Programmed Necrosis, Not Apoptosis, in the Heart

Abstract: It is well known that apoptosis is an actively mediated cell suicide process. In contrast, necrosis, a morphologically distinct form of cell death, has traditionally been regarded as passive and unregulated. Over the past decade, however, experiments in Caenorhabditis elegans and mammalian cells have revealed that a significant proportion of necrotic death is, in fact, actively mediated by the doomed cell. Although a comprehensive understanding of necrosis is still lacking, some key molecular events have come into focus. Cardiac myocyte apoptosis and necrosis are prominent features of the major cardiac syndromes. Accordingly, the recognition of necrosis as a regulated process mandates a reexamination of cell death in the heart. This review discusses pathways that mediate programmed necrosis, how they intersect with apoptotic pathways, roles of necrosis in heart disease, and new therapeutic opportunities that the regulated nature of necrosis presents. (Circ Res. 2011;108:1017-1036.) Key Words: cell death necrosis apoptosis myocardial infarction heart failure As recently as 30 years ago, cell death was viewed as apassive and unregulated process. Irreversible cellular injury (from physical/chemical/biological insults) was thought to kill solely by overwhelming cellular homeostasis. In this model, the cell was merely the recipient of damage an