Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy
Open accessAbstract
Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function 1,2 and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts 3,4, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGFβ1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.
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Existing snRNA-seq and scRNA-seq studies did not identify human cardiac fibroblast populations that drive fibrosis.
“However, they did not identify human cardiac fibroblast populations that drive fibrosis.”
From Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure (2022) · cites this paper as [20]
The ‘Activated fibroblasts in DCM and HCM’ section reports that the study identified a distinct activated cardiac fibroblast population nearly exclusive to cardiomyopathy patients, contrary to the claim that it did not identify such a population. The ‘Cardiac fibrosis assay’ section also tests genes from that population’s activation trajectory for effects on myofibroblast formation. These findings do not establish that the population drives fibrosis in patients, but they contradict the claim’s categorical statement that no relevant population was identified. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredExisting snRNA-seq studies of the human heart rely on nuclear RNA and lack cellular transcriptomic, epigenetic and proteomic profiling needed for a granular picture of immune and fibroblast populations in the failing heart.
“However, these studies rely on nuclear RNA information and lack cellular transcriptomic, epigenetic and proteomic profiling information necessary to obtain a granular picture of the precise immune and fibroblast populations that emerge in the failing human heart and collaborate to drive cardiac fibrosis.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [19]
The Methods describe single-nucleus RNA sequencing, supporting the claim that this study relies on nuclear RNA rather than integrated cellular transcriptomic, epigenetic and proteomic profiling. But the ‘Changes in cell sub-populations’ and ‘Activated fibroblasts in DCM and HCM’ sections identify macrophage sub-populations and a disease-associated activated fibroblast population. The paper therefore does not support the implication that its approach cannot provide a granular picture of those populations, or establish that the additional profiling is necessary to do so. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCultured human primary cardiac and dermal fibroblasts and immortalized cardiac fibroblasts were relatively poor models of human cardiac fibroblast diversity under resting or stimulated conditions.
“By contrast, cultured human primary cardiac and dermal fibroblasts and immortalized cardiac fibroblasts were relatively poor models of human cardiac fibroblast diversity under resting or stimulated (TGFβ (refs. 19,39,40), IL-1β (ref. 41)) conditions.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [19]
The Cardiac fibrosis assay and Methods sections (pages unavailable) describe stimulating cultured human cardiac fibroblasts with TGFβ1, supporting the TGFβ condition cited in the sentence. The paper does not compare cultured cardiac, dermal, and immortalized fibroblasts as models of human cardiac fibroblast diversity. Its Discussion instead says it is not yet known how well the cultured-cell transition reflects the trajectory inferred from single-nucleus data. (LLM, conf=0.82)
Experimental — accuracy not yet measuredNumerous studies have implicated a role for TGFβ signaling in maladaptive cardiac remodeling and scar formation in HF.
“While numerous studies have implicated a role for TGFβ signaling in maladaptive cardiac remodeling and scar formation in HF 20,33”
From Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure (2022) · cites this paper as [20]
The Cardiac fibrosis assay section (page unavailable) reports that TGFβ1 stimulated cardiac fibroblasts to become myofibroblasts and that disrupting TGFβ-signaling genes reduced this response. This supports a role in a fibrosis-related process, but the paper does not establish that TGFβ signaling causes maladaptive remodeling or scar formation in heart failure, nor does it substantiate the claim about numerous studies. (LLM, conf=0.82)
Experimental — accuracy not yet measuredNumerous single-nucleus RNA sequencing studies have investigated the healthy and failing human heart.
“Numerous single-nucleus RNA sequencing (snRNA-seq) studies have investigated the healthy and failing human heart18–22.”
From Targeting immune–fibroblast cell communication in heart failure (2024) · cites this paper as [19]
Numerous snRNA-seq and scRNA-seq studies have profiled the healthy human and failing human heart and observed expansion of immune cells and fibroblast diversification in the failing heart.
“Numerous single-nucleus (snRNA-seq) and single-cell RNA sequencing (scRNA-seq) studies have profiled the healthy human and failing human heart 19-23 and observed expansion of immune cells 21 and fibroblast diversification in the failing heart 20,23 .”
From Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure (2022) · cites this paper as [20]
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 [20]
Primary human cardiac fibroblasts, primary human dermal fibroblasts, and immortalized human cardiac fibroblasts were relatively poor models of human cardiac fibroblast diversity under resting or stimulated (TGFβ, IL-1β) conditions.
“In contrast, primary human cardiac fibroblasts, primary human dermal fibroblasts, and immortalized human cardiac fibroblasts were relatively poor models of human cardiac fibroblast diversity under resting or stimulated (TGFβ 20,33,34 , IL-1 β 35 ) conditions.”
From Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure (2022) · cites this paper as [20]
Fine-tuned Geneformer to distinguish cardiomyocytes from non-failing hearts (n=9) or hearts affected by hypertrophic (n=11) or dilated (n=9) cardiomyopathy with an overall out-of-sample accuracy of 90%.
“First, we fine-tuned Geneformer to distinguish cardiomyocytes35 from non-failing hearts (n=9) or hearts affected by hypertrophic (n=11) or dilated (n=9) cardiomyopathy with an overall out-of-sample accuracy of 90% (Fig. 6b, Extended Data Fig. 10a).”
From Transfer learning enables predictions in network biology (2023) · cites this paper as [35]
Cardiomyocytes are very large cells that generate significantly more RNA-Seq reads than other cell types in the heart.
“An example of this issue could arise for cardiomyocytes, which are very large cells that generate a significantly greater number of RNA-Seq reads than other cell types in the heart [44, 45].”
From Benchmarking of computational demultiplexing methods for single-nucleus RNA sequencing data (2025) · cites this paper as [44]
The Expression profiles section reports sequencing cardiomyocyte nuclei alongside other heart-cell nuclei, and Methods > Single nuclei RNA-sequencing processing discusses read-quality measures. Neither passage, nor searches for cardiomyocyte size and reads per cell, establishes that cardiomyocytes are larger or generate significantly more RNA-seq reads than other heart-cell types. No page numbers are available in our copy. (LLM, conf=0.72)
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Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy
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From Cell to Gene: Deciphering the Mechanism of Heart Failure With Single‐Cell Sequencing
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- Authors
- Chaffin, M., Papangeli, I., Simonson, B., Akkad, A.-D., Hill, M. C., Arduini, A., Fleming, S. J., Melanson, M., Hayat, S., Kost-Alimova, M., Atwa, O., Ye, J., Bedi, K. C., Nahrendorf, M., Kaushik, V. K., Stegmann, C. M., Margulies, K. B., Tucker, N. R., & Ellinor, P. T.
- Affiliations
- Broad Institute (US)
- University of Pennsylvania (US)
- Massachusetts General Hospital (US)
- Masonic Medical Research Laboratory (US)
- Corresponding author
- Ellinor, Patrick T.
- ORCID
- Venue
- Nature
- Published
- 2022-06-22
- Volume
- 608
- Issue
- 7921
- Pages
- 174-180
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC12591363
- OpenAlex
- W4283257569
- Cited by
- 418
- References
- 61
- Citations by year
- 2026: 110 · 2025: 120 · 2024: 100 · 2023: 67 · 2022: 19 · 2021: 1 · 2019: 1
- FWCI
- 54.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Heart Association
- National Institutes of Health (1s10od026839-01)
- National Heart, Lung, and Blood Institute (K01HL140187, R01HL128914, R01HL105993, K24HL105780, R01HL092577, T32HL007208)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- dilated cardiomyopathy, hypertrophic cardiomyopathy, heart failure, single-nucleus RNA sequencing, cardiac fibroblasts, myofibroblast differentiation, myocardial fibrosis, TGF-β1 signaling, CRISPR knockout screen, cardiac transcriptome, left ventricle, biomarkers, therapeutic target
- MeSH terms
- RNA-Seq, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Cell Nucleus, Cells, Cultured, Heart Failure, Heart Ventricles, Humans, Myocardium, Transcription, Genetic, Case-Control Studies, Gene Expression Profiling, Transforming Growth Factor beta1, Gene Knockout Techniques, Myofibroblasts, Single-Cell Analysis, CRISPR-Cas Systems
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