Tricuspid valve leaflet remodeling in sheep with biventricular heart failure: A comparison between leaflets

Tricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to different in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. Diseased animals exhibited significantly larger septal and anterior leaflets, thicker anterior and posterior leaflets, and stiffer anterior leaflets. Additionally, the septal leaflet's anisotropy index significantly decreased. Also, the septal and anterior leaflets showed increased collagen fiber dispersion near the atrial surface. As for remodeling markers, alpha-smooth muscle actin (αSMA), Ki67, matrix-metalloprotease 13 (MMP13), and transforming growth factor beta-1 (TGF-β1) were upregulated in spatially and leaflet-dependent patterns. That is, we observed increased expression of these markers within septal leaflets' near-annulus and belly regions, increased expression in anterior leaflets' belly region, and varied expression in posterior leaflets. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models.

Statement of significance

Our study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression.