BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension

NCT04086537 | Completed

• 1 other identifier: 2019-03IM
• Study Type: observational
• Target: 109
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Arterial Hypertension

Keywords

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

Outcome Measures

Primary Outcomes (2)

• The relationship between absolute values of hepcidin levels and BMPR2 expression

  assessed as correlation between BMPR2 expression levels and hepcidin levels

  at enrollment

• The relationship between hepcidin levels and BMPR2 expression

  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)

  at enrollment

Secondary Outcomes (45)

• Correlation of BMPR2 expression levels with ferritin levels

  at enrollment

• Correlation of BMPR2 expression levels with transferrin levels

  at enrollment

• Correlation of BMPR2 expression levels with soluble transferrin receptor saturation and concentration

  at enrollment

• Correlation of BMPR2 expression levels with iron levels

  at enrollment

• Correlation of BMPR2 expression levels with red blood distribution cell width

  at enrollment

Study Arms (3)

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.

Diagnostic Test: hepcidin levels and BMPR2 expression

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.

Diagnostic Test: hepcidin levels and BMPR2 expression

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.

Diagnostic Test: hepcidin levels and BMPR2 expression

Interventions

hepcidin levels and BMPR2 expression 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

BMPR2-mutation carriers; healthy controls; non-BMPR2 mutation carriers

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Informed consent
• Male or female PAH, including idiopathic, heritable and other forms of group 1 PAH (according to Nice classification) patients 18-80 years of age
• Invasively diagnosed PAH by right heart catheter (invasively confirmed diagnosis according to the current PAH definition of valid guidelines at time of initial diagnosis)
• 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
• Able to understand and willing to sign the Informed Consent Form
• Informed consent
• Male or female healthy controls 18-80 years of age
• Able to understand and willing to sign the Informed Consent Form

You may not qualify if:

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

Sponsors & Collaborators

• Heidelberg University: lead
• University Hospital Heidelberg: collaborator
• Hannover Medical School: collaborator
• University Hospital Carl Gustav Carus: collaborator
• University of Leipzig: collaborator
• University of Giessen: collaborator

Study Sites (1)

Centre for Pulmonary Hypertension at the Thoraxklinik, Heidelberg University Hospital

Heidelberg, 69126, Germany

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

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.

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: September 9, 2019
• First Posted: September 11, 2019
• Study Start: May 2, 2019
• Primary Completion: January 31, 2020
• Study Completion: February 28, 2021
• Last Updated: April 29, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)