Simpson Catherine E, Griffiths Megan, Yang Jun, Nies Melanie K, Vaidya R Dhananjay, Brandal Stephanie, Martin Lisa J, Pauciulo Michael W, Lutz Katie A, Coleman Anna W, Austin Eric D, Ivy D Dunbar, Nichols William C, Everett Allen D, Hassoun Paul M, Damico Rachel L
Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
Dept of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University, Baltimore, MD, USA.
ERJ Open Res. 2021 Oct 11;7(4). doi: 10.1183/23120541.00378-2021. eCollection 2021 Oct.
Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival , has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models. Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics. Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p<0.01). Mortality risk doubled for each log higher endostatin (hazard ratio 2.3, 95% CI 1.6-3.4, p<0.001). Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models. Adding endostatin to REVEAL-based and ESC/ERS criteria-based risk assessment strategies improved mortality risk prediction. Endostatin is a robust, independent predictor of mortality in PAH. Adding endostatin to existing PAH risk prediction strategies improves PAH risk assessment.
目前可用于评估肺动脉高压（PAH）疾病严重程度和死亡风险的非侵入性标志物与疾病的基本生物学特性无关。内皮抑素是一种已知可抑制肺动脉内皮细胞迁移、增殖和存活的血管生成抑制肽，在小型PAH队列研究中，它与不良血流动力学和缩短生存期有关。这项观察性队列研究旨在评估：1）在一个大型多中心PAH队列中循环内皮抑素水平的预后性能；2）将内皮抑素纳入现有PAH风险预测模型所获得的附加价值。对从2017名有详细临床数据（包括生存时间）的PAH受试者收集的入组样本进行内皮抑素酶联免疫吸附测定（ELISA）。使用多变量回归和Cox比例风险模型检查内皮抑素与包括生存在内的临床变量之间的关联。使用似然比检验、赤池信息准则和贝叶斯信息准则以及C统计量，将包括内皮抑素的扩展生存模型与基于REVEAL风险预测工具和欧洲心脏病学会/欧洲呼吸学会（ESC/ERS）低风险标准的空模型进行比较。较高的内皮抑素水平与较高的右心房压力、平均肺动脉压力和肺血管阻力相关，且与6分钟步行距离较短相关（p<0.01）。内皮抑素每升高一个对数单位，死亡风险增加一倍（风险比2.3，95%置信区间1.6 - 3.4，p<0.001）。当将内皮抑素纳入现有风险预测模型时，它仍然是生存的独立预测因子。将内皮抑素添加到基于REVEAL和基于ESC/ERS标准的风险评估策略中可改善死亡风险预测。内皮抑素是PAH死亡率的一个强大的独立预测因子。将内皮抑素添加到现有的PAH风险预测策略中可改善PAH风险评估。
