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

• 批准号: 10531884
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10531884
• 关键词: Adult; Adverse effects; Affect; Animal Model; Attenuated; Blood; Blood flow; Brain; Calcium; Cardiac; Cardiopulmonary Resuscitation; Cardiovascular system; Cause of Death; Cell Signaling Process; Cells; Cerebrovascular Circulation; Chest; Child; Cholesterol; Circulation; Clinical; Coronary; Coronary Arteriosclerosis; Diabetes Mellitus; Dose; Epinephrine; Extracorporeal Circulation; Generations; Glucose; Heart; Heart Arrest; Heart Injuries; Heart failure; High Prevalence; Hospitals; Hour; Human; Hypertension; Impairment; Individual; Injury; Intervention; Ischemia; Laboratory Research; Left; Left Ventricular Function; Mediating; Medicine; Metabolic; Mitochondria; Molecular; Myocardial; Myocardium; Natural regeneration; Nervous System Physiology; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Protein Isoforms; Protocols documentation; Reactive Oxygen Species; Reperfusion Injury; Research; Resuscitation; Risk Factors; Science; Secure; Signal Pathway; Signal Transduction; Smoking; Sodium; Sodium-Hydrogen Antiporter; Techniques; Tissues; Translating; Translations; United States; Universities; Vasoconstrictor Agents; Vasopressins; Ventricular; Ventricular Fibrillation; Veterans; Work; attenuation; clinical translation; clinically relevant; design; drug repurposing; experimental study; heart function; hemodynamics; improved; inhibitor; ischemic injury; neurological recovery; pharmacologic; porcine model; symporter; tissue injury

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.

项目摘要 院外心脏骤停是全球死亡的主要原因，每天影响1000例 美国。鉴于其冠状动脉疾病的高流行，这些人中的许多人是退伍军人 以及潜在的风险因素。尽管心肺复苏（CPR），但不到10％成功恢复 - 浓缩并随后以良好的神经功能生存。结果不佳与损害有关 由于心脏骤停过程中缺乏血液流动，组织尤其是心脏和大脑。 进行心肺复苏术并将含氧血液返回到具有的器官时，会发生其他组织损伤 被剥夺了含氧血液。这种伤害被称为再灌注损伤，到目前为止，没有 可用于减少CPR期间这种伤害的治疗方法。我们多年的研究实验室表明一个小组 CPR期间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。 但是，这些药物目前尚未用于临床使用。但是，一组称为gliflozins的药物， 最初是为治疗2型糖尿病而开发的，还可以对心脏造成有利的影响 血管系统。我们在心脏骤停的猪模型中进行了初步实验，发现Em- CPR期间给出的帕格鲁嗪可保护心脏免受这种伤害，从而在重新损伤后产生更好的心脏功能 怀疑。我们现在建议在高高的心脏骤停模型中进行全面研究 转化价值检查empagliflozin是否可以引起（如我们的初步实验）心脏 在临床价值复苏期间的影响，同时了解这些作用的机制。提议 研究分为两个具体目标。在特定目标1下，实验将检查 心脏复苏期间和心脏活性恢复后，心脏上的empagliflozin。这些研究会 确定empagliflozin是否可以引起与上述药物相似的效果 进入，还将检查雌性产生这些作用的机制。我们将使用一个开放 体外循环的胸猪胸猪模型。在特定目标下 2，实验将检查对应用相同的心脏骤停猪猪模型的影响 目前用于人类复苏的复苏协议。我们将检查empagliflozin对 临床相关的结果，包括自发循环的回报率，72小时的生存和 恢复神经功能。我们还将检查empagliflozin与加压剂的相互作用 在CPR期间给出以及empagliflozin是否可以最大程度地减少受害后的悬念后效应 肾上腺素。在其他实验中，我们将检查Canagliflozin是否可以引起类似的效果， 提示链霉酶类别的效应，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，则大链霉素复苏的临床翻译将是极大的 鉴于它们的临床可用性以及现有的505（b）（2）FDA途径，可用于重新利用药物。