Abstract Body: Introduction: Right ventricular (RV) failure is the leading cause of mortality in pulmonary hypertension (PH). Although the disease occurs more frequently in females, males develop worse RV dysfunction and poor outcomes. The mechanisms underlying sex differences in RV adaptation to pulmonary vascular pressure overload remain poorly understood. We tested whether sex-dependent inflammatory and myocardial stress signaling contributes to divergent RV remodeling in PH.
Methods: Male and female mice were exposed to normoxia (Nx), hypoxia (Hx), or sugen/hypoxia (SuHx) for 6 weeks. RV function was assessed using pressure–volume loops to quantify contractility via the end-systolic pressure–volume relationship (ESPVR). Cardiac remodeling was evaluated morphologically. Expression of Hmgb1, Lcn2, Nppa, and Nppb was quantified in RV and left ventricular (LV) tissues. Human RV RNA-seq data from control, compensated, and decompensated RV tissues were analyzed to assess translational relevance.
Results: Hx and SuHx induced PH in both sexes. Males developed RV hypertrophy, dilation, and reduced ejection fraction with a downward shift of ESPVR, indicating impaired contractile adaptation. Females exhibited attenuated hypertrophy with relative preservation of RV ejection fraction and ESPVR. In mice, RV Hmgb1 expression was increased in SuHx females compared with Nx females (P=0.004) while Hmgb1 upregulation in Hx vs Nx females did not reach significance (P=0.062). Hmgb1 expression was higher in SuHx females than males, while no changes were observed across treatment groups in males. Lcn2 demonstrated a significant sex-disease interaction (P for interaction=0.03), with higher baseline expression in Nx females compared with Nx males and no change across PH groups. Hmgb1 and Lcn2 levels were unchanged in LV tissues. In human RV tissues, Hmgb1 expression differed significantly across RV functional states (P<0.001), with higher levels in decompensated RV compared with control and compensated RV, independent of sex. There was no effect of sex and no sex-RV function interaction.
Conclusions: Biological sex influences RV adaptation to pulmonary vascular pressure overload, with males exhibiting impaired contractile adaptation and females showing relative preservation of RV function. These findings identify inflammatory stress signaling, including Hmgb1 and Lcn2, as regulators of RV remodeling, with conserved upregulation of Hmgb1 in decompensated human RV independent of sex.