Effects of DHEA in Pulmonary Hypertension (DiPH)

摘要 肺动脉高压(PAH)是一种进行性的、限制生命的肺血管病变。 尽管有许多已获批准的血管扩张疗法。右室衰竭是心力衰竭的最终决定因素。 更常见的心肺疾病对PAH和肺动脉高压的转归，但没有 房车故障的批准治疗。PAH在女性中更常见，但女性有更好的RV功能和 与患有PAH的男性相比，存活率更高。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)及其硫酸酯会增加男性和女性患PAH的风险， 低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不依赖于包括雌激素在内的其他性激素。脱氢表雄酮对一氧化氮(NO)和 内皮素-1(ET-1)的合成和信号转导是PAH的两个主要病理生物学驱动因素和治疗靶点。 对心肌细胞有直接的抗肥大作用。我们的长期目标是将脱氢表雄酮作为一种治疗药物 对PAH和RV衰竭的干预，以提供基于性别或性激素的精确PAH治疗 周围的环境。这项建议将测试DHEA对RV表型的影响，并提供关键的机制见解 在肺血管水平、右室水平和在主要疾病背景下探讨PAH的性别二型性 建立了PAH的治疗目标。随机双盲安慰剂对照的概念验证 计划进行交叉试验，研究脱氢表雄酮对患有PAH的男性(n=13)和女性(n=13)的治疗。在我们的第一次 目的：我们将确定连续18周每天DHEA 50 mg是否会影响心脏测量的RV纵向应变 磁共振成像和适应性不良的右室肥大和重塑的标志物。我们还将评估 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的积极治疗是否影响PAH患者NO和ET-1的生物合成。 第三，我们将确定DHEA是否促进肺组织中NO的产生和抑制ET-1的合成 分离PAH患者动脉内皮细胞。这项工作将是内源性性行为的第一次临床试验。 PAH中的激素，并将提供对基于性别的心肺表型差异的机械洞察， 导致DHEA作为一种新的RV疗法的更大的平行臂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.