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Cited by 27Cardiovascular Effects of ExerciseCardiac electrophysiology and arrhythmiasCardiomyopathy and Myosin Studies

Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy

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Fu, Mengxia, Hua, Xiumeng, Shu, Songren, Xu, Xinjie, Zhang, Hang, Peng, Zhiming, Mo, Han, Liu, Yanyun +8 more·2024·BMC Medicine
DOI 10.1186/s12916-023-03232-8PMC PMC10773142
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Abstract

Background: Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. Methods: Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2) mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. Results: Right ventricle of ARVC was enriched of CCL3 + proinflammatory macrophages and TNMD + fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3 + proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2 mut/mut mice (an ARVC mouse model). Conclusions: This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

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  • The cardiomyocyte-specific Dsg2mut/mut model recapitulates key ACM phenotypes including progressive ventricular dysfunction, cardiomyocyte loss, inflammatory cell infiltration, and fibrotic remodeling, supporting a primary role for cardiomyocyte injury in driving disease progression.

    “this model recapitulates key ACM phenotypes, including progressive ventricular dysfunction, cardiomyocyte loss, inflammatory cell infiltration, and fibrotic remodeling, supporting a primary role for cardiomyocyte injury in driving disease progression [63].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [63]

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  • Pharmacological inhibition of NLRP3 mitigated ventricular dilation and dysfunction in the cardiomyocyte-specific Dsg2mut/mut model.

    “pharmacological inhibition of NOD-like receptor protein 3 (NLRP3) mitigated ventricular dilation and dysfunction [63].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [63]

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Cited by

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Authors
Fu, M., Hua, X., Shu, S., Xu, X., Zhang, H., Peng, Z., Mo, H., Liu, Y., Chen, X., Yang, Y., Zhang, N., Wang, X., Liu, Z., Yue, G., Hu, S., & Song, J.
Affiliations
  • Capital Medical University (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
  • Hu, Shengshou
  • Song, Jiangping
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2024-01-08
Volume
22
Issue
1
Pages
11-11
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-023-03232-8
PMC
PMC10773142
OpenAlex
W4390655873
Cited by
27
References
8
Citations by year
2026: 9 · 2025: 13 · 2024: 5
FWCI
8.12
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82000225, 82125004)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
arrhythmogenic right ventricular cardiomyopathy, NLRP3 inflammasome, end-stage heart failure, right ventricular dilatation, inflammatory macrophages, cardiac fibroblasts, cardiac arrhythmias, therapeutic target, myocardial transcriptome, macrophage-fibroblast interaction
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Arrhythmias, Cardiac, Heart Failure, Humans, Sequence Analysis, RNA, Arrhythmogenic Right Ventricular Dysplasia, Mice, Genome-Wide Association Study

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