Different Cytokine Patterns in BMPR2-Mutation-Positive Patients and Patients With Pulmonary Arterial Hypertension Without Mutations and Their Influence on Survival

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.