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

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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.