Inflammatory biomarkers may help predict mortality in left-heart PH

4 proteins linked to TNF-alpha ID'd as useful in new study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Four proteins related to a pro-inflammatory signaling molecule called TNF-alpha may serve as biomarkers to predict mortality in adults with pulmonary hypertension (PH) caused by left heart failure, a new study shows.

Elevated blood levels of two such proteins, both belonging to the TRAIL family, correlated with most standard tests to assess PH severity — and best predicted mortality after adjusting for age and sex.

“These proteins were … prognostic, where higher levels were associated with worse survival rates,” the researchers wrote, noting, however, that data showed that all four proteins returned to normal levels following a heart transplant in a subgroup of patients.

Larger studies are needed to validate these findings and investigate the roles these proteins play in the development of left heart failure-associated PH, the researchers noted.

The biomarker study, “Plasma tumour necrosis factor-alpha-related proteins in prognosis of heart failure with pulmonary hypertension,” was published in the journal ESC Heart Failure.

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Researchers say less invasive inflammatory biomarkers needed in PH

Heart failure — the reduced ability of the heart muscles to pump blood — is a growing health problem among the world’s aging population. Failure of the left side of the heart is a common cause of PH, known as LHF-PH, a condition marked by high blood pressure in the pulmonary arteries, which are the blood vessels that pass through the lungs. In severe cases, a heart transplant is a treatment option.

Because early PH symptoms such as fatigue and shortness of breath are common among other heart and lung diseases, including other types of PH, it can be challenging to diagnose LHF-PH accurately.

Noninvasive blood-based biomarkers have the potential to help diagnose this type of PH but also monitor disease progression, and predict a patient’s most likely outcomes, or prognosis.

“There is a need of less invasive methods to improve risk stratification [classification], predict disease progression, and provide prognostic information of LHF-PH patients,” the scientists wrote, adding, “Blood-borne biomarkers have been proposed to aid in the clinical management of LHF-PH.”

As inflammation is thought to play a role in heart failure, pro-inflammatory signaling proteins, such as those related to TNF-alpha, may serve as LHF-PH biomarkers. But in the context of heart transplant, the role of these proteins has yet to be fully established, according to researchers.

To learn more, a team from Lund University, in Sweden, examined the levels of 20 proteins related to TNF-alpha in blood samples collected from adults with confirmed LHF-PH. Among the 67 patients who provided samples, 39% were women. Of them, 19 patients had undergone a heart transplant.

As a control population, a group of 20 individuals without a past medical history of cardiovascular diseases was included.

Patient follow-up was for up to five years for 27  individuals (40%) and more than five years for 40 (60%). During follow-up, 36 underwent a heart transplant, and 23 died.

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Blood biomarkers seen that may help in diagnosing, managing PAH

4 of 6 proteins found to be good predictors

Blood tests detected six TNF-alpha-related proteins — LTBR, TNFRSF6B, TRAIL-R1, TRAIL-R2, TNFSF13B, and TNFRSF13B — that were significantly higher in LHF-PH patients compared with controls. These same six proteins also were significantly lower after heart transplant, reaching control levels.

Four of the six proteins were statistically significant in their ability to predict mortality. These were LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2.

Based on the cut-off values generated by this analysis, those with blood levels above this value had worse survival rates than did patients with levels below this threshold.

TRAIL-R2 significantly correlated with most blood flow measures regularly used to assess PH severity. Such tests included mean pulmonary arterial pressure (mPAP), mean right atrial pressure (MRAP), NT-proBNP, a marker for heart failure, and pulmonary vascular resistance (PVR), or the resistance to pulmonary blood flow.

Elevated levels of LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2, as well as older age, all were significantly associated with higher mortality risk. Sex and NT-proBNP levels, in contrast, were not. After adjusting for age and sex, all four proteins significantly predicted mortality, with high TRAIL-R1 levels related to an increased relative mortality risk of 28%.

The same research team recently had identified TRAIL proteins as potential biomarkers for a type of PH caused by the narrowing of the pulmonary arteries, known as pulmonary arterial hypertension.

“The present study demonstrated that plasma levels of LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2 were higher in patients with LHF-PH compared with healthy controls,” the team concluded.

“High levels of these four proteins predicted mortality in LHF-PH patients … and may have the potential to be part of a multi-marker panel in prognostication of LHF-PH,” the researchers wrote, adding, “Our results warrant further investigations of TNF-[alpha]-related proteins and LHF-PH progression.”

A Conversation With Rare Disease Advocates