Thrombospondin-1 and Thrombospondin-2 are associated with biatrial fibrotic remodeling in human valvular heart disease

Abstract

Purpose

Atrial fibrosis is a key structural substrate of atrial fibrillation and atrial cardiomyopathy. Thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) regulate TGF-β signaling and matrix organization, but their roles in human atrial remodeling remain incompletely understood. Therefore, this study aimed to compare atrial TSP-1 and TSP-2 expression in mitral and aortic valve disease and examine their associations with fibrosis, inflammation, and adhesion-related remodeling.

Methods

This observational cross-sectional study included 67 cardiac surgery patients: 30 with mitral valve disease, 23 with aortic valve disease, and 14 undergoing coronary artery bypass grafting without significant valvular disease. Left and right atrial tissues were examined using RT-qPCR, ELISA, histology, and immunofluorescence. Molecular assays used pooled tissue preparations. Systemic inflammation was evaluated using the neutrophil-to-lymphocyte ratio.

Results

TSP-1 and TSP-2 transcript levels were increased in both valve disease groups, alongside greater collagen deposition and increased inflammatory gene expression. Transcript changes were particularly marked in left atrial tissue from patients with mitral valve disease. TSP-1 protein was significantly increased in right atrial tissue from the mitral valve group, whereas TSP-2 protein did not differ significantly between groups. Cadherin transcript levels were also altered. The neutrophil-to-lymphocyte ratio was higher in both valve disease groups than in the surgical comparator group.

Conclusions

Atrial TSPs expression was associated with fibrotic and inflammatory remodeling in valvular heart disease. Differences between transcript and protein findings and the use of pooled preparations warrant cautious interpretation. These observational findings require validation in independent cohorts and do not establish causality.