Preamyloid Oligomers and Susceptibility to Atrial Fibrillation

前淀粉样蛋白寡聚物和心房颤动的易感性

• 批准号: 7884892
• 负责人: KATHERINE T MURRAY
• 金额: $ 40.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884892
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloidosis; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arrhythmia; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Tachycardia; Boxing; Canis familiaris; Cardiac Surgery procedures; Cells; Chronic; Clinical; Complex; Data; Degenerative Disorder; Deposition; Development; Disease; Employee Strikes; Epidemic; Exhibits; General Population; Generations; Genes; Goals; Heart Atrium; Heart failure; Hour; Human; In Vitro; Incidence; Inflammation; Ion Channel; Link; Morbidity - disease rate; Mutation; Neurodegenerative Disorders; Oxidative Stress; Pathogenesis; Persons; Play; Population; Postoperative Period; Predisposition; Process; Proteins; Research; Risk; Risk Factors; Role; Sampling; Stretching; Stroke; Testing; Tissues; Up-Regulation; base; common treatment; heart function; heart rhythm; improved; in vivo; lifetime risk; mortality; mutant; new therapeutic target; novel; novel strategies; oxidant stress; prevent; protein misfolding; public health relevance; response

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common cardiac arrhythmia, resulting in substantial morbidity and mortality. An important risk factor for developing AF is age, with a lifetime risk of 1 in 6 for the condition. The incidence of AF is increasing in epidemic proportion as the US population ages, and currently available treatment is often ineffective. The clinical course of AF is typically progressive, due to electrical and structural remodeling in the atria with rapid stimulation that increases arrhythmia susceptibility. Oxidative stress and inflammation play an important role in generating the AF substrate and promoting this remodeling process. Recently, we showed that atrial cells rapidly stimulated in culture undergo remodeling very similar to that observed in human AF. Importantly, transcriptional profiling in paced cells exhibited striking concordance with changes seen in vivo. Unexpectedly, we observed conserved transcriptional upregulation in proteins involved in amyloidosis, a process associated with protein misfolding and deposition in multiple neurodegenerative diseases, notably Alzheimer's disease. Substantial evidence indicates that the toxic species in these disorders are soluble preamyloid oligomer intermediates, rather than the mature fibrillar, amyloid-positive deposits. Indeed, our preliminary data demonstrate striking accumulation of preamyloid oligomers in rapidly-paced atrial cells, with similar results in experimental and human AF. Taken together, these data form a strong rationale for the proposed studies. The goal of this proposal is to test the hypothesis that atrial preamyloid oligomers are pathophysiologically linked to the development of AF in humans. In Specific Aim 1, human atrial samples obtained during routine cardiac surgery at multiple centers will be used to examine the relationship of preamyloid oligomer formation to age, the risk of postoperative AF, and established AF in humans. Indicators of oxidative stress will also be investigated in these samples. In Specific Aim 2, we will explore the effects of potent antioxidant/anti-inflammatory compounds that are also known to inhibit soluble oligomer formation, on the generation of atrial preamyloid oligomers in response to rapid stimulation in vitro and during experimental AF. Atrial natriuretic peptide (ANP) is known to form amyloid fibrils, and it is present in isolated atrial amyloidosis, a process that increases with aging in humans. Recently, mutations in ANP were causally linked to familial AF. In Specific Aim 3, we will determine whether these ANP mutations promote the formation of preamyloid oligomers as a potential mechanism to increase AF susceptibility. The proposed studies have substantial significance, since preamyloid oligomers may not only provide a mechanistic link between oxidative stress, aging, and AF, but they may also provide a novel therapeutic target in the treatment of this common and difficult to treat arrhythmia. PUBLIC HEALTH RELEVANCE: The studies described in this proposal will improve our understanding of the basic mechanisms that cause a heart rhythm disturbance known as atrial fibrillation. This is important because atrial fibrillation is common in the general population, and it causes a substantial number of strokes each year, as well as weakened heart function, or heart failure. We anticipate that we will identify new mechanisms that increase a person's susceptibility to atrial fibrillation, and thus new approaches should develop to prevent its occurrence.

描述（由申请人提供）：心房颤动（AF）是最常见的心律失常，导致大量的发病率和死亡率。发生房颤的一个重要风险因素是年龄，一生中患房颤的风险为六分之一。随着美国人口老龄化，房颤的发病率呈流行趋势，而目前可用的治疗方法往往无效。房颤的临床病程通常是进行性的，这是由于心房的电和结构重塑以及快速刺激增加了心律失常的易感性。氧化应激和炎症在生成 AF 底物和促进这一重塑过程中发挥着重要作用。最近，我们发现，在培养物中快速刺激的心房细胞会经历与人类房颤中观察到的非常相似的重塑。重要的是，起搏细胞的转录谱与体内观察到的变化表现出惊人的一致性。出乎意料的是，我们观察到淀粉样变性相关蛋白质中保守的转录上调，淀粉样变性是一种与多种神经退行性疾病（尤其是阿尔茨海默病）中蛋白质错误折叠和沉积相关的过程。大量证据表明，这些疾病中的有毒物质是可溶性前淀粉样蛋白寡聚物中间体，而不是成熟的纤维状淀粉样蛋白阳性沉积物。事实上，我们的初步数据表明，前淀粉样蛋白寡聚物在快节奏的心房细胞中显着积累，在实验和人类 AF 中也有类似的结果。总而言之，这些数据为拟议的研究提供了强有力的理由。该提案的目的是检验心房前淀粉样蛋白寡聚体与人类 AF 的发生在病理生理学上相关的假设。在具体目标 1 中，将使用在多个中心的常规心脏手术中获得的人类心房样本来检查前淀粉样蛋白寡聚体的形成与年龄、术后 AF 的风险以及人类中已确定的 AF 的关系。还将在这些样品中研究氧化应激指标。在具体目标 2 中，我们将探讨强效抗氧化剂/抗炎化合物（已知也能抑制可溶性低聚物形成）对体外和实验性 AF 期间快速刺激的心房前淀粉样蛋白低聚物生成的影响。心房钠尿肽 (ANP) 已知可形成淀粉样原纤维，并且存在于孤立性心房淀粉样变性中，这种过程随着人类衰老而加剧。最近，ANP 突变与家族性房颤有因果关系。在具体目标 3 中，我们将确定这些 ANP 突变是否促进前淀粉样蛋白寡聚体的形成，作为增加 AF 易感性的潜在机制。拟议的研究具有重大意义，因为前淀粉样蛋白寡聚体不仅可能提供氧化应激、衰老和房颤之间的机制联系，而且还可能为这种常见且难以治疗的心律失常的治疗提供新的治疗靶点。 公共卫生相关性：本提案中描述的研究将提高我们对导致心律失常（称为心房颤动）的基本机制的理解。这一点很重要，因为心房颤动在普通人群中很常见，每年会导致大量中风以及心脏功能减弱或心力衰竭。我们预计我们将确定增加人对心房颤动的易感性的新机制，因此应该开发新的方法来预防其发生。