Myocardial Effects of Erythropoietin During Resuscitation from Cardiac Arrest

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，平均存活率只有7%。心脏活动的恢复需要用含氧血对缺血组织进行再灌注。然而，再灌注同时激活了多种致病机制，统称为“再灌注损伤”。目前的复苏方法不包括可以减轻这种伤害的干预措施。然而，促红细胞生成素激活强大的细胞保护机制(其中许多机制汇聚在线粒体上)的发现可能提供了减轻心脏骤停时这种损伤的手段，并建立了心脏复苏的新范例。在室颤(VF)和开胸复苏的大鼠模型上，我们报道了促红细胞生成素可以产生良好的心肌效应，从而导致血流动力学更有效的胸部按压，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，红细胞生成素的应用与初始复苏速度和出院存活率的增加有关。我们假设，促红细胞生成素的应用可以迅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，从而在心脏复苏期间产生以下结果：1)保存左室心肌的扩张性，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-伴随着更高的复苏率-更高的神经完整存活率。我们建议首先使用允许精确控制冠脉灌注压和直接进入心肌的开胸猪VF和体外循环模型来研究：(1)促红细胞生成素是否能够防止线粒体生物能量功能的恶化，从而在VF期间保持左室顺应性，并在自主循环恢复后保持左心功能；(2)这些作用是否通过激活和线粒体移位PKC5和Akt而介导，导致线粒体呼吸受阻；(3)鉴于手动CPR质量的不一致和血液动力学更有效的CPR方法的日益可用，促红细胞生成素的作用是否随冠脉血流量而变化。然后，我们将使用猪的室性心动过速和闭胸复苏的模型来研究促红细胞生成素在有或没有同时给予肾上腺素的情况下对胸部按压、初始复苏、复苏后的心肌功能以及神经功能完整的72小时存活期的血液动力学效果的影响。证明促红细胞生成素保护线粒体的生物能量功能，从而为复苏带来功能性心肌益处将是新颖的，并有助于计划和进行更多的临床试验，以及最终的临床实施。 公共卫生相关性： 在美国，每年有近33万人发生心脏骤停。考虑到冠状动脉疾病的高患病率以及吸烟、高血压、高胆固醇和糖尿病等潜在危险因素，这些人中的许多人都是退伍军人。目前的复苏技术未能提高超过7%的患者的神经完整存活率。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存活下来。这项申请将检验一种通过在心肺复苏期间应用促红细胞生成素来改善心跳骤停复苏的方法。促红细胞生成素是一种自然产生的激素，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可能会导致美国每年挽救数千人的生命，并在世界各地挽救更多的人的生命。

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.