Heart Failure and Atrial Fibrillation

心力衰竭和心房颤动

• 批准号: 7636862
• 负责人: CYNTHIA A CARNES
• 金额: $ 37.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636862
• 关键词: Action Potentials; Address; Arts; Atrial Fibrillation; Biochemical; Canis familiaris; Cessation of life; Chronic; Data; Disease; Electron Spin Resonance Spectroscopy; Electrophysiology (science); Equilibrium; Glutathione; Goals; 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; public health relevance; research study

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；弗雷明汉研究的数据表明，心力衰竭与心房颤动风险增加4.5-5.9倍有关。在患有晚期心力衰竭的患者中，房颤显着增加了死亡的风险。实验研究表明，心力衰竭会产生心房电生理学变化，从而促进房颤。此外，心力衰竭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，我们有特定氧化性调节形式的心房电生理学变化的初步证据。在这种慢性心力衰竭模型中，有一个用于房颤的底物，在试验实验中，我们能够诱导持续的（月）房颤。因此，我们可以研究心力衰竭和心房颤动如何有助于心房颤动的发病机理。该建议的目的是了解心力衰竭期间心房颤动的机械基础，其长期目标是确定特定的靶向治疗干预措施，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HF和具有叠加的慢性AF的慢性HF期间，有特定形式的氧化介导的病理心房重塑。体内（电生理学和非侵入性成像技术）和体外（细胞电生理学，电子顺磁性共振光谱，HPLC分析，免疫组织化学和蛋白质组学）技术的结合，可通过以下目标测试中心假设。具体目标1将检验以下假设：在HF-和HF期间，会发生具有离散形式的心房重塑形式。将检查房屋心肌重塑的氧化调节。具体目标2将检验以下假设：在HF和具有AF的HF期间，发生特定形式的心房氧化应激形式会导致心房电生理学的特定改变。特定目标3将检验以下假设：氧化应激特定来源的衰减将减少房颤和病理心房电生理重塑。公共卫生相关性：心力衰竭（由于心脏肌肉收缩受损而导致的）和心房颤动（心脏上腔的异常节奏）在美国人群中越来越普遍造成残疾和死亡的原因。这项研究的信息可能会改善治疗心力衰竭期间心房颤动的治疗方法。