; Female sex is the best established risk factor for pulmonary arterial hypertension (PAH), yet women have preserved right ventricular (RV) function and survival compared to men with PAH. This so-called "estrogen paradox" is as yet unexplained. RV function determines outcome in disease, but the mechanisms and determinants of RV failure are unknown. We hypothesize that high estrogen states promote pulmonary vascular angiogenesis and RV myocardial collateral flow, resulting in pleiotropic effects on the pulmonary vasculature and the RV. In postmenopausal women, the hormonal mileu (e.g., sex hormone and estradiol [E2] metabolite levels) can be characterized;in premenopausal women the normal menstrual cycle (marked by a predictable spike in E2) provides a physiologic model to characterize these relationships. We propose: 1) a prospective cohort study (N=75) to determine whether the sex hormone milieu is associated with markers of angiogenesis (vascular endothelial growth factor [VEGF], angiopoietins [Ang], endothelial progenitor cells [EPCs]) and RV function assessed by hemodynamics in postmenopausal women wdth PAH and 2) a prospective case-control study (N = 40) to determine whether the menstrual cycle is associated with markers of angiogenesis (VEGF, Ang, EPCs) and RV function assessed by echocardiography in premenopausal women with PAH as compared to controls. We anticipate that in both pre and postmenopausal women, high E2 states will be associated with higher levels of angiogenesis markers but improved surrogates of RV function. The extent to which the influence of sex hormones on markers of angiogenesis and RV function can be defined is supported by 1) the use of separate studies to incorporate both pre and postmenopausal women and 2) the combination of a variety of carefully selected biomarkers aimed at both angiogenesis and RV function.
Sex hormones are highly relevant targets for study, since RV function varies by sex and likely drives survival differences. If we find significant relationships between sex hormones and markers of angiogenesis/endothelial health, our next studies could focus on treatment or prevention strategies aimed at manipulation of E2 in those at risk for RV failure, a very innovative approach.
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