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

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Presentation transcript:

Involvement of apoptosis in neurological injury after hypothermic circulatory arrest: a new target for therapeutic intervention? Christian Hagl, MD, Nadine A. Tatton, PhD, Nawid Khaladj, Ning Zhang, MD, Sarah Nandor, Stephanie Insolia, PhD, Donald J. Weisz, PhD, David Spielvogel, MD, Randall B. Griepp, MD The Annals of Thoracic Surgery Volume 72, Issue 5, Pages 1457-1464 (November 2001) DOI: 10.1016/S0003-4975(01)02897-1

Fig 1 Behavioral recovery of pigs after 90 minutes of hypothermic circulatory arrest at 20°C. The gray bars represent medians (lines represent ranges) for all animals [n] evaluated at each time point. The bars with diagonal lines are the median scores for only those animals undergoing elective sacrifice at each point. The behavioral score ranges from 0 (coma or death) to 9 (normal). POD = postoperative day. The Annals of Thoracic Surgery 2001 72, 1457-1464DOI: (10.1016/S0003-4975(01)02897-1)

Fig 2 Confocal images of in situ end labeling-nucleic acid-binding cyanine dye (ISEL/YOYO)-stained cells from the CA1,2,3 region of the hippocampus in pigs subjected to 90 minutes of hypothermic circulatory arrest at 20°C, showing apoptotic, Type 1, and Type 2 degenerative neuronal morphologies. The top row depicts YOYO-stained cells; the bottom row shows the same section viewed for ISEL fluorescence. A1 shows a highly condensed YOYO-bright apoptotic nucleus (arrow), with a moderate ISEL signal seen in A2. Neurons undergoing Type 1 degenerative change (B1) typically show highly condensed YOYO-bright smooth-edged nuclear bodies of varying size, some of which display a low-level ISEL signal (arrows) (B2) within an apparently intact nuclear membrane. Neurons undergoing Type 2 degenerative change (C1) typically show irregular-edged YOYO-bright bodies (arrow) of similar size, which are usually ISEL-negative (C2). Scale bar is 10 μm. The Annals of Thoracic Surgery 2001 72, 1457-1464DOI: (10.1016/S0003-4975(01)02897-1)

Fig 3 Graph of frequency of different types of neuronal cell death morphologies in the hippocampus after hypothermic circulatory arrest for 90 minutes at 20°C in pigs sacrificed at different intervals postoperatively. Each value represents the mean of the occurrence of each cell type, shown in Figure 2, from 3 pigs, as detailed in the text, with standard errors. Levels of apoptosis were significantly higher than in unoperated controls (C) at 6, 48, and 72 hours (p = 0.05 by Mann-Whitney U test). Levels of Type 1 cell death were significantly elevated at 6, 24, 48, and 72 hours (p = 0.05). Type 2 cell death was significantly higher than controls throughout the period of observation (p = 0.05). (d = days; h = hours.) The Annals of Thoracic Surgery 2001 72, 1457-1464DOI: (10.1016/S0003-4975(01)02897-1)

Fig 4 Graph of frequency of different types of neuronal cell death morphologies in the hippocampus after hypothermic circulatory arrest (HCA) for 90 minutes at 20°C in pigs sacrificed at different intervals postoperatively. In A, levels of apoptosis are represented on a linear time scale by histograms. The straight dotted line represents control levels of apoptosis. To calculate the increase in apoptosis resulting from HCA, the area under the curve but above the dotted line was estimated. By this approximation, apoptosis constituted 21% of neuronal cell death within 12 days after HCA, and 29% of neuronal cell death within the first 72 hours after HCA. In B, the same calculation is made for Type 1 neuronal cell death, but is simplified by the absence of any Type 1 cells in the control animals. Type 1 cells constitute approximately 39% of neuronal cell death within 12 days after HCA, and 45% of neuronal cell death within the first 72 hours after HCA. In C, the same calculation is made for Type 2 neuronal cell death: Type 2 cells constitute approximately 39% of neuronal cell death within 12 days after HCA, and 25% of neuronal cell death within the first 72 hours after HCA. (d = days; h = hours.) The Annals of Thoracic Surgery 2001 72, 1457-1464DOI: (10.1016/S0003-4975(01)02897-1)

Fig 5 Graph comparing the different neuronal cell death morphologies 72 hours after 90 minutes of hypothermic circulatory arrest under different circumstances: at 20°C, at 10°C, and at 20°C after treatment with CsA as described in the text. Controls were unoperated. Levels of apoptosis were not significantly different in any of the groups after HCA, but all were significantly higher than controls (p = 0.05 by Mann-Whitney U test). The levels of both Type 1 and 2 neuronal cell death were higher after HCA at 20°C than at 10°C (p = 0.05). The levels of Type 1 cells were significantly lower in pigs treated with CsA (p = 0.05). (CsA = cyclosporine A; HCA = hypothermic circulatory arrest.) The Annals of Thoracic Surgery 2001 72, 1457-1464DOI: (10.1016/S0003-4975(01)02897-1)