Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia

Abstract

This study shows that a single dose of intravenous iron reduces the effects of hypoxia on the pulmonary circulation in a manner that persists for at least several weeks. This is long after the foreign iron-sugar complex has been cleared from the blood. It raises the possibility that manipulating iron stores, even in people who are not initially iron deficient, could be used for therapeutic gain in some forms of pulmonary hypertension .

Abstract

Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days ( days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 ( P < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly ( P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly ( P < 0.001). These changes remained significant at day 43. We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.