The Prescient Prognosticator? Hepatoma-derived Growth Factor in Pulmonary Hypertension.
The Prescient Prognosticator? Hepatoma-derived Growth Factor in Pulmonary Hypertension.
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DOI：
10.1164/rccm.201606-1159ed
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发表时间：
2016
影响因子：
24.7
通讯作者：
Fineman,JeffreyR
中科院分区：
文献类型：
--
作者：
Kameny,RebeccaJohnson;Fineman,JeffreyR
在本期杂志中，杨和同事（pp. 1264-1272）提供了关于测量循环血管生成因子、肝癌衍生生长因子（HDGF）的新技术的有趣数据（1）。此外，他们还建立了HDGF表达与肺动脉高压（PAH）疾病严重程度和生存率之间的相关性。这些研究者认为HDGF可能是评估PAH患者疾病进展和预后的一个新的临床指标。HDGF是一种具有多种功能的分泌蛋白，包括作为在肺内皮细胞中高度表达的血管生成因子（2，3）。此外，HDGF刺激支气管和肺泡上皮细胞的生长，有助于肺重塑（4）。鉴于微血管重塑对PAH发病机制的重要作用，因此，HDGF表达是PAH疾病发展和进展的生物学合理介质。事实上，作者证明了来自其衍生队列的与先天性心脏病相关的PAH患者的肺血管内皮细胞内存在强烈的HDGF抗体染色。在目前的研究中，作者报告了一种新的夹心ELISA的发展，具有良好的内和试验间的可靠性。值得注意的是，作者使用这种ELISA方法确定了关于一致的HDGF测量的几个因素，包括尽管重复冻融循环但HDGF水平恒定，HDGF在室温下数天的稳定性，以及血清或血浆中的等效值。应该赞扬作者建立这些实际问题，因为该测定似乎有希望转化为临床实践。为了确定PAH患者的HDGF水平，研究人员首先确定了特发性PAH（IPAH）和先天性心脏病相关PAH患者衍生队列的HDGF血清浓度。这些患者患有重度PAH，并被列为肺移植患者。他们还测量了一个验证队列中与结缔组织病相关的IPAH和PAH患者的HDGF水平。此外，还有两个对照队列：一名健康志愿者，年龄、种族和性别与衍生队列相匹配，另一名患有合并症的患者--尽管重要的是，充血性心力衰竭是被排除的合并症之一。（中位数，1.93 ng/ml）和更多样化的验证队列（0.82 ng/ml）与健康或慢性病对照受试者（分别为0.29 ng/ml和0.20 ng/ml）相比。使用来自验证组和健康对照组的HDGF浓度生成接受者工作曲线，曲线下面积为0.89，推导的阈值为0.7 ng/ml。使用这个阈值，HDGF在验证和慢性病队列中作为区分性测试表现得相当好，灵敏度和特异性分别为76%和89%。最重要的是，在验证队列中，HDGF水平高于0.7 ng/ml阈值与死亡风险显著增加相关，未经校正的风险比为4.5;这些HDGF水平高的患者还具有功能能力降低，如通过6分钟步行距离和纽约心脏协会功能分级量化的。HDGF与有创血流动力学参数无相关性。这些数据提供了可靠测量的生物标志物的令人兴奋的证据，该生物标志物可能提供超越肺血流动力学数据和无创成像的PAH疾病进展的预后见解。尽管它的…
In this issue of the Journal, Yang and colleagues (pp. 1264–1272) present intriguing data regarding a new technique for measuring the circulating angiogenic factor, hepatoma-derived growth factor (HDGF)(1). In addition, they establish an association between expression of HDGF and pulmonary arterial hypertension (PAH) disease severity and survival. These investigators suggest that HDGF may be a new clinical indicator to assess disease progression and prognosis in patients with PAH. HDGF is a secreted protein with multiple functions, including as an angiogenic factor highly expressed in pulmonary endothelial cells (2, 3). In addition, HDGF stimulates growth of bronchial and alveolar epithelial cells, contributing to lung remodeling (4). Given the significant contribution of microvascular remodeling to the pathogenesis of PAH, HDGF expression is, thus, a biologically plausible mediator of PAH disease development and progression. In fact, the authors demonstrate intense HDGF antibody staining within pulmonary vascular endothelial cells in a patient with PAH associated with congenital heart disease from their derivation cohort. In the current study, the authors report the development of a novel sandwich ELISA with favorable both intra-and interassay reliability. Notably, the authors determined several factors regarding consistent HDGF measurement using this ELISA method, including constant HDGF levels despite repeated freeze-thaw cycles, stability of HDGF for several days at room temperature, and equivalent values in either serum or plasma. The authors should be commended for establishing these practical matters, as the assay appears promising for translation to clinical practice. To establish HDGF levels in patients with PAH, the investigators first determined HDGF serum concentrations in a derivation cohort of patients with idiopathic PAH (IPAH) and PAH associated with congenital heart disease. These patients had severe PAH and were listed for lung transplantation. They also measured HDGF levels in a validation cohort of patients with IPAH and PAH associated with connective tissue disease at enrollment. Additionally, there were two control cohorts: one of healthy volunteers, matched by age, race, and sex to the derivation cohort, and one of patients with comorbidities—although, importantly, congestive heart failure was among the excluded comorbid conditions.Median HDGF levels were significantly higher among both the derivation cohort with severe disease (median, 1.93 ng/ml) and the more varied validation cohort (0.82 ng/ml) compared with either healthy or chronically ill control subjects (0.29 ng/ml and 0.20 ng/ml, respectively.) A receiver operating curve was generated using HDGF concentrations from the validation and healthy control cohorts, with area under the curve of 0.89 and a derived threshold value of 0.7 ng/ml. Using this threshold value, HDGF performed reasonably well as a discriminatory test in the validation and chronically ill cohorts, with a sensitivity and specificity of 76 and 89%, respectively. Most significantly, among the validation cohort, HDGF levels above the 0.7 ng/ml threshold were associated with a significantly increased risk of death, with an unadjusted hazard ratio of 4.5; these patients with high HDGF also had diminished functional ability, as quantified by 6-minute-walk distance and New York Heart Association functional class. HDGF did not correlate with invasive hemodynamic parameters. These data provide exciting evidence of a reliably measured biomarker that might provide prognostic insight into PAH disease progression beyond pulmonary hemodynamic data and noninvasive imaging. Despite its …