BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension

NCT ID: NCT04086537

Last Updated: 2021-04-29

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 109 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-05-02
• Study Completion Date: 2021-02-28

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.

Conditions

Pulmonary Arterial Hypertension

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

BMPR2-mutation carriers

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.

hepcidin levels and BMPR2 expression

Intervention Type: DIAGNOSTIC_TEST

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

non-BMPR2 mutation carriers

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.

hepcidin levels and BMPR2 expression

Intervention Type: DIAGNOSTIC_TEST

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

healthy controls

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.

hepcidin levels and BMPR2 expression

Intervention Type: DIAGNOSTIC_TEST

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

Interventions

hepcidin levels and BMPR2 expression

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 Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

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

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

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital Heidelberg

OTHER

Sponsor Role: collaborator

Hannover Medical School

OTHER

Sponsor Role: collaborator

University Hospital Carl Gustav Carus

OTHER

Sponsor Role: collaborator

University of Leipzig

OTHER

Sponsor Role: collaborator

University of Giessen

OTHER

Sponsor Role: collaborator

Heidelberg University

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. med. Ekkehard Gruenig

Prof. Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Centre for Pulmonary Hypertension at the Thoraxklinik, Heidelberg University Hospital

Heidelberg, , Germany

Countries

Germany

Other Identifiers

2019-03IM

Identifier Type: -

Identifier Source: org_study_id