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改善这种损伤的干预措施。然而，发现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）可能提供改善心脏骤停期间这种损伤的方法，并建立心脏复苏的新范例。我们在大鼠心室颤动（VF）和闭胸复苏模型中报道了促红细胞生成素（EPO）对心肌的有利作用，导致血流动力学上更有效的胸部按压，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，促红细胞生成素的给药与初始复苏率增加和出院存活率增加相关。我们假设，促红细胞生成素的给药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，导致心脏复苏期间：1）保持左心室心肌扩张性，使血液动力学更有效的CPR和更高的复苏率，2）更好的复苏后心肌功能，与更高的复苏率相结合-更高的神经系统完整存活率。我们建议首先使用VF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，以研究：（1）促红细胞生成素是否防止线粒体生物能量功能的恶化，从而能够在VF期间保持左心室顺应性和在自主循环恢复后保持左心室功能，（2）这些作用是否是通过PKC 5和Akt的激活和线粒体移位介导的，从而导致线粒体呼吸的保护，以及（3）鉴于手动心肺复苏的质量不一致以及血液动力学更有效的心肺复苏方法的可用性不断增加，促红细胞生成素的作用是否因冠状动脉血流而异。然后，我们将使用VF和闭胸复苏的猪模型来检查促红细胞生成素在存在或不存在肾上腺素伴随给药的情况下对胸部按压的血液动力学功效、初始复苏、复苏后心肌功能和具有完整神经功能的72小时存活率的影响。证明促红细胞生成素保留线粒体生物能量功能，导致功能性心肌复苏益处，这将是新颖的，并有助于计划和实施额外的临床试验，以及最终的临床实施。 公共卫生关系： 在美国，每年有近33万人遭受心脏骤停的发作。这些人中的许多人是退伍军人，因为冠状动脉疾病的患病率很高，而且存在吸烟、高血压、高胆固醇和糖尿病等潜在风险因素。目前的复苏技术未能促进超过7%的这些人的神经完整的生存。迫切需要新的和更有效的治疗心脏骤停的方法，使更多的人能够在没有器官功能障碍的情况下生存。本申请将研究在心肺复苏期间通过给予促红细胞生成素来改善心脏骤停复苏的一种方法。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缺乏血流而造成的损伤。这种新的心脏复苏方法的成功开发可能会导致美国每年挽救数千人的生命，并在全世界范围内挽救更多的生命。