Death hath a thousand doors to let out life...

Abstract

Myocardial structural remodeling, a progressive, often self-perpetuating process, is an important marker of progressive heart failure. Myocardial cell loss, through any number of mechanisms mediating cellular death, is an important component in its genesis.1 Traditionally, necrosis has been regarded as the pathological hallmark of myocardial cell death. However, there is accumulating evidence that cells can die through a number of other mechanisms including programmed and nonprogrammed cell death. The elegant study in this issue of Circulation Research by Kostin and colleagues2 makes an important addition to the list of intriguing ways that life or death decisions are made in the failing heart. They found that in addition to apoptosis and necrosis,R3-128044 3,4 cardiac cells can also die through autophagy associated with ubiquitylated protein accumulation. Apart from mechanistic insights, these kinds of new data might have a therapeutic potential. A broad look at cell survival or death and its implications may thus be in order. Traditionally, distinct types of cell death have been identified based on morphological characteristics.4 Cells were considered to have died due to necrosis if there were severe disruption of cellular membranes and cell contents. Apoptosis was thought to involve a genetically programmed cell death with preserved cell boundary and minimal inflammatory response. Other forms of cell death, with a less clear morphology or mechanism, were then identified including lysosome- or proteosome-mediated cell death. These distinctions were reinforced when reproducible mechanisms were found to underlie the different morphologies of cell death. This classification also offered the promise that therapeutic strategies could be designed to selectively influence some of these pathogenetic mechanisms. A number of findings have raised the possibility that various forms of death may be a part of the same spectrum. For one, multiple morphologies of cell death may coexist in the same microscopic …