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)的最佳危险因素，但与男性相比，女性保留了右室(RV)功能和存活率。这一所谓的“雌激素悖论”至今仍未得到解释。RV功能决定疾病的结局，但RV失效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生成和右室心肌侧支循环，从而对肺血管和右室产生多效性作用。在绝经后妇女中，荷尔蒙水平(例如，性激素和雌二醇[E2]代谢物水平)可以被表征；在绝经前妇女中，正常的月经周期(以可预测的E2峰值为标志)提供了一个生理模型来表征这些关系。我们建议：1)一项前瞻性队列研究(N=75)，以确定性激素环境是否与血管生成标记物(血管内皮生长因子[VEGF]、血管生成素[Ang]、内皮祖细胞[EPC])和血流动力学评估的绝经后PAH患者的RV功能相关；2)一项前瞻性病例对照研究(N=40)，以确定与对照组相比，绝经前PAH患者的月经周期是否与血管生成标记物(VEGF、Ang、EPC)和RV功能相关。我们预计，在绝经前和绝经后的女性中，高E2状态将与更高水平的血管生成标记物相关，但改善RV功能的替代者。 性激素对血管生成标记物和RV功能的影响程度可以通过1)对绝经前和绝经后妇女的单独研究以及2)针对血管生成和RV功能的各种精心挑选的生物标记物的组合来支持。

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.