Valvular Leaflets Are Not Innocent Bystanders: Divergent Fibrotic Remodeling Accompanies Functional Mitral and Tricuspid Regurgitation.
Functional valve regurgitation (FVR) progression has traditionally been attributed to external anatomic alterations, without consideration of leaflet-intrinsic pathology. Emerging evidence now implicates valvular leaflets as active contributors rather than passive bystanders in FVR pathogenesis. Systematic investigations into leaflet-specific pathomechanisms remain absent for major FVR subtypes, particularly functional mitral regurgitation (FMR) and functional tricuspid regurgitation (FTR).
The association of FVR with clinical parameters was analyzed in a heart transplantation cohort. Comprehensive microscopic pathology evaluated fibrotic remodeling in mild, moderate, and severe FMR/FTR leaflets, validated in an independent bulk RNA sequencing cohort (FMR/FTR: n=41 each). Single-cell RNA sequencing was performed on 19 FVR leaflets (FMR: 3 mild/2 moderate/3 severe; FTR: 5 mild/3 moderate/3 severe). Subsequent analyses (cluster annotation, cellular proportions, trajectory inference, and cell-cell communication) explored cellular mechanisms of fibrotic remodeling in FVR, focusing on unique and shared changes between FMR and FTR. Histopathology and bulk transcriptomics validated single-cell RNA sequencing findings. Primary valvular endothelial cells and valvular interstitial cells from FVR patients underwent pharmacological intervention. A monocrotaline-induced rat pulmonary hypertension model established FTR, followed by pharmacological treatment to assess leaflet-directed therapy efficacy.
Fibrotic leaflet remodeling scores independently predicted FMR/FTR severity with high precision and significantly improved prediction beyond anatomic anomalies. Fibrotic remodeling showed divergent mechanisms between FMR and FTR. In FMR, suppressed retinoic acid metabolism drove antifibrotic-to-neutral valvular interstitial cell transition. In FTR, impaired IFN (interferon) signaling promoted antifibrotic-to-profibrotic valvular interstitial cell transdifferentiation, worsened by endothelial-to-mesenchymal transition-derived profibrotic valvular endothelial cells. Targeted PDK4 (pyruvate dehydrogenase kinase 4) upregulation or IFN signaling activation reduced FTR severity in vitro and in vivo.
Leaflet-specific organic fibrotic remodeling actively involves FVR beyond functional adaptation, with distinct fibrotic mechanisms in FMR versus FTR. PDK4 and IFN modulation demonstrate therapeutic potential for FTR.
The association of FVR with clinical parameters was analyzed in a heart transplantation cohort. Comprehensive microscopic pathology evaluated fibrotic remodeling in mild, moderate, and severe FMR/FTR leaflets, validated in an independent bulk RNA sequencing cohort (FMR/FTR: n=41 each). Single-cell RNA sequencing was performed on 19 FVR leaflets (FMR: 3 mild/2 moderate/3 severe; FTR: 5 mild/3 moderate/3 severe). Subsequent analyses (cluster annotation, cellular proportions, trajectory inference, and cell-cell communication) explored cellular mechanisms of fibrotic remodeling in FVR, focusing on unique and shared changes between FMR and FTR. Histopathology and bulk transcriptomics validated single-cell RNA sequencing findings. Primary valvular endothelial cells and valvular interstitial cells from FVR patients underwent pharmacological intervention. A monocrotaline-induced rat pulmonary hypertension model established FTR, followed by pharmacological treatment to assess leaflet-directed therapy efficacy.
Fibrotic leaflet remodeling scores independently predicted FMR/FTR severity with high precision and significantly improved prediction beyond anatomic anomalies. Fibrotic remodeling showed divergent mechanisms between FMR and FTR. In FMR, suppressed retinoic acid metabolism drove antifibrotic-to-neutral valvular interstitial cell transition. In FTR, impaired IFN (interferon) signaling promoted antifibrotic-to-profibrotic valvular interstitial cell transdifferentiation, worsened by endothelial-to-mesenchymal transition-derived profibrotic valvular endothelial cells. Targeted PDK4 (pyruvate dehydrogenase kinase 4) upregulation or IFN signaling activation reduced FTR severity in vitro and in vivo.
Leaflet-specific organic fibrotic remodeling actively involves FVR beyond functional adaptation, with distinct fibrotic mechanisms in FMR versus FTR. PDK4 and IFN modulation demonstrate therapeutic potential for FTR.
Authors
Shi Shi, Shu Shu, Chen Chen, Chen Chen, Wang Wang, Wang Wang, Wang Wang, Song Song, Hu Hu, Han Han, Song Song, Liu Liu
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