Myocardial redox status, catecholamine metabolism and post-operative arrhythmia

描述（由申请人提供）：心脏手术后发生的术后房颤（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进行了严格的研究，但我们对它发生的原因，特别是为什么它只发生在某些患者身上的理解仍然存在重大差距。我们 实验室已经获得了令人兴奋的初步数据，表明单胺氧化酶（MAO）的高活性与POAF密切相关，而与其他已知的危险因素无关，MAO是一种线粒体外膜结合酶，也是心房心肌中H2 O2的主要产生者。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，两者对于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）中测量的。从机制的角度来看，这些发现是令人信服的，科学上是合理的，因为它们整合了心房心肌中的儿茶酚胺过载，线粒体功能障碍和氧化还原失衡，围手术期的所有因素都是已知的促成心肌梗死的因素。在目前的建议中，通过获得组织并使用更大的心脏手术患者队列进行分析，我们将建立在这个非常有希望的数据基础上，以建立基于MAO作为预测生物标志物的POAF风险的统计模型，并通过专门关注心房心肌细胞中的线粒体能量学来阐明右心房中MAO活性升高与POAF之间的联系机制。在目标1中，我们将通过从接受心脏手术的大型成人患者队列（N=770）中获得术中RAA组织并立即测量这些酶的活性，验证MAO单独或与其他氧化还原酶联合作为POAF的预测生物标志物。作为该目的的探索性组成部分，我们将检查术前从同一患者队列中分别获得的血小板和RBC中的MAO和/或GPx是否可替代地用作POAF的预测性生物标志物。在目标2中，使用目标1招募的患者队列的一个小得多的子集，我们将开始通过关注心房心肌中MAO与线粒体功能之间的相互作用来剖析心房中高MAO活性导致POAF的机制。因此，这些研究既有实际的应用研究部分（目标1），也有基础研究部分（目标2）。预计第一个Aim的结果将产生即时和持续的临床影响，因为它们将使临床医生能够以高概率预测哪些患者易患POAF，因此具有高风险。这将在不久的将来创造一种专门针对“高危”患者的预防性抗疟疾药物的途径。我们希望我们的基础研究的结果之间的相互作用的心脏单胺氧化酶和线粒体能量学，以提高我们的理解的机制，连接高水平的单胺氧化酶活性的右心房POAF。

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.