Farhan Chaudhry1, Hideki Kawai2, Kipp W Johnson3, Navneet Narula4, Aditya Shekhar3, Fayzan Chaudhry3, Takehiro Nakahara3, Takashi Tanimoto3, Dongbin Kim3, Matthew K M Y Adapoe3, Francis G Blankenberg5, Jeffrey A Mattis6, Koon Y Pak6, Phillip D Levy7, Yukio Ozaki8, Eloisa Arbustini9, H William Strauss10, Artiom Petrov11, Valentin Fuster12, Jagat Narula3. 1. Icahn School of Medicine at Mount Sinai, New York, New York; Wayne State University School of Medicine, Detroit, Michigan. 2. Icahn School of Medicine at Mount Sinai, New York, New York; Department of Cardiology, Fujita Health University, Toyoake, Aichi, Japan. 3. Icahn School of Medicine at Mount Sinai, New York, New York. 4. New York University Langone Medical Center, New York, New York. 5. Lucile Salter Packard Children's Hospital, Stanford, California. 6. Molecular Targeting Technologies, Inc., West Chester, Pennsylvania. 7. Wayne State University School of Medicine, Detroit, Michigan. 8. Department of Cardiology, Fujita Health University, Toyoake, Aichi, Japan. 9. Policlinico San Matteo Pavia Fondazione IRCCS, Pavia, Italy. 10. Icahn School of Medicine at Mount Sinai, New York, New York; Memorial Sloan Kettering Cancer Center, New York, New York. 11. Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: artiom.petrov@mssm.edu. 12. Icahn School of Medicine at Mount Sinai, New York, New York; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Abstract
BACKGROUND: Apoptosis in atherosclerotic lesions contributes to plaque vulnerability by lipid core enlargement and fibrous cap attenuation. Apoptosis is associated with exteriorization of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell membrane. Although PS-avid radiolabeled annexin-V has been employed for molecular imaging of high-risk plaques, PE-targeted imaging in atherosclerosis has not been studied. OBJECTIVES: This study sought to evaluate the feasibility of molecular imaging with PE-avid radiolabeled duramycin in experimental atherosclerotic lesions in a rabbit model and compare duramycin targeting with radiolabeled annexin-V. METHODS: Of the 27 rabbits, 21 were fed high-cholesterol, high-fat diet for 16 weeks. Nine of the 21 rabbits received 99mTc-duramycin (test group), 6 received 99mTc-linear duramycin (duramycin without PE-binding capability, negative radiotracer control group), and 6 received 99mTc-annexin-V for radionuclide imaging. The remaining normal chow-fed 6 animals (disease control group) received 99mTc-duramycin. In vivo microSPECT/microCT imaging was performed, and the aortas were explanted for ex vivo imaging and for histological characterization of atherosclerosis. RESULTS: A significantly higher duramycin uptake was observed in the test group compared with that of disease control and negative radiotracer control animals; duramycin uptake was also significantly higher than the annexin-V uptake. Quantitative duramycin uptake, represented as the square root of percent injected dose per cm (√ID/cm) of abdominal aorta was >2-fold higher in atherosclerotic lesions in test group (0.08 ± 0.01%) than in comparable regions of disease control animals (0.039 ± 0.0061%, p = 3.70·10-8). Mean annexin uptake (0.060 ± 0.010%) was significantly lower than duramycin (p = 0.001). Duramycin uptake corresponded to the lesion severity and macrophage burden. The radiation burden to the kidneys was substantially lower with duramycin (0.49% ID/g) than annexin (5.48% ID/g; p = 4.00·10-4). CONCLUSIONS: Radiolabeled duramycin localizes in lipid-rich areas with high concentration of apoptotic macrophages in the experimental atherosclerosis model. Duramycin uptake in atherosclerotic lesions was significantly greater than annexin-V uptake and produced significantly lower radiation burden to nontarget organs.
BACKGROUND: Apoptosis in atherosclerotic lesions contributes to plaque vulnerability by lipid core enlargement and fibrous cap attenuation. Apoptosis is associated with exteriorization of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell membrane. Although PS-avid radiolabeled annexin-V has been employed for molecular imaging of high-risk plaques, PE-targeted imaging in atherosclerosis has not been studied. OBJECTIVES: This study sought to evaluate the feasibility of molecular imaging with PE-avid radiolabeled duramycin in experimental atherosclerotic lesions in a rabbit model and compare duramycin targeting with radiolabeled annexin-V. METHODS: Of the 27 rabbits, 21 were fed high-cholesterol, high-fat diet for 16 weeks. Nine of the 21 rabbits received 99mTc-duramycin (test group), 6 received 99mTc-linear duramycin (duramycin without PE-binding capability, negative radiotracer control group), and 6 received 99mTc-annexin-V for radionuclide imaging. The remaining normal chow-fed 6 animals (disease control group) received 99mTc-duramycin. In vivo microSPECT/microCT imaging was performed, and the aortas were explanted for ex vivo imaging and for histological characterization of atherosclerosis. RESULTS: A significantly higher duramycin uptake was observed in the test group compared with that of disease control and negative radiotracer control animals; duramycin uptake was also significantly higher than the annexin-V uptake. Quantitative duramycin uptake, represented as the square root of percent injected dose per cm (√ID/cm) of abdominal aorta was >2-fold higher in atherosclerotic lesions in test group (0.08 ± 0.01%) than in comparable regions of disease control animals (0.039 ± 0.0061%, p = 3.70·10-8). Mean annexin uptake (0.060 ± 0.010%) was significantly lower than duramycin (p = 0.001). Duramycin uptake corresponded to the lesion severity and macrophage burden. The radiation burden to the kidneys was substantially lower with duramycin (0.49% ID/g) than annexin (5.48% ID/g; p = 4.00·10-4). CONCLUSIONS: Radiolabeled duramycin localizes in lipid-rich areas with high concentration of apoptotic macrophages in the experimental atherosclerosis model. Duramycin uptake in atherosclerotic lesions was significantly greater than annexin-V uptake and produced significantly lower radiation burden to nontarget organs.
Authors: F D Kolodgie; J Narula; A P Burke; N Haider; A Farb; Y Hui-Liang; J Smialek; R Virmani Journal: Am J Pathol Date: 2000-10 Impact factor: 4.307
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Authors: Eric J Meester; B J Krenning; J de Swart; M Segbers; H E Barrett; M R Bernsen; K Van der Heiden; Marion de Jong Journal: Front Med (Lausanne) Date: 2019-03-11
Authors: Farhan Chaudhry; Jenna Isherwood; Tejeshwar Bawa; Dhruvil Patel; Katherine Gurdziel; David E Lanfear; Douglas M Ruden; Phillip D Levy Journal: Front Cardiovasc Med Date: 2019-12-10