Adventitial inflammation: a possible pathogenic link to the instability of atherosclerotic plaque

A variety of cells, including fibroblasts, mast cells, macrophages, and ganglionic cells, are present in coronary artery adventitia. In the infarct-related coronary arteries of myocardial infarction patients, the majority of mast cells are found in the outer layer of the adventitia. Neurogenic stimulation of mast cells in the adventitia of coronary arteries may release vasoactive compounds, such as histamine and leukotrienes, which can contribute to the complex neurohormonal response that leads to abnormal coronary vasoconstriction. Lymphocytes and bacteria are also present mainly in the adventitial layer. Chlamydia pneumoniae is directly involved in the development of adventitial and plaque inflammation (pan-arteritis), leading to plaque rupture. Adventitial O(2)(-) may also play an extensive role in the control of vascular tone. Therefore, adventitial inflammation may play a pivotal role for atherosclerotic lesion development and atheroma instability.     

Inflammation: a possible pathogenic link to atrial fibrillation

Atrial fibrillation (AF) is the most common sustained dysrhythmia in clinical practice. Despite the extensive studies, the pathophysiological mechanisms in AF, however, remain unclear. More recently, the data has been suggested that inflammatory process has been associated with development of AF. The evidence for the hypotheses included that: (1) Histological studies have demonstrated inflammatory infiltrates in AF patients and in animal models of AF; (2) inflammatory markers are increased in AF patients and is associated with successful cardioversion. And also, Inflammatory markers are not only associated with the presence of AF but also independently predicted increased risk for the development of future AF; (3) treatment with anti-inflammatory agents is associated with a decreased recurrence of AF. Although the studies suggest the existence of an association between inflammation and AF, many aspects remain elusive and require further investigation. Specifically, whether inflammation is an initiator or a perpetuator of AF; the effects of anti-inflammatory drugs on atrial remodeling and their exact role in the recurrence and perpetuation of AF. Inflammation may provide a potential target for pharmacological interruption of AF and may favorably affect atrial remodeling leading to important clinical benefits.     

Inflammation: a possible pathogenic link to cardiac syndrome X

Cardiac syndrome X is defined as a typical angina pectoris, positive treadmill exercise test, negative intravenous ergonovine test and normal coronary angiography. The pathogenesis of cardiac syndrome X has previously ascribed to myocardial ischemia that may be caused by microvascular dysfunction and increased sensitivity to intracardiac pain. Despite the extensive studies, the pathophysiological mechanisms in cardiac syndrome, however, remain unclear. More recently, the data has been suggested that chronic inflammation has been associated with cardiac syndrome X. The evidence for the hypotheses included that inflammatory marker are increased, and associated with the disease activity in patients with cardiac syndrome X. And also, statin, a lipid-lowering as well as anti-inflammatory drug, has significantly modified the disease process in this special syndrome. Despite the good prognosis of cardiac syndrome X, the chronic, frequent nature of the persistent angina and reduced exercise tolerance can significantly impair quality of life. Thus, lowering inflammatory response by, for example, use of statin and/or aspirin, might improve coronary microvascular dysfunction. Whether this is a valid approach, however, is still unknown and deserves further investigation. Indeed, as mediators of inflammation are multiple, the strategy of identifying triggers and mechanisms of inflammation in each special clinical setting and directing treatment at the special triggers or to rate limiting steps in effector pathways appears more reasonable or a promising strategy.     

Determinants of plaque instability in atherosclerotic vascular disease

BACKGROUND: Despite numerous advances in the understanding of the pathogenesis of atherosclerosis, the factors that determine atheromatous plaque instability remain unclear. The prediction of the vulnerability of a plaque to rupture and subsequent thrombosis would be useful in guiding development of diagnostic and therapeutic approaches. METHODS: Aortas with areas of gross atherosclerosis were obtained from seven autopsy cases. These were then serially sectioned at 3-mm intervals, analyzed histologically, and scored as to plaque size, calcification, lipid content, intraplaque hemorrhage, inflammation, plaque disruption, and plaque thrombosis. Bivariate correlations and binary multivariate regression analyses were performed using SPSS software. RESULTS: Plaque instability was highly correlated with intraplaque hemorrhage, lipid content, and plaque size. Weaker but statistically significant correlations were found with inflammation and calcification. However, in multivariate regression analyses, only plaque size, intraplaque hemorrhage, and lipid content, independent predictors of plaque instability, were significant. CONCLUSIONS: Atheromatous plaques may be rendered unstable by increases in size, increased intra- and extracellular lipid accumulation, and intraplaque hemorrhage. Based on these results, diagnostic modalities that detect plaque size, plaque hemorrhage, and/or lipid content are most likely to be useful in predicting unstable plaques.     

Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability

Atherosclerosis is a continuous pathological process that starts early in life and progresses frequently to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, stroke and atherothrombosis. The vulnerable lesion has several structural and functional hallmarks that distinguish it from the stable plaque. The unstable plaque has large necrotic core (over 40% plaque volume) composed of cholesterol crystals, cholesterol esters, oxidized lipids, fibrin, erythrocytes and their remnants (haeme, iron, haemoglobin), and dying macrophages. The fibrous cap is thin, depleted of smooth muscle cells and collagen, and is infiltrated with proinflammatory cells. In unstable lesion, formation of neomicrovessels is increased. These neovessels have weak integrity and leak thereby leading to recurrent haemorrhages. Haemorrhages deliver erythrocytes to the necrotic core where they degrade promoting inflammation and oxidative stress. Inflammatory cells mostly presented by monocytes/macrophages, neutrophils and mast cells extravagate from bleeding neovessels and infiltrate adventitia where they support chronic inflammation. Plaque destabilization is an evolutionary process that could start at early atherosclerotic stages and whose progression is influenced by many factors including neovascularization, intraplaque haemorrhages, formation of cholesterol crystals, inflammation, oxidative stress and intraplaque protease activity.     

Reflection spectroscopy of atherosclerotic plaque

Heart disease is the primary cause of death in the western world. Many of these deaths are caused by the rupture of vulnerable plaque. Vulnerable plaques are characterized by a large lipid core covered by a thin fibrous cap. One method for detecting these plaques is reflection spectroscopy. Several studies have investigated this method using statistical methods. A more analytic and quantitative study might yield more insight into the sensitivity of this detection modality. This is the approach taken in this work. Reflectance spectra in the spectral region from 400 to 1700 nm are collected from 77 measurement points from 23 human aortas. A measure of lipid content in a plaque based on reflection spectra is presented. The measure of lipid content is compared with the thickness of the lipid core, determined from histology. Defining vulnerable plaque as having a lipid core >500 microm and fibrous cap <500 microm, vulnerable plaques are detected with a sensitivity of 88% and a specificity of 94%. Although the method can detect lipid content, it is not very sensitive to the thickness of the fibrous cap. Another detection modality is necessary to detect this feature.     

转染野生型p53基因诱发家兔动脉粥样硬化斑块不稳定性的实验研究

目的：探讨野生型p53基因对血管平滑肌细胞（VSMC）的促凋亡作用在构建动脉粥样硬化（As）不稳定斑块动物模型中的价值。方法： 54只雄性新西兰纯种兔用球囊损伤腹主动脉+高脂喂养10周, 于8周末随机分成A组（p53基因组，27只）和B组（LacZ基因组，27只），在腹主动脉斑块形成处分别转染携带野生型p53基因或LacZ基因的重组腺病毒载体；2周后，A组和B组各处死10只，观察斑块的自发破裂情况。然后两组剩余实验兔给予中国斑点蝰蛇毒（CRVV）和组胺药物触发，比较两组发生斑块破裂的发生率。应用免疫组织化学染色、流式细胞仪、原位末端脱氧核苷酸转移酶介导的缺口末端标记法（TUNEL）及电镜检测基因转染部位的平滑肌细胞的凋亡情况。结果： A组TUNEL测定的凋亡阳性细胞率显著高于B组（分别为2.5%±0.8%,1.0%±0.3%，P<0.05），流式细胞仪测定的细胞凋亡率亦明显高于B组（分别为20.04%±6.20%，6.89%±1.20%，P<0.01）；电镜结果显示胞核中异染色体边聚明显，凋亡小体多见；斑块中的VSMC显著减少，纤维帽变薄以及纤维帽/内中膜厚度明显少于B组（纤维帽厚度分别为132.9±56.7，181.8±59.7，P<0.05；纤维帽/内中膜厚度0.20±0.18，0.21±0.11，P<0.05），药物触发后斑块破裂的发生率显著高于B组（分别为85.7%，23.1%，P<0.01）。结论： 外源性人野生型p53基因转染As家兔后，可促进VSMC的凋亡的发生，导致As斑块向不稳定方向发展。     

Compressive stress-relaxation of human atherosclerotic plaque

Knowledge of the mechanical properties of human atherosclerotic plaque is fundamental to understanding atherosclerosis and its treatment. Data are scant, however, particularly with respect to the time-dependent nature of plaque behavior. Previous experiments in our lab showed that human plaques do not exhibit the traditional preconditioning behavior common to most soft tissues. In particular, the behaviors of three classes of plaques differed fundamentally in response to multiple, successive, cyclic compression protocols. In this report, we demonstrate that plaques exhibit different responses to successive relaxation tests in uniaxial compression. Not only is there significant relaxation, but there are composition-dependent differences in the general character of the relaxation responses. Such information on the time-dependent behavior is important for the design of clinical protocols such as stenting or angioplasty wherein the atherosclerotic vessel is subjected to persistent or multiple short duration loadings. This study presents a step toward a better understanding of the biomechanical behavior of atherosclerotic plaques; however, the need for much more data remains.     

The origin of the autophagosomal membrane in human atherosclerotic plaque: a preliminary ultrastructural study

Autophagy is an evolutionarily conserved process that occurs ubiquitously and functions as a primary route for the degradation of damaged organelles and proteins in response to starvation, oxidative stress, and other harmful conditions. The initial event upon autophagy induction is the formation of a membranous cistern called the phagophore or isolation membrane, a cup-shaped structure that elongates, engulfs cytoplasmic “cargo”, and fuses at its rims to give rise to the autophagosome within which cytoplasmic material is enclosed. Although thoroughly studied in diverse cell culture systems, few attempts have been made to analyze the membrane dynamics during phagophore biogenesis in tissues. With respect to the cardiovascular system, no structural information is currently available regarding the sources that may contribute to the nucleation and growth of the phagophore membrane. The results presented here demonstrate that in the cells of human atherosclerotic plaque the phagophores are in contact with the endoplasmic reticulum (ER) membranes. Initially, the phagophore appears as a membrane sac that enwraps injured organelles and dysfunctional proteins and then matures into a double-membrane, closed structure often containing portions of the ER. These structural data indicate that the membrane source that elongates the phagophore might probably come from the ER. The topographical relationship between the ER tubules and the phagophore might also favor an efficient mechanism to transfer lipids from their site of synthesis to the nascent membrane, thus promoting its elongation and, ultimately, the formation of the autophagosome.     

PI3K/Akt/mTOR信号通路在巨噬细胞自噬及动脉粥样硬化斑块不稳定中的作用

 目的：探讨磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B(Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路在巨噬细胞自体吞噬以及动脉粥样硬化斑块不稳定中的作用。方法：利用Akt抑制剂康士得（20 μmol/L）、mTOR抑制剂雷帕霉素（10 nmol/L）及mTOR-siRNA（30 nmol/L）体外处理小鼠RAW 264.7 巨噬细胞株 48 h后,透射电镜观察巨噬细胞自噬体的变化,细胞免疫荧光法及Western blotting法检测微管相关蛋白LC3-II表达,实时荧光定量qRT-PCR和Western blotting法检测Akt、mTOR及自噬相关蛋白Beclin 1的表达,ELISA检测巨噬细胞分泌炎症因子水平。体内实验中, 24只雄性新西兰兔给予球囊损伤+ 1%胆固醇喂养8周,然后随机分为对照组、康士得（1.0 mg·kg-1·d-1）组和雷帕霉素（0.5 mg·kg-1·d-1）组,每组8只,干预4周。血管内超声（IVUS）检测斑块的影像学特征,透射电镜观察斑块中巨噬细胞超微结构的改变,免疫荧光法检测微管相关蛋白LC3-II表达,免疫组织化学法检测巨噬细胞Akt和mTOR的蛋白表达。 结果：与对照组比较,康士得、雷帕霉素及mTOR-siRNA干预巨噬细胞后,透射电镜下观察到自噬体明显增多,微管相关蛋白LC3-II和自噬相关蛋白Beclin 1的表达水平明显上调,而Akt及mTOR 的mRNA及蛋白表达水平明显减少,巨噬细胞分泌的IL-10明显降低,而IFN-γ的分泌显著增加。体内实验： IVUS显示,与对照组比较,康士得组及雷帕霉素组的外弹性膜面积（EEMA）、斑块面积（PA）及斑块负荷（PB）明显减少,透射电镜下观察到巨噬细胞中自噬体增加,组织免疫荧光法示LC3-II明显增加,HE染色显示斑块纤维帽的厚度明显增加,内、中膜厚度显著减低,组织免疫组化染色显示巨噬细胞RAM-11及p-mTOR染色显著减少。结论：选择性抑制PI3K/Akt/mTOR信号通路能诱导巨噬细胞自噬,减少斑块巨噬细胞的浸润, 抑制炎症反应进而稳定动脉粥样硬化易损斑块。     

Potential pathogenic aspects of denture plaque

Oral health status declines with age and as a result the need for removable prostheses increases. Oral health is a reflection of one's general health, affecting the ability of an individual to eat and speak, and contributes significantly to a sense of confidence and well-being. Currently, there are 15 million denture wearers in the UK, representing a significant consumer base and a special healthcare consideration. The microbiology of denture plaque has received little attention in comparison with dental plaque, yet it differs in location and composition. Denture plaque and poor denture hygiene is associated with stomatitis (Candida infection), may also serve as a reservoir of potentially infectious pathogens, and may contribute to oral malodour and to caries and periodontitis in people who have remaining natural teeth. Oral bacteria have been implicated in bacterial endocarditis, aspiration pneumonia, gastrointestinal infection and chronic obstructive pulmonary disease, among others, and dentures offer a reservoir for microorganisms associated with these infections. An effective oral hygiene regimen is important to control denture plaque biofilm and contributes to the control of associated oral and systemic diseases.     

Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases

The association of depression with insulin resistance (IR) and athersclerotic vascular diseases has been well documented. This review examines the relevance of IR as a link between depressive disorder and atherosclerotic vascular diseases. Relevant articles collected from Medline database over the period of 1966-2001 were reviewed. Studies have shown that IR is a state-dependent abnormality in depression and depression increases the risk of vascular morbidity and mortality. Given that IR is a central component of cardiovascular risk factors, depression-related IR might play a role in the development and progression of coronary and cerebral atherosclerosis in chronic-resistant depression. Further, IR may contribute to the pathophysiology of depressive disorder. In conclusion IR could account for the linkage between depression and atherosclerotic vascular diseases. More studies are needed to examine the importance of improving insulin sensitivity in the treatment of chronic-resistant depression and prevention of depression-related vascular morbidity and mortality.     

Parkinson's disease and cytochrome P450: a possible link?

The possibility that idiopathic Parkinson's disease may be linked to a deficiency of an important detoxifying enzyme such as the cytochrome P450 enzyme bufuralol hydroxylase is examined. A hypothetical model of how this might operate to produce early onset Parkinson's disease is suggested.     

Left ventricular dysfunction and altered autonomic activity: a possible link to sudden cardiac death

There is now a growing body of clinical evidence that suggests a strong association between left ventricular dysfunction and sudden cardiac death in patients recovering from myocardial infarction. The mechanisms underlying this association remain to be determined. Alterations within the autonomic nervous system may represent one factor that links an impairment in cardiac function to an increased mortality. Since ventricular dysfunction would tend to reduce stroke volume, an increased sympathetic and/or decreased parasympathetic efferent activity may compensate for this fall in stroke volume by increasing heart rate and/or the force of contraction (inotropic state) in an attempt to maintain a more normal cardiac output. Similar changes in autonomic activity are, in fact, known to increase the vulnerability to ventricular fibrillation. Therefore, I propose that myocardial infarction induces changes in cardiac function which in turn elicits autonomic efferent changes. As a consequence of these compensatory reflex changes the heart becomes less electrically stable and thereby more prone to lethal arrhythmias.