Author + information
- Received August 23, 2017
- Revision received November 28, 2017
- Accepted November 29, 2017
- Published online December 3, 2018.
- Hideki Kawai, MD, PhDa,∗,
- Farhan Chaudhry, MSa,∗,
- Aditya Shekhara,
- Artiom Petrov, PhDa,∗∗ (, )
- Takehiro Nakahara, MD, PhDa,
- Takashi Tanimoto, MD, PhDa,
- Dongbin Kim, MDa,
- Jiqiu Chen, MDa,
- Djamel Lebeche, PhDa,
- Francis G. Blankenberg, PhDb,
- Koon Y. Pak, PhDc,
- Frank D. Kolodgie, PhDd,
- Renu Virmani, MDd,
- Partho Sengupta, MDa,
- Navneet Narula, MDe,
- Roger J. Hajjar, MDa,
- Harry W. Strauss, MDa and
- Jagat Narula, MD, PhDa,∗ ()
- aIcahn School of Medicine at Mount Sinai, New York, New York
- bLucile Salter Packard Children’s Hospital, Stanford, California
- cMolecular Targeting Technologies, Inc., West Chester, Pennsylvania
- dCardiovascular Pathology Institute, Inc., Gaithersburg, Maryland
- eWeill-Cornell Medical College, New York, New York
- ↵∗Address for correspondence:
Dr. Jagat Narula, Mount Sinai Heart, One Gustave L. Levy Place, Guggenheim Pavilion 1-West, 1190 Fifth Avenue, New York, New York 10029.
- ↵∗∗Dr. Artiom Petrov, Mount Sinai Heart, One Gustave L. Levy Place, Guggenheim Pavilion 1-West, 1190 Fifth Avenue, New York, New York 10029.
Objectives The purpose of this study was to evaluate the feasibility of imaging apoptosis in experimental ischemia-reperfusion model by technetium-99m (99mTc)-labeled Duramycin, and compare it to an established tracer, 99mTc-labeled Annexin-V, which has a relative disadvantage of high radiation burden to nontarget organs.
Background During apoptosis, the cell membrane phospholipids-phosphatidylserine (PS) and phosphatidylethanolamine (PE) are exposed and can be targeted by Annexin-V and Duramycin, respectively, for in vivo imaging. Identification of a reversible cell death process should permit therapeutic intervention to help reduce myocyte loss and left ventricle dysfunction.
Methods In a 40-min left coronary artery ischemia-reperfusion model in 17 rabbits, 7 mCi of 99mTc-labeled Duramycin (n = 10), 99mTc-linear Duramycin (a negative tracer control; n = 3), or 99mTc-Annexin-V (a positive tracer-control; n = 4) were intravenously administered 30 min after reperfusion. Of the 10 Duramycin group animals, 4 animals were treated with an antiapoptotic agent, minocycline at the time of reperfusion. In vivo and ex vivo micro–single-photon emission computed tomography (μSPECT) and micro-computed tomography (μCT) imaging was performed 3 h after reperfusion, followed by quantitative assessment of tracer uptake and pathological characterization. Fluorescent Duramycin and Annexin-V were injected in 4 rats to visualize colocalization in infarct areas in a 40-min left coronary artery occlusion and 30-min reperfusion model.
Results Intense uptake of Duramycin and Annexin-V was observed in the apical (infarcted) areas. The percent injected dose per gram uptake of Duramycin in apical region (0.751 ± 0.262%) was significantly higher than remote area in same animals (0.045 ± 0.029%; p < 0.01). Duramycin uptake was insignificantly lower than Annexin-V uptake (1.23 ± 0.304%; p > 0.01) but demonstrated substantially lower radiation burden to kidneys (0.358 ± 0.210% vs. 1.58 ± 0.316%, respectively; p < 0.001). Fluorescence studies with Duramycin and Annexin V showed colocalization in infarct areas. Minocycline treatment substantially resolved Duramycin uptake (0.354% ± 0.0624%; p < 0.01).
Conclusions Duramycin is similarly effective in imaging apoptotic cell death as Annexin-V with lower nontarget organ radiation. Clinical feasibility of apoptosis imaging with a PE-seeking tracer should be tested.
↵∗ Drs. Kawai and Chaudhry contributed equally to this work.
Dr. Pak is an employee of and owns stock in of Molecular Targeting Technologies. Dr. Virmani as an employee of CVPath Institute; and has a relationship with 480 Biomedical, Abbott Vascular, ART, BioSensors International, Biotronik, Boston Scientific, Celonova, Claret Medical, Cook Medical, Cordis, Edwards Lifescience, Medtronic, MicroPort, MicroVention, Celonova, OrbusNeich, ReCore, SINO Medical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis; and has received honoraria from 480 Biomedical, Abbott Vascular, Boston Scientific, Cook Medical, Lutonix, Medtronic, Terumo Corporation, and W.L. Gore. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Thomas Schindler, MD, served as the Guest Editor for this paper.
- Received August 23, 2017.
- Revision received November 28, 2017.
- Accepted November 29, 2017.
- 2018 American College of Cardiology Foundation
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