Contrast-enhanced intravascular ultrasound: combining morphology with activity-based assessment of plaque vulnerability

Acute coronary syndromes are the result of coronary plaque rupture in the majority of cases. Available diagnostic techniques that focus on the early detection of plaques that are prone to rupture are still limited. Increased neovascularization in the vasa vasorum of the atherosclerotic plaque has been identified recently as a common feature of inflammation and plaque vulnerability. Microbubbles, which have been used for ultrasound imaging, can be used to trace neovascularization. We present recent advances in contrast agents and contrast-enhanced intravascular ultrasound that may be used for the detection of vasa vasorum, including fundamental and harmonic contrast imaging. Identification of vasa vasorum proliferation in atherosclerotic plaques presents important clinical implications; in particular it could provide a means to detect vulnerability in vivo, thereby guiding targeted treatments.     

Contrast-enhanced intravascular ultrasound: combining morphology with activity-based assessment of plaque vulnerability

Acute coronary syndromes are the result of coronary plaque rupture in the majority of cases. Available diagnostic techniques that focus on the early detection of plaques that are prone to rupture are still limited. Increased neovascularization in the vasa vasorum of the atherosclerotic plaque has been identified recently as a common feature of inflammation and plaque vulnerability. Microbubbles, which have been used for ultrasound imaging, can be used to trace neovascularization. We present recent advances in contrast agents and contrast-enhanced intravascular ultrasound that may be used for the detection of vasa vasorum, including fundamental and harmonic contrast imaging. Identification of vasa vasorum proliferation in atherosclerotic plaques presents important clinical implications; in particular it could provide a means to detect vulnerability in vivo, thereby guiding targeted treatments.     

冠状动脉易损斑块CT及MR成像进展

易损斑块破裂或侵蚀导致继发血栓形成是急性冠状动脉综合征的主要发病机制。传统影像学手段关注引起管腔严重狭窄的冠状动脉斑块,而忽略了对易损斑块的显示。随着对粥样斑块病理生理学认识的深入,冠状动脉管壁成像及识别易损斑块成为研究热点。基于无创影像学技术识别斑块成分及形态特征、进而评估斑块易损性,有助于临床识别高危患者,预测及预防未来心血管事件,具有重大临床应用价值。     

Etiology of acute coronary syndrome--unstable plaque

Our perception of the mechanisms underlying the acute complications of atherosclerosis has significantly changed in the last decade. Most coronary thromboses result from a rupture or a fissure in the protective fibrous cap of atherosclerotic plaque, but less common from a superficial erosion. The extent of thrombosis is a determinant of the clinical picture of acute coronary syndromes. Until now, we held a high grade stenosis responsible for the vast majority of acute coronary syndromes. However, current findings establish the relevance of qualitative aspects of plaques as important determinants of the vulnerability of plaques, i.e. the risk to cause acute complications. Among morphologic and functional features of plaques, inflammation has emerged as a leading pathophysiologic mechanism. In addition to local effect of inflammation at the level of the unstable plaque itself, systemic factors of the inflammatory response may alter the thrombogenicity of a vulnerable plaque. Knowledge of the role of inflammation helps us to understand the mechanisms by which therapeutic efforts can reduce clinical events. The clinical benefits of dietary modifications, pharmacotherapy with statins, and ACE inhibitors may be due in part to an anti-inflammatory action.     

Optical Coherence Tomography and Fibrous Cap Characterization

The pathophysiology of acute coronary syndromes has long been associated with atherosclerotic plaque rupture. Inflammation, thinning, and disruption of the fibrous cap have been implicated with the final processes leading to plaque rupture, but confirmation of these mechanisms of coronary thrombosis in humans has been hampered by the lack of imaging methods with sufficient resolution to resolve fibrous cap characterization and thickness in vivo. Intravascular optical coherence tomography (OCT) provides images with micron-level axial and lateral resolution, enabling detailed visualization of micro-structural changes of the arterial wall. The present article provides an overview of the potential role of OCT in identifying and characterizing fibrous cap morphology, thickness, and inflammation in human coronary plaques.     

Detection of the Vulnerable Coronary Atherosclerotic Plaque—Promises and Limitations

Purpose of Review

The merit of imaging “vulnerable atherosclerotic plaques” remains highly controversial. This review aims at providing current evidence for both its benefit and limitations.

Recent Findings

Results from optical coherence tomography and intravascular ultrasound imaging in patients with coronary heart disease suggest that certain individual coronary atherosclerotic plaque characteristics, e.g., large lipid core in a fibroatheroma, are associated with greater risk of adverse patient outcome. However, a closer look at these studies reveals that these associations are confounded by the relationship of “vulnerable plaque” characteristics with baseline lumen obstruction, which is a known predictor of recurrent angina and the main component of the reported adverse patient outcome. Recent insights into the pathophysiology of acute coronary syndromes suggest it to be an exceedingly complex process involving numerous local and systemic factors, which hinders outcome prediction.

Summary

The quest for the vulnerable plaque rests on the erroneous assumption that detecting coronary atherosclerotic lesions, which are prone to rupture or erode, will identify individuals at high risk of suffering acute coronary events. However, there is strong and consistent evidence suggesting that plaques most commonly rupture without associated clinical symptoms. Instead, ruptured plaques typically heal clinically silently and lead to plaque progression. The atherosclerotic disease burden, its metabolic activity, and risk factors for an inadequate response by the coagulation system to plaque disruption, on the other hand, are important predictors of acute coronary event risk and deserve our attention more than individual plaques.

     

Present-day investigations cannot adequately determine the risk of acute coronary syndromes

It is an important irony that present-day clinical stress testing methods including exercise electrocardiogram, stress echocardiography and even coronary angiography are not able to demonstrate vulnerable coronary plaques at risk of rupture. A vulnerable plaque may in fact be invisible on clinical stress test and perhaps only visualized directly through less available techniques such as coronary angioscopy. Landmark pathological studies have deepened our understanding of the mechanisms behind acute coronary syndromes over the last decade. Thrombosis plays a key role and is a unifying feature in the pathogenesis. Platelet-rich thrombus superimposed over the disrupted atherosclerotic plaque or eroded plaque endothelium, with or without fibrin-thrombus extension, is evident in post-mortem necropsy and angioscopic studies. However features which contribute to the risk of acute events lie in the atherosclerotic plaque itself. Plaque content and not plaque size is the important factor. Clinical stress testing demonstrates plaque size but not plaque content. A plaque will be prone to rupture if it has only a thin cap and a proportionally larger lipid core. In such a plaque there is preponderance of activated macrophages and T-lymphocytes, and high activity of matrix metalloproteinases. Smooth muscle cell proliferation and collagen synthesis are downregulated. These features may serve as possible targets for devising clinical methods to detect plaques at risk or for reversing the risk in vulnerable plaques.     

Pathophysiology of acute coronary syndromes leading to acute myocardial infarction

Acute coronary syndromes, including unstable angina, myocardial infarction, and sudden death, account for more than 250,000 deaths annually. They are the manifestation of a progressive atherosclerotic process, which culminates in the rupture of atherosclerotic plaques and the formation of mural thrombi. This article reviews recent and current research, which has shed light on key events and evolutionary processes leading to acute coronary syndromes. The article details the development of vulnerable plaques, factors that promote plaque rupture, and triggering events related to plaque rupture. Also discussed are sequelae of acute coronary syndromes, including Q wave and non-Q wave infarction and left ventricular remodeling.     

Gamma imaging of atherosclerotic plaques

Noninvasive gamma imaging of atherosclerotic plaques targets various metabolic aspects of atherogenesis. Vascular endothelial dysfunction or denudation resulting in the expression of adhesion molecules that attract inflammatory cells and increased vascular permeability has also been targeted. Enzymes and molecules associated with apoptosis of these inflammatory cells have provided additional targets, such as oxidized low-density lipoprotein, matrix metalloproteinases, and phosphatidylserine. In late atherosclerotic lesions, the lipid core as well as proliferating smooth muscle cells have been imaged successfully. Platelets and fibrin deposition may also be targeted to demonstrate thrombosis in plaque rupture or erosion. However, no unimodal approach can diagnose plaque vulnerability. It will require multi-modal, multitasking approaches for molecular diagnostic prediction of plaque vulnerability and impending rupture. Existing experimental and clinical gamma imaging applications in atherosclerotic lesion imaging are reviewed. Improvement by signal amplification to image small lesion and the concept of multimodal applications are introduced.     

Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical,cellular and molecular MRI Part I and II

Atherosclerotic plaque disruption accounts for the major part of cardiovascular mortality and the risk of disruption appears to depend on plaque composition. Carotid plaques in patients, scheduled for endarterectomy, have been successfully characterised with MRI. MRI has the advantage of combining information about morphology and function. Unfortunately, the tortuosity and size of the coronary arteries, and the respiratory and cardiac motion hinder the in vivo characterisation of human coronary plaque. In addition to plaque composition several molecular markers of the different processes involved in atherosclerosis, such as integrins, matrix metalloproteinases and fibrin seem to correlate with risk of plaque rupture and clinical outcome. These molecular markers can be targeted with antibodies coupled to carriers, which are loaded with gadolinium for detection (molecular MRI). Several cellular/molecular MRI studies in animal models and some in human patients have been conducted with varying levels of success. The advent of clinical high field magnets, the development of contrast agent carriers with high relaxivity and the development of relatively new MR contrast techniques are promising in the field of plaque imaging. Future MRI studies will have to focus on the molecular target of the atherosclerotic process, which has the highest prognostic value with regard to acute coronary syndromes and on the most suitable contrast agent to visualize that target.     

Angioscopy and Unstable Coronary Plaques: Findings Beyond Thrombus

Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo. Coronary angioscopy is especially suitable for identifying thrombus, plaque disruption, and variations in color of the coronary arterial wall. Intracoronary thrombus and disruption of glistening yellow plaque at the site of culprit lesions are seen more commonly in patients with acute myocardial infarction and unstable angina than in patients with stable angina. Acute coronary syndromes occur more frequently in patients with yellow plaque than in those with white plaques. Angioscopy can also be used to assess the effect of preventive treatment. Lipid-lowering therapies with statin change lesions from yellow to white, suggesting plaque stabilization. Coronary angioscopy provides a great opportunity to understand pathophysiology of acute coronary syndrome and would play an important role to evaluate the risk of the future coronary events.     

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.     

Intravascular MRI

In patients with vascular disease, acute coronary syndromes and ischemic strokes develop suddenly and often unpredictably. In most patients, these clinical scenarios result from arterial thrombosis from one of three mechanisms: plaque rupture, plaque erosion, or calcified nodule. A number of diagnostic modalities have been used in the evaluation of these unstable, high-risk lesions that predispose to arterial thrombosis. Noninvasive MRI allows three-dimensional imaging with evaluation of vascular structures and depiction of components of atherosclerotic plaque. However, noninvasive MRI is limited in the evaluation of arteries of smaller caliber and deeper location, such as coronary, iliac, and renal arteries. To overcome these inherent limitations of noninvasive MRI, invasive approaches have been developed that include intravascular coils for lesion assessment and characterization, and a novel intravascular MRI catheter within which the magnets, radiofrequency transmitters, and receivers are miniaturized. This self-contained MRI catheter holds promise in the in vivo assessment of lipid-rich, potentially vulnerable plaques.     

Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical,cellular and molecular MRI part III

Atherosclerotic plaque disruption accounts for the major part of cardiovascular mortality and the risk of disruption appears to depend on plaque composition. Carotid plaques in patients, scheduled for endarterectomy, have been successfully characterised with MRI. MRI has the advantage of combining information about morphology and function. Unfortunately, the tortuosity and size of the coronary arteries, and the respiratory and cardiac motion hinder the in vivo characterisation of human coronary plaque. In addition to plaque composition several molecular markers of the different processes involved in atherosclerosis, such as integrins, matrix metalloproteinases and fibrin seem to correlate with risk of plaque rupture and clinical outcome. These molecular markers can be targeted with antibodies coupled to carriers, which are loaded with gadolinium for detection (molecular MRI). Several cellular/molecular MRI studies in animal models and some in human patients have been conducted with varying levels of success. The advent of clinical high field magnets, the development of contrast agent carriers with high relaxivity and the development of relatively new MR contrast techniques appear to be promising in the field of plaque imaging. Future MRI studies will have to focus on the molecular target of the atherosclerotic process, which has the highest prognostic value with regard to acute coronary syndromes and on the most suitable contrast agent to visualize that target.     

Inflammation and infection in acute coronary syndrome

Basic science research has revealed that monocytes and macrophages are important factors in atherogenesis. Immune system activation occurs at all stages of plaque formation, from the fatty streak to an advanced, complicated lesion. The inflammatory response not only stimulates changes in coronary artery endothelial cells causing endothelial injury and dysfunction, but also plays a role in plaque instability and rupture. New perspectives of atherosclerosis and acute coronary syndromes will be discussed in relation to inflammation. In addition, discussion will focus on bacterial and viral infectious microorganisms as a potential factor that may induce and promote inflammation and lead to acute coronary events. Clinical studies in humans have provided insight relating inflammation and infectious agents to atherosclerosis and plaque vulnerability. Other studies focus on specific interventions that may aid in diagnosis and treatment.     

冠状动脉粥样硬化斑块磁共振成像研究进展

当前直接显示冠状动脉管壁和粥样斑块为磁共振成像(MRI)研究的热点之一,这是因为不引起冠状动脉管腔50%以上狭窄程度的粥样硬化斑块常为具有破裂倾向的易损斑块,斑块破裂随后血栓形成是导致心肌梗死的主要原因。无创性、高分辨率MRI具有显示冠状动脉粥样硬化斑块、判定斑块成分的潜力。本综述总结冠脉斑块MR成像原理,描述现有MRI技术下斑块的信号特点,并讨论MR在斑块成像的新对比剂、靶向分子成像等方面的研究进展。     

Imaging of vulnerable plaque: Potential breakthrough or pipe dream?

Atherosclerotic plaque rupture is the main cause of acute cardiac events. The detection of these unstable plaques before rupture is clinically very important, and recently there have been considerable efforts to develop imaging methods for plaque visualization and characterization. It is likely that multiple approaches are needed, from simple screening tests to advanced invasive imaging studies. The strength of nuclear imaging techniques is the outstanding sensitivity. Although the spatial resolution of clinical nuclear imaging does not allow anatomical characterization of plaques, the recent hybrid imaging techniques offer possibility for combined anatomical and molecular imaging. We discuss the current progress on nuclear imaging techniques in assessing unstable plaques.     

Intracoronary Near-Infrared Spectroscopy (NIRS) Imaging for Detection of Lipid Content of Coronary Plaques: Current Experience and Future Perspectives

Acute coronary syndromes are frequently caused by “vulnerable” coronary plaques with a lipid-rich core. In 1993 near-infrared spectroscopy (NIRS) was first used to detect the lipid (cholesterol) content of atherosclerotic plaques in an experimental animal study. NIRS was then carefully validated using human atherosclerotic plaques (ex vivo), and has subsequently been developed for intracoronary imaging in humans, for which now an FDA-approved catheter-based NIRS system is available. NIRS provides a “chemogram” of the coronary artery wall and is used to detect lipid-rich plaques. Using this technology, recent studies have shown that lipid-rich plaques are very frequent in the culprit lesion of patients with an acute coronary syndrome, and are also common in non-culprit coronary lesions in these patients as compared to patients with stable coronary disease. First studies are evaluating the impact of statin therapy on coronary NIRS-detected lipid cores. Intracoronary NIRS imaging represents a highly interesting method for coronary plaque characterization in humans and may become a valuable tool for the development of novel therapies aiming to impact on the biology of human coronary artery plaques, likely in combination with other intracoronary imaging techniques, such as optical coherence tomography.     

The role of inflammation in the pathophysiology of acute coronary syndromes

All stages of atherosclerotic plaques are characterized by an inflammatory component, in which T lymphocytes and macrophages orchestrate lesion progression and destabilization by releasing cytokines (e.g., interferon-gamma, tumor necrosis factor-alpha, tissue factor). At the extreme end of this process plaque rupture occurs, which may manifest clinically as an acute coronary syndrome. Hence, measuring this atherosclerosis-inherent inflammation may help predicting cardiovascular events. Accordingly, different soluble inflammatory markers were studied for their predictive value in acute coronary syndromes. Special attention was paid to high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L). The latter seems not only to be a marker of inflammation and platelet activation, but is suggested to directly destabilize atherosclerotic plaques by stimulating pro-inflammatory T lymphocytes. Therefore, reduction of soluble inflammatory markers is an attractive target for future therapeutic strategies. Statins and glycoprotein IIb/IIIa antagonists, well-established treatments in acute coronary syndromes, were demonstrated to decrease hs-CRP and sCD40L. Whether this reduction translates into a better prognosis has to be investigated in further studies.