Estimates of the global population of humans living at high altitude vary widely, and such data at the country level are unavailable. Herein, we use a geographic information system (GIS)-based approach to quantify human population at 500-m elevation intervals for each country. Based on georeferenced data for population (LandScan Global 2019) and elevation (Global Multiresolution Terrain Elevation Data), 500.3 million humans live at ≥1,500 m, 81.6 million at ≥2,500 m, and 14.4 million at ≥3,500 m. Ethiopia has the largest absolute population at ≥1,500 m and ≥2,500 m, while China has the greatest at ≥3,500 m. Lesotho has the greatest percentage of its population above 1,500 m, while Bolivia has the greatest at ≥2,500 m and ≥3,500 m. High altitude presents a myriad of environmental stresses that provoke physiological responses and adaptation, and consequently impact disease prevalence and severity. While the majority of high-altitude physiology research is based upon lowlanders from western, educated, industrialized, rich, and democratic countries ascending to high altitude, the global population distribution of high-altitude residents encourages an increased emphasis on understanding high-altitude physiology, adaptation, epidemiology, and public health in the ∼500 million permanent high-altitude residents.

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P <0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P =0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r ² =0.303; P<0.001) and Hb ( r ² =0.230; P =0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P <0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P =0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress following the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress (sustained stimulus (SS)-FMD), most often created with limb heating or exercise. Exercise in particular creates a physiologically-relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH- versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and as such, SS-FMD and RH-FMD appear to offer unique insight regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding i) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and ii) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes.

Our aim was to quantify the end-tidal-to-arterial gas gradients for O₂ (P_ET-PaO₂) and CO₂ (Pa-P_ETCO₂) during a CO₂ reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO−, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-P_ETCO₂ would be greater in hypoxia compared with normoxia, 2) the Pa-P_ETCO₂ would be similar, whereas the P_ET-PaO₂ gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against P_ETCO₂ compared with PaCO₂, and 4) previously derived prediction algorithms will accurately target PaCO₂. P_ETCO₂ was controlled by dynamic end-tidal forcing in steady-state steps of −8, −4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇_E), internal carotid artery blood flow (Q̇_ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇_E and relative changes in Q̇_ICA, and MCAv against P_ETCO₂, predicted PaCO₂, and measured PaCO₂. The Pa-P_ETCO₂ was similar between hypoxia and normoxia and PFO+ and PFO−. The P_ET-PaO₂ was greater in PFO+ by 2.1 mmHg during normoxia ( P = 0.003). HCVR and CVR plotted against P_ETCO₂ underestimated HCVR and CVR indexed against PaCO₂ in normoxia and hypoxia. Our PaCO₂ prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to P_ETCO₂ compared with PaCO₂.