Pulmonary Arterial Hypertension is a severe disease defined by sustained elevated pulmonary arterial pressures. This progressive vasculopathy is characterized by structural and mechanical remodeling of the pulmonary arteries that chronically impose a pressure overload on the right ventricle, stimulating myocardial hypertrophy and remodeling of the RV chamber. Although PAH is confirmed in the pulmonary arteries, the health and function of the right ventricle is the most important clinical predictor of patient outcomes. The RV progressively adapts to pressure overload and can transiently maintain its output, but PAH commonly leads to RV dysfunction and premature death. Why and how the RV transitions from adaptive to maladaptive function remains unknown. This knowledge gap helps to explain why, despite its significant role in determining morbidity and mortality, no current therapies specifically target the RV.Importantly, clinical management of PAH is confounded by the estrogen paradox, whereby PAH primarily and disproportionally affects women, but with women also exhibiting improved RV function and outcomes in the face of PAH compared to men. Clinical studies have highlighted the association between sex and RV hemodynamic function, with previous research indicating correlations between improved RV function and both endogenous and exogenous estrogens. However, most animal studies have focused on males, resulting in limited sex-specific RV data. Consequently, the role of sex and ovarian hormones in PAH remains unclear.
In this dissertation, we explore the pathological remodeling of the right ventricle in pulmonary arterial hypertension and the evolution of hemodynamic, structural, and mechanical properties of the RV during the progression of PAH. By leveraging experimental measurements of cardiac hemodynamics, morphology, and myocardial mechanics, and by analyzing computational biomechanics models, we investigate organ, tissue, and cell changes to enhance our understanding of right ventricular remodeling in the context of PAH.
We characterized the longitudinal evolution of RV hemodynamics during the progression of PAH using an established animal model. Implementing a computational model of RV biomechanics, we decoupled the relative contributions of geometric and material remodeling of the RV myocardium to changes in RV function. We identified distinct stages of RV adaptation whereby myocardial hypertrophy initially stabilized systolic function after which substantial diastolic myocardial stiffening occurred and prevented RV dilation. We then investigated the effects of sex- and ovarian-hormone presence on systolic and diastolic function. We identified distinct phenotypes of RV adaptation that were sex- and ovarian hormone dependent. We found that male rats responded to PAH with the most severe diastolic stiffening of any group. Female rats that were ovariectomized demonstrated increases in systolic elastance that were explained by myocyte contractility upregulation via calcium transient enhancement. By contrast, ovary-intact female rats adapted to PAH with the fewest changes to RV mechanical properties compared to the other groups. These results provide evidence of sex-dependent changes that could be specifically targeted for therapies. By combining in-vivo measurements with our computational modeling, we reached important conclusions about the decoupled effects of myocardial changes to RV function at varying stages of disease. These findings provide new insights into the mechanisms underlying stages of adaptation to PAH.
