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 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 Sugen5416/hypoxia (SuHx) model in a comparison of male and female mice.
Methods: PH was induced in C57BL/6 mice of both sexes (n=26) using the SuHx model. We examined 4 experimental groups: male normoxic mice (MNx, n=8), female normoxic mice (FNx, n=5), SuHx-induced PH in male mice (MSuHx, n=8), and SuHx-induced PH in female mice (FSuHx, n=5). 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, MSuHx (85.2±11.4mmHg, p=0.006) and FSuHx (76.6±8.2mmHg, p=0.048) compared to respective normoxic mice, with no significant difference between MSuHx and FSuHx. Echocardiographic parameters were remarkably impaired after PH induction in both sexes. No significant sex differences were observed in RVbasal in PH induced mice, whilst TAPSE demonstrated a significantly greater impairment of systolic right ventricular function in FSuHx compared to MSuHx (p=0.018). Histological evaluation revealed significant lung tissue damage after PH induction in both MSuHx (p=0.006) and FSuHx (p=0.024) when compared to respective normoxic groups, whereas no significant differences could be shown between MSuHx and FSuHx. The extent of myocardial tissue damage was significantly higher in FSuHx compared to MSuHx (p=0.015). Immunohistochemical evaluation of pulmonary vasculopathy and immune cell infiltration revealed no significant differences between both sexes.
Conclusions: Despite marginal sex differences, successful PH induction in the SuHx model was achieved regardless of murine sex. Although a significantly increased overall disease severity cannot be conclusively determined, female mice, most notably, exhibited more pronounced alterations regarding right ventricular damage and function in response to pressure overload.
Further research is required to elucidate the underlying mechanisms of sex-specific characteristics and disease expression in PH.
