Right Ventricular Stiffening and Anisotropy Alterations in Pulmonary Hypertension: Mechanisms and Relations to Right Heart Failure

BACKGROUND: Pulmonary hypertension (PH) results in increased right ventricular (RV) afterload, leading to RV dysfunction and fail-ure. 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 stiff-ness, 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 differen-tiated 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 un-coupling. Collagen fiber remodeling and the loss of tissue anisotropy can provide an improved understanding of the transition from adaptive to maladaptive RV remodeling.