Blood Levels of Endostatin Seen to Aid Models of Likely PAH Outcomes
Circulating endostatin, a protein that inhibits new blood vessel formation, appears to correlate well with mortality and disease severity in people with pulmonary arterial hypertension (PAH) in a large, observational study.
Blood levels of endostatin show a “clear potential … as a robust prognostic biomarker in PAH” and could help assessments by being added to existing PAH risk predictive models, its researchers wrote. Significant associations between these levels and mortality were particularly evident in idiopathic PAH patients.
Findings were reported in the study “The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension” published in the European Respiratory Journal, the journal of the European Respiratory Society.
Researchers in the U.S., noting that endostatin’s potential as a blood biomarker of likely outcomes in PAH “remains uncertain,” assessed its performance using patient data from the PAH Biobank repository run by the National Institutes of Health.
The team hypothesized that endostatin levels would correlate with PAH severity, predict mortality risk, and add value to existing predictive models of PAH risk. To determine if this was so, the researchers included endostatin levels into two different mortality prediction models for PAH, and analyzed levels in a large group of patients.
Data analyzed covered up to 2,017 people with PAH. The cohort’s mean age was 55, most were female (about 80%), and approximately 82% were of European ancestry. Of them, 870 had idiopathic PAH and 623 had connective tissue disease-associated PAH (CTD-PAH).
Endostatin levels, measured in all patients, were found to be highest in those with CTD-PAH, and lowest in those with portopulmonary hypertension — a condition defined as PAH associated with portal hypertension, or high pressure within the portal vein (the vein that carries blood from the digestive organs to the liver).
The protein’s levels among the CTD-PAH and portopulmonary hypertension groups were significantly different from those in the overall cohort.
Across the entire group, analysis showed that each log increase of endostatin was associated with various measures of disease severity. (A log increase measures changes on a magnitude scale, in ways similar to that used to indicate earthquake magnitudes.)
Disease severity measures included higher right arterial pressure, higher mean pulmonary arterial pressure, higher pulmonary vascular resistance, decreased stroke volume, lower pulmonary arterial compliance, and a shorter distance traveled in the 6-minute walking distance test.
Among patient subgroups, endostatin’s association with right arterial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, and the 6-minute walking test were greater in those with idiopathic PAH than those with CTD-PAH.
A significant link between cardiac output (the amount of blood the heart pumps per minute) and endostatin levels was also seen in idiopathic PAH patients.
Of the 1,984 patients with available follow-up data, 338 died during the follow-up period.
An unadjusted analysis found poorer survival in patients with higher endostatin levels, those above group’s median level of 37,515 picograms per milliliter (pg/mL), than in those with lower endostatin measures. This association between higher endostatin levels and mortality was also present in the idiopathic PAH and CTD-PAH patient subgroups.
When this analysis was adjusted for multiple potential confounders of the link between endostatin and survival, that each log higher in endostatin levels was associated with a 2.32 times greater risk of mortality. The greatest magnitude of this association was observed in people with idiopathic PAH, in which endostatin with each log rise associated with a nearly six times increase in mortality.
Researchers then tested endostatin levels as a risk criteria in predictive disease models.
Here ,820 patients had enough data for an assessment using the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria. The ESC/ERS is a non-invasive predictive model using multiple biological measures to predict mortality risk.
Including endostatin levels below those of the median (37,515 pg/mL) as a low-risk variable helped to improve distinctions among ESC/ERS risk groups, and added an additional mortality risk level.
REVEAL 2.0 risk scores, another mortality model, were evaluated in 1,984 patients with relevant data. Modifying REVEAL risk scores by subtracting one point for endostatin levels below the median, and adding a point for those above it, helped to improve the distinction of subgroups among the lower risk categories in the first 12 to 24 months of follow-up.
These findings led researchers to conclude that adding endostatin levels to both risk prediction models improved their predictive capabilities, indicating that new markers like endostatin could help to refine PAH risk assessments.
“Our findings demonstrate significant associations between circulating endostatin levels and important measures of disease severity,” the researchers wrote.
“More importantly, our results show strong, significant associations between endostatin levels and mortality, particularly in IPAH, even with adjustment for potential confounders and other disease severity markers,” they concluded. “Collectively, these results show that endostatin has clear potential for clinical use as a robust prognostic biomarker in PAH.”