Heart Failure and Atrial Fibrillation

心力衰竭和心房颤动

基本信息

批准号：
8099629
负责人：
CYNTHIA A CARNES
金额：
$ 42.86万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099629
关键词：
Action Potentials Address Atrial Fibrillation Biochemical Canis familiaris Cessation of life Chronic Data Disease Electron Spin Resonance Spectroscopy Electrophysiology (science)Equilibrium Glutathione Goals Health Heart Heart Atrium Heart failure High Pressure Liquid Chromatography Image Imaging Techniques Immunohistochemistry In Vitro Intervention Ion Channel Ion Channel Protein Ions Measures Mediating Modeling Muscle Cells Myocardial Myocardium Nitric Oxide Synthase Oxidants Oxidation-Reduction Oxidative Stress Pathogenesis Pathologic Patients Placebos Population Prevalence Prevention Production Proteomics Public Health Risk Role Signal Transduction Source Study models Superoxides Techniques Testing Therapeutic Intervention Time animal tissue attenuation base clinically relevant cofactor disability efficacy testing improved in vivo insight novel prevent research study

项目摘要

DESCRIPTION (provided by applicant): Heart failure and atrial fibrillation are common coexisting disease states; data from the Framingham study indicate that heart failure is associated with a 4.5- to 5.9-fold increase in the risk of atrial fibrillation. In patients with advanced heart failure, atrial fibrillation significantly increases the risk of death. Experimental studies have shown that heart failure produces atrial electrophysiologic changes which promote atrial fibrillation; furthermore heart failure induces significant increases in myocardial oxidants. Using a chronic model of nonischemic heart failure, we have preliminary evidence of specific oxidatively-modulated forms of atrial electrophysiologic changes. In this chronic heart failure model, there is a substrate for atrial fibrillation, and in pilot experiments we are able to induce sustained (months) atrial fibrillation. Thus, we can study how both heart failure and atrial fibrillation contribute to the pathogenesis of atrial fibrillation. The purpose of this proposal is to understand the mechanistic bases of atrial fibrillation during heart failure, with a long-term goal of identifying specific targeted therapeutic interventions to effectively prevent or treat atrial fibrillation during heart failure. The central hypothesis of this proposal is that during chronic HF, and chronic HF with superimposed chronic AF, there are specific forms of oxidatively-mediated pathologic atrial remodeling. A combination of in vivo (electrophysiologic and non-invasive imaging techniques) and in vitro (cellular electrophysiology, electron paramagnetic resonance spectroscopy, HPLC analyses, immunohistochemistry and proteomics) techniques will be used to test the central hypothesis, through the following aims. Specific Aim 1 will test the hypothesis that during HF-, and HF with AF-, discrete forms of atrial remodeling occur. Oxidative modulation of atrial myocyte remodeling will be examined. Specific Aim 2 will test the hypothesis that during HF, and HF with AF, specific forms of atrial oxidative stress occur which result in specific alterations in atrial electrophysiology. Specific Aim 3 will test the hypothesis that attenuation of a specific source of oxidative stress will reduce atrial fibrillation and pathologic atrial electrophysiologic remodeling. PUBLIC HEALTH RELEVANCE: Heart failure (resulting from impaired contraction of the heart muscle) and atrial fibrillation (abnormal rhythm of the upper chambers of the heart) are increasingly common causes of disability and death in the U.S. population. Information from this study may result in improved treatments for the prevention and treatment of atrial fibrillation during heart failure.

描述（由申请人提供）：心力衰竭和心房颤动是常见的共存疾病状态； Framingham 研究的数据表明，心力衰竭与心房颤动风险增加 4.5 至 5.9 倍相关。对于晚期心力衰竭患者，心房颤动会显着增加死亡风险。实验研究表明，心力衰竭会产生心房电生理变化，从而促进心房颤动；此外，心力衰竭还会导致心肌氧化剂显着增加。使用非缺血性心力衰竭的慢性模型，我们获得了心房电生理变化的特定氧化调节形式的初步证据。在这种慢性心力衰竭模型中，存在心房颤动的基质，并且在初步实验中，我们能够诱导持续（数月）的心房颤动。因此，我们可以研究心力衰竭和心房颤动如何导致心房颤动的发病机制。该提案的目的是了解心力衰竭期间房颤的机制基础，长期目标是确定具体的有针对性的治疗干预措施，以有效预防或治疗心力衰竭期间的房颤。该提议的中心假设是，在慢性心力衰竭期间，以及慢性心力衰竭叠加慢性房颤期间，存在特定形式的氧化介导的病理性心房重构。体内（电生理学和非侵入性成像技术）和体外（细胞电生理学、电子顺磁共振波谱、HPLC 分析、免疫组织化学和蛋白质组学）技术的结合将用于通过以下目标来检验中心假设。具体目标 1 将检验以下假设：在 HF- 和 HF 合并 AF- 期间，会发生离散形式的心房重塑。将检查心房肌细胞重塑的氧化调节。具体目标 2 将检验以下假设：在心力衰竭和心力衰竭合并房颤期间，会发生特定形式的心房氧化应激，从而导致心房电生理学的特定变化。具体目标 3 将检验以下假设：减弱特定氧化应激源将减少心房颤动和病理性心房电生理重塑。公共卫生相关性：心力衰竭（由心肌收缩受损引起）和心房颤动（心脏上腔节律异常）越来越成为美国人口残疾和死亡的常见原因。这项研究的信息可能会改善心力衰竭期间心房颤动的预防和治疗方法。