Abstract
BACKGROUND: Pulmonary hypertension (PH) results in increased right ventricular (RV) afterload, leading to RV dysfunction and failure. The mechanisms underlying maladaptive RV remodeling are poorly understood. In this study, we investigated the multiscale and mechanistic nature of RV free-wall (RVFW) biomechanical remodeling and its correlations with RV function adaptations. METHODS: Mild and severe models of PH, consisting of a hypoxia model in Sprague-Dawley rats (n=6 each, control and PH) and a Sugen-hypoxia model in Fischer rats (n=6 each, control and PH), were used. Organ-level function, tissue-level stiffness, and microstructure were quantified through in vivo and ex vivo measures, respectively. Multiscale analysis was used to determine the association between fiber-level remodeling, tissue-level stiffness and anisotropy, and organ-level dysfunction. RESULTS: Decreased RV-pulmonary artery coupling correlated strongly with RVFW stiffening but showed a weaker association with the loss of RVFW anisotropy. Machine-learning classification identified the range of adaptive and maladaptive RVFW stiffening. Multiscale modeling revealed that increased collagen fiber tautness was a key remodeling mechanism that differentiated severe from mild stiffening. Myofiber orientation analysis indicated a shift away from the predominantly circumferential fibers observed in healthy RVFW specimens, leading to a significant loss of tissue anisotropy. CONCLUSIONS: Multiscale biomechanical analysis indicated that, although hypertrophy and fibrosis occur in both mild and severe PH, certain fiber-level remodeling events, including increased tautness of collagen fibers and significant reorientations of myofibers, contributed to excessive biomechanical maladaptation of the RVFW leading to severe RV-pulmonary artery uncoupling. Collagen fiber remodeling and the loss of tissue anisotropy can provide an improved understanding of the transition from adaptive to maladaptive RV remodeling.