Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, USA.
Cardiovasc Res. 2021 Jun 16;117(7):1760-1775. doi: 10.1093/cvr/cvaa307.
Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programmes underlying cell type-specific atrial remodelling and AF progression.
We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue, and isolated cardiomyocytes (CMs) from control, intermediate (transition), and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful three-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression programme. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment.
Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial CMs, and genes related to neural function and cell proliferation.
心房颤动（AF）是一种进行性心律失常，会增加住院和不良心血管事件的风险。人们显然需要更具包容性和大规模的方法来了解导致 AF 的分子驱动因素，以及控制阵发性向持续性和永久性转变的基本机制。在这项研究中，我们旨在绘制 AF 的分子图谱，并找到导致细胞类型特异性心房重构和 AF 进展的不同分子程序。
我们使用长期、快节奏起搏诱导的 AF 绵羊模型，采集右心房和左心房组织，并从 AF 进展的对照、中间（过渡）和晚期时间点分离心肌细胞（CMs），进行转录组和蛋白质组谱分析。我们将所有这些信息层合并到一个有意义的三组件空间中，在该空间中我们探索了检测到的基因和蛋白质及其共同的表达模式。我们的数据驱动分析指出细胞外基质重塑、炎症、离子通道、肌原纤维结构、线粒体复合物、染色质重塑以及与神经功能相关的基因，以及细胞增殖的关键调节剂是 AF 进展的标志。最重要的是，我们证明这些变化发生在疾病的早期过渡阶段，但不在晚期阶段，并且左心房在其表达程序中比右心房经历更显著的变化。基因和蛋白质表达的动态变化模式复制了以前在绵羊和人类中证明的电和结构重塑，并揭示了可能与疾病治疗相关的新机制。
在大型动物模型中对 AF 进展的转录组和蛋白质组分析表明，早期阶段会发生重大变化，其中包括以前未描述的 CM 中线粒体增加、心房 CM 染色质变化以及与神经功能和细胞增殖相关的基因。
