In vivo detection of apoptotic cell death: A necessary measurement for evaluating therapy for myocarditis, ischemia, and heart failure

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 induci ng an inflammatory response. In the heart, apoptosis plays pivotal roles in the development of myocarditis, cardiomyopathies, transplant rejection, th e periinfarct zone in myocardial infarction, and reperfusion injury. Apopto sis is triggered either by a decrease in factors required to maintain the c ell in good health or by an increase in factors which cause damage to the c ell. When these factors tilt in the direction of death and the cell has suf ficient time to respond, a common proteolytic cascade involving cysteine as partic acid-specific proteases (caspases) is activated to initiate apoptosi s, Cells that die by apoptosis autodigest their DNA and nuclear proteins, c hange the phospholipid composition on the outer surface of their cell membr ane, and form lipid enclosed vesicles, which contain noxious intracellular contents, organelles, autodigested cytoplasm, and DNA, The compositional ce ll 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 extern al leaflet of the membrane. The constant exposure of PS during apoptosis ma kes 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 rad iolabeled and binds to cells undergoing apoptosis in vivo, This review outl ines some of the key features of apoptosis as contrasted to necrosis (unreg ulated cell death) and describes how these processes can be imaged with rad ionuclide techniques.