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

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.

Keywords: hypoxia inducible factor; pulmonary circulation; pulmonary hypertension.

Fig. 1.

Protocol for the study. Twenty-two participants were recruited. Participants were block randomized 1:1 to iron or saline. Participants were exposed to sustained isocapnic hypoxia for 6 h on days 0, 1, 8, and 43. Day 0 was a baseline measurement day that was undertaken at least 3 days before day 1. An infusion of iron or saline was given on day 1.

Fig. 2.

Hematology results. No significant effects of infusion of 1 g of iron were detected in hemoglobin concentration (Hb), hematocrit (Hct), or mean cell volume (MCV). Erythropoietin concentration (EPO) appeared mildly elevated at day 8 following iron infusion compared with controls. Values and error bars are means ± SE. P values refer to the interactive term for the change over time between groups and are calculated using linear mixed-effects modeling. N.S, not significant.

Fig. 3.

Iron indexes. Following infusion of 1 g of iron, there were significant increases in the concentration of ferritin, transferrin saturation (Tsat), and hepcidin and a significant fall in transferrin concentration (Tf). No significant effects were observed in soluble transferrin receptor concentration (sTfR). Ferritin n = 6 for both groups at day 43. Values and error bars are means ± SE. P values refer to the interactive term for the change over time between groups and are calculated using linear mixed-effects modeling.

Fig. 4.

Gas control during exposure to hypoxia. A and B: end-tidal oxygen (Pet_O2) levels over 6 h for saline and iron groups, respectively. C and D: end-tidal carbon dioxide (Pet_CO2) levels for saline and iron groups, respectively. E and F: arterial hemoglobin saturation (SpO₂) for saline and iron groups, respectively. Values and error bars are means at each hour of hypoxia ± SE.

Fig. 5.

Pulmonary artery systolic pressure (PASP) during exposure to hypoxia. A and B: PASP responses in saline and iron groups, respectively. Responses to sustained hypoxia were blunted following iron infusion on day 1 and remained blunted at days 8 and 43 (P < 0.001). Values and error bars are means ± SE.