BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia.
METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography.
RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups.
CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health.
FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.
Matthew C. Frise, Hung-Yuan Cheng, Annabel H. Nickol, M. Kate Curtis, Karen A. Pollard, David J. Roberts, Peter J. Ratcliffe, Keith L. Dorrington, Peter A. Robbins
(A) First study day (saline infusion). (B) Second study day (iron infusion). (C) Difference in response between study days. Responses for the ID group are shown in red, and those for the IR group are shown in blue (data are means ± SEM; n = 13 in each group). Solid black bars indicate the 6-hour periods of eucapnic hypoxia. Continuous lines represent responses during hypoxia. Broken lines indicate the change in air-breathing PASP induced by the 6-hour period of hypoxia, which reflects the degree of acclimatization of the pulmonary vasculature. On the first study day, the increase in PASP during hypoxia was significantly greater in the ID group. On the second study day, following iron infusion, the increase in PASP was significantly attenuated in both groups. Euoxic PASP was significantly elevated following exposure to 6 hours of hypoxia in both groups on the first study day, but this effect was abolished by prior administration of i.v. iron on the second day. Panel C illustrates that the effect on PASP of prior iron administration was minimal for the first 2 hours of hypoxia. Thereafter, iron administration attenuated hypoxic pulmonary hypertension to a greater extent in the ID group. Asterisks indicate significance of comparisons between or within groups: *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant (mixed-effects model).