In vivo detection of apoptotic cell death: A necessary measurement for evaluating therapy for myocarditis, ischemia, and heart failure
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If life is to continue, cells that have completed their useful function(s) must die in a timely manner. Apoptosis, programmed cell death, is a natural, orderly, energy-dependent process that causes cells to die without inducing an inflammatory response. In the heart, apoptosis plays pivotal roles in the development of myocarditis, cardiomyopathies, transplant rejection, the periinfarct zone in myocardial infarction, and reperfusion injury. Apoptosis is triggered either by a decrease in factors required to maintain the cell in good health or by an increase in factors which cause damage to the cell. When these factors tilt in the direction of death and the cell has sufficient time to respond, a common proteolytic, cascade involving cysteine aspartic acid-specific proteases (caspases) is activated to initiate apoptosis. Cells that die by apoptosis autodigest their DNA and nuclear proteins, change the phospholipid composition on the outer surface of their cell membrane, and form lipid enclosed vesicles, which contain noxious intracellular contents, organelles, autodigested cytoplasm, and DNA. The compositional cell membrane phospholipid change that occurs with the onset of apoptosis is marked by the sudden expression of phosphatidylserine (PS), a phospholipid that ordinarily appears on the inner leaflet of the membrane, on the external leaflet of the membrane. The constant exposure of PS during apoptosis makes it an attractive target for radiopharmaceutical imaging. An endogenous human protein, annexin V, has a high affinity (kd=7 nmol/L) for PS bound to the cell membrane. Fluorescence-labeled annexin V is used for histologic and cell-sorting studies to identify apoptotic cells. Annexin has been radiolabeled and binds to cells undergoing apoptosis in vivo. This review outlines some of the key features of apoptosis as contrasted to necrosis (unregulated cell death) and describes how these processes can be imaged with radionuclide techniques.
- Cotran R, Kumar V, Robbins SL, editors. Robbins pathologic basis of disease 5th ed. Philadelphia Saunders 1994.
- Kerr JF, Willie AH, Currie AR. Apoptosis: a basic, biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
- Thompson BC. Apoptosis in the pathogenesis and treatment of disease. Science 1995;267:1456–62. CrossRef
- Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998;281:1312–6. CrossRef
- Nagata S, Golstein F. The fas death factor. Science 1995;267:1449–56. CrossRef
- Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182–9. CrossRef
- Narula J, Hajjar RJ, Dec GW. Apoptosis in heart failure. Cardiol Clin 1998;16:691–710. CrossRef
- Martin SJ, Reutelingsperger CPM, McGahon AJ. Early redistribution of plasma membrane phosphatidylserine in a general feature of apoptosis regardless of the initiating stimulus. J Exp Med 1995;182:1545–56. CrossRef
- Vermes I, Haanen C, Steffens-Nakken H. Reutelingsperger CPM. A novel assay for apoptosis flow cytometry detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled annexin V. J Immuno Methods 1995;184:39–51. CrossRef
- Blankenberg FG, Katsikis PF, Tait JF, et al. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci USA 1998;95:6349–54. CrossRef
- Tait JF, Cerqueira MD, Dewhurst TA. Evaluation of annexin V as a platelet-directed thrombus targeting agent. Thromb Res 1994;75:491–501. CrossRef
- Vriens PW, Blankenberg FG, Stoot JH, et al. The use of technetium Tc 99m annexin V for in vivo imaging of apoptosis during cardiac allograft rejection. J Thorac Cardiovasc Surg 1998;116:844–53. CrossRef
- Ohtsuki K Akashi K, Aoka Y, et al. 99m Tc-HYNIC Annexin V: a potential radiopharmaceutical for the in-vivo detection of Apoptosis. Eur J Nucl Med. In Press.
- Blankenberg FG, Katsikis PD, Tait JF, et al. Imaging of Apoptosis (Programmed Cell Death) with 99mTc Annexin V J Nucl Med 1999; 40: 84–91.
- Blankenberg FG, Katsikis PD, Storrs RW, etal. Quantitative analysis of apoptotic cell death using proton nuclear magnetic resonance spectroscopy. Blood 1997;89:3778–86.
- Veale MF, Dingley AJ, King GF, etal. 1H-NMR visible neutral lipids in activated T lymphocytes: relationship to phosphatidylcholine cycling. Biochim Biophys. Acta 1996;1303:215–21.
- Evan G, Littlewood T. A matter of life and cell death. Science 1998;281:1317–22. CrossRef
- Moreno A, Ziegler A, et al. Evidence that mobile lipids detected in rat brain glioma by 1h nuclear magnetic resonance correspond to lipid droplets. Cancer Res 1997;57:407–14.
- Leist M, Single B, Castoldi AF, et al. Intracellular Adenosine Triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997;185:1481–6. CrossRef
- Thiemermann C, Bowes J, Myint FP, etal. Inhibition of the activity of poly (ADP ribose) synthetase reduces ischemia-reperfusion injury in the heart and skeletal muscle. PNAS 1997;94:679–83. CrossRef
- D'Arceuil HE, deCrespigny AJ, Rother J, etal. Diffusion and perfusion magnetic resonance imaging of the evolution of hypoxic ischemic encephalopathy in the neonatal rabbit JMRI 1998;8:820–8. CrossRef
- Kajstura J, Leri A, Finato N, etal. Myocyte proliferation in end-stage cardiac failure in humans PNAS 1998;95:8801–5. CrossRef
- Anversa P, Leri A, Beltrami CA, etal. Myocyte death and growth in the failing heart Lab Invest 1998;78:767–82.
- In vivo detection of apoptotic cell death: A necessary measurement for evaluating therapy for myocarditis, ischemia, and heart failure
Journal of Nuclear Cardiology
Volume 6, Issue 5 , pp 531-539
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- 1. Division of Nuclear Medicine, Stanford University School of Medicine, 300 Pasteur Drive, H0101, 94305-5281, Stanford, CA
- 2. Department of Radiology, Stanford University School of Medicine, Stanford, Calif.
- 3. Division of Cardiovascular Diseases, Heart Failure and Transplantation Center, Hahnemann University School of Medicine, Philadelphia, Pa.