Oxidative Stress and Atrial Fibrillation

超过两百万的美国人患有各种形式的心房颤动（AF）。房颤是中风的主要原因，也是死亡的独立危险因素。房颤发生后，由于心房的电生理重塑，房颤倾向于自我延续。心房纤颤的高频率活动具有多种电生理、代谢和血流动力学后果。房颤使心房耗氧量增加2-3倍，并增加活性氧的可用性（氧化应激）。在心脏手术后患者中，氧化应激的增加是惊人的，其中三分之一的患者发展为术后房颤。本应用的目的是确定氧化应激与房颤期间发生的电生理重构之间的关系。氧化应激调节对正常心房功能重要的几个离子通道（Ca， K和ryanodine受体）的活性。在初步研究中，我们已经证明，犬心房快速起搏会导致氧化损伤的增加，而维生素C（一种抗氧化剂）治疗患者可以降低术后房颤的发生率。因此，我们认为氧化应激的增加是房颤发生的主要危险因素之间的关键联系，而伴随房颤发作的电生理重构是氧化应激的结果。为了验证我们的假设，将在患者和快速心房颤动犬模型中进行平行研究。本研究的目的是：1)确定氧化应激对分离心房肌细胞动作电位、Ca、K电流和缩短的影响；2)利用生物化学和免疫组织化学技术评估心房组织氧化损伤，并将其与体内电生理特性相关联；3)血浆氧化应激标志物水平和抗氧化能力与体内电生理变化的相关性；4)前瞻性评估抗氧化疗法降低氧化应激标志物水平的能力，并减弱发生在颤动犬心房的电生理重构；最后，直接评价维生素C对患者术后房颤发生率的影响。成功的治疗应防止氧化损伤，使房颤发病时心房有效不应期缩短，减少房颤的持续时间，促进房颤的终止。我们预计这些早期干预将被证明是长期治疗和预防房颤的最有效方法。

More than two million Americans suffer from various forms of atrial fibrillation (AF). AF is a major cause of stroke and an independent risk factor for mortality. Following initiation, AF tends to self-perpetuate, due in part to electrophysiological remodeling of the atria. The high rate activity of the fibrillating atria has multiple electrophysiological, metabolic, and hemodynamic consequences. AF increases atrial oxygen consumption 2-3 fold, and increases the availability of reactive oxygen species (oxidative stress). In post-cardiac surgery patients the increase in oxidative stress is striking, and one-third of these patients develop post- operative AF. The goal of this application is to determine the relationship between oxidative stress and the electrophysiological remodeling that occurs during AF. Oxidative stress modulates the activity of several ion channels (Ca, K, and ryanodine receptor) important for normal atrial function. In preliminary studies, we have demonstrated that rapid pacing of canine atria results in increased oxidative injury, and that treating patients with vitamin C (an antioxidant) can decrease the incidence of post-operative AF. Thus, we propose that increased oxidative stress is a key link between the major risk factors for the development of AF, and that the electrophysiological remodeling accompanying the onset of atrial fibrillation is the result of oxidative stress. To test our hypothesis, parallel studies will be performed in patients and in a rapidly paced canine model of AF. The aims of this study are: 1) to determine the impact of oxidative stress on action potentials, Ca, K currents, and shortening in isolated atrial myocytes; 2) to assess the oxidative injury in atrial tissue using biochemical and immunohistochemical techniques, and to correlate this with in vivo electrophysiological properties; 3) to correlate plasma levels of oxidative stress markers and anti-oxidant capacity with electrophysiological changes in vivo; 4) to prospectively evaluate antioxidant therapies, with respect to their capacity to decrease levels of markers of oxidative stress and attenuate the electrophysiological remodeling that occurs in fibrillating canine atria; and finally, to directly evaluate the impact of vitamin C on the incidence of post-operative AF in patients. Successful therapies should prevent oxidative Injury, blunting the reduction in atrial effective refractory period that accompanies the onset of AF, minimizing its perpetuation, and facilitating Its termination. We anticipate that these early interventions will prove to be the most effective approach to the long term treatment and prevention of AF.