Impaired BMPR2 signalling across pulmonary hypertension subgroups: a multicentre study

In heritable pulmonary arterial hypertension (HPAH) patients, bone morphogenetic protein receptor 2 (BMPR2) signalling and blood mRNA expression are disturbed and reduced. It is unclear whether BMPR2 expression is also altered in other pulmonary arterial hypertension (PAH) forms or in chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to investigate the expression of BMPR2 signalling pathway components in different subgroups of pulmonary hypertension (PH) patients and healthy controls.

In this multicentre, cross-sectional study, a total of 234 subjects were included in seven cohorts: 30 HPAH patients, 38 idiopathic PAH without and 40 idiopathic PAH with comorbidities, 38 systemic sclerosis-associated PAH, 47 CTEPH patients, 9 healthy BMPR2 pathogenic variant carriers and 32 healthy controls. ELISAs and qPCR were performed on peripheral blood samples for BMP10, BMPR2, SMAD5, ID1 and EIF2AK4. Univariate ANOVA was used to compare expression across groups.

BMPR2 mRNA expression was significantly reduced in all PH subgroups compared with healthy controls (p<0.001). Lower BMPR2 mRNA expression correlated with worse haemodynamics. BMP10 protein expression showed significant differences between the analysed groups (p<0.001). Higher BMP10 protein levels correlated with worse cardiac output (p=0.005), World Health Organization functional class (p=0.002), N-terminal pro-brain natriuretic peptide (p=0.003) and 6-min walking distance (p=0.003).

Our data suggest that BMPR2 mRNA expression is not only significantly reduced in carriers of pathogenic BMPR2 variants, but also across all other assessed PAH subgroups and in CTEPH, indicating a potential general impairment of BMPR2 signalling. BMPR2 mRNA and BMP10 protein expression in blood may serve as novel biomarkers for disease severity.