Spironolactone Therapy in Pulmonary Arterial Hypertension (PAH)

肺动脉高压是一种罕见的疾病与生存率低。 由1）遗传易感性和2）引发肺血管损伤的触发刺激（两次打击假说）导致的内皮功能障碍似乎在PAH的发病机制和进展中发挥核心作用。 炎症似乎驱动这种功能失调的内皮表型，在遗传易感的特发性IPAH患者和疾病相关的DaPAH患者中传播损伤和修复周期。 靶向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（RV）衰竭和死亡的治疗尚未进行过测试。 螺内酯是一种盐皮质激素受体（MR）和雄激素受体（AR）拮抗剂，已被证明可改善内皮功能并减少炎症。 重度PAH和NYHA IV级症状患者的当前管理包括在病程后期，一旦发生临床右心衰竭，使用MR拮抗剂进行利尿和利钠作用。目前，在PAH早期阶段检查MR拮抗剂治疗的安全性和有效性的随机临床试验中，没有充分描述的数据。 该方案的概念在2011年获得了NIH Bench-to-Bedside奖，正式方案于2012年9月首次获得NHLBI IRB批准。随后，在合作研究中心寻求并获得了IRB批准，并在2013年夏季之前在所有机构进行了各种修订。2013 - 2015年，我们在NIH建立了一个PAH临床研究项目，该项目由具有心脏病学、肺部和重症监护专业知识的多学科医务人员以及在确保遵守临床方案同时保持最高临床护理标准方面具有丰富经验的监管和研究护理支持人员组成。目前正在从多个地点收到推荐信。迄今为止，在我们的自然史方案（13-CC-0012）中入组的24例受试者中，有8例已入组本研究（螺内酯随机干预试验）。 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）心肺运动试验; 3）炎症标志物的血浆分析; 4）外周血单核细胞（PBMC）的基因表达分析;和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停药的发生率，评估螺内酯在PAH中的安全性和耐受性。我们假设，在PAH受试者的疾病早期开始螺内酯治疗可通过抗炎作用和改善肺动脉内皮功能提供额外获益 加强招募和增加入学人数的计划包括： 1)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，并计划在未来向区域支持团体进行介绍。 2)研究护士继续定期访问当地转诊中心，以促进与诊所工作人员和PAH患者的沟通。 3)除了接触区域学术中心，我们继续接触区域临床实践。当地肺科和心脏科的做法表示有兴趣转介病人。 4)我们正在与宾夕法尼亚州（利哈伊谷医疗中心）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，最近增加了INOVA费尔法克斯作为转诊网站。 5)探索NIH PAH研究网站和社交媒体途径。

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.