Association between BMPR2 mutations and iron metabolism in pulmonary arterial hypertension patients

Background: Iron deficiency is common in pulmonary arterial hypertension (PAH) patients and leads to a significantly reduced 6-minute walking distance (6MWD), a higher WHO functional class and greater mortality. Iron metabolism is regulated via the hormone hepcidin, which is upregulated by the binding of bone morphogenetic proteins, to the bone morphogenetic protein receptor 2 (BMPR2). Hepcidin is increased in iron deficient idiopathic and hereditary PAH (I/HPAH) patients falsely signaling iron abundance. At the same time, 25% of IPAH and 85% of HPAH patients carry pathogenic variants in the BMPR2 gene. Objective: We aim to investigate the effect of an unbalanced BMPR2 pathway on iron metabolism and clinical parameters in BMPR2 mutation carriers and non-carriers. Methods: In this explorative cross-sectional study BMPR2 expression of 20 HPAH, 40 IPAH patients and 20 healthy controls will be measured by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The primary endpoint will be the relationship between hepcidin and BMPR2 expression in mutation carriers and non-carriers. Secondary endpoints include iron related parameters, expression level of BMP6, as well as clinical parameters including 6MWD, echocardiographic and haemodynamic values. Additionally, iron staining of lung tissue from HPAH, IPAH patients and controls will reveal information about intracellular iron concentrations. Current status: So far 53 study participants have been successfully enrolled. The expression levels remain to be analysed jointly once recruitment has terminated. Hypothesis: We hypothesize that BMPR2 mutation carriers with lower mRNA expression of BMPR2 show higher hepcidin levels and will suffer from more severe iron deficiency than non-BMPR2 mutation carriers and healthy controls with slightly reduced or normal expression rates, respectively.