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Title: Investigation of the dose and temporal effects of intravenous iron on human cardiopulmonary physiology
Author: Bart, Nicole
ISNI:       0000 0004 7234 2106
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Sustained hypoxia induces a progressive rise in pulmonary artery systolic pressure (PASP). Intravenous (IV) iron administered immediately prior to the hypoxic exposure attenuates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Not yet understood is the duration of effect of IV iron, or the dose-response relationship between clinical indices of iron status and modest loading of iron in non-iron deficient individuals. To address this, two placebo-controlled, double-blind, sustained isocapnic hypoxia studies were conducted in healthy iron-replete participants. In Study A, 22 participants were randomised to a single intravenous bolus dose of iron as ferric carboxymaltose (FCM), or saline on day 1 and exposed to six hours of hypoxia on days 0, 1, 8 and 43. Following the administration of FCM the concentrations of ferritin and hepcidin plus transferrin saturation rose significantly (p < 0.001, p < 0.005, p < 0.001 respectively), and transferrin concentration decreased significantly (p < 0.001); changes that persisted for the study. FCM significantly attenuated the rise in PASP in response to hypoxia (p < 0.001), an effect that persisted at day 43. In Study B, 18 participants were randomised to saline or 250 mg FCM, administered monthly for six months. To avoid iron overload, FCM was only administered to participants who had a ferritin < 300 μg/L and transferrin saturation < 45%. PASP was measured during eight hours of hypoxia, before and after the six month period. Serum ferritin concentration was robustly elevated by FCM by 0.21 μg/L/mg of iron delivered (95% CI: 0.15-0.26 μg/L/mg). Both iron dose and increase in ferritin concentration correlated with an attenuation in PASP rise with hypoxia (p < 0.05 and p < 0.01, respectively). In summary, a bolus dose of iron resulted in an increase in iron indices and altered the cardiorespiratory response to hypoxia for at least 43 days. This was also achieved by incremental doses of iron that did not cause iron overload. The persistent effect of intravenous iron suggests that it may be of therapeutic benefit in some forms of pulmonary hypertension and other hypoxic cardiorespiratory diseases.
Supervisor: Robbins, Peter ; Dorrington, Keith Sponsor: Colt Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available