Direct influence of BMPR2 mutations on cytokine patterns and biomarker effectiveness in pulmonary arterial hypertension
Authors: Schwiening Max , Swietlik Emilia M , Pandya Divya , Burling Keith , Barker Peter , Treacy Carmen , Abreu Susana , Wort S. John , Pepke-Zaba Joanna , Graf Stefan , Marciniak Stefan J , Morrell Nicholas , Soon Elaine ,   members of the UK National Cohort Study of Idiopathic and Heritable PAH
Published: May 2021

Background

Pulmonary arterial hypertension (PAH) covers a range of life-limiting illnesses characterized by increased pulmonary arterial pressures leading to right heart failure and death, if untreated. 15-25% of patients have genetic mutations, the most common affecting bone morphogenetic protein receptor type 2 (BMPR2). The aim was to define an inflammatory cytokine profile in BMPR2-mutation positive patients and analyze their influence on survival.

Methods

Levels of cytokines were measured in plasma samples from BMPR2-mutation positive patients (BMPR2mut, n=54), patients without any driving mutations (n=54), and healthy controls (n=56) recruited from the United Kingdom cohort.

Findings

BMPR2-mutation positive patients and patients without mutations had high levels of interleukin-6, interleukin-8, tumor necrosis factor-α, and vascular endothelial growth factor-A compared to controls. Only BMPR2-mutation carrying patients had higher G-CSF levels compared to controls. VEGF-A levels were substantially higher in patients without mutations compared to the BMPR2mut group. Interleukin-6 was a significant discriminator for mortality in the BMPR2mut cohort (cumulative survival with interleukin-6≥1.6pg/ml at 3 years was 65% compared to 96% with interleukin-6<1.6pg/ml, P=0·0013). N-Terminal pro-B-Type natriuretic peptide levels did not discriminate for survival in our BMPR2mut cohort (cumulative survival for patients with an NT-proBNP>130ng/ml at 3 years was 76% compared to 84% for patients with an NT-proBNP≤130ng/ml, P=0·37). NT-proBNP outperformed interleukin-6 in PAH without mutations.

Interpretation

BMPR2-mutation positivity has a direct impact not only on inflammatory profiles but also on effectiveness of prognostic biomarkers. In our BMPR2-mutation positive cohort IL-6 was the strongest prognostic biomarker and NT-proBNP failed to discriminate for survival.

Key messages

What is the key question?

Do pulmonary arterial hypertension patients who are BMPR2-mutation positive have a different cytokine signature than PAH patients without mutations?

What is the bottom line?

BMPR2-mutation positive and PAH patients without mutations display different patterns of cytokine elevation and these cytokines differ in the way they influence transplant-free survival.

Why read on?

In our cohort of BMPR2-mutation positive patients, IL-6 is the best prognostic biomarker while NT-proBNP failed to discriminate for survival – this implies that prognostic biomarkers and by inference treatments could be genotype-specific.

Graphical Abstract

TAKE HOME MESSAGE

BMPR2-mutation positive patients have different inflammatory and growth factor profiles compared to PAH patients without mutations. Interleukin-6 is an effective biomarker for transplant-free survival in our cohort of BMPR2-mutation positive patients while NT-proBNP is ineffective. Conversely, NT-proBNP appears to be a more effective biomarker for pulmonary arterial patients without any mutations.