Cardiomyocyte apoptosis in the failing heart--a critical review from definition and classification of cell death

It has been suggested that apoptosis may be responsible for a significant amount of the cardiomyocyte death that contributes to the development and progression of heart failure. However, studies of actual heart disease and in vivo experimental models have provided little or no direct morphological evidence that cardiomyocyte apoptosis occurs at any stage of heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. The Nomenclature Committee on Cell Death (NCCD), an international organization consulting on cell death, proposed an international standard for the definition and classification of cell death, in which cell death was defined based purely on morphological criteria. This is because there is no clear-cut equivalence between ultrastructural alterations and biochemical cell death characteristics. This review will first introduce the NCCD definition and classification of cell death and, based on this classification, survey the available data from both animals and humans to critically assess the impact of cardiomyocyte apoptosis during the progression of heart failure of various etiologies. Particularly noteworthy is the wide variation in the reported rates of apoptosis--e.g., the difference was >1000-fold in one heart failure model--but even more importantly, no morphological (ultrastructural) data has ever been shown definitively demonstrating apoptosis of a cardiomyocyte. We conclude from our survey that even the existence of cardiomyocyte apoptosis in heart failure remains controversial.