Blood Levels of Growth Factor Tied to PAH Severity, Outcomes in Study

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by Lindsey Shapiro PhD |

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Higher blood levels of hepatoma-derived growth factor (HDGF), involved in blood vessel remodeling, associated with greater disease severity and mortality risk in pulmonary arterial hypertension (PAH) patients in a large biobank study.

Based on additional work in a rat model, its researchers suggested these outcomes were due to the factor’s effects on vessel remodeling.

Elevated HGDF levels also correlated with portopulmonary hypertension (PoPH), a PAH subtype associated with portal hypertension whose main cause is scarring in the liver.

“We confirmed the association of serum HDGF with PAH severity, mortality, and expanded our analysis across PAH subtypes,” the researchers wrote, adding that HDGF measures are valuable in helping to stratify PAH and might be “particularly important for PoPH.”

The study, “Hepatoma-derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival,” was published in the journal Pulmonary Circulation.

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PAH is characterized by a narrowing of the pulmonary arteries that supply blood to the lungs, leading to higher blood pressure that can ultimately cause heart failure.

While its underlying mechanisms are not fully understood, the uncontrolled growth, or proliferation, of cells lining blood vessels can contribute to their narrowing. Several growth factors, which stimulate cell proliferation, have been linked to PAH’s development.

A team led by researchers at Johns Hopkins University previously reported that hepatoma-derived growth factor levels were elevated in the lungs of PAH patients compared with healthy individuals, and were even higher in those with severe disease. These findings led the team to propose HDGF as a potential biomarker of disease progression.

The researchers now analyzed HDGF levels in a larger PAH patient group  — 2,017 people covering several PAH subtypes — whose blood samples and clinical data were stored in a PAH biobank. HDGF was measured from samples collected at participants’ enrollment, while clinical data was collected over a median 41 months (nearly 3.5 years) of follow-up.

Over this time, 324 of these patients (16.3% of 1,984 people with full follow-up data) died.

Results showed that higher HDGF levels associated with worse hemodynamic measurements, or evaluations of blood flow, across several clinical tests, including pulmonary artery pressure. Increased levels of this growth factor also associated with dyspnea, or labored or difficult breathing at rest.

Together, the results indicated greater disease severity in patients with higher HDGF, the researchers noted.

The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator analyzes multiple clinical features to predict the risk of death in PAH populations. Analysis showed a significantly greater mortality risk, as seen in higher REVEAL scores, in people with higher HDGF levels.

Highest HDGF levels were seen in people with idiopathic (unknown cause) pulmonary hypertension (43%) or PoPH (5.5%) relative to other PAH types. Increased HDGF levels also significantly raised the likelihood of a patient having PoPH. HDGF is normally highly expressed in the liver, which could explain its association with PoPH, the team suggested.

Researchers then turned to a rat model to further evaluate the role of HDGF in PAH. With disease progression, HDGF levels in these animals were seen to rise in blood from the heart’s left ventricle. Since the left ventricle receives oxygenated blood from the lungs, it is likely that the lungs are the source of elevated HDGF, the researchers noted.

HDGF, which is normally present in endothelial cells that line lung blood vessels, was also found in smooth muscle cells that had proliferated in the lungs of PAH rats, similar to observations made in lung tissue from PAH patients.

The researchers suggested this could be part of vascular remodeling — a process of reorganizing the structure and arrangement of blood vessels — that is known to contribute to PAH progression.

“Our data here indicates that HDGF is actively participating in pulmonary vascular remodeling, but it could also play a multifunctional role in PAH pathology,” they noted.

“In conclusion,” the researchers wrote, “HDGF is actively involved in pulmonary vascular remodeling, higher serum HDGF levels are associated with PAH clinical severity, and predict worse survival in PAH.”

Further work is needed to understand how “HDGF is involved in the pathophysiology [disease-contributing biological processes] of PAH” and if it might be of use in developing better treatments.

They noted their study’s findings are limited by HDGF measures coming from samples taken at study enrollment, as levels may have differed at timepoints when clinical data were collected.