Oxidative Stress and Atrial Fibrillation

氧化应激和心房颤动

基本信息

批准号：
6743718
负责人：
David R Van Wagoner
金额：
$ 35.69万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-10 至 2006-04-30
项目状态：
已结题

项目摘要

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.

超过200万美国人患有各种形式的房颤（AF）。 AF是中风的主要原因，也是死亡率的独立风险因素。启动后，AF倾向于自我延伸，部分原因是心房的电生理重塑。纤维化心房的高率活性具有多种电生理，代谢和血液动力学后果。 AF增加了心房消耗2-3倍，并增加了活性氧的可用性（氧化应激）。在后手术后患者中，氧化应激的增加令人震惊，其中三分之一的患者发生了手术后AF。该应用的目的是确定AF期间发生的氧化应激与电生理重塑之间的关系。氧化应激调节了几个离子通道（CA，K和Ryanodine受体）的活性，对正常的心房功能很重要。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，并且治疗维生素C（一种抗氧化剂）患者可以降低术后AF的发生率。因此，我们建议增加的氧化应激是AF发展的主要风险因素之间的关键联系，而伴随房颤发作的电生理重塑是氧化应激的结果。为了检验我们的假设，将在患者和快速节奏的AF犬模型中进行平行研究。这项研究的目的是：1）确定氧化应激对分离的心肌细胞中作用电位，CA，K电流的影响； 2）使用生化和免疫组织化学技术评估心房组织中的氧化损伤，并将其与体内电生理特性相关联； 3）将氧化应激标志物的血浆水平与抗氧化能力与体内的电生理变化相关联； 4）预期评估抗氧化剂疗法，就其降低氧化应激水平的能力而言，并衰减了在颤振犬室中发生的电生理重塑；最后，直接评估维生素C对术后AF发生率在患者中的影响。成功的疗法应防止氧化损伤，削弱伴随AF发作的心房有效耐火周期的减少，最大程度地减少其持久性并促进其终止。我们预计，这些早期干预将被证明是长期治疗和预防AF的最有效方法。