A Natural History Study of Novel Biomarkers in Pulmonary Arterial Hypertension

肺动脉高压新型生物标志物的自然历史研究

• 批准号: 9549534
• 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/9549534
• 关键词: Age; Amendment; Biological Markers; Blood Vessels; Cardiac; Cardiology; Cardiopulmonary; Characteristics; Classification; Clinical; Clinical Protocols; Clinical Research; Collaborations; Comorbidity; Connective Tissue Diseases; Critical Care; Diagnostic; Disease; Echocardiography; Enrollment; Evolution; Future; Gender; Gene Expression; Gene Expression Profiling; Genetic Predisposition to Disease; Genomics; Heart-Lung Transplantation; Hereditary hemorrhagic telangiectasia; Human; Imaging Techniques; Immunoassay; Immunology; Immunophenotyping; Inflammation; Inflammatory; Infusion procedures; Inherited; Injury; Institution; International; Intervention Trial; Laboratories; Linear Regressions; Lung; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Medical Staff; Modeling; Molecular Profiling; National Heart, Lung, and Blood Institute; Natural History; Nursing Research; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Play; Process; Prostaglandins; Proteomics; Protocols documentation; Pulmonary function tests; Race; Rare Diseases; Recruitment Activity; Reporting; Resolution; Role; Sampling; Serum; Severity of illness; Site; Societies; Spironolactone; Stimulus; Stress Tests; Testing; Therapeutic Intervention; Transplantation; United States National Institutes of Health; Vascular remodeling; Ventricular; Walking; Whole Blood; Work; base; cell free DNA; circulating biomarkers; clinical care; clinical predictors; clinically relevant; congenital heart disorder; cytokine; endothelial dysfunction; experience; high standard; inflammatory marker; injury and repair; meetings; multidisciplinary; new therapeutic target; novel marker; primary pulmonary hypertension; prognostic value; programs; pulmonary arterial hypertension; synthetic polymer Bioplex; tool; vascular inflammation

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.

肺动脉高压（WHO I 组）是一种与生存率低相关的罕见疾病。 1) 遗传易感性和 2) 引发肺血管损伤的触发刺激（二次打击假说）引起的内皮功能障碍似乎在 PAH 的发病机制和进展中发挥着核心作用。炎症似乎会导致这种功能失调的内皮表型，在遗传易感性 IPAH 和 DaPAH 患者中传播损伤和修复的循环。然而，尽管越来越多的证据表明 PAH 患者存在血管炎症，但对该过程的时间演变及其对右心室 (RV) 和肺血管重塑的贡献缺乏详细的表型研究。 在该方案中，通过超声心动图、6 分钟步行、心肺压力测试、肺功能测试、心脏 CT、先进的心脏 MRI 技术、基因表达谱和血清生物标志物来彻底表征受试者。我们假设，对这些受试者的详细描述，结合 PAH 中血管炎症的时间演变及其对 RV 和肺血管功能的影响的更严格的描述，将为传统的疾病严重程度测量增加预后价值，并提出新的治疗靶点未来的研究。 该方案最初于 2012 年 10 月获得 NHLBI IRB 批准。随后，在合作地点寻求并获得了 IRB 批准，并于 2013 年夏季在所有机构进行了各种修订。2013 年 -15 年，我们在 NIH 建立了临床研究 PAH该计划由具有心脏病学、肺科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水平方面拥有丰富经验的监管和研究护理支持人员组成临床护理标准。 在 2015-16 报告期内，我们与 NIH 人类免疫学中心合作，进行了一项蛋白质组学分析研究，以确定螺内酯对与 PAH 相关的循环介质的影响。基于荧光珠的免疫测定 (Bio-Plex) 用于测量健康对照 (N=24) 和 PAH 受试者 (N=55) 的细胞因子，分为 3 个诊断组（IPAH/遗传性 PAH，n=26；结缔组织病相关性 PAH，n=19；其他先天性心脏病相关性 PAH，n=7；遗传性 PAH；出血性毛细血管扩张相关的 PAH，n=1 和门肺性 PAH，n=1）。使用多元线性回归模型来调整 PAH 临床特征：年龄、性别、种族、NYHA/WHO 分类（I/II 与 III/IV）、6 分钟步行距离 (6MWD)、前列腺素输注、当前使用 1 种 PAH -特异性疗法和螺内酯。与健康对照相比，不同肺动脉高压患者样本的循环细胞因子水平均升高。功能分类和 6MWD 适度跟踪测试细胞因子的子集。目前的治疗似乎并未影响这种炎症特征，但混杂的临床合并症和相对较少的受试者数量可能阻碍了我们检测 PAH 治疗相关差异的能力。这项工作的摘要题为“PAH 中的血清细胞因子分析”，已在 2016 年国际心肺移植学会第 36 届年会和科学会议上发表（JHLT 35(4S):S360, 2016）。 在 2016-17 报告期间，我们与人类免疫学中心 (CHI) 建立了合作。我们将为 CHI 提供样本，他们将对其进行处理以进行炎症标记物和全血基因表达研究，以扩大我们对 PAH 受试者进行免疫表型分析的能力。我们还与 NHLBI 移植基因组学实验室 (LTG) 合作，使用基于游离 DNA 的工具进行探索性研究，以评估 PAH 的发病机制和相关损伤。 该协议开放注册。目前正在从多个网站收到推荐。迄今为止（2017 年 8 月），本研究已审查了 203 个潜在受试者图表，并已入组 47 名受试者。