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）是最常见的心律不齐，具有高死亡率和病态风险。在 一般AF人群，新发术术后房颤（POAF）是开放后最常见的并发症 心脏手术可显着增加死亡率并扩大医院和患者费用。机制 基本的POAF尚不清楚，因此有效的预测和/或预防仍然不可用。该建议旨在 通过识别应力 - 响应激酶JNK作为手术患者的新型POAF生物标志物来填补这一知识空白 并探索局部JNK在心房中的转化潜力，作为一种新型的抗POAF治疗 方法。 POAF的诱发因素包括高级年龄，暴饮暴食以及术中和 术后心房损伤和/或缺血。这些因素中的一个共同元素是巨大增加 细胞应激，已知会激活C-JUN N末端激酶（JNKS），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 异常的细胞电池通信（通过间隙连接通道）以及异常的CA触发活动 增强AF倾向。我们有趣的初步发现表明，心房JNK激活与 冠状动脉搭接移植物（CABG）手术10天内患者的POAF发病率，表明POAF可能 涉及JNK激活和可能由JNK驱动的心律失常发生。有趣的是，我们的初步结果表明 JNK首次出现在血液中。心脏中的JNK激活增加了血液JNK。因此， 一致的心房JNK激活和血浆JNK水平的升高与AF发生率的增加非常相关。 接下来，我们发现大多数血浆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，心脏细胞脱离JNK-Microparticle（JNK-MP）。所有这些有趣的初步结果 结合我们以前的发现表明，与AF发病机理联系起来的独特的心血关系。 在这里，我们将在手术上使用一系列尖端的生化测定和电生理技术 从CABG患者和人类供体心脏中移除了完整的心房组织，孤立的心肌细胞和血液样本 以及概括AF危险因素（衰老和暴饮暴食）的动物模型。我们的具体目的是：1）建立 JNK的电生理学和生物化学概况，促炎细胞因子和心律失常的底物 CABG患者的心房组织/血液及其与POAF发病率的相关性； 2）证明血液中激活的JNK 是POAF风险的生物标志物，并测试潜在的AF治疗性心房绘画基因转移干预措施 兔子。在这里，将心房/血液jnk建立为POAF风险的可能生物标志物是完全新颖的。临床 心房组织和血液样本和POAF事件的可及性使CABG患者成为理想人群 研究人类的JNK-AF链接。开发可应用的心房绘画基因转移干预措施 手术期间高POAF风险患者具有创新性。心脏研究专业知识和 新型的电生理/生物化学技术使该建议在技术上和实验上创新。