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，具有很高的死亡率和发病率。在