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）是一种与存活不良有关的罕见疾病。 由1）遗传敏感性引起的内皮功能障碍，以及2）引发肺血管损伤的触发刺激，两次打击的假设似乎在PAH的发病机理和进展中起着核心作用。 炎症似乎会促进这种功能失调的内皮表型，从而传播了特发性PAH（IPAH）的遗传易感患者的损伤和修复周期和与疾病相关的PAH患者。 靶向肺血管炎症的治疗尚未测试，从而延迟或预防RV衰竭和死亡。 螺内酯是一种矿物皮质受体（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轻炎症。 当前对患有严重PAH和NYHA/WHO IV级症状的患者的治疗包括使用MR拮抗剂用于其利尿剂和脂肪尿疗法，这是在课程的后期，一旦临床右心力衰竭发展出来。目前，没有充分描述的数据来自随机临床试验，该试验检查了MR拮抗剂治疗在PAH的早期阶段的安全性和功效。 该协议的概念在2011年获得了NIH基准奖，并于2012年9月批准了NHLBI IRB的正式协议。随后在合作站点进行了IRB批准，并在2013年夏季在所有机构中都对所有机构进行了一致的批准。 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； 2）心肺运动测试； 3）炎症和神经激素标记的血浆分析； 4）外周血单核细胞（PBMC）的基因表达分析； 5）基于高分辨率MRI的肺血管和RV结构和功能的测定。 通过定期监测高钾血症和肾功能不全以及药物停用的发病率，可以评估螺内酯在PAH中的安全性和耐受性。 迄今为止，在我们的自然历史协议中招募的14名受试者（13-CC-0012）中已招募了四名研究（螺内酯随机介入试验）。四个受试者中有两个已经完成了这项研究。 加强招聘和登记越来越多的计划包括： 1）我们的主要研究人员每周都会参加当地的肺诊所，以促进在定期预约期间与诊所工作人员和PAH患者的沟通。 2）我们继续向局部肺动脉高压支持小组介绍我们的研究，因此，患者自我推荐具有重要的潜在受试者来源。我们计划继续与肺动脉高压协会保持密切的工作关系，并计划向包括目前在马里兰州南部组织的新小组进行的区域支持小组计划未来的演讲。 3）研究护士继续定期访问当地推荐地点，以促进与临床人员和PAH患者的沟通。 4）除了与区域学术中心接触外，我们还继续接触区域临床实践。局部肺和心脏病学实践对转诊患者表示兴趣。