Introduction—cell death in heart failure

In the not too distant past, most cell death was thought to occur by ‘‘accident’’ rather than through deliberate cell suicide. It has become increasingly clear that the cell is often an active participant in its own demise. The recognition that cell death is actively mediated has raised the exciting possibility that it may be manipulated to therapeutic advantage. In cancer, where defective cell death often contributes to tumorigenesis, the goal would be to induce certain cells to die [1]. Conversely, in disorders such as myocardial infarction, heart failure, stroke, and some neurodegenerative diseases, where excessive cell death occurs, the objective would be to promote cell survival. Although disease mechanisms are inevitably more complex than this simple formulation, animal work over the past 15 years has provided proof of principle that cell death is an important causal component of a variety of disorders. This, in turn, has provided the conceptual basis for therapies directed at increasing or decreasing cell death. Several death programs operate in the cell, alone or in combination: apoptosis, necrosis, and perhaps autophagy. Pending more complete delineation of mechanisms, each of these processes is defined morphologically. Apoptosis, the most understood cell suicide process, is characterized by maintenance of plasma membrane integrity until late in the process. Apoptosis is mediated by two inter-connected pathways [2]. The extrinsic or death receptor pathway transmits death signals from relatively specialized ligands such as Fas ligand or tumor necrosis factor-a. In contrast, the more ancient intrinsic or mitochondrial/ER pathway transduces a wide spectrum of death signals that originate both outside and inside the cell. These include deficiency of nutrients/survival factors/oxygen, oxidative stress, physical and chemical toxins (radiation, drugs), DNA damage, and misfolded proteins. Stimulation of these pathways triggers the translocation of death-promoting proteins (e.g. cytochrome c) from the mitochondria to the cytosol [3] and the activation of a class of cysteine proteases called caspases. Caspases, in turn, fragment multiple cellular proteins to bring about apoptotic death. In contrast to the well-developed cascade that mediates apoptosis, necrosis remains poorly understood. Necrosis is characterized by early loss of plasma membrane integrity and cellular ATP depletion, although it is unclear which, if either, is the primary lesion. Studies in lower organisms have implicated cell surface sodium and calcium channels, calpains, and cathepsins [4–6]. The most unequivocal mediator of necrosis delineated thus far in mammalian cells, however, is cyclophilin D, a component of the mitochondrial permeability transition pore located on the inner mitochondrial membrane [7, 8]. Strikingly, mice lacking cyclophilin D are resistant to necrosis but not apoptosis. In addition to providing a glimpse at the mechanism of necrosis, this observation suggests that the classic view of necrosis as a passive process needs reconsideration. Autophagy is an intracellular recycling process in which proteins and organelles traffic in double membrane vesicles to the lysosome for breakdown to provide the cell with R. N. Kitsis (&) Departments of Medicine and Cell Biology, Cardiovascular Research Center, and Cancer Center, Albert Einstein College of Medicine, Forchheimer G46, 1300 Morris Park Avenue, Bronx, NY 10461, USA e-mail: kitsis@aecom.yu.edu