Circulating Angiopoietin-1 Is Not a Biomarker of Disease Severity or Prognosis in Pulmonary Hypertension

BackgroundCirculating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry.MethodsPatients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan—Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression.Results151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan—Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity.ConclusionsDespite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH.

背景 循环血管生成素-1（circulating angiopoietin-1, Ang-1）已在多项实验研究中被证实与肺动脉高压（pulmonary hypertension, PH）存在关联。然而，Ang-1作为肺动脉高压生物标志物的临床相关性仍未明确。本研究依托正在前瞻性招募的吉森肺动脉高压注册研究（Giessen PH Registry）数据，旨在探究Ang-1在肺动脉高压患者中的预后价值与临床意义。
方法 纳入2003年7月至2012年5月期间，在本国家转诊中心接受首次右心导管术（right heart catheterization, RHC）的疑似肺动脉高压患者，所有患者均未接受过特异性肺动脉动脉高压（pulmonary arterial hypertension, PAH）治疗；若患者同意接受可选的生物标志物检测，且经诊断为特发性PAH、结缔组织病相关PAH（connective tissue disease-associated PAH, CTD-PAH）、左心疾病相关性肺动脉高压（PH due to left heart disease, PH-LHD）、慢性血栓栓塞性肺动脉高压（chronic thromboembolic PH, CTEPH），或经RHC排除肺动脉高压（非PH对照组），则纳入本研究。采用线性回归分析Ang-1水平与疾病严重程度（6分钟步行距离及肺血流动力学指标）的相关性；采用Kaplan-Meier曲线、受试者工作特征（receiver operating characteristic, ROC）分析及Cox回归模型，评估Ang-1水平对无移植生存期（主要终点）及临床恶化事件的影响。
结果 共纳入151例肺动脉高压患者（其中特发性PAH、CTD-PAH、PH-LHD、CTEPH分别为39例、39例、32例、41例）及41例非PH对照组。各组间Ang-1水平无显著统计学差异（p=0.8）；在各肺动脉高压亚组中，Ang-1水平与疾病严重程度亦无显著关联（p≥0.07）。Kaplan-Meier分析显示，按四分位数分层的Ang-1水平，对各PH亚组的无移植生存期（p≥0.27）及临床恶化事件（p≥0.51）均无显著影响。回归模型亦未发现Ang-1水平与预后结局存在显著关联（p≥0.31）。受试者工作特征分析未找到可同时最大化灵敏度与特异度的最佳截断值。
结论 尽管实验研究已证实Ang-1与肺动脉高压存在紧密的病理生理关联，但本研究首次针对PH亚组开展的Ang-1综合分析表明，Ang-1并非肺动脉高压中具备预测价值与临床相关性的生物标志物。