Targeting the inflammatory component in atherosclerotic lesions vulnerable to rupture

Thrombosis of the coronary artery following plaque rupture is the commonest substrate of acute coronary events. The detection of atherosclerotic plaques prone to rupture would allow identifying patients at risk for acute coronary events and aggressive intervention. It has been assumed that the plaque morphology happens to be the major determinant for clinical outcome. The risk of plaque rupture depends upon the prevalence of plaques that have a large lipid core, a thin fibrous cap, and a dense inflammation of the fibrous cap. Evaluating monocytes and the lipid core and their proportions in the atherosclerotic lesion by novel radionuclide imaging strategies may predict a likelihood of an acute coronary event.     

Arithmetic of vulnerable plaques for noninvasive imaging

Sudden cardiac death and acute myocardial infarction often occur as the first manifestation of coronary artery disease. Otherwise asymptomatic individuals with subclinical atherosclerosis almost always have a classic risk-factor profile and it is essential that they are identified before the occurrence of an acute coronary event. The ability to recognize such individuals requires the development of strategies that can localize unstable atherosclerotic lesions. Plaques that are vulnerable to rupture demonstrate distinct histological characteristics, including large plaque and necrotic core volumes, extensive remodeling of the vessel at the lesion site, and attenuated fibrous caps. Precise metrics of typical vulnerable atherosclerotic plaque dimensions will need to be defined to facilitate their identification by noninvasive imaging modalities.     

Techniques characterizing the coronary atherosclerotic plaque: influence on clinical decision making?

The composition of the atherosclerotic lesion rather than the degree of stenosis is currently considered to be the most important determinant for acute clinical events. Modalities capable of characterizing the atherosclerotic lesion may be helpful in understanding its natural history and detecting lesions with high risk for acute events. Speaking grossly, three histologic features of the vulnerable plaque have been reported: size of the atheroma, thickness of the fibrous cap, and inflammation. Imaging techniques are currently being deployed and are under development to aid visualization of the vulnerable coronary plaque. Most of these diagnostic modalities have the potential to detect locally one or more of the three histologically defined features of vulnerable plaque. This review will focus on imaging techniques that have been developed to characterize the atherosclerotic lesion. Most catheter-based visualization techniques will provide insight into components of the local atherosclerotic plaque which may limit their predictive value for the occurrence of a clinical event. Therefore, the clinical relevance of these imaging tools will be discussed.     

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.     

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.     

Intracoronary Thermography: Does It Help Us in Clinical Decision Making?

The concept of the "vulnerable" plaque has recently emerged to explain how quiescent atherosclerotic lesions evolve to cause clinical events. The morphologic and immunologic determinants specific for the vulnerable plaque have been reported: a large lipid core (>or=40% plaque volume) composed of free cholesterol crystals, cholesterol esters, and oxidized lipids impregnated with tissue factor; a thin fibrous cap depleted of smooth muscle cells and collagen; an outward (positive) remodeling; inflammatory cell infiltration of fibrous cap and adventitia (mostly monocyte-macrophages, some activated T cells, and mast cells); and increased neovascularity. Despite the large amount of information regarding the morphological characteristics of remote lesions, we lack studies with functional assessment of non-culprit lesions. Coronary thermography is a technique for functional assessment of coronary atherosclerotic plaques. Several catheter designs have been proposed. There are catheters with thermistor(s) and wires with thermal sensors at the distal tip. All designs have several advantages and disadvantages. Despite the current limitations of coronary thermography, we gained important pathophysiological and clinical information regarding the vulnerability of atheromatic plaques. It has been documented both experimentally and clinically that increased heat generation is associated with increased macrophage concentration within the plaque. The correlation between local inflammatory involvement and local heat generation has also been observed with the peripheral inflammatory markers such as C-reactive protein. Whether systemic treatment, with agents such as statins or interventional techniques, such as drug-eluting stents, will have an impact on stabilizing vulnerable plaques need to be determined in future studies. In conclusion, although there are several techniques for evaluating morphologically atheromatic plaques, thermography is a promising method for the functional assessment of vulnerable plaque and has been introduced into clinical practice, with a good predictive value for clinical events in patients with increased temperature in the atherosclerotic plaque.     

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.     

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.     

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.     

Evolving Concepts in the Triad of Atherosclerosis,Inflammation and Thrombosis

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to "passive" disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.     

Mechanisms of acute coronary syndromes and the potential role of statins

The conventional concepts of the pathogenesis of acute coronary syndromes are changing. High-risk lesions are not necessarily the angiographicaly 'tight' stenoses. Rather, vulnerable lesions are those that are unstable, with a large lipid core and a thin fibrous cap. Plaque instability is closely related to the development of inflammation within the intima and acute coronary syndromes result from rupture of a vulnerable atherosclerotic plaque. Stabilization of lesions by modification of structure and content, rather than simple improvement in the luminal diameter, provides a new therapeutic target. Stabilization may be accomplished through lifestyle changes and appropriate pharmacologic therapy. In the past few years, it has become evident that a major beneficial effect of statins is to induce plaque stability and regression. In fact, statins, in addition to lowering low-density lipoprotein cholesterol, have a variety of pleiotropic, or cholesterol-independent, effects that make them a particularly suitable choice in patients with acute coronary syndromes. Among these are improvements in endothelial function, smooth muscle cells, thrombus formation/platelet function, and inflammation.     

Plaque instability in peripheral vessels

Vulnerable atherosclerotic plaques, those that are prone to rupture, are soft and lipid rich. Other factors that contribute to destabilizing these plaques are inflammation and vasoconstriction. Although less information is available regarding noncoronary vulnerable plaques than the more frequently studied coronary plaques, it appears that the amount of soft lipid “gruel” as well as in situ inflammation plays a crucial role in destabilizing peripheral vascular atherosclerotic plaque, eventually causing its rupture. As in the coronary circulation, it is likely that the majority of acute plaque rupture events are clinically silent. Nevertheless, preventing plaque rupture in the noncoronary circulation is of the utmost importance because this is the presumed mechanism of progression of peripheral vascular atherosclerotic lesions. Copyright 2002, Elsevier Science (USA). All rights reserved.     

急性冠状动脉综合征的诊断与治疗新进展

急性冠状动脉综合征导致心血管事件的主要原因是动脉粥样硬化斑块的破裂和血栓形成。不稳定斑块纤维帽较薄,脂质成分多,大量炎性细胞浸润,基质金属蛋白酶含量多。不稳定斑块的临床识别手段有冠状动脉造影、血管内超声、高分辨核磁共振、冠状动脉血管镜、电子束CT及C反应蛋白、CD40L、基质金属蛋白酶、胰岛素样生长因子、白介素(IL)-1、IL-6、IL-8等的测定。急性冠状动脉综合征的治疗有药物治疗与再灌注治疗两大方面,药物治疗包括抗血小板、抗凝、抗缺血、调脂治疗等。再灌注治疗对于无条件进行经皮冠状动脉介入治疗的ST段抬高型心肌梗死患者,在急性心肌梗死3～12 h内溶栓治疗为首选,经皮冠状动脉介入治疗适宜于所有急性冠状动脉综合征患者。目前治疗性血管生成、干细胞移植尚处于试验阶段。     

Plaque Rupture and Thrombosis: the Value of the Atherosclerotic Rabbit Model in Defining the Mechanism

Persistent inflammation and mechanical injury associated with cholesterol crystal accretion within atherosclerotic plaques typically precedes plaque disruption (rupture and/or erosion) and thrombosis—often the terminal events of atherosclerotic cardiovascular disease. To elucidate the mechanisms of these events, the atherosclerotic rabbit model provides a unique and powerful tool that facilitates studies of atherogenesis starting with plaque buildup to eventual disruption. Examination of human coronary arteries obtained from patients who died with myocardial infarction demonstrates evidence of cholesterol crystals perforating the plaque cap and intimal surface of the arterial wall that can lead to rupture. These observations were made possible by omitting ethanol, an avid lipid solvent, from the tissue processing steps. Importantly, the atherosclerotic rabbit model exhibits a similar pathology of cholesterol crystals perforating the intimal surface as seen in ruptured human plaques. Local and systemic inflammatory responses in the model are also similar to those observed in humans. The strong parallel between the rabbit and human pathology validates the atherosclerotic rabbit model as a predictor of human pathophysiology of atherosclerosis. Thus, the atherosclerotic rabbit model can be used with confidence to evaluate diagnostic imaging and efficacy of novel anti-atherosclerotic therapy.     

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.     

FDG PET Imaging and Cardiovascular Inflammation

The underlying pathologic mechanism of most acute coronary syndromes is atherosclerotic plaque rupture. One cause of rupture is plaque inflammation, leading to fibrous cap destabilization. Several imaging techniques, including x-ray coronary angiography and multislice CT, can be used for the detection of coronary atherosclerosis. However, these anatomical methods cannot measure arterial inflammation. Positron emission tomography imaging of atherosclerosis using the metabolic marker fluorodeoxyglucose allows quantification of arterial inflammation across multiple vessels. This review discusses the rationale, utility, potential future applications, and limitations of this emerging biomarker of cardiovascular risk.     

Clinical applicability of coronary atherosclerotic lesion characterization

Native coronary atherosclerosis (CAS) is a diffuse and progressive disease process that is occasionally associated with either clinical atherothrombosis and/or major adverse cardiac events (MACE) including: ST elevation myocardial infarction (STEMI), acute coronary syndromes without ST elevation (ACSWSTE), heart failure, cardiac arrest and sudden cardiac death. Both, the timing and coronary site responsible for the MACE are currently unpredictable. Cardiovascular investigators have engaged in the task of characterizing CAS lesions in order to enhance our knowledge of CAS pathophysiology. It was expected that the knowledge acquired will allow scientists and clinicians to develop effective strategies to detect and treat "vulnerable plaque" (VP) prior to the evolution of MACE. This review discusses the emerging data regarding the pathology and natural history of the VP and vulnerable patient and the progress made in characterizing atherosclerotic plaque instability and vulnerability. Future directions in the field of plaque characterization and their potential clinical and research applications are discussed.     

Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior

Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions, where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaque exhibits an individual natural history of progression, regression, or stabilization, which is dependent not only on the formation and progression of atherosclerosis but also on the vascular remodeling response. Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall are incompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS in particular, and the biology of the wall is likely to be important. In this review, we explore the molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different natural history trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessive expansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promoting continued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventually further plaque progression and excessive expansive remodeling. An enhanced understanding of the pathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for early identification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients and prevention of acute coronary syndromes.     

稳定斑块——治疗急性冠状动脉综合征的新策略

急性冠状动脉综合征主要由于不稳定的冠状动脉粥样硬化斑块受侵蚀或破裂继发血栓引起。不稳定斑块的特征包括巨大的脂核、炎症细胞和炎症介质的增多以及较薄的纤维帽。对此进行干预可望达到稳定斑块的目的,从而给急性冠状动脉综合征的防治带来新的前景。