Linking redox chemistry and mitochondria in atrium to post-operative arrhythmia

将心房中的氧化还原化学和线粒体与术后心律失常联系起来

基本信息

批准号：
8092793
负责人：
Ethan John Anderson
金额：
$ 17.94万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-17 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092793
关键词：
Address Adult Adverse effects Antioxidants Applications Grants Arrhythmia Atrial Fibrillation Biochemical Markers Biopsy Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiopulmonary Bypass Catecholamines Cessation of life Chemistry Clinics and Hospitals Complication Coronary Artery Bypass Data Development Dissection Electrocardiogram Environment Enzymes Glutathione Glutathione Disulfide Glutathione Reductase Goals Health Care Costs Healthcare Heart Heart Atrium Hospitals Human Hydrogen Peroxide Hypotension In Situ Incidence Individual Inflammation Institution Laboratories Length of Stay Link Measurement Measures Mechanics Methods Mitochondria Monitor Morbidity - disease rate Myocardial Myocardial tissue Natural regeneration Operative Surgical Procedures Oxidants Oxidation-Reduction Oxidative Stress Pathology Patients Pericardial body location Postoperative Period Production Prophylactic treatment Publishing Pump Reactive Oxygen Species Reduced Glutathione Risk Sampling Series Sinus Stroke Testing Time Tissue Sample Tissues auricular appendage base care burden cohort enzyme activity glutathione peroxidase high risk mortality novel oxidation prevent prophylactic public health relevance revascularization surgery uptake

项目摘要

DESCRIPTION (provided by applicant): Post-operative atrial fibrillation (POAF) in patients following cardiac revascularization surgery is a significant health care burden and estimates of occurrence range from 15-65%. The mechanisms by which this occurs remain unknown, and a bio-marker for identifying those patients that are more vulnerable, or pre-disposed, to POAF would be highly valuable to clinicians. The studies proposed in this grant proposal will have a target cohort of 300 adult patients undergoing elective cardiac revascularization surgery via cardiopulmonary bypass. Samples of right atrial appendage will be obtained from these patients during surgery, and the following Specific Aims have been constructed to test the CENTRAL HYPOTHESIS that a diminished glutathione antioxidant capacity in myocardial tissue at the time of surgery pre-disposes a patient to developing POAF, and that this diminished antioxidant capacity is linked to increased mitochondrial oxidant emission. Aim 1): To determine if decreased glutathione content or glutathione-related enzyme activity in a patient's atrium at the time of surgery is linked to the development of POAF. The concentration of intracellular reduced (GSH) and oxidized (GSSG) glutathione will be assessed in samples of right atrial appendage obtained from patients directly prior to institution of cardiopulmonary bypass as outlined above. The specific activities of glutathione peroxidase (H2O2 scavenging) and glutathione reductase (regenerates GSH from GSSG) will also be assessed in each sample. Patients will then be continuously monitored with ECG post-operatively until discharge from hospital, and the glutathione data for each patient will then be compared with the post-operative ECG profile of that patient to determine whether there is a link between glutathione content and/or glutathione-related enzyme activity in a patient's atrium at the time of surgery and the development of POAF. Aim 2): To determine whether elevated rates of mitochondrial oxidant emission are linked to diminished glutathione antioxidant capacity in myocardial tissue of patients undergoing CABG surgery. Mitochondrial H2O2 emission supported by endogenous substrate oxidation at baseline and following exogenous Ca2+ uptake will be assessed in permeabilized atrial myofibers prepared from samples of right atrial appendage obtained from patients directly prior to institution of cardiopulmonary bypass. These data will then be analyzed together with the glutathione data, to establish whether high rates of mitochondrial H2O2 emission are associated with reduced glutathione content and/or enzyme activity in atrial tissue. CLINICAL SIGNIFICANCE: It is anticipated that the findings from this project will result in identification of biochemical markers that may be able to identify patients at higher risk for developing POAF, in addition to providing a first step towards elucidating a potential mechanism by which POAF occurs. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (irregular heartbeat) is one of the most common complications after open heart surgery. Its incidence ranges from 20% to 40% in most published series. Significant adverse effects include stroke, increased risk of death, and increased length of stay in hospital, resulting in a large financial burden to hospitals and clinics. Little is known about the mechanism for the development of this arrhythmia, and more importantly why it occurs in some patients and not in others. The studies proposed here are directed towards identifying a biochemical marker which could identify patients who are at increased risk of developing postoperative atrial fibrillation, and towards further understanding of the causative factors underlying its development.

描述（由申请人提供）：心脏血运重建手术后患者的术后心房颤动 (POAF) 是一项重大的医疗保健负担，估计发生率在 15-65% 之间。这种情况发生的机制仍然未知，而用于识别那些更容易或易患 POAF 的患者的生物标记对于临床医生来说非常有价值。本拨款提案中提出的研究将以 300 名通过体外循环接受选择性心脏血运重建手术的成年患者为目标队列。将在手术期间从这些患者中获取右心耳样本，并构建了以下具体目标来检验中心假设，即手术时心肌组织中谷胱甘肽抗氧化能力的降低使患者容易发生 POAF，并且这种抗氧化能力的降低与线粒体氧化剂排放的增加有关。目标 1)：确定手术时患者心房中谷胱甘肽含量或谷胱甘肽相关酶活性的降低是否与 POAF 的发生有关。细胞内还原型 (GSH) 和氧化型 (GSSG) 谷胱甘肽的浓度将在如上所述进行体外循环之前直接从患者获得的右心耳样本中进行评估。还将评估每个样品中谷胱甘肽过氧化物酶（H2O2 清除）和谷胱甘肽还原酶（从 GSSG 再生 GSH）的比活性。然后，术后将持续使用心电图监测患者直至出院，然后将每位患者的谷胱甘肽数据与该患者术后心电图资料进行比较，以确定谷胱甘肽含量和/或手术时患者心房中谷胱甘肽相关酶的活性以及 POAF 的发生。目标 2)：确定接受 CABG 手术的患者心肌组织中谷胱甘肽抗氧化能力降低是否与线粒体氧化剂排放率升高有关。基线时由内源性底物氧化支持的线粒体 H2O2 排放以及外源性 Ca2+ 吸收后的线粒体 H2O2 排放将在透化心房肌纤维中进行评估，该肌纤维是由在体外循环机构之前直接从患者获得的右心耳样本制备的。然后将这些数据与谷胱甘肽数据一起进行分析，以确定线粒体 H2O2 的高排放率是否与心房组织中谷胱甘肽含量和/或酶活性的降低有关。临床意义：预计该项目的研究结果将导致生化标志物的鉴定，这些标志物可能能够识别发生 POAF 风险较高的患者，此外还为阐明 POAF 发生的潜在机制迈出了第一步。公众健康相关性：心房颤动（心律不齐）是心脏直视手术后最常见的并发症之一。在大多数已发表的系列文章中，其发生率在 20% 到 40% 之间。严重的不良反应包括中风、死亡风险增加和住院时间增加，给医院和诊所带来巨大的经济负担。人们对这种心律失常的发生机制知之甚少，更重要的是，对于为什么它发生在某些患者身上而不是其他患者身上，我们知之甚少。这里提出的研究旨在确定一种生化标记物，该标记物可以识别术后发生房颤风险增加的患者，并进一步了解其发生的致病因素。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stressing the heart of the matter: re-thinking the mechanisms underlying therapeutic effects of n-3 polyunsaturated fatty acids.

DOI：
10.3410/m4-13
发表时间：
2012-01-01
期刊：
F1000 medicine reports
影响因子：
0
作者：
Anderson, Ethan J;Taylor, David A
通讯作者：
Taylor, David A

Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation.

DOI：
10.1161/jaha.113.000713
发表时间：
2014-02-26
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Anderson EJ;Efird JT;Davies SW;O'Neal WT;Darden TM;Thayne KA;Katunga LA;Kindell LC;Ferguson TB;Anderson CA;Chitwood WR;Koutlas TC;Williams JM;Rodriguez E;Kypson AP
通讯作者：
Kypson AP

Aldehyde stress and up-regulation of Nrf2-mediated antioxidant systems accompany functional adaptations in cardiac mitochondria from mice fed n-3 polyunsaturated fatty acids.