Abstract-Atherosclerotic cardiovascular disease results in Ͼ19 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
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.
Background-It has been found recently that the MRI contrast agent superparamagnetic iron oxide (SPIO) localizes to aortic atherosclerotic plaques. We therefore asked whether SPIO might be used to monitor monocyte recruitment into aortic atherosclerotic plaques. Methods and Results-Eleven female apo E knockout (K/O) mice, each 11 months old, were divided into 2 groups. Six mice received tissue necrosis factor-␣ (0.2 g IP once), interleukin-1 (0.2 g IP once), and interferon-␥ (100 U/g per day IP for 5 days); 5 received 0.5 mL saline containing1% BSA and served as sham-treated atherosclerotic controls. Two wild-type C57BL/6 mice served as sham-treated nonatherosclerotic controls. Three hours after initial cytokine or sham treatment, all mice received SPIO by intravenous injection (1 mmol/kg iron). Six days later, all mice were euthanized, the hearts and aortas were perfused under physiological pressure, and the entire aortas were studied histologically. Atherosclerotic plaques in cytokine-treated mice contained more iron-positive macrophages per cross section than did those in sham-treated apo E K/O control mice (42Ϯ11.8 versus 11.6Ϯ5.9) (PϽ0.0001). Iron-laden macrophages were present either in subendothelial plaque surfaces or in thin layers overlying the internal elastic lamina, often at the edges of atherosclerotic plaques. No iron deposition was seen in aortas of the wild-type nonatherosclerotic control mice. Immunocytochemistry showed mostly macrophages and few T lymphocytes in atherosclerotic plaques of cytokinetreated mice. Key Words: atherosclerosis Ⅲ imaging Ⅲ magnetic resonance imaging Ⅲ leukocytes Ⅲ interleukins A therosclerosis is an inflammatory disease. 1 Inflammatory cells play a pivotal role in its initiation and progression. Increased macrophage density and/or activation in atherosclerotic plaque and the subsequently increased secretion of matrix metalloproteinases and possibly other proteases may induce the breakdown of collagen in the fibrous cap, thus contributing to the plaque's vulnerability to rupture. 2,3 Finding a noninvasive method for detecting monocyte recruitment into atherosclerotic plaques is a topic of great interest in atherosclerosis research. 4 -7 Such a technique could be used to assess plaque initiation, progression, and complications. Our group has been interested in the detection of inflammation in plaques by MRI 5 to 7 days after intravenous administration of superparamagnetic iron oxide (SPIO). SPIO is a nanoparticle that is avidly taken up by the reticuloendothelial system. 8 In studies performed in Watanabe heritable hyperlipidemic rabbits (transgenic rabbit in which atherosclerosis develops spontaneously), Schmitz et al 9 have shown that SPIO also homes to aortic atherosclerotic plaques, thus suggesting a potential noninvasive means for assessing atherosclerotic plaque. Conclusions-SPIOCytokines have long been known to enhance the recruitment of monocytes into atherosclerotic lesions. 6,10,11 The purpose of the present study was to compare the uptake of iron (in the form...
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