Defining the TBX5-Dependent Gene Regulatory Networks of Atrial Fibrillation

摘要 心房颤动 (AF) 是最常诊断的心律失常，影响超过 3300 万人 世界各地的个人。 40 岁以上的美国人中四分之一将被诊断为 AF 他或她的一生。房颤占所有中风的四分之一，并且与风险增加相关 痴呆、心力衰竭和死亡的风险，即使是在接受最佳循证护理的患者中。尽管 AF 造成严重的医疗负担，但对其机制的了解有限 引起患者心律失常。因此，关于 AF 易感性的新的病理生理学见解是 对于指导改进治疗和预防策略以减少不可接受的负担至关重要 与 AF 相关的中风、死亡和住院治疗。 TBX5 通过以下方式与 AF 相关联： GWAS 和家族遗传。然而，TBX5 在成人心房中的具体作用尚未明确。 调查了。我们现在使用成人中 Tbx5 的条件删除生成令人信服的初步数据 使用他莫昔芬诱导型 Cre 重组酶的小鼠。这种在成年小鼠中进行条件删除的策略 绕过 TBX5 的开发要求并允许在正常开发的环境中研究 TBX5 成人的心。我们发现成熟心肌中 Tbx5 的缺失会导致可重复的、 在没有心脏病或任何结构异常的情况下发生自发性心房颤动。初步 去除 Tbx5 后心房中的基因表达分析揭示了与 AF，包括许多离子通道和最常涉及的转录因子 Pitx2 AF 易感位点。我们假设 TBX5 驱动成人心房中的基因网络，其中包括 PITX2 协调成人心脏中心房节律的维持。该提案将定义 成人去除 Tbx5 导致心房颤动的机制，并通过以下方式描述途径 其中 TBX5 并维持正常的心房节律。定义这些心房转录网络将允许 AF 风险预测和一级预防策略。

ABSTRACT Atrial fibrillation (AF) is the most commonly-diagnosed cardiac arrhythmia, affecting more than 33 million individuals throughout the world. One in four Americans above the age of 40 will be diagnosed with AF in his or her lifetime. AF accounts for one-fourth of all strokes and is also associated with an increased risk of dementia, heart failure, and death, even in patients receiving optimal evidence-based care. Despite the profound healthcare burden caused by AF, there is a limited understanding of the mechanisms that provoke the arrhythmia in patients. Hence, new pathophysiologic insights into AF susceptibility are essential to guide improved therapeutic and preventive strategies to reduce the unacceptable burden of stroke, death, and hospitalizations associated with AF. TBX5 has been associated with AF both through GWAS and familial inheritance. However, the role of TBX5 specifically in the adult atrium has not been investigated. We now generate compelling preliminary data using conditional deletion of Tbx5 in the adult mouse using a tamoxifen-inducible Cre recombinase. This strategy of conditional deletion in adult mice bypasses the developmental requirements of TBX5 and permits study of TBX5 in normally developed adult hearts. We found that deletion of Tbx5 in the mature myocardium leads to reproducible, spontaneous atrial fibrillation in the absence of heart disease or any structural abnormalities. Preliminary gene expression analysis in the atria after removal of Tbx5 reveals misregulation of many genes linked to AF, including a number of ion channels and the transcription factor Pitx2, the most frequently implicated AF susceptibility locus. We hypothesize that TBX5 drives a gene network in the adult atria which includes PITX2 and coordinates the maintenance of atrial rhythm in the adult heart. This proposal will define the mechanisms by which adult removal of Tbx5 results in atrial fibrillation, and delineate the pathways by which TBX5 and maintains normal atrial rhythm. Defining these atrial transcriptional networks will allow prediction of AF risk and a strategy for primary prevention.