BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Diagnostic Test: hepcidin levels and BMPR2 expression
- Registration Number
- NCT04086537
- Lead Sponsor
- Heidelberg University
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 109
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description healthy controls hepcidin levels and BMPR2 expression Healthy controls free of heart and lung disease or any comorbidities affecting iron metabolism. This control group will be age and gender matched to non-BMPR2 mutation carriers. non-BMPR2 mutation carriers hepcidin levels and BMPR2 expression Patients affected by Pulmonary arterial hypertension (PAH) who resulted negative at the routinely-performed (according to current guidelines) BMPR2 analysis (Idiopathic PAH, IPAH) or patients with Idiopathic PAH (IPAH) and other forms of PAH who are newly diagnosed within the duration of the study and resulted negative for mutation at the routinely-performed (according to current guidelines) BMPR2 analysis. BMPR2-mutation carriers hepcidin levels and BMPR2 expression Patients affected by pulmonary arterial hypertension (PAH) with already determined BMPR2 mutation status (hereditary PAH, HPAH) or patients with idiopathic PAH (IPAH) and other forms of PAH who are newly diagnosed within the duration of the study and resulted positive for mutation at the routinely-performed (according to current guidelines) BMPR2 analysis.
- Primary Outcome Measures
Name Time Method The relationship between absolute values of hepcidin levels and BMPR2 expression at enrollment assessed as correlation between BMPR2 expression levels and hepcidin levels
The relationship between hepcidin levels and BMPR2 expression at enrollment analysis of differences of hepcidin levels in BMPR2 mutation carriers and non-carriers (BMPR2 mutation carriers are assumed to have a lower expression level of BMPR2)
- Secondary Outcome Measures
Name Time Method Correlation of BMPR2 expression levels with BMP6 protein levels at enrollment BMP6 protein levels
Correlation of BMPR2 expression levels with right ventricle area (RV-area) at enrollment right ventricle area (RV-area) determined by echocardiography
Correlation of BMPR2 expression levels with myocardial performance index (Tei) at enrollment myocardial performance index (Tei) determined by echocardiography
Correlation of BMPR2 expression levels with ferritin levels at enrollment Ferritin levels
Correlation of BMPR2 expression levels with erythroferrone levels at enrollment Erythroferrone levels
Correlation of BMPR2 expression levels with interleukin 6 (IL6) levels at enrollment Interleukin 6 (IL6) levels to approximate inflammation
Correlation of BMPR2 expression levels with NT-proBNP levels at enrollment NT-proBNP levels
Correlation of BMPR2 expression levels with overall transcriptomic analysis in blood samples and formalin fixed human PAH lung tissue samples at enrollment overall transcriptomic analysis in blood samples and formalin fixed human PAH lung tissue samples
Correlation of BMPR2 expression levels with transferrin levels at enrollment Transferrin levels
Correlation of BMPR2 expression levels with hemoglobin levels at enrollment Hemoglobin levels
Correlation of BMPR2 expression levels with erythropoietin (EPO) levels at enrollment Erythropoietin (EPO) levels
Correlation of BMPR2 expression levels with BMP2 messenger ribonucleid acid (mRNA) expression levels at enrollment BMP2 mRNA expression levels
Correlation of BMPR2 expression levels with BMP6 messenger ribonucleid acid (mRNA) expression levels at enrollment BMP6 mRNA expression levels
Correlation of BMPR2 expression levels with WHO functional class at enrollment WHO functional class
Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of oxygen at enrollment partial pressure of oxygen
Correlation of BMPR2 expression levels with right atrium area (RA-area) at enrollment right atrium area (RA-area) determined by echocardiography
Correlation of BMPR2 expression levels with hematocrit at enrollment Hematocrit
Correlation of BMPR2 expression levels with BMP2 protein levels at enrollment BMP2 protein levels
Correlation of BMPR2 expression levels with BORG Scale of 6-minute walking distance (6-MWD) at enrollment Borg Scale of 6-minute walking distance (6-MWD)
Correlation of BMPR2 expression levels with soluble transferrin receptor saturation and concentration at enrollment Soluble transferrin receptor saturation and concentration
Correlation of BMPR2 expression levels with red blood distribution cell width at enrollment Red blood distribution cell width
Correlation of BMPR2 expression levels with C-reactive protein levels at enrollment C-reactive protein levels
Correlation of BMPR2 expression levels with BMPR2 protein levels at enrollment BMPR2 protein levels
Correlation of BMPR2 expression levels with iron levels at enrollment Iron levels
Correlation of BMPR2 expression levels with 6-minute walking distance (6-MWD) at enrollment 6-minute walking distance (6-MWD)
Correlation of BMPR2 expression levels with total lung capacity (TLC) at enrollment total lung capacity (TLC)
Correlation of BMPR2 expression levels with residual volume at enrollment residual volume, normally accounting for about 25% of total lung capacity
Correlation of BMPR2 expression levels with blood gas analysis including supplemental oxygen "yes" or "no" at enrollment supplemental oxygen "yes" or "no"
Correlation of BMPR2 Expression with systolic pulmonary artery pressure at enrollment systolic pulmonary artery pressure determined by echocardiography
Correlation of BMPR2 expression levels with forced vital capacity (FVC) at enrollment forced vital capacity (FVC)
Correlation of BMPR2 expression levels with cardiac output (CO) at enrollment cardiac output (CO) measured by right heart catheterization
Correlation of BMPR2 expression levels with tricuspid annular plane systolic excursion (TAPSE) at enrollment tricuspid annular plane systolic excursion (TAPSE) determined by echocardiography
Correlation of BMPR2 Expression with left ventricular function at enrollment left ventricular function determined by echocardiography
Correlation of BMPR2 expression levels with forced expiratory volume in one second (FEV1) at enrollment forced expiratory volume in one second (FEV1)
Correlation of BMPR2 expression levels with blood gas analysis including oxygen saturation at enrollment oxygen saturation
Correlation of BMPR2 expression levels with mixed venous oxygen saturation (SvO2) at enrollment mixed venous oxygen saturation (SvO2) measured by right heart catheterization
Correlation of BMPR2 expression levels with forced expiratory flow (FEV) at enrollment forced expiratory flow (FEV)
Correlation of BMPR2 expression levels with diffusion-limited carbon monoxide (DLCo) at enrollment diffusion-limited carbon monoxide (DLCo)
Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of carbon dioxide at enrollment partial pressure of carbon dioxide
Correlation of BMPR2 expression levels with cardiac index (CI) at enrollment cardiac index (CI) measured by right heart catheterization
Correlation of BMPR2 expression levels with pulmonary capillary wedge pressure (PAWP) at enrollment pulmonary capillary wedge pressure (PAWP) measured by right heart catheterization
Correlation of BMPR2 Expression with right ventricular function at enrollment right ventricular function determined by echocardiography
Correlation of BMPR2 Expression with right ventricular pressure at enrollment systolic, diastolic and mean right ventricular pressure measured by right heart catheterization
Correlation of BMPR2 Expression with pulmonary vascular resistance at enrollment pulmonary vascular resistance measured by right heart catheterization
Correlation of BMPR2 Expression with pulmonary artery pressure at enrollment systolic, diastolic and mean pulmonary artery pressure measured by right heart catheterization
Trial Locations
- Locations (1)
Centre for Pulmonary Hypertension at the Thoraxklinik, Heidelberg University Hospital
🇩🇪Heidelberg, Germany