Effects of DHEA in Pulmonary Hypertension (DiPH)

DHEA 对肺动脉高压 (DiPH) 的影响

基本信息

批准号：
10402875
负责人：
Corey E Ventetuolo
金额：
$ 73.74万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402875
关键词：
Adrenal Glands Affect Anabolism Attenuated Binding Biological Brain natriuretic peptide Cardiac Cardiac Myocytes Cardiopulmonary Cause of Death Cells Clinical Trials Complement Cross-Over Trials Data Disease Double-Blind Method Endothelin Receptor Endothelin Receptor Antagonist Endothelin-1 Endothelium Environment Esters Estradiol Estrogens Experimental Models Galectin 3 Goals Gonadal Steroid Hormones Heart Diseases Heart failure Hormonal Hormones Intervention Studies Left Life Lung Lung diseases Measures Mediating Mediator of activation protein Morbidity - disease rate N-terminal NADH oxidase Nitric Oxide Nitric Oxide Synthase Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Peptides Peroxidases Phase Phenotype Placebo Control Placebos Plasma Prevalence Production Public Health Pulmonary Heart Disease Pulmonary Hypertension Randomized Right Ventricular Function Right Ventricular Hypertrophy Risk Role Safety Serum Sex Bias Signal Transduction Steroids Sulfate Testing Therapeutic Therapeutic Intervention Vascular Endothelium Vasodilator Agents Ventricular Ventricular Ejection Fractions Ventricular Remodeling Walking Woman Work active method anastrozole animal data arm base cardiac magnetic resonance imaging dehydroepiandrosterone effective therapy health related quality of life human data hypertension treatment imaging biomarker improved inhibitor insight men mortality novel novel therapeutics phase II trial phosphoric diester hydrolase prohormone pulmonary arterial hypertension pulmonary artery endothelial cell pulmonary vascular disorder randomized trial receptor for advanced glycation endproducts response right ventricular failure right ventricular remodeling sex sexual dimorphism side effect therapeutic target treatment response

项目摘要

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.

抽象的肺动脉高压（PAH）是一种肺血管病，保持渐进和生命限制尽管有许多批准的血管扩张疗法。右心（RV）失败是最终决定因素 PAH的结局以及来自更常见的心脏和肺部疾病的肺动脉高压，但没有批准的RV故障治疗方法。 PAH在女性中更为普遍，但女性具有更好的RV功能，并且与患有PAH的男人相比，生存。我们和其他人表明肾上腺类固醇的水平较低脱氢雌激素（DHEA）及其硫酸酯酯增加男性和女性的PAH风险，并且较低的水平与更严重的肺血管疾病，RV功能较差以及死亡率有关 PAH独立于包括雌激素在内的其他性激素。 DHEA对一氧化氮（NO）和内皮素-1（ET-1）合成和信号传导，两个主要病原体驱动因素和PAH治疗靶标，和直接对心肌细胞的抗血性作用。我们的远程目标是追求DHEA作为治疗性干预PAH和RV失败，以提供基于性别或性激素的精确治疗环境。该建议将测试DHEA对RV表型的影响，并提供关键的机械见解在肺脉管系统，RV和主要背景下，在PAH中进入PAH的性二态性在PAH中建立的治疗目标。概念证明，随机双盲安慰剂控制计划研究男性（n = 13）的DHEA治疗的分频试验和PAH的女性（n = 13）。在我们的第一个目的，我们将确定DHEA每天50 mg持续18周是否会影响心脏测量的RV纵向应变适应不良的RV肥大和重塑的磁共振成像和标记。我们还将评估 DHEA对下游激素水平的影响，其他PAH中间点，副作用和安全性。其次，我们将确定使用DHEA的主动治疗是否影响PAH患者的NO和ET-1生物合成。第三，我们将确定DHEA是否增强了不产生的生产并减弱肺中的ET-1合成从PAH患者中分离出的动脉内皮细胞。这项工作将是内源性的首次临床试验 PAH中的激素将提供有关心肺表型基于性别的差异的机械洞察力，导致DHEA作为新型RV治疗的较大平行ARM II期试验。