A MODEL OF ATRIAL FIBRILATION TRIGGERS

描述（由申请人提供）：心房颤动（AF）是最常见的需要医疗干预的心律失常，仅在美国就影响200万人，每年花费超过60亿美元。AF导致中风风险增加3-5倍，死亡风险增加1.9倍。目前的治疗是不完全有效的，因为引发AF的机制知之甚少。最近的证据表明，肺静脉（PV）的异常电活动启动某些类型的AF。最近，我们确定了一个以前未被识别的细胞群在成年小鼠，仅限于肺静脉和部分心房。这些细胞表达黑素细胞标记物，包括多巴色素互变酶（Dct），并且是电兴奋的，产生类似于心房肌细胞中记录的动作电位。我们将这些细胞称为“心脏黑素细胞样细胞”（CMLC）。在缺乏Dct蛋白的小鼠（Dct-/-）中进行的实验显示，与对照Dct同窝小鼠相比，自发性和诱导性房性心律失常增加。重要的是，尽管Dct-/-心脏结构正常，Dct-/-小鼠的心房有效不应期与Dct小鼠相似，但Dct-/- CMLC动作电位延长。此外，早期后去极化（埃兹）在Dct-/-CMLC中普遍存在，但在Dct-/-心房肌细胞中不存在，这表明CMLC在Dct-/-动物中明显增加的心肌发生中起关键作用。本提案中包含的实验旨在：1：表征CMLCs中动作电位复极化的离子电导。2：确定Dct-/-CMLC中动作电位延长的离子决定因素。对CMLCs在调节心脏兴奋性中的作用的深入了解可能最终导致可能导致开发新的治疗性AF治疗策略的见解。 公共卫生相关性：该项目将建立在以前描述房性心律失常动物模型的工作基础上。进一步的工作预计将导致确定潜在的新药物靶点，用于房颤治疗。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia requiring medical intervention, affecting 2 million people in the United States alone and costing over $6 billion dollars annually. AF results in a 3-5 fold increased stroke risk and a 1.9 fold increased risk of death. Current therapies are incompletely effective, because mechanisms initiating AF are poorly understood. Recent evidence demonstrates abnormal electrical activity from pulmonary veins (PV) initiates some types of AF. Recently, we identified a previously unrecognized cell population in the adult mouse that is confined to the pulmonary veins and portions of the atria. These cells express melanocyte markers, including Dopachrome Tautomerase (Dct), and are electrically excitable, generating action potentials that resemble those recorded in atrial myocytes. We refer to these cells as "cardiac melanocyte-like cells" (CMLCs). Experiments in mice (Dct-/-) lacking the Dct protein, show increased spontaneous and induced atrial arrhythmia when compared to control Dct littermates. Importantly, although Dct-/- hearts are structurally normal and Dct-/- mice have atrial effective refractory periods similar to Dct mice, Dct-/- CMLC action potentials are prolonged. Furthermore, early after-depolarizations (EADs) are prevalent in Dct-/- CMLCs, but not in Dct-/- atrial myocytes, suggesting a critical role for CMLCs in the increased arrhythmogenesis evident in Dct-/- animals. Experiments contained in this proposal are designed to: 1: Characterize the ionic conductances underlying action potential repolarization in CMLCs. 2: Identify the ionic determinants of action potential prolongation in Dct-/- CMLCs. Insights into the roles of CMLCs in regulating cardiac excitability may ultimately result in insights that could lead to the development of novel therapeutic AF treatment strategies. PUBLIC HEALTH RELEVANCE: This project will build upon previous work describing an animal model of atrial arrhythmias. Further work is expected to result in identifying potential new drug targets to for atrial fibrillation treatment.