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

项目总结 院外心脏骤停是全世界主要的死亡原因，#年每天影响1,000例患者。 美国。这些人中的许多人都是退伍军人，因为他们冠状动脉疾病的发病率很高 和潜在的风险因素。尽管进行了心肺复苏(CPR)，但成功复苏的不到10%。 并随后存活，神经功能良好。糟糕的结果与 由于心脏骤停时血流不足，组织会受到损害，特别是心脏和大脑。 当实施CPR时，会发生额外的组织损伤，含氧血液被返回到具有 被剥夺了含氧血液。这种损伤被称为再灌注损伤，到目前为止，还没有 在心肺复苏术中，可用来减少这种伤害的治疗。我们多年的研究实验室表明，有一组人 在心肺复苏过程中，能够减少钠进入心肌细胞的药物可以显著减少再灌注损伤。 然而，这些药物目前还不能用于临床。然而，一组被称为优降糖的药物， 最初是为治疗2型糖尿病而开发的，也可以对心脏起到良好的作用。 血管系统。我们在一种猪心脏骤停模型上进行了初步实验，发现EM- 心肺复苏术中应用帕格列酮可保护心脏免受此类损伤，使心功能恢复良好。 停职。我们现在建议在猪心脏骤停模型中进行全面的研究。 检测埃帕利福秦是否能诱导(正如我们的初步实验所表明的)心脏 在复苏过程中了解这些影响的机制的同时具有临床价值。建议数 研究分为两个具体目标。在具体目标1下，实验将检查 在心脏复苏期间和恢复心脏活动后，依帕格列酮对心脏的影响。这些研究将 确定依帕格列酮是否能产生与上述限制钠的药物类似的效果 此外，他还将研究埃帕利福秦引起这些影响的机制。我们将使用一个开放的- 体外循环心脏复苏术建立猪心脏颤动模型。在特定的目标下 2，实验将检验应用相同的方法对闭胸猪心脏骤停模型的影响。 目前用于人类复苏的复苏方案。我们将研究埃帕利氟秦对 与临床相关的结果包括自主循环的返回率、72小时的存活率和 神经功能的恢复。我们还将研究埃帕利福秦与血管升压药的相互作用。 在心肺复苏期间给予，以及依帕格列酮是否可以最大限度地减少复苏后的不良影响 肾上腺素。在更多的实验中，我们将研究卡那格列酮是否能产生类似的效果， 提示存在优降糖类效应，并确定在心肺复苏期间延迟给药是否会损害 预期的效果。如果该项目成功，用于复苏的格列氟津素的临床翻译将大大 考虑到它们的临床可获得性和FDA现有的改变药物用途的505(B)(2)途径，这种方法更加便利。

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.