Clinical trial NCT04086537: BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension
Official title: Association Between BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension Patients: an Explorative Cross-sectional Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension
BMPR2
Iron Metabolism
Hepcidin
Mutations
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: University Hospital Heidelberg
name: Hannover Medical School
name: University Hospital Carl Gustav Carus
name: University of Leipzig
name: University of Giessen
First posted: 2019-09-11
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
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.

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.

Eligibility criteria: Inclusion Criteria Patients:

1. Informed consent
2. Male or female PAH, including idiopathic, heritable and other forms of group 1 PAH (according to Nice classification) patients 18-80 years of age
3. Invasively diagnosed PAH by right heart catheter (invasively confirmed diagnosis according to the current PAH definition of valid guidelines at time of initial diagnosis)
4. Optimized medical therapy for PAH (such as endothelin-receptor-antagonists, inhaled prostanoids, phosphodiesterase-5-inhibitors, diuretics and if useful, supplemental oxygen) for at least 2 months before entering the study
5. Able to understand and willing to sign the Informed Consent Form

Inclusion Criteria Healthy Controls:

1. Informed consent
2. Male or female healthy controls 18-80 years of age
3. Able to understand and willing to sign the Informed Consent Form

Exclusion Criteria Patients:

1. Pregnancy or lactation
2. Change in disease-specific medication within 8 weeks before enrolment
3. Intravenous iron supplementation within the preceding 2 months
4. Acute infection
5. Comorbidities affecting iron metabolism such as hemolytic anemias, genetic disorders of hemoglobin, diabetes, systemic cardiovascular disease, sickle cell disease, thalassemia

Exclusion Criteria Healthy Controls:

1. Pregnancy or lactation
2. Intravenous iron supplementation within the preceding 2 months
3. Acute infection
4. Heart or lung disease
5. Comorbidities affecting iron metabolism such as hemolytic anemias, genetic disorders of hemoglobin, diabetes, systemic cardiovascular disease, sickle cell disease, thalassemia

Primary outcomes:
measure: The relationship between absolute values of hepcidin levels and BMPR2 expression
timeFrame: at enrollment
measure: The relationship between hepcidin levels and BMPR2 expression
timeFrame: at enrollment
Secondary outcomes:
measure: Correlation of BMPR2 expression levels with ferritin levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with transferrin levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with soluble transferrin receptor saturation and concentration
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with iron levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with red blood distribution cell width
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with erythroferrone levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with hemoglobin levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with hematocrit
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with erythropoietin (EPO) levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with C-reactive protein levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with interleukin 6 (IL6) levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with NT-proBNP levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BMP2 messenger ribonucleid acid (mRNA) expression levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BMP6 messenger ribonucleid acid (mRNA) expression levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with overall transcriptomic analysis in blood samples and formalin fixed human PAH lung tissue samples
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BMPR2 protein levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BMP2 protein levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BMP6 protein levels
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with 6-minute walking distance (6-MWD)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with BORG Scale of 6-minute walking distance (6-MWD)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with WHO functional class
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with forced vital capacity (FVC)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with forced expiratory volume in one second (FEV1)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with forced expiratory flow (FEV)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with total lung capacity (TLC)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with diffusion-limited carbon monoxide (DLCo)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with residual volume
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of oxygen
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of carbon dioxide
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with blood gas analysis including oxygen saturation
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with blood gas analysis including supplemental oxygen "yes" or "no"
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with cardiac output (CO)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with cardiac index (CI)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with pulmonary capillary wedge pressure (PAWP)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with mixed venous oxygen saturation (SvO2)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with right atrium area (RA-area)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with right ventricle area (RV-area)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with myocardial performance index (Tei)
timeFrame: at enrollment
measure: Correlation of BMPR2 expression levels with tricuspid annular plane systolic excursion (TAPSE)
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with systolic pulmonary artery pressure
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with right ventricular function
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with left ventricular function
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with right ventricular pressure
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with pulmonary artery pressure
timeFrame: at enrollment
measure: Correlation of BMPR2 Expression with pulmonary vascular resistance
timeFrame: at enrollment
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Centre for Pulmonary Hypertension at the Thoraxklinik, Heidelberg University Hospital
Study officials:
References: