99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries.
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We used a model of porcine coronary atherosclerosis characterized by smooth muscle cell apoptosis to test the hypothesis that apoptosis of cells in the vascular wall of coronary arteries can be detected on SPECT images using a technetium-labeled radiotracer that targets apoptosis.Eleven juvenile male swine received a high-fat diet combined with injury to 22 coronary vessels. After 51 +/- 9 d (mean +/- SD), the animals underwent coronary angiography, were injected with 403.3 +/- 48.1 MBq of 99mTc-annexin V, underwent SPECT, and were sacrificed. The coronary arteries underwent autoradiography and well counting, and immunostaining was performed for alpha-actin, caspase, and macrophages.Atherosclerotic lesions were predominantly of American Heart Association class II. Thirteen of the 22 injured vessels showed focal uptake of 99mTc-annexin V in vivo (scan positive), and 9 injured vessels and all control vessels showed no focal uptake (scan negative). The count ratios of the injured vessels to the control vessels were 2.38 +/- 0.61 for scan-positive vessels and 1.27 +/- 0.23 for scan-negative vessels (P < 0.001). The percentages of injected dose for the scan-positive and scan-negative vessels were 1.73 +/- 0.83 x 10(-3) and 0.68 +/- 0.20 x 10(-3), respectively (P < 0.001). Immunohistopathologic examination found that the cells undergoing apoptosis were smooth muscle cells. The apoptotic index (caspase-positive cells to total cells) was 63% +/- 7% for scan-positive vessels and 16% +/- 10% for scan-negative vessels (P < 0.001). Both the count ratio of injured vessels to control vessels and the percentage injected dose correlated significantly with death rate by regression analysis.Annexin is a noninvasive method to identify plaque apoptosis in the coronary vessels.Keywords:
Coronary arteries
Immunostaining
Annexin A5
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To the Editor: Although progressive stenosis of the arterial lumen constitutes the basis for ischemic symptoms in atherosclerotic vascular disease, acute vascular events are for the most part assoc...
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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.
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The rupture of atherosclerotic plaques and the subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Thus, the detection of vulnerable plaques in atherosclerotic lesions is a desirable goal, and attempts to image these plaques with (18)F-FDG have been made. In the present study, the relationship between the accumulation of (18)F-FDG and the biologic characteristics of atherosclerotic lesions was investigated. Furthermore, PET imaging of vulnerable plaques was performed with an animal model of atherosclerosis, Watanabe heritable hyperlipidemic (WHHL) rabbits.WHHL (n = 11) and control (n = 3) rabbits were injected intravenously with (18)F-FDG, and the thoracic and abdominal aortas were removed 4 h after injection. The accumulated radioactivity was measured, and the number of macrophages and the intimal area were investigated by examination of stained sections. PET and CT images were also acquired at 210 min after injection of the radiotracer.(18)F-FDG accumulated to a significantly higher level in the aortas of the WHHL rabbits (mean +/- SD differential uptake ratio [DUR], 1.47 +/- 0.90) than in those of the control rabbits (DUR, 0.44 +/- 0.15); DUR was calculated as (tissue activity/tissue weight)/(injected radiotracer activity/animal body weight), with activities given in becquerels and weights given in kilograms. (18)F-FDG uptake and the number of macrophages were strongly correlated in the atherosclerotic lesions of the WHHL rabbits (R = 0.81). In the PET analysis, intense (18)F-FDG radioactivity was detected in the aortas of the WHHL rabbits, whereas little radioactivity was seen in the control rabbits.The results suggest that macrophages are responsible for the accumulation of (18)F-FDG in atherosclerotic lesions. Because vulnerable plaques are rich in macrophages, (18)F-FDG imaging should be useful for the selective detection of such plaques.
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Malondialdehyde
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Background — Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [ 18 F]-fluorodeoxyglucose ( 18 FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18 FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques. Methods and Results — Eight patients with symptomatic carotid atherosclerosis were imaged using 18 FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18 FDG-PET images acquired 3 hours post- 18 FDG injection. The estimated net 18 FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18 FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque. Conclusions — This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18 FDG-PET, and that symptomatic, unstable plaques accumulate more 18 FDG than asymptomatic lesions.
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Matrix metalloproteinases (MMPs) are enzymes involved in the proteolytic degradation of extracellular matrix. They play an important role in several disease processes, such as inflammation, cancer, and atherosclerosis.In this study, we have used the broad-spectrum MMP inhibitor CGS 27023A to develop the radioligand [123I]I-HO-CGS 27023A for in vivo imaging of MMP activity. Using this radioligand, we were able to specifically image MMP activity by scintigraphy in vivo in the MMP-rich vascular lesions that develop after carotid artery ligation and cholesterol-rich diet in apolipoprotein E-deficient mice. These results were confirmed by gamma counting of lesional tissue (counts per minute per milligram).Imaging of MMP activity in vivo is feasible using radiolabeled MMP inhibitors. Additional studies are needed to test the potential of this approach as a novel noninvasive clinical diagnostic tool for the management of human MMP-related diseases.
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Matrix metalloproteinase inhibitor
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Coronary arteries
Fibrous cap
Lumen (anatomy)
Coronary atherosclerosis
Vulnerable plaque
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Background— The ability to image vascular inflammatory responses may allow early diagnosis and treatment of atherosclerosis. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression with contrast-enhanced ultrasound (CEU) could be used for this purpose. Methods and Results— Attachment of VCAM-1–targeted and control microbubbles to cultured endothelial cells was assessed in a flow chamber at variable shear stress (0.5 to 12.0 dynes/cm 2 ). Microbubble attachment to aortic plaque was determined by en face microscopy of the thoracic aorta 10 minutes after intravenous injection in wild-type or apolipoprotein E–deficient mice on either chow or hypercholesterolemic diet. CEU molecular imaging of the thoracic aorta 10 minutes after intravenous microbubble injection was performed for the same animal groups. VCAM-1–targeted but not control microbubbles attached to cultured endothelial cells, although firm attachment at the highest shear rates (8 to 12 dynes/cm 2 ) occurred only in pulsatile flow conditions. Aortic attachment of microbubbles and targeted CEU signal was very low in control wild-type mice on chow diet. Aortic attachment of microbubbles and CEU signal for VCAM-1–targeted microbubbles differed between treatment groups according to extent of VCAM-1–positive plaque formation (median CEU videointensity, 1.8 [95% CI, 1.2 to 1.7], 3.7 [95% CI, 2.9 to 7.3], 6.8 [95% CI, 3.9 to 7.6], and 11.2 [95% CI, 8.5 to 16.0] for wild-type mice on chow and hypercholesterolemic diet and for apolipoprotein E–deficient mice on chow and hypercholesterolemic diet, respectively; P <0.001). Conclusions— CEU molecular imaging of VCAM-1 is capable of rapidly quantifying vascular inflammatory changes that occur in different stages of atherosclerosis. This method may be potentially useful for early risk stratification according to inflammatory phenotype.
Molecular Imaging
VCAM-1
Pulsatile flow
Thoracic aorta
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Background— Noninvasive imaging of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) may identify early stages of inflammation in atherosclerosis. We hypothesized that a novel, second-generation VCAM-1–targeted agent with enhanced affinity had sufficient sensitivity to enable real-time detection of VCAM-1 expression in experimental atherosclerosis in vivo, to quantify pharmacotherapy-induced reductions in VCAM-1 expression, and to identify activated cells in human plaques. Methods and Results— In vivo phage display in apolipoprotein E–deficient mice identified a linear peptide affinity ligand, VHPKQHR, homologous to very late antigen-4, a known ligand for VCAM-1. This peptide was developed into a multivalent agent detectable by MRI and optical imaging (denoted VINP-28 for VCAM-1 internalizing nanoparticle 28, with 20 times higher affinity than previously reported for VNP). In vitro, VINP-28 targeted all cell types expressing VCAM-1. In vivo, MRI and optical imaging in apolipoprotein E–deficient mice (n=28) after injection with VINP-28 or saline revealed signal enhancement in the aortic root of mice receiving VINP-28 ( P <0.05). VINP-28 colocalized with endothelial cells and other VCAM-1–expressing cells, eg, macrophages, and was spatially distinct compared with untargeted control nanoparticles. Atheromata of atorvastatin-treated mice showed reduced VINP-28 deposition and VCAM-1 expression. VINP-28 enhanced early lesions in juvenile mice and resected human carotid artery plaques. Conclusions— VINP-28 allows noninvasive imaging of VCAM-1–expressing endothelial cells and macrophages in atherosclerosis and spatial monitoring of anti–VCAM-1 pharmacotherapy in vivo and identifies inflammatory cells in human atheromata. This clinically translatable agent could noninvasively detect inflammation in early, subclinical atherosclerosis.
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