MRI of atherosclerosis: diagnosis and monitoring therapy

Atherosclerosis is a prevalent disease affecting millions of Americans. Despite our advances in diagnosis and treatment, atherosclerosis is the leading cause of death in America. High-resolution magnetic resonance imaging has overcome the limitations of current angiographic techniques and has emerged as a leading noninvasive imaging modality for atherosclerotic disease. Atherosclerosis of the arterial wall of the human carotid, aortic, peripheral and coronary arteries have all been successfully evaluated. In addition, the power of magnetic resonance imaging to differentiate the major components of atherosclerotic plaque has been validated. The ability to image the vessel wall and risk stratify atherosclerotic plaque will create management decisions not previously faced, and has the potential to change the way atherosclerosis is treated.     

磁共振评估冠状动脉粥样硬化斑块的研究进展

冠状动脉粥样硬化性心脏病(coronary atherosclerosis heart disease,CHD)是人类主要死亡原因之一,其中急性冠脉综合征(acute coronary syndromes,ACS)是导致患者预后不良和发生猝死的主要原因。尸检病理结果发现,ACS发病的主要原因为动脉粥样硬化易损斑块破裂或内皮表面糜烂导致冠脉内血栓形成。磁共振成像(magnetic resonance imaging,MRI)作为一种无创、可重复性强、组织分辨率高的检查方法,多对比成像序列经过20余年的研发在颈动脉粥样硬化斑块中的应用已得到广泛证实,并在临床上及病理对照上得到进一步的验证。但冠状动脉管壁成像由于成像技术复杂,目前尚处于研究阶段。本文就磁共振成像评估冠状动脉粥样硬化斑块的研究进展进行综述。     

Current Development of Molecular Coronary Plaque Imaging using Magnetic Resonance Imaging towards Clinical Application

Cardiovascular disease (CVD) remains the leading cause of death in Western countries despite improvements in prevention, diagnosis and treatment. Atherosclerosis is a chronic inflammatory disease that remains clinically silent for many decades. Sudden rupture of “high-risk/vulnerable” plaques has been shown to be responsible for the majority of acute cardiovascular events, including myocardial infarction and stroke. Therefore, early detection of biological processes associated with atherosclerosis progression and plaque instability may improve diagnosis and treatment and help to better monitor the effectiveness of therapeutic interventions. Molecular magnetic resonance imaging (MRI) is a promising tool to detect molecular and cellular changes in the carotid, aortic and coronary vessel wall including endothelial dysfunction, inflammation, vascular remodelling, enzymatic activity, intraplaque haemorrhage and fibrin deposition and thus may allow early detection of unstable lesions and improve the prediction of future coronary events. Evaluation of atherosclerosis at both, the preclinical and clinical level includes non-contrast-enhanced (NCE) and contrast-enhanced (CE) MRI with and without the use of MR contrast agents. To increase the biological information obtained by MRI a variety of targeted-specific molecular probes have been developed for the non-invasive visualization of particular biological processes at the molecular and cellular level. This review will discuss the recent advances in molecular MRI of atherosclerosis, covering both pulse sequence development and also the design of novel contrast agents, for imaging atherosclerotic disease in vivo.     

Imaging of the vulnerable plaque: new modalities

Atherosclerosis is currently considered to be an inflammatory and thus a systemic disease affecting multiple arterial beds. Recent advances in intravascular imaging have shown multiple sites of atherosclerotic changes in coronary arterial wall. Traditionally, angiography has been used to detect and characterize atherosclerotic plaque in coronary arteries, but recently it has been found that plaques that are not significantly stenotic on angiography cause acute myocardial infarction. As a result, newer imaging and diagnostic modalities are required to predict which of the atherosclerotic plaque are prone to rupture and hence distinguish "stable" and "vulnerable" plaques. Intravascular ultrasound can identify multiple plaques that are not seen on coronary angiography. Thermography has shown much promise and is based on the concept that the inflammatory plaques are associated with increased temperature and can also identify "vulnerable patients." Of all these newer modalities, magnetic resonance imaging has shown the most promise in identification and characterization of vulnerable plaques. In this article, we review the newer coronary artery imaging modalities and discuss the limitations of traditional coronary angiography.     

Magnetic Resonance Imaging of Carotid Atherosclerosis and the Risk of Stroke

Stroke attributable to carotid atherosclerosis is a leading cause of mortality and morbidity. The clinical management of carotid atherosclerosis presently relies on the degree of stenosis determined by angiography. Degree of stenosis is limited in stratifying patients’ risk of stroke. Advances in magnetic resonance imaging have resulted in the ability to directly assess atherosclerotic plaque components, morphology, and biomechanical stress levels. Components of atherosclerosis, including lipid-rich necrotic core, fibrous cap thickness/disruption, and intraplaque hemorrhage, are promising emerging indicators of stroke. Information beyond luminal stenosis from magnetic resonance imaging may allow for improved detection of patients at risk of stroke from carotid atherosclerosis. We review the recent literature on the relationship of magnetic resonance imaging detected plaque components and cerebrovascular events. Clinical applications of magnetic resonance imaging of carotid plaque components are discussed.     

Positron emission tomography of the vulnerable atherosclerotic plaque in man – a contemporary review

Atherosclerosis is the primary underlying cause of cardiovascular disease (CVD). It is the leading cause of morbidity and mortality in the Western world today and is set to become the prevailing disease and major cause of death worldwide by 2020. In the 1950s surgical intervention was introduced to treat symptomatic patients with high‐grade carotid artery stenosis due to atherosclerosis – a procedure known as carotid endarterectomy (CEA). By removing the atherosclerotic plaque from the affected carotid artery of these patients, CEA is beneficial by preventing subsequent ipsilateral ischemic stroke. However, it is known that patients with low to intermediate artery stenosis may still experience ischemic events, leading clinicians to consider plaque composition as an important feature of atherosclerosis. Today molecular imaging can be used for characterization, visualization and quantification of cellular and subcellular physiological processes as they take place in vivo; using this technology we can obtain valuable information on atherosclerostic plaque composition. Applying molecular imaging clinically to atherosclerotic disease therefore has the potential to identify atherosclerotic plaques vulnerable to rupture. This could prove to be an important tool for the selection of patients for CEA surgery in a health system increasingly focused on individualized treatment. This review focuses on current advances and future developments of in vivo atherosclerosis PET imaging in man.     

Plaque progression and regression in atherothrombosis

Summary.  Atherosclerotic disease is a pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall. The deposition of these materials and the subsequent thickening of the wall may significantly compromise the vessel lumen. Atherosclerosis is a diffuse disease with focal clinical manifestations that are the consequence of thrombotic complications on disrupted atherosclerotic lesions. Until recently, atherosclerosis development was envisaged as an incessant progressing process; however, new evidence has shown that atherosclerotic plaque homeostasis is not necessarily a constantly progressing process. There are many data showing that atherosclerotic plaque formation can be slowed, stopped or even reversed. Comprehension of the underlying mechanisms involved in the homeostasis of atherosclerotic plaque (progression/regression) should allow the development of interventions enhancing the regression pathway. Novel imaging technology has allowed the accurate evaluation of plaque progression, vital in the assessment of the efficacy of interventions. In this review we discuss the processes involved in the formation and progression of atherosclerotic lesions, the triggers for plaque disruption, as well as new therapies. We also deal with the potential pathways of plaque regression, as well as tools for accurate serial atherosclerotic quantification.     

MRI对易损斑块的临床研究进展

动脉粥样硬化斑块破裂和血栓形成是诱发心脑血管疾病的直接原因。及时识别斑块的易损性逐渐成为近年的研究热点。影像学技术能直观易损斑块相关特征,提供相应治疗策略。核磁共振作为一项无创检查手段,可以对斑块的形态和功能进行综合评价。本文就核磁共振对颈动脉斑块的形态功能学检查做一简要综述。     

Subclinical atherosclerosis: what it is, what it means and what we can do about it

Atherosclerosis is a chronic, progressive, inflammatory disease with a long asymptomatic phase. Disease progression can lead eventually to the occurrence of acute cardiovascular events such as myocardial infarction, unstable angina pectoris and sudden cardiac death. While the disease is still in a subclinical stage, however, the presence of atherosclerosis can be identified by several methods, including coronary angiography, intravascular ultrasonography, B-mode ultrasonography, computed tomography and magnetic resonance imaging. Based on the results of imaging studies, statin therapy can slow, halt or even reverse the progression of atherosclerotic disease, depending on the intensity of treatment. Whether to screen and treat patients for subclinical atherosclerosis remains controversial. Although atheromatous plaque burden reduction has not yet been definitively correlated with significant decreases in risk for acute coronary events in asymptomatic patients, statin therapy contributes significantly to the risk reduction observed in clinical trials in patients with and without overt coronary disease.     

ARFI imaging for noninvasive material characterization of atherosclerosis

Cardiovascular disease (CVD) is the leading cause of death in the United States, with 70% of CVD mortalities the result of sequelae of atherosclerosis. An urgent need for enhanced delineation of vulnerable plaques has catalyzed the development of novel atherosclerosis imaging strategies that use X-ray computed tomography, magnetic resonance and ultrasound modalities. As suggested by the pathophysiology of plaque development and progression to vulnerability, insight to the focal material, i.e., mechanical, properties of arterial walls and plaques may enhance atherosclerosis characterization. We present acoustic radiation force impulse (ARFI) ultrasound in application to mechanically characterizing a raised focal atherosclerotic plaque in an iliac artery extracted from a relevant pig model. ARFI results are correlated to matched immunohistochemistry, indicating elastin and collagen composition. In regions of degraded elastin, slower recovery rates from peak ARFI-induced displacements were observed. In regions of collagen deposition, lower ARFI-induced displacements were achieved. This work demonstrates ARFI for characterizing the material nature of an atherosclerotic plaque.     

Noninvasive imaging of atherosclerotic vessels by MRI for clinical assessment of the effectiveness of therapy

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized countries. Despite advances in our understanding of the mechanisms of pathogenesis and new treatment modalities, the absence of an adequate noninvasive method for early detection limits prevention or treatment of patients with various degrees and localizations of atherothrombotic disease. The ideal clinical imaging modality for atherosclerosis should be safe, inexpensive, noninvasive or minimally invasive, accurate, and reproducible, thus allowing longitudinal studies in the same patients. Additionally, the results should correlate with the extent of atherosclerotic disease and have high predictive values for clinical events. In vivo, high-resolution magnetic resonance imaging (MRI) has recently emerged as one of the most promising techniques for the noninvasive study of atherothrombotic disease in several vascular beds such as the aorta, the carotid arteries, and the coronary arteries. Most importantly MRI can be used to characterize plaque composition as it allows the discrimination of lipid core, fibrosis, calcification, and intra-plaque hemorrhage deposits. MRI findings have been extensively validated against pathology in ex vivo studies of carotid, aortic, and coronary artery specimens obtained at autopsy and using experimental models of atherosclerosis. In vivo MRI of carotid arteries of patients referred for endarterectomy has shown a high correlation with pathology and with previous ex vivo results. A recent study in patients with plaques in the thoracic aorta showed that compared with transesophageal echocardiography plaque composition and size are more accurately characterized and measured using in vivo MRI. The composition of the plaque rather than the degree of stenosis determines the patient outcome. Therefore, a reliable noninvasive imaging tool able to detect early atherosclerotic disease in the various regions and identify the plaque composition is clinically desirable. MRI has potential in the detection arterial thrombi and in the definition of thrombus age. MRI has been used to monitor plaque progression and regression in several animal model of atherosclerosis and more recently in human. Advances in diagnosis prosper when they march hand-in-hand with advances in treatment. We stand at the threshold of accurate noninvasive assessment of atherosclerosis. Thus, MRI opens new strategies ranging from screening of high-risk patients for early detection and treatment as well as monitoring the target areas for pharmacological intervention.     

The assessment of the vulnerable atherosclerotic plaque using MR imaging: a brief review

The study of atherosclerotic disease during its natural history and after therapeutic intervention may enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate medical treatments or surgical interventions. Several invasive and non-invasive imaging techniques are available to assess atherosclerotic disease vessels. Most of these techniques are strong in identifying the morphological features of the disease such as lumenal diameter and stenosis or wall thickness, and in some cases provide an assessment of the relative risk associated with the atherosclerotic disease. However, none of these techniques can fully characterize the composition of the atherosclerotic plaque in the vessel wall and therefore are incapable of identifying the vulnerable plaques. High-resolution, multi-contrast, magnetic resonance (MR) can non-invasively image vulnerable plaques and characterize plaques in terms of lipid and fibrous content and identify the presence of thrombus or calcium. Application of MR imaging opens up whole new areas for diagnosis, prevention, and treatment of atherosclerosis.     

Aortic plaque imaging and monitoring atherosclerotic plaque interventions

The atherosclerotic process that results in coronary artery disease (CAD) is recognized to be a generalized process that may involve the entire vasculature. The association between CAD and atherosclerotic plaques in the thoracic aorta has often been reported using transesophageal echocardiography. An autopsy study showed plaques in the abdominal aorta, but not in the thoracic aorta, to be severe in patients with cardiac events. However, studies evaluating an association between abdominal aortic plaques and CAD are scarce. Recently, magnetic resonance imaging (MRI) has become a useful tool for the noninvasive evaluation of atherosclerotic plaques in both the thoracic and abdominal aortas. Plaques in the thoracic and abdominal aortas were found to be characteristically associated with hypercholesterolemia and smoking, respectively, suggesting different susceptibilities to risk factors. Because patients have various risk factors, it seems to be preferable to evaluate atherosclerosis in multiple vascular beds than in just 1 bed. Magnetic resonance imaging can evaluate atherosclerosis in multiple vascular beds in the same examination session. Complex aortic plaques, especially in the abdominal aorta, were found to be associated with myocardial infarction and complex coronary lesions, suggesting a link between aortic and coronary plaque instability. Aortic MRI may thus be useful for identifying vulnerable patients. Moreover, MRI is a powerful tool to serially evaluate plaque progression and regression. Intensive lipid-lowering therapy can regress aortic plaques, but the susceptibility to lipid lowering and the process of plaque regression may differ between the thoracic and abdominal aortic plaques.     

F-18-FDG Imaging for Atherosclerotic Plaque Characterization

Atherosclerosis is a dynamic inflammatory disease of the arterial vessel wall which is still the “number one killer” in Western civilization. It turned out recently that the molecular composition and the metabolic state of atherosclerotic plaques rather than their size or degree of stenosis is of crucial importance to predict the fate of individual plaques. Thus, an imaging modality noninvasively characterizing plaques is needed. In this context, FDG-PET has great potential since FDG accumulates in plaque macrophages and uptake is correlated with macrophage density which is high in highly inflammatory atherosclerotic plaques. FDG uptake in atherosclerosis of large arteries is observed frequently, is associated with cardiovascular risk factors on the one hand, and is probably correlated with the occurrence of cardiovascular events. Moreover, it is reported that vascular FDG uptake can be attenuated by cholesterol-lowering therapies and therefore could also serve as a tool of therapy monitoring. Despite some positive results of preliminary studies, imaging of rupture-prone atherosclerotic plaques with FDG-PET still remains a challenge and is not yet established. The following article provides the biological basis of FDG imaging of atherosclerotic plaques, an overview of preclinical studies, important clinical studies and approaches of coronary artery imaging.     

A focus on inflammation as a major risk factor for atherosclerotic cardiovascular diseases

Atherosclerosis is a dynamic, pathogenic process in the artery wall, with potential adverse outcome for the host. Acute events such as myocardial infarction and ischemic stroke often result from rupture of unstable atherosclerotic lesions. Understanding the underlying pathology of such lesions and why and when they rupture, is therefore of great interest for the development of new diagnostics and treatment. Inflammation is one of the key drivers of atherosclerotic plaque development and the interplay between inflammation and lipids constitutes the hallmark of atherosclerotic disease. This review summarizes the role of inflammation in atherosclerosis and presents some of the latest discoveries as well as unmet needs regarding the role of inflammation as major risk factor in atherosclerotic disease.     

Molecular Imaging to Identify the Vulnerable Plaque—From Basic Research to Clinical Practice

Cardiovascular disease (CVD) is still the leading cause of death in the Western World. Adverse outcomes of CVD include stroke, myocardial infarction, and heart failure. Atherosclerosis is considered to be the major cause of CVD and is estimated to cause half of all deaths in developed countries. Atherosclerotic lesions of the vessel wall may obstruct blood flow mechanically through stenosis, but rupture of atherosclerotic plaques causing formation of occlusive thrombi is far more prevalent. Unfortunately, conventional diagnostic tools fail to assess whether a plaque is vulnerable to rupture. Research over the past decade identified the biological processes that are implicated in the course towards plaque rupture, like cell death and inflammation. Knowledge about plaque biology propelled the development of imaging techniques that target biologic processes in order to predict the vulnerable plaque. This paper discusses novel and existing molecular imaging targets and addresses advantages and disadvantages of these targets and respective imaging techniques in respect of clinical application and socio-economic impact.     

Peripheral arterial disease assessment: wall, perfusion, and spectroscopy

INTRODUCTION: Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to atherosclerosis and is increasingly common. Presently used methods for diagnosis and follow-up as well as for assessment of novel therapies are limited. MATERIALS AND METHODS: Three distinct magnetic resonance examinations were developed. The first was high-resolution black-blood atherosclerotic plaque imaging of the superficial femoral artery using a surface coil and flow saturation. Second, first-pass contrast-enhanced dual-contrast perfusion imaging of the calf muscle was performed at peak exercise using a magnetic resonance (MR)-compatible pedal ergometer. Lastly, (31)P MR spectroscopy was also performed at peak exercise to measure phosphocreatine (PCr) recovery kinetics. RESULTS: Seventeen patients (age, 63 +/- 10 yrs) with mild to moderate PAD were studied with black-blood atherosclerotic plaque imaging. Mean atherosclerotic plaque volume measured was 7.27 +/- 3.73 cm(3). Eleven patients (age, 61 +/- 11 yrs) with mild to moderate symptomatic PAD and 22 normal control subjects were studied with first-pass contrast-enhanced perfusion imaging. Perfusion index was stepwise increased from patients to normal subjects with matched workload to normal subjects at maximal exercise. For PCr recovery kinetics, 20 patients with mild to moderate PAD and 14 controls were studied. The median recovery time constant of PCr was 34.7 seconds in the controls and 91.0 seconds in the PAD patients (P < 0.0001). CONCLUSIONS: Three distinct MR examinations of different aspects of peripheral arterial disease have been developed and tested and shown to differentiate patients with mild to moderate PAD from normal controls. Taken together, these tests are potential quantitative end points for clinical trials of novel therapies in PAD.     

ARFI Imaging for Noninvasive Material Characterization of Atherosclerosis Part II: Toward In Vivo Characterization

Seventy percent of cardiovascular disease (CVD) deaths are attributed to atherosclerosis. Despite their clinical significance, nonstenotic atherosclerotic plaques are not effectively detected by conventional atherosclerosis imaging methods. Moreover, conventional imaging methods are insufficient for describing plaque composition, which is relevant to cardiovascular risk assessment. Atherosclerosis imaging technologies capable of improving plaque detection and stratifying cardiovascular risk are needed. Acoustic radiation force impulse (ARFI) ultrasound, a novel imaging method for noninvasively differentiating the mechanical properties of tissue, is demonstrated for in vivo detection of nonstenotic plaques and plaque material assessment in this pilot investigation. In vivo ARFI imaging was performed on four iliac arteries: (1) of a normocholesterolemic pig with no atherosclerosis as a control, (2) of a familial hypercholesterolemic pig with diffuse atherosclerosis, (3) of a normocholesterolemic pig fed a high-fat diet with early atherosclerotic plaques and (4) of a familial hypercholesterolemic pig with diffuse atherosclerosis and a small, minimally occlusive plaque. ARFI results were compared with spatially matched immunohistochemistry, showing correlations between elastin and collagen content and ARFI-derived peak displacement and recovery time parameters. Faster recoveries from ARFI-induced peak displacements and smaller peak displacements were observed in areas of higher elastin and collagen content. Importantly, spatial correlations between tissue content and ARFI results were consistent and observable in large and highly evolved as well as small plaques. ARFI imaging successfully distinguished nonstenotic plaques, while conventional B-mode ultrasound did not. This work validates the potential relevance of ARFI imaging as a noninvasive imaging technology for in vivo detection and material assessment of atherosclerotic plaques. (E-mail: russbehler@unc.edu)     

Magnetic resonance molecular imaging contrast agents and their application in atherosclerosis

Heart disease is the most prevalent cause of mortality in the Western world and is most frequently caused by rupture of lesions in the arteries, which are formed by atherosclerosis. Atherosclerosis is a progressive disease, and therefore, there is a strong motivation to be able to image the stages of this disease in vivo. The pathogenesis of this disease is now well established, and a number of markers such as macrophages, vascular adhesion molecules, fibrin, and the alphanubeta3-integrin have been identified that are of particular interest for imaging. Furthermore, the differentiation between the stable and unstable plaque with imaging is a central goal of the field. Contrast can be generated in magnetic resonance imaging through the application of several types of agents such as T1, T2, chemical exchange saturation transfer or 19F-based imaging agents. Subsequent to the discussion of the above topics, we will describe some examples of molecular imaging agents that successfully detect specific markers in atherosclerotic plaques that are of interest in several stages of this disease.     

PET/CT无创检测动脉粥样硬化斑块研究进展

动脉粥样硬化是一种慢性、动态的炎症性疾病.急性临床事件的主要决定因素是动脉粥样硬化斑块的生物组成和炎性状况,而非其狭窄程度和大小.PET/CT作为一种无创检查技术,是对机体全身功能和结构相结合的成像方式.从基础科学、动物和临床研究中得来的数据均支持PET/CT在评估大动脉的动脉粥样硬化疾病中的作用.