Spironolactone Therapy in Pulmonary Arterial Hypertension (PAH)

螺内酯治疗肺动脉高压（PAH）

• 批准号: 9154159
• 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/9154159
• 关键词: Amendment; Androgen Receptor; Anti-Inflammatory Agents; Anti-inflammatory; Award; Blood Vessels; Cardiology; Cardiopulmonary; Cessation of life; Clinic; Clinical; Clinical Protocols; Clinical Research; Communication; Critical Care; Data; Disease; Diuretics; Double-Blind Method; Early treatment; Echocardiography; Enrollment; Exercise; Exercise stress test; Failure; Future; Gene Expression Profiling; Genetic Predisposition to Disease; Healthcare; Heart failure; Incidence; Incidence Study; Inflammation; Injury; Institution; Institutional Review Boards; Intervention Trial; Kidney Failure; Late Effects; Lung; Magnetic Resonance Imaging; Medical Staff; Medical center; Mineralocorticoid Receptor; Monitor; National Heart, Lung, and Blood Institute; Natural History; Nursing Research; Pathogenesis; Patients; Pennsylvania; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Placebos; Plasma; Play; Protocols documentation; Pulmonary Hypertension; Pulmonary artery structure; Randomized; Randomized Clinical Trials; Rare Diseases; Recruitment Activity; Relative (related person); Resolution; Right ventricular structure; Role; Safety; Site; Source; Spironolactone; Staging; Stimulus; Support Groups; Symptoms; Testing; United States National Institutes of Health; Universities; Ventricular; Visit; Walking; West Virginia; Work; base; bench to bedside; clinical care; clinical practice; drug intolerance; endothelial dysfunction; experience; high standard; hyperkalemia; improved; in vivo; inflammatory marker; injury and repair; interest; multidisciplinary; placebo controlled study; prevent; programs; pulmonary arterial hypertension; saluretic; social; targeted treatment; vascular inflammation; web site

Pulmonary arterial hypertension 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 IPAH and patients with disease-associated DaPAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular (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 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. In 2013 -15 we established at the NIH a clinical research PAH program consisting of a multidisciplinary medical staff with expertise in cardiology, pulmonary, and critical care as well as a regulatory and research nursing support staff with extensive experience in assuring compliance with clinical protocols while maintaining the highest standards of clinical care. Referrals are currently being received from multiple sites. To date of the 24 subjects enrolled in our Natural History protocol (13-CC-0012) eight have been enrolled in this study (Spironolactone Randomized Interventional Trial). Subjects undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory 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. We hypothesize that initiating therapy with spironolactone at an earlier stage of disease in subjects with PAH could provide additional benefits through anti-inflammatory effects and improvements in pulmonary artery endothelial function Plans for bolstering recruitment and increasing enrollment included: 1) We continue to present our study to local pulmonary hypertension support groups and as a result, patient self-referrals have been 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. 2) Research nurses continue to conduct periodic visits to local referral sites in order to facilitate communication with clinic staff and PAH patients. 3) 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. 4) We are in discussions with additional institutions in Pennsylvania (Lehigh Valley Medical Center) and West Virginia (West Virginia University Healthcare) to increase recruitment and recently added INOVA Fairfax as a referral site. 5) Exploring an NIH PAH studies website and avenues in social media.

肺动脉高压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。 炎症似乎会驱动这种功能失调的内皮表型，从而传播了特发性伊帕（IPAH）遗传易感患者的损伤和修复周期和与疾病相关的DAPAH患者。 靶向肺血管炎症的治疗尚未测试，从而延迟或预防右心室（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 IV级症状的患者的治疗包括使用MR拮抗剂来进行利尿剂和发作性效果，这是在课程的后期，一旦临床右心力衰竭就出现了。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，最初由NHLBI IRB批准了正式的协议，于2012年9月获得了IRB的批准。随后在合作站点进行了IRB的批准，并获得了各种修正案，并在2013年夏季的所有机构中都在NIH的培训中构建了各种机构。心脏病学，肺部和重症监护以及具有丰富经验的监管和研究护理支持人员，可以确保遵守临床方案，同时保持最高的临床护理标准。目前正在从多个站点收到推荐。迄今为止，在我们的自然历史方案中注册的24名受试者（13-CC-0012）已招募了八项研究（螺内酯随机介入试验）。 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。我们假设在患有PAH的受试者的早期疾病阶段开始使用螺内酯治疗可以通过抗炎作用和改善肺动脉内皮功能提供额外的益处 加强招聘和登记越来越多的计划包括： 1）我们继续向局部肺动脉高压支持小组展示我们的研究，因此，患者自我推荐是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，并计划向区域支持小组进行未来的演讲。 2）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。 3）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。 4）我们正在与宾夕法尼亚州（Lehigh Valley Medical Center）和西弗吉尼亚州（西弗吉尼亚大学医疗保健）的其他机构进行讨论，以增加招聘，并最近将Inova Fairfax作为推荐地点。 5）在社交媒体上探索NIH PAH研究网站和大道。