Background and Aims: Pulmonary hypertension (PH) is an aetiologically and clinically heterogeneous disorder predominantly driven by cardiovascular remodelling, ultimately leading to right heart failure (RHF). Female sex is considered a risk factor for the development of PH, at least for group 1 PH, albeit associated with a less severe extent of disease as well as significantly favourable female survival prognosis (“estrogen paradox”). Given the contradictory results in previous studies, indicating both, detrimental and beneficial effects of female sex in PH, we aimed to elucidate sex differences in the manifestation of PH and subsequent RHF by employing the preclinical Monocrotaline (MCT) model in a comparison of male and female mice.
Methods: PH was induced in C57BL/6 mice of both sexes (n=35) using the MCT model. We examined 4 experimental groups: sham-induced male control mice (MCtrl, n=5), sham-induced female control mice (FCtrl, n=9), MCT-induced PH in male mice (MMCT, n=8), and MCT-induced PH in female mice (FMCT, n=13). All animals underwent detailed echocardiographic evaluation of right ventricular (RV) morphology and function (e.g., basal RV diameter, RVbasal or tricuspid annular plane systolic excursion, TAPSE), right heart catheterization (RHC) to determine right ventricular systolic pressure (RVPsys) and histological as well as immunohistochemical tissue analyses.
Results: RHC displayed a significant elevation of RVPsys in both, MMCT (108.5±32.9mmHg, p=0.036) and FMCT (87.37±19.25mmHg, p=0.006) compared to respective control mice, with no significant difference between MMCT and FMCT. Echocardiographic parameters were remarkably impaired after PH induction in both sexes, whereas no significant sex-related differences were observed in RVbasal or TAPSE between MMCT and FMCT. Histological evaluation revealed significant damage to lung tissue and RV cardiac tissue following PH induction in both, MMCT (p=0.012 for lung and RV) and FMCT (p=0.032 for lung and RV), compared to respective control groups. However, no significant sex differences could be shown between MMCT and FMCT. Immunohistochemical evaluation of pulmonary vasculopathy and immune cell infiltration revealed no significant differences between both sexes.
Conclusions: Successful PH induction in the MCT model was achieved irrespective of murine sex, with no observed sex-related differences in PH-associated alterations or overall disease severity. Our findings indicate that, under preclinical experimental conditions using the MCT model, PH manifestation and progression occur independently of biological sex. Further research is required to elucidate the underlying mechanisms of sex-specific characteristics and disease expression in PH.
