BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension, BMPR2, Iron Metabolism, Hepcidin, Mutations

Previously characterised PAH patients, including idiopathic, heritable and other forms of group 1 PAH with and without BMPR2 mutation which have already been analysed and are regularly seen in the Center for Pulmonary Hypertension may be contacted to participate in the study. Clinical and laboratory values will be collected prospectively. Patients with IPAH/HPAH and other forms of PAH who are newly diagnosed within the duration of the trial will receive routine diagnostic workup including the routine information about a possible BMPR2 mutation analysis for IPAH/HPAH patients according to guidelines. During their routine visit the patients' medical history will be obtained and physical examination will be conducted. Moreover, an electrocardiogram (ECG), determination of World Health Organization (WHO)-functional class, laboratory testing (NT-proBNP and routine laboratory), echocardiography will be routinely carried out. BMPR2 expression levels will be measured in blood samples. Additionally, laboratory samples will be collected for analysis of further parameters reflecting iron metabolism such as hepcidin, ferritin, iron levels, IL6 and circulating soluble transferrin receptor Levels. In addition, healthy controls will be invited to participate in this study to obtain comparable levels of hepcidin and BMPR2 pathway members.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by an increase in pulmonary arterial pressure and pulmonary vascular resistance, which result in right heart hypertrophy and decompensation. It crucially affects exercise capacity, quality of life and prognosis. Idiopathic and heritable forms of PAH (IPAH and HPAH) are often associated with mutations of the bone morphogenetic protein receptor 2 (BMPR2) accompanied by disease development at an earlier age, more severe hemodynamic phenotype and a higher mortality rate. Other forms of PAH also show reduced expression levels of BMPR2, even if no BMPR2 mutation has been identified in these patients. Moreover, the balance of iron metabolism was shown to be disturbed in IPAH patients. IPAH patients suffered from iron deficiency with low levels of serum iron concentrations and while at the same time displaying high levels of the iron uptake regulating hormon hepcidin. The hormone hepcidin, which inhibits iron absorption from the intestine, is upregulated by the BMPR2 signaling pathway (via BMP6). The impact of BMPR2 expression on iron homeostasis, however, has not been investigated yet. Mutation and non-mutation carriers with invasively diagnosed PAH by right heart catheter and under optimized medical therapy will be enrolled in this study. An explicit exclusion criterion is intravenous iron supplementation in the last 2 months to capture their natural iron metabolic status. Subjects will be recruited at the Center for Pulmonary Hypertension at Thoraxklinik Heidelberg University Hospital. The measurement of BMPR2 expression will be performed with real-time polymerase chain reaction. In addition, routine laboratory parameters of iron metabolism and clinical parameters will be statistically correlated with the BMPR2 expression of BMPR2 mutation carriers and non-mutation carriers. Clinical examinations will comprise of routine diagnostic workup. No study specific clinical assessments will be performed. For diagnostic workup, an extended blood analysis for BMPR2 expression will be performed, which is mentioned in the informed consent document. In addition, healthy controls will be invited to participate in this study.Healthy controls will only receive a blood collection to obtain control values for hepcidin, BMPR2 expression rate and levels of BMPR2 pathway members such as Bone Morphogenetic Protein 2 and 6 (BMP2 and BMP6). They will not receive any further examinations. BMPR2 mutation status will not be investigated. The control group will be age and gender matched to non-BMPR2 mutation carriers. Therefore, this study aims to investigate whether PAH patients with a reduced expression rate of BMPR2 have altered serum levels of hepcidin and further iron related metabolites compared to PAH patients with normal expression levels and whether these patients present with more pronounced limitations in clinical parameters. This study could help to understand iron metabolism in PAH and generate new therapeutic targets for the treatment of the disease.

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