Spironolactone Therapy in Pulmonary Arterial Hypertension (PAH)

螺内酯治疗肺动脉高压（PAH）

• 批准号: 8952911
• 负责人: Michael Solomon
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8952911
• 关键词: Amendment; Androgen Receptor; Appointments and Schedules; Award; Blood Vessels; Cardiology; Cardiopulmonary; Cessation of life; Clinic; Clinical; Communication; Data; Disease; Diuretics; Double-Blind Method; Early treatment; Echocardiography; Enrollment; Exercise; Exercise stress test; Failure; Future; Gene Expression Profiling; Genetic Predisposition to Disease; Heart failure; Incidence; Incidence Study; Inflammation; Inflammatory; Injury; Institution; Institutional Review Boards; Kidney Failure; Late Effects; Lead; Lung; Magnetic Resonance Imaging; Maryland; Mineralocorticoid Receptor; Monitor; National Heart, Lung, and Blood Institute; Natural History; Nursing Research; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Play; Protocols documentation; Pulmonary Hypertension; Randomized; Randomized Clinical Trials; Rare Diseases; Recruitment Activity; Relative (related person); Research Personnel; Resolution; Role; Safety; Site; Source; Spironolactone; Staging; Stimulus; Structure; Support Groups; Symptoms; Testing; United States National Institutes of Health; Visit; Walking; Work; base; bench to bedside; clinical practice; drug intolerance; endothelial dysfunction; hyperkalemia; improved; in vivo; injury and repair; interest; placebo controlled study; prevent; pulmonary arterial hypertension; saluretic; vascular inflammation

Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent RV failure and death has not been tested. Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for their diuretic and natriuretic effects, late in the course, once clinical right heart failure has developed. Currently, no well described data exists from randomized clinical trials examining the safety and efficacy of MR antagonist therapy in early stages of PAH. The concept for the protocol received an NIH Bench-to-Bedside Award in 2011 and a formal protocol was initially approved by the NHLBI IRB in September 2012. Subsequently IRB approval was sought and obtained at collaborating sites and various amendments were brought into alignment at all institutions by summer 2013. Subjects undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function. Safety and tolerability of spironolactone in PAH is assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. To date of the 14 subjects enrolled in our Natural History protocol (13-CC-0012) four have been enrolled in this study (Spironolactone Randomized Interventional Trial). Two of the four subjects have completed the study. Plans for bolstering recruitment and increasing enrollment included: 1) Our lead investigator has been participating at a local pulmonary clinic weekly in order to facilitate communication with clinic staff and PAH patients during regularly scheduled appointments. 2) We continue to present our study to local pulmonary hypertension support groups and as a result, patient self-referrals have ben a significant source of potential subjects. We plan to continue to maintain a close working relationship with the Pulmonary Hypertension Association and are planning future presentations to regional support groups including a new group currently being organized in Southern Maryland. 3) Research nurses continue to conduct periodic visits to local referral sites in order to facilitate communication with clinic staff and PAH patients. 4) In addition to reaching out to regional academic centers we continue to reach out to regional clinical practices. Local pulmonary and cardiology practices, have expressed interest in referring patients.

肺动脉高压（PAH）是一种与生存率低相关的罕见疾病。 1) 遗传易感性和 2) 引发肺血管损伤的触发刺激（二次打击假说）引起的内皮功能障碍似乎在 PAH 的发病机制和进展中发挥着核心作用。 炎症似乎会导致这种功能失调的内皮表型，在遗传易感的特发性 PAH (IPAH) 患者和疾病相关 PAH 患者中传播损伤和修复的循环。 针对肺血管炎症以中断损伤和修复周期从而延迟或预防右心室衰竭和死亡的治疗尚未经过测试。 螺内酯是一种盐皮质激素受体 (MR) 和雄激素受体 (AR) 拮抗剂，已被证明可以改善内皮功能并减少炎症。 目前对患有严重 PAH 和 NYHA/WHO IV 级症状的患者的治疗包括在病程后期，一旦出现临床右心衰竭，就使用 MR 拮抗剂来发挥其利尿和利尿钠作用。目前，尚无详细描述的随机临床试验数据来检验 MR 拮抗剂治疗在 PAH 早期的安全性和有效性。 该方案的概念于 2011 年获得了 NIH Bench-to-Bedside Award，正式方案最初于 2012 年 9 月获得了 NHLBI IRB 的批准。随后，在合作地点寻求并获得了 IRB 的批准，并对各种修正案进行了协调一致。 2013 年夏季之前的机构。 受试者接受1）标准临床检查，包括6分钟步行距离和超声心动图检查； 2）心肺运动试验； 3) 炎症和神经激素标志物的血浆分析； 4）外周血单个核细胞（PBMC）的基因表达谱； 5) 基于高分辨率 MRI 的肺血管和 RV 结构和功能测定。 通过定期监测高钾血症和肾功能不全以及因不良反应而停药的发生率来评估螺内酯在 PAH 中的安全性和耐受性。 迄今为止，在我们的自然历史方案 (13-CC-0012) 中登记的 14 名受试者中，有 4 名受试者已登记参加本研究（螺内酯随机干预试验）。四名受试者中的两名已完成研究。 加强招聘和增加入学人数的计划包括： 1) 我们的首席研究员每周都会参加当地的一家肺部诊所，以便在定期预约期间与诊所工作人员和 PAH 患者进行沟通。 2) 我们继续向当地肺动脉高压支持小组介绍我们的研究，因此，患者的自我推荐已成为潜在受试者的重要来源。我们计划继续与肺动脉高压协会保持密切的工作关系，并计划未来向区域支持团体（包括目前在马里兰州南部组建的一个新团体）进行演示。 3) 研究护士继续定期访问当地转诊点，以促进与诊所工作人员和 PAH 患者的沟通。 4) 除了联系区域学术中心外，我们还继续联系区域临床实践。当地的肺科和心脏病科诊所已表示有兴趣转诊患者。