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

Autor: Amrute JM; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.; These authors contributed equally: Junedh M. Amrute, Lulu Lai., Lai L; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.; These authors contributed equally: Junedh M. Amrute, Lulu Lai., Ma P; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Koenig AL; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Kamimoto K; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA., Bredemeyer A; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Shankar TS; Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health & School of Medicine, Salt Lake City, UT, USA., Kuppe C; Institute of Experimental Medicine and Systems Biology and Division of Nephrology, RWTH Aachen University, Aachen, Germany., Kadyrov FF; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Schulte LJ; Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA., Stoutenburg D; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Kopecky BJ; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Navankasattusas S; Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health & School of Medicine, Salt Lake City, UT, USA., Visker J; Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health & School of Medicine, Salt Lake City, UT, USA., Morris SA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA., Kramann R; Institute of Experimental Medicine and Systems Biology and Division of Nephrology, RWTH Aachen University, Aachen, Germany.; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands., Leuschner F; Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Heidelberg, Germany., Mann DL; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Drakos SG; Division of Cardiovascular Medicine & Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health & School of Medicine, Salt Lake City, UT, USA., Lavine KJ; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2023 Apr; Vol. 2 (4), pp. 399-416. Date of Electronic Publication: 2023 Apr 06.
DOI: 10.1038/s44161-023-00260-8
Abstrakt: 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.
Competing Interests: Competing interests The authors declare no competing interests.
Databáze: MEDLINE
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