Apoptotic versus autophagic cell death in heart failure

Objective: Progressive loss of cardiomyocytes is one of the most important pathogenic characteristics of heart failure. Apoptosis may be an important mode of cell death in heart failure but it must be demonstrated by multiple criteria and not just TUNEL staining alone. Previously, we and others have demonstrated that besides apoptosis other phenomena like active gene trans cription can result in TUNEL positivity. Moreover, other types of cell deat h that are caspase-independent could be important in heart failure. This st udy examined the hypothesis whether TUNEL labeling parallels caspase activa tion. Methods: Cardiac tissue of patients in the terminal stage of heart fa ilure as a consequence of ischaemic cardiomyopathy (ICM) or dilated cardiom yopathy (DCM) were studied. Embryonic mice hearts were used for positive co ntrol for detection of the classical apoptosis. Results: In mice embryonic hearts we could clearly find apoptotic cell death detected by TUNEL labelin g and immunohistochemistry for activated caspase-3. In heart failure, TUNEL -positive cardiomyocytes were negative for active caspase-3 but showed sign s of active gene transcription (SC-35). However, autophagic cell death coul d be found in 0.3% of the cardiomyocytes. Autophagic cell death was demonst rated by granular cytoplasmic ubiquitin inclusions, an established marker o f autophagocytosis in neurons. Interestingly, these autophagic cardiomyocyt es were TUNEL and activated caspase-3 negative but were also negative for C 9, a marker for necrosis. Western blot analysis confirmed that in cardiomyo pathies no cleavage of caspase-3 and caspase-7 occurred. Conclusion: The pr esent study demonstrates two fundamentally different situations of cell dea th in cardiac tissue. In embryonic mice, cardiomyocytes undergo caspase-dep endent cell death. However, cardiomyocytes in heart failure show caspase-in dependent autophagic cell death rather than apoptotic cell death. (C) 2001 Elsevier Science BY. All rights reserved.