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

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 de greesC 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 addit ion, 3 animals that had HCA at 10 degreesC, and 3 treated with cyclosporine A (CsA) in conjunction with HCA at 20 degreesC, were examined 72 hours aft er HCA. After selective perfusion and cryopreservation, all brains were exa mined to visualize apoptotic DNA fragmentation and chromatin condensation o n 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 dege nerative morphological cell types (not seen in controls) were characterized after HCA. Cell death began 6 hours after HCA and reached its peak at 72 h ours, but continued for at least 7 days. Compared with the standard protoco l at 20 degreesC, HCA at 10 degreesC and CsA treatment both significantly r educed 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 degreesC, other pathways of cell death, probably including necrosis, predominate. Although preliminary results sugg est that the neuroprotective effects of lower temperature and of CsA are no t a consequence of blockade of apoptotic pathways, inhibition of apoptosis nevertheless seems promising as a strategy to protect the brain from the su btle neurological injury that is associated with prolonged HCA at clinicall y relevant temperatures. (C) 2001 by The Society of Thoracic Surgeons.