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Abstract ObjectivesThe Sherpa ethnic group living at altitude in Nepal may have experienced natural selection in response to chronic hypoxia. We have previously shown that Sherpa in Kathmandu (1400 m) possess larger spleens and a greater apnea‐induced splenic contraction compared to lowland Nepalis. This may be significant for exercise capacity at altitude as the human spleen responds to stress‐induced catecholamine secretion by an immediate contraction, which results in transiently elevated hemoglobin concentration ([Hb]). MethodsTo investigate splenic contraction in response to exercise at high‐altitude (4300 m; P_b = ~450 Torr), we recruited 63 acclimatized Sherpa (29F) and 14 Nepali non‐Sherpa (7F). Spleen volume was measured before and after maximal exercise on a cycle ergometer by ultrasonography, along with [Hb] and oxygen saturation (SpO₂). ResultsResting spleen volume was larger in the Sherpa compared with Nepali non‐Sherpa (237 ± 62 vs. 165 ± 34 mL,p < .001), as was the exercise‐induced splenic contraction (Δspleen volume, 91 ± 40 vs. 38 ± 32 mL,p < .001). From rest to exercise, [Hb] increased (1.2 to 1.4 g.dl⁻¹), SpO₂decreased (~9%) and calculated arterial oxygen content (CaO₂) remained stable, but there were no significant differences between groups. In Sherpa, both resting spleen volume and the Δspleen volume were modest positive predictors of the change (Δ) in [Hb] and CaO₂with exercise (p‐values from .026 to .037 and R²values from 0.059 to 0.067 for the predictor variable). ConclusionsLarger spleens and greater splenic contraction may be an adaptive characteristic of Nepali Sherpa to increase CaO₂during exercise at altitude, but the direct link between spleen size/function and hypoxia tolerance remains unclear. 

Abstract The human spleen contracts in response to stress‐induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non‐Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr;  = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation (). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non‐Sherpa (165 ± 34 mL;P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3–1.6). In response to hyperoxia, non‐Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7–48.9;P < 0.001; ES = 1.8, 95% CI: 0.93–2.66), while spleen size remained unchanged in Sherpa (−2 ± 13 mL, 95% CI: −2.4 to 7.3;P = 0.640; ES = 0.18, 95% CI: −0.10 to 0.47). Our findings suggest that Sherpa and non‐Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude‐related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non‐Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb]. 

With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid–base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid–base acclimatization (PCO₂, [HCO₃⁻], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO₂(P<0.0001) and [HCO₃⁻] (P<0.0001), and higher pH (P= 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO₂(P< 0.0001) and [HCO₃⁻] (P< 0.0001), but unchanged pH (P= 0.1), suggesting full renal compensation, with significantly lower PCO₂(P= 0.01), [HCO₃⁻] (P< 0.0001) and pH (P= 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization.