Mitochondrial Dysfunction and Susceptibility to Atrial Fibrillation in the Elderl

老年人线粒体功能障碍和房颤易感性

基本信息

批准号：
7848048
负责人：
ARSHAD JAHANGIR
金额：
$ 66.1万
依托单位：
MAYO CLINIC ARIZONA
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：
2010-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848048
关键词：
Address Age Aging Applications Grants Arrhythmia Atrial Fibrillation Blood Vessels Calcium Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiology Cell Death Cell Membrane Permeability Cells Cessation of life Clinical Competence Confocal Microscopy Coronary Artery Bypass Data Defect Development Diabetes Mellitus Disease Down-Regulation Elderly Electrophysiology (science)Epidemic Failure Fibrosis Functional disorder Gene Expression Gene Proteins Genes Genomics Goals Health Heart Heart Atrium Heart Valve Diseases Heart failure High Prevalence Homeostasis Human Hypertension Image Impairment In Vitro Individual Inflammation Injury Lead Metabolic Metabolic stress Mitochondria Mitral Valve Mitral Valve Insufficiency Molecular Molecular Genetics Morbidity - disease rate Muscle Cells Myocardium Operative Surgical Procedures Oxidants Pathway interactions Patients Permeability Physiology Predisposition Prevalence Prevention Production Proteins Proteomics Public Health Rattus Recording of previous events Risk Risk Factors Role Signal Pathway Signal Transduction Stress Stroke Structure Tissues Up-Regulation abstracting auricular appendage base cell injury clinical practice clinically significant cost disability hemodynamics high risk hypertensive heart disease impaired capacity in vivo inhibitor/antagonist innovation insight interest interstitial mitochondrial dysfunction mitochondrial membrane mortality novel prevent protective effect senescence therapeutic development young adult

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to obtain mechanistic insights into the role of cardiac mitochondria in defining the substrate for atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice. With a projected 6-fold increase in the prevalence and a cost exceeding $15 billion per year, AF remains a major national health problem. Despite the recognition that aging increases susceptibility of the atria to fibrillation, with a 100 fold higher prevalence in the older-elderly compared to young adults, the molecular bases for this remains unknown. Changes in hemodynamic, vascular, and metabolic factors that accompany aging or associated disease contribute to functional and structural atrial remodeling promoting cardiomyocytes loss and fibrosis that increases susceptibility to fibrillation, however, the molecular bases for such alterations contributing to the progression of atrial dysfunction are not well defined. In our preliminary studies, using human atrial tissue, a distinct transcriptional downregulation of genes regulating mitochondrial energetics and signaling pathways involved in energy production and utilization, cell loss and fibrosis was demonstrated with aging and AF. Additionally, functional defects with impaired capacity to maintain cellular energetics and ionic homeostasis under stress were demonstrated in senescent mitochondria that can be ameliorated by modulating mitochondrial membrane permeability. Based on these, we hypothesize that susceptibility to AF in the elderly results from diminished mitochondrial functional reserves in the atria that promote cardiomyocyte loss and fibrosis due to enhanced sensitivity of the myocardium to energetic failure, calcium overload and oxidative injury during stress, thus facilitating development and progression of the substrate for AF. We propose 1) to identify differences in atrial structure and function, energetics and mitochondrial susceptibility to stress in patients with low or high risk for the development of AF and those with paroxysmal, persistent or permanent AF; 2) to identify mechanisms underlying atrial energetic deficits and mitochondrial dysfunction predisposing to enhanced cell loss and fibrosis; and 3) to determine the protective role of mitochondrial modulation against mitochondrial and cellular injury during metabolic stress in patients at risk for or with AF. These aims will be achieved using atrial tissue obtained from patients undergoing coronary artery bypass surgery without or with risk factors for AF (heart failure, hypertension, or mitral regurgitation) or a history of paroxysmal, persistent or permanent AF. An integrative approach combining clinical information with in vivo and in vitro atrial structural and functional data obtained by imaging with comprehensive cellular and mitochondrial studies assessing differences in ultrastructural, functional, molecular, genetic and proteomic changes in atrial tissue between those at risk of AF, who develops AF following surgery and those with AF, not only is highly innovative but also of high clinical significance. The results will provide new insights into the role of mitochondria priming the substrate for AF and identify novel targets for the development of therapeutics toward prevention of AF. (End of Abstract)

描述（由申请人提供）：该提案的目的是获得对心脏线粒体在定义心房颤动（AF）底物（AF）的作用的机械见解，这是临床实践中最常见的心律不齐。预计患病率增加了6倍，每年成本超过150亿美元，AF仍然是一个重大的国家健康问题。尽管认识到衰老会增加心房对纤颤的敏感性，而与年轻人相比，老年人的患病率高100倍，但这种分子碱基仍然未知。伴随衰老或相关疾病的血液动力学，血管和代谢因子的变化有助于促进心肌细胞损失和纤维化的功能和结构性心房重塑，从而增加了对纤维化的易感性，但是，分子碱基碱导致促进性疾病的进展不佳。在我们的初步研究中，使用人类心房组织，通过衰老和AF，证明了调节线粒体能量的基因的独特转录下调，以及与能量产生和利用相关的信号通路，细胞损失和纤维化证明。此外，在衰老线粒体中证明了在应激下保持细胞能量和离子稳态能力受损的功能缺陷，可以通过调节线粒体膜的渗透性来改善，这可以改善。基于这些，我们假设在老年人中对AF的敏感性是由于心房中线粒体功能储备的减少而导致的，从而促进心肌衰竭敏感性增强的心肌细胞损失和纤维化，从而促进能量衰竭的敏感性，钙超负荷和氧化作用在压力期间，因此在压力中受伤，从而促进了对衰局的发展和进展。我们建议1）确定心房结构和功能的差异，能量和线粒体对AF发展的患者以及具有阵发性，持久性或永久性AF的患者的压力的敏感性； 2）确定心房能量缺陷的基础机制和线粒体功能障碍易受增强的细胞损失和纤维化； 3）确定在有AF或患有AF的患者的代谢应激期间，线粒体调节对线粒体和细胞损伤的保护作用。这些目标将使用从接受冠状动脉搭桥手术的患者获得的心房组织来实现，而没有AF的危险因素（心力衰竭，高血压或二尖瓣反流）或阵发性，持续或永久性AF的病史。一种结合临床信息与体内和体外心房结构和功能数据结合的整合方法，通过对全面的细胞和线粒体研究进行成像，评估超微结构，功能，分子，遗传，遗传和蛋白质组织的差异，以及在AF的风险中，在经过临时的临时，以及高度强大的人群中，在AF的风险中，在心理组织中的差异，以及高度强大，并且是全面的。结果将为线粒体启动AF的底物的作用提供新的见解，并确定用于预防AF的疗法的新靶标。（抽象的结尾）