Biomechanical structural stresses of atherosclerotic plaques

Atherosclerotic plaques may rupture without warning, causing fatal clinical events such as myocardial infarction and stroke. Degree of stenosis, which is the current criterion for assessment of atherosclerotic disease severity, has been observed to have poor correlation with plaque vulnerability. Under physiological conditions, plaque undertakes mechanical loadings due to blood pressure and flow. From the material view point, rupture possibly occurs when the extra loading exceeds the material strength of the plaque. Therefore, morphological and mechanical features should be considered in an integrated way for a more accurate assessment of plaque vulnerability and for identification of the at-risk patient. Biomechanical stress analysis is a technique that allows such comprehensive assessment. This article focuses on the mechanical stresses in the plaque structure, which are believed to be of greater magnitude than the associated wall shear stress and are thought to be more closely associated with plaque rupture. We discuss the basic mechanics that govern plaque behavior, the material properties of atherosclerotic tissues and the studies investigating the association between high biomechanical stresses and plaque rupture. Parameter studies investigating the effect of morphologic factors on the critical biomechanical stresses and limitations of current simulation models are also reviewed.     

Biomechanical structural stresses of atherosclerotic plaques

Atherosclerotic plaques may rupture without warning, causing fatal clinical events such as myocardial infarction and stroke. Degree of stenosis, which is the current criterion for assessment of atherosclerotic disease severity, has been observed to have poor correlation with plaque vulnerability. Under physiological conditions, plaque undertakes mechanical loadings due to blood pressure and flow. From the material view point, rupture possibly occurs when the extra loading exceeds the material strength of the plaque. Therefore, morphological and mechanical features should be considered in an integrated way for a more accurate assessment of plaque vulnerability and for identification of the at-risk patient. Biomechanical stress analysis is a technique that allows such comprehensive assessment. This article focuses on the mechanical stresses in the plaque structure, which are believed to be of greater magnitude than the associated wall shear stress and are thought to be more closely associated with plaque rupture. We discuss the basic mechanics that govern plaque behavior, the material properties of atherosclerotic tissues and the studies investigating the association between high biomechanical stresses and plaque rupture. Parameter studies investigating the effect of morphologic factors on the critical biomechanical stresses and limitations of current simulation models are also reviewed.     

Tissue factor in human coronary atherosclerotic plaques

The rupture or fissuring of a coronary atherosclerotic plaque and subsequent thrombosis is considered the key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque disruption frequently occurs during the evolution of atherosclerosis, only a minority of ruptured plaques develop thrombosis. The content and procoagulant activity of tissue factor in human coronary atherosclerotic plaques varies widely, and different studies confirm that it is higher in the plaques extracted from patients with unstable angina, myocardial infarction or histologic/angiographic evidence of coronary thrombosis than in those taken from patients with stable angina or uncomplicated coronary lesions. Variations in tissue factor content and activity may be responsible for the different thrombotic responses to human coronary atherosclerotic plaque rupture.     

Age-associated changes in human carotid atherosclerotic plaques

Little is known about changes in carotid plaque morphology during aging and the possible impact on cardiovascular events. Only few studies addressed so far age-related modifications within atherosclerotic lesions. Therefore, in this work we endeavored to summarize the current knowledge about changing of plaque composition in elderly. The data from hitherto existing studies confirm that atherosclerotic plaques undergo distinct alternations with advanced age. However, the results are often ambiguous and the changes do not seem to be as disastrous as expected. Interestingly, none of the studies could definitely evidence increased plaque vulnerability with advanced age. Nevertheless, based on the previous work showing decrease in elastin fibers, fibroatheroma, SMCs, overall cellularity and increase in the area of lipid core, hemorrhage, and calcification, the plaque morphology appears to transform toward unstable plaques. Otherwise, even if inflammatory cells often accumulate in plaques of younger patients, their amount is reduced in the older age and so far no clear association has been observed between thin fibrous cap and aging. Thus, the accurate contribution of age-related changes in plaque morphology to cardiovascular events has yet to be elucidated.

• KEY MESSAGES

• Composition of carotid atherosclerotic lesions changes during aging. These alternations are however, just moderate and depend upon additional variables, such as life style, accompanying disease, genetics, and other factors that have yet to be determined.

• Based on the current data, the age-associated plaque morphology seems to transform toward vulnerable plaques. However, the changes do not seem to be as disastrous as expected.

     

冠状动脉斑块超声影像学特征与血浆内皮素及一氧化氮的相关研究

目的探讨冠心病患者冠状动脉斑块超声影像学特征及其与血浆内皮素(ET)、一氧化氮(NO)的关系。方法44例冠心病患者分为不稳定型和稳定型心绞痛组,比较两组患者靶血管内超声特征及血浆ET和NO水平,进行相关研究。结果不稳定型心绞痛组血管内超声检出脂质斑块23例(23/28,82.1%),其罪犯病变的血管外弹力膜面积(EEMA)、斑块面积(PA)及管腔面积狭窄率(LAS)、重构指数(RI)明显大于稳定型心绞痛组,差异有显著性意义(均P<0.05)。两组间在纤维帽厚度、脂核或无回声带大小、脂核与斑块比之间存在统计学差异。血浆ET1与EEMA、RI呈正相关,NO与EEMA、RI呈负相关。结论易损斑块为偏心分布的低回声脂质斑块,具有较大的斑块面积和明显的正性重构;血浆ET1、NO参与了粥样硬化的形成,ET1、NO可望作为冠脉斑块易损性预测的参考指标。     

不稳定斑块血管内超声特征的实验研究

目的　明确不稳定斑块的血管内超声 (IVUS)影像学特点。方法　 2 7只雄性新西兰纯种兔随机分成A组 (17只 )与B组 (10只 ) ,A组用球囊损伤腹主动脉 高脂喂养 10周 ,B组仅给予高脂喂养 10周。于 8周末将A组在腹主动脉斑块形成处转染携带人野生型 p5 3基因的重组腺病毒载体 ,于 10周末 ,两组实验兔分别给予中国斑点蝰蛇毒和组胺药物触发斑块破裂。应用IVUS分别测量、比较斑块破裂前的腹主动脉同一血管段中多个病变部位及其参考部位的IVUS指标 ,明确不稳定斑块的IVUS影像学特点。结果　破裂与未破裂斑块的参考部位的血管外弹力膜面积 (EEMA)、管腔面积、斑块面积及管腔面积狭窄率相比 ,差异无显著性意义 (P >0 .0 5 )。与未破裂斑块相比较 ,破裂斑块具有较大的偏心性 (P <0 .0 0 1) ,EEMA、斑块面积及管腔面积狭窄率明显大于前者 ,差异有显著性意义 (均P <0 .0 0 1)。破裂斑块呈现明显的正性重构 ,而稳定斑块主要表现为负性重构。结论　IVUS应用于已建立的动脉粥样硬化不稳定斑块动物模型上 ,能够准确地识别动脉粥样硬化不稳定斑块 ,本研究为临床早期发现不稳定斑块并预测斑块破裂奠定了实验基础。     

Serum albumin and biomolecular oxidative damage of human atherosclerotic plaques

Objectives

To investigate the association of serum albumin (SA) with oxidative damage of human atherosclerotic plaques and the severity of atherosclerosis.

Design and methods

Correlation of the levels of SA with those of lipid and protein oxidation of endarterectomy-removed carotid atherosclerotic plaques; SA and plaque oxidative biomarkers comparison between 2 groups of patients with different severity of atherosclerotic carotid stenosis, i.e. < 90% (group I) or ≥ 90% (group II).

Results

SA was strongly inversely correlated with plaque oxidative damage; SA was lower and plaque oxidative damage higher in group II than group I.

Conclusions

Lowered SA is associated with oxidative damage of atherosclerotic plaques and the severity of atherosclerosis.     

Identification of vulnerable atherosclerotic plaques

There has been great interest in the possibility of identifying plaques that might be the site of future acute coronary events. These plaques are termed vulnerable and the majority are lipid-rich with an abundance of inflammatory cells and a thin fibrous cap. Several techniques developed to identify these plaques are in various stages of development and in the near future, one might employ a strategy to potentially identify and therapeutically modify such lesions during percutaneous intervention to avoid future acute events. Although this approach of identifying the vulnerable plaque seems promising, there are significant potential limitations. The natural history of a vulnerable plaque is unknown and clinical trials utilizing this strategy of identification and therapeutic intervention are lacking. Moreover, in any given patient, multiple vulnerable plaques are likely to be present. This article reviews some of the techniques for identifying a vulnerable plaque and discusses the potential advantages and limitations of this strategy.     

Gamma imaging of atherosclerotic plaques

Noninvasive gamma imaging of atherosclerotic plaques targets various metabolic aspects of atherogenesis. Vascular endothelial dysfunction or denudation resulting in the expression of adhesion molecules that attract inflammatory cells and increased vascular permeability has also been targeted. Enzymes and molecules associated with apoptosis of these inflammatory cells have provided additional targets, such as oxidized low-density lipoprotein, matrix metalloproteinases, and phosphatidylserine. In late atherosclerotic lesions, the lipid core as well as proliferating smooth muscle cells have been imaged successfully. Platelets and fibrin deposition may also be targeted to demonstrate thrombosis in plaque rupture or erosion. However, no unimodal approach can diagnose plaque vulnerability. It will require multi-modal, multitasking approaches for molecular diagnostic prediction of plaque vulnerability and impending rupture. Existing experimental and clinical gamma imaging applications in atherosclerotic lesion imaging are reviewed. Improvement by signal amplification to image small lesion and the concept of multimodal applications are introduced.     

Identification of vulnerable atherosclerotic plaques

There has been great interest in the possibility of identifying plaques that might be the site of future acute coronary events. These plaques are termed vulnerable and the majority are lipid-rich with an abundance of inflammatory cells and a thin fibrous cap. Several techniques developed to identify these plaques are in various stages of development and in the near future, one might employ a strategy to potentially identify and therapeutically modify such lesions during percutaneous intervention to avoid future acute events. Although this approach of identifying the vulnerable plaque seems promising, there are significant potential limitations. The natural history of a vulnerable plaque is unknown and clinical trials utilizing this strategy of identification and therapeutic intervention are lacking. Moreover, in any given patient, multiple vulnerable plaques are likely to be present. This article reviews some of the techniques for identifying a vulnerable plaque and discusses the potential advantages and limitations of this strategy.     

Ultrasound imaging of atherosclerotic plaques

The development of techniques for imaging the molecular mediators of atherosclerosis is an area of great interest. The ability to image vascular phenotype will create new opportunities for assessing patient risk for aggressive disease at a very early stage and for choosing appropriate treatment strategies in late stages of disease. Ultrasound will undoubtedly play an important role in molecular imaging because of its practicality as a screening test and because intravascular imaging approaches are already widely used as an adjunct to angiographic procedures. This review focuses on the biophysical principles for the diverse set of tools used to evaluate atherosclerosis. General strategies for imaging vascular phenotype include: 1) assessment of histomorphometry by radiofrequency analysis of high-frequency ultrasound; 2) assessment of plaque content by vascular elastic properties; 3) detection of remodeling of the vasa vasorum by contrast ultrasound; and 4) imaging endothelial molecular phenotype with targeted ultrasound contrast agents.     

冠状动脉斑块超声影像学特征与超敏C反应蛋白的相关研究

目的探讨冠心病患者冠状动脉斑块超声影像学特征与血清超敏C反应蛋白的关系。方法将46例冠心病患者分为不稳定型组和稳定型心绞痛组，对两组患者靶血管内超声特征与血清超敏C反应蛋白进行相关研究。结果不稳定型心绞痛组血管内超声检出脂质斑块25例（25／30，83．3％），其病变血管的外弹力膜面积（EEMA）、斑块面积（PA）、管腔面积狭窄率（LAS）及重构指数（Pa）明显大于稳定型心绞痛组，差异有显著性意义（均P〈0．05）。两组间在纤维帽厚度、脂核或无回声带大小、脂核与斑块比之间存在统计学差异。血清超敏C反应蛋白与EEMA、Pd呈正相关。结论易损斑块为偏心分布的低回声脂质斑块，具有较大的斑块面积和明显的正性重构；血清超敏C反应蛋白参与了粥样硬化的形成，血清超敏C反应蛋白可望作为冠脉斑块易损性预测的参考指标。     

The potential of RF backscattered IVUS data and multidetector-row computed tomography images for tissue characterization of human coronary atherosclerotic plaques

The aim is to compare virtual histology which uses spectral analysis of backscattered intravascular ultrasound (VH–IVUS) and multidetector-row computed tomography (MDCT) for the characterization of coronary atherosclerotic plaques obtained by directional coronary atherectomy (DCA). We performed DCA in 15 de novo native coronary stenotic lesions (15 patients) and selected one or two segments within the plaque from each patient (total 29 segments). Then, we evaluated the accuracy of the VH–IVUS findings in 50 sites among the 29 segments compared with the histopathology findings. MDCT was performed in all patients before percutanous coronary intervention (PCI), and CT density values were measured. VH–IVUS data analysis correlated well with histopathological examination (predictive accuracy: 66.7% for fibrous, 100% for fibro-fatty, 100% for necrotic core, and 100% for dense calcium regions, respectively). In addition, CT density values between fibrous and fibro-fatty plaques classified by histopathology were 100.0 ± 26.0 HU versus 110.4 ± 67.9 HU, there were no difference among them (P = 0.594). These findings indicated that the validation of plaque characteristics using VH–IVUS correlates well with histopathology. While tissue characterization using CT density could be difficult to distinguish between fibro-fatty and fibrous tissue.     

Identification and quantification of Chlamydia pneumoniae in human atherosclerotic plaques by LightCycler real-time-PCR

A real-time PCR assay for Chlamydia pneumoniae in human atherosclerotic plaques by the use of novel probes and FRET LightCycler technology, is described. The assay proved particularly suitable for the specific and quantitative detection of a low DNA copy number in conventional PCR-negative samples. Among fifteen nested-PCR negative atherosclerotic plaques examined, our method detected three positive plaques containing 50(+/-3), 37(+/-2) and 24(+/-2) DNA copy number+/-SD in three independent experiments. Real-time PCR holds promise for C. pneumoniae quantitation in human atherosclerotic plaques.     

High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.     

Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques.

Oxidized LDL is present in human atherosclerotic lesions, but the mechanisms responsible for oxidation in vivo have not been definitively demonstrated. Circumstantial evidence has implicated the enzyme 15-lipoxygenase as a contributor to the formation of oxidized lipids in this disease. To assess whether oxidized lipids are indeed formed by the action of 15-lipoxygenase on polyunsaturated fatty acids (PUFAs) in vivo, we have used a sensitive and specific method (chiral phase HPLC) to analyze the lipid oxidation products present in human atherosclerotic lesions. Human 15-lipoxygenase is an omega-6 lipoxygenase that has previously been shown to oxidize esterified PUFA in a stereospecific manner, forming predominantly cholesteryl hydroperoxy-octadecadienoate (13(S)-HPODE) from cholesteryl linoleate substrate in LDL. This property allows its activity to be distinguished from nonenzymatic oxidation, which results in the formation of equal quantities of the S and R stereoisomers of the same oxidation product. A total of 80 specimens of human atherosclerotic plaque were analyzed. Esterified, oxidized linoleate was purified from human atherosclerotic lesions and from LDL oxidized by copper, and the chirality of these oxidation products was compared. There was significantly greater stereospecificity of oxidation in the oxidized linoleate from human atherosclerotic lesions. Even greater stereospecificity was detected in the HPODE derived from cholesteryl ester, purified from human lesions. Cholesteryl HPODE is the primary oxidation product from cholesteryl linoleate, the major esterified PUFA that accumulates in atherosclerotic vessels. Cholesteryl HPODE and its reduced form, cholesteryl hydroxy-octadecadienoate, were detected in all lesions analyzed. Neither the stereospecificity of oxidation nor the percentage of available substrate oxidized to primary oxidation products was correlated with the stage of disease of the lesions examined. We conclude that 15-lipoxygenase contributes to the formation of oxidized lipids in human atherosclerotic lesions.     

颈动脉粥样硬化斑块CEUS研究进展

CEUS在临床应用日益普及,通过观察造影剂在组织内的灌注过程,实现对病灶的分析,在判断颈动脉粥样硬化斑块的稳定性和评估药物治疗效果方面的应用已较为成熟。目前,CEUS用于颈动脉斑块的靶向显影和治疗方面研究也在逐步开展。本文对CEUS在颈动脉粥样硬化斑块诊疗领域的应用现状及新技术、新进展进行综述。