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。炎症似乎驱动了这种功能失调的内皮表型，从而传播了遗传上易感性IPAH和DAPAH患者的损伤和修复周期。然而，尽管PAH患者的血管炎症有越来越多的证据，但该过程的时间演变及其对右心（RV）和肺血管重塑的贡献缺乏详细的表型研究。 在此方案中，受试者的特征是超声心动图，步行6分钟，心肺应力测试，肺功能测试，心脏CT，高级心脏MRI技术，基因表达分析和血清生物标志物。我们假设这些受试者的详细表征与PAH中血管炎症的时间演化的更严格概率及其对RV和肺血管功能的影响将为传统的疾病严重程度增加预后价值，并建议对未来研究的新型治疗靶标的预后价值。 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在确保遵守临床方案的同时，具有丰富经验的工作人员，同时保持最高的临床护理标准。 在2015 - 16年度的报告期间，与NIH的人类免疫学中心合作，我们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）用于测量健康对照中的细胞因子（n = 24）和PAH受试者（n = 55）分为3个诊断组（IPAH/HEREDITARIT-PAH，n = 26；结缔组织疾病；结缔组织疾病；缔结组织疾病相关的PAH，n = 19; n = 19; n = 10 compennitial n = 10;其他n = 10; n = 10; telangiectasia相关的PAH，n = 1和Porto-Pulonary PAH，n = 1）。多个线性回归模型用于调整PAH临床特征：年龄，性别，种族，NYHA/WHO分类（I/II与III/IV），步行6分钟的步行距离（6MWD）（6MWD），前列腺素注入，当前使用1 PAH特异性治疗和螺旋罗替酮。与健康对照组相比，各种PAH患者的循环细胞因子水平升高。用测试细胞因子的子集适度跟踪功能分类和6MWD。当前的疗法似乎没有影响这种炎症性特征，但是临床合并症的混淆，相对较少的受试者可能会阻碍我们检测到与PAH治疗相关的差异的能力。 2016年国际心脏和肺移植学会第36届年度会议和科学会议（JHLT 35（4S）：S360，2016），在2016年国际心脏和肺移植学会第36届年度会议上发表了这项名为“血清细胞因子分析”的摘要。 在2016 - 17年的报告期间，我们与人类免疫学中心（CHI）进行了合作。我们将为CHI提供样品，它们将为炎症标记和全血基因表达研究进行处理，以扩大我们使用PAH进行免疫表型受试者的能力。我们还与NHLBI的移植基因组学实验室（LTG）进行了合作，使用基于无细胞的DNA的工具进行探索性研究，以评估与PAH有关的发病机理和损伤。 该协议开放供注册。目前正在从多个站点收到推荐。迄今为止（2017年8月）203本研究审查了潜在受试者的图表，并已注册了47个受试者。