Defining cardiac functional recovery in end-stage heart failure at single-cell resolution

心力衰竭 下调和上调 运行x1 心功能曲线 转录组 生物 成纤维细胞 细胞 心脏病学 细胞生物学 医学 内科学 基因表达 体外 干细胞 生物化学 造血 基因
作者
Junedh M. Amrute,Lulu Lai,Pan Ma,Andrew L. Koenig,Kenji Kamimoto,Andrea L. Bredemeyer,Thirupura S. Shankar,Christoph Kuppe,Farid F. Kadyrov,Linda Schulte,Dylan Stoutenburg,Benjamin J. Kopecky,Sutip Navankasattusas,Joseph R. Visker,Samantha A. Morris,Rafael Kramann,Florian Leuschner,Douglas L. Mann,Stavros G. Drakos,Kory J. Lavine
出处
期刊:Nature Cardiovascular Research [Springer Nature]
卷期号:2 (4): 399-416 被引量:15
标识
DOI:10.1038/s44161-023-00260-8
摘要

Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts. Within these cell types, inflammatory signatures were negative predictors of recovery, and downregulation of RUNX1 was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. Cardiac recovery mediated by BET inhibition in mice led to decreased macrophage and fibroblast Runx1 expression and diminished chromatin accessibility within a Runx1 intronic peak and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery. Amrute, Lai et al. performed single-nucleus RNA sequencing and compared the cellular and transcriptomic features of hearts from non-diseased donors, from patients with heart failure who recovered systolic function after left ventricular assist device implantation and from patients who did not recover. The analyses identified cell-type-specific signatures of recovery and revealed the downregulation of RUNX1 expression in macrophages and fibroblasts as a predictor of recovery, as confirmed by in silico simulations and re-analysis of data from a mouse model of cardiac functional recovery.
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