(D-127) The Relationship between Right Ventricular Hemodynamic Parameters and Observed Sex Differences in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder that primarily results in the remodeling of the pulmonary vasculature and the right ventricle of the heart [1]. The right ventricle (RV) undergoes structural changes characterized by increased wall thickness and contractility as it adapts to the increase in afterload in the pulmonary arteries [1]. In the short term, RV remodeling can compensate for the increased afterload and maintain necessary cardiac output, but it is often insufficient and tends to manifest into right ventricular failure and dysfunction [2]. Sex differences in the prevalence and progression of PAH are well documented. PAH is more prevalent in women than in men but survival among male patients is worse than in females [3]. Studies have shown that estrogen and estrogen metabolites may contribute to this difference in lung pathophysiology in PAH patients [3]. 

The end-systolic elastance (Ees) is a metric of heart contractility and is calculated as the slope of the end-systolic pressure-volume relationship. The end-diastolic elastance (Eed) is obtained from the end-diastolic pressure-volume relationship and is an index of diastolic stiffness. Currently, the use of these indices of heart function is limited due to the technical difficulty to measure clinically. Therefore, the relationship between the elastances and the sex differences in PAH is not well understood. This study seeks to compare the changes in end-systolic and end-diastolic elastances over the course of 12 weeks post-PAH induction to determine the correlation between sex differences in PAH progression and changes in heart contractility and stiffness.

Pulmonary arterial hypertension was modeled using sugen-hypoxia (SuHx) treated rats. In-vivo hemodynamic measurements were obtained during right ventricular (RV) catheterization surgeries at time points up to 12 weeks post-SuHx treatment. RV pressure-volume loops representative of the animal’s steady-state heart function and occlusion of the inferior vena cava were recorded. A MATLAB code was used to separate the pressure-volume measurements into single heartbeats which were then averaged to produce a representative loop that was used to identify the end-systolic and end-diastolic points and calculate hemodynamic parameters including end-systolic pressure (ESP) and end-diastolic pressure (EDP). P-V loops during the occlusion were used to determine the end-systolic elastance (Ees) and end-diastolic elastance (Eed). The Ees was calculated using a linear fit of the end-systolic points and the Eed was calculated by using an exponential fit through the end-diastolic points. The RV wall samples were dissected and weighed to observe the effects of hypertrophy on the myocardial wall as a function of longitudinal disease progression. These hemodynamic measurements were compared between males, females, and ovariectomized (OVX) rats over the timecourse of 12 weeks post-PAH induction.

This study analyzed RV hemodynamic parameters to determine the correlation between clinically observed sex differences in PAH disease prevalence and progression and the changes in RV compliance and stiffness that occurs during ventricular remodeling. The SuHx model was used to compare males, females, and ovariectomized rats over the course of 12 weeks post-treatment. There was no significant sex difference observed in the increase in ESP or Ees. The ESP initially increased for all groups and then plateaued at approximately 8 weeks. Similarly, the Ees in males exhibited a consistent increase from 3 to 9 weeks compared to the control group whereas the females and OVX groups increased during the first 4 weeks but then either decreased or remained unchanged. The significant differences observed between the males, females, and OVX groups were observed in the Eed, EDP, and RV mass. The male group had the greatest Eed, EDP, and RV mass whereas the females had the smallest for each respective hemodynamic parameter. The trend in Eed for OVX SuHx animals was more similar to that of the female group, suggesting that the absence of estrogen may play a role in the increase in Eed over time. Therefore, these findings suggest that the sex differences observed in PAH may be contributed more to the changes in diastolic stiffness and prevalence of RV hypertrophy than to changes in cardiac compliance. The specific mechanisms which determine PAH prevalence and progression are not well understood. Since the Eed is not easily obtained clinically, understanding the correlation between the Eed and the EDP and RV mass can help physicians better diagnose patients based on obtainable hemodynamic parameters. 

[1] van de Veerdonk, Mariëlle C et al. “The right ventricle and pulmonary hypertension.” Heart failure reviews vol. 21,3 (2016): 259-71. doi:10.1007/s10741-016-9526-y.

[2] Anton Vonk-Noordegraaf, François Haddad, Kelly M. Chin, Paul R. Forfia, Steven M. Kawut, Joost Lumens, Robert Naeije, John Newman, Ronald J. Oudiz, Steve Provencher, Adam Torbicki, Norbert F. Voelkel, Paul M. Hassoun, Right Heart Adaptation to Pulmonary Arterial Hypertension: Physiology and Pathobiology, Journal of the American College of Cardiology, Volume 62, Issue 25, Supplement, 2013, Pages D22-D33, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2013.10.027.