Exploring Mechanisms of Atrial Fibrillation through use of Transgenic Mouse Models

 描述（由申请人提供）：房颤是临床实践中观察到的最常见的持续性心律失常，估计影响约6%的65岁及以上的美国人。心房颤动使死亡风险增加一倍，占所有中风的15-20%。药物和射频消融/手术相对较低的疗效以及高复发率已经困扰了该领域数十年。房颤的深入实验室研究一直受到缺乏真正的小鼠模型的阻碍，该模型准确地再现了在人类中观察到的典型的自发性房颤发作和持续发作。尽管全身性和心脏疾病是房颤的易感因素，但最近的全基因组关联研究和K+通道、Na+通道和兰尼碱受体中相对罕见的突变体的鉴定表明，遗传易感性也可能是一个重要组成部分，突出了离子通道功能障碍在房颤发病机制中的作用。我们研究心肌细胞中信息性Na+通道突变体的新方法使转基因小鼠的发展成为可能，该转基因小鼠早在5-6周龄时就具有轻度-中度心房扩大、轻度左心室功能障碍以及频繁和持续的自发性阵发性心房颤动和室性心律失常的表型。这些小鼠表型模仿了功能获得性人类SCN 5A突变，这些突变与扩张型心肌病和肥大以及心律失常如长QT综合征、尖端扭转型室性心动过速和心房颤动有关。持续性和自发性的房性心律失常，一个相对不寻常的表型在小鼠中，使我们能够探索的机制，启动和维持心房颤动使用体内（遥测），离体（Langendorff灌注心脏的光学电压映射），和体外（细胞电生理学）技术。提出了两个特定的目的，旨在表征突变型SCN 5A表达引起的心房颤动的细胞电生理机制。所提出的实验旨在进一步开发和表征这种独特的心房颤动小鼠模型， 目标是识别和测试新疗法。

 DESCRIPTION (provided by applicant): Atrial fibrillation is the most frequently sustained arrhythmia observed in clinical practice, estimated to affect about six percent of Americans who are 65 years of age and older. Atrial fibrillation doubles the risk of death, and accounts for 15-20% percent of all strokes. The relatively low efficacy of pharmaceuticals and radiofrequency ablation/surgery, and high rates of recurrence have plagued the field for decades. In-depth laboratory studies of atrial fibrillation have been hindered by the lack of a bona fide mouse model that accurately recapitulates the typical spontaneous initiation and sustained episodes of atrial fibrillation observed in humans. Although systemic and cardiac disorders are predisposing contributors to atrial fibrillation, there is also likely an important component of genetic susceptibility, shown by recent genome-wide association studies and identification of relatively rare mutants in K+ channels, Na+ channels and ryanodine receptors, highlighting the role of ion channel dysfunction in the pathogenesis of atrial fibrillation. Our novel method of studying informative Na+ channel mutants in cardiomyocytes has enabled the development of a transgenic mouse with a phenotype of mild-moderate atrial enlargement, mild left ventricular dysfunction, and frequent and sustained episodes of spontaneous paroxysmal atrial fibrillation and ventricular arrhythmias as early as 5-6 weeks of age. These mice phenocopied gain-of-function human SCN5A mutations, which have been implicated in dilated cardiomyopathy and hypertrophy, and arrhythmias such as long QT syndrome, torsade de pointes and atrial fibrillation. The sustained and spontaneous nature of the atrial arrhythmias, a relatively unusual phenotype in mice, has enabled us to explore mechanisms of initiation and maintenance of atrial fibrillation using in vivo (telemetry), ex vivo (optical voltage mapping of Langendorff-perfused hearts), and in vitro (cellular electrophysiology) techniques. Two Specific Aims are proposed, designed to characterize the cellular electrophysiological mechanisms of atrial fibrillation caused by mutant SCN5A expression. The proposed experiments are designed to further develop and characterize this unique murine model of atrial fibrillation, with the ultimate goal of identifying and testing novel therapies.