Impact of Iron Supplementation on Right Ventricular Function and Exercise Performance in Hypoxia

Study Overview
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Brief Summary
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The purpose of this study is to determine if taking iron supplement pills improves exercise performance in low-oxygen conditions.

Detailed Description
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Hypoxia (low oxygen) causes the blood vessels in the lungs to constrict (hypoxic pulmonary vasoconstriction). This increases the pressure (afterload) the right ventricle faces as it pumps blood to the lungs. Increased right ventricular afterload during hypoxia may compromise exercise capacity. Intravenous iron administration prior to hypoxic exposure has been shown to blunt the hypoxia-induced increase in right ventricular afterload. This may be through iron's action in the Hypoxia Inducible Factor (HIF) pathway. Iron is a cofactor for prolyl hydroxylases that degrade HIF subunits and thus may turn off HIF-related pathways of pulmonary artery vasoconstriction and remodeling. However, it is not known whether oral iron supplementation similarly reduces right ventricular afterload in hypoxia, or what impact iron has on right ventricular function and exercise capacity in hypoxia. This is a human physiology study that will characterize the impact of oral iron supplementation on right ventricular function and exercise performance in hypoxia. It is a follow-up sub-study to a separate, parent study (NCT05272514) by the same investigators which evaluates resting and exertional right ventricular performance in normoxia and hypoxia in 10 healthy individuals. In this follow-up study, 5 individuals who completed the parent study will be eligible to enroll. As part of the parent study, participants will complete baseline echocardiography to assess right ventricular function and cardiopulmonary exercise testing to assess exercise performance in normoxia and hypoxia. After enrolling in this study, participants will take an oral iron supplement (ferrous sulfate 325 mg oral daily) for 30 days. They will then return for one visit. First, participants will complete submaximal exercise while breathing room air. Submaximal exercise will include 5 minutes each at 40% and 60% of baseline hypoxic (fraction of inspired oxygen [FiO2] 12%) maximal oxygen uptake (VO2max) achieved during parent study. After 10 minutes' rest, echocardiographic measurements will be obtained at upright rest with FiO2 21%, 17%, 15%, and 12% to characterize the impact of progressive hypoxia on resting right ventricular function. Participants will then repeat submaximal exercise tests at FiO2 12%, followed by a short period of recovery. Thereafter, participants will complete a symptom-limited cardiopulmonary exercise test at FiO2 12%. Measurements will include heart rate/rhythm, oxygen saturation, blood pressure, gas exchange parameters (oxygen uptake [VO2], carbon dioxide production [VCO2], and minute ventilation), rated perceived exertion and resting echocardiographic measurements.

Official Title
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Impact of Iron Supplementation on Right Ventricular Function and Exercise Performance in Hypoxia (A Sub-Study)

Conditions
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Right Ventricular Dysfunction, Hypoxia

Intervention / Treatment
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* Drug: Ferrous sulfate 325mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 60 For women, premenopausal status Exclusion Criteria: Active cardiovascular or pulmonary disease (e.g. hypertension, coronary artery disease, cardiomyopathy, arrhythmia, valvular abnormalities, diabetes, peripheral vascular disease, tobacco use, chronic obstructive pulmonary disease, asthma, interstitial lung disease, restrictive lung disease, or pulmonary hypertension) Use of cardiac- or pulmonary-related medications Prior history of high altitude pulmonary edema or high altitude cerebral edema Body mass index < 18.5 or > 30 Anemia Iron deficiency Iron supplementation (oral or intravenous) in the preceding 60 days Systemic anticoagulation or aspirin use that cannot be temporarily held for the study Pregnancy Non-cardiopulmonary disorders that adversely influence exercise ability (e.g. arthritis or peripheral vascular disease) Dedicated athletic training (defined here as spending >9 hours per week in vigorous physical activity [≥6 mets]) Regular high-altitude exercise (defined here as engaging in vigorous physical activity [≥1 hour at ≥6 mets] at ≥8,000 ft for >2 days per week over the preceding 4 weeks) Residence at ≥8,000 ft for 3 or more consecutive nights in the preceding 30 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Prevention
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All participants will complete resting echocardiography and exercise testing as part of parent study prior to oral iron supplementation. Participants who enroll in this study will complete 30 days of oral iron supplementation and then repeat resting echocardiography and exercise testing.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Healthy individuals - pre-iron<br>Five healthy participants will be enrolled. Baseline echocardiography and exercise data prior to oral iron supplementation will be obtained as part of the parent study to this study (NCT05272514). | Drug: Ferrous sulfate 325mg<br>* Participants will take one tab of ferrous sulfate 325 mg (equivalent to 65 mg elemental iron) daily for 30 days.<br>|
| Active Comparator: Healthy individuals - post-iron<br>The same five healthy participants will complete echocardiography and exercise testing after taking 30 days of oral iron supplementation. | Drug: Ferrous sulfate 325mg<br>* Participants will take one tab of ferrous sulfate 325 mg (equivalent to 65 mg elemental iron) daily for 30 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum workload | Workload in Watts at peak exercise on upright cycle ergometer | Up to 1 hour | 
| Maximal oxygen uptake | Maximal oxygen uptake at peak exercise (VO2max) in L/min | Up to 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen saturation at peak exercise | Peripheral oxygen saturation (SpO2) | Up to 1 hour | 
| Submaximal Stage 1 workload | Workload in Watts at 40% x hypoxic VO2max (obtained during baseline hypoxic exercise test) | Up to 1 hour | 
| Submaximal Stage 2 workload | Workload in Watts at 60% x hypoxic VO2max (obtained during baseline hypoxic exercise test) | Up to 1 hour | 
| Ventilatory threshold | Oxygen uptake (VO2 in L/min) at which slope of VCO2/VO2 relationship increases | Up to 1 hour | 
| Tricuspid annular plane systolic excursion measured by echocardiography | In mm | Up to 1 hour | 
| Pulmonary artery systolic pressure measured by echocardiography | In mmHg | Up to 1 hour |