Clinical Translational Research Program in Pulmonary Arterial Hypertension (PAH): Disease Mechanisms, Biomarkers, and Novel Therapeutic Targets

肺动脉高压 (PAH) 临床转化研究项目：疾病机制、生物标志物和新治疗靶点

• 批准号: 10915306
• 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/10915306
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Pulmonary hypertension (PH) due to direct pulmonary vascular injury is collectively referred to as pulmonary arterial hypertension (PAH), & is distinct from other causes of PH such as left sided heart failure, parenchymal lung disease with hypoxemia & chronic thromboembolic disease. Idiopathic PAH (IPAH) is an unexplained form of PAH where the triggering insult to the endothelium is unclear. Several diseases may manifest PAH that is identical in histopathology to IPAH. Diseases resulting in PAH (referred to as disease-associated PAH) include autoimmune disorders (i.e. limited systemic sclerosis, mixed connective tissue disease, & systemic lupus erythematosus), HIV infection, congenital heart disease, & liver disease with portal hypertension. Contemporary paradigms of PAH pathobiology include endothelial damage and disruption, genetic & epigenetic contributions, metabolic derangements with a hyper-proliferative, anti-apoptotic cellular phenotype, & both systemically & locally dysregulated inflammation. In the absence of PAH-specific surrogate markers for assessing disease severity & prognosis, risk prediction continues to rely on subjective functional assessments & invasive hemodynamic measurements. There is continued interest in the discovery of novel, biologically relevant, non-invasive biomarkers that may simplify PAH risk stratification & serve as markers of ongoing disease progression &, ideally, response to therapy. In PAH, inflammation appears to drive the dysfunctional endothelial phenotype, propagating cycles of injury & repair. However, detailed phenotypic studies are lacking on the temporal evolution of this process & its contribution to RV & pulmonary vascular remodeling. At the NIH Clinical Center patients with WHO group 1 PAH are being enrolled in a natural history study (13-CC-0012) assessing patients at baseline, biannually in the 1st year and then annually to: 1) Characterize the contribution of inflammation to disease progression & long-term outcomes in PAH & 2) Identify non-invasive markers of vascular inflammation that add prognostic value to traditional measures of disease severity & suggest novel therapeutic targets for future research. In addition, to standard clinical testing, patients undergo serial assessments using innovative imaging techniques, flow cytometric analyses of circulating endothelial cells & bone marrow progenitor cells, genome-wide blood transcriptomic profiles and novel biomarkers such as plasma cfDNA. The collective data will be used to investigate the ability of blood markers of vascular inflammation and/or high-resolution cardiac CT & MRI to stage disease severity & predict clinically relevant outcomes. The study has enrolled 89 individuals (66 patients / 23 healthy volunteers). Total study population will be 150 adult PAH subjects & 50 age & gender matched controls (i.e. healthy volunteer matched to 3 PAH patients). Inflammation is recognized as a feature of the abnormal pulmonary arteries in PAH patients, & it has been hypothesized, but remains unknown as to whether drugs that block inflammation could be beneficial in patients with PAH. Mineralocorticoid receptor (MR) antagonists, like spironolactone, have been widely used in patients with left sided heart failure or LV dysfunction post-MI. Evidence suggests spironolactone improves endothelial function & reduces inflammation. Patients with WHO group 1 PAH are being enrolled in the Spironolactone Interventional Trial (SPIRIT-PAH, 12-CC-0211); a phase 1-2 randomized, double blinded, placebo-controlled 6-month study of spironolactone treatment in PAH. The trial examines the safety & tolerability of spironolactone & its efficacy as assessed by effects on exercise capacity & clinical worsening. We seek to determine if spironolactone provides benefits in PAH through anti-inflammatory effects & improvements in endothelial function. The study has enrolled 40 individuals & per statistical assessment plan targets at least 50. Our original PAH protocol (05-CC-0041: n = 31) assessed whether CECs and/or PBMC may serve as PAH biomarkers. The project used flow cytometry to develop a methodology for isolating relevant numbers of viable CECs from healthy & PAH subjects. CECs & PBMCs were obtained from peripheral blood (PB) specimens. A subset of subjects had a right heart catheterization to assess pulmonary pressures and obtain pulmonary blood specimens. Available data suggested no trend towards CEC enrichment in pulmonary vein blood compared to PB for healthy (4.4 vs 4.8 CEC/ml) & PAH (2.4 vs 3.0 CEC/ml) subjects. There was a trend towards CEC enrichment in pulmonary artery blood compared to PB for healthy (13.8 vs 4.8 CEC/ml) & PAH (3.3 vs 3.0 CEC/ml) subjects. We published a manuscript (Am J Physiol Lung Cell Mol Physiol, 318(1): L98-L111, 2019) containing our PBMC data as part of a larger meta-analysis. The meta-analysis defined a robust & generalizable transcriptomic signature in the blood of PAH patients that can help inform the identification of biomarkers & therapeutic targets. This protocol (1 of 3) is closed to enrollment & open for data analysis. Remaining bio-specimens include RNA, plasma, serum, circulating endothelial cells & T-Cells. We are further evaluating systemic inflammation in PAH by using CT to assess Coronary Artery Plaque Burden in Patients with PAH. Preliminary data was presented at the American Thoracic Society (ATS) International Conference (AJRCCM, 199:A6795, 2019). Compared to controls (n = 7) matched for traditional risk factors of coronary artery disease, PAH subjects (n = 7) tended to have a higher burden of coronary artery plaque as determined by CT angiography. These findings & their relevance to symptoms & functional capacity, need to be further investigated in a larger PAH cohort which we are accumulating. We also investigated whether or not PAH Patients display normal kinetics of clot Formation. Preliminary data was presented at the AHA Scientific Sessions (Circulation, 140:A10714, 2019) & the complete analysis subsequently published (Pulm Circ, 11(3):1-9, 2021). PAH patients on stable medical therapy did not demonstrate abnormal clotting kinetics or fibrinolysis by thrombelastography (TEG). Additionally, these patients did not demonstrate abnormal levels of hematologic markers associated with thrombosis & fibrosis. In addition, we investigated whether or not HSCs, CPCs & CECs are altered in PAH patients compared to healthy controls. Preliminary data was presented at the ATS International Conf (AJRCCM, 207:A3790, 2023). Analysis revealed an increased number of CECs in PAH patients thereby supporting the pathobiological paradigm of endothelial injury. In collaboration with the NHLBI Laboratory of Applied Precision Omics (APO) we are investigating Plasma Cell-free DNA (cfDNA) as a novel marker of disease severity in PAH. Preliminary data was submitted to the ACC 68th Annual Scientific Session (J Am Coll Cardiol, 73(9, S1): S1897, 2019). Based on the encouraging preliminary results, we entered into an MTA with PAH programs at Allegheny General Hospital & Tufts Medical Center, receiving 48 plasma samples from Allegheny (exploratory cohort) & 161 samples from tufts (validation cohort) along with clinical data. We not only measured cfDNA levels in patients & healthy volunteers (n=48), but also subjected a subset of the samples to bisulfite sequencing and a deconvolution algorithm to map tissue-specific sources of cfDNA. The complete analysis published during this reporting period (Circulation, 146(14):1033-1045, 2022) revealed that in patients with PAH, circulating cfDNA is elevated, correlates with disease severity & predicts worse survival. cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis, thus providing biologic plausibility for cfDNA as a PAH bio

直接肺血管损伤引起的肺动脉高压（pH）被统称为肺动脉高压（PAH），并且与其他pH的原因不同，例如左侧心力衰竭，伴有低氧血症和慢性血栓栓塞性势力势力疾病的实质性肺部疾病。特发性PAH（IPAH）是PAH的一种无法解释的形式，其中触发对内皮的损害尚不清楚。几种疾病可能表现出与IPAH相同的PAH。导致PAH（称为疾病相关的PAH）的疾病包括自身免疫性疾病（即有限的全身性硬化症，混合结缔组织疾病和全身性红斑狼疮），HIV感染，先天性心脏病和肝病患有门毒素。 PAH病理生物学的当代范式包括内皮损害和破坏，遗传和表观遗传学贡献，具有过度增殖，抗凋亡性细胞表型的代谢危险，以及全身和局部失调的炎症。 在缺乏评估疾病严重性和预后的PAH特异性替代标记的情况下，风险预测继续依赖于主观功能评估和侵入性血液动力学测量。人们对发现新颖的，生物学相关的非侵入性生物标志物的发现一直持感兴趣，这些生物标志物可以简化PAH风险分层并成为正在进行的疾病进展的标志，理想情况下，对治疗的反应。 在PAH中，炎症似乎驱动了功能失调的内皮表型，从而传播了损伤和修复周期。但是，缺乏该过程的时间演变及其对RV和肺血管重塑的贡献的详细表型研究。在NIH临床中心患者中，谁正在参加一项自然史研究（13-CC-0012），该研究（13-cc-0012）评估基线时的患者，一年一年，每年在第一年，然后每年至：1）炎症对疾病进展的贡献，表征了PAH中疾病进展和长期表征的疾病进展和长期衡量标准，以识别出不可变的病情易变性标记，以识别出疾病的高度价值和疾病的疾病，以识别出疾病的疾病，并鉴定出疾病的疾病进展和疾病进展。未来研究的治疗靶标。此外，对于标准的临床测试，患者使用创新成像技术，循环内皮细胞和骨髓祖细胞的流式细胞仪分析，全基因组的血液转录谱以及新型生物标记物（如Polasma CFDNA）进行了连续评估。集体数据将用于研究血管炎症和/或高分辨率心脏CT和MRI的血液标志物对疾病严重程度的能力，并预测临床上相关的结果。该研究已招募89名个人（66名患者 / 23名健康志愿者）。总研究人群将为150名成人PAH受试者和50岁的年龄和性别匹配的对照组（即，与3名PAH患者相匹配的健康志愿者）。 炎症被认为是PAH患者肺动脉异常的特征，并且已经假设炎症，但对于阻断炎症的药物是否可能对PAH患者有益，但尚不清楚。矿物皮质激素受体（MR）拮抗剂（如螺内酯）已被广泛用于左侧心力衰竭或MI后LV功能障碍的患者。有证据表明，螺内酯可以改善内皮功能并减少炎症。 WHO 1组PAH的患者正在参加螺内酯介入试验（Spirit-Pah，12-CC-0211）；一项1-2期随机，双盲，安慰剂对照的6个月研究PAH的螺内酯治疗研究。该试验检查了螺内酯的安全性和耐受性及其功效，这些影响通过对运动能力和临床恶化的影响评估。我们试图通过抗炎作用和内皮功能的改善来确定螺内酯是否会为PAH提供益处。这项研究已招募了40个个人，并且每个统计评估计划目标至少50个。 我们最初的PAH协议（05-CC-0041：n = 31）评估了CEC和/或PBMC是否可以用作PAH生物标志物。该项目使用流式细胞术来开发一种方法，用于从健康和PAH受试者中隔离相关数量的可行CEC。 CECS和PBMC是从外周血（PB）标本获得的。一部分受试者具有右心导管插入术，以评估肺部压力并获得肺部血液标本。与健康（4.4 vs 4.8 CEC/ml）和PAH（2.4 vs 3.0 CEC/mL）受试者相比，可用的数据表明，与PB相比，肺静脉血液中CEC富集的趋势没有趋势。与健康（13.8 vs 4.8 CEC/ml）和PAH（3.3 vs 3.0 vs 3.0 CEC/ml）受试者的PB相比，肺动脉血的CEC富集的趋势是富含CEC的趋势。我们发表了一份手稿（Am J Physiol肺细胞Mol Physiol，318（1）：L98-L111，2019），其中包含我们的PBMC数据，作为较大的荟萃分析的一部分。荟萃分析定义了PAH患者血液中可靠且可推广的转录组签名，可以帮助您识别生物标志物和治疗靶标的识别。该协议（1 of 3）被关闭以注册并打开以进行数据分析。剩余的生物特异性包括RNA，血浆，血清，循环内皮细胞和T细胞。 我们通过使用CT评估PAH患者的冠状动脉菌斑负担，进一步评估PAH的全身性炎症。初步数据在美国胸部学会（ATS）国际会议上介绍（AJRCCM，199：A6795，2019）。与冠状动脉疾病的传统危险因素相匹配的对照组（n = 7）相比，PAH受试者（n = 7）往往具有CT血管造影确定的冠状动脉菌斑的较高负担。这些发现及其与症状和功能能力的相关性，需要在我们正在积累的较大的PAH队列中进一步研究。 我们还研究了PAH患者是否表现出凝块形成的正常动力学。初步数据在AHA科学会议上（Circulation，140：A10714，2019）和随后发布的完整分析（Pulm Circ，11（3）：1-9，2021）。稳定药物治疗的PAH患者未表现出通过血小板术（TEG）（TEG）的异常凝血动力学或纤维蛋白溶解。此外，这些患者没有表现出与血栓形成和纤维化相关的血液学标记水平异常。 此外，我们研究了与健康对照组相比，PAH患者的HSC，CPC和CEC是否改变了。初步数据在ATS International Conf（AJRCCM，207：A3790，2023）中介绍。分析显示，PAH患者的CEC数量增加，从而支持内皮损伤的病理学范例。 在与NHLBI应用精确法（APO）的NHLBI实验室合作，我们正在研究PAH中疾病严重程度的新颖标志物等离子体细胞DNA（CFDNA）。初步数据已提交给ACC第68届年度科学会议（J Am Coll Cardiol，73（9，S1）：S1897，2019）。基于令人鼓舞的初步结果，我们在Allegheny General Hospital＆Tufts医疗中心使用PAH计划进入了MTA，从Allegheny（探索性群体）接收48个血浆样品，并从Tufts（验证群体）（验证群体）收到161个样本以及临床数据。我们不仅测量了患者和健康志愿者的CFDNA水平（n = 48），而且还测量了一部分样品的子集，并将其作为亚硫酸盐测序，并通过将反卷积的算法绘制为CFDNA的组织特异性来源。在此报告期间发表的完整分析（循环，146（14）：1033-1045，2022）表明，在PAH患者中，循环CFDNA升高，与疾病的严重程度相关，并预测生存率较差。 PAH患者中的CFDNA甲基化分析与疾病发病机理的流行范式一致，因此为CFDNA提供了生物学合理性作为PAH Bio