Effects of DHEA in Pulmonary Hypertension (DiPH)

摘要 肺动脉高压（PAH）是一种持续进行性和限制生命的肺血管病变 尽管有许多批准的血管扩张剂疗法。右心室（RV）衰竭是 肺动脉高压和肺动脉高压更常见的心脏和肺部疾病的结果，但没有 治疗右心室衰竭的药物PAH在女性中更常见，但女性具有更好的RV功能， 与PAH男性患者相比，我们和其他人已经证明，肾上腺类固醇水平较低， 脱氢表雄酮（DHEA）及其硫酸酯增加男性和女性PAH的风险， 较低的水平与更严重的肺血管疾病、更差的RV功能和死亡率相关， PAH不依赖于其他性激素，包括雌激素。DHEA对一氧化氮（NO）有直接作用， 内皮素-1（ET-1）的合成和信号传导是肺动脉高压的两个主要病理生物学驱动因素和治疗靶点， 和对心肌细胞的直接抗肥大作用。我们的长期目标是追求DHEA作为治疗 对PAH和RV衰竭进行干预，以提供基于性别或性激素的精确PAH治疗 环境。该提案将测试DHEA对RV表型的影响，并提供关键的机制见解 在肺血管、RV水平和主要肺动脉高压背景下， 建立PAH治疗目标。概念验证随机双盲安慰剂对照 计划在PAH男性（n = 13）和女性（n = 13）中开展一项研究DHEA治疗的交叉试验。在我们的第一 目的：我们将确定DHEA 50 mg/d持续18周是否会影响心脏测量的RV纵向应变。 磁共振成像和适应不良RV肥大和重塑的标志物。我们亦会评估 DHEA对下游激素水平、其他PAH中间终点、副作用和安全性的影响。 其次，我们将确定DHEA的积极治疗是否会影响PAH患者的NO和ET-1生物合成。 第三，我们将确定DHEA是否能增强肺组织中NO的产生和减弱ET-1的合成， 从PAH患者分离的动脉内皮细胞。这项工作将是第一个内源性的临床试验 并将提供心肺表型中基于性别差异的机制性见解， 导致DHEA作为新型RV治疗剂的更大平行臂II期试验。

Abstract Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that remains progressive and life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) failure is the ultimate determinant of outcome in PAH and in pulmonary hypertension from more common heart and lung diseases, but there are no approved treatments for RV failure. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. We and others have shown that lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester increase the risk of PAH in men and women and that lower levels are associated with more severe pulmonary vascular disease, worse RV function, and mortality in PAH independent of other sex hormones including estrogen. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, two major pathobiologic drivers and therapeutic targets in PAH, and direct antihypertrophic effects on cardiomyocytes. Our long-range goal is to pursue DHEA as a therapeutic intervention in PAH and RV failure in order to provide precision PAH treatment based on sex or sex hormone milieu. This proposal will test the impact of DHEA on RV phenotype and provide critical mechanistic insights into sexual dimorphism in PAH at the level of the pulmonary vasculature, the RV and in the context of major established treatment targets in PAH. A proof of concept randomized double-blind placebo controlled crossover trial to study DHEA treatment in men (n = 13) and women (n = 13) with PAH is planned. In our first aim, we will determine whether DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging and markers of maladaptive RV hypertrophy and remodeling. We will also assess the impact of DHEA on downstream hormone levels, other PAH intermediate end points, side effects and safety. Second, we will determine whether active treatment with DHEA affects NO and ET-1 biosynthesis in PAH patients. Third, we will determine whether DHEA enhances NO production and attenuates ET-1 synthesis in pulmonary artery endothelial cells isolated from PAH patients. This work will be the first clinical trial of an endogenous sex hormone in PAH and will provide mechanistic insight into sex-based differences in cardiopulmonary phenotypes, leading to a larger parallel arm Phase II trial of DHEA as a novel RV therapeutic.