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.

房颤(房颤)是最常见的心律失常，具有很高的死亡率和致残率。在这些人中 普通房颤人群中，新发的术后心房颤动(POAF)是开放手术后最常见的并发症。 心脏手术，这显著增加了死亡率，并放大了医院和患者的成本。其作用机制 POAF的潜在原因尚不清楚，因此仍然无法进行有效的预测和/或预防。这项建议旨在 通过确定应激反应激酶JNK作为手术患者的新的POAF生物标志物来填补这一知识空白 并探索心房局部JNK抑制作为一种新的抗POAF治疗方法的翻译潜力 接近。POAF的易感因素包括高龄、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因素是极大地增加了 细胞应激激活c-jun氨基末端激酶(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活性和心脏JNK活性之间以前未被发现的因果联系 异常的细胞-细胞通讯(通过缝隙连接通道)以及异常的钙触发的活动 增强房颤倾向。我们耐人寻味的初步发现表明，心房JNK激活与 冠状动脉旁路移植术(CABG)术后10天内POAF的发生率，表明POAF可能 涉及JNK的激活和可能的JNK驱动的房性心律失常的发生。有趣的是，我们的初步结果显示 这是JNK第一次出现在血液中。心脏中JNK的激活会增加血液中的JNK。因此， 协调的心房JNK激活和血浆JNK水平的升高与房颤发生率的增加密切相关。 接下来，我们发现大多数血浆JNK是由血液中循环的微粒(MPS)携带的。我们的飞行员 数据进一步表明，心脏细胞排出JNK微粒(JNK-MPS)。所有这些耐人寻味的初步结果 结合我们以前的发现，我们发现了一种独特的心脏-血液JNK关系，与房颤的发病机制有关。 在这里，我们将在外科手术中使用一系列尖端的生化分析和电生理技术 从CABG患者和供者心脏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和生化特征 冠状动脉旁路移植术患者的心房组织/血液及其与POAF发生率的关系2)证明血液中JNK活化 是POAF风险的生物标志物，并测试一种潜在的治疗老年房颤的房颤基因转移干预 兔子。将心房/血液JNK确定为POAF风险的可能生物标记物在这里是全新的。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 研究人类的JNK-AF联系。开发一种可应用于临床的心房画基因转移干预 POAF高危患者在手术中是创新的。心脏研究专业知识和心脏研究的独特结合 新的电生理学/生物化学技术使这一提议在技术和实验上具有创新性。