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.

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