Manipulation of iron status on cerebral blood flow at high altitude in lowlanders and adapted highlanders

Abstract

Cerebral blood flow (CBF) increases during hypoxia to counteract the reduction in arterial oxygen content. The onset of tissue hypoxemia coincides with the stabilization of hypoxia-inducible factor (HIF) and transcription of downstream HIF-mediated processes. It has yet to be determined, whether HIF down- or upregulation can modulate hypoxic vasodilation of the cerebral vasculature. Therefore, we examined whether: 1) CBF would increase with iron depletion (via chelation) and decrease with repletion (via iron infusion) at high-altitude, and 2) explore whether genotypic advantages of highlanders extend to HIF-mediated regulation of CBF. In a double-blinded and block-randomized design, CBF was assessed in 82 healthy participants (38 lowlanders, 20 Sherpas and 24 Andeans), before and after the infusion of either: iron(III)-hydroxide sucrose, desferrioxamine or saline. Across both lowlanders and highlanders, baseline iron levels contributed to the variability in cerebral hypoxic reactivity at high altitude (R² = 0.174, P < 0.001). At 5,050 m, CBF in lowlanders and Sherpa were unaltered by desferrioxamine or iron. At 4,300 m, iron infusion led to 4 ± 10% reduction in CBF (main effect of time p = 0.043) in lowlanders and Andeans. Iron status may provide a novel, albeit subtle, influence on CBF that is potentially dependent on the severity and length-of-stay at high altitude.

Keywords: Iron; cerebral blood flow; high altitude; high-altitude residents; hypoxia.

Figure 1.

Summary of experimental protocol of each study. In Study 1, lowlanders and Sherpa hiked to 5050 m over 9–10 days. Prior to flying to Lukla: the ascending Sherpa group had already descended and been in Kathmandu for 5–15 days (median: 7 days); lowlanders had been in Kathmandu (1400 m) for 3–9 days (median: 6 days). Additional Sherpa were recruited at high altitude – typically ascending from 3800–4200 m in 1–2 days, and were tested 1–2 days following arrival to 5050 m. In Study 2, lowlanders were driven over 8 hours from Lima to 4300 m, Cerro de Pasco (where all Andeans were residents). Experimental P_IO₂ conditions are included, that were repeated pre- and post-infusion.

Figure 2.

Influence of baseline iron status on gCBF in pooled lowlanders and pooled highlanders at high altitude. Panels a and b illustrate the relationship between gCBF during room air breathing and exaggerated hypoxia. Panel d indicates that the change in hypoxic reactivity of gCBF is greater in those with lower iron levels, compared to those with more elevated iron levels. Panel C and E highlight the relationship between baseline iron and [Hb], with hypoxic reactivity of gCBF, respectively. Panel f highlights serum iron levels in each group [lowlanders (LL), Andeans (AN) and Sherpas (SH) at their respective altitudes] at baseline (i.e. pre-infusion), and the absolute increase in serum iron following iron infusion (i.e. Δpost-infusion).

Figure 3.

Summary of global CBF during prolonged stay at high altitude (5,050 m and 4,300 m refer to Studies 1 and 2, respectively). Cortical HIF-1α expression adapted from literature and CBF during early exposure to 5,050 in lowlanders adapted from literature. Since most of the lowlanders tested during Study 1 of the current study, were also included in the study by Hoiland and colleagues, the dashed line is included to illustrated the change in CBF across time.