Association Between BMPR2 Mutations and Iron Metabolism in Pulmonary Arterial Hypertension Patients: an Explorative Cross-sectional Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 109
- 试验地点
- 1
- 主要终点
- The relationship between absolute values of hepcidin levels and BMPR2 expression
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
The relationship between absolute values of hepcidin levels and BMPR2 expression
时间窗: at enrollment
assessed as correlation between BMPR2 expression levels and hepcidin levels
The relationship between hepcidin levels and BMPR2 expression
时间窗: 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)
次要结局
- Correlation of BMPR2 expression levels with ferritin levels(at enrollment)
- Correlation of BMPR2 expression levels with erythroferrone levels(at enrollment)
- Correlation of BMPR2 expression levels with interleukin 6 (IL6) levels(at enrollment)
- Correlation of BMPR2 expression levels with NT-proBNP levels(at enrollment)
- Correlation of BMPR2 expression levels with overall transcriptomic analysis in blood samples and formalin fixed human PAH lung tissue samples(at enrollment)
- Correlation of BMPR2 expression levels with BMP6 protein levels(at enrollment)
- Correlation of BMPR2 expression levels with transferrin levels(at enrollment)
- Correlation of BMPR2 expression levels with hemoglobin levels(at enrollment)
- Correlation of BMPR2 expression levels with erythropoietin (EPO) levels(at enrollment)
- Correlation of BMPR2 expression levels with BMP2 messenger ribonucleid acid (mRNA) expression levels(at enrollment)
- Correlation of BMPR2 expression levels with BMP6 messenger ribonucleid acid (mRNA) expression levels(at enrollment)
- Correlation of BMPR2 expression levels with WHO functional class(at enrollment)
- Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of oxygen(at enrollment)
- Correlation of BMPR2 expression levels with right atrium area (RA-area)(at enrollment)
- Correlation of BMPR2 expression levels with hematocrit(at enrollment)
- Correlation of BMPR2 expression levels with BMP2 protein levels(at enrollment)
- Correlation of BMPR2 expression levels with BORG Scale of 6-minute walking distance (6-MWD)(at enrollment)
- Correlation of BMPR2 expression levels with soluble transferrin receptor saturation and concentration(at enrollment)
- Correlation of BMPR2 expression levels with red blood distribution cell width(at enrollment)
- Correlation of BMPR2 expression levels with C-reactive protein levels(at enrollment)
- Correlation of BMPR2 expression levels with BMPR2 protein levels(at enrollment)
- Correlation of BMPR2 expression levels with iron levels(at enrollment)
- Correlation of BMPR2 expression levels with 6-minute walking distance (6-MWD)(at enrollment)
- Correlation of BMPR2 expression levels with total lung capacity (TLC)(at enrollment)
- Correlation of BMPR2 expression levels with residual volume(at enrollment)
- Correlation of BMPR2 expression levels with blood gas analysis including supplemental oxygen "yes" or "no"(at enrollment)
- Correlation of BMPR2 Expression with systolic pulmonary artery pressure(at enrollment)
- Correlation of BMPR2 expression levels with forced vital capacity (FVC)(at enrollment)
- Correlation of BMPR2 expression levels with cardiac output (CO)(at enrollment)
- Correlation of BMPR2 expression levels with right ventricle area (RV-area)(at enrollment)
- Correlation of BMPR2 expression levels with myocardial performance index (Tei)(at enrollment)
- Correlation of BMPR2 expression levels with tricuspid annular plane systolic excursion (TAPSE)(at enrollment)
- Correlation of BMPR2 Expression with left ventricular function(at enrollment)
- Correlation of BMPR2 expression levels with forced expiratory volume in one second (FEV1)(at enrollment)
- Correlation of BMPR2 expression levels with blood gas analysis including oxygen saturation(at enrollment)
- Correlation of BMPR2 expression levels with mixed venous oxygen saturation (SvO2)(at enrollment)
- Correlation of BMPR2 expression levels with forced expiratory flow (FEV)(at enrollment)
- Correlation of BMPR2 expression levels with diffusion-limited carbon monoxide (DLCo)(at enrollment)
- Correlation of BMPR2 expression levels with blood gas analysis including partial pressure of carbon dioxide(at enrollment)
- Correlation of BMPR2 expression levels with cardiac index (CI)(at enrollment)
- Correlation of BMPR2 expression levels with pulmonary capillary wedge pressure (PAWP)(at enrollment)
- Correlation of BMPR2 Expression with right ventricular function(at enrollment)
- Correlation of BMPR2 Expression with right ventricular pressure(at enrollment)
- Correlation of BMPR2 Expression with pulmonary vascular resistance(at enrollment)
- Correlation of BMPR2 Expression with pulmonary artery pressure(at enrollment)
研究者
Prof. Dr. med. Ekkehard Gruenig
Prof. Dr. med.
Heidelberg University