Towards a greater understanding of Atrial Fibrillation: Proteomics and genomics of a common global cardiac rhythm disorder

心脏病是全球发病率和死亡率的主要原因，随着全球人口老龄化，其数量不断增加。房颤（AF）是世界上最常见的心律失常，影响全球总人口的1-2%，导致重大的公共卫生影响，特别是由于卒中和住院的风险增加。由蛋白质表达改变引起的心脏重构导致电、收缩和结构改变，导致患者心律改变，这在许多患者中可能是进行性的。房颤的严重程度从阵发性房颤（通常在48小时内）到长期持续性房颤（心律失常持续1年或更长时间，通常通过导管消融使用心律控制策略）到永久性房颤（当心律失常持续存在时）。在这个项目中，我们的目标是了解房颤多个亚型的差异，作为理解个体表现、疾病进展和衰老过程的一种手段。该项目将使用人类患者样本，并比较突发性、持续性和永久性房颤之间的蛋白质和遗传差异。由于已知房颤在衰老过程中严重程度不断提高，我们将进一步使用房颤动物模型来监测功能和结构随时间的变化。总之，我们的目标是确定导致房颤风险增加的分子、细胞和生理水平的变化。我们将使用高端蛋白质组学和基因组学来确定与疾病相关的途径和生物标志物。一旦鉴定出差异表达蛋白，我们将在体外建立的2D和3D心脏系统中进一步研究这些蛋白。导管消融是房颤患者恢复正常心律的常用治疗方法。该项目将进一步比较消融前和消融后的样本，以了解节律管理如何改变患者的蛋白质谱。

Heart disease is the leading cause of global morbidity and mortality with numbers continually increasing as the global population ages. Atrial fibrillation (AF) is the most common heart rhythm disorder in the world effecting between 1-2% of the general global population, leading to a major public health impact, especially due to increased risk of stroke and hospitalizations. Cardiac remodelling arising from altered protein expression results in electrical, contractile and structural changes leading to an altered heart rhythm in patients which can be progressive in a large number of patients. The severity of AF ranges from paroxysmal AF which is self-terminating (usually within 48 h) to longstanding persistent AF (where the arrhythmia has lasted for 1 year or more in which a rhythm control strategy is used normally via catheter ablation) through to permanent AF (when the presence of the arrhythmia is constant). In this project we aim to understand the differences in the multiple sub-types of AF as a means of understanding individual manifestations as well as progression of disease and the ageing process. This project will use human patient samples, and compare protein and genetic differences between paroxysmal, persistent and permanent AF. Since AF is known to progress in severity over the ageing process we will further use animal models of AF to monitor functional and structural changes over time. Taken together we aim to identify changes at the molecular, cellular and physiological levels that lead to an increased risk of AF. We will use high-end proteomics and genomics to identify pathways and biomarkers involved in disease. Once differentially expressed proteins have been identified we will investigate these further using in vitro 2D and 3D cardiac systems established within our group. Catheter ablation is a frequently used treatment method for the restoration of normal heart rhythm in AF patients. This project will further compare samples pre- and post-ablation to see how rhythm management alters the protein profile in patients.