Xingyu Nie1, Gwendalyn J Randolph2, Andrew Elvington2, Nilantha Bandara3, Alexander Zheleznyak3, Robert J Gropler3, Pamela K Woodard4, Suzanne E Lapi5. 1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis. 2. Division of Biology and Biomedical Sciences, Washington University in St. Louis. 3. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO. 4. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University in St. Louis; Diabetic Cardiovascular Disease Center, Washington University in St. Louis. 5. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Division of Biology and Biomedical Sciences, Washington University in St. Louis; Department of Biomedical Engineering, Washington University in St. Louis. Electronic address: lapis@mir.wustl.edu.
Abstract
INTRODUCTION: Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. METHODS: (64)Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET. RESULTS: (64)Cu-ATSM uptake was increased in the aortic arch in SCD ApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCD ApoE(-/-) mice in comparison to controls was also observed at delayed time points. CONCLUSION: This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients.
INTRODUCTION:Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. METHODS: (64)Cu-ATSM PET was performed in 21 atheroscleroticapolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCDApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET. RESULTS: (64)Cu-ATSM uptake was increased in the aortic arch in SCDApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCDApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCDApoE(-/-) mice in comparison to controls was also observed at delayed time points. CONCLUSION: This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in humanpatients.
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