The Prescient Prognosticator? Hepatoma-derived Growth Factor in Pulmonary Hypertension

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 promise, there are several limitations to this study. First, both the derivation and validation cohorts contain patients with three subgroups of PAH: IPAH, PAH associated with congenital heart disease, or PAH associated with connective tissue disease. Although these represent important cohorts of patients with PAH, they may also represent more conserved pathobiological mechanisms as compared with patients with PAH associated with lung disease, PAH associated with left-sided heart disease, or even heritable PAH. This may limit the application of HDGF measurement to determine risk among all patients with PAH, regardless of etiology. Additionally, as alluded to by the authors when enumerating the limitations of N-terminal prohormone brain natriuretic peptide as a biomarker for PAH, this study does not include pediatric patients, and it is unclear if HDGF levels and their relationship with outcome can be translated to this important PAH population.

Another important limitation to this study is that HDGF levels do not correlate with invasive hemodynamic parameters, and the relationship of HDGF with outcome is not preserved after adjusting for 6-minute-walk distance or New York Heart Association functional class. Although this may likely represent a confounding effect or a common causality of these clinical parameters on the relationship of HDGF and outcome as the authors suggest, this also limits the additive clinical benefit of HDGF measurement in predicting outcome, as these measures are already obtained as part of routine clinical practice. In PAH, there is an important need for biomarkers or other noninvasive measures that reliably predict invasive hemodynamics to limit the need for serial cardiac catheterizations, with the attendant risk for morbidity and mortality (5). From the authors’ analysis, HDGF does not appear to meet this need.

However, if HDGF can be validated as a novel predictive biomarker that precedes disease progression or if changes in HDGF levels are reflective of meaningful hemodynamic or clinical response to therapy, its measurement may become a significantly valuable clinical tool. Furthermore, HDGF has the benefit over other functional clinical parameters in that it is wholly objective and reliable. In this study, Yang and colleagues present promising data on a dichotomy among survivors and nonsurvivors (1); presumably, those patients with elevated HDGF levels may warrant earlier, more aggressive pharmacologic and surgical interventions.

Beyond its potential role as a biomarker, future studies are need to determine the potential role of HDGF in pathogenesis for PAH—as the authors present, this is biologically plausible. If proven, this may represent a promising new therapeutic target. Indeed, anti-HDGF antibody is already being studied as an adjuvant chemotherapeutic agent in non–small cell lung cancer (6). Overall, the authors should be commended for their development of a novel ELISA, high-fidelity methodology for measuring HDGF and identification of a clinical indicator with promise for practical application in certain subgroups of PAH.