Where is the trace? Molecular imaging of vulnerable atherosclerotic plaques

Serious cardiovascular events frequently arise from rupture of vulnerable atherosclerotic plaques. Not infrequently, these plaques are clinically silent and suddenly cause acute complications such as myocardial infarction, which in a high percentage are fatal. Thus, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in clinical medicine. This review highlights noninvasive scintigraphic techniques, which use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing their biological activity. One major principle is the molecular imaging of inflammation with radionuclide tracers, including detection of metabolic activity, chemotaxis, cell recruitment, and lipoprotein enrichment. Additional studies focus on visualization of apoptosis, angiogenesis, or proteolysis. A central feature of plaque vulnerability is its thrombogenicity. Therefore, detection of thrombogenic plaques is another promising principle of molecular imaging. If a reliable protocol to image vulnerable plaques, which are prone to rupture, can be established and introduced into clinical practice, the required measures such as atheroprotective medication or revascularization could be undertaken to prevent serious cardiovascular events.     

Radionuclide imaging: a molecular key to the atherosclerotic plaque

Despite primary and secondary prevention, serious cardiovascular events such as unstable angina or myocardial infarction still account for one-third of all deaths worldwide. Therefore, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in cardiovascular medicine. Several noninvasive techniques, such as magnetic resonance imaging, multislice computed tomography, and electron beam tomography are currently being tested for their ability to identify such patients by morphological criteria. In contrast, molecular imaging techniques use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing their biological activity. Based upon the knowledge about the pathophysiology of atherosclerosis, various studies in vitro and in vivo and the first clinical trials have used different tracers for plaque imaging studies, including radioactive-labeled lipoproteins, components of the coagulation system, cytokines, mediators of the metalloproteinase system, cell adhesion receptors, and even whole cells. This review gives an update on the relevant noninvasive plaque imaging approaches using nuclear imaging techniques to detect atherosclerotic vascular lesions.     

Noninvasive imaging of the vulnerable atherosclerotic plaque

Atherosclerosis is an inflammatory disease, complicated by progressively increasing atherosclerotic plaques that eventually may rupture. Plaque rupture is a major cause of cardiovascular events, such as unstable angina, myocardial infarction, and stroke. A number of noninvasive imaging techniques have been developed to evaluate the vascular wall in an attempt to identify so-called vulnerable atherosclerotic plaques that are prone to rupture. The purpose of the present review is to systematically investigate the accuracy of noninvasive imaging techniques in the identification of plaque components and morphologic characteristics associated with plaque vulnerability, assessing their clinical and diagnostic value.     

From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization

There is a strong need for biomarkers to identify patients at risk for future cardiovascular events related with progressive atherosclerotic disease. Ideally, increasing knowledge of the mechanisms of atherosclerotic plaque destabilization should be translated in clinical practice. Currently, the following commonly followed strategies can be identified with the objective to detect either the local vulnerable plaque that is prone to rupture and gives rise to a thrombotic occlusion, or the systemic vulnerable patient, who has a high probability to suffer from an adverse clinical event. On the one hand, studies are ongoing to determine local atherosclerotic plaque characteristics to predict future local plaque rupture and subsequent vascular thrombosis. Newly developed imaging modalities are being developed and validated to detect these plaques in vivo. On the other hand, systemic approaches are pursued to discover serum biomarkers that are applicable to define patients at risk for future cardiovascular events. We propose a third original approach that is optional but yet unexplored, that is, to use local plaque characteristics as a biomarker not just for local plaque destabilization but for future cardiovascular events due to plaque progression in any vascular system. This review aims to provide an overview of the current standings of the identification of the vulnerable plaque and the vulnerable patient.     

Molecular imaging of plaques in coronary arteries with PET and SPECT

Coronary artery disease remains a major cause of mortality. Presence of atherosclerotic plaques in the coronary artery is responsible for lu-men stenosis which is often used as an indicator for determining the severity of coronary artery disease. However, the degree of coronary lumen stenosis is not often related to compromising myocardial blood flow, as most of the cardiac events that are caused by atherosclerotic plaques are the result of vulnerable plaques which are prone to rupture. Thus, identification of vulnerable plaques in coronary arteries has become increas-ingly important to assist identify patients with high cardiovascular risks. Molecular imaging with use of positron emission tomography （PET） and single photon emission computed tomography （SPECT） has fulfilled this goal by providing functional information about plaque activity which enables accurate assessment of plaque stability. This review article provides an overview of diagnostic applications of molecular imaging tech-niques in the detection of plaques in coronary arteries with PET and SPECT. New radiopharmaceuticals used in the molecular imaging of coro-nary plaques and diagnostic applications of integrated PET/CT and PET/MRI in coronary plaques are also discussed.     

<Superscript>18</Superscript>F-Fluorodeoxyglucose PET Imaging of Coronary Atherosclerosis and Plaque Inflammation

The emphasis of current cardiovascular imaging modalities is on the anatomic detection of coronary artery luminal narrowing. However, in the clinical setting, vulnerable plaques that are not flow limiting may account for the majority of cardiovascular events. Thus, the pursuit for developing noninvasive imaging techniques that target vulnerable plaques is a laudable goal. Recent studies have demonstrated the clinical feasibility of direct visualization and characterization of coronary and carotid artery plaques with ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography imaging. In experimental studies, the intensity of FDG uptake has been shown to correlate with macrophage density and inflammatory state of plaques. Vascular plaque FDG uptake has been linked to cardiovascular events such as myocardial infarction and stroke. Anti-inflammatory drugs and statins have been shown to attenuate FDG uptake in plaques. Thus, the identification of FDG uptake in vascular plaques may have important clinical implications for predicting and preventing future cardiovascular events.     

Imaging the vulnerable plaque

Cardiovascular diseases are still the primary causes of mortality in the United States and in Western Europe. Arterial thrombosis is triggered by a ruptured atherosclerotic plaque and precipitates an acute vascular event, which is responsible for the high mortality rate. These rupture-prone plaques are called "vulnerable plaques." During the past decades, much effort has been put toward accurately detecting the presence of vulnerable plaques with different imaging techniques. In this review, we provide an overview of the currently available invasive and noninvasive imaging modalities used to detect vulnerable plaques. We will discuss the upcoming challenges in translating these techniques into clinical practice and in assigning them their exact place in the decision-making process.     

预测颈动脉粥样硬化易损斑块的新型生物标志物研究进展

易损斑块是指动脉壁内稳定性差的斑块,其易破裂、脱落,导致原位血栓或多发微栓子形成。颈动脉粥样硬化易损斑块是缺血性脑卒中的主要致病机制,颈动脉斑块易损性增加脑缺血事件的发生。因此,早期鉴别易损斑块,对干预脑卒中高危因素、改善脑卒中预后具有重要意义。除各类影像技术外,循环生物标志物为识别颈动脉易损斑块提供了辅助手段。本综述回顾以往研究,讨论能够识别颈动脉易损斑块的新型生物标志物。     

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.     

The vulnerable plaque: Current concepts and future perspectives on coronary morphology,composition and wall stress imaging

Cardiovascular imaging plays an important role in the identification and characterization of the vulnerable plaque. A major goal is the ability to identify individuals at risk of plaque rupture and developing an acute coronary syndrome. Early recognition of rupture‐prone atherosclerotic plaques may lead to the development of pharmacologic and interventional strategies to reduce acute coronary events.We review state‐of‐the‐art cardiovascular imaging for identification of the vulnerable plaque. There is ample evidence of a close relationship between plaque morphology and patient outcome, but molecular imaging can add significant information on tissue characterization, inflammation and subclinical thrombosis. Additionally, identifying arterial wall exposed to high shear stress may further identify rupture‐prone arterial segments. These new modalities may help reduce the individual, social and economic burden of cardiovascular disease.     

Thermography of the cardiovascular system

The identification of vulnerable plaque is one of the primary goals in cardiology during the last years. Several techniques have been developed for the anatomic and functional assessment of atherosclerotic plaques. Thermography is a new method for the evaluation of the inflammatory process locally within the atherosclerotic plaque. Several animal and clinical studies demonstrated the value of thermography not only for the detection of inflamed atherosclerotic plaques, but its use in new fields like in the evaluation of inflammation in the coronary vascular bed and the cardiovascular system. This article reviews the developments and the clinical implications of thermography.     

Intracoronary Imaging in the Detection of Vulnerable Plaques

Coronary artery disease is the result of atherosclerotic changes to the coronary arterial wall, comprising endothelial dysfunction, vascular inflammation and deposition of lipid-rich macrophage foam cells. Certain high-risk atherosclerotic plaques are vulnerable to disruption, leading to rupture, thrombosis and the clinical sequelae of acute coronary syndrome. Though recognised as the gold standard for evaluating the presence, distribution and severity of atherosclerotic lesions, invasive coronary angiography is incapable of identifying non-stenotic, vulnerable plaques that are responsible for adverse cardiovascular events. The recognition of such limitations has impelled the development of intracoronary imaging technologies, including intravascular ultrasound, optical coherence tomography and near-infrared spectroscopy, which enable the detailed evaluation of the coronary wall and atherosclerotic plaques in clinical practice. This review discusses the present status of invasive imaging technologies; summarises up-to-date, evidence-based clinical guidelines; and addresses questions that remain unanswered with regard to the future of intracoronary plaque imaging.     

Atherosclerotic plaque biomarkers: beyond the horizon of the vulnerable plaque

Cardiovascular disease (CVD) is the number one cause of death globally, and the majority of CVD is caused by atherosclerosis. Atherosclerosis is a systemic inflammatory disease that leads to myocardial infarction, stroke and lower limb ischemia. Pathological studies have given insight to development of atherosclerosis and the importance of local plaque vulnerability, leading to thrombus formation and cardiovascular events. Due to the burden of cardiovascular disease, identification of patients at risk for cardiovascular events and treatment stratification is needed. The predictive power of classical risk factors is limited, especially in patients with manifest atherosclerosis. Imaging modalities have focused on the characteristics of the vulnerable plaque. However, it has become evident that not all so-called vulnerable plaques lead to rupture and subsequent thrombosis. The latter obviously limits the positive predictive value for imaging assessment of plaques and patients at risk. Serum biomarkers have also been studied extensively, but have very limited application in a clinical setting for risk stratification. In line with the important relation between vulnerable plaques and cardiovascular events, plaque biomarker studies have been initiated. These longitudinal studies are based on the concept, that a vulnerable plaque contains predictive information for future cardiovascular events, also in other territories of the vascular tree. Results look promising and plaque markers can be used to develop imaging modalities to identify patients at risk, or to monitor treatment effect. Plaque biomarker studies do not challenge the definition of the vulnerable plaque, but use its concept in favor of prediction improvement for vascular patients.     

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.     

Non-FDG imaging of atherosclerosis: will imaging of MMPs assess plaque vulnerability?

Acute ruptures of atherosclerotic plaques with subsequent occlusion account for the vast majority of clinical events such as myocardial infarction or stroke. New imaging approaches focusing on the visualization of inflammation in the vessel wall could emerge as tools for individualized risk assessment and prevention of events. To this end, PET employing (18)F-fluorodeoxyglucose (FDG) has recently been introduced for the first clinical trials. Although this approach nicely visualizes plaques inflammation questions remain with respect to if and how this inflammatory signal can be employed for predicting individual plaque rupture. Molecular imaging of proteases such as matrix-metalloproteinases (MMPs) involved in several steps in plaque progression driving plaques into vulnerable, rupture-prone states seems a promising alternative approach. This review introduces and discusses the vulnerable plaque concept, animal models with human-like plaque ruptures and the potential of a FDG versus a non-FDG MMP-targeted strategy to image rupture-prone plaques.     

Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque

Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.     

Identifying the vulnerable plaque: A review of invasive and non-invasive imaging modalities

Atherosclerotic cardiovascular disease is the current leading cause of death in industrialized countries. The vast majority of acute cardiovascular events (50-70%) are ascribed to thrombosis following rupture of a vulnerable plaque. Therefore there is an urgent need to discern vulnerable, unstable plaques from stable plaques. A variety of imaging modalities, both invasive and non-invasive, have been developed for the assessment of visualization and quantification of atherosclerosis. In this review, we discuss the advantages and limitations of the available imaging techniques, and their clinical potential for assessment of plaque vulnerability.     

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。     

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.     

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.