Blood biomarkers seen that may help in diagnosing, managing PAH

One protein, TRAIL, distinguished those with disease from other PH forms

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Certain proteins implicated in the immune response and inflammation showed a potential to serve as blood biomarkers of pulmonary arterial hypertension (PAH) in a recent study.

A possible diagnostic biomarker was seen in the TNF‐related apoptosis‐inducing ligand (TRAIL) protein. It demonstrated an ability to distinguish PAH patients not only from healthy people, but also from adults with other diseases that cause breathlessness, including other forms of pulmonary hypertension (PH).

The annexin A1 (ANXA1) protein was found at different levels in PAH patients alive for more than three years after a diagnosis compared with those who weren’t. The scientists thought it could serve as a prognostic marker for PAH, guiding treatment.

The study, “Plasma TRAIL and ANXA1 in diagnosis and prognostication of pulmonary arterial hypertension,” was published in Pulmonary Circulation.

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PAH biomarkers in blood samples could quicken time to a diagnosis

Early PAH symptoms such as breathlessness (dyspnea) and fatigue can occur in a variety of diseases, including other PH types, as well as in a range of other cardiac and lung conditions.

As such, it can be difficult to identify PAH in its early manifestations, leading to diagnostic delays that are associated with a poorer prognosis, an estimate of a patient’s likely outcomes.

“The identification of new blood-borne biomarkers … that could differentiate among various causes of dyspnea including pulmonary hypertension (PH), could if clinically used potentially lead to earlier diagnosis and treatment initiation and consequently improved prognosis,” the researchers wrote.

Such biomarkers also could help to more accurately monitor disease progression and in grouping patients by their prognosis, they added.

As inflammation is thought to be a key process in PAH onset and progression, proteins related to inflammatory and immune processes could serve as disease biomarkers.

Researchers at Lund University in Sweden examined how well certain inflammatory markers were able to distinguish between PAH patients and other causes of dyspnea, and whether they had value for predicting PAH outcomes.

They examined 25 inflammatory markers in the blood of 152 patients with symptoms of “unclear dyspnea,” compared with samples from 20 healthy adults as controls.

Among the patients, 48 were diagnosed with PAH, 20 with chronic thromboembolic pulmonary hypertension, 33 with PH due to left heart failure with preserved ejection fraction, 36 with reduced ejection fraction, and 15 with heart failure without PH. Ejection fraction is the amount of blood the heart pumps each time it beats.

Lower TRAIL levels seen in PAH patients relative to others with dyspnea

Overall, 16 proteins were found to be at significantly different levels in the blood of PAH patients compared with healthy controls, but only one — TRAIL — was able to distinguish those with PAH from healthy adults, and distinguish PAH from all other causes of dyspnea.

This protein was found at lower levels in PAH patients compared with other groups with dyspnea. Because the protein could distinguish PAH from these other disease groups with reasonable accuracy, the researchers considered that TRAIL “showed diagnostic potential for PAH.”

TRAIL is an inflammatory molecule involved in a type of cell death called apoptosis. Blocking the protein was found to improve survival in animal models of PAH.

In accordance with European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, eight PAH patients were considered low risk, 26 intermediate risk, and 14 at a high risk of a poor prognosis when diagnosed.

ESC/ERS guidelines are the current clinical standard for assessing a patient’s prognosis and for guiding treatment decisions.

Overall, the PAH patients lived for a median of 3.3 years after diagnosis.

Those who survived for more than three years showed different blood levels of seven inflammatory proteins compared with patients who did not. These proteins are ANXA1, CEACAM8, CXCL17, GDF‐15, IL‐6, PSP‐D, and TRAIL‐R2.

In statistical analyses adjusted for age and sex, ANXA1 emerged as the most significant predictor of death for PAH patients. It was found at significantly higher levels in those who died in three or fewer years after a diagnosis.

However, when the data were adjusted for patients’ ESC/ERS diagnostic risk category, the association was no longer statistically significant.

“Further studies addressing whether ANXA1 have an added value to the ESC/ERS risk score” are warranted, the scientists wrote.

They also noted that other causes of dyspnea in this study were related to cardiac disease, rather than to lung disease.

“Future studies evaluating discriminative ability versus lung disease, for example, chronic obstructive lung disease would be of value,” the researchers wrote.

Given this study’s the relatively small sample size, “future multicenter studies are encouraged to validate our results in other external cohorts,” the team concluded.

A Conversation With Rare Disease Advocates