LTBP-2 Protein May Help Predict Long-term Survival in PAH: Analysis

Protein levels 'significantly' elevated in PAH patients, biomarker study finds

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A protein called LTBP-2 was found to be significantly elevated in people with pulmonary arterial hypertension (PAH), according to a new analysis — and the data suggest that measuring its levels may help predict long-term survival among PAH patients.

Further, blood levels of LTBP-2 were also able to predict transplant-free survival in people with PAH, highlighting the protein’s potential use as a biomarker for better determining prognosis in this patient population.

The comprehensive tissue analysis found high levels of the protein in the diseased right heart ventricle tissue and in the bloodstream of PAH patients.

Additional studies are now needed to understand the role of LTBP-2 in heart function and to confirm its potential value as a predictive biomarker for PAH, according to researchers.

“The identification of new therapeutic targets and [specific] prognostic biomarkers …. is of great importance,” the team wrote.

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The biomarker study, “Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension,” was published in the journal Nature Cardiovascular Research.

In PAH, narrowing of the pulmonary arteries, the blood vessels that transport blood through the lungs, restricts blood flow, causing high blood pressure, or hypertension. This makes it harder for the right ventricle of the heart to pump blood through the body, leading to the enlargement of the heart muscle.

Right ventricular function is a main determining factor in the functional abilities and survival of PAH patients. But despite progress in understanding right ventricular failure, knowledge gaps remain in the cellular and molecular mechanisms leading to remodeling of the right ventricle and hypertension.

Investigating molecular players in PAH

An improved understanding of the molecular players involved in disease processes could lead to the identification of better prognostic markers and potential targets for the development of PAH therapies.

Accordingly, finding currently unidentified molecules that play a role in right ventricle dysfunction and their relationship to risk in PAH are key priorities.

To address that, a team led by researchers at the Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, in Canada, conducted a comprehensive tissue analysis to identify and characterize new blood biomarkers that could help monitor right ventricular failure in PAH.

The team tested gene activity and protein profiles of diseased right ventricular tissue, with and without overt problems in blood flow, and healthy controls. Overall, there were a total of 58 genes whose activity and resulting protein production were different in diseased right ventricle tissue compared with control right ventricle tissue.

To further reduce the biomarker candidates, the team also assessed the protein profiles in the bloodstream of 60 PAH patients in Canada and 28 healthy controls. When this data was joined with the gene and protein levels in the heart tissue, five proteins related to fibrosis, or tissue scarring — LTBP-2, COL6A3, COL18A1, TNC, and CA1 — were found to be significantly increased in people with PAH.

Statistical analysis was applied to determine whether these potential biomarkers could predict transplant-free survival. During a median follow-up of 2.5 years after blood sample collection, 31 PAH patients died, and two underwent a lung transplant.

The analysis confirmed that LTBP-2, COL6A3, COL18A1, and TNC significantly predicted the time to requiring a transplant or dying. However, after adjusting the data for early and long-term pulmonary arterial (REVEAL) risk scores, as well as age, sex, and risk scores from the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS), only LTBP-2 remained an independent predictive factor for transplant-free survival.

These factors are known to influence currently available prognostic biomarkers of PAH, such as the N-terminal fragment of brain natriuretic peptide.

Similar results were obtained when an independent group of 61 PAH patients in the U.K. was assessed as validation.

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LTBP-2 predicts long-term survival in PAH

When the Canadian and U.K. groups were combined, LTBP-2 remained the only independent predictive factor after adjusting for REVEAL risk scores, age, sex, and ESC/ERS scores. After adjusting for only age, sex, and ESC/ERS scores, TNC was also found to be an independent predictive risk factor.

Additional analysis demonstrated that LTBP-2, COL6A3, COL18A1, and TNC significantly identified PAH patients with poorer transplant-free survival, with LTBP-2 having the highest predictive value. Notably, blood levels of LTBP-2 improved risk assessment when added to current risk evaluation tools.

“These data underscore the importance of circulating LTBP-2 levels in the prediction of cardiopulmonary disease outcomes,” the researchers wrote.

Lastly, results showed that LTBP-2 and COL6A3 levels were higher in males than females. LTBP-2, COL6A3, and TNC significantly distinguished poorer transplant-free survival in males, whereas all five biomarkers did in females. There were no differences in these biomarkers when patients received treatment.

“We demonstrated that plasma latent transforming growth factor beta binding protein 2 (LTBP-2) level correlates with [right ventricle] function in human PAH and adds incremental value to current risk stratification models to predict long-term survival in two independent PAH cohorts,” the researchers wrote.

“Further studies are needed to clarify the function of identified proteins and to assess their full potential value as prognostic biomarker for PAH,” they added.