Preamyloid Oligomers and Susceptibility to Atrial Fibrillation

描述（由申请人提供）：房颤（AF）是最常见的心律失常，导致大量发病率和死亡率。发生房颤的一个重要风险因素是年龄，其终生风险为1/6。随着美国人口老龄化，AF的发病率在流行比例中增加，目前可用的治疗通常无效。房颤的临床过程通常是进行性的，这是由于心房的电重构和结构重构以及快速刺激增加了心律失常的易感性。氧化应激和炎症在产生AF底物和促进这种重塑过程中起重要作用。最近，我们发现，心房细胞在培养中迅速刺激进行重塑非常类似于在人类AF中观察到的。重要的是，在起搏细胞的转录谱表现出惊人的一致性与体内观察到的变化。出乎意料的是，我们观察到保守的转录上调蛋白质参与淀粉样变性，一个过程与蛋白质错误折叠和沉积在多种神经退行性疾病，特别是阿尔茨海默氏病。大量证据表明，这些疾病中的毒性物质是可溶性淀粉样低聚物中间体，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，在快速起搏的心房细胞，与类似的结果在实验和人类AF，这些数据形成了一个强有力的理由拟议的研究。本提案的目的是检验心房类磷脂寡聚体与人类AF发展存在病理生理学联系的假设。在特定目标1中，将使用在多个中心的常规心脏手术期间获得的人心房样本来检查类磷脂寡聚体形成与年龄、术后AF风险和人类已确立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，我们将探讨有效的抗氧化剂/抗炎化合物，也被称为抑制可溶性低聚物的形成，对生成的心房类淀粉样低聚物在体外快速刺激和实验性AF。心房利钠肽（ANP）是已知的形成淀粉样纤维，它存在于孤立的心房淀粉样变性，一个过程中，随着人类的衰老而增加。最近，在ANP的突变与家族性AF的因果关系。在具体目标3，我们将确定这些ANP突变是否促进形成类淀粉低聚物作为一个潜在的机制，以增加AF的易感性。所提出的研究具有实质性意义，因为类磷脂寡聚体不仅可以提供氧化应激、衰老和AF之间的机制联系，而且还可以为治疗这种常见且难以治疗的心律失常提供新的治疗靶点。

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.