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.     

Non-invasive detection of vulnerable coronary plaque

Critical coronary stenosis have been shown to contribute to only a minority of acute coronary syndromes and sudden cardiac death.Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis.Consequently,a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease.Recent advances in invasive and non-invasive imaging techniques have shown the potential to identify these high-risk plaques.Non-invasive imaging with magnetic resonance imaging,computed tomography and positron emission tomography holds the potential to differentiate between low-and highrisk plaques.There have been significant technological advances in non-invasive imaging modalities,and the aim is to achieve a diagnostic sensitivity for these technologies similar to that of the invasive modalities.Molecular imaging with the use of novel targeted nanoparticles may help in detecting high-risk plaques that will ultimately cause acute myocardial infarction.Moreover,nanoparticle-based imaging may even provide non-invasive treatments for these plaques.However,at present none of these imaging modalities are able to detect vulnerable plaque nor have they been shown to definitively predict outcome.Further trials are needed to provide more information regarding the natural history of high-risk but non-flow-limiting plaque to establish patient specific targeted therapy and to refine plaque stabilizing strategies in the future.     

Update on coronary angioscopy: review of a 20-year experience and potential application for detection of vulnerable plaque

Predicting the occurrence of future acute coronary syndromes remains an important challenge of contemporary cardiology. It is thought that detecting the individual vulnerable plaques in patients can be an important step to preventing myocardial infarction and sudden cardiac death. Coronary angioscopy can provide detailed information of the luminal surface of plaque, such as color, thrombus, or disruption, and is one of a few possibly useful imaging modalities for identifying vulnerable plaques. During its 20-year history, coronary angioscopy has been used as a diagnostic tool or to guide coronary angioplasty, and has contributed to our understanding of the pathophysiology of coronary artery disease. Yellow plaques seen during angioscopy seem to have many characteristics of high risk or vulnerable plaques, most consistent with the thin-cap fibroatheroma. Moreover, differences in yellow color have been reported to reflect differences in the structure or composition of plaques. Development of quantitative methods to assess plaque color and histopathologic correlations in conjunction with prospective natural history studies may lead to advances in vulnerable plaque detection by coronary angioscopy. Although current angioscopic devices are limited by the need to displace the column of blood in order to see the vessel wall, and by the lack of quantitative colorimetric methods, advances in technology may lead to new device versions that could be practical for expanded clinical use.     

Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion

Coronary artery disease is the leading cause of death in much of the western world. Atherosclerotic plaques in the coronary arteries contribute to luminal obstruction leading to myocardial ischemia; however, abrupt coronary artery occlusion most frequently results from superimposition of a thrombus on a disrupted plaque, leading to the most serious clinical manifestations of coronary artery disease, ie, unstable angina, acute myocardial infarction, and sudden death. Plaque that have undergone disruption and, by inference, plaques at risk for disruption (vulnerable plaques), tend to demonstrate outward vessel remodeling, contain a large lipid core, thinned out fibrous cap, reduced collagen content, and increased inflammatory cell infiltration. Plaque stabilization through change in plaque composition may be responsible for reduced frequency of acute vaso-occlusive events observed with lipid and other risk-factor modifying interventions.     

Unstable coronary plaque and its relation to coronary calcium

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for "unstable." Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertinent "unstable patient." Almost all patients with a recent acute coronary syndrome have measurable coronary calcium because moderate-to-advanced coronary plaque disease is already present, although obstructive disease frequently is not. Prospective studies have demonstrated that extensive coronary calcium detected by EBCT is associated with a significantly increased incidence of subsequent myocardial infarction, need for revascularization, and coronary death. The incremental prognostic value of coronary calcium compared with that of risk factor assessment remains to be fully defined. The occurrence of an acute coronary syndrome is determined by many factors apart from the extent of atherosclerotic plaque disease. Large prospective trials in the general population are needed to define the subgroups that will benefit most from quantitative assessment of coronary calcium.     

冠状动脉CT血管造影综合评估易损斑块的进展

急性冠状动脉综合征（ACS）是以冠状动脉粥样硬化斑块破裂或侵袭,继发完全或不完全闭塞性血栓形成为病理基础的一组临床综合征。与稳定斑块相比,容易破裂的斑块具有明显的影像学特征：大斑块体积,低衰减斑块,餐巾指环标志,正性重构和点状钙化,这为在导致临床事件之前运用非侵入性成像识别易损斑块提供了独特的机会。随着影像技术的发展,冠状动脉CT 血管造影（CCTA）无创性评价冠状动脉易损斑块的作用已成为国内外研究热点。笔者就CCTA在评估冠状动脉斑块易损性方面的临床应用现状与进展等方面作一综述。     

Invasive imaging techniques for the assessment of vulnerable plaque

Coronary artery disease is the leading cause of mortality and morbidity in the Western world and an ever-increasing problem in developing countries. Unheralded acute coronary syndromes (ACS) are common initial manifestations of coronary atherosclerosis and are often caused by lesions which have previously not generated symptoms. Histopathological studies have identified several plaque morphologies associated with ACS. However, the natural history of these high-risk or vulnerable lesions remains unknown and the limited knowledge about their eventual prognosis is provided by retrospective histopathological studies. Detection of these vulnerable plaques in vivo is essential to study their natural history and to evaluate potential treatment modalities and, therefore, may ultimately have an important impact on the prevention of acute myocardial infarction and death. Currently, there are several diagnostic imaging tools capable of evaluating determinants of plaque vulnerability. These techniques can provide information on the vessel lumen and wall size, tissue composition and the status of inflammation. This article aims to review the current status of these imaging techniques.     

Current status of vulnerable plaque detection

Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high‐risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high‐risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high‐risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high‐risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow‐limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high‐risk but non flow‐limiting plaque to establish patient‐specific targeted therapy and to refine plaque stabilizing strategies in the future. © 2009 Wiley‐Liss, Inc.     

Multifocal coronary plaque instability

Recent observations document that many patients with acute coronary syndromes harbor multiple complex plaques by angiography, which correlate with multiple plaque ruptures and clots at necropsy. Multifocal plaque instability is evident not only in coronary vessels but also in peripheral vessels where peripheral and coronary plaque instability may exist concomitantly. These observations support the concept that plaque instability is not merely a local vascular accident but instead reflects more systemic pathophysiological processes with potential to destabilize atherosclerotic plaques throughout the cardiovascular system. Copyright 2002, Elsevier Science (USA). All rights reserved.     

New developments in the detection of vulnerable plaque

Failure of coronary angiography (luminography) in prediction of future acute coronary syndromes has cast a shadow of doubt over the value of this old gold-standard technique. The fact that angiographically invisible or nonsignificant lesions cause the majority of acute coronary syndromes has driven scientists to develop new diagnostic methods. In this article, we review the ongoing worldwide research on both invasive techniques (such as intravascular angioscopy and colorimetry, ultrasound, thermography, optical coherence tomography, near infrared spectroscopy, Raman spectroscopy, fluorescence emission spectroscopy, elastography, magnetic resonance imaging [MRI] and spectroscopy, nuclear immunoscintigraphy, electrical impedance imaging, vascular tissue doppler, and shear stress imaging) and noninvasive techniques (such as MRI, contrast-enhanced MRI with and without immunolabeled agents, electron beam computed tomography, multi-slice spiral / helical computed tomography, and nuclear imaging, including positron emission tomography). Each of these techniques and their potential combination holds promise for characterization of plaques responsible for acute coronary syndromes, namely vulnerable plaque.     

Imaging of the vulnerable plaque: noninvasive and invasive techniques

In a large proportion of previously asymptomatic individuals, sudden coronary death or acute myocardial infarction occurs as the first manifestation of coronary atherosclerosis. Imaging of coronary atheromatous plaques has traditionally centered on assessing the degree of luminal stenosis. The angiographic techniques that are routinely used to identify stenotic atherosclerotic lesions are unable to identify high-risk plaques; plaques prone to rupture and cause a cardiovascular event. This is partly due to the fact that the majority of culprit lesions that produce acute cardiovascular syndromes are not severely stenotic, possibly due to significant positive remodeling and reduced protective collateral circulation as well as because the risk of plaque rupture is more closely related to plaque content than plaque size. Recently, the focus of new imaging techniques is to identify the high risk plaques; the "vulnerable plaques." In this review, we will refer to the noninvasive and invasive techniques that can detect the vulnerable plaque.     

Mechanical and structural characteristics of vulnerable plaques: analysis by coronary angioscopy and intravascular ultrasound.

OBJECTIVES: Mechanical and structural characteristics of vulnerable plaques were evaluated using coronary angioscopy and intravascular ultrasound. BACKGROUND: Mechanical stress and composition of plaques play an important role in plaque disruption. METHODS: Thirty-eight lesions in 38 patients were examined pre-interventionally. The plaques were classified as either yellow or white using coronary angioscopy. Intravascular ultrasound imaging was performed simultaneously with electrocardiographic and intracoronary pressure recordings to calculate distensibility index and stiffness beta. Moreover, the type of remodeling was classified. RESULTS: We identified 27 patients with yellow plaques and 11 patients with white plaques. Patients with yellow plaques presented acute coronary syndromes more frequently than stable angina (85% vs. 36%, p < 0.01). The distensibility index in yellow plaques was significantly greater than it was in white plaques (2.7 +/- 0.8 mm Hg(-1) vs. 0.7 +/- 0.8 mm Hg(-1), p < 0.0001), while stiffness beta for white plaques was significantly greater than it was for yellow plaques (34.9 +/- 16.3 vs. 8.7 +/- 2.7, p < 0.0001). Compensatory enlargement occurred more frequently with yellow plaques than with white plaques (56% vs. 9%, p < 0.01), while paradoxical shrinkage occurred more frequently with white plaques than it did with yellow plaques (64% vs. 4%, p < 0.001). CONCLUSIONS: Yellow plaques with an increased distensibility and a compensatory enlargement may be mechanically and structurally weak. As a result, mechanical "fatigue," caused by repetitive stretching, may lead to plaque disruption. Plaques with a high distensibility and a compensatory enlargement may be vulnerable.     

New insights towards catheter-based identification of vulnerable plaque

Sudden cardiac death or unheralded acute coronary syndromes are common initial manifestations of coronary atherosclerosis and most such events occur at sites of non-flow limiting coronary atherosclerosis. Autopsy data suggests that plaque composition is a key determinant of the propensity of atherosclerotic lesions to provoke clinical events. Most of these events are related to plaque rupture and subsequent thrombotic occlusion at the site of non-flow limiting atherosclerotic lesions in epicardial coronary arteries. Detection of these non-obstructive, lipid rich, high-risk plaques may have an important impact on the prevention of acute myocardial infarction and sudden death. Currently, there are several intravascular tools capable of locally evaluating determinants of plaque vulnerability such as the size of the lipid core, thickness of the fibrous cap, inflammation within the cap and positive remodeling. These new modalities have the potential to provide insights into the pathophysiology of the natural history of coronary plaque by means of prospective studies.     

Angiographic patterns and the natural history of the vulnerable plaque

Coronary angiography is the gold standard for the identification of obstructive coronary artery disease (CAD). The use of this diagnostic test in the evaluation of many clinical syndromes of CAD has yielded a wealth of angiographic data relative to the vulnerable atherosclerotic plaque. This chapter reviews these important data including the limitations of the angiogram in vulnerable plaque detection, angiographic patterns of complex plaques or "culprit lesions," and the natural history of the complex angiographic lesion.     

微观结构在易损斑块进展中的作用

急性冠状动脉综合征常常导致严重的心血管事件,而冠状动脉粥样硬化斑块破裂是绝大多数急性冠状动脉综合征发生的原因,因此检测高破裂风险的易损斑块,对筛选和干预急性冠状动脉综合征具有重要意义。随着研究的不断进展,易损斑块内的一些微观结构如斑块内新生血管、微小钙化、胆固醇结晶,在易损斑块的进展中起到重要的作用。因此,本文以易损斑块内最常见的3种微观结构为重点,综述斑块内微观结构在易损斑块进展中的作用。     

Plaque disruption and thrombosis. Potential role of inflammation and infection.

Considerable data from in vitro and in vivo studies of vascular biology, together with indirect evidence from clinical trials of lipid-lowering or modifying and lifestyle or risk factor modifying interventions, provide strong support for the concept that disruption of atherosclerotic plaque and subsequent thrombosis is a key precipitant of potentially lethal, acute coronary syndromes. Certain characteristics of plaques, including the size and composition of the lipid core, the structure and composition of the fibrous cap, and the presence of a local inflammatory process, predispose the plaque to disruption. Stresses resulting from biomechanical and hemodynamic forces acting on plaques may then trigger disruption, releasing the thrombogenic contents of the lipid core. Alterations in endothelial function may also contribute to vulnerability of plaque rupture and thrombosis. Therefore, interventions aimed at decreasing plaque vulnerability to disruption--all based on the concept of plaque stabilization--may reduce the risk of acute coronary syndromes. Although not yet rigorously validated in humans, plaque stabilization may prove to be an important clinical strategy for preventing the lethal consequences of coronary atherosclerosis.     

The vulnerable plaque and acute coronary syndromes

The interaction between the vulnerable atherosclerotic plaque and thrombus formation, a process referred to as atherothrombosis, is the cornerstone of acute coronary syndromes. Advances in noninvasive imaging have helped to identify novel approaches to plaque stabilization, with the potential to prevent plaque rupture, including lifestyle modification and dietary adjustments, as well as pharmacologic interventions such as statins. Following an acute coronary event, strategies combining mechanical and pharmacologic therapies provide considerable advances in prevention of subsequent cardiac events. Pharmacologic strategies to prevent and treat thrombotic complications related to acute coronary syndromes have been developed to dissolve preformed thrombi and to inhibit thrombogenesis. These regimens focus on inhibiting thrombin, preventing thrombi generation, blocking the initiation of coagulation, inhibiting platelet activation, and increasing fibrinolysis.     

多层螺旋计算机断层扫描血管造影对冠状动脉易损斑块的检测作用

目的 评价多层螺旋计算机断层扫描（computed tomography,CT）血管造影（multislice computed tomography angiography,MSCTA）检测冠状动脉易损斑块的可靠性,建立急性冠脉综合征积分（score system of acute coronary syndromes,SACS）,用于评估冠状动脉粥样硬化性心脏病（冠心病）患者危险分层.方法 研究20例非急性冠脉综合征及41例急性冠脉综合征且冠状动脉MSCTA发现斑块的患者,比较两组斑块CT值、重构指数（RI）等指标,进而构建急性冠脉综合征发病风险预测模型.结果 两组病变血管99支,可分析斑块1 17个,非急性冠脉综合征组36个,以钙化斑块为主（88.9％,32/36）;急性冠脉综合征组81个,以脂质斑块为主（37.0％,30/81）.两组正性重构比例比较,差异有统计学意义（61.1％ vs.32.1％,P＜0.01）;负性重构比例比较,差异有统计学意义（25.0％vs.19.8％,P＜0.01）.由RI建立SACS,所得模型为：SACS=0.003PA＋2.255RI-4.22,预测准确率为76.9％（P＜0.01）,受试者工作曲线下面积为0.815（P＜0.01）.结论 急性冠脉综合征患者冠状动脉斑块多为脂质斑块,以正性重构为主,SACS对急性冠脉综合征发病具有较高的预测价值,有助于临床指导冠心病危险分层及早期干预.     

Biologic aspects of vulnerable plaque

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized world. The progression of atherosclerotic plaques in coronary circulation is modulated by several risk factors. It is now clear that plaque composition is a major determinant of plaque disruption and superimposed thrombosis. Plaque vulnerability, defined as the propensity of plaques to disrupt, is further determined by intrinsic and extrinsic triggering factors. After disruption, the fatty core of the plaque and its high content of tissue factor provide a powerful substrate for the activation of the coagulation cascade. Plaque disruption can be clinically silent or cause symptoms of ischemia depending on thrombus burden and the degree of vessel occlusion. In addition, plaque disruption and subsequent healing are recognized to play key roles in the rapid plaque progression. This review looks at the mechanisms underlying the development and progression of atherosclerotic plaques, factors leading to plaque rupture and subsequent thrombosis, and their clinical consequences as potential targets for future research.