Role of Endothelin-1 signaling in the development and progression of atrial fibrillation

摘要房颤是最常见的持续性心律失常。它与重要的 发病率和死亡率，是中风的主要原因。由于年龄是房颤的主要危险因素，这种心律失常是 成为一种流行病，造成重大的社会经济负担。不幸的是，目前治疗房颤的方法是 次优：药物治疗和导管消融有50%的疗效，特别是对持续性房颤。一个 更好地了解房颤的分子机制将是开发新的治疗方法的关键。 房颤是一种多因素疾病，慢性的侮辱会导致心肌的进行性改变。 电气、结构和自主神经重塑。内皮功能障碍是房颤大多数危险因素的标志 包括心力衰竭、高血压和糖尿病。虽然多项研究表明 内皮功能障碍与房颤之间的因果关系尚不清楚。Pfenniger博士建议研究 血管内皮细胞功能障碍，特别是其主要效应因子内皮素-1在房颤中的作用 与房颤相关的大型动物模型，以及利用具有高翻译潜力的新型基因治疗工具。 这项建议旨在首先描述内皮功能障碍之间的时间和空间关系 和房颤，特别关注从阵发性房颤到持续性房颤的过渡。此外，这项工作将旨在 为了确定内皮素-1通过促进自主神经而产生房颤底物的机制， 电性和结构性的心房重构。该提案的目标与NHLBI确定的目标密切一致 战略视野，调查新发现的对发病和死亡具有重要意义的病理生物学机制 心、肺、血液和睡眠(HLBS)健康的进展。这一职业发展奖将支持Dr。 芬尼格转变为一名独立的内科医生兼科学家。Pfenniger博士目前是哈佛大学的助理教授 西北大学，在KL2指导职业发展奖和AHA职业生涯的支持下 发展奖。芬尼格博士将在范伯格心血管和肾脏研究中心开展这项工作 在Rishi Arora博士的主要指导下，在西北大学的研究所。作为一名内科科学家 电生理学方面，芬尼格博士将独特地受益于由阿罗拉博士领导的指导团队的支持， 国际公认的内科科学家，具有基础、翻译和临床方面的专长 电生理学，拥有房颤大型动物模型方面的专业知识。导师与 独特的专业知识-EC耦合(Wasserstrom博士)、高通量细胞电生理学(George博士)、 血管生物学(沃恩博士)、转化性房颤研究(帕斯曼博士)、高级心血管成像 (Lee和Shah博士)和心血管遗传学(Roy-Puckelwartz博士)将使Pfenniger博士在她的基础上再接再厉 目前的技能，并帮助她在心律紊乱领域开拓自己的利基市场。接近尾声的时候 获奖期内，Pfenniger博士将申请NIH R01奖项，利用这项提案的结果制定 进一步研究内皮功能障碍在房颤中的作用的独立研究计划。

SUMMARY Atrial fibrillation (AF) is the most common sustained arrhythmia. It is associated with significant morbidity and mortality, being a leading cause of stroke. As age is a major risk factor for AF, this arrhythmia is becoming an epidemic, with significant socioeconomic burden. Unfortunately, current therapies for AF are suboptimal: pharmacologic therapies and catheter ablation have <50% efficacy, particularly in persistent AF. A better understanding of the molecular mechanisms of AF will be crucial for the development of new therapies. AF is a multifactorial disease, with chronic insults leading to progressive changes in the myocardium with electrical, structural and autonomic remodeling. Endothelial dysfunction is a hallmark of most risk factors for AF including heart failure, hypertension and diabetes. While multiple studies showed an association between endothelial dysfunction and AF, the causal relationship remains unknown. Dr Pfenniger proposes to investigate the role of endothelial dysfunction, and specifically of its major effector Endothelin-1, in AF using two clinically relevant large animal models of AF, and harnessing novel gene therapy tools with high translational potential. This proposal aims to first characterize the temporal and spatial relationship between endothelial dysfunction and AF, with a particular focus on the transition from paroxysmal to persistent AF. In addition, this work will aim to determine the mechanisms by which Endothelin-1 creates an AF substrate by promoting autonomic, electrical and structural atrial remodeling. The objective of this proposal aligns closely with NHLBI's identified strategic vision to investigate newly discovered pathobiological mechanisms important to the onset and progression of heart, lung, blood, and sleep (HLBS) health. This Career Development Award will support Dr. Pfenniger's transition to an independent physician-scientist. Dr. Pfenniger is currently an Assistant Professor at Northwestern University, with the support of a KL2 Mentored Career Development Award and an AHA Career Development Award. Dr. Pfenniger will carry out this work at the Feinberg Cardiovascular and Renal Research Institute at Northwestern University under the primary mentorship of Dr. Rishi Arora. As a physician-scientist in electrophysiology, Dr. Pfenniger will uniquely benefit from the support of her mentoring team led by Dr. Arora, an internationally recognized physician-scientist with specialization in basic, translational and clinical electrophysiology, who possesses expertise in large animal models of AF. The combination of mentors with distinct expertise – EC coupling (Dr. Wasserstrom), high-throughput cellular electrophysiology (Dr. George), vascular biology (Dr. Vaughan), translational AF research (Dr. Passman), advanced cardiovascular imaging (Drs. Lee and Shah), and cardiovascular genetics (Dr. Roy-Puckelwartz) will allow Dr. Pfenniger to build on her current skills and help her carve out her own niche in the field of heart rhythm disorders. Near the end of the award period, Dr. Pfenniger will apply for a NIH R01 award, using the results of this proposal to develop an independent research program to further study the role of endothelial dysfunction in AF.