Plasma Soluble Erythropoietin Receptor is Decreased During Sleep in Andean Highlanders with Chronic Mountain Sickness

Abstract

Excessive erythrocytosis (EE) is the main sign of Chronic Mountain Sickness (CMS), a maladaptive syndrome with significant prevalence in high‐altitude inhabitants. Although chronic hypoxemia represents its underlying stimulus, the fundamental pathophysiological mechanism is still debatable. Studies during sleep in CMS patients consistently find lower average pulse O2 saturation (SpO2) compared to healthy highlanders (HH). Although, whether accentuated hypoxemia during sleep has a significant impact on the Epo system that could explain the occurrence of EE is still unclear. We have recently shown that morning soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in CMS patients suggesting increased circulating Epo availability (increased Epo/sEpoR). The aim of the present study was to characterize the concentration profile of sEpoR and serum Epo during night‐time, and their relationship with SpO2 and hematocrit (Hct) in HH and CMS patients, as well as the association between testosterone concentration and Epo and sEpoR at early morning. Thirty‐nine male participants (CMS, n=23; HH, n=16) from Cerro de Pasco, Perú at 4340m, between 21 and 65 years old and with normal iron status participated in the study. Blood samples were taken every 4h from 6pm–6am for Epo and sEpoR measurements; the morning sample was also used for evaluation of serum iron, ferritin, transferrin and testosterone concentrations. SpO2 was assessed at 6pm and continuously monitored from 10pm–6am. Mean SpO2 during sleep was lower in CMS patients compared to HH (75.2±1.5 vs 79.9±0.9%), and the percentage of sleep‐time spent with SpO2 below 80% was higher (67.2±7.2 vs 37.9±8.5%). The CMS group showed higher Epo from 6pm–2am (24.1±2.6 vs 14.0±2.2, 26.4±4.4 vs 10.5±0.9 and 25.3±3.8 vs 11.3±1.3mIU/mL, respectively) and lower sEpoR from 10pm–6am (1.4±0.1 vs 2.2±0.1, 1.5±0.2 vs 2.2±0.2 and 1.5±0.1 vs 2.2±0.2 ng/mL, respectively). Consequently, the Epo/sEpoR was significantly higher in the CMS group from 6pm–6am (15.8±2.5 vs 7.7±1.0, 20.9±3.7 vs 5.2±0.7, 20.5±3.8 vs 5.7±0.8 and 20.7±3.9 vs 6.8±0.8 mIU/ng, respectively). Multiple regression analysis showed mean sleep‐time SpO2 and Epo/sEpoR as significant predictors of Hct corrected for potential confounders (age, body mass index and serum testosterone). Total and free testosterone levels were not associated to Hct, nor to the erythropoietic factors. In conclusion, our results show a sustained erythropoietic stimulus driven by the Epo system in CMS patients, further enhanced by the continuous exposure to accentuated hypoxemia during sleep.Support or Funding InformationSupported by The Wellcome Trust grant 097275/Z/11/Z