Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude

Anecdotal reports suggest that Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude despite exhibiting a lower arterial oxygen content than acclimatised Lowlanders. This study tested the hypothesis that Sherpas exposed to hypobaric hypoxia on ascent to 5300m, develop increased microcirculatory blood flow as a means of maintaining normal tissue oxygen delivery. Images of the sublingual microcirculation were obtained from 64 Sherpas and 69 Lowlanders using incident dark field imaging. Serial measurements were obtained from participants undertaking an ascent from baseline testing (35m or 1300m) to Everest base camp (5300m), and following subsequent descent in Kathmandu (1300m). Microcirculatory flow index and heterogeneity index were used to provide indices of microcirculatory flow, whilst capillary density was assessed using small vessel density. Sherpas, when compared to Lowlanders, demonstrated significantly greater microcirculatory blood flow at Everest Base Camp, but not at baseline testing or on return in Kathmandu. Additionally, Sherpa blood flow exhibited greater homogeneity at 5300m and 1300m (descent) when compared to Lowlanders. Sublingual small vessel density was not different between the two cohorts at baseline testing or at 1300m, however at 5300m Sherpas capillary density was up to 30% greater. These data suggest that Sherpas have the ability to maintain a significantly greater microcirculatory flow per unit time, and flow per unit volume of tissue at high altitude, when compared to Lowlanders. These findings support the notion that peripheral vascular factors at the microcirculatory level may be important in the process of adaptation to hypoxia

Dietary nitrate supplementation does not alter exercise efficiency at high altitude – further results from the Xtreme Alps study

Introduction: Nitrate supplementation in the form of beetroot juice (BRJ) ingestion has been shown to improve exercise tolerance during acute hypoxia, but its effect on exercise physiology remains unstudied during sustained terrestrial high altitude exposure. We hypothesized that performing exercise at high altitude would lower circulating nitrate and nitrite levels and that BRJ ingestion would reverse this phenomenon while concomitantly improving key determinants of aerobic exercise performance. Methods: Twenty seven healthy volunteers (21 male) underwent a series of exercise tests at sea level (SL, London, 75 m) and again after 5-8 days at high altitude (HA, Capanna Regina Margherita or "Margherita Hut," 4,559 m). Using a double-blind protocol, participants were randomized to consume a beetroot/fruit juice beverage (three doses per day) with high levels of nitrate (∼0.18 mmol/kg/day) or a nitrate-depleted placebo (∼11.5 μmoles/kg/day) control drink, from 3 days prior to the exercise trials until completion. Submaximal constant work rate cycle tests were performed to determine exercise efficiency and a maximal incremental ramp exercise test was undertaken to measure aerobic capacity, using breath-by-breath pulmonary gas exchange measurements throughout. Concentrations of nitrate, nitrite and nitrosation products were quantified in plasma samples collected at 5 timepoints during the constant work rate tests. Linear mixed modeling was used to analyze data. Results: At both SL and HA, plasma nitrate concentrations were elevated in the nitrate supplementation group compared to placebo (P < 0.001) but did not change throughout increasing exercise work rate. Delta exercise efficiency was not altered by altitude exposure (P = 0.072) or nitrate supplementation (P = 0.836). V̇O2peak decreased by 24% at high altitude (P < 0.001) and was lower in the nitrate-supplemented group at both sea level and high altitude compared to placebo (P = 0.041). Dietary nitrate supplementation did not alter other peak exercise variables or oxygen consumption at anaerobic threshold. Circulating nitrite and S-nitrosothiol levels unexpectedly rose in a few individuals right after cessation of exercise at high altitude. Conclusion: Whilst regularly consumed during an 8 days expedition to terrestrial high altitude, nitrate supplementation did not alter exercise efficiency and other exercise physiological variables, except decreasing V̇O2peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure

Microcirculatory blood flow in hypoxia: a comparative study between Sherpas and Lowlanders

Sherpas are the direct descendants of nomadic Tibetans, a population known to have resided at altitude for well over 500 generations. As such, it is plausible that their genome has adapted, through natural selection, to cope with the surrounding hypobaric hypoxic environment. The resultant phenotypic changes, which could account for their anecdotal extraordinary hypoxic tolerance, remain poorly described. By comparing Sherpas and an altitude-naïve population - ‘Lowlanders’- this thesis attempts to investigate whether improved microcirculatory flow is a physiological mechanism utilised by indigenous high altitude native populations to aid successful adaptation (and thus tolerance) to hypoxia. Five studies were undertaken to assess the effects of acute, subacute, and sustained hypoxia on the microcirculation. In a normobaric hypoxic chamber study, Sherpas were seen to maintain significantly greater finger microcirculatory blood flow upon acute hypoxic exposure, as compared to Lowlanders. On ascent to Mount Everest Base Camp, Sherpas demonstrated greater resting sublingual, peripheral (finger) and forearm blood flow, in addition to increased sublingual capillary density. Lastly, when Lowlanders were exposed to sustained hypobaric hypoxia, their microcirculatory vessel density increased to levels indistinct from Sherpa values; however their microvascular blood flow remained significantly lower. The results from this thesis thus support the hypothesis that at the microcirculatory level, phenotypic differences exist between an indigenous high- altitude population and an altitude-naïve population. Accordingly, the findings sustain the notion that augmentation of oxygen delivery at the level of the microcirculation may be one physiological mechanism, sanctioned through evolutionary selection pressure, to aid successful adaptation to hypoxia

The Smell of Hypoxia: using an electronic nose at altitude and proof of concept of its role in the prediction and diagnosis of acute mountain sickness

Electronic nose (e‐nose) devices may be used to identify volatile organic compounds (VOCs) in exhaled breath. VOCs generated via metabolic processes are candidate biomarkers of (patho)physiological pathways. We explored the feasibility of using an e‐nose to generate human “breathprints” at high altitude. Furthermore, we explored the hypothesis that pathophysiological processes involved in the development of acute mountain sickness (AMS) would manifest as altered VOC profiles. Breath analysis was performed on Sherpa and lowlander trekkers at high altitude (3500 m). The Lake Louise Scoring (LLS) system was used to diagnose AMS. Raw data were reduced by principal component (PC) analysis (PCA). Cross validated linear discriminant analysis (CV‐LDA) and receiver‐operating characteristic area under curve (ROC‐AUC) assessed discriminative function. Breathprints suitable for analysis were obtained from 58% (37/64) of samples. PCA showed significant differences between breathprints from participants with, and without, AMS; CV‐LDA showed correct classification of 83.8%, ROC‐AUC 0.86; PC 1 correlated with AMS severity. There were significant differences between breathprints of participants who remained AMS negative and those whom later developed AMS (CV‐LDA 68.8%, ROC‐AUC 0.76). PCA demonstrated discrimination between Sherpas and lowlanders (CV‐LDA 89.2%, ROC‐AUC 0.936). This study demonstrated the feasibility of breath analysis for VOCs using an e‐nose at high altitude. Furthermore, it provided proof‐of‐concept data supporting e‐nose utility as an objective tool in the prediction and diagnosis of AMS. E‐nose technology may have substantial utility both in altitude medicine and under other circumstances where (mal)adaptation to hypoxia may be important (e.g., critically ill patients)

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