Right ventricular stiffening and anisotropy alterations in pulmonary hypertension: Mechanisms and relations to function

Abstract

Aims: Pulmonary hypertension (PH) results in an increase in RV afterload, leading to RV dysfunction and failure. The mechanisms underlying maladaptive RV remodeling poorly understood. In this study, we investigate the multiscale and mechanistic nature of RVFW biomechanical remodeling and its correlations with RV function adaptations. Methods and Results: Mild and severe models of PH, consisting of hypoxia (Hx) in Sprague-Dawley (SD) rats (n=6 each WT and PH) and Sugen- hypoxia (SuHx) in Fischer (CDF) rats (n=6 each WT and PH), were developed. Organ-level function and 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 stiffening, and organ-level dysfunction. Multiple animal models provided a wide range of RVFW stiffening and anisotropy alterations in PH. Decreased RV-pulmonary artery (PA) coupling correlated strongly with 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 a key mechanism differentiating severe from mild stiffening was increases in collagen fiber tautness. Myofiber orientation analysis indicated a shift away from the predominantly circumferential fibers observed in healthy RVFW specimens, leading to a significant loss of anisotropy of the tissue. Conclusion: Multiscale biomechanical analysis indicated that although hypertrophy and fibrosis occur in both mild and severe PH, certain fiber-level remodeling events, including reduced undulations in the newly deposited collagen fibers and significant reorientations of myofibers, contributed excessive biomechanical maladaptation of the RVFW leading to severe RV-PA uncoupling. Collagen fiber remodeling, combined with the loss of tissue anisotropy, can provide an improved understanding of the transition from adaptive to maladaptive remodeling.