Iron Status and Hypoxic Pulmonary Vascular Responses

Study Overview
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Brief Summary
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On exposure to hypoxia (low oxygen) the normal response is for pulmonary arterial systolic blood pressure (PASP, blood pressure through the lungs) to increase. We have previously shown that raising iron by giving an infusion of iron into a vein reduces this pressure rise and that lowering iron by giving a drug that binds iron, magnifies this response. This is potentially a clinically important observation since iron-deficient people may be at increased risk of pulmonary hypertension if exposed transiently or permanently to hypoxia due to lung disease or residence at high altitude; furthermore if this were true then intravenous iron could be an important treatment in this patient group in the event of hypoxic exposure. The observed effects of iron on PASP are likely to be because iron levels affect oxygen sensing. Low iron levels make the body behave as if exposed to low oxygen by inhibiting the breakdown of the family of oxygen-sensing transcription factors, 'hypoxia inducible factor' or HIF. This includes one of the body's normal responses to low oxygen levels - raising blood pressure through the lungs. This study will answer the question (1) do iron-deficient volunteers have a greater rise in PASP with hypoxia than those who are iron-replete, and (2) does giving intravenous iron cause a greater reduction in the rise in PASP in those who are iron-deficient than iron-replete? The purpose of this study is not to test the safety or clinical efficacy of iron which is already known.

Official Title
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Effect of Endogenous Iron Status on Hypoxic Pulmonary Vascular Responses and Their Attenuation by Intravenous Iron

Conditions
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Lung Hypoxia, Pulmonary Arterial Hypertension, Iron Deficiency

Intervention / Treatment
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* Drug: Intravenous administration of ferric carboxymaltose
* Other: Subacute hypoxic exposures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give informed consent for participation in the study Men and women aged 18 years or older and generally in good health Detectable tricuspid regurgitation on echocardiography during both normoxia and hypoxia enabling measurement of pulmonary arterial pressure For iron-deficient volunteers: ferritin ≤15microg/L and transferrin saturation <16% For iron-replete volunteers: ferritin ≥20microg/L and transferrin saturation ≥20% Exclusion Criteria: Haemoglobin <8.0g/dl Haemoglobinopathy Iron overload defined as ferritin >300microg/L Hypoxia at rest or on walking (SaO2 <94%) or significant comorbidity that may affect haematinics, pulmonary vascular or ventilatory responses, e.g. current infection, a chronic inflammatory condition, known cardiovalvular lesion or pulmonary hypertension, uncontrolled asthma or chronic obstructive pulmonary disease Exposure to high altitude (>2,500m) within the previous six weeks or air travel >4 hours within the previous week Iron supplementation or blood transfusion within the previous 6 weeks Pregnancy or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Iron-deficient<br>Healthy volunteers meeting iron-deficient entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures | Drug: Intravenous administration of ferric carboxymaltose<br>* Intravenous administration of ferric carboxymaltose 15mg/kg up to a maximum dose of 1000mg<br>* Other names: Ferinject;Other: Subacute hypoxic exposures<br>* Exposure to six hours of isocapnic hypoxia with end-tidal partial pressure of oxygen clamped at 55 Torr, with and without prior iron infusion<br>* Other names: Hypoxic challenge;|
| Other: Iron-replete<br>Healthy volunteers meeting iron-replete entry criteria; Intravenous administration of ferric carboxymaltose; Subacute hypoxic exposures | Drug: Intravenous administration of ferric carboxymaltose<br>* Intravenous administration of ferric carboxymaltose 15mg/kg up to a maximum dose of 1000mg<br>* Other names: Ferinject;Other: Subacute hypoxic exposures<br>* Exposure to six hours of isocapnic hypoxia with end-tidal partial pressure of oxygen clamped at 55 Torr, with and without prior iron infusion<br>* Other names: Hypoxic challenge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ∆PASP in iron-replete compared to iron-deficient volunteers | Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers | During six hours of hypoxia without prior iron infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ∆PASP, with versus without prior iron infusion, in iron-replete compared to iron-deficient volunteers | Difference between the rise in pulmonary artery systolic pressure during a hypoxic challenge in iron-replete compared to iron-deficient volunteers, with versus without a prior iron infusion | During two six-hour periods of hypoxia; assessments separated by at least a week | 
| Blood parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers |  | After six hours of hypoxia, at both study assessments | 
| Ventilation parameter changes, pre- versus post-intravenous iron, in iron-replete compared to iron-deficient volunteers |  | During six hours of hypoxia, at both study assessments | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxia, Pulmonary hypertension, Iron deficiency, Hypoxic pulmonary vasoconstriction