Defining Cardiac Recovery at Single Cell Resolution
Open accessAbstract
Recovery of cardiac function is the ultimate goal of heart failure therapy. Unfortunately, cardiac recovery remains a rare and poorly understood phemomenon. Herein, we performed single nucleus RNA-sequencing (snRNA-seq) from non-diseased donors and heart failure patients. By comparing patients who recovered LV systolic function following LV assist device implantation to those who did not recover and donors, we defined the cellular and transcriptional landscape and predictors of cardiac recovery. We sequenced 40 hearts and recovered 185,881 nuclei with 13 distinct cell types. Using pseudobulk differential expression analysis to explicate cell specific signatures of cardiac recovery, we observed that recovered cardiomyocytes do not revert to a normal state, and instead, retain transcriptional signatures observed in heart failure. Macrophages and fibroblasts displayed the strongest signatures of recovery. While some evidence of reversion to a normal state was observed, many heart failure associated genes remained elevated and recovery signatures were predominately indicative of a biological state that was unique from donor and heart failure conditions. Acquisition of recovery states was associated with improved LV systolic function. Pro-inflammatory macrophages and inflammatory signaling in fibroblasts were identified as negative predictors of recovery. We identified downregulation of RUNX1 transcriptional activity in macrophages and fibroblasts as a central event associated with and predictive of cardiac recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of cardiac recovery. This prediction was corroborated in a mouse model of cardiac recovery mediated by BRD4 inhibition where we observed a decrease in macrophage and fibroblast Runx1 expression, diminished chromatin accessibility within peaks linked to the Runx1 locus, and acquisition of 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.
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Human cell atlases have provided new insights into the cellular landscape of heart failure and identified unexpected cell diversity within the stromal compartment.
“These human cell atlases have provided new insights into the cellular landscape of HF and identified unexpected cell diversity within the stromal compartment.”
From Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure (2022) · cites this paper as [28]
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- Authors
- Amrute, J. M., Lai, L., Ma, P., Koenig, A. L., Kamimoto, K., Bredemeyer, A., Shankar, T. S., Kuppe, C., Kadyrov, F. F., Schulte, L. J., Stoutenburg, D., Kopecky, B. J., Navankasattusas, S., Visker, J., Morris, S. A., Kramann, R., Leuschner, F., Mann, D. L., Drakos, S. G., & Lavine, K. J.
- Affiliations
- Washington University in St. Louis (US)
- University of Utah (US)
- RWTH Aachen University (DE)
- Erasmus MC (NL)
- University Hospital Heidelberg (DE)
- Corresponding author
- Lavine, Kory J.
- ORCID
- 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.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2022-09-13
- OpenAlex
- W4296130788
- Cited by
- 6
- References
- 61
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- American Heart Association (916955, 826325)
- Washington University in St. Louis
- Children's Discovery Institute (PM-LI-2019-829, CH-II-2015-462)
- Alvin J. Siteman Cancer Center (CA91842, #P30 CA91842)
- Fondation Leducq (20CVD02)
- National Institutes of Health (CA91842)
- National Heart, Lung, and Blood Institute (R01HL138466, R01HL151078, R01HL139714)
- National Cancer Institute (P30 CA 91842, CA91842, P30CA091842)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR073752)
- National Center for Research Resources (P30 CA91842)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Physical Sciences › Engineering › Biomedical Engineering › Mechanical Circulatory Support Devices
- Keywords
- cardiac function recovery, heart failure, left ventricular assist device, single-nucleus RNA sequencing, cardiomyocytes, macrophages, fibroblasts, RUNX1, inflammatory macrophages, chromatin accessibility, BRD4 inhibition, gene expression signatures, predictors of recovery
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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