Evaluation of the Safety and Efficacy of Angiotensin 1-7 to Enhance Cognitive Function in Participants Undergoing Coronary Artery Bypass Graft (CABG) Surgery

项目摘要 每年，在美国有超过50万患者进行冠状动脉搭桥手术（CABG）以治疗冠状动脉疾病。 动脉疾病然而，术后结果因卒中的显著发生率而复杂化， 认知障碍术后认知功能障碍导致这些人的生活质量下降 和更高的再入院率。有一个明确的未满足的医疗需要，找到治疗，以减轻或 预防心脏病和CABG引起的认知障碍。虽然确切的触发因素还在争论中， CABG增加脑缺氧和循环细胞因子。循环炎性细胞因子增加， 脑缺氧导致脑活性氧（ROS）产生增加，脑组织活化， 炎症途径导致神经元功能障碍和认知障碍。我们小组最近的工作 其他人已经在动物中表明血管紧张素-（1-7）（Ang-（1 -7））可以抑制ROS的产生，增加一氧化氮合酶（NO）的活性， 氧化物的产生，并减少脑、微血管和外周组织中的炎性细胞因子， 激活Mas受体。治疗冠状动脉旁路移植术所致认知功能障碍的理想药物 将通过作用于血脑屏障的两侧，即脑血管， 内皮和神经元细胞。Ang-（1-7）符合这些标准，因为Ang-（1-7）作用于Mas受体， 已知对内皮细胞和神经元都具有抗炎作用。2014年第二季度， 来自NHLBI SMARTT项目的监管支持，向FDA提交使用Ang-（1-7）的IND， 治疗CABG患者的认知障碍，该IND于2015年8月获得批准。目前UO 1 本申请旨在评估Ang-（1-7）增强认知功能的安全性和有效性， 接受CABG手术的受试者。此外，通过与NIH临床研究中心的独特能力合作， 中心，这些研究将首次测量CABG手术后的脑炎症和 通过[11 C] PBR 28的PET成像测量的小胶质细胞活化，并检验Ang-（1- 7)将导致冠状动脉旁路移植术患者的脑炎症和小胶质细胞活化减少。当 完成后，这项临床研究将进一步开发一种新的治疗方法， 冠状动脉旁路移植术患者的损伤。

PROJECT SUMMARY Every year, more than 500,000 patients in the US have coronary artery bypass surgery (CABG) to treat coronary artery disease. However, postoperative outcomes are complicated by a significant incidence of stroke and cognitive impairment. Postoperative cognitive impairment results in decreased quality of life for these individuals and higher hospital readmission rates. There is a clear unmet medical need to find treatments to attenuate or prevent cardiac disease and CABG induced cognitive impairment. Although the precise triggers are debated, CABG increases brain hypoxia and circulating cytokines. Increases in circulating inflammatory cytokines and brain hypoxia result in increased brain reactive oxygen species (ROS) production, activation of brain inflammatory pathways leading to neuronal dysfunction and cognitive impairment. Recent work by our group and others have shown in animals that Angiotensin-(1-7) (Ang-(1-7) can inhibit ROS production, increase nitric oxide production and reduce inflammatory cytokines in the brain, microvasculature and peripheral tissue via activation of the Mas receptor. The ideal therapeutic candidate to treat CABG induced cognitive impairment would be designed to interrupt this cascade by working at both sides of the blood-brain barrier, the brain vascular endothelium and neuronal cells. Ang-(1-7) meets these criteria because Ang-(1-7), acting at the Mas receptor, is known to have anti-inflammatory effects at both endothelial cells and neurons. In Q2 2014, we received regulatory support from the NHLBI SMARTT program to submit an IND to the FDA for the use of Ang-(1-7) to treat cognitive impairment in CABG patients and this IND was approved in August 2015. The present UO1 application is designed to evaluate the safety and efficacy of Ang-(1-7) to enhance cognitive function in participants undergoing CABG surgery. Further, by teaming with the unique capabilities of the NIH Clinical Center, these studies will measure, for the first time, post CABG surgery brain inflammation and microglia activation as measured by PET imaging of [11C]PBR28 and the test the hypothesis that Ang-(1- 7) will result in a decrease in brain inflammation and microglia activation in CABG patients. When completed, this clinical study will have advanced development of a new therapy with potential to treat cognitive impairment in CABG patients.