Preamyloid Oligomers and Susceptibility to Atrial Fibrillation

描述(申请人提供)：房颤(房颤)是最常见的心律失常，导致相当大的发病率和死亡率。发生房颤的一个重要风险因素是年龄，这种情况的终生风险为1/6。随着美国人口的老龄化，房颤的发病率正在以流行的比例增加，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构以及快速刺激增加了心律失常的易感性。氧化应激和炎症在房颤底物的产生和促进这一重塑过程中起着重要作用。最近，我们发现在培养中快速刺激的心房细胞经历了与人类房颤非常相似的重塑。重要的是，在有节奏的细胞中的转录图谱显示出与活体中看到的变化惊人的一致性。出人意料的是，我们观察到与淀粉样变性有关的蛋白质中保守的转录上调，这一过程与多种神经退行性疾病中的蛋白质错误折叠和沉积有关，特别是阿尔茨海默病。大量证据表明，这些疾病中的有毒物质是可溶性前叶样低聚物中间体，而不是成熟的纤维蛋白，淀粉样阳性沉积。事实上，我们的初步数据显示，在快起搏的心房细胞中，前叶样低聚物显著积累，在实验性和人类房颤中的结果相似。综上所述，这些数据构成了拟议研究的强有力的理由。这项建议的目的是验证这一假说，即心房前叶低聚物在病理生理学上与人类房颤的发生有关。在具体目标1中，在多个中心的常规心脏手术中获得的人的心房样本将被用来检测前叶样寡聚体的形成与年龄、术后房颤的风险以及人类已建立的房颤的关系。氧化应激指标也将在这些样本中进行调查。在具体目标2中，我们将探索有效的抗氧化剂/抗炎化合物在体外和实验性房颤快速刺激下对心房前叶低聚物生成的影响，这些化合物也被认为可以抑制可溶性寡聚体的形成。已知心房利钠肽(ANP)可形成淀粉样纤维，它存在于孤立性心房淀粉样变性中，这一过程在人类中随着年龄的增长而增加。最近，ANP基因突变与家族性房颤有因果关系。在特定的目标3中，我们将确定这些ANP突变是否促进前叶样低聚物的形成，作为增加房颤易感性的潜在机制。所提出的研究具有重要意义，因为前叶低聚物不仅可能在氧化应激、衰老和房颤之间提供机制联系，而且它们还可能为这种常见且难以治疗的心律失常的治疗提供一个新的治疗靶点。

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.