在捐赠后循环死亡（DCD）大鼠离体心脏模型中，再灌注早期的线粒体完整性-缺血持续时间的后果。
Mitochondrial integrity during early reperfusion in an isolated rat heart model of donation after circulatory death-consequences of ischemic duration.
机构信息
Department of Cardiovascular Surgery, Inselspital, University Hospital Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
Center of Laboratory Medicine, University Institute of Clinical Chemistry, Bern, Switzerland.
出版信息
J Heart Lung Transplant. 2019 Jun;38(6):647-657. doi: 10.1016/j.healun.2018.12.013. Epub 2018 Dec 21.
BACKGROUND
Cardioprotection and graft evaluation after ischemia-reperfusion (IR) are essential in facilitating heart transplantation with donation after circulatory death. Given the key role of mitochondria in IR, we aimed to investigate the tolerance of cardiac mitochondria to warm, global ischemia and to determine the predictive value of early reperfusion mitochondria-related parameters for post-ischemic cardiac recovery.
METHODS
Isolated, working rat hearts underwent 0, 21, 24, 27, 30, or 33 minutes of warm, global ischemia, followed by 60 minutes of reperfusion. Functional recovery (developed pressure × heart rate) was determined at 60 minutes of reperfusion, whereas mitochondrial integrity was measured at 10 minutes of reperfusion.
RESULTS
Functional recovery at 60 minutes of reperfusion decreased with ≥ 27 minutes of ischemia vs no ischemia (n = 7-8/group; p < 0.01). Cytochrome c, succinate release, and mitochondrial Ca content increased with ≥ 27 minutes of ischemia vs no ischemia (p < 0.05). Ischemia at ≥ 21 minutes decreased mitochondrial coupling, adenosine 5'-triphosphate content, mitochondrial Ca retention capacity, and increased oxidative damage vs no ischemia (p < 0.05). Reactive oxygen species (ROS) from reverse electron transfer increased with 21 and 27 minutes of ischemia vs no ischemia and 33 minutes of ischemia (p < 0.05), whereas ROS from forward electron transfer increased only with 33 minutes of ischemia vs no ischemia (p < 0.05). Mitochondrial coupling and adenosine 5'-triphosphate content correlated positively and cytochrome c, succinate, oxidative damage, and mitochondrial Ca content correlated negatively with cardiac functional recovery (p < 0.05).
CONCLUSIONS
Mitochondrial dysfunction occurs with shorter periods of ischemia than cardiac dysfunction. Mitochondrial coupling, ROS emission from reverse electron transfer, and calcium retention are particularly sensitive to early reperfusion injury, reflecting potential targets for cardioprotection. Indicators of mitochondrial integrity may be of aid in evaluating suitability of donation after circulatory death grafts for transplantation.
背景
在进行捐赠后循环死亡（DCD）的心脏移植时，缺血再灌注（IR）后的心脏保护和移植物评估至关重要。鉴于线粒体在 IR 中的关键作用，我们旨在研究心脏线粒体对温暖、全脑缺血的耐受性，并确定早期再灌注时与线粒体相关的参数对缺血后心脏恢复的预测价值。
方法
分离的工作大鼠心脏经历 0、21、24、27、30 或 33 分钟的温暖、全脑缺血，随后进行 60 分钟的再灌注。在再灌注 60 分钟时确定功能恢复（发展压力×心率），而在再灌注 10 分钟时测量线粒体完整性。
结果
与无缺血相比，再灌注 60 分钟时的功能恢复在缺血≥27 分钟时降低（n=7-8/组；p<0.01）。与无缺血相比，细胞色素 c、琥珀酸释放和线粒体 Ca 含量在缺血≥27 分钟时增加（p<0.05）。与无缺血相比，缺血≥21 分钟时线粒体偶联、三磷酸腺苷含量、线粒体 Ca 保留能力降低，氧化损伤增加（p<0.05）。与无缺血相比，来自逆向电子传递的活性氧物种（ROS）在缺血 21 和 27 分钟时增加，而在缺血 33 分钟时增加（p<0.05），而来自正向电子传递的 ROS 仅在缺血 33 分钟时增加（p<0.05）。线粒体偶联和三磷酸腺苷含量与心脏功能恢复呈正相关，而细胞色素 c、琥珀酸、氧化损伤和线粒体 Ca 含量与心脏功能恢复呈负相关（p<0.05）。
结论
与心脏功能障碍相比，较短时间的缺血即可发生线粒体功能障碍。线粒体偶联、逆向电子传递产生的 ROS 释放和钙保留对早期再灌注损伤特别敏感，反映了潜在的心脏保护靶点。线粒体完整性的指标可能有助于评估捐赠后循环死亡供体移植物是否适合移植。
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