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

格列净减轻心脏骤停期间的再灌注损伤，改善复苏后心肌功能和生存率

基本信息

批准号：
10366212
负责人：
Raul Jaime Gazmuri
金额：
--
依托单位：
EDWARD HINES JR VA HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

项目摘要

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.

项目概要院外心脏骤停是全球死亡的主要原因，每天影响 1,000 例病例美国。由于冠状动脉疾病的患病率很高，这些人中的许多人都是退伍军人和潜在的风险因素。尽管进行了心肺复苏 (CPR)，但成功复苏的人数仍不足 10% 被引用并随后以良好的神经功能存活。不良结果与损害有关由于心脏骤停期间血流不足，组织尤其是心脏和大脑受到损害。进行心肺复苏时会发生额外的组织损伤，含氧血液会返回到已发生心肺复苏的器官。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，还没有可用于减少心肺复苏期间此类伤害的治疗。我们的实验室多年的研究表明，一组能够减少心肺复苏过程中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，一组称为格列净的药物，最初开发用于治疗2型糖尿病，还可以对心脏功能产生良好的作用血管系统。我们在猪的心脏骤停模型中进行了初步实验，发现在心肺复苏期间给予帕格列净可以保护心脏免受此类损伤，从而在重新进行心肺复苏后获得更好的心功能。苏醒。我们现在建议在高心率猪心脏骤停模型中进行全面研究转化价值检查恩格列净是否可以引发（正如我们的初步实验表明的）心脏复苏期间的影响的临床价值，同时了解这些影响的机制。拟议的研究分为两个具体目标。在具体目标 1 下，实验将检验以下因素的直接影响：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可以产生与上述限钠药物类似的作用并将研究恩格列净引发这些作用的机制。我们将使用一个开放式心室颤动和体外循环复苏的胸部猪模型。在特定目标下 2、实验将检验应用相同方法对心脏骤停的闭胸猪模型的影响目前用于人体复苏的复苏方案。我们将研究恩格列净对临床相关结果，包括自主循环恢复率、72 小时生存率以及神经功能恢复。我们还将研究恩格列净与血管加压药的相互作用心肺复苏期间给予恩格列净是否可以最大限度地减少由以下原因引起的有害的复苏后影响肾上腺素。在其他实验中，我们将检查卡格列净是否可以引起类似的效果，提示格列净类效应，并确定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，格列净用于复苏的临床转化将得到极大的促进。考虑到它们的临床可用性和现有的 505(b)(2) FDA 药物再利用途径，这为它们提供了便利。