ABSTRACT
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 differential 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. 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.
Competing Interest Statement
Manuel K Rausch has a speaking arrangement with Edwards Lifesciences. The other authors have no conflicts to declare.
Footnotes
↵† Colton Kostelnik and William Meador are co-first authors
We extended the analysis to include the previously reported anterior leaflet findings to compare the remodeling response between the tricuspid leaflets. We changed the statistical methods to a linear mixed effects model to compare leaflet remodeling responses. This model now includes fixed effects for animal group (healthy vs. disease), leaflet type (anterior, posterior, septal), direction (X vs. Y) where applicable, and their interactions. We performed one-tailed pairwise comparisons between healthy and diseased animals for each leaflet type, and performed two-tailed pairwise comparisons using Tukey's method to compare between leaflets from the healthy and diseased animals. We revised all figures to reflect these changes. We removed the collagen quantification from the study.
