Publications (9)67.21 Total impact
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Article: Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis.
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ABSTRACT: Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked. Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with (99m)Tc-labeled matrix metalloproteinase inhibitor (MPI) and (111)In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes. MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 +/- .018%) and AA5 (.03 +/- .01%) uptake was higher in HC than control (n = 6) animals (.014 +/- .004%, P < .0001; .0007 +/- .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes. The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.Journal of Nuclear Cardiology 08/2009; 16(5):753-62. · 2.67 Impact Factor -
Article: Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy.
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ABSTRACT: This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m-labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity. The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture. Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro-single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays. The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 +/- 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 +/- 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 +/- 0.011%, p < 0.0005) and diet withdrawal groups (0.043 +/- 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques. The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.Journal of the American College of Cardiology 01/2009; 52(23):1847-57. · 14.16 Impact Factor -
Article: Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging.
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ABSTRACT: The purpose of this study was to evaluate the role of caspase inhibitors on acute resolution of apoptosis in atherosclerotic lesions as evaluated by imaging with annexin A5. Extensive apoptosis of macrophages has been reported at the site of plaque rupture in patients dying of acute coronary syndrome. Of 31 New Zealand White atherosclerotic rabbits, 6 received broad caspase, 3 received caspase-1, 3 received caspase-3, 3 received caspase-8, and 4 received caspase-9 inhibitors; 12 animals did not receive any caspase inhibitors (treatment control group). Six unmanipulated rabbits were used for comparison (disease control group). Technetium-99m-labeled annexin A5 was used for imaging atherosclerotic lesions; 6 of the 12 uninhibited atherosclerotic rabbits received (99m)Tc-labeled mutant annexin A5 (radiotracer control group). Gamma images were obtained, and quantitative radiotracer uptake was compared with pathologic findings. Atherosclerotic lesions were best visible in untreated atherosclerotic rabbits. Quantitative annexin uptake, defined as the percent of injected dose per g of abdominal aorta tissue, was significantly higher in untreated atherosclerotic animals (mean +/- SD = 0.0515 +/- 0.0099) compared with the normal rabbits (0.0065 +/- 0.0008; p < 0.0001) or atherosclerotic rabbits receiving mutant annexin (0.014 +/- 0.0024; p < 0.0001). Among all caspase inhibitor-treated rabbits, uptake was 39% lower (0.0314 +/- 0.0151) than in untreated atherosclerotic animals (p < 0.01). Uptake was also significantly lower in rabbits receiving broad caspase (0.0206 +/- 0.0058; p < 0.0001) or caspase-1, -3, or -9 (0.0272 +/- 0.0088, p < 0.01; 0.0286 +/- 0.0095, p < 0.01; 0.0300 +/- 0.0021, p < 0.01, respectively) inhibitors. Caspase-8 inhibitor did not affect apoptosis (0.0618 +/- 0.0047; p = NS). Upon histologic characterization, a substantial decrease in macrophage apoptosis was observed in caspase-inhibited animals. Molecular imaging, using radiolabeled annexin A5, allows the detection of acute resolution of apoptosis as a result of caspase inhibition in experimental atherosclerosis. If proven clinically, this may allow development of novel intervention strategies in acute vascular events.Journal of the American College of Cardiology 01/2008; 50(24):2305-12. · 14.16 Impact Factor -
Article: Radiolabeled Monocyte Chemotactic Protein 1 for the detection of inflammation in experimental atherosclerosis.
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ABSTRACT: Chemotactic peptides, such as Monocyte Chemotactic Protein 1 (MCP-1), play a key role in transendothelial migration of mononuclear cells during the development and progression of atherosclerotic disease. Because atherosclerotic plaques that are precursors of acute coronary events harbor abundant macrophage infiltration, we hypothesized that the detection of a high concentration of MCP-1 receptors on inflammatory cells should noninvasively identify vulnerable plaques. Atherosclerotic lesions were induced by balloon deendothelialization of the abdominal aorta, which was followed by a 0.5% cholesterol diet for 16 wk in 7 New Zealand White rabbits; 5 unmanipulated rabbits, fed normal chow for 16 wk, were used as controls. Radionuclide imaging was performed immediately after intravenous (99m)Tc-labeled MCP-1 administration and 3 h later. At the end of imaging session, aortas were explanted and submitted for estimation of quantitative MCP-1 uptake (in percentage injected dose per gram, %ID/g) and pathologic characterization. Atherosclerotic lesions were clearly visible in all hyperlipidemic animal gamma-imaging. No tracer uptake was seen in the control rabbits. The mean quantitative MCP-1 uptake in atherosclerotic lesions was 4-fold higher than that of the aortic specimens from the control rabbits (0.065 +/- 0.005 vs. 0.016 +/- 0.006; P < 0.0001). Histology confirmed a strong correlation between MCP-1 uptake and the number of macrophages in American Heart Association type II-IV lesions (r = 0.87, P < 0.0001). Noninvasive radionuclide imaging of inflammation is feasible by MCP-1 in experimentally induced atherosclerosis. It is proposed that detection of the extent of inflammation in advanced atherosclerotic plaques may allow identification of unstable plaques.Journal of Nuclear Medicine 12/2007; 48(11):1816-21. · 6.38 Impact Factor -
Article: Targeting of matrix metalloproteinase activation for noninvasive detection of vulnerable atherosclerotic lesions.
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ABSTRACT: INTRODUCTION: Inflammation plays an important role in vulnerability of atherosclerotic plaques to rupture and hence acute coronary events. The monocyte-macrophage infiltration in plaques leads to upregulation of cytokines and metalloproteinase enzymes. Matrix metalloproteinases result in matrix dissolution and consequently expansive remodeling of the vessel. They also contribute to attenuation of fibrous cap and hence susceptibility to rupture. Assessment of metalloproteinase expression and activity should provide information about plaque instability.European journal of nuclear medicine and molecular imaging 07/2007; 34 Suppl 1:S1-8. · 4.99 Impact Factor -
Article: Valve-sparing operation for aortic root aneurysm late after Mustard procedure.
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ABSTRACT: The aortic valve reimplantation technique leads to excellent clinical outcome in patients with aortic valve incompetence and aneurysms of the ascending aorta. This technique is now applied for aneurysms of ascending aorta, aortic dissection type A, and even dilatation of pulmonary autograft after the Ross operation. We report a case of aortic root dilatation late after a Mustard operation for transposition of the great arteries that was successfully managed by valve-sparing aortic root reimplantation.The Annals of thoracic surgery 07/2007; 83(6):2224-6. · 3.74 Impact Factor -
Article: Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy.
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ABSTRACT: Although apoptosis within atherosclerotic plaques is associated with plaque vulnerability and rupture, the role of inhibition of the apoptotic process is not clear. We evaluated the impact of dietary modification and statin therapy (measures known to favorably influence outcomes in coronary disease) on the incidence of apoptosis in experimental atherosclerotic lesions. A total of 30 animals were studied; 1 group of 6 animals served as the controls (group 1), and the remaining 24 animals were subjected to balloon de-endothelialization of the abdominal aorta and a high-cholesterol diet. These atherosclerotic animals were randomized as follows: high-cholesterol diet for 4 mo (n=6; untreated atherosclerotic group [group 2]), high-cholesterol diet for 3 mo and normal chow diet for 1 mo (n=6; diet withdrawal group [group 3]), and high-cholesterol diet for 4 mo and simvastatin orally every day of the last month (n=6; statin therapy group [group 4]). 99mTc-Annexin A5 was used for noninvasive detection of apoptosis in groups 1-4. The remaining 6 rabbits on a high-cholesterol diet for 4 mo were studied with radiolabeled mutant annexin A5 (n=6; nonspecific control group [group 5]). Quantitative annexin A5 uptake in the abdominal aorta was determined and compared with the histologic and immunohistochemical characteristics of the atherosclerotic lesions. Maximum annexin A5 uptake (mean+/-SD, 0.051+/-0.009 percentage injected dose per gram [%ID/g] of tissue) was observed in the untreated atherosclerotic animals. The uptake was substantially reduced in the diet withdrawal (0.03+/-0.006%ID/g; P<0.0001) and statin therapy (0.03+/-0.006%ID/g; P<0.0001) groups. The plaques in the untreated high-cholesterol group demonstrated advanced atherosclerotic lesions. On the other hand, the diet withdrawal and statin therapy groups showed histologic characteristics of stabilization, including the resolution of macrophage infiltration and an increase in smooth muscle cell content. There was a marked reduction in the apoptosis of macrophages. No significant uptake of annexin A5 or mutant annexin A5 was seen in rabbits on the normal chow diet or atherosclerotic rabbits, respectively. Dietary modification and statin therapy in atherosclerosis lead to a reduction in apoptosis and contribute to plaque stabilization. It can be hypothesized that a reduction in apoptosis is a favorable process in atherosclerotic disease.Journal of Nuclear Medicine 12/2005; 46(12):2051-6. · 6.38 Impact Factor -
Article: Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque.
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ABSTRACT: Apoptosis is common in advanced human atheroma and contributes to plaque instability. Because annexin V has a high affinity for exposed phosphatidylserine on apoptotic cells, radiolabeled annexin V may be used for noninvasive detection of apoptosis in atherosclerotic lesions. Atherosclerotic plaques were produced in 5 rabbits by deendothelialization of the infradiaphragmatic aorta followed by 12 weeks of cholesterol diet; 5 controls were studied without manipulation. Animals were injected with human recombinant annexin V labeled with technetium-99m before imaging. Aortas were explanted for ex vivo imaging, macroautoradiography, and histological characterization of plaque. Radiolabeled annexin V cleared rapidly from the circulation (T1/2, alpha 9 and beta 46 minutes). There was intense uptake of radiolabel within lesions by 2 hours; no uptake was seen in controls. The results were confirmed in the ex vivo imaging of the explanted aorta. Quantitative annexin uptake was 9.3-fold higher in lesion versus nonlesion areas; the lesion-to-blood ratio was 3.0+/-0.37. Annexin uptake paralleled lesion severity and macrophage burden; no correlation was observed with smooth muscle cells. DNA fragmentation staining of apoptotic nuclei was increased in advanced lesions with evolving necrotic cores, predominantly in macrophages; the uptake of radiolabel correlated with the apoptotic index. Because annexin V clears rapidly from blood and targets apoptotic macrophage population, it should constitute an attractive imaging agent for the noninvasive detection of unstable atherosclerotic plaques.Circulation 01/2004; 108(25):3134-9. · 14.74 Impact Factor -
Chapter: 99mTc-Monocyte chemoattractant protein-1
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ABSTRACT: Chemotactic cytokines, such as monocyte chemoattractant protein-1 (chemotactic protein-1; MCP-1), play a pivotal role in the inflammatory process associated with the development and progression of atherosclerosis (1, 2). MCP-1, a low molecular weight monomeric peptide (9–15 kDa), is initially upregulated at the site of vessel wall injury by vascular smooth muscle cells (SMC) and endothelial cells (3). MCP-1, in interaction with several cytokines and cell adhesion molecules, mediates the transendothelial migration of monocytes to the subendothelial layer via cysteine-cysteine motif chemokine receptor-2 (CCR-2) receptor (4-7). As a response to the chemotactic signal, monocytes upregulate the number of CCR-2 receptors on their cell surface (8). The recruited monocytes then express MCP-1 by themselves, which accelerates the further influx of mononuclear cells. Once resident within the neointima, the monocytes differentiate to macrophages, express matrix metalloproteinases (MMPs), transform to foam cells by digesting oxidized low-density lipoproteins via expression of scavenger receptors, and form a necrotic core by undergoing apoptosis or necrosis (1). The MMPs expressed by macrophages and foam cells induce dissolution of SMCs and collagen, which causes the plaque cap to thin and makes the cap susceptible to rupture (9, 10). Because the extent of macrophage inflammation in atherosclerotic plaque is positively related to plaque instability, and because the receptor for MCP-1 is only expressed by infiltrating monocytes, the detection of MCP-1 receptors should allow monitoring of the extent of inflammation in atherosclerotic plaque. The use of radiolabeled MCP-1 for non-invasive imaging of the CCR-2 receptor density in atherosclerotic plaque might provide to be a useful clinical tool for the detection of plaques vulnerable to rupture. Ohtsuki et al. (11) demonstrated the feasibility of using 125I-MCP-1 to identify lesional monocytes and macrophages in experimental atherosclerosis with autoradiography. Blankenberg et al. (12) successfully labeled recombinant human MCP-1 with 99mTc using the nicotinic acid analog hydrazinonicotinamide (HYNIC) as the chelator. The study demonstrated that 99mTc-MCP-1 could detect abnormally increased numbers of perivascular mononuclear cells in native and grafted hearts in prediabetic rats. Kown et al. (13) reported that 99mTc-MCP-1 could be used to assess graft coronary artery disease in rats. Hartung et al. (14) evaluated 99mTc-MCP-1 for detection of inflammation in rabbits with induced atherosclerotic lesions. The study concluded that non-invasive detection of inflammation in experimental atherosclerotic lesions was feasible using 99mTc-MCP-1.
Top co-authors
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Institutions
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2007–2009
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University of California, Irvine
Irvine, CA, USA
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2005
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Medizinische Hochschule Hannover
Hannover, Lower Saxony, Germany
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2004
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Armed Forces Institute of Pathology
Rāwalpindi, Punjab, Pakistan
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