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，估计发生范围为15-65％。发生这种情况的机制尚不清楚，并且是识别那些对POAF更脆弱或预先侵害的患者的生物标志物，对临床医生来说非常有价值。该赠款提案中提出的研究将具有目标队列，包括300名通过心肺旁路进行选择性心脏血运重建手术的成年患者。在手术期间，将从这些患者那里获得右心房附件的样本，并且已经构建了以下特定目的，以检验中心假设，即在手术中，在手术时，心肌组织中的谷胱甘肽抗氧化能力降低，预先分解了患者的患者以形成孔隙的毒液，并且这种减小的抗氧化能力较小的氧化剂均与MITOCTIANT链接在一起。目标1）：确定手术时患者中庭中谷胱甘肽含量减少或与谷胱甘肽相关的酶活性是否与POAF的发展有关。细胞内还原（GSH）和氧化（GSSG）谷胱甘肽的浓度将在从上述概述的心肺旁路之前直接从患者那里获得的正确心房附属物中进行评估。在每个样品中也将评估谷胱甘肽过氧化物酶（H2O2清除）和谷胱甘肽还原酶（GSSG再生GSH）的特定活性。然后，将对患者进行手术后的ECG对患者进行连续监测，直到出院出院为止，然后将每个患者的谷胱甘肽数据与该患者的术后心电图概况进行比较，以确定在手术时和Pro of Pro of Profergergerger和Proffergery时，患者的Atrium中与谷胱甘肽含量和/或谷胱甘肽相关的酶活性之间是否存在联系。目标2）：确定线粒体氧化剂排放率是否升高与接受CABG手术的患者心肌组织中谷胱甘肽抗氧化能力的降低有关。内源性底物在基线时和外源性Ca2+摄取后由内源性底物氧化支持的线粒体H2O2发射将在透化的心房肌纤维中评估，从直接从患者的右心房附属物样本中制备的透化心房肌纤维中，直接是在心脏通行率之前的患者中获得的。然后将与谷胱甘肽数据一起分析这些数据，以确定高线粒体H2O2发射率是否与心房组织中谷胱甘肽含量降低和/或酶活性有关。临床意义：预计该项目的发现将导致鉴定生化标志物，这些标志物可能能够鉴定出患有较高风险的POAF风险的患者，此外还提供了阐明POAF发生的潜在机制的第一步。公共卫生相关性：心房颤动（不规则的心跳）是心脏病手术后最常见的并发症之一。在大多数已发表系列中，其发病率范围从20％到40％。严重的不利影响包括中风，增加死亡风险以及增加医院的住院时间，从而给医院和诊所带来了巨大的财务负担。关于这种心律不齐的发展机制知之甚少，更重要的是，为什么它发生在某些患者而不是其他患者中。此处提出的研究旨在识别生化标记，该标志物可以确定患者患术后房颤的风险增加，并进一步理解其发育开发的因素。

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.