UC San Diego

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by elevated pressures and remodeling in the pulmonary arteries, leading to an overloaded right ventricle (RV) and eventual right heart failure, making RV function a key indicator of the disease. PAH exhibits a strong sexual dimorphism, where females are more frequently afflicted with the disease, but pre-menopausal women tend to have better survival outcomes. Many studies have investigated how the RV adapts in PAH, and others have looked for mechanisms behind the so-called sex-paradox, but the reason females have a survival advantage is unclear. In this thesis, the remodeling process of the RV was quantified along the time-progression of PAH in male, intact female, and ovariectomized (OVX) female rats treated with Sugen-Hypoxia (SuHx). Planar biaxial mechanical testing of the RV myocardium was performed to generate stress-strain relationships, which were then fit to a Fung-type exponential strain energy model to generate surfaces for group averaging and comparison. RV samples were decellularized and retested to characterize the mechanical behavior of the collagen extracellular matrix (ECM), and collagen content was quantified in distinct regions of the RV myocardium. It was shown that, in normotension, the RV behaves preferentially in the apex-outflow direction in control males, but isotropically in female rats. In SuHx-PAH, the RV shows enlarged thickness and mass, and increased stiffness compared to controls; however, this remodeling is sex-specific, with RV myocardium and collagen ECM from intact females stiffening the least. As the disease progresses, we see male and intact female RVs reach peak stiffness at 8 weeks of PAH, while OVX female RVs stiffen more in early weeks of the disease and maintain that stiffening through the late stage. Collagen content increases in PAH, with regional variation. This study can be used as a quantitative reference for RV passive stiffening in the SuHx rat model of PAH, and findings of differences in the collagen ECM may help future studies identify underlying mechanisms of differential RV stiffening between sexes.