酸(HCY)蛋白与颈动脉粥样硬化的关系.方法:收集58例糖尿病患者和42例体检正常者血浆,测定血hs-CRP、HCY蛋白水平,应用多普勒超声诊断仪检测颈动脉内膜、中层厚度(MT),观察颈动脉粥样斑块,并分析hs-CRP、HCY蛋白水平与颈动脉粥样硬化的关系.结果:糖尿病患者血hs-CRP、HCY含量、颈动脉MT和粥样斑块数较对照组明显增加(P<0.05);血hs-CRP、HCY水平与颈动脉MT及斑块数分别呈正相关(P<0.01).结论:hs-CRP、HCY可能在促进糖尿病及动脉粥样硬化的发生和发展中发挥了重要作用.可作为判断糖尿病患者病情程度和预后的评价指标.     

Emerging approaches for imaging vulnerable plaques in patients

The diagnosis of vulnerable plaques, which have the propensity to develop atherothrombosis, remains an elusive goal in clinical medicine. The most accepted features of vulnerable plaques, such as a large lipid core, increased inflammatory milieu and thin fibrous caps, have been well characterized through pathological studies. The ability to image a vulnerable plaque in susceptible patients would theoretically result in useful prognostic information that can be used to either monitor or treat patients at risk more aggressively. Several invasive techniques, such as integrated backscatter, virtual histology, palpography, optical coherence tomography and thermal heterogeneity, have been validated ex vivo and are now being evaluated in clinical studies. Non-invasive techniques, such as nuclear imaging, show promise in identifying increased metabolic activity and characteristic features of vulnerable plaques in patients. Natural history and intervention studies will need to be performed to determine whether identifying and treating vulnerable plaques will lead to improved clinical outcomes.     

Ligation of macrophage Fcγ receptors recapitulates the gene expression pattern of vulnerable human carotid plaques

Stroke is a leading cause of death in the United States. As ～60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (FcγR, higher in vulnerable) and FcγR signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C-reactive protein, or TNF-α, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of FcγR recapitulates the pattern of gene expression in vulnerable plaques suggests that the FcγR → macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated.     

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。     

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.     

Macrophage autophagy regulates mitochondria‐mediated apoptosis and inhibits necrotic core formation in vulnerable plaques

The vulnerable plaque is a key distinguishing feature of atherosclerotic lesions that can cause acute atherothrombotic vascular disease. This study was designed to explore the effect of autophagy on mitochondria‐mediated macrophage apoptosis and vulnerable plaques. Here, we generated the mouse model of vulnerable carotid plaque in ApoE^?/? mice. Application of ApoE^?/? mice with rapamycin (an autophagy inducer) inhibited necrotic core formation in vulnerable plaques by decreasing macrophage apoptosis. However, 3‐methyladenine (an autophagy inhibitor) promoted plaque vulnerability through deteriorating these indexes. To further explore the mechanism of autophagy on macrophage apoptosis, we used macrophage apoptosis model in vitro and found that 7‐ketocholesterol (7‐KC, one of the primary oxysterols in oxLDL) caused macrophage apoptosis with concomitant impairment of mitochondria, characterized by the impairment of mitochondrial ultrastructure, cytochrome c release, mitochondrial potential dissipation, mitochondrial fragmentation, excessive ROS generation and both caspase‐9 and caspase‐3 activation. Interestingly, such mitochondrial apoptotic responses were ameliorated by autophagy activator, but exacerbated by autophagy inhibitor. Finally, we found that MAPK‐NF‐κB signalling pathway was involved in autophagy modulation of 7‐KC–induced macrophage apoptosis. So, we provide strong evidence for the potential therapeutic benefit of macrophage autophagy in regulating mitochondria‐mediated apoptosis and inhibiting necrotic core formation in vulnerable plaques.     

FTO and obesity: the missing link

The field of vascular molecular imaging is searching for the "holy grail" of an imaging technique that will quantitatively and reliably assess vulnerable coronary plaques. Fluorescence imaging with indocyanine green specifically identifies lipid-rich plaques in rabbits and in humans and represents a promising, though invasive, approach.     

Atherosclerotic Plaque Destabilization in Mice: A Comparative Study

Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.     

Identification of High-Risk Plaques by MRI and Fluorescence Imaging in a Rabbit Model of Atherothrombosis

IntroductionThe detection of atherosclerotic plaques at risk for disruption will be greatly enhanced by molecular probes that target vessel wall biomarkers. Here, we test if fluorescently-labeled Activatable Cell Penetrating Peptides (ACPPs) could differentiate stable plaques from vulnerable plaques that disrupt, forming a luminal thrombus. Additionally, we test the efficacy of a combined ACPP and MRI technique for identifying plaques at high risk of rupture.ConclusionsOur targeted fluorescence ACPP probes distinguished disrupted plaques from stable plaques with high sensitivity and specificity. The combination of anatomic, MRI-derived predictors for disruption and ACPP uptake can further improve the power for identification of high-risk plaques and suggests future development of ACPPs with molecular MRI as a readout.     

Non-invasive characterization of coronary artery atherosclerotic plaque using dual energy CT: Explanation in ex-vivo samples

PurposeIn this study non-calcified plaque composition is evaluated by Dual Energy CT (DECT). Energy Dispersive X-ray Spectroscopy (EDS) has been used to study the Plaque composition. An attempt has been made to explain the DECT results with EDS analysis.MethodsThirty-two ex-vivo human cadaver coronary artery samples were scanned by DECT and data was evaluated to calculate their effective atomic number and electron density (Z_eff & ρ_e) by inversion method. Result of DECT was compared with pathology to assess their differentiating capability. The EDS study was used to explain DECT outcome.ResultsDECT study was able to differentiate vulnerable plaque from stable with 87% accuracy (area under the curve (AUC):0.85 [95% confidence interval {CI}:0.73–0.98}] and Kappa Coefficient (KC):0.75 with respect to pathology. EDS revealed significant compositional difference in vulnerable and stable plaque at p < .05. The weight percentage of higher atomic number elements like F, Na, Mg, S, Si, P, Cl, K and Ca was found to be slightly more in vulnerable plaques as compared to a stable plaque. EDS also revealed a significantly increased weight percentage of nitrogen in stable plaques.ConclusionsThe EDS results were able to explain the outcomes of DECT study. This study conclusively explains the physics of DECT as a tool to assess the nature of non-calcified plaques as vulnerable and stable. The method proposed in this study allows for differentiation between vulnerable and stable plaque using DECT.     

Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation

Background

Vascularization is an exciting and complex mechanism involving angiogenesis and arteriogenesis. The metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are associated with multiple metabolic toxicities, which result in reactive oxygen species (ROS) due to an elevated tension of oxidative-redox stress and an accelerated atherosclerosis termed atheroscleropathy.

Results

This atheroscleropathy is associated with accelerated angiogenesis within the vulnerable, thin-cap fibro-atheroma, prone to rupture resulting in acute coronary syndromes (ACS). The resulting intimopathy with its neovascularization due to angiogenesis of the adventitial vasa vasorum (Vv) is prone to intraplaque hemorrhage (IPH). These IPH are associated with destabilization of the vulnerable plaques resulting in plaque erosion and plaque rupture resulting in ACS. In atheroscleropathy the adventitial Vv invades the plaque in a malignant-like fashion and concurrently is associated with chronic inflammation, as macrophages are being deposited within the shoulder regions of these vulnerable plaques. These angiogenic Vv provide a custom delivery vascular network for multiple detrimental substrates, which further accelerates the growth of these vulnerable plaques and atheroscleropathy. There exists a vascularization paradox in MS and T2DM, in that, angiogenesis within the plaque is induced and arteriogenesis is impaired.

Conclusion

This review will attempt to provide a database of knowledge regarding the vascularization process (angiogenesis and arteriogenesis) and its mechanisms to better understand the increased cardiovascular risk and the increased morbidity and mortality associated with MS and T2DM.