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）： 心脏骤停是一个公共卫生幅度的问题，每年在美国影响33万人，平均生存率仅为7％。心脏活性的恢复需要对血液的缺血组织再灌注。然而，再灌注同时激活多种致病性机制，统称为“再灌注损伤”。当前的复苏方法不包括可以改善这种伤害的干预措施。然而，发现促红细胞生成素会激活有效的细胞保护性机制（其中许多在线粒体上汇聚）可能提供了在持久停滞期间改善这种损伤的手段，并建立了一种新颖的心脏复苏范式。我们已经在大鼠模型的心室纤颤（VF）和闭合胸部复苏中报道了促红细胞生成素引起有利的心肌作用，从而导致血液动力学上更有效的胸部压缩并表现出散发后的血液动力学功能。此外，在与斯洛文尼亚同事合作进行的最近临床试验中，促红细胞生成素的给药与初始复苏的增加和增加医院出院的生存率增加有关。我们假设给药迅速激活非基因组细胞保护机制，促使线粒体抗拒再灌注损伤并保持生物能的功能，从而在：1）在：1）保存左心室心肌较高的较高的cpr速率和更高的cpr速度和2次，并在：1）在：1）在：1）降低了cpr的左心室性较高和2次。屈服 - 与较高的复苏率结合使用 - 神经系统完整生存率较高。我们建议首先使用VF的开式猪模型和体外循环模型，以精确控制冠状动脉灌注压力，并直接进入心肌进行调查：（1）促红细胞生成素是否阻止了线粒体生物能量的日益下降，从而使左心室循环的左旋循环且在左右的循环循环2遍布左右的循环，该功能是左右的，该功能是在左右的循环范围。这些作用是通过PKC5和AKT的激活和线粒体易位介导的，导致线粒体呼吸的实现，以及（3）鉴于手动CPR的不一致性和增加血小板的可用性较高的可用性，促红细胞生成素对冠状动脉血流的影响是否会改变冠状动脉血流。然后，我们将使用VF和闭合胸的复苏模型在存在或不存在肾上腺素施用对胸部压缩的血液动态功效，初始响应，呼吸后心肌功能以及72小时生存具有完整神经学功能的影响。证明了红细胞生成素可以保留线粒体生物能功能，从而导致功能性肌强射线效果以复苏将是新颖的，并促进了额外的临床试验的计划和行为，并最终实施临床实施。 公共卫生相关性： 在美国，每年有近33万人遭受心脏骤停的发作。鉴于冠状动脉疾病的高流行以及吸烟，高血压，高胆固醇和糖尿病等危险因素的高度流行，其中许多人是退伍军人。当前的复苏技术无法促进7％以上这些人的神经系统完整的生存。迫切需要新的心脏骤停治疗方法，这些治疗将使大量的个体生存而无需器官功能障碍。该申请将检查一种方法，通过在心肺复苏期间通过促红细胞生成素改善心脏骤停的复苏方法。促红细胞生成素是一种天然存在的激素，在最近的研究中已显示，以帮助心脏和其他器官抵抗缺乏血液引起的损伤。这种新的心脏复苏方法的成功发展可能会导致每年在美国挽救成千上万的生命，并且在全球范围内更多。