Bahram Mirani, John D. Dauz, Kana Yazaki, Neda Latifi, J. Paul Santerre, Michelle P. Bendeck, Craig A. Simmons, Mark K. Friedberg
University of Toronto, Ted Rogers Centre for Heart Research and Hospital for Sick Children. Beth Israel Deaconess Medical Center and Harvard Medical School. University of South Florida.
Canada and United States
Arteriosclerosis, Thrombosis and Vascular Biology
Arterioscler, Thromb Vasc Biol 2025;
DOI: 10.1161/ATVBAHA.124.321354
Abstract
Background: Coupling between right ventricular (RV) function and the pulmonary vasculature determines outcomes in pulmonary arterial (PA) hypertension. The mechanics of the main PA (mPA) is an important but understudied determinant of RV-PA coupling. To investigate the histology and mechanics of PA in relationship to RV remodeling, mechanics, hemodynamics, and coupling in experimental PA hypertension.
Methods: In a sugen-hypoxia rat model of PA hypertension, RV hemodynamics were assessed by conductance catheters. Active tension-strain curves were generated using echocardiography. mPA and RV free wall were harvested to determine their macrostructure and microstructure, composition, and mechanical properties. Comprehensive multivariate analyses elucidated relationships between PA and RV mechanics, structure, and coupling.
Results: Pulmonary hypertensive mPAs developed fibrosis relative to healthy controls, as did RVs, which also hypertrophied, with reorientation of muscle fibers toward a trilayer architecture reminiscent of normal left ventricular architecture. Increased glycosaminoglycan deposition and increased collagen-to-elastin ratio in PA, and increased collagen, as well as hypertrophy and reorganization of myofibers in RV, led to increased stiffness. This increase in stiffness was more pronounced in the longitudinal direction in the high- and low-strain regime for PA and RV, respectively, causing increased mechanical anisotropy. mPA stiffening correlated significantly with RV tissue mechanical remodeling and reduced systolic performance, cardiac output, and RV-PA coupling.
Conclusions: Compositional, structural, and mechanical changes in mPA correlate with adverse RV remodeling, mechanics, function, and coupling in PA hypertension. Therefore, increasing mechanical compliance of the large PAs may be an important and novel therapeutic strategy for mitigating RV failure.
Category
Right Heart Dysfunction Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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