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

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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.