A Natural History Study of Novel Biomarkers in Pulmonary Arterial Hypertension

肺动脉高压（世卫组织第一类）是一种罕见的与低生存率相关的疾病。由于1)遗传易感性和2)引发肺血管损伤的触发刺激导致的内皮功能障碍，双重打击假说似乎在PAH的发病和进展中都起着核心作用。炎症似乎驱动这种功能失调的内皮表型，在遗传易感的IPAH和DaPAH患者中传播损伤和修复周期。然而，尽管越来越多的证据表明PAH患者存在血管炎症，但缺乏详细的表型研究来研究这一过程的时间演变及其对右心室（RV）和肺血管重构的贡献。

Pulmonary arterial hypertension (WHO Group I) 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 IPAH and DaPAH. However, despite mounting evidence of vascular inflammation in patients with PAH, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to right ventricular (RV) and pulmonary vascular remodeling. In this protocol subjects are thoroughly characterized by echocardiogram, 6-minute walk, cardiopulmonary stress testing, pulmonary function testing, cardiac CT, advanced cardiac MRI techniques, gene expression profiling, and serum biomarkers. We hypothesize that a detailed characterization of these subjects in conjunction with a more rigorous profile of the temporal evolution of vascular inflammation in PAH and its impact on RV and pulmonary vascular function will add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research. The protocol was initially approved by the NHLBI IRB in October 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. In 2015-16 reporting period, in collaboration with the Center of Human Immunology at the NIH, we conducted a proteomic profiling study in order to determine the effects of spironolactone on circulating mediators relevant to PAH. Fluorescent bead-based immunoassay (Bio-Plex) was used to measure cytokines in healthy controls (N=24) and PAH subjects (N=55) divided into 3 diagnostic groups (IPAH/Hereditary-PAH, n=26; Connective Tissue Disease Associated-PAH, n=19; and Other n=10 Congenital Heart Disease Associated-PAH, n=7; drug-induced PAH, n=1; hereditary hemorrhagic telangiectasia-associated PAH, n=1 and porto-pulmonary PAH, n=1). Multiple linear regression models were used to adjust for PAH clinical characteristics: Age, gender, race, NYHA/WHO classification (I/II versus III/IV), 6-minute walk distance (6MWD), prostanoid infusion, current use of 1 PAH-specific therapy, and spironolactone. Circulating cytokine levels were elevated across a diverse sample of PAH patients compared to healthy controls. Functional classification and 6MWD modestly tracked with a subset of the tested cytokines. Current therapies did not appear to influence this inflammatory signature, but confounding clinical comorbidities and the relatively small number of subjects may have hindered our ability to detect PAH-treatment related differences. An abstract from this work entitled "Serum Cytokine Profiling in PAH" was presented at the 2016 International Society for Heart and Lung Transplantation 36th Annual Meeting and Scientific Sessions (JHLT 35(4S):S360, 2016). During the 2016-17 reporting period we entered into a collaboration with the Center for Human Immunology (CHI). We will provide CHI with samples that they will process for markers of inflammation, and whole blood gene expression studies in order to expand our ability to immunophenotype subjects with PAH. We also entered into a collaboration with the Laboratory of Transplantation Genomics (LTG) of the NHLBI to do exploratory studies using cell-free DNA based tools to evaluate the pathogenesis of and injury related to PAH. The protocol is open for enrollment. Referrals are currently being received from multiple sites. To date (August 2017) 203 charts of potential subjects have been reviewed for this study and 47 subjects have been enrolled.