Background: Iron deficiency is common in idiopathic and heritable pulmonary arterial hypertension patients (I/HPAH). A previous report suggested a dysregulation of the iron hormone hepcidin, which is controlled by BMP/SMAD signalling involving bone morphogenetic protein receptor 2 (BMPR2). Pathogenic variants in the BMPR2 gene are the most common cause of HPAH. Their effect on patient hepcidin levels has not been investigated.

Objective: The aim of this study was to assess whether iron metabolism and control of the iron regulatory hormone hepcidin was disturbed in I/HPAH patients with and without a pathogenic variant in the gene BMPR2 compared to healthy controls.

Methods: In this explorative, cross-sectional study hepcidin serum levels were quantified by enzyme-linked immunosorbent assay. Iron status, inflammatory parameters and hepcidin modifying proteins such as IL6, erythropoietin and BMP2, BMP6 were measured in addition to BMPR-II protein and mRNA levels. Clinical routine parameters were correlated with hepcidin levels.

Results: In total 109 I/HPAH patients and controls, separated into 3 groups, 23 BMPR2 mutation carriers, 56 non-carriers and 30 healthy controls were enrolled. Of these, 84% had iron deficiency requiring iron supplementation. Hepcidin levels were not different between groups and corresponded to the degree of iron deficiency. By contrast, the upstream signals IL6, erythropoietin, BMP2 or BMP6 did not correlate with hepcidin expression, suggesting that decreased iron availability in PAH patients directly controls hepcidin levels.

Conclusion: I/HPAH patients showed an adequate iron regulation. Iron deficiency was  prevalent albeit independent of pathogenic variants in the gene BMPR2.