How and when do myocytes die during ischemia and reperfusion: the late phase

While the majority of the cardiac myocyte death that makes up the final infarct occurs during ischemia and the first few minutes of reperfusion, cell death does not stop there. In fact necrosis and apoptosis, and potentially autophagy, can continue in the previously ischemic area for up to 3 days post-reperfusion. Several mechanisms can potentially contribute to this death continuum: (1) myocytes that have already passed the point of no return despite reperfusion; (2) continued dysfunction of the coronary microvasculature; and (3) infiltration of inflammatory cells. The latter in particular leads to elevated myocardial concentrations of reactive oxygen species (ROS), inflammatory cytokines, activation of toll-like receptors, secretion of toxic enzymes, and activation of the complement cascade--all of which can lead to myocyte death. However, there is a considerable lack of studies that comprehensively examine the time course, nature, and mechanisms of post-reperfusion myocyte death. Moreover, cell death types (apoptosis, necrosis, and autophagy) are inextricably linked to one another. Therefore, we do not know whether specific blockade of necrosis during the acute phase of myocyte death will instead enhance apoptosis during the late phase, that is, will we be simply delaying the inevitable? Consequently, the purpose of this article is to briefly review what we do, and more importantly what we do not, know about cardiac cell death in the reperfused heart and what is needed to advance our understanding of this phenomenon.