Effect of Diabetes on Outcome after Cardiac Arrest and Cardiopulmonary Resuscitation with Postconditioning Strategies in a Rodent Model

即使采用最好的心肺复苏术（CPR），在德国每年约10万例院外心脏骤停（CA）患者中，超过90%的患者死亡或有严重的神经功能缺陷。这是由于CPR的成功结果与未经治疗的CA持续时间成反比。不幸的是，60-80%的患者没有接受旁观者CPR，急救人员平均在紧急呼叫后8-10分钟到达。CA期间全身缺血时间延长后，突然再灌注导致的分子和代谢变化，即胸按压开始时血流的重新引入，可能比初始缺血本身造成的损伤更严重。在心肺复苏术中应用的一种新策略是缺血后适应（IPostC），以减轻心脏和大脑的IR损伤的发展。与常规动物模型相比，CA受害者很少健康，通常患有各种慢性疾病，如肥胖和2型糖尿病（T2DM），这增加了他们发生不良事件的风险。此外，当接受最佳治疗时，2型糖尿病患者常规服用一种或多种降糖药物。然而，T2DM及其治疗可能分别通过取消或恢复其益处来干扰其他高效调节策略（如IPostC）的重要信号通路。因此，我的博士后研究经费的总体目标是通过Zucker糖尿病脂肪（ZDF）大鼠建立复苏模型，探索T2DM及其治疗与CA和CPR±IPostC后预后的相互作用。我的目标是：1)确定与CA后标准(S)-CPR相比，IPostC对瘦、健康ZDF大鼠预后的影响；2)确定T2DM对糖尿病ZDF大鼠CA后S-CPR与ipost - c - cpr预后的影响；3)确定胰岛素治疗对糖尿病大鼠CA后S-CPR与ipost - c - cpr预后的影响；4)用二甲双胍代替胰岛素治疗。从这一高度创新的、具有翻译意义的建议中获得的知识，将首次为糖尿病及其标准治疗与CA后成功复苏的能力之间的相互作用提供急需的新视角，并通过后处理进一步改善结果。

Even with the best methods of cardiopulmonary resuscitation (CPR), more than 90% of the estimated 100,000 patients with out-of-hospital cardiac arrest (CA) in Germany each year die or have severe neurological deficits. This is due to the fact that successful outcome from CPR is inversely proportional to the duration of untreated CA. Unfortunately, 60-80% of patients do not receive bystander CPR, and first responders arrive on average 8-10 minutes after the emergency call. The molecular and metabolic changes resulting from abrupt reperfusion, i.e. reintroduction of blood flow during the start of chest compressions, after prolonged global ischemia during CA, may be of greater consequence than the injury caused by the initial ischemia itself. A novel strategy applied during CPR is ischemic postconditioning (IPostC), to mitigate the development of IR injury to the heart and brain. In contrast to regular animal models, CA victims are rarely healthy, often suffering from a variety of chronic diseases, such as obesity and type 2 diabetes mellitus (T2DM), that increase their risk for adverse events. Moreover, when optimally treated, T2DM patients are routinely on one or more antidiabetic medications. Both T2DM and its treatments, however, may differentially interfere with important signaling pathways of otherwise highly efficacious conditioning strategies like IPostC, by abrogating or restoring their benefit, respectively. Thus, the overall goal of my postdoctoral research grant is to explore the interaction of T2DM and its treatments with outcome after CA and CPR ± IPostC in an established rat model of resuscitation by using the Zucker diabetic fatty (ZDF) rat. I aim to 1) determine the effect of IPostC on outcome in lean, healthy ZDF rats compared to standard (S)-CPR following CA; 2) determine the effect of T2DM on outcome in diabetic ZDF rats after S-CPR vs IPostC-CPR following CA; 3) determine the effect of insulin treatment on outcome after S-CPR vs IPostC-CPR following CA in diabetic rats; and 4) metformin treatment instead of insulin. Knowledge from this highly innovative, translationally relevant proposal would, for the first time, shed much needed new light on the interaction of diabetes and its standard treatments with the ability to successfully resuscitate after CA and to further improve outcome by postconditioning.