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Involvement of apoptosis in neurological injury after hypothermic circulatory arrest: a new target for therapeutic intervention?

The Annals of Thoracic Surgery
Publication Date
DOI: 10.1016/s0003-4975(01)02897-1
  • Original Article: Cardiovascular
  • Medicine


Abstract Background. This study was undertaken to evaluate the role of apoptosis in neurological injury after hypothermic circulatory arrest (HCA). Methods. Twenty-one pigs (27 to 31 kg) underwent 90 minutes of HCA at 20°C and were electively sacrificed at 6, 24, 48, and 72 hours, and at 7, 10, and 12 days after HCA, and compared with unoperated controls. In addition, 3 animals that had HCA at 10°C, and 3 treated with cyclosporine A (CsA) in conjunction with HCA at 20°C, were examined 72 hours after HCA. After selective perfusion and cryopreservation, all brains were examined to visualize apoptotic DNA fragmentation and chromatin condensation on the same cryosection of the hippocampus: fluorescent in situ end labeling (ISEL) was combined with staining with a nucleic acid-binding cyanine dye (YOYO). Results. In addition to apoptosis, which was seen at a significantly higher level ( p = 0.05) after HCA than in controls, two other characteristic degenerative morphological cell types (not seen in controls) were characterized after HCA. Cell death began 6 hours after HCA and reached its peak at 72 hours, but continued for at least 7 days. Compared with the standard protocol at 20°C, HCA at 10°C and CsA treatment both significantly reduced overall cell death after HCA, but not apoptosis. Conclusions. The data establish that significant neuronal apoptosis occurs as a consequence of HCA, but at 20°C, other pathways of cell death, probably including necrosis, predominate. Although preliminary results suggest that the neuroprotective effects of lower temperature and of CsA are not a consequence of blockade of apoptotic pathways, inhibition of apoptosis nevertheless seems promising as a strategy to protect the brain from the subtle neurological injury that is associated with prolonged HCA at clinically relevant temperatures.

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