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Cited by 18Cardiovascular Effects of ExerciseCardiomyopathy and Myosin StudiesCardiac Fibrosis and Remodeling

Dominant Myocardial Fibrosis and Complex Immune Microenvironment Jointly Shape the Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy

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Lu, Wenzhao, Li, Yao, Dai, Yan, Chen, Keping·2022·Frontiers in Cardiovascular Medicine
DOI 10.3389/fcvm.2022.900810PMC PMC9278650
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Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable life-threatening myocardial disease characterized by ventricular arrhythmias and sudden cardiac death. Few studies used RNA-sequencing (RNA-seq) technology to analyze gene expression profiles, hub genes, dominant pathogenic processes, immune microenvironment in ARVC. This study aimed to explore these questions via integrated bioinformatics analysis. Methods: RNA-sequencing datasets of GSE107475, GSE107311, GSE107156, and GSE107125 were obtained from the Gene Expression Omnibus database, including right and left ventricular myocardium from ARVC patients and normal controls. Weighted gene co-expression network analysis identified the ARVC hub modules and genes. Functional enrichment and protein-protein interaction analysis were performed by Metascape and STRING. Single-sample gene-set enrichment analysis (ssGSEA) was applied to assess immune cell infiltration. Transcription regulator (TF) analysis was performed by TRRUST. Results: Three ARVC hub modules with 25 hub genes were identified. Functional enrichment analysis of the hub genes indicated that myocardial fibrosis was the dominant pathogenic process. Higher myocardial fibrosis activity existed in ARVC than in normal controls. A complex immune microenvironment was discovered that type 2 T helper cell, type 1 T helper cell, regulatory T cell, plasmacytoid dendritic cell, neutrophil, mast cell, central memory CD4 T cell, macrophage, CD56dim natural killer cell, myeloid-derived suppressor cell, memory B cell, natural killer T cell, and activated CD8 T cell were highly infiltrated in ARVC myocardium. The immune-related hub module was enriched in immune processes and inflammatory disease pathways, with hub genes including CD74, HLA-DRA, ITGAM, CTSS, CYBB, and IRF8. A positive linear correlation existed between immune cell infiltration and fibrosis activity in ARVC. NFKB1 and RELA were the shared TFs of ARVC hub genes and immune-related hub module genes, indicating the critical role of NFκB signaling in both mechanisms. Finally, the potential lncRNA–miRNA–mRNA interaction network for ARVC hub genes was constructed. Conclusion: Myocardial fibrosis is the dominant pathogenic process in end-stage ARVC patients. A complex immune microenvironment exists in the diseased myocardium of ARVC, in which T cell subsets are the primary category. A tight relationship exists between myocardial fibrosis activity and immune cell infiltration. NFκB signaling pathway possibly contributes to both mechanisms.

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  • The adaptive immune system plays a critical role in the cellular microenvironment of ACM hearts.

    “The adaptive immune system also plays a critical role in the cellular microenvironment that composes the hearts of ACM subjects.”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [75]

  • Systems-level transcriptomic analyses of end-stage human ACM hearts identified a complex landscape enriched with Th1, Th2, and Treg populations.

    “Systems-level transcriptomic analyses of end-stage human ACM hearts identified a complex landscape enriched with specific T-cell subsets, including Th1, Th2, and Treg populations.”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [75]

  • A significant positive linear correlation exists between the degree of total immune cell infiltration and extracellular matrix organization enrichment score in human ACM hearts.

    “Notably, a significant positive linear correlation existed between the degree of total immune cell infiltration and extracellular matrix organization enrichment score, highlighting the interdependence of immune activation and fibrotic remodeling in disease progression [75].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [75]

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Cited by

Sorted by citations

Authors
Lu, W., Li, Y., Dai, Y., & Chen, K.
Affiliations
Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
Chen, Keping
ORCID
Venue
Frontiers in Cardiovascular Medicine
Publisher
Frontiers Media SA
Published
2022-06-29
Volume
9
Pages
900810-900810
ISSN
2297-055X (ISSN-L)
DOI
10.3389/fcvm.2022.900810
PMC
PMC9278650
OpenAlex
W4283699548
Cited by
18
References
2
Citations by year
2026: 2 · 2025: 7 · 2024: 6 · 2023: 1 · 2022: 1 · 2021: 1
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
arrhythmogenic right ventricular cardiomyopathy, myocardial fibrosis, tumor immune microenvironment, immune cell infiltration, T cell subsets, NF-κB signaling, transcription factors, hub genes, pathogenesis

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