Amrute Junedh M, Lai Lulu, Ma Pan, Koenig Andrew L, Kamimoto Kenji, Bredemeyer Andrea, Shankar Thirupura S, Kuppe Christoph, Kadyrov Farid F, Schulte Linda J, Stoutenburg Dylan, Kopecky Benjamin J, Navankasattusas Sutip, Visker Joseph, Morris Samantha A, Kramann Rafael, Leuschner Florian, Mann Douglas L, Drakos Stavros G, Lavine Kory J
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
These authors contributed equally: Junedh M. Amrute, Lulu Lai.
Nat Cardiovasc Res. 2023 Apr;2(4):399-416. doi: 10.1038/s44161-023-00260-8. Epub 2023 Apr 6.
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.
心脏功能的恢复是心力衰竭治疗的圣杯，但很少能观察到，且仍知之甚少。在本研究中，我们对接受左心室辅助装置植入后左心室收缩功能恢复的心力衰竭患者、未恢复的患者以及非患病供体进行了单核RNA测序。我们确定了恢复的细胞特异性转录特征，最显著的是在巨噬细胞和成纤维细胞中。在这些细胞类型中，炎症特征是恢复的负预测因子，而RUNX1的下调与恢复相关。在巨噬细胞和成纤维细胞中对RUNX1进行计算机模拟扰动重现了恢复的转录状态。小鼠中由BET抑制介导的心脏恢复导致巨噬细胞和成纤维细胞Runx1表达降低，Runx1内含子峰内的染色质可及性减弱，并获得人类恢复特征。这些发现表明心脏恢复是一种独特的生物学状态，并确定RUNX1是促进心脏恢复的一个可能的治疗靶点。
