Exploring Mechanisms of Atrial Fibrillation through use of Transgenic Mouse Models

 描述(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。房颤使死亡风险增加一倍，占所有中风的15%-20%。药物和射频消融/手术的相对较低的疗效和较高的复发率几十年来一直困扰着该领域。由于缺乏一个真正的小鼠模型来准确概括在人类中观察到的典型的自发性和持续性的房颤发作，阻碍了对房颤的深入实验室研究。尽管全身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ryanodine受体上相对罕见的突变的发现表明，也可能是遗传易感性的重要组成部分，突显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Na+通道信息突变的新方法使转基因小鼠得以发展，其表型为轻-中度心房扩大，轻度左心功能障碍，以及早在5-6周龄时频繁和持续的自发性阵发性心房颤动和室性心律失常。这些小鼠发现了人类SCN5A的功能获得突变，这种突变与扩张型心肌病和肥大以及长QT综合征、尖端扭结和心房颤动等心律失常有关。房性心律失常是一种在小鼠中相对不常见的表型，其持续和自发的性质使我们能够使用体内(遥测)、体外(朗宁多夫灌流心脏的光学电压标测)和体外(细胞电生理学)技术来探索房颤的启动和维持机制。提出了两个特定的目标，旨在表征由突变的SCN5A表达引起的心房颤动的细胞电生理机制。拟议的实验旨在进一步开发和表征这种独特的房颤小鼠模型，最终 确定和测试新疗法的目标。

 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.