BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): hepcidin levels and BMPR2 expression
Intervention type(s): Diagnostic Test
Intervention description(s): Samples will be collected in the three groups. Hepcidin levels will be measured in serum using ELISA and BMPR2 expression will be assessed as previously described using real time-qPCR
Intervention MeSH terms: Hepcidins
Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        BMPR2-mutation carriers and non-BMPR2 mutation carriers will be asked for participation in
        the study.

        Healthy controls will be invited to participate in this study to obtain comparable levels
        of hepcidin and BMPR2 pathway members. This control group will be age and gender matched to
        non-BMPR2 mutation carriers. They will not receive any further examinations. BMPR2 mutation
        status will not be investigated.
      
Biospecimen description: 
      Routine clinical laboratory investigations: Iron metabolism:Hepcidin, iron, ferritin,
      interleukin 6, transferrin, circulating soluble transferrin receptor levels;
      Hematology:Leucocytes, erythrocytes, hemoglobin, hematocrit, platelets; Substrates:
      Bilirubin, cholesterol, triglycerides, creatinine, uric acid, urea, total protein, albumin,
      glucose; Electrolytes:Sodium, potassium, calcium, chloride; Enzymes:serum glutamate
      oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), Gamma-GT,
      Glutamate Dehydrogenase (GLDH), alkaline phosphatase (AP), lactate dehydrogenase (LDH),
      creatine kinase (CK); Others:international normalized Ratio (INR), partial thromboplastin
      time (PTT); Biomarkers:C-reactive Protein (CRP), NT-proBNP; BMPR2 expression with real time
      quantitative polymerase chain reaction (qPCR), RNA extraction with Quiacube, cDNA production
      using Transcriptor First Strand cDNA Synthesis Kit; Laboratory assessments will be determined
      locally on-site.
    
Keywords: Pulmonary Arterial Hypertension; BMPR2; Iron Metabolism; Hepcidin; Mutations