Atrial and blood JNK in Postoperative AF

AF 术后心房和血液 JNK

• 批准号: 10660602
• 负责人: Xun Ai
• 金额: $ 69.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-14 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660602
• 关键词: Abnormal Cell; Affect; Age; Aging; Alcohol consumption; Alcohols; Animal Model; Arrhythmia; Atrial Fibrillation; Biochemical; Biochemistry; Biological Assay; Biological Markers; Blood; Blood specimen; Cardiac; Cardiac Surgery procedures; Cardiovascular Diseases; Cell Communication; Cellular Stress; Clinic; Clinical; Clinical Research; Collaborations; Complication; Coronary Artery Bypass; Coupling; Data; Development; Disease; Dominant-Negative Mutation; Elderly; Electrophysiology (science); Elements; Event; Excision; Exhibits; Experimental Designs; Foundations; Functional disorder; Funding; Future; Gene Transfer; Genes; Goals; Health Care Costs; Heart; Heart Atrium; Heart Research; Heart failure; Hospitals; Human; Image; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Internet; Intervention; Ischemia; Knowledge; Link; MAPK8 gene; MAPK9 gene; Measures; Medical center; Morbidity - disease rate; Mus; Muscle Cells; N-terminal; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Paint; Pathogenesis; Patient-Focused Outcomes; Patients; Phosphotransferases; Pilot Projects; Plasma; Population; Postoperative Period; Predisposing Factor; Predisposition; Prevention; Procedures; Property; Protein Isoforms; Proteins; Pump; Recording of previous events; Reporting; Retrospective cohort study; Risk; Risk Factors; RyR2; Series; Stimulus; Stress; Stress Tests; Stroke; Surgeon; TNF gene; Techniques; Testing; Therapeutic; Thoracic Surgical Procedures; Time; Tissue Sample; Tissues; Work; aged; alcohol exposure; biological adaptation to stress; clinical biomarkers; clinically significant; cost; cytokine; exosome; gap junction channel; heart cell; high risk; human model; in vivo; innovation; mortality; mortality risk; mouse model; novel; novel therapeutics; overexpression; particle; patient biomarkers; prevent; prospective; response; sex; surgery outcome; therapeutic target; translational potential

Atrial fibrillation (AF) is the most common arrhythmia and has a high risk of mortality and morbidities. Among the general AF population, new-onset postoperative atrial fibrillation (POAF) is the most common complication after open- heart surgery, which significantly increased mortality and amplifies hospital and patient costs. The mechanisms underlying POAF are unclear, thus effective prediction and/or prevention remain unavailable. This proposal aims to fill this knowledge gap by identifying stress-response kinase JNK as a novel POAF biomarker for surgery patients and exploring the translational potential of local JNK inhibition in atria as a novel anti-POAF therapeutic approach. Predisposing factors for POAF include advanced age, binge alcohol, as well as intraoperative and postoperative atrial injury and/or ischemia. One common element among these factors is tremendously increased cellular stress, which is known to activate the c-Jun N-terminal kinases (JNKs), an important stress-response kinase. We recently discovered and reported a previously unrecognized causal link between cardiac JNK activation and abnormal cell-cell communication (via gap junction channels) as well as abnormal Ca triggered activities which enhance AF propensity. Our intriguing preliminary findings suggest that atrial JNK activation is well correlated to POAF incidence in patients within 10 days of coronary artery bypass graft (CABG) surgery, indicating POAF likely involves JNK activation and possible JNK-driven atrial arrhythmogenesis. Intriguingly, our preliminary results show for the first time that JNK is present in blood. And JNK activation in the heart increases blood JNK. Accordingly, the concordant atrial JNK activation and rise in plasma JNK levels correlates nicely to the increased incidence of AF. Next, we found that most of the plasma JNKs are carried by microparticles (MPs) circulating in the blood. Our pilot data further suggest that heart cells shed JNK-microparticles (JNK-MPs). All these intriguing preliminary results combined with our previous findings point to a unique heart-blood JNK relationship that links to AF pathogenesis. Here, we will use a series of cutting-edge biochemical assays and electrophysiological techniques on surgically removed intact atrial tissue, isolated atrial myocytes and blood samples from CABG patients and human donor hearts as well as animal models recapitulating AF risk factors (aging & binge alcohol). Our Specific Aims are: 1) Establish the electrophysiology & biochemistry profiles of JNK, pro-inflammatory cytokins, and arrhythmic substrates in atrial tissue/blood of CABG patients and their correlation to POAF incidence; 2) Prove activated JNK in the blood is a biomarker of POAF risk and test a potential AF therapeutic atrial painting gene transfer intervention in aged rabbits. Establishing the atrial/blood JNK as a possible biomarker of POAF risk is entirely novel here. Clinical accessibility for both atrial tissue and blood samples and POAF events make CABG patients an ideal population for studying the JNK-AF link in humans. Developing an atrial painting gene transfer intervention that could be applied to high POAF risk patients during surgery is innovative. The unique combination of cardiac research expertise and novel electrophysiology/biochemistry techniques makes this proposal technically & experimentally innovative.

心房颤动（AF）是最常见的心律失常，具有很高的死亡和发病风险。其中 对于一般 AF 人群，术后新发心房颤动 (POAF) 是开放性房颤术后最常见的并发症。 心脏手术显着增加了死亡率并增加了医院和患者的费用。机制 潜在的 POAF 尚不清楚，因此仍无法进行有效的预测和/或预防。该提案旨在 通过将应激反应激酶 JNK 确定为手术患者的新型 POAF 生物标志物来填补这一知识空白 并探索心房局部 JNK 抑制作为新型抗 POAF 治疗的转化潜力 方法。 POAF 的诱发因素包括高龄、酗酒以及术中和 术后心房损伤和/或缺血。这些因素中的一个共同点是大大增加 细胞应激，已知它会激活 c-Jun N 末端激酶 (JNK)，这是一种重要的应激反应激酶。 我们最近发现并报告了心脏 JNK 激活与心脏 JNK 之间以前未被认识到的因果关系。 异常的细胞间通讯（通过间隙连接通道）以及异常的 Ca 触发活动 增强自动对焦倾向。我们有趣的初步发现表明心房 JNK 激活与 冠状动脉搭桥术 (CABG) 手术后 10 天内患者发生 POAF，表明 POAF 很可能 涉及 JNK 激活和可能的 JNK 驱动的房性心律失常发生。有趣的是，我们的初步结果显示 JNK 首次出现在血液中。并且心脏中的JNK激活会增加血液中的JNK。据此， 心房 JNK 的一致激活和血浆 JNK 水平的升高与 AF 发病率的增加密切相关。 接下来，我们发现大部分血浆JNK是由血液中循环的微粒（MP）携带的。我们的飞行员 数据进一步表明心脏细胞脱落 JNK 微粒（JNK-MP）。所有这些有趣的初步结果 结合我们之前的研究结果，我们发现了一种与 AF 发病机制相关的独特的心脏-血液 JNK 关系。 在这里，我们将使用一系列尖端的生化检测和电生理技术来进行手术 从 CABG 患者和人类供体心脏中取出完整的心房组织、分离的心房肌细胞和血液样本 以及概括房颤危险因素（衰老和酗酒）的动物模型。我们的具体目标是： 1) 建立 JNK、促炎细胞因子和心律失常底物的电生理学和生物化学特征 CABG患者的心房组织/血液及其与POAF发生率的相关性； 2) 证明血液中JNK被激活 是 POAF 风险的生物标志物，并测试老年人潜在的 AF 治疗心房绘画基因转移干预 兔子。建立心房/血液 JNK 作为 POAF 风险的可能生物标志物在这里是完全新颖的。临床 心房组织和血液样本的可及性以及 POAF 事件使 CABG 患者成为理想的人群 研究人类的 JNK-AF 联系。开发一种心房绘画基因转移干预措施，可应用于 对高 POAF 风险患者进行手术是创新的。心脏研究专业知识和 新颖的电生理学/生物化学技术使该提案在技术和实验上具有创新性。