Abstract
Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17β-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s′). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s′ were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s′ in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.
Highlights
Pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension) is an idiopathic chronic lung disease characterized by pulmonary vascular remodeling and a Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.It has been reported that gender differences exist in both experimental animals and patients with PAH
The differences in right ventricular (RV) function are at least partly mediated by the effects of sex hormones, as evidenced by studies which demonstrated higher estradiol levels are associated with better RV systolic function in postmenopausal women
We evaluated RV function comprehensively by echocardiography and tried to explain the sex differences in PAH from echocardiographic and histochemical perspectives
Summary
Despite females having higher prevalence and incidence rates of PAH [2–4], women with PAH exhibit better survival than men [3–5]. This incongruous finding is termed the “estrogen paradox in PAH” [6]. Female PAH patients have a higher RV ejection fraction (RVEF) than males at baseline [7, 8] and a better RVEF response after medical treatment [9] than their male counterparts. Recent studies demonstrated that the preserved RVEF in women is a major contributor to the female survival advantage in PAH [9]. The differences in RV function are at least partly mediated by the effects of sex hormones, as evidenced by studies which demonstrated higher estradiol levels are associated with better RV systolic function in postmenopausal women
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