Gender Differences in Cardiac Arrest/CPR

描述（由申请人提供）： 尽管关于心脏骤停/CPR的研究已经进行了四十年，但临床结果仍然很差。 只有大约5%的心脏骤停患者成功复苏，恢复了正常生活，其余95%的患者仍然普遍存在神经和神经心理缺陷。 女性患心血管疾病的风险低于男性，包括中风（局灶性脑缺血），但脑缺血事件确实发生在所有年龄段的男性和女性中。 虽然女性心脏性猝死的发生率低于男性，但男性和女性心脏骤停后的生存差异以及神经学和神经心理学评估尚未得到密切研究。 血管活性激素，雌激素，历来被认为是冠心病的保护，但目前尚不清楚，如果类固醇也是一个重要的神经保护剂在女性或男性。 更重要的是，一旦心脏骤停/心肺复苏术正在进行，女性和男性对脑组织损伤的相对脆弱性仍然未知。 我们的初步研究结果表明，女性的大脑比男性更好地保护心脏骤停/心肺复苏术，雌激素可能与这种神经保护有关。 虽然雌激素提供的保护在生物学上是可行的，但具体的神经保护机制尚不清楚。 该项目的目标是确定在实验性心脏骤停/CPR中是否存在固有的性连锁神经损伤机制，以及哺乳动物中主要的生物活性雌激素17 α-雌二醇是否在心脏骤停/CPR后挽救脑组织中发挥关键作用。 在目标1中，我们将确定心脏骤停/CPR后的组织病理学和神经行为结果是否在雌性小鼠中比雄性小鼠更有利，以及外源性雌激素是否是神经保护的来源。 在目标2中，我们将确定在雌激素受体缺陷（雌激素受体敲除）的转基因小鼠中，心脏骤停/CPR引起的神经损伤是否加重。 最后，我们将研究神经元机制，假设雌激素通过依赖于核雌激素受体的Bcl-2介导的机制减少心脏骤停/CPR的组织损伤。 这项拟议的研究将有助于我们了解女性心脏骤停/心肺复苏术引起的神经损伤，以及雌激素作为一种潜在的神经保护疗法对男女患者的作用。

DESCRIPTION (provided by applicant): Despite four decades of research concerning cardiac arrest/CPR, clinical outcome remains poor. Only about 5% of individuals who suffer cardiac arrest are successfully resuscitated to the extent that they are returned to productive lives, and neurologic and neuropsychologic deficiencies remain prevalent in the remaining 95% of patients. Women are at lower risk than men for cardiovascular disease, including stroke (focal cerebral ischemia), yet cerebral ischemic events do occur in both sexes at all ages. Although women have less sudden cardiac death than men, survival differences and neurologic and neuropsychologic evaluations between men and women after cardiac arrest have not been closely examined. The vasoactive hormone, estrogen, has historically been considered to be protective in coronary heart disease, but it is not clear if the steroid is also an important neuroprotectant in either women or men. More critically, the comparative vulnerability of females and males to brain tissue injury once cardiac arrest/CPR is ongoing remains unknown. Our preliminary findings suggest that brains of females are better protected from cardiac arrest/CPR than males, and that estrogen may be involved with this neuroprotection. While protection conferred by estrogen is biologically feasible, specific neuroprotective mechanisms are unknown. The goal of this project is to determine if there are inherent sex-linked neural injury mechanisms in experimental cardiac arrest/CPR, and if 17a-estradiol, the principal biologically active estrogen in mammals, plays a key role in salvaging brain tissue after cardiac arrest/CPR. In Aim 1, we will determine if histopathological and neurobehavioral outcomes after cardiac arrest/CPR are more favorable in female vs male mice, and if exogenous estrogen is the source of neuroprotection. In Aim 2, we will determine if neural injury from cardiac arrest/CPR is exacerbated in transgenic mice deficient in estrogen receptors (estrogen receptor knockouts). Finally, we will examine a neuronal mechanism, hypothesizing that estrogen reduces tissue injury from cardiac arrest/CPR by a Bcl-2 mediated mechanism which is dependent on nuclear estrogen receptors. The proposed study will contribute to our understanding of neurological injury resulting from cardiac arrest/CPR in females and the role of estrogen as a potential neuroprotective therapy for patients of either sex.