Abstract
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.
| Original language | English |
|---|---|
| Number of pages | 44 |
| Journal | Nature Cardiovascular Research |
| Volume | 2 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 6 Apr 2023 |
Bibliographical note
Funding Information:K.L. is supported by the Washington University in St. Louis Rheumatic Diseases Research Resource-Based Center Grant (National Institutes of Health (NIH) P30AR073752, NIH R01 HL138466, R01 HL139714, R01 HL151078, R01 HL161185 and R35 HL161185); the Leducq Foundation Network (20CVD02); the Burroughs Welcome Fund (1014782); the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CH-II-2015-462, CH-II-2017-628 and PM-LI-2019-829); the Foundation of Barnes-Jewish Hospital (8038-88); and generous gifts from Washington University School of Medicine. S.D. is supported by the American Heart Association Heart Failure Strategically Focused Research Network (grant 16SFRN29020000); National Heart, Lung, and Blood Institute (NHLBI) RO1 grant HL135121, NHLBI RO1 grant HL132067, NHLBI R01 grant HL156667 and NHLBI R01 grant HL151924; Merit Review Award I01 CX002291, US Department of Veterans Affairs; and Nora Eccles Treadwell Foundation grants. J.M.A. is supported by an American Heart Association Predoctoral Fellowship (826325) and the Washington University in St. Louis School of Medicine Medical Scientist Training Program. P.M. is supported by an American Heart Association Postdoctoral Fellowship (916955). T.S. is supported by an American Heart Association Postdoctoral Fellowship (23POST1019351). Figures , and were created with BioRender. Histology was performed in the Digestive Diseases Research Core Centers Advanced Imaging and Tissue Analysis Core, supported by grant P30 DK52574. Imaging was performed in the Washington University Center for Cellular Imaging, which is funded, in part, by the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770). We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. The center is partially supported by National Cancer Institute Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center. This publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH. The authors are grateful to the donor families for their generosity, and DonorConnect ( https://www.donorconnect.life/ ), Salt Lake City, Utah, for facilitating the work of our research team members acquiring myocardial tissue in the operating rooms of several hospitals in Utah and several other states. The authors are grateful to the University of Utah cardiothoracic surgery team for the invaluable help acquiring the myocardial tissue from chronic heart failure patients.
Funding Information:
K.L. is supported by the Washington University in St. Louis Rheumatic Diseases Research Resource-Based Center Grant (National Institutes of Health (NIH) P30AR073752, NIH R01 HL138466, R01 HL139714, R01 HL151078, R01 HL161185 and R35 HL161185); the Leducq Foundation Network (20CVD02); the Burroughs Welcome Fund (1014782); the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CH-II-2015-462, CH-II-2017-628 and PM-LI-2019-829); the Foundation of Barnes-Jewish Hospital (8038-88); and generous gifts from Washington University School of Medicine. S.D. is supported by the American Heart Association Heart Failure Strategically Focused Research Network (grant 16SFRN29020000); National Heart, Lung, and Blood Institute (NHLBI) RO1 grant HL135121, NHLBI RO1 grant HL132067, NHLBI R01 grant HL156667 and NHLBI R01 grant HL151924; Merit Review Award I01 CX002291, US Department of Veterans Affairs; and Nora Eccles Treadwell Foundation grants. J.M.A. is supported by an American Heart Association Predoctoral Fellowship (826325) and the Washington University in St. Louis School of Medicine Medical Scientist Training Program. P.M. is supported by an American Heart Association Postdoctoral Fellowship (916955). T.S. is supported by an American Heart Association Postdoctoral Fellowship (23POST1019351). Figures 1a , 2d and 6c,j were created with BioRender. Histology was performed in the Digestive Diseases Research Core Centers Advanced Imaging and Tissue Analysis Core, supported by grant P30 DK52574. Imaging was performed in the Washington University Center for Cellular Imaging, which is funded, in part, by the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770). We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. The center is partially supported by National Cancer Institute Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center. This publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH. The authors are grateful to the donor families for their generosity, and DonorConnect (https://www.donorconnect.life/), Salt Lake City, Utah, for facilitating the work of our research team members acquiring myocardial tissue in the operating rooms of several hospitals in Utah and several other states. The authors are grateful to the University of Utah cardiothoracic surgery team for the invaluable help acquiring the myocardial tissue from chronic heart failure patients.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
