Plaque disruption and thrombosis: potential role of inflammation and infection

Acute coronary syndromes (unstable angina, acute myocardial infarction, and ischemic sudden death) result from coronary thrombosis superimposed on an atherosclerotic plaque. Thrombosis is generally a consequence of disruption of the atherosclerotic plaque in the form of a fissure/rupture in the fibrous cap overlying a lipid-rich pool or superficial endothelial erosion covering a smooth muscle and proteoglycan-rich matrix with or without a lipid-core. Approximately 2/3 of acute coronary syndromes evolve from atherosclerotic plaques that are minimally or mildly obstructive of the lumen before the acute event. Inflammation with accumulation of activated mononuclear cells may play a potential role in plaque disruption through the elaboration of proteases, such as matrix degrading neutral metalloproteinases and other proteases, inhibition of function and/or survival, or promotion of apoptosis of matrix synthesizing smooth muscle cells. Inflammation may also contribute to thrombosis after plaque disruption by providing a source for tissue factor in the plaque. Inflammation in the plaque may result from accumulation of modified lipids, oxidant and hemodynamic stress, and infectious agents, such as Chlamydia pneumoniae or pro-inflammatory triggers from distant sites of infection and inflammation (eg, chronic gingivitis and chronic bronchitis). Improved insights into the pathophysiology of plaque disruption and thrombosis are likely to provide new and improved methods of stabilizing atherosclerotic disease process.     

Inflammation and acute coronary syndromes

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.     

Analysis of apoptotic markers Fas/FasL (CD95/CD95L) expression on the lymphocytes in patients with acute coronary syndrome

BACKGROUND: Acute coronary syndromes are caused by the rupture or erosion of an atherosclerotic plaque which by secreting a variety of proteases is capable of degrading pericellular matrix components induces death of endothelial cells. This mechanism plays the main role in apoptosis. AIM: To estimate expression of apoptotic Fas/FasL (CD95/CD95L) on lymphocytes in the peripheral blood. METHODS: We examined patients with acute myocardial infarction (n=18, mean age 62+/-8 years), in unstable angina pectoris (n=31, mean age 62+/-10 years) and in a control group (n=20, mean age 62+/-9 years) without coronary risk factors and inflammatory condition. All investigations of Fas/FasL were performed by flow cytometry. Inflammatory parameters and standard risk factors were investigated by standard methods (ELISA). RESULTS: The analysis revealed a higher expression of Fas and FasL molecules on the lymphocytes from patients with acute myocardial infarction (p<0.001, p<0.002) and unstable angina (p<0.01, p<0.02) compared to the control group. Moreover we found a statistically significant positive correlation between the level of LDL cholesterol and hypertension and prevalence of CD95 (p<0.001, p<0.01) and CD95L (p<0.02, p<0.03) in patients with acute myocardial infarction. CONCLUSIONS: A higher expression of apoptotic molecules (Fas and FasL) on lymphocytes occurs before the onset of acute ischaemia and contributes to the plaque rupture and acute coronary syndrome. Furthermore, antiapoptotic therapy leads to plaque stabilisation.     

Strategies to achieve coronary arterial plaque stabilization.

Acute coronary syndromes result from fissure, erosion or rupture of a vulnerable atherosclerotic plaque. The characteristics of a vulnerable plaque include a large lipid pool, an abundance of inflammatory cells and mediators, a reduced smooth muscle cell and collagen content and a thin overlying fibrous cap. Potential therapeutic strategies at achieving plaque stabilization have targeted these features. Lipid lowering agents, beta-adrenergic blockers, angiotensin converting enzyme inhibitors and antioxidants have been shown to reduce the incidence of acute coronary syndromes, presumably through plaque stabilization. Matrix metalloproteinase inhibitors as well as macrolide antibiotics and gene therapy approaches show promise in achieving plaque stabilization. The evidence supporting plaque stabilization by these agents and the mechanisms by which these agents stabilize plaques are discussed in detail in this review.     

Selective depletion of macrophages in atherosclerotic plaques via macrophage-specific initiation of cell death

Macrophages play a central role in atherosclerotic plaque destabilization, leading to acute coronary syndromes and sudden death. Removal of macrophages from plaques via pharmacological therapy may therefore represent a promising approach to stabilize vulnerable, rupture-prone lesions. In this review, we summarize the current therapeutic means to induce macrophage cell death in atherosclerotic plaques without affecting smooth muscle cell viability, and their potential pitfalls.     

Clinical implications and mechanisms of plaque rupture in the acute coronary syndromes

Coronary atherosclerosis complicated by plaque rupture or disruption and thrombosis is primarily responsible for the development of acute coronary syndromes. Plaques with a large extracellular lipid-rich core, a thin fibrous cap due to reduced collagen content and smooth muscle density, and increased numbers of activated macrophages and mast cells appear to be vulnerable to rupture. Plaque disruption tends to occur at points at which the plaque surface is weakest and most vulnerable, which coincide with points at which stresses resulting from biomechanical and hemodynamic forces acting on plaques are concentrated. Reduced matrix synthesis as well as increased matrix degradation predisposes vulnerable plaques to rupture in response to extrinsic mechanical or hemodynamic stresses. Modification of endothelial dysfunction and reduction of vulnerability to plaque rupture and thrombosis may lead to plaque stabilization. These concepts have significant clinical implications that are just beginning to be explored and incorporated into clinical practice. This article reviews the mechanism of coronary atherosclerosis development and the pathophysiology of acute coronary syndromes to provide a framework for understanding how plaque passivation might be accomplished in clinical medicine.     

Monocyte chemoattractant protein-1 in acute coronary syndromes: complex vicious interaction

Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role both in the initiation and progression of atherosclerosis. MCP-1 is a unique cytokine produced by macrophages, smooth muscle cells and endothelial cells within atherosclerotic plaques and seems to be a reliable indicator of atherosclerotic plaque burden. Higher levels of MCP-1 have been associated with a poor prognosis and increased risk for death independent of other risk factors in patients with acute coronary syndromes. In this paper, we discussed the role of MCP-1 in the pathogenesis of acute coronary syndromes.     

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。     

Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability.

OBJECTIVE: Instability of coronary atheroma leads to the onset of acute coronary syndromes including myocardial infarction and death, as well as to the progression of the arteriosclerotic disease. As yet, the underlying factors and mechanisms causing plaque rupture are not completely understood. Since a low content of smooth muscle cells (SMCs) apparently plays a key role, the question points to the events leading to the loss of intimal SMCs. METHODS: We compared coronary atherectomy specimens from 25 patients with unstable angina to those from 25 patients with stable angina. Transmission electron microscopy was used to identify intimal cell population, to detect stage and cell type of apoptosis, and to differentiate between apoptosis and necrosis. RESULTS: Plaques associated with unstable angina contained more macrophages/lymphocytes and significantly less SMCs (P = 0.01), compared with stable angina plaques. Specific cell death forms, apoptosis and necrosis, were present in all coronary atheroma. As key findings, both the proportion of SMCs undergoing apoptosis and the frequency of cytoplasmic remnants of apoptotic SMCs (matrix vesicles) were significantly increased in unstable versus stable angina lesions (P = 0.002 and P = 0.002). In addition, cellular necrosis was more frequent in the first coronary atheroma group (P = 0.02). Positive correlations were found between the frequency of apoptotic cells and necrosis (r = 0.41, P = 0.04), and that of matrix vesicles and necrosis (r = 0.63, P = 0.001) only in plaques with unstable angina, but not in those with stable angina. CONCLUSIONS: Our data demonstrate that high cell death due to apoptosis and necrosis is a basic in situ feature found in advanced coronary primary lesions associated with unstable angina, possibly explaining their low density of (viable) SMCs. Thus, antagonization of intimal cell death should be considered in order to stabilize the intimal plaque texture of coronary atheroma with the ultimate goal to prevent plaque rupture.     

Increased levels of neutrophil-activating peptide-2 in acute coronary syndromes: possible role of platelet-mediated vascular inflammation.

OBJECTIVES: We sought to investigate the role of the CXC chemokine neutrophil-activating peptide-2 (NAP-2) in atherogenesis and plaque destabilization. BACKGROUND: Chemokines are involved in atherogenesis, but the role of NAP-2 in atherosclerotic disorders is unclear. Based on its potential pro-atherogenic properties, we hypothesized a pathogenic role for NAP-2 in coronary artery disease. METHODS: We tested this hypothesis by differential experimental approaches including studies in patients with stable (n = 40) and unstable angina (n = 40) and healthy control subjects (n = 20). RESULTS: The following results were discovered: 1) patients with stable, and particularly those with unstable, angina had markedly raised plasma levels of NAP-2 compared with control subjects, accompanied by increased expression of CXC receptor 2 in monocytes; 2) platelets, but also peripheral blood mononuclear cells (PBMCs), released large amounts of NAP-2 upon stimulation, with a particularly prominent PBMC response in unstable angina; 3) NAP-2 protein was detected in macrophages and smooth muscle cells of atherosclerotic plaques and in monocytes and platelets of coronary thrombi; 4) in vitro, recombinant and platelet-derived NAP-2 increased the expression of adhesion molecules and chemokines in endothelial cells; and 5) whereas aspirin reduced plasma levels of NAP-2, statin therapy increased NAP-2 with stimulating effects both on platelets and leukocytes. CONCLUSIONS: Our findings suggest that NAP-2 has the potential to induce inflammatory responses within the atherosclerotic plaque. By its ability to promote leukocyte and endothelial cell activation, such a NAP-2-driven inflammation could promote plaque rupture and acute coronary syndromes.     

Expression of matrix metalloproteinase 3 in experimental atherosclerotic plaques.

In atherosclerotic lesions, matrix metalloproteinases produced by foam cells (macrophages) are thought to increase plaque instability, promote plaque rupture, by degradating extracellular matrix. To investigate the relationship between the expression of these proteinases and the histologic appearance of atheromas, immunohistochemical analysis of matrix metalloproteinase 3 and cell-type markers was performed in atherosclerotic plaques induced in rabbit abdominal aortas by high-cholesterol diets and mechanical injury. In addition to an antibody against matrix metalloproteinase 3, RAM-11 and HHF-35 were used to detect macrophages and smooth muscle cells, respectively. Matrix metalloproteinase 3 was expressed diffusely within the plaques with a fibrofatty histologic pattern. In plaques with foam cell accumulation, matrix metalloproteinase 3 was seen in areas rich in foam cells and the smooth muscle cells near the lumen. In the plaques with fewer macrophages, the proteinase was expressed only in such smooth muscle cells. Matrix metalloproteinase 3 was expressed in the smooth muscle cells in plaques of all histologic types, and macrophages also expressed the metalloproteinase when present in significant numbers. These findings suggest that macrophage accumulation plays an important pathophysiologic role in causing the instability of atherosclerotic lesions by increasing the levels of matrix metalloproteinase 3.     

Pathophysiology and clinical significance of atherosclerotic plaque rupture.

Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes. These syndromes include unstable angina, non-Q-wave myocardial infarction (MI) and Q-wave MI. In addition, many cases of sudden cardiac death may be attributable to atherosclerotic plaque disruption and its immediate complications. Our understanding of the atherosclerotic process and the pathophysiology of plaque disruption has advanced remarkably. Despite these advances, event rates after acute coronary syndromes remain unacceptably high. This review will focus on the pathophysiology underlying atherosclerotic plaque development, the sequellae of coronary plaque rupture, and current therapies designed to treat the acute coronary syndromes. It is hoped that as our understanding of the atherosclerotic plaque improves, treatment strategies for the acute coronary syndromes will advance.     

Biomarkers of Plaque Instability

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.     

Circulating markers of inflammation and atherosclerosis

Atherosclerosis is nowadays generally accepted as an inflammatory disease. It is known that local inflammation occurs in the formation the plaques, as macrophages and other immuno-competent cells are present in the lesions from an early stage, and it is also known that inflammation plays an important role in the weakening of the fibrous cap of the advanced plaque, eventually leading to plaque rupture and acute coronary syndromes. The present review focuses on two questions. First, if circulating markers of inflammation could differentiate between healthy subjects and those with atherosclerotic manifestations. Second, if those markers could differentiate between those with a stable atherosclerotic disease, such as stable angina pectoris, and those prone to unstable manifestations of atherosclerosis, such as acute coronary syndromes. Using data from both cross-sectional and prospective studies it could be shown that the majority of the studies which had investigated the role of markers for systemic inflammation, such as CRP, leukocyte count, serum fibrinogen and different cytokines, found elevated levels in patients with atherosclerosis and especially so in those with an unstable coronary disease. The same pattern was found when inflammatory markers with a vascular origin, such as the adhesion molecules, were investigated. Thus, based on the literature it is obvious that circulating markers of inflammation have a role as risk factors for unstable manifestations of atherosclerosis, but it is still unclear whether the different inflammatory markers merely are markers, or if they in an active way contribute to the development and progression of the atherosclerotic disease in their own.     

老年患者股动脉和颈动脉及冠状动脉粥样硬化斑块稳定性的比较

目的　探讨股动脉、颈动脉、冠状动脉粥样硬化斑块的稳定性。方法　收集我院老年尸体解剖病例 15例 ,将所有病例的两侧股动脉、两侧颈动脉、左冠状动脉前降支进行连续取材 ,常规病理检查 ,部分节段行α 平滑肌肌动蛋白、CD6 8、bax染色。结果　股动脉粥样硬化斑块中的平滑肌细胞、巨噬细胞数量与颈动脉相近。与冠状动脉比较 ,股动脉粥样硬化斑块中的平滑肌细胞相对多 ,巨噬细胞相对少 ;bax在巨噬细胞的表达多 ,在平滑肌细胞的表达少。结论　平滑肌细胞、巨噬细胞数量的不同导致了 3种动脉粥样硬化斑块不同的稳定性。股动脉中的粥样硬化斑块较冠状动脉更稳定。     

Pathophysiological bases of unstable coronary syndrome

BACKGROUND: The acute coronary syndrome is the manifestation of a plaque rupture in a coronary artery, which can lead to intermittent or prolonged regional myocardial ischemia. In such a situation, the underlying atherosclerotic lesion is a complex one. Moreover, the mechanisms leading to the instability of an atherosclerotic plaque are complex themselves. This makes it problematic to systematically analyze the nature of the acute coronary syndrome. Moreover, no animal model is available to study this process. PATHOMORPHOLOGICAL AND CLINICAL STUDIES: Substantial insights into the basis of the acute coronary syndrome have been gathered by pathomorphological analyses, which have helped to identify a number of criteria describing a vulnerable plaque. Clinical studies have helped to identify the thrombotic component as an important aspect of the clinical manifestation of the acute coronary syndrome. Based on such data, well-defined antithrombotic strategies play an important role in today's therapy of the acute coronary syndrome. TRIGGERING MECHANISMS: Concerning the triggering mechanisms for an acute coronary syndrome, there is a number of suspected processes, the most important of which is local inflammation of the coronary plaque. Inflammatory processes have recently been recognized as important stimulators of vascular modeling during atherogenesis. These inflammatory mechanisms involve a number of different cytokines, cells of the immune system and other components of the immune systems such as the complement cascade. C-reactive protein may even be a link between systemic and local inflammatory processes, because it has been shown to be systemically elevated in patients with unstable angina, and--most recently--has been shown to be involved in the initiation and progression of early atherosclerotic lesions. Local inflammation of the atherosclerotic plaques induces the expression of a number of growth factors and other potent molecules that contribute to vascular remodeling. These substances are acting on smooth muscle cells, fibroblasts as well as on the extracellular matrix and include growth factors, matrixmetalloproteinases and tissue inhibitors of metalloproteinase. Another component of potential significance within the unstable plaque is the process called plaque-angiogenesis. Plaque-angiogenesis occurs within complicated atherosclerotic plaques, the process of angiogenesis leads to destabilization of the extracellular matrix and, moreover, newly formed capillaries are more likely to rupture and may therefore be an important trigger of plaque rupture and of the acute coronary syndrome. THERAPEUTIC APPROACHES: A number of molecular strategies including inhibition of matrix metalloproteinasis or inhibitors of angiogenesis may turn out to stabilize the vulnerable plaque. Until these therapeutic concepts may be used in the clinic, our therapeutic repertoire will mostly consist of antithrombotic and entire antiinflammatory approaches.     

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.