Attenuation of Reperfusion Injury by Gliflozins During Cardiac Arrest Leading to Improved Post-Resuscitation Myocardial Function and Survival

项目摘要 院外心脏骤停是全世界死亡的主要原因， 美国的这些人中的许多人是退伍军人，因为他们的冠状动脉疾病患病率很高 和潜在的风险因素。尽管有心肺复苏术（CPR），但只有不到10%的人成功复苏。 被引用，随后以良好的神经功能存活。不良结局与以下损害有关： 由于在心脏骤停期间缺乏血流，组织尤其是心脏和大脑受到损害。 当进行心肺复苏术时，会发生额外的组织损伤，含氧血液会返回到已经受损的器官。 被剥夺了含氧血液这种损伤被称为再灌注损伤，截至今天， 在CPR过程中，可以使用治疗来减少这种损伤。我们的研究实验室多年来的研究表明， 在心肺复苏过程中，能够减少钠进入心脏细胞的药物可以显着减少再灌注损伤。 然而，这些药物目前还不能用于临床。然而，一组被称为格列净的药物， 最初是为治疗2型糖尿病而开发的，也可以对心血管系统产生有利的影响， 血管系统我们在猪心脏骤停模型中进行了初步实验，发现EM- 在心肺复苏术中给予帕利哌酮可保护心脏免受这种损伤，从而在重新复苏后改善心脏功能。 怀疑我们现在建议在猪心脏骤停模型中进行全面的研究， 翻译价值，检查恩格列净是否可以引起（如我们的初步实验所示）心脏 在复苏过程中的临床价值的影响，同时了解这些影响的机制。拟议 研究分为两个具体目标。在具体目标1下，将通过实验研究以下方面的直接影响： 在心脏复苏期间和心脏活动恢复后，恩格列净对心脏的影响。这些研究将 确定恩格列净是否能产生与上述限制钠的药物相似的作用 并将检查恩格列净发挥这些作用的机制。我们会用一个开放的- 胸部猪室颤模型和体外循环复苏。具体目标下 2.实验将检查应用相同的药物对心脏骤停的闭胸猪模型的影响。 目前用于人类复苏的复苏方案。我们将检查恩格列净对 临床相关结局包括自主循环恢复率、72小时生存率和 恢复神经功能。我们还将检查恩格列净与血管加压药的相互作用 CPR期间给予恩格列净，以及恩格列净是否可以最大限度地减少 肾上腺素在其他实验中，我们将检查卡格列净是否可以引起类似的作用， 提示胶质细胞类效应，并确定CPR期间延迟给药是否可能损害 预期效果。如果该项目成功，用于复苏的格列净的临床转化将大大提高 鉴于其临床可用性和现有的505（B）（2）FDA药物再利用途径，

PROJECT SUMMARY Out-of-hospital sudden cardiac arrest is a leading cause of death worldwide affecting 1,000 cases every day in the United States. Many of these individuals are Veterans given their high prevalence of coronary artery disease and underlying risk factors. Despite cardiopulmonary resuscitation (CPR), less than 10% are successfully resus- citated and subsequently survive with good neurological function. Poor outcome is related to the damage that tissues suffer, especially the heart and the brain, consequent to the lack of blood flow during cardiac arrest. Additional tissue injury occurs when CPR is performed, and oxygenated blood is returned to organs that have been deprived of oxygenated blood. This injury is known as reperfusion injury and, as of today, there is no treatment available to reduce such injury during CPR. Our research lab for many years has shown that a group of drugs able to reduce sodium entry into cardiac cells during CPR can significantly reduce reperfusion injury. Yet, these drugs are not currently available for clinical use. However, a group of drugs known as gliflozins, originally developed for the treatment of type 2 diabetes mellitus, can also exert favorable effects on the cardio- vascular system. We conducted preliminary experiments in a swine model of cardiac arrest and found that em- pagliflozin given during CPR protected the heart from such injury resulting in a better cardiac function after re- suscitation. We now propose to conduct comprehensive studies in a swine model of cardiac arrest with high translational value examining whether empagliflozin could elicit (as our preliminary experiments suggest) cardiac effects during resuscitation of clinical value while understanding the mechanisms of these effects. The proposed studies are divided into two specific aims. Under Specific Aim 1, experiments will examine the direct effects of empagliflozin on the heart during cardiac resuscitation and after the return of cardiac activity. These studies will determine whether empagliflozin can elicit effects similar to those of the aforementioned drugs that limit sodium entry and will also examine the mechanisms by which empagliflozin elicits these effects. We will use an open- chest swine model of ventricular fibrillation and resuscitation with extracorporeal circulation. Under Specific Aim 2, experiments will examine the effects on a closed-chest swine model of cardiac arrest applying the same resuscitation protocols currently used for human resuscitation. We will examine the effects of empagliflozin on clinically relevant outcomes including the rate of return of spontaneous circulation, survival at 72 hours, and the recovery of neurological function. We will also examine the interaction of empagliflozin with vasopressor agents given during CPR and whether empagliflozin could minimize detrimental post-resuscitation effects elicited by epinephrine. In additional experiments, we will examine whether similar effects can be elicited by canagliflozin, suggesting a gliflozin class effect, and determine whether delayed administration during CPR may compromise the intended effect. If this project is successful, clinical translation of gliflozins for resuscitation will be greatly facilitated given their clinical availability and the existing 505(b)(2) FDA pathway for repurposing drugs.