Myocardial redox status, catecholamine metabolism and post-operative arrhythmia

描述(由申请人提供)：心脏手术后发生的房颤(POAF)仍然是最常见和最昂贵的术后并发症。尽管医生和科学家对POAF进行了严格的调查，但对于它为什么会发生，特别是为什么它只发生在某些患者身上，我们的理解仍然存在重大差距。我们的 实验室已经获得了令人振奋的初步数据，表明单胺氧化酶(MAO)的高活性与POAF密切相关，而不受其他已知危险因素的影响。MAO是一种线粒体外膜结合酶，是心房心肌中过氧化氢的主要生成物。谷胱甘肽(GSH)和谷胱甘肽过氧化物酶(GPX)在较小程度上也是如此，这两种物质都对维持细胞内氧化还原平衡至关重要。这些酶都是在心脏手术期间获得的废弃右心耳(RAA)中测定的。从机械学的角度来看，这些发现是令人信服的和科学上可信的，因为它们结合了儿茶酚胺超载、线粒体功能障碍和心房心肌氧化还原失衡，所有这些都是围手术期已知的导致心律失常发生的因素。在目前的方案中，通过获取组织并使用更大的心脏手术患者队列进行分析，我们将基于这一非常有希望的数据来建立基于MAO作为预测生物标志物的POAF风险的统计模型，并通过特别关注心房心肌细胞中的线粒体能量学来阐明右心房MAO活性升高与POAF之间的联系机制。在目标1中，我们将通过术中从一大批接受心脏手术的成人患者(N=770)获取RAA组织并立即测量这些酶的活性，验证MAO作为POAF的预测生物标记物，单独或与其他氧化还原酶结合使用。作为这一目标的一个探索性组成部分，我们将检查是否可以替代地将术前从同一组患者中获得的血小板和红细胞中的MAO和/或GPX用作POAF的预测生物标志物。在目标2中，我们将利用为目标1招募的患者队列中的一个小得多的子集，通过关注MAO与心房心肌线粒体功能之间的相互作用，开始剖析心房高MAO活性导致POAF的机制。因此，这些研究将既有实用的应用研究部分(目标1)，也有基础研究部分(目标2)。预计第一个目标的发现将产生直接和持续的临床影响，因为它们将为临床医生提供高概率预测哪些患者易患POAF并因此具有发展为POAF的高风险的能力。这将创造一种途径，在不久的将来专门针对“高危”患者使用预防性抗心律失常药物。我们期待我们对心脏MAO和线粒体能量学之间相互作用的基础研究结果能够加强我们对右心房高水平MAO活性与POAF之间联系机制的理解。

DESCRIPTION (provided by applicant): The onset of post-operative atrial fibrillation (POAF) after cardiac surgery continues to be the most common and costly post-operative complication. Despite rigorous investigation of POAF by physicians and scientists, significant gaps remain in our understanding as to why it occurs, and specifically why it only occurs in certain patients. Our laboratory has obtained exciting preliminary data showing that high activity of the enzyme monoamine oxidase (MAO), a mitochondrial outer membrane-bound enzyme and substantial generator of H2O2 in atrial myocardium, is strongly correlated with POAF independent of other known risk factors. So are, to a lesser extent, glutathione (GSH) and glutathione peroxidase (GPx), both critical for maintaining intracellular redox balance. These enzymes were all measured in discarded right atrial appendage (RAA) obtained during cardiac surgery. From a mechanistic perspective, these findings are compelling and scientifically plausible because they integrate catecholamine overload, mitochondrial dysfunction and redox imbalance in the atrial myocardium, all factors in the peri-operative period that are known to contribute to arrhythmogenesis. In the current proposal, by obtaining tissue and performing analyses using a much larger cohort of cardiac surgery patients, we will build on this highly promising data in order to establish a statistical model of POAF risk based on MAO as a predictive biomarker, and to elucidate mechanisms connecting elevated MAO activity in right atrium to POAF by focusing specifically on mitochondrial energetics in the atrial cardiomyocytes. In Aim 1, we will validate MAO as a predictive biomarker of POAF, alone or in combination with other redox enzymes, by obtaining the RAA tissue intra-operatively from a large cohort (N=770) of adult patients undergoing cardiac surgery and immediately measuring activity of these enzymes. As an exploratory component of this Aim we will examine if MAO and/or GPx in platelets and RBC's, respectively, obtained pre- operatively from this same cohort of patients, can alternatively be used as predictive biomarkers of POAF. In Aim 2, using a much smaller subset of the patient cohort recruited for Aim 1, we will begin to dissect mechanisms by which high MAO activity in atrium leads to POAF by focusing on the interaction between MAO and mitochondrial function in atrial myocardium. Thus, these studies will have both a practical, applied research component (Aim 1) as well as a basic research component (Aim 2). It is anticipated that the findings from the first Aim will have immediate and sustained clinical impact because they will provide clinicians the ability to predict with high probability which patients are predisposed and therefor at high risk to develop POAF. This would create a pathway to specifically target the 'high-risk' patients with prophylactic anti- arrhythmic medication in the near future. We expect the findings from our basic research on interactions between cardiac MAO and mitochondrial energetics to enhance our understanding of mechanisms connecting high levels of MAO activity in right atrium to POAF.