TY - JOUR
T1 - Defining cardiac functional recovery in end-stage heart failure at single-cell resolution
AU - Amrute, Junedh M.
AU - Lai, Lulu
AU - Ma, Pan
AU - Koenig, Andrew L.
AU - Kamimoto, Kenji
AU - Bredemeyer, Andrea
AU - Shankar, Thirupura S.
AU - Kuppe, Christoph
AU - Kadyrov, Farid F.
AU - Schulte, Linda J.
AU - Stoutenburg, Dylan
AU - Kopecky, Benjamin
AU - Navankasattusas, Sutip
AU - Visker, Joseph
AU - Morris, Samantha A.
AU - Kramann, Rafael
AU - Leuschner, Florian
AU - Mann, Douglas L.
AU - Drakos, Stavros G.
AU - Lavine, Kory J.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160252226&partnerID=8YFLogxK
U2 - 10.1038/s44161-023-00260-8
DO - 10.1038/s44161-023-00260-8
M3 - Article
C2 - 37583573
AN - SCOPUS:85160252226
SN - 2731-0590
VL - 2
SP - 399
EP - 416
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 4
ER -