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

Junedh M. Amrute; Lulu Lai; Pan Ma; Andrew L. Koenig; Kenji Kamimoto; Andrea Bredemeyer; Thirupura S. Shankar; Christoph Kuppe; Farid F. Kadyrov; Linda J. Schulte; Dylan Stoutenburg; Benjamin J. Kopecky; Sutip Navankasattusas; Joseph Visker; Samantha A. Morris; Rafael Kramann; Florian Leuschner; Douglas L. Mann; Stavros G. Drakos; Kory J. Lavine

doi:10.1038/s44161-023-00260-8

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

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

Junedh M. Amrute, Lulu Lai, Pan Ma, Andrew L. Koenig, Kenji Kamimoto, Andrea Bredemeyer, Thirupura S. Shankar, Christoph Kuppe, Farid F. Kadyrov, Linda J. Schulte, …

NATURE CARDIOVASCULAR RESEARCH, Vol.2(4), pp.399-416

04/01/2023

DOI: 10.1038/s44161-023-00260-8

PMCID: PMC10426763

PMID: 37583573

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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. 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.

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Life Sciences & Biomedicine

Science & Technology

Details

Title: Subtitle: Defining cardiac functional recovery in end-stage heart failure at single-cell resolution
Creators: Junedh M. Amrute - Washington University in St. Louis
Lulu Lai - Washington University in St. Louis
Pan Ma - Washington University in St. Louis
Andrew L. Koenig - Washington University in St. Louis
Kenji Kamimoto - Washington University in St. Louis
Andrea Bredemeyer - Washington University in St. Louis
Thirupura S. Shankar - University of Utah
Christoph Kuppe - RWTH Aachen University
Farid F. Kadyrov - Washington University in St. Louis
Linda J. Schulte - Washington University in St. Louis
Dylan Stoutenburg - Washington University in St. Louis
Benjamin J. Kopecky - Washington University in St. Louis
Sutip Navankasattusas - University of Utah
Joseph Visker - University of Utah
Samantha A. Morris - Washington University in St. Louis
Rafael Kramann - Erasmus MC
Florian Leuschner - Heidelberg University
Douglas L. Mann - Washington University in St. Louis
Stavros G. Drakos - University of Utah
Kory J. Lavine - Washington University in St. Louis
Resource Type: Journal article
Publication Details: NATURE CARDIOVASCULAR RESEARCH, Vol.2(4), pp.399-416
DOI: 10.1038/s44161-023-00260-8
PMID: 37583573
PMCID: PMC10426763
NLM abbreviation: Nat Cardiovasc Res
ISSN: 2731-0590
eISSN: 2731-0590
Publisher: Springer Nature
Number of pages: 31
Grant note: 23POST1019351; P30 DK52574 / Washington University in St. Louis School of Medicine Medical Scientist Training Program NHLBI R01 grant P30 CA91842 / Foundation for Barnes-Jewish Hospital CDI-CORE-2015-505; CDI-CORE-2019-813 / Children's Discovery Institute of Washington University 3770 / American Heart Association Postdoctoral Fellowship; American Heart Association US Department of Veterans Affairs P30AR073752; R01 HL138466; R01 HL139714; R01 HL151078; R01 HL161185; R35 HL161185 / American Heart Association (American Heart Association, Inc.); American Heart Association 23POST1019351; 826325 / American Heart Association (AHA); American Heart Association 20CVD02; 1014782 / Washington University in St. Louis Rheumatic Diseases Research Resource-Based Center Grant (National Institutes of Health (NIH)); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; Office of the Administrator (NIH) Leducq Foundation Network; Leducq Foundation
Language: English
Date published: 04/01/2023
Academic Unit: Stead Family Department of Pediatrics
Record Identifier: 9985161355102771

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