TranspulmonarY Estrogen Gradient and Estrogen Receptors (TYEGER) in PAH

The strongest established risk factor for the progressively fatal disease pulmonary arterial hypertension (PAH) is female sex (\~3:1 female:male ratio). Investigators and others have found higher circulating estrogen levels, and enhanced estrogen signaling, in PAH patients. Evidence suggests that exuberant estrogen signaling causes a perturbation of mitochondrial function and energy substrate utilization in both sexes. However, systemic estrogen level elevation is not uniform among patients, and the affinity of the pulmonary vascular bed for estrogens is unknown. In preliminary studies of prevalent PAH patients, estradiol (E2) levels dropped across the pulmonary vasculature suggestive of E2 uptake by the lungs; those patients with a high transpulmonary gradient (pre- minus post-capillary) had a higher mean pulmonary artery pressure at diagnosis. Investigators previously confirmed that urine 16α-hydroxyestrone (16αOHE1) is elevated at least 2-fold in females and males with PAH, consistent with data from other groups that estrogens are elevated in PAH. 16αOHE1 is an estrogen metabolite with high affinity for the canonical estrogen receptors (ESRα and ESRβ) and thus an active estrogen. Investigators published that in a transgenic mouse model of PAH, administration of 16αOHE1 significantly increased PAH penetrance concomitant with features of oxidant stress including elevated isoprostanes (IsoPs) and isofurans (IsoFs). Those animals also developed insulin resistance and mitochondrial dysfunction, characteristics investigators have described during the current PPG in humans with PAH. Concomitantly, through ESR signaling, 16αOHE1 reduced PPARγ expression via reduction in PGC1α. By co-administering drugs to block extra-gonadal estrogen synthesis and receptor signaling investigators were able to prevent or reverse the cellular metabolic defects and pulmonary vascular phenotype in investigators' transgenic model system. The capacity for enhanced estrogen signaling, represented by elevated blood E2 levels, elevated urinary 16αOHE1, and specific genetic variants, is a characteristic of PAH patients of both sexes in several studies. Experimental data from investigators' group and others support the concept that estrogen antagonism may be beneficial for humans with PAH. However, investigators recognize that not all subjects will benefit from estrogen antagonism, making a 'one size fits all' approach too narrow. Investigators and others have shown that estrogens directly alter pulmonary vascular cell homeostasis and gene expression, including reduction in BMPR2 expression and signaling via ESR; and, experimental PAH models demonstrate increased expression of aromatase, an enzyme which converts androgens to estrogens, in the lungs. But no human studies investigate the direct contribution of the pulmonary circulation to estrogen avidity, ESR density, and outcomes. Investigators propose to evaluate the influence of estrogens on the pulmonary vasculature and cardiac function, using incident and prevalent PAH cases to reduce confounding by disease course. Findings from this study should help determine patients most likely to have a beneficial response to estrogen antagonism, supporting the overall project goal to improve "precision medicine" approaches in PAH. Investigators hypothesize that blood-based and radiologic markers of estrogen burden will support the determination of a phenotype profile of subjects with PAH for whom estrogen antagonism will be an effective therapeutic approach. In a cohort of PAH patients, investigators will determine if transpulmonary (change pre- to post-pulmonary capillary bed) E2 levels and/or lung ESR density associate with disease severity at cardiac catheterization, functional capacity, time to clinical worsening, and oxidant stress. Specific Aim 1: To test the hypothesis that among PAH patients, transpulmonary (TP) E2 gradient associates with a more severe hemodynamic profile and worse 1 year outcomes. Specific Aim 2: To test the hypothesis that among PAH patients, higher lung ESR density associates with a more severe hemodynamic profile and worse 1 year outcomes. These studies may ultimately lead to novel discoveries in the transpulmonary gradient of sex hormones, investigate a novel imaging approach in PAH, optimize the ability to precisely determine the correct patient for sex hormone modification, and potentially support the development of novel therapeutic targets in PAH. The data collected in this study will also synergize with an ongoing NIH-supported clinical trial to investigate the use of sex hormone modification as a therapeutic approach for PAH: ClinicalTrials.gov Identifier: NCT03528902.