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1.
High-altitude exposures and intestinal barrier dysfunction.
McKenna, ZJ, Gorini Pereira, F, Gillum, TL, Amorim, FT, Deyhle, MR, Mermier, CM
American journal of physiology. Regulatory, integrative and comparative physiology. 2022;(3):R192-R203
Abstract
Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.
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Independent and combined impact of hypoxia and acute inorganic nitrate ingestion on thermoregulatory responses to the cold.
Arnold, JT, Bailey, SJ, Hodder, SG, Fujii, N, Lloyd, AB
European journal of applied physiology. 2021;(4):1207-1218
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Abstract
PURPOSE This study assessed the impact of normobaric hypoxia and acute nitrate ingestion on shivering thermogenesis, cutaneous vascular control, and thermometrics in response to cold stress. METHOD Eleven male volunteers underwent passive cooling at 10 °C air temperature across four conditions: (1) normoxia with placebo ingestion, (2) hypoxia (0.130 FiO2) with placebo ingestion, (3) normoxia with 13 mmol nitrate ingestion, and (4) hypoxia with nitrate ingestion. Physiological metrics were assessed as a rate of change over 45 min to determine heat loss, and at the point of shivering onset to determine the thermogenic thermoeffector threshold. RESULT Independently, hypoxia expedited shivering onset time (p = 0.05) due to a faster cooling rate as opposed to a change in central thermoeffector thresholds. Specifically, compared to normoxia, hypoxia increased skin blood flow (p = 0.02), leading to an increased core-cooling rate (p = 0.04) and delta change in rectal temperature (p = 0.03) over 45 min, yet the same rectal temperature at shivering onset (p = 0.9). Independently, nitrate ingestion delayed shivering onset time (p = 0.01), mediated by a change in central thermoeffector thresholds, independent of changes in peripheral heat exchange. Specifically, compared to placebo ingestion, no difference was observed in skin blood flow (p = 0.5), core-cooling rate (p = 0.5), or delta change in rectal temperature (p = 0.7) over 45 min, while nitrate reduced rectal temperature at shivering onset (p = 0.04). No interaction was observed between hypoxia and nitrate ingestion. CONCLUSION These data improve our understanding of how hypoxia and nitric oxide modulate cold thermoregulation.
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The influence of carbohydrate ingestion on peripheral and central fatigue during exercise in hypoxia: A narrative review.
Paris, HL, Sinai, EC, Shei, RJ, Keller, AM, Mickleborough, TD
European journal of sport science. 2021;(10):1423-1435
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Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.
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Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.
Rock, CR, White, TA, Piscopo, BR, Sutherland, AE, Miller, SL, Camm, EJ, Allison, BJ
International journal of molecular sciences. 2021;(14)
Abstract
Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).
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Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure.
Mathews, KS, Soh, H, Shaefi, S, Wang, W, Bose, S, Coca, S, Gupta, S, Hayek, SS, Srivastava, A, Brenner, SK, et al
Critical care medicine. 2021;(7):1026-1037
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Abstract
OBJECTIVES Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure. DESIGN Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of Pao2 over the corresponding Fio2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. SETTING ICUs at 68 U.S. sites. PATIENTS Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of Pao2 over the corresponding Fio2 less than or equal to 200 mm Hg. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97). CONCLUSIONS In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.
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Blood glucose concentration is unchanged during exposure to acute normobaric hypoxia in healthy humans.
Chan, JS, Chiew, AE, Rimke, AN, Chan, G, Rampuri, ZH, Kozak, MD, Boulé, NG, Steinback, CD, Davenport, MH, Day, TA
Physiological reports. 2021;(15):e14932
Abstract
Normal blood [glucose] regulation is critical to support metabolism, particularly in contexts of metabolic stressors (e.g., exercise, high altitude hypoxia). Data regarding blood [glucose] regulation in hypoxia are inconclusive. We aimed to characterize blood [glucose] over 80 min following glucose ingestion during both normoxia and acute normobaric hypoxia. In a randomized cross-over design, on two separate days, 28 healthy participants (16 females; 21.8 ± 1.6 years; BMI 22.8 ± 2.5 kg/m2 ) were randomly exposed to either NX (room air; fraction of inspired [FI ]O2 ~0.21) or HX (FI O2 ~0.148) in a normobaric hypoxia chamber. Measured FI O2 and peripheral oxygen saturation were both lower at baseline in hypoxia (p < 0.001), which was maintained over 80 min, confirming the hypoxic intervention. Following a 10-min baseline (BL) under both conditions, participants consumed a standardized glucose beverage (75 g, 296 ml) and blood [glucose] and physiological variables were measured at BL intermittently over 80 min. Blood [glucose] was measured from finger capillary samples via glucometer. Initial fasted blood [glucose] was not different between trials (NX:4.8 ± 0.4 vs. HX:4.9 ± 0.4 mmol/L; p = 0.47). Blood [glucose] was sampled every 10 min (absolute, delta, and percent change) following glucose ingestion over 80 min, and was not different between conditions (p > 0.77). In addition, mean, peak, and time-to-peak responses during the 80 min were not different between conditions (p > 0.14). There were also no sex differences in these blood [glucose] responses in hypoxia. We conclude that glucose regulation is unchanged in young, healthy participants with exposure to acute steady-state normobaric hypoxia, likely due to counterbalancing mechanisms underlying blood [glucose] regulation in hypoxia.
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Exposure to Normobaric Hypoxia Combined with a Mixed Diet Contributes to Improvement in Lipid Profile in Trained Cyclists.
Płoszczyca, K, Czuba, M, Langfort, J, Baranowski, M
Nutrients. 2021;(10)
Abstract
This study aimed to analyze the effects of live high-train low method (LH-TL) and intermittent hypoxic training (IHT) with a controlled mixed diet on lipid profile in cyclists. Thirty trained male cyclists at a national level with at least six years of training experience participated in the study. The LH-TL group was exposed to hypoxia (FiO2 = 16.5%) for 11-12 h a day and trained under normoxia for 3 weeks. In the IHT group, participants followed the IHT routine three times a week under hypoxia (FiO2 = 16.5%) at lactate threshold intensity. The control group (N) lived and trained under normoxia. The results showed that the 3-week LH-TL method significantly improved all lipid profile variables. The LH-TL group showed a significant increase in HDL-C by 9.0% and a decrease in total cholesterol (TC) by 9.2%, LDL-C by 18.2%, and triglycerides (TG) by 27.6%. There were no significant changes in lipid profiles in the IHT and N groups. ∆TG and ∆TC were significantly higher in the LH-TL group compared to the N group. In conclusion, hypoxic conditions combined with a mixed diet can induce beneficial changes in lipid profile even in highly trained athletes. The effectiveness of the hypoxic stimulus is closely related to the hypoxic training method.
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Investigating gene methylation signatures for fetal intolerance prediction.
Zhang, YH, Li, Z, Zeng, T, Chen, L, Li, H, Gamarra, M, Mansour, RF, Escorcia-Gutierrez, J, Huang, T, Cai, YD
PloS one. 2021;(4):e0250032
Abstract
Pregnancy is a complicated and long procedure during one or more offspring development inside a woman. A short period of oxygen shortage after birth is quite normal for most babies and does not threaten their health. However, if babies have to suffer from a long period of oxygen shortage, then this condition is an indication of pathological fetal intolerance, which probably causes their death. The identification of the pathological fetal intolerance from the physical oxygen shortage is one of the important clinical problems in obstetrics for a long time. The clinical syndromes typically manifest five symptoms that indicate that the baby may suffer from fetal intolerance. At present, liquid biopsy combined with high-throughput sequencing or mass spectrum techniques provides a quick approach to detect real-time alteration in the peripheral blood at multiple levels with the rapid development of molecule sequencing technologies. Gene methylation is functionally correlated with gene expression; thus, the combination of gene methylation and expression information would help in screening out the key regulators for the pathogenesis of fetal intolerance. We combined gene methylation and expression features together and screened out the optimal features, including gene expression or methylation signatures, for fetal intolerance prediction for the first time. In addition, we applied various computational methods to construct a comprehensive computational pipeline to identify the potential biomarkers for fetal intolerance dependent on the liquid biopsy samples. We set up qualitative and quantitative computational models for the prediction for fetal intolerance during pregnancy. Moreover, we provided a new prospective for the detailed pathological mechanism of fetal intolerance. This work can provide a solid foundation for further experimental research and contribute to the application of liquid biopsy in antenatal care.
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Influence of Dietary Nitrate Supplementation on High-Intensity Intermittent Running Performance at Different Doses of Normobaric Hypoxia in Endurance-Trained Males.
Robinson, GP, Killer, SC, Stoyanov, Z, Stephens, H, Read, L, James, LJ, Bailey, SJ
International journal of sport nutrition and exercise metabolism. 2021;(1):1-8
Abstract
This study investigated whether supplementation with nitrate-rich beetroot juice (BR) can improve high-intensity intermittent running performance in trained males in normoxia and different doses of normobaric hypoxia. Eight endurance-trained males (V˙O2peak, 62 ± 6 ml·kg-1·min-1) completed repeated 90 s intervals at 110% of peak treadmill velocity, from an initial step incremental test, interspersed by 60 s of passive recovery until exhaustion (Tlim). Participants completed the first three experimental trials during days 3, 5, and 7 of BR or nitrate-depleted beetroot juice (PLA) supplementation and completed the remaining experimental visits on the alternative supplement following at least 7 days of washout. The fraction of inspired oxygen during visits 1-3 was either 0.209, 0.182, or 0.157, equivalent to an altitude of 0, 1,200, and 2,400 m, respectively, and this order was replicated on visits 4-6. Arterial oxygen saturation declined dose dependently as fraction of inspired oxygen was lowered (p < .05). Plasma nitrite concentration was higher pre- and postexercise after BR compared with PLA supplementation (p < .05). There was no difference in Tlim between PLA and BR at 0 m (445 [324, 508] and 410 [368, 548] s); 1,200 m (341 [270, 390] and 332 [314, 356] s); or 2,400 m (233 [177, 373] and 251 [221, 323] s) (median and [interquartile range]; p > .05). The findings from this study suggest that short-term BR supplementation does not improve high-intensity intermittent running performance in endurance-trained males in normoxia or at doses of normobaric hypoxia that correspond to altitudes at which athletes typically train while on altitude training camps.
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Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors.
Schneider, MA, Linecker, M, Fritsch, R, Muehlematter, UJ, Stocker, D, Pestalozzi, B, Samaras, P, Jetter, A, Kron, P, Petrowsky, H, et al
Nature communications. 2021;(1):3807
Abstract
Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.