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: 9237744
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237744
• 关键词: Adrenergic beta-Antagonists; Adverse effects; Affect; Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Area; Arrhythmia; Atrial Fibrillation; Atrial Function; Bathing; Biological Assay; Blood; Blood Circulation; Canis familiaris; Cardiac; Cardiac Surgery procedures; Cells; Cessation of life; Characteristics; Complication; Coronary Artery Bypass; Data; Development; Disease; Dose; Drops; Electrophysiology (science); Environment; 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; inflammatory marker; mitral valve replacement; monocyte; mortality; neutrophil; peripheral blood; prevent; stressor

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.

术后心房颤动是心脏手术后最常见的并发症之一。 退伍军人也不能幸免于这种常见的并发症：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 对于接受CABG和二尖瓣置换术的患者，为64%。可能增大 术后卒中的发生率，重症监护室和住院时间的延长， 室性心动过速和室颤的增加，与住院率和长期住院率较高有关。 mortality.尽管采取了许多措施，但这一问题的发生率或严重程度基本上没有减少 在过去的二十年里，新的预防性治疗被引入并坚持。值得注意的是，温和的- 在手术时给予一定剂量的类固醇，可以直接抑制全身炎症， 在多项研究中一致显示房颤发生率降低。不幸的是， 类固醇的作用禁止常规使用这种疾病。迫切需要制定战略， 我们的长期目标是开发一种术后房颤的治疗方法 这是有效的，并可用于大多数接受手术的患者。许多研究 显示与POAF相关的外周血中的显著变化。然而， 容纳心脏的生理区域（心包空间）中的扰动在很大程度上被忽略。 外周循环炎症增加，包括与白色血细胞计数升高相关 高水平的炎症标志物一直被证明与POAF相关， 心脏手术我们的初步数据表明，增加的动力学与外周血 在某些细胞因子中，但在其他细胞因子中明显不同。心包内的一些炎症标志物 流体（PCF）处于高得多的浓度，高达十个数量级或更高。这种损害 可能会导致术后心律失常我们的第一个目标是确认这些高 局部水平（即心包）的特定细胞因子和其他细胞产物有助于巨大的 POAF的问题。目的1将允许确认中性粒细胞，单核细胞，和他们的产品有助于 到POAF。此外，我们还将确定炎症途径中导致炎症反应的特定因素。 心律失常和心脏功能受损 基于初步数据，我们的工作假设是心包炎性应激 环境，由中性粒细胞和单核细胞（这是两个最丰富的细胞群）驱动 在大多数人发生POAF时，心包腔中的血液会直接影响心房， 心房纤颤的症状有哪些？除了划定 我们的第二个目的是证明PCF的炎症成分是POAF的贡献者， 心包腔内中性粒细胞和/或单核细胞的活化是致炎性心肌炎的关键因素。 手术后心脏周围的环境。我们将使用我们的犬心脏跳动心房组织模型， 使我们能够监测添加活化细胞及其产物对 超灌注液（添加到浴中以模拟PCF）。我们将激活中性粒细胞， 单核细胞，然后测量对引发心房纤颤的能力的影响。接下来我们将介绍 使用H2 O2，然后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（我们在 我们的初步研究，并将确认目标1的完成）。这将有助于确定具体的 炎症途径中有助于POAF发展的步骤，以及随后的 干预以改善疾病。