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Ann Thorac Surg 2004;77:382
© 2004 The Society of Thoracic Surgeons
a Institute of Pathology, University of Luebeck, Luebeck, Germany
b Klinik für Herzchirurgie, Universitaetsklinikum Luebeck, Ratzeburger Allee 160, Luebeck D-23538, Germany
e-mail: bartels{at}medinf.mu-luebeck.de
To the Editor:
We write with reference to the interesting and impressively well designed study of Schmitt and co-workers [1] concerning the mode of cardiomyocyte death in the context of cardioplegic arrest and reperfusion. Damage to single cardiomyocytes was investigated by electron microscopy, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling of fragmented DNA [deoxyribonucleic acid]), and quantification of cytochrome c and citrate synthase release and was interpreted as apoptosis. However, some questions concerning this interpretation should be addressed.
Apoptosis and necrosis are two distinct forms of cell death, discriminated by morphologic and biochemical criteria [2–4]. Methodologically, identification of apoptosis requires a multiple approach to correlate distinctive ultrastructural features with an apoptotic DNA–fragmentation pattern and molecular events, eg, cytochrome c release or activation of key caspases (Caspase-3) [2, 4]. Morphologic criteria are considered the most reliable evidence of apoptosis [4]. In contrast, TUNEL is known to be nonspecific [2, 5].
In their study, Schmitt and associates [1] described and illustrated severe mitochondrial swelling and disruption after cardioplegic arrest. Margination and clumping of chromatin into ill-defined masses were also observed. These morphologic features are characteristic of the necrotic form of ischemic cell damage [2, 5], which is also termed oncosis. In contrast, in the early apoptotic phase, nuclear chromatin is normally condensed into sharply delineated, compact masses, and mitochondria are well preserved [4–6].
Cytochrome c release from mitochondria into the cytoplasm, as found by the authors, is linked to the initial phase of apoptosis. However, some release of citrate synthase, indicating damage to the mitochondrial matrix, was also observed. The ischemia and reperfusion associated with cardioplegic arrest produces a mixture of pro-apoptotic and necrosis-promoting signals, the target of both being the mitochondria [4]. Therefore, there might be some overlap between these two processes under the conditions of cardioplegia [4]. Taking the morphologic and biochemical findings in this study together, one might speculate that the apoptotic pathway was initially started but subsequently aborted, resulting in a mixture of apoptotic and oncotic features [3, 4], ie, cytochrome c release but oncotic morphology. In our opinion, morphologic and histochemical criteria fail to prove apoptosis in this study.
References
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