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

术后房颤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频繁的并发症：新发房性心律失常的发生率 需要接受治疗的患者从30%接受冠状动脉旁路移植(CABG)到 对于接受冠状动脉旁路移植术和二尖瓣置换术的患者，%。也有增加的 术后中风的发生率、重症监护病房的时间和住院时间增加了两倍 室性心动过速和纤颤的增加，与较高的住院率和长期住院率有关 死亡率。问题的发生率或严重性基本上没有减少，尽管有许多 在过去的二十年里，新的预防治疗方法被引入和坚持。值得注意的是，温和的- 在手术时给予直接抑制全身炎症的剂量类固醇，有 在多项研究中，房颤的发生率一直在下降。不幸的是，这一边 类固醇的作用阻止了这种疾病的常规使用。迫切需要制定战略来缓解 这个问题；我们的长期目标是开发一种治疗术后房颤的方法。 这是有效的，可以用于大多数接受手术的患者。许多研究都有 与POAF相关的外周血有明显变化。然而，中国的贡献 安置心脏的生理区域(心包间隙)的扰动在很大程度上被忽略了。 外周循环炎症增加，包括与白细胞计数升高的相关性 炎症标志物水平的升高与POAF的发生有一致的相关性 心脏手术。我们的初步数据显示，升高的动力学与外周血相似 对于一些细胞因子，但在其他方面却有明显的不同。心包组织中的一些炎性标志物 流体(PCF)的浓度要高得多，高达十个数量级或更高。这一损害 可能与术后心律失常的发生有关。我们的首要目标是确认这些高 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。目标1将允许确认中性粒细胞、单核细胞及其产物 敬战警。此外，我们将确定炎症途径中的特定因素(S)，导致 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内的炎性应激 环境，由中性粒细胞和单核细胞(这两种最丰富的细胞群体)驱动 在心包间隙的时候，大多数人会发生POAF)，直接影响到心房 电生理，导致房颤的可能性增加。除了描述 PCF的炎性成分是POAF的贡献者，我们的第二个目标是证明 心包腔内中性粒细胞和/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心脏跳动心房组织模型 使我们能够监测添加激活细胞及其产物的电生理效应 超级灌流液(加入浴缸以模拟PCF)。我们会起诉激活的中性粒细胞然后 单核细胞，然后测量对刺激心房颤动能力的影响。我们将在这之后进行一个 使用过氧化氢和已知的细胞因子产物的高度相关的炎症细胞产物模型 中性粒细胞和单核细胞通过多变量分析与POAF(我们已经在 我们的初步研究，并将随着目标1的完成而得到确认。这将允许描述特定的 炎症途径中的几个步骤有助于POAF的发展，以及随后 采取干预措施以改善这种疾病。

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.