Sex Hormones and Pulmonary Vascular and Right Ventricular Dysfunction

项目总结（见说明）; 女性是肺动脉高压（PAH）的最佳既定风险因素，但与PAH男性相比，女性保留了右心室（RV）功能和生存率。这种所谓的“雌激素悖论”至今仍无法解释。RV功能决定疾病的结局，但RV衰竭的机制和决定因素尚不清楚。我们假设高雌激素状态促进肺血管新生和右心室心肌侧支血流，导致对肺血管和右心室的多效性效应。在绝经后妇女中，激素环境（例如，性激素和雌二醇[E2]代谢物水平）;在绝经前妇女中，正常月经周期（以E2的可预测峰值为标志）提供了表征这些关系的生理模型。我们建议：1）前瞻性队列研究（N=75），以确定性激素环境是否与血管生成标志物相关（血管内皮生长因子[VEGF]，血管生成素[Ang]，内皮祖细胞[EPCs]）和通过血流动力学评估的RV功能，以及2）一项前瞻性病例对照研究（N = 40）确定绝经前PAH女性与对照组相比，月经周期是否与血管生成标志物（VEGF、Ang、EPCs）和通过超声心动图评估的RV功能相关。我们预计，在绝经前和绝经后妇女，高E2状态将与较高水平的血管生成标志物，但改善替代RV功能。 性激素对血管生成和RV功能标志物的影响程度可以通过以下方式确定：1）使用单独的研究纳入绝经前和绝经后女性，2）结合各种精心选择的旨在血管生成和RV功能的生物标志物。

PROJECT SUMMARY (See instructions); 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.