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.

术后心房颤动（POAF）是心脏手术后最​​常见的并发症之一。 退伍军人也未能幸免于这种常见并发症：新发房性心律失常的发生率 需要治疗的范围从接受冠状动脉旁路移植术 (CABG) 的患者的 30% 到 接受 CABG 和二尖瓣置换术联合治疗的患者的这一比例也有所增加。 术后中风的发生率、重症监护病房时间和住院时间增加，增加两倍 室性心动过速和颤动的增加，与较高的住院率和长期住院率有关 尽管存在许多问题，但该问题的发生率或严重程度基本上没有降低。 值得注意的是，在过去二十年中引入并坚持了新的预防性治疗。 手术时给予类固醇剂量，可直接抑制全身炎症， 不幸的是，多项研究一致证明心房颤动的发生率有所下降。 类固醇的影响阻碍了这种疾病的常规使用，因此迫切需要缓解策略。 这个问题；我们的长期目标是开发一种术后房颤的治疗方法 许多研究表明，这是有效的，可用于大多数接受手术的患者。 外周血显示出与 POAF 相关的显着变化。 心脏所在的生理区域（心包腔）的扰动在很大程度上被忽视了。 外周循环炎症增加，包括与白细胞计数升高的相关性 并且较高水平的炎症标志物始终证明与 POAF 后的相关性 我们的初步数据表明，增加的动力学与外周血相似。 对于某些细胞因子，但在其他心包炎症标记物中明显不同。 液体 (PCF) 的浓度要高得多，这种损害高达十个数量级或更高。 我们的首要目标是确认这些高值可能导致术后心律失常的发生。 特定细胞因子和其他细胞产物的局部水平（即心包）促成了巨大的 POAF 问题将允许确认中性粒细胞、单核细胞及其产物的贡献。 此外，我们将确定导致 POAF 的炎症途径中的特定因素。 心律失常和心脏功能受损。 根据初步数据，我们的工作假设是心包的炎症应激 环境，由中性粒细胞和单核细胞（这是两种最丰富的细胞群）驱动 大多数人发生 POAF 时位于心包腔），直接影响心房 电生理学，导致心房颤动的可能性增加。 PCF 的炎症成分是 POAF 的促成因素，我们的第二个目标是证明 心包间隙中性粒细胞和/或单核细胞的激活是致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跳动心房组织模型。 使我们能够监测添加活化细胞及其产物的电生理效应 超级灌注液（添加到浴中以模拟 PCF），然后我们将起诉激活的中性粒细胞。 单核细胞，然后测量对引发心房颤动的能力的影响，我们将对此进行跟踪。 使用 H2O2 建立高度相关的炎症细胞产物模型，然后使用已知的细胞因子产物 通过多变量分析与 POAF 相关的中性粒细胞和单核细胞（我们已在 我们的初步研究将在目标 1) 完成后予以确认。这将有助于描述具体的情况。 炎症途径中导致 POAF 发展的步骤，以及随后的 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