Key result
Moderate-to-severe functional tricuspid regurgitation was associated with fibrosis activation in valve interstitial cells based on single-cell RNA sequencing of 84,102 cells from 10 patients.
Why the study?
Treatment of functional TR remains controversial, and characterizing tricuspid valve cellular composition and molecular alterations could advance mechanistic understanding and guide therapy.
Observational (n=10)
Single-cell transcriptomics of human tricuspid valves reveals that valve interstitial cells with fibrosis activation accumulate in functional tricuspid regurgitation, highlighting potential therapeutic targets like COMP-CD47 and FGF2-FGFR1 interactions.
Hypothesis-generating for fibrosis-targeted therapies in functional tricuspid regurgitation; leaves open whether modulating valve interstitial cells alters progression.
BACKGROUND: The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell type in valves with TR will advance our understanding of the mechanisms of TR and guide improvements in treatment. OBJECTIVES: The authors aimed to investigate the changes in cellular composition and gene expression patterns of cells in regurgitant tricuspid valves and shed light on the mechanisms of functional TR. METHODS: To improve our understanding of the pathogenesis of functional TR, we performed single-cell RNA sequencing of tricuspid valve from 10 patients, including 5 patients with moderate-to-severe functional TR and 5 nondiseased control subjects. Multiplexed fluorescence was used to detect the spatial distributions of valvular cell states and validated the cell-cell interaction. RESULTS: We assessed the transcriptional profiles of 84,102 cells and identified 6 major cell clusters, along with 25 cell subtypes, in the specimens. Valve interstitial cells (VICs) were the largest population. VICs and lymphoid cells exhibited more heterogeneity in TR patients. VICs exhibited higher transcriptional activity toward matrifibrocyte-like cells and myofibroblast-like cell differentiation, myeloid cells activated immune response, and lymphoid cells promoted fibrosis. In TR, the alternation of COMP-CD47 and FGF2-FGFR1 interaction may occur in TR specimens, which may serve as promising therapeutic targets for TR. CONCLUSIONS: Our single-cell atlas highlights the transcriptomic heterogeneity underlying the cell functions and interactions in human tricuspid valves and defines molecular and cellular perturbations in functional TR. We identified VIC clusters with fibrosis activation accumulated in TR valves.
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Zhao et al. (2025) conducted an observational in functional tricuspid regurgitation (n=10). Moderate-to-severe functional tricuspid regurgitation vs. Nondiseased control subjects was evaluated on Cellular composition and gene expression patterns (transcriptional profiles). Moderate-to-severe functional tricuspid regurgitation was associated with fibrosis activation in valve interstitial cells based on single-cell RNA sequencing of 84,102 cells from 10 patients.
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