Myocardial redox status, catecholamine metabolism and post-operative arrhythmia

心肌氧化还原状态、儿茶酚胺代谢与术后心律失常

• 批准号: 9295043
• 负责人: Ethan John Anderson
• 金额: $ 40.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295043
• 关键词: Adult; Applied Research; Arrhythmia; Atrial Fibrillation; Basic Science; Biochemical Markers; Biological Markers; Blood; Blood Platelets; Blood specimen; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Catecholamines; Clinical; Complication; Consumption; Data; Day Surgery; Development; Electrophysiology (science); Enzymes; Equilibrium; Experimental Models; Freezing; Frequencies; Fresh Tissue; Functional disorder; Future; Generations; Glutathione; Goals; Healthcare Systems; Heart Atrium; Human; Hydrogen Peroxide; Incidence; Infection; Investigation; Laboratories; Length of Stay; Link; Liquid substance; Measurement; Measures; Metabolism; Mitochondria; Monoamine Oxidase; Monoamine Oxidase A; Myocardial; Myocardium; Operative Surgical Procedures; Outcome; Outer Mitochondrial Membrane; Oxidation-Reduction; Pathway interactions; Patient risk; Patients; Perioperative; Pharmaceutical Preparations; Physicians; Population; Postoperative Period; Probability; Prophylactic treatment; Pump; Reactive Oxygen Species; Recruitment Activity; Reporting; Right atrial structure; Risk; Risk Factors; Role; Sampling; Scientist; Statistical Models; Stroke; Testing; Time; Tissues; auricular appendage; base; cohort; cost; enzyme activity; glutathione peroxidase; high risk; improved; mitochondrial dysfunction; oxidation; patient subsets; predictive marker; prevent; prophylactic; prospective; public health relevance; uptake

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.

描述（由申请人提供）：心脏手术后发生术后心房颤动（POAF）仍然是最常见且费用最高的术后并发症。尽管医生和科学家对 POAF 进行了严格的研究，但我们对 POAF 发生原因的理解仍然存在重大差距，特别是为什么它只发生在某些患者中。我们的 实验室获得了令人兴奋的初步数据，表明单胺氧化酶 (MAO) 的高活性（一种线粒体外膜结合酶，也是心房心肌中 H2O2 的重要生成器）与 POAF 密切相关，独立于其他已知的危险因素。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都至关重要。这些酶都是在心脏手术期间获得的废弃右心耳 (RAA) 中进行测量的。从机制的角度来看，这些发现令人信服且在科学上合理，因为它们整合了儿茶酚胺超载、线粒体功能障碍和心房心肌氧化还原失衡，这些已知的围手术期导致心律失常的因素。在当前的提案中，通过获取组织并使用更大的心脏手术患者队列进行分析，我们将在这些非常有前途的数据的基础上建立基于 MAO 作为预测生物标志物的 POAF 风险统计模型，并阐明通过特别关注心房心肌细胞中的线粒体能量学，研究将右心房 MAO 活性升高与 POAF 联系起来的机制。在目标 1 中，我们将验证 MAO 作为 POAF 的预测生物标志物，单独或与其他氧化还原酶联合使用，方法是在术中从接受心脏手术的一大群 (N = 770) 成年患者中获取 RAA 组织并立即测量这些酶的活性。作为该目标的探索性组成部分，我们将检查术前从同一组患者中分别获得的血小板和红细胞中的 MAO 和/或 GPx 是否可以用作 POAF 的预测生物标志物。在目标 2 中，我们将使用为目标 1 招募的一小部分患者队列，通过关注心房心肌中 MAO 与线粒体功能之间的相互作用，开始剖析心房中高 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 Aim 的研究结果将产生直接和持续的临床影响，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，从而具有发生 POAF 的高风险。这将在不久的将来创建一条专门针对“高风险”患者预防性抗心律失常药物的途径。我们期望关于心脏 MAO 和线粒体能量学之间相互作用的基础研究结果能够增强我们对右心房高水平 MAO 活性与 POAF 之间联系机制的理解。