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.     

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.     

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.     

Genomic view of factors leading to plaque instability

The manifestations of coronary artery disease are varied. They all arise as a consequence of the deposition of atherosclerotic plaque within the vessel wall. The most feared sequela of coronary artery disease is sudden and unexpected death in the ostensibly healthy patient. Plaque rupture of hemodynamically insignificant atherosclerotic plaques and ensuing thrombosis is likely responsible for a large proportion of such deaths. Identifying populations at increased risk for sudden death would represent a major advance. Such screening is contingent upon identification of DNA sequence variants that predispose individuals to plaque rupture. Phenotyping is not sufficiently nuanced to detect such variants on a large scale, so we are limited to end points that are crude surrogates for plaque rupture. As imaging modalities are refined and our ability to recruit large numbers of appropriate patients is facilitated by the formation of alliances, our ability to probe this conundrum via a genome-wide approach will improve.     

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.     

Technology insight: in vivo coronary plaque classification by intravascular ultrasonography radiofrequency analysis

Acute coronary syndromes or sudden coronary death are often the first manifestations of coronary artery disease. In the majority of patients, acute coronary syndrome events are caused by plaque rupture in flow-limiting and non-flow-limiting angiographically intermediate stenoses. Histopathologic analyses have shown that plaque composition is related to the occurrence of acute clinical events and, therefore, to the vulnerability of the plaque. The emerging importance of adaptive coronary remodeling processes, such as the compensatory enlargement of the coronary artery in response to initial lesion development, has focused our interest on the nonstenotic lesions of the coronary tree. In vivo intravascular ultrasonography can demonstrate the discrepancies between the actual extent of coronary atherosclerosis and that seen by angiographic imaging. The spectral analysis of intravascular ultrasonography derived radiofrequency data enables more precise analysis of plaque composition and type than grayscale intravascular ultrasonography.     

冠状动脉粥样硬化斑块破裂的临床危险因素分析

目的　研究临床危险因素与冠状动脉粥样硬化斑块破裂的关系 ,探讨斑块破裂的危险因素。方法　选取 1992～ 1998年间的尸检病例 ,急性心肌梗死 (AMI) 2 0例 ,不稳定心绞痛 (UA) 10例 ,稳定心绞痛 (SA) 12例 ,对所有冠状动脉连续取材制片 ,常规及免疫组化染色 ,光镜观察斑块破裂的形态改变及血栓伴随情况 ,并调查 8个相应的临床危险因素。结果　 8个危险因素中 ,血浆甘油三酯水平与斑块破裂有关 (P <0 .0 5 )。结论　高血浆甘油三酯是国人急性冠状动脉综合征患者斑块破裂的一个重要危险因素。     

Intravascular modalities for detection of vulnerable plaque: current status

Progress in the diagnosis, treatment, and prevention of atherosclerotic coronary artery disease is dependent on a greater understanding of the mechanisms of coronary plaque progression. Autopsy studies have characterized a subgroup of high-risk, or vulnerable, plaques that result in acute coronary syndromes or sudden cardiac death. These angiographically modest plaques share certain pathologic characteristics: a thin, fibrous cap, lipid-rich core, and macrophage activity. Diagnostic techniques for vulnerable-plaque detection, including serologic markers and noninvasive and invasive techniques, are needed. Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo by using various features of plaque vulnerability as methods of identification. The characteristic anatomy of a thin, fibrous cap overlying a lipid pool has promoted high-resolution imaging, such as intravascular ultrasound, optical coherence tomography, and intracoronary magnetic resonance. The lipid-rich core is identifiable by angioscopically detected color changes on the plaque surface or by its unique absorption of energy, or "Raman shift," of its cholesterol core, driving coronary spectroscopy. Finally, temperature heterogeneity arising at foci of plaque inflammation has prompted the development of intracoronary thermography. In this review, we will discuss these techniques, their relative advantages and limitations, and their potential clinical application.     

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.     

Coronary artery imaging in the new millennium

Atherosclerotic disease and its thrombotic complications remain the leading causes of mortality and morbidity in Western society. In Australia, cardiovascular disease is responsible for one in every 2.4 (41%) deaths and is the leading single cause of mortality. The crucial final common process for the conversion of a non-occlusive, often clinically silent, atherosclerotic lesion to a potentially fatal condition is plaque disruption. The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death. There is substantial clinical, experimental and postmortem evidence demonstrating the role acute thrombosis upon a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes. Atherosclerotic plaque composition, rather than the stenotic severity, appears to be central in determining risk of both plaque rupture and subsequent thrombogenicity. In particular, a large lipid core and a thin fibrous cap render an atherosclerotic lesion susceptible or vulnerable to these complications. We are currently limited in our ability to accurately identify patients at risk for an acute coronary event. The armamentarium of diagnostic investigations, both non-invasive and invasive, currently clinically available is only able to provide us with data related to the stenotic severity of a coronary artery. The non-invasive testing includes stress-induced (exercise or pharmacological) ischaemic changes in electrical repolarisation, wall motion or myocardial radioactive-tracer uptake. The invasive test of coronary angiography, although the current 'gold standard' for the detection of coronary atherosclerotic disease, provides us with no data about the composition of the atherosclerotic lesion. However, the vast majority of acute coronary events involve a non-critically stenosed atherosclerotic lesion, and thus with currently available means of identification, these lesions would be undetected by stress testing/imaging techniques. Given the critical role that atherosclerotic lesion composition has been shown to play in the risk of both plaque rupture and subsequent thrombogenicity and, consequently, an acute coronary event, new detection techniques need to be investigated for the task of documenting atherosclerotic lesion composition. In the present review we will focus on the status of imaging modalities available for coronary artery imaging and how they may advance our understanding and management of patients with and at risk of coronary artery disease in the new millennium.     

Pathogenesis of Acute Ischemic Coronary Syndromes

Understanding of the pathogenesis of acute ischemic coronary syndromes has lead to the development of novel diagnostic and therapeutic modalities offering the possibility of improved clinical outcomes. This article details the importance of the vulnerable atherosclerotic plaque, invlammaiton and plaque rupture and thronbosis in the development of the clinical manifestations of an acute ischemic coronary syndrome.     

Assessing coronary plaque burden and plaque vulnerability: atherosclerosis imaging with IVUS and emerging noninvasive modalities

Despite significantly improved preventive and therapeutic options, coronary artery disease remains the major cause of mortality in North America. A large number of acute coronary events, including acute myocardial infarction and sudden cardiac death, occur in patients without prior symptoms because these events are initiated by sudden rupture of mildly stenotic but vulnerable lesions. Recent results demonstrate a high prevalence of such plaques many years before clinical events occur. Because these lesions are mildly stenotic before the event, the angiographic evaluation of the lumen is not sufficient for their detection. Therefore, direct observation of coronary plaque burden and plaque vulnerability with in vivo tomographic imaging modalities is increasingly utilized. Intravascular ultrasound is the most established invasive method with a long clinical track record. More recently, noninvasive modalities including computed tomography and magnetic resonance imaging are emerging.     

Prevalence of Chlamydia pneumoniae in the atherosclerotic plaque of patients with unstable angina and its relation with serology

BACKGROUND: Chlamydia pneumoniae has been associated with coronary artery disease by both seroepidemiological studies, and by direct detection of the micro-organism in atherosclerotic lesions. This bacteria could play a potential role in the development of acute coronary events. We examined coronary arteries from patients with unstable angina in order to verify an endovascular presence of C. pneumoniae, and to determine if there is any relationship between serology of acute infection by this pathogen and its presence inside the atherosclerotic plaque of these patients. METHODS: We analysed a total of 76 atherosclerotic plaques obtained from 45 patients who underwent coronary artery bypass surgery. In all patients unstable angina was present within the prior 3 weeks. The presence of C. pneumoniae in the plaque was determined by nested polymerase chain reaction (PCR). Antichlamydial immunoglobulin G (IgG), A (IgA) and M (IgM) was examined by microimmunofluorescence and compared to the PCR result. FINDINGS: DNA of C. pneumoniae was detected in 57 (75%) of 76 atherosclerotic lesions. In most cases (74/76: 97%) a positive IgA, IgM or IgG result was seen. Seven (12%) and 54 (94%) of the 57 PCR positive plaques came from patients with a positive IgM and IgA result, respectively. There was no statistical significant difference between PCR positive and PCR negative plaques in patients with a positive or negative serological result. Clinical characteristics were similarly distributed in patients with and without infected lesions. INTERPRETATION: C. pneumoniae organisms are frequently found in the atherosclerotic lesions of patients undergoing coronary surgery for unstable angina. Neither serological results of acute or recent infection by C. pneumoniae nor clinical characteristics are useful in predicting the individual risk of harbouring C. pneumoniae in the coronary lesions of patients with unstable angina.     

Pathophysiology of acute coronary syndromes

The natural history of coronary artery disease is punctuated by clinical manifestations of unstable angina, acute myocardial infarction, and ischemic sudden death. These acute coronary syndromes share common pathophysiologic mechanisms that include fissuring of a plaque followed by varying degrees of dynamic coronary obstruction, which is due to vasoconstriction and coronary thrombosis. The response to plaque fissure is likely to be modulated by local and/or systemic procoagulant and anticoagulant-fibrinolytic activities. The key role of coronary thrombosis in acute coronary syndromes has substantial implications for prevention and treatment of complications of coronary atherosclerosis.     

Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome

OBJECTIVES: To determine the morphologic features of coronary plaques associated with acute coronary syndrome, we prospectively followed patients with atherosclerotic disease identified by intravascular ultrasound (IVUS). BACKGROUND: Although clinical evaluation of the vulnerable atherosclerotic plaque is important, few data exist regarding the morphology of the vulnerable plaque in clinical settings. METHODS: We examined 114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patients. All the sites exhibited atherosclerotic lesions by IVUS. These lesions consisted of 22 concentric and 92 eccentric plaques with a percent plaque area averaging 59 +/- 12%. RESULTS: During the follow-up period of 21.8 +/- 6.4 months (range 1 to 24), 12 patients had an acute coronary event at a previously examined coronary site at an average of 4.0 +/- 3.4 months after the initial IVUS study. All the preexisting plaques related to the acute events exhibited an eccentric pattern and the mean percent plaque area was 67 +/- 9%, which was greater than plaque area in the other 90 patients without acute events (57 +/- 12%, p < 0.05). There was no statistically significant difference in lumen area between two patient groups (6.7 +/- 3.0 vs. 7.5 +/- 3.7 mm2). Among 12 coronary sites with an acute occlusion, 10 sites contained the echolucent zones, eight of these shallow and two deep, likely representing a lipid-rich core. In 90 sites without acute events, an echolucent zone in the shallow portion was seen at only four sites (p < 0.05). CONCLUSIONS: Large eccentric plaque containing an echolucent zone by IVUS can be at increased risk for instability even though the lumen area is preserved at the time of initial study. Compensatory enlargement of vessel wall due to remodeling may contribute to the relatively small degree of stenosis by angiography.     

Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes

Unstable angina appears to be a good clinical marker for rapidly progressing coronary artery disease. Pathologically, an unstable atherothrombotic coronary lesion, represented by a raised atherosclerotic plaque with ruptured surface causing variable degree of hemorrhage into the plaque and luminal thrombosis (rapid plaque progression), usually is present in patients at autopsy after a period of unstable angina. The thrombus at the rupture site may be mural and limited (just sealing the rupture) or occlusive, depending on the degree of preexisting atherosclerotic stenosis. An occlusive thrombus is seldom seen over ruptured plaques causing less than 75% stenosis (histologic cross-sectional area reduction), but it is found with increasing frequency when severity of stenosis increases beyond 75%. Most occlusive thrombi have a layered structure with thrombus material of differing age indicating an episodic growth by repeated mural deposits, and microemboli/microinfarcts are frequently found in the myocardium downstream to coronary thrombi, indicating intermittent thrombus fragmentation with peripheral embolization. Such a "dynamic thrombosis" (with or without a concomitant focal vasospastic phenomenon) at the site of an unstable (ruptured) atherosclerotic lesion obviously may lead to the other thrombus-related acute coronary events: myocardial infarction or sudden death. Accordingly, progression of unstable angina to myocardial infarction or sudden death should, in principle, be preventable by the correct timing of current available therapies aimed to prevent or eliminate (1) the chronic atherosclerotic obstruction, (2) the acute plaque disruption, (3) luminal thrombosis, and (4) vasospasm.     

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.     

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。     

冠状动脉粥样斑块的治疗现状与进展

冠状动脉粥样斑块是冠状动脉粥样硬化性心脏病的基本病理改变，斑块的破裂可以导致急性冠脉综合征。如何干预动脉粥样斑块是目前的研究热点，大量研究已证实，药物治疗、内皮祖细胞移植、生活方式干预等方法可以早期干预动脉粥样斑块。本文将从以上方面介绍冠状动脉粥样斑块的治疗方法研究现状及相关机制。