Contribution of Inflammation and Oxidative Stress in Pericardial Fluid to Postoperative Atrial Fibrillation After Cardiac Surgery

心脏手术后心包液中炎症和氧化应激对术后心房颤动的影响

• 批准号: 10179344
• 负责人: Spencer J Melby
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179344
• 关键词: Adrenergic beta-Antagonists; Affect; Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Area; Arrhythmia; Atrial Fibrillation; Atrial Function; Bathing; Biological Assay; Blood; Blood Circulation; Canis familiaris; Cardiac Surgery procedures; Cells; Cessation of life; Characteristics; Complication; Coronary Artery Bypass; Data; Development; Disease; Dose; Drops; Electrophysiology (science); Environment; Exposure to; Flow Cytometry; Generations; Goals; Grant; Heart; Heart Atrium; Hospitals; Hour; Housing; Human; Hydrogen Peroxide; Hypotension; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Institution; Intensive Care Units; Interleukin-10; Intervention; Kinetics; Lead; Length; Length of Stay; Leukocytes; Liquid substance; Logistic Regressions; Measures; Modeling; Monitor; Muscle Cells; Myocardium; Myoglobin; Neutrophil Activation; Operative Surgical Procedures; Oxidative Stress; Pathway interactions; Patients; Pericardial body location; Peripheral; Pharmacology; Phase; Physiological; Population; Postoperative Period; Prevention; Probability; Prophylactic treatment; Reaction; Reactive Oxygen Species; Regression Analysis; Reporting; Right atrial structure; Risk; Sampling; Severities; Statistical Data Interpretation; Sterility; Steroids; Stress; Stroke; Testing; Time; Tissue Model; Tissues; Ventricular Fibrillation; Ventricular Tachycardia; Veterans; White Blood Cell Count procedure; base; chemokine; cytokine; heart function; inflammatory marker; mitral valve replacement; monocyte; mortality; neutrophil; peripheral blood; prevent; side effect; stressor; systemic inflammatory response

Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery. Veterans are not spared from this frequent complication: the incidence of new onset atrial arrhythmias requiring treatment ranges from 30% for patients undergoing coronary artery bypass grafting (CABG) to 64% for patients undergoing a combined CABG and mitral valve replacement. There is also an increased incidence of postoperative stroke, increased length of intensive care unit and hospital stay, and a two fold increase in ventricular tachycardia and fibrillation and it is tied to a higher rate of hospital and long-term mortality. There has been essentially no reduction in the incidence or severity of the problem despite many new prophylactic treatments introduced and adhered to in the last twenty years. It is notable that moderate- dose steroid administration at the time of surgery, which directly suppresses systemic inflammation, has consistently demonstrated decreased rates of atrial fibrillation in multiple studies. Unfortunately the side effects of steroids prohibit routine use for this disease. There is a critical need for strategies to mitigate this problem; our long term objective is to develop a treatment for postoperative atrial fibrillation that is effective and can be used in the majority of patients undergoing surgery. Many studies have shown significant changes in the peripheral blood which correlate with POAF. However, the contribution of perturbations in the physiologic area housing the heart (the pericardial space) has been largely ignored. Increased inflammation in the peripheral circulation including correlation with raised white blood cell counts and higher levels of inflammatory markers has consistently demonstrated correlation with POAF after cardiac surgery. Our preliminary data show that the kinetics of increase are similar to the peripheral blood for some cytokines, but markedly different in others. Some of the inflammatory markers in the pericardial fluid (PCF) are at much higher concentrations, by up to ten orders of magnitude or greater. This damage likely contributes to the development of postoperative arrhythmias. Our first aim is to confirm that these high local levels (i.e. pericardial) of specific cytokines and other cellular products contribute to the immense problem of POAF. Aim 1 will allow confirmation that neutrophils, monocytes, and their products contribute to POAF. Furthermore, we will identify the specific factors in the inflammatory pathway(s) that lead to the arrhythmia and compromised cardiac function. Based on preliminary data, our working hypothesis is that inflammatory stress in the pericardial environment, driven by neutrophils and monocytes (which are the two vastly most abundant cell population in the pericardial space at the time the majority of people develop POAF), directly affects atrial electrophysiology, resulting in an increased probability of atrial fibrillation. In addition to delineation of the inflammatory components of PCF which are contributors to POAF, our second aim is to demonstrate that activation of neutrophils and/or monocytes in the pericardial space is a key factor in the arrhythmogenic milieu surrounding the heart after surgery. We will use our canine beating-heart atrial tissue model which allows us to monitor the electrophysiological effect of the addition of activated cells and their products on the super-perfusate (addition to the bath to simulate PCF). We will sue activated neutrophils and then monocytes, and then measure the effect on the ability to incite atrial fibrillation. We will follow this with a highly relevant model of inflammatory cells’ product using H2O2 and then with a known cytokine product of neutrophils and monocytes that correlates by multivariable analysis with POAF (which we have identified in our preliminary studies and will confirm with completion of Aim 1). This will allow for delineation of specific steps in the pathway of inflammation which contribute to the development of POAF, and subsequent intervention to ameliorate the disease.

术后房颤（POAF）是心脏手术后最​​常见的并发症之一。 退伍军人不受这种经常并发症的困扰：新发作心律不齐的事件 需要治疗的范围从接受冠状动脉搭桥术（CABG）的患者的30％到 接受CABG和二尖瓣置换组合的患者为64％。也有增加 术后中风的发病率，重症监护病房和住院时间的增加以及两倍 心室心动过速和纤颤的增加，并与更高的医院和长期相关 死亡。问题目的地的事件或严重性基本上没有降低 在过去的二十年中，引入并遵守了新的预防治疗。值得注意的是 手术时剂量类固醇的给药，直接抑制全身注射，已具有 在多项研究中，一贯表明房颤率降低。不幸的是一方 类固醇的作用禁止常规使用这种疾病。迫切需要减轻策略 这个问题；我们的长期目标是开发用于术后房颤的治疗方法 这是有效的，可以用于大多数接受手术的患者。许多研究有 显示与POAF相关的外周血的显着变化。但是， 在生理区域内的心脏（心包空间）的扰动在很大程度上被忽略了。 外周循环中的炎症增加，包括与升高的白细胞计数的相关性 较高水平的炎症标记始终显示出与POAF的相关性 心脏手术。我们的初步数据表明，增加的动力学与外围血相似 对于某些细胞因子，但在另一些细胞因子中有明显不同。心包中的一些炎症标记 流体（PCF）的浓度高得多，多达十个数量级或更高。这个损坏 可能有助于术后心律不齐的发展。我们的第一个目的是确认这些很高 特定细胞因子和其他细胞产品的局部水平（即心包）有助于巨大 POAF的问题。 AIM 1将允许确认中性粒细胞，单核细胞及其产品有贡献 到Poaf。此外，我们将确定导致炎症途径中的特定因素 心律不齐和心脏功能受损。 基于初步数据，我们的工作假设是心包中的炎症应激 由中性粒细胞和单核细胞驱动的环境（这是两个最丰富的细胞种群 在大多数人开发POAF的人时，在心包空间中，直接影响心房 电生理学，导致心房颤动的可能性增加。除了描绘 PCF的炎症成分是POAF的贡献者，我们的第二个目的是证明 心包空间中嗜中性粒细胞和/或单核细胞的激活是心律失常的关键因素 手术后心脏周围的环境。我们将使用我们的犬只跳动心房组织模型 允许我们监视添加活化细胞及其产物对的电生理效应 超舒适的（在浴缸中增加以模拟PCF）。我们将起诉中性粒细胞，然后 单核细胞，然后测量对煽动房颤能力的影响。我们将以一个 使用H2O2的炎性细胞产物的高度相关模型，然后使用已知的细胞因子产物 通过与POAF通过多变量分析相关的中性粒细胞和单核细胞（我们已经在 我们的初步研究，并将在AIM 1完成后确认。这将允许划定特定的 注射途径的步骤有助于POAF的发展，然后 干预以改善疾病。

项目成果

Pericardial Mitochondrial DNA Levels Are Associated With Atrial Fibrillation After Cardiac Surgery.

• DOI: 10.1016/j.athoracsur.2020.07.011
• 发表时间: 2021-05
• 期刊: The Annals of thoracic surgery
• 作者: Manghelli JL;Kelly MO;Carter DI;Gauthier JM;Scozzi D;Lancaster TS;MacGregor RM;Khiabani AJ;Schuessler RB;Gelman AE;Damiano RJ;Melby SJ
• 通讯作者: Melby SJ