Oxidative Stress and Atrial Fibrillation

超过200万美国人患有各种形式的心房颤动（AF）。AF是卒中的主要原因，也是死亡的独立危险因素。在开始之后，AF倾向于自我延续，部分原因是心房的电生理重构。心房的高频率活动具有多种电生理、代谢和血液动力学后果。AF使心房耗氧量增加2-3倍，并增加活性氧（氧化应激）的可用性。在心脏手术后的患者中，氧化应激的增加是惊人的，并且这些患者中的三分之一发展为术后AF。本申请的目标是确定氧化应激和AF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增加，（一种抗氧化剂）可以降低术后AF的发生率。因此，我们认为氧化应激增加是AF发生的主要危险因素之间的关键联系，而伴随心房颤动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，我们将在房颤患者和快速起搏犬模型中进行平行研究。本研究的目的是：1）确定氧化应激对离体心房肌细胞动作电位、Ca、K电流和缩短的影响; 2）应用生化和免疫组化技术评价心房组织的氧化损伤，并将其与体内电生理学特性相关联; 3）将氧化应激标记物和抗氧化能力的血浆水平与体内电生理学变化相关联; 4）前瞻性评估抗氧化剂疗法，关于它们降低氧化应激标志物水平和减弱在心房收缩中发生的电生理重构的能力;最后，直接评价维生素C对患者术后AF发生率的影响。成功的治疗应防止氧化损伤，减缓伴随AF发作的心房有效不应期的减少，最大限度地减少其永久性，并促进其终止。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.