Pulmonary vascular reactivity to supplemental oxygen in Sherpa and lowlanders during gradual ascent to high altitude

Abstract

New findings: What is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de-acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non-ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction.

Abstract: Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n = 11) left altitude and after de-acclimatization in Kathmandu for ∼7 days re-ascended with the lowlanders over 8-10 days to 5050 m. The second Sherpa group (non-ascent Sherpa, n = 12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P = 0.02) and PVR (P = 0.02). After ∼14 days at 5050 m, PASP decreased with supplemental oxygen (mean decrease: 3.9 mmHg, 95% CI 2.1-5.7 mmHg, P < 0.001); however, PVR was unchanged (P = 0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following ∼14 days at 5050 m altitude, there was no change in PVR to hypoxia or O₂ supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia.

Keywords: Sherpa; high altitude; hypoxia; hypoxic pulmonary vascular remodelling; hypoxic pulmonary vasoconstriction.

FIGURE 1

Ascent profile for the expedition showing testing sites and times by the filled circles on the continuous ascent profile line. Also shown is the barometric pressure (dotted line) during the ascent. Filled circles denote times and altitudes where echocardiographic measurements were obtained

FIGURE 2

Time course of changes in PASP across altitude among lowlanders and ascent Sherpa. Larger bold symbols represent the mean values with the individual data points in lighter symbols. All values are in mmHg. (a) Ambient air PASP in lowlanders. (b) PASP breathing supplemental oxygen in lowlanders. (c) Change in PASP from ambient air to supplemental oxygen in lowlanders. (d) Ambient air PASP in Ascent Sherpa. (e) PASP breathing supplemental oxygen in ascent Sherpa. (f) Change in PASP from ambient air to supplemental oxygen in ascent Sherpa. *Significant increase in PASP with increasing altitude, P < 0.001. †Significant interaction between altitude and ancestry, P < 0.003. ‡Significant reduction in PASP following oxygen administration, P < 0.001. PASP, pulmonary artery systolic pressure

FIGURE 3

Time course of changes in PVR across altitude among lowlanders and ascent Sherpa. Larger bold symbols represent the mean values with the individual data points in lighter symbols. (a) Ambient air PVR in lowlanders. (b) PVR breathing supplemental oxygen in lowlanders. (c) Change in PVR from ambient air to supplemental oxygen in lowlanders. (d) Ambient air PVR in ascent Sherpa. (e) PVR breathing supplemental oxygen in ascent Sherpa. (f) Change in PVR from ambient air to supplemental oxygen in ascent Sherpa. *Significant increase in PVR with increasing altitude, P < 0.001. †Significant interaction between altitude and ancestry, P < 0.001. ‡Significant reduction in PVR following oxygen administration, P < 0.001. PVR, pulmonary vascular resistance

FIGURE 4

Individual data for PASP and PVR on ambient air and on supplemental oxygen on arrival to the Pyramid Laboratory (a, b) and after ∼2 weeks additional acclimatization at 5050 m (c, d). Circles are lowlanders, triangles are ascent Sherpa, and diamonds are non‐ascent Sherpa. Continuous diagonal lines show the line of identity (no change with oxygen). Dashed lines show the median values with the thin dotted lines showing the 25th percentile and 75th percentile. P‐values reflect the paired comparison on and off supplemental oxygen

FIGURE 5

Change in PVR from breathing ambient air to supplemental oxygen plotted as a function of time at altitude. Duration at altitude reflects the time each subject spent at altitude above Kathmandu. Filled symbols represent the individual subject data while the open symbols with error bars represent the mean change ±95% CI for the PVR change with oxygen. Circles represent the lowlanders, triangles are the ascent Sherpa, and the diamonds are the non‐ascent Sherpa. A few of the data points have been shifted slightly along the x‐axis to avoid overlapping symbols. Note, values less than zero represent a decrease in PVR while breathing supplemental oxygen

FIGURE 6

Changes in PASP and PVR (from ambient air to oxygen breathing) normalized to the accompanying changes in $S_{\mathrm{p}{\mathrm{O}}_2}$ (ambient air to oxygen breathing) at different altitudes. (a) Changes in PASP normalized to the accompanying changes in $S_{\mathrm{p}{\mathrm{O}}_2}$ (ΔPASP/Δ$S_{\mathrm{p}{\mathrm{O}}_2}$) at increasing altitudes. *P < 0.001 for altitude effect in the linear mixed model (LMM). There was no significant effect of ancestry (P = 0.255) or altitude by ancestry interaction (P = 0.885). Addition of cardiac output to the LMM did not improve the model fit. (b) Changes in PVR from ambient air to oxygen normalized to the accompanying changes in $S_{\mathrm{p}{\mathrm{O}}_2}$ (ΔPVR/Δ$S_{\mathrm{p}{\mathrm{O}}_2}$) at increasing altitude. LMM analysis showed no significant effects, altitude effect (P = 0.171), ancestry effect (P = 0.311) and interaction (P = 0.767). The addition of cardiac output to the LMM did not improve the fit of the model