The Leon H. Charney Division of Cardiology (N.Y., J.X., D.N., D.S., X.L., E.O., A.S., D.S.P.), New York University Grossman School of Medicine.
NYU Applied Bioinformatics Labs (A.K.-J.), New York University Grossman School of Medicine.
Circulation. 2021 Feb 23;143(8):805-820. doi: 10.1161/CIRCULATIONAHA.120.048121. Epub 2020 Nov 23.
Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.
We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of cardiomyocyte-selective knockout ().
Using the Cleveland Clinic biobank of human LA specimens, we found that expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between expression level and , , , and levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of , , , and and upregulation of profibrotic gene programming, which includes , and numerous collagen genes. mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with showed reciprocal changes.
ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.
心力衰竭导致的中心腔内压力升高会引起左心房（LA）的电重构和结构重构，进而导致心房心肌病和心律失常。在心脏压力超负荷期间驱动心房重构的潜在分子途径尚未明确。本研究的目的是描述在人类和小鼠模型中心脏压力超负荷期间 ETv1（ETS 易位变体 1）信号轴在左心房中的反应，并探讨 ETv1 在心房电重构和结构重构中的作用。
我们对 265 例接受心脏手术的患者的左心房样本进行了基因表达谱分析。比较了两种心脏压力超负荷模型（升主动脉缩窄带和血管紧张素 II 输注）和心肌细胞特异性敲除（）的基因表达谱。
利用克利夫兰诊所的人类左心房标本生物库，我们发现，在射血分数降低的患者中表达减少。与作为 NRG1（神经调节蛋白 1）信号通路的重要介质和快速传导基因编程的激活剂的作用一致，我们在人类左心房样本中发现表达水平与、、和之间存在直接相关性。与心力衰竭患者相似，我们发现 ETv1 在左心房的 RNA 和蛋白水平在小鼠压力超负荷模型中均下调。升主动脉缩窄和血管紧张素 II 处理小鼠的左心房 RNA 测序数据集的比较分析显示出高度的 Pearson 相关性，反映了左心房经历电重构和结构重构的高度有序过程。心脏压力超负荷导致、、、和上调，以及促纤维化基因编程上调，包括、和许多胶原基因。ETv1 敲除小鼠表现出心房传导疾病和心律失常。相应地，来自 ETv1 敲除小鼠的左心房表现出快速传导基因下调和促纤维化基因编程上调，而分析来自转导 ETv1 的新生大鼠心室肌细胞的功能获得性 ETv1 RNA 测序数据集显示出相反的变化。
ETv1 在心脏压力超负荷期间在左心房中下调，导致电重构和结构重构。
