The role of apoptosis in cardiac disease remains controversial. Much of the apoptosis detected, by chemical or molecular means, reflects inflammatory reaction and responding blood cells rather than myocytes, though their apoptosis in situ may exacerbate a bad situation, and their direct action against myocytes has not been excluded definitely. Myocyte apoptosis may reflect end-stage cardiac failure rather than causing it. If this is the case, then preventing apoptosis so that the cells can undergo necrosis does not accomplish much. Apoptosis is a consistent and important finding in many forms of cardiovascular disease. As determined by ultra-structure, apoptosis is common in cardiomyocytes, fibroblasts, vascular endothelial cells, and smooth muscle cells in cardiovascular disease of many origins. (62) Even though smooth muscle cells in atheromatous plaques appear to be necrotic,l it is likely that this is an evolved situation of apoptotic cells that were not removed. Given the prevalence of apoptotic processes in diseased heart and the very limited capacity of this organ to repair itself, (56) it is appropriate and justified to continue to explore the significance of apoptosis in cardiac disease and, above all, to explore the use of antiapoptotic agents in acute situations. Researchers must pay explicit attention to how they document cell death and in what tissues or cells it occurs. Otherwise, clinicians risk being deluded by preservation of morphology in nonfunctional cells and by confusion of what happened and where death occurred in the sequence of causality. Cell death in the heart is a matter of substantial theoretical and practical concern. A major problem in analyzing it is that, although apoptosis may be demonstrated easily in myocytes, particularly embryonic myocytes, under conditions of culture, interpretation is much more complex in an intact organ. The first issue is one of timing. In situations of severe, acute loss of cells, such as in an infarct, apoptotic cells may not be cleared rapidly and may progress to a more oncotic or necrotic morphology. Second, in situations of inflammation, biochemical or molecular techniques may confound apoptosis of inflammatory cells with apoptosis of myocytes. Third, priorities in the sequence of apoptosis differ between large, generally nonmitotic cells with massive cytoplasm (as differentiated myocytes) and small mitotic cells in culture, which usually are studied. The appearance and many markers of physiological cell death may differ from the most widely recognized forms of apoptosis, including late collapse of the nucleus and primacy of lysosomal or other proteases as opposed to caspases. Investigators should always strive to establish multiple criteria for apoptosis, with good documentation of timing and cell type. When these factors are taken into consideration, it seems that aggressive action against apoptosis may be of value in acute situations, such as infarct, in which buying short increments of time may reduce damage. In more chronic situations, much of the apoptosis detected derives from invading lymphocytes, mast cells, or other cells relating to inflammation. The apoptosis of these cells may exacerbate an already difficult situation, and intervention may prove of value. Otherwise, apoptosis of myocytes is more typically an end-stage situation, and it is more fruitful to alleviate the problem before this stage is reached.