Myocardial Effects of Erythropoietin During Resuscitation from Cardiac Arrest

心脏骤停复苏期间促红细胞生成素对心肌的影响

• 批准号: 8262624
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262624
• 关键词: Acute; Affect; Bioenergetics; Biological Preservation; Blood; Blood Circulation; Blood flow; Cardiac; Cardiopulmonary Resuscitation; Cells; Chest; Cholesterol; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Coronary; Coronary Arteriosclerosis; Deterioration; Development; Diabetes Mellitus; Effectiveness; Epinephrine; Erythropoietin; Extracorporeal Circulation; Failure; Family suidae; Functional disorder; Heart; Heart Arrest; High Prevalence; Hormones; Hospitals; Hour; Hypertension; Independent Living; Individual; Injury; Intervention; Knowledge; Laboratories; Lead; Left; Left Ventricular Function; Manuals; Mediating; Methods; Mitochondria; Modeling; Myocardial; Myocardium; Nervous System Physiology; Organ; Outcome; Patients; Preparation; Protein Isoforms; Public Health; Rattus; Recovery; Reperfusion Injury; Reperfusion Therapy; Reporting; Respiration; Resuscitation; Risk Factors; Saline; Signal Transduction; Slovenia; Smoking; Sodium-Hydrogen Antiporter; Survival Rate; Techniques; Testing; Time; Tissues; United States; Ventricular; Ventricular Fibrillation; Veterans; Work; clinically relevant; coronary perfusion; design; effective therapy; hemodynamics; hospital discharge rate; improved; improved functioning; inhibitor/antagonist; non-genomic; novel; novel strategies; pressure; prevent

DESCRIPTION (provided by applicant): Sudden cardiac arrest is a problem of public health magnitude affecting 330,000 individuals annually in the United States with an averaged survival rate of only 7%. Return of cardiac activity requires reperfusion of ischemic tissues with oxygenated blood. Yet, reperfusion concomitantly activates multiple pathogenic mecha- nisms, collectively known as "reperfusion injury." Current resuscitation methods do not include interventions that could ameliorate such injury. Yet, the discovery that erythropoietin activates potent cell protective mecha- nisms (many of which converge on mitochondria) may provide the means to ameliorate such injury during car- diac arrest and to establish a novel paradigm for cardiac resuscitation. We have reported in a rat model of ventricular fibrillation (VF) and closed-chest resuscitation that erythropoietin elicits favorable myocardial effects that result in hemodynamically more effective chest compression and im- proved post-resuscitation hemodynamic function. Moreover, in a recently clinical trial conducted in collabora- tion with colleagues in Slovenia, administration of erythropoietin was associated with increased rate of initial resuscitation and increased rate of survival to hospital discharge. We hypothesize that administration of erythropoietin rapidly activates non-genomic cell protective mechanisms prompting mitochondria to resist reperfusion injury and remain bioenergetically functional, resulting during car- diac resuscitation in: 1) preservation of left ventricular myocardial distensibility enabling hemodynamically more effective CPR and higher resuscitation rates and 2) better post-resuscitation myocardial function yielding - in conjunction with higher resuscitation rates - higher rates of neurologically intact survival. We propose to use first an open-chest pig model of VF and extracorporeal circulation allowing precise control of coronary perfusion pressure and direct access to the myocardium to investigate: (1) whether erythropoietin prevents deterioration of mitochondrial bioenergetic function enabling preservation of left ventricular compli- ance during VF and preservation of left ventricular function after return of spontaneous circulation, (2) whether these effects are mediated through activation and mitochondrial translocation of PKC5 and Akt leading to pres- ervation of mitochondrial respiration, and (3) whether the effects of erythropoietin vary contingent on coronary blood flow, given the inconsistent quality of manual CPR and the increasing availability of hemodynamically more potent CPR methods. We will then use a pig model of VF and closed-chest resuscitation to examine the effects of erythropoietin in the presence or absence of concomitant administration of epinephrine on the hemo- dynamic efficacy of chest compression, initial resuscitation, post-resuscitation myocardial function, and 72-hour survival with intact neurological function. Demonstration that erythropoietin preserves mitochondrial bioenergetic function leading to functional myocar- dial benefits for resuscitation would be novel and facilitate the planning and conduct of additional clinical trials, and eventual clinical implementation. PUBLIC HEALTH RELEVANCE: Nearly 330,000 individuals suffer an episode of sudden cardiac arrest every year in the United States. Many of these individual are Veterans given the high prevalence of coronary artery disease and underling risk factors such as smoking, hypertension, high cholesterol, and diabetes mellitus. Current resuscitation techniques fail to promote neurologically intact survival in more than 7% of these individuals. New and more effective treatments for sudden cardiac arrest that will enable a substantially higher number of individuals to survive without organ dysfunction are urgently needed. This application will examine one approach for improving resuscitation from cardiac arrest by administration of erythropoietin during cardiopulmonary resuscitation. Erythropoietin is a naturally occurring hormone that has been shown in recent studies to help the heart and other organs resist the injury caused by lack of blood flow. Successful development of this new approach to cardiac resuscitation could lead to thousands of lives saved every year in the United States and many more worldwide.

描述（由申请人提供）： 心脏骤停是一个严重的公共卫生问题，在美国每年影响 33 万人，平均存活率仅为 7%。心脏活动的恢复需要用含氧血液对缺血组织进行再灌注。然而，再灌注同时激活多种致病机制，统称为“再灌注损伤”。目前的复苏方法不包括可以减轻这种损伤的干预措施。然而，促红细胞生成素激活有效的细胞保护机制（其中许多集中在线粒体上）的发现可能提供改善心脏骤停期间此类损伤的方法，并建立心脏复苏的新范例。我们在心室颤动（VF）和闭胸复苏大鼠模型中报道，促红细胞生成素可引起有利的心肌效应，从而导致血流动力学上更有效的胸外按压并改善复苏后的血流动力学功能。此外，在最近与斯洛文尼亚同事合作进行的一项临床试验中，促红细胞生成素的施用与初始复苏率和出院生存率的增加有关。我们假设促红细胞生成素的施用快速激活非基因组细胞保护机制，促使线粒体抵抗再灌注损伤并保持生物能量功能，从而在心脏复苏过程中导致：1）保留左心室心肌扩张性，从而在血流动力学上实现更有效的心肺复苏和更高的复苏率2) 更好的复苏后心肌功能——连同更高的复苏率——更高的神经系统完整存活率。我们建议首先使用心室颤动和体外循环的开胸猪模型，允许精确控制冠状动脉灌注压并直接进入心肌来研究：（1）促红细胞生成素是否可以防止线粒体生物能功能恶化，从而保留左心室顺应性。 VF 期间的 ance 和自主循环恢复后左心室功能的保存，（2）这些效应是否是通过 PKC5 和 Akt 的激活和线粒体易位介导的，从而导致压力升高。线粒体呼吸的维持，以及（3）考虑到手动心肺复苏质量的不一致以及血流动力学上更有效的心肺复苏方法的不断增加，促红细胞生成素的作用是否会因冠脉血流而变化。然后，我们将使用室颤和闭胸复苏的猪模型来检查促红细胞生成素在同时给予或不给予肾上腺素的情况下对胸外按压、初始复苏、复苏后心肌功能和心脏功能的血流动力学功效的影响。 72 小时存活且神经功能完好。证明促红细胞生成素保留线粒体生物能功能，从而对功能性心肌复苏有益，这将是新颖的，并且有助于计划和进行额外的临床试验以及最终的临床实施。 公共卫生相关性： 在美国，每年有近 330,000 人发生心脏骤停。这些人中的许多人都是退伍军人，因为冠状动脉疾病的患病率很高，并且存在吸烟、高血压、高胆固醇和糖尿病等潜在危险因素。目前的复苏技术无法促进这些人中超过 7% 的神经系统完整存活。迫切需要新的、更有效的心脏骤停治疗方法，使更多的人能够在没有器官功能障碍的情况下生存。本申请将研究一种通过在心肺复苏期间施用促红细胞生成素来改善心脏骤停复苏的方法。促红细胞生成素是一种天然存在的激素，最近的研究表明，它可以帮助心脏和其他器官抵抗因血流不足而造成的损伤。这种心脏复苏新方法的成功开发每年可以在美国和全世界挽救数千人的生命。