Author + information
- Received August 7, 2020
- Accepted August 20, 2020
- Published online October 12, 2020.
- Farhan Chaudhry, MSa,b,∗,
- Hideki Kawai, MD, PhDa,c,∗,
- Kipp W. Johnson, PhDa,
- Navneet Narula, MDd,
- Aditya Shekhar, BSa,
- Fayzan Chaudhry, BSa,
- Takehiro Nakahara, MD, PhDa,
- Takashi Tanimoto, MD, PhDa,
- Dongbin Kim, PhDa,
- Matthew K.M.Y. Adapoe, MSa,
- Francis G. Blankenberg, PhDe,
- Jeffrey A. Mattis, PhDf,
- Koon Y. Pak, PhDf,
- Phillip D. Levy, MD, MPHb,
- Yukio Ozaki, MD, PhDc,
- Eloisa Arbustini, MDg,
- H. William Strauss, MDa,h,
- Artiom Petrov, PhDa,∗ (, )
- Valentin Fuster, MD, PhDa,i and
- Jagat Narula, MD, PhDa
- aIcahn School of Medicine at Mount Sinai, New York, New York
- bWayne State University School of Medicine, Detroit, Michigan
- cDepartment of Cardiology, Fujita Health University, Toyoake, Aichi, Japan
- dNew York University Langone Medical Center, New York, New York
- eLucile Salter Packard Children’s Hospital, Stanford, California
- fMolecular Targeting Technologies, Inc., West Chester, Pennsylvania
- gPoliclinico San Matteo Pavia Fondazione IRCCS, Pavia, Italy
- hMemorial Sloan Kettering Cancer Center, New York, New York
- iCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- ↵∗Address for correspondence:
Dr. Artiom Petrov, Mount Sinai Heart, One Gustave L. Levy Place, Guggenheim Pavilion West, 1190 Fifth Avenue, New York, New York 10029.
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.
↵∗ Drs. Chaudhry and Kawai contributed equally to the manuscript.
Part of the data was presented by Dr. Farhan Chaudhry at The Society of Nuclear Medicine and Molecular Imaging Mid-Winter Meeting and the American College of Nuclear Medicine Annual Meeting in January 2016 in Orlando, Florida, and won the Best Young Investigator Award.
This manuscript is dedicated to the memory of Dr. Farooq A. Chaudhry (August 30, 2017), who initiated the project in collaboration with Drs. Narula and Fuster.
Drs. Mattis and Pak are employees of Molecular Targeting Technologies, Inc. Funding support was received from NIH SBIR Contract Research grant (project # 268201400043C-0-0-1) to Dr. Narula. Dr. Chaudhry’s research fellowship was partially funded by the Society of Academic Emergency Medicine Foundation and the Jewish Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Ahmed Tawakol, MD, served as Guest Associate Editor for this paper. Deepak L. Bhatt, MD, MPH, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received August 7, 2020.
- Accepted August 20, 2020.
- 2020 American College of Cardiology Foundation
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