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Brewster, L. Madden, Anthony R. Bain, Vinicius P. Garcia, Noah M. DeSouza, Michael M. Tymko, Jared J. Greiner, and Philip N. Ainslie. Global REACH 2018: high altitude-related circulating extracellular microvesicles promote a proinflammatory endothelial phenotype in vitro . High Alt Med Biol . 24:223-229, 2023. Introduction: Ascent to high altitude (HA) can induce vascular dysfunction by promoting a proinflammatory endothelial phenotype. Circulating microvesicles (MVs) can mediate the vascular endothelium and inflammation. It is unclear whether HA-related MVs are associated with endothelial inflammation. Objectives: We tested the hypothesis that MVs derived from ascent to HA induce a proinflammatory endothelial phenotype. Methods: Ten healthy adults (8 M/2 F; age: 28 ± 2 years) residing at sea level (SL) were studied before and 4-6 days after rapid ascent to HA (4,300 m). MVs were isolated and enumerated from plasma by centrifugation and flow cytometry. Human umbilical vein endothelial cells were treated with MVs collected from each subject at SL (MV-SL) and at HA (MV-HA). Results: Circulating MV number significantly increased at HA (26,637 ± 3,315 vs. 19,388 ± 1,699). Although intracellular expression of total nuclear factor kappa beta (NF-κB; 83.4 ± 6.7 arbitrary units [AU] vs. 90.2 ± 6.9 AU) was not affected, MV-HA resulted in ∼55% higher ( p  < 0.05) active NF-κB (129.6 ± 19.8 AU vs. 90.7 ± 10.5 AU) expression compared with MV-SL. In addition, MV-HA induced higher interleukin (IL)-6 (63.9 ± 3.9 pg/ml vs. 53.3 ± 3.6 pg/ml) and IL-8 (140.2 ± 3.6 pg/ml vs. 120.7 ± 3.8 pg/ml) release compared with MV-SL, which was blunted with NF-κB blockade. Conclusions: Circulating extracellular MVs increase at HA and induce endothelial inflammation, potentially contributing to altitude-related vascular dysfunction.

Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A. Howe, David MacLeod, James D. Anholm, Christopher Gasho, and Michael M. Tymko. Global REACH 2018: characterizing acid-base balance over 21 days at 4,300 m in lowlanders. High Alt Med Biol . 23:185-191, 2022. Introduction: High altitude exposure results in hyperventilatory-induced respiratory alkalosis, followed by metabolic compensation to return arterial blood pH (pHa) toward sea level values. However, previous work has limited sample sizes, short-term exposure, and pharmacological confounders (e.g., acetazolamide). The purpose of this investigation was to characterize acid-base balance after rapid ascent to high altitude (i.e., 4,300 m) in lowlanders. We hypothesized that despite rapid bicarbonate ([HCO 3 - ]) excretion during early acclimatization, partial respiratory alkalosis would still be apparent as reflected in elevations in pHa compared with sea level after 21 days of acclimatization to 4,300 m. Methods: In 16 (3 female) healthy volunteers not taking any medications, radial artery blood samples were collected and analyzed at sea level (150 m; Lima, Peru), and on days 1, 3, 7, 14, and 21 after rapid automobile (∼8 hours) ascent to high altitude (4,300 m; Cerro de Pasco, Peru). Results and Discussion: Although reductions in [HCO 3 - ] occurred by day 3 ( p  < 0.01), they remained stable thereafter and were insufficient to fully normalize pHa back to sea level values over the subsequent 21 days ( p  < 0.01). These data indicate that only partial compensation for respiratory alkalosis persists throughout 21 days at 4,300 m.

Carr, Jay, Rachel Stone, Courtney Tymko, Kaitlyn Tymko, Geoff B. Coombs, Ryan L. Hoiland, Connor A. Howe, Michael M. Tymko, Philip N. Ainslie, and Alexander Patrician. Global REACH 2018: the effect of an expiratory resistance mask with dead space on sleep and acute mountain sickness during acute exposure to hypobaric hypoxia. High Alt Med Biol . 21:297-302, 2020. We hypothesized that an expiratory resistance and dead space (ER/DS) mask, a version of which was previously shown to partially alleviate sleep-disordered breathing and headache severity during acute normobaric hypoxia (Patrician et al.), would exhibit similar results in conditions of hypobaric hypoxia. In a randomized, single-blinded, sham-controlled, and sex-matched design, 31 healthy lowlanders rapidly (6-8 hours) ascended from sea level to 4300 m (Cerro de Pasco, Peru) and slept with either an ER/DS mask ( n  = 15) or sham mask ( n  = 16). Sleep was assessed (via WatchPAT) and questionnaires collected before sleep and upon waking the morning after. There was no difference in apnea-hypopnea index (AHI) between the ER/DS (77 ± 20 events/h) or sham mask (84 ± 27 events/h; p  = 0.57). In addition, there was no alleviation of headache scores, improvement in sleep quality, or acute mountain sickness symptom severity. Both the sham and ER/DS masks were poorly tolerated (∼50% subject noncompliance in both groups). These findings highlight the importance and necessity of field-testing and demonstrate that more testing is needed before ER/DS devices, such as these, can be recommended for prophylactic benefits at high altitude.

We examined the hypothesis that an expiratory resistance mask containing a small amount of dead space (ER/DS) would reduce the apnea-hypopnea index (AHI) during sleep, attenuate the severity of acute mountain sickness (AMS), and offset decrements in cognitive function compared with a sham mask. In a double-blinded, randomized, sham-controlled, crossover design, 19 volunteers were exposed to two nights of normobaric hypoxia (F I O 2 0.125), using a ER/DS mask (3.5 mm restrictive expiratory orifice; 125 mL DS volume) and sham mask (zero-flow resistance; 50 mL DS volume). Cognitive function, AMS, and ventilatory acclimatization were assessed before and after the 12-hour normobaric hypoxia exposure. Polysomnography was conducted during sleep. AHI was reduced using the ER/DS sleep mask compared with the sham (30.1 ± 23.9 events·hr = 0.125), using a ER/DS mask (3.5 mm restrictive expiratory orifice; 125 mL DS volume) and sham mask (zero-flow resistance; 50 mL DS volume). Cognitive function, AMS, and ventilatory acclimatization were assessed before and after the 12-hour normobaric hypoxia exposure. Polysomnography was conducted during sleep. AHI was reduced using the ER/DS sleep mask compared with the sham (30.1 ± 23.9 events·hr -1 vs. 58.9 ± 34.4 events·hr -1 , respectively; p = 0.01). Likewise, oxygen desaturation index and headache severity were reduced (both p < 0.05). There were also benefits on limiting the hypoxia-induced reductions in select measures of reaction speed and attention (p < 0.05). Our study indicates that a simple noninvasive and portable ER/DS mask resulted in reductions (49%) in AHI, and reduced headache severity and aspects of cognitive decline. The field applications of this ER/DS mask should be investigated before recommendations can be made to support its benefit for travel to high altitude.