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

即使使用最好的心肺复苏(CPR)方法，在德国每年估计有10万名院外心脏骤停(CA)患者中，超过90%的人死亡或有严重的神经功能障碍。这是因为CPR的成功结果与未经治疗的CA的持续时间成反比。不幸的是，60%-80%的患者没有接受旁观者的心肺复苏，急救人员平均在紧急呼叫后8-10分钟到达。在CA期间长时间的全脑缺血后，突然再灌流引起的分子和代谢变化可能比最初的缺血本身造成的损伤更严重。心肺复苏期间应用的一种新策略是缺血后处理(IPostC)，以减轻IR对心脏和大脑的损伤。与常规动物模型相比，CA患者很少是健康的，通常患有各种慢性病，如肥胖和2型糖尿病(T2 DM)，这增加了他们发生不良事件的风险。此外，当得到最佳治疗时，T2 DM患者通常会服用一种或多种抗糖尿病药物。然而，T2 DM及其治疗方法可能通过分别取消或恢复它们的益处来不同地干扰IPostC等高效调节策略的重要信号通路。因此，我的博士后研究基金的总体目标是探索T2 DM及其治疗与CA和CPR±IPostC术后结果的交互作用。本研究的目的是：1)通过对比标准(S)心脏复苏术对消瘦健康ZDF大鼠预后的影响；2)比较S心肺复苏与胰岛素后C心肺复苏对糖尿病ZDF大鼠预后的影响；3)比较胰岛素治疗对糖尿病大鼠冠状动脉病变后S心肺复苏与胰岛素治疗后预后的影响；4)二甲双胍替代胰岛素治疗糖尿病大鼠。来自这一高度创新、翻译相关的提案的知识将第一次为糖尿病及其标准治疗与CA后成功复苏和通过后处理进一步改善结果的能力之间的相互作用提供亟需的新线索。

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.