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：
8301837
负责人：
ARSHAD JAHANGIR
金额：
$ 43.5万
依托单位：
AURORA HEALTH CARE, INC.
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/8301837
关键词：
Address Age Factors 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关于心脏线粒体在定义心房颤动（AF）（临床实践中最常见的心律失常）的基础中的作用的机制见解。预计 AF 的患病率将增加 6 倍，每年造成的损失将超过 150 亿美元，AF 仍然是一个主要的国民健康问题。尽管人们认识到衰老会增加心房颤动的易感性，且老年人心房颤动的患病率比年轻人高 100 倍，但其分子基础仍然未知。伴随衰老或相关疾病的血流动力学、血管和代谢因素的变化有助于功能和结构性心房重塑，促进心肌细胞损失和纤维化，从而增加心房颤动的易感性，然而，这种导致心房功能障碍进展的改变的分子基础并不明确。定义明确。在我们使用人类心房组织的初步研究中，随着衰老和房颤的发生，调节线粒体能量和信号通路的基因明显转录下调，这些信号通路涉及能量的产生和利用、细胞损失和纤维化。此外，在衰老线粒体中发现了在压力下维持细胞能量和离子稳态的能力受损的功能缺陷，可以通过调节线粒体膜通透性来改善。基于这些，我们假设老年人对房颤的易感性是由于心房线粒体功能储备减少所致，由于应激期间心肌对能量衰竭、钙超载和氧化损伤的敏感性增强，从而促进心肌细胞丢失和纤维化，从而促进发育和 AF 底物的进展。我们建议 1) 确定发生 AF 的低风险或高风险患者以及阵发性、持续性或永久性 AF 患者的心房结构和功能、能量学和线粒体对应激的敏感性的差异； 2) 确定心房能量不足和线粒体功能障碍导致细胞丢失和纤维化加剧的潜在机制； 3) 确定线粒体调节对有房颤风险或患有房颤的患者代谢应激期间线粒体和细胞损伤的保护作用。这些目标将通过使用从接受冠状动脉搭桥手术的患者身上获得的心房组织来实现，这些患者无或有房颤危险因素（心力衰竭、高血压或二尖瓣反流）或有阵发性、持续性或永久性房颤病史。一种综合方法，将临床信息与通过成像获得的体内和体外心房结构和功能数据相结合，通过全面的细胞和线粒体研究评估心房组织中超微结构、功能、分子、遗传和蛋白质组变化的差异，这些变化有房颤风险，对手术后发生房颤以及患有房颤的患者进行研究，不仅具有高度创新性，而且具有很高的临床意义。这些结果将为线粒体启动房颤底物的作用提供新的见解，并确定开发预防房颤的治疗方法的新靶点。（摘要完）