Atrial and blood JNK in Postoperative AF

心房颤动（AF）是最常见的心律失常，具有高死亡率和发病率的风险。中 在一般房颤人群中，新发术后房颤（POAF）是开放手术后最常见的并发症， 心脏手术，这大大增加了死亡率和放大医院和病人的成本。的机制 潜在的POAF尚不清楚，因此有效的预测和/或预防仍然不可用。这项建议旨在 通过鉴定应激反应激酶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 并探索心房局部JNK抑制作为新型抗POAF治疗剂的翻译潜力 approach. POAF的诱发因素包括高龄、酗酒以及术中和术后并发症。 术后心房损伤和/或缺血。这些因素中的一个共同点是， 细胞应激，已知其激活c-Jun N-末端激酶（JNKs），一种重要的应激反应激酶。 我们最近发现并报道了一种以前未被认识的心脏JNK激活与 异常的细胞间通讯（通过缝隙连接通道）以及异常的Ca触发的活动， 增强AF倾向。我们有趣的初步研究结果表明，心房JNK激活与 冠状动脉旁路移植术（CABG）后10天内患者的POAF发生率，表明POAF可能 涉及JNK激活和可能的JNK驱动的心房肌发生。有趣的是，我们的初步结果显示 JNK首次出现在血液中心脏中JNK的激活增加了血液中的JNK。因此 一致的心房JNK激活和血浆JNK水平的升高与AF发病率的增加很好地相关。 接下来，我们发现大多数血浆JNK由血液中循环的微粒（MP）携带。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 结合我们以前的发现，我们发现了一种独特的心脏-血液JNK关系，它与AF发病机制有关。 在这里，我们将使用一系列尖端的生化分析和电生理技术， 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品 以及再现AF风险因素（衰老和酗酒）的动物模型。我们的目标是：（1）建立 JNK、促炎细胞因子和细胞基质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）证明血液中激活的JNK 是POAF风险的生物标志物，并在老年人中测试潜在的AF治疗性心房彩绘基因转移干预 家兔建立心房/血液JNK作为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的可及性以及POAF事件使CABG患者成为 研究JNK-AF在人类中的联系开发一种心房彩绘基因转移干预， 高POAF风险患者手术中是创新的。心脏研究专业知识和 新颖的电生理学/生物化学技术使得该提议在技术上和实验上具有创新性。

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.