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Abstract Microvascular impairments are typical of several cardiovascular diseases. Near‐infrared spectroscopy (NIRS) combined with a vascular occlusion test provides non‐invasive insights into microvascular responses by monitoring skeletal muscle oxygenation changes during reactive hyperaemia. Despite increasing interest in the effects of sex and ageing on microvascular responses, evidence remains inconsistent. Therefore, the present study aimed to investigate the effects of sex and age on microvascular responsiveness. Twenty‐seven participants (seven young men and seven young women; seven older men and six older women; aged 26 ± 1, 26 ± 4, 67 ± 3 and 69 ± 4 years, respectively) completed a vascular occlusion test consisting of 5 min of arterial occlusion followed by 5 min reperfusion. Oxygenation changes in the vastus lateralis were monitored by near‐infrared spectroscopy. The findings revealed that both women (referring to young and older women) and older participants (referring to both men and women) exhibited lower microvascular responsiveness. Notably, both women and older participants demonstrated reduced desaturation (−38% and −59%, respectively) and reperfusion rates (−24% and −40%, respectively) along with a narrower range of tissue oxygenation (−39% and −39%, respectively) and higher minimal tissue oxygenation levels (+34% and +21%, respectively). Women additionally displayed higher values in resting (+12%) and time‐to‐peak (+15%) tissue oxygenation levels. In conclusion, this study confirmed decreased microvascular responses in women and older individuals. These results emphasize the importance of considering sex and age when studying microvascular responses. Further research is needed to uncover the underlying mechanisms and clinical relevance of these findings, enabling the development of tailored strategies for preserving vascular health in diverse populations.

The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure.

Introduction The acute mountain sickness (AMS) prevalence increases with altitude; i.e.,10-25% at 2,500 m and 50-85% at ~5,000 m (Bärtsch & Swenson, 2013). Women are more likely affected by AMS than men (Richalet et al., 2012). AMS can affect exercise performance. However, the effects of the menstrual cycle (MC) on physiological responses to exercise and on tolerance to high-altitude (HA) remain underexplored. It has been reported that ovarian hormones stimulate ventilation in normoxic conditions (Saaresranta & Polo, 2002). Early findings suggest that running economy is lower in the mid-luteal (ML) compared to the early-follicular (EF) phase in normoxia (Goldsmith & Glaister, 2020). However, cycling efficiency at HA has not been explored yet. Thus, we investigated the effects of acute HA exposure on ventilatory responses at rest and during exercise in healthy females during two different phases of their MC. Methods Sixteen eumenorrheic women (age: 33 ± 7 yr; MC length: 27 ± 2 days; not taking any hormonal contraceptive) took part in this study. First, over a 6-month period, the participants’ MC were monitored using a calendar method. Then, they reached the Torino Hut (3,375 m) by cable car and spent one night at HA on two different MC phases; i.e., during the early-follicular (EF; MC day 4 ± 1) and the mid-luteal (ML; day 20 ± 2) phases. Each time, they underwent a submaximal (1.2 W/kg) test on a cycle ergometer ~17 h after arrival at HA. In addition to this, participants filled in two questionnaires, the Lake Louise AMS Score and the Groningen Sleep Quality Scale, ~16 h after arrival at HA. Results Resting ventilation was significantly higher during EF compared to ML (15.2 ± 1.9 vs. 13.2 ± 2.5 L/min, p = 0.039), while no differences were found for ventilation during exercise (53.9 ± 13.2 vs. 53.5 ± 13.4 L/min, p = 0.695), cycling efficiency (21.7 ± 0.0% vs. 19.8 ± 0.0%, p = 0.244), saturation at rest (92.4 ± 1.3 vs. 91.3 ± 3.2%, p = 0.142) and during exercise (87.2 ± 5.7 vs. 89.0 ± 4.0%, p = 0.528). Moreover, no differences in the Lake Louise AMS (2.2 ± 1.5 vs. 1.7 ± 1.5, p = 0.266) or Groningen (8.0 ± 3.3 vs. 7.5 ± 3.4, p = 0.668) scores were noted between the two MC phases. Discussion/Conclusion Despite a slightly higher resting ventilation during EF, when both oestrogens and progesterone are at their lowest levels, there were no differences in ventilatory responses to exercise and in AMS between the different phases of the MC. Consequently, there is currently very little evidence to aptly recommend a specific MC phase for mountaineering or any other HA activities (Burtscher et al., 2023). Further investigations are requested to assess whether other physiological responses to HA may be influenced by hormonal variations. References Bärtsch, P., & Swenson, E. R. (2013). Acute high-altitude illnesses. New England Journal of Medicine, 368, 2294–2302. https://doi.org/10.1056/NEJMcp1214870 Burtscher, J., Raberin, A., Brocherie, F., Malatesta, D., Manferdelli, G., Citherlet, T., Krumm, B., Bourdillon, N., Antero, J., Rasica, L., Burtscher, M. & Millet, G. P. (2023). Recommendations for women in mountain sports and hypoxia training/conditioning. Sports Medicine. Advance online publication. https://doi.org/10.1007/s40279-023-01970-6 Goldsmith, E., & Glaister, M. (2020). The effect of the menstrual cycle on running economy. The Journal of Sports Medicine and Physical Fitness, 60(4), 610–617. https://doi.org/10.23736/s0022-4707.20.10229-9 Richalet, J.-P., Larmignat, P., Poitrine, E., Letournel, M., & Canouï-Poitrine, F. (2012). Physiological risk factors for severe high-altitude illness: A prospective cohort study. American Journal of Respiratory and Critical Care Medecine, 185(2), 192–198. https://doi.org/10.1164/rccm.201108-1396OC Saaresranta, T., & Polo, O. (2002). Hormones and breathing. American College of Chest Physicians, 122(6), 2165–2182. https://doi.org/10.1378/chest.122.6.2165

Elderly represents a growing population and cardiovascular diseases (CVD) is one of the leading causes of mortality in this population. Sex differences are involved in CVD with middle-aged males being at higher risk than females. After menopause, females are no longer protected by hormones and the role of sex on cardiovascular parameters involved in CVD, such as endothelial function and blood viscosity, is still unclear. The purpose of this study was to investigate the effect of sex on endothelial function, blood viscosity and CVD in elderly. Clinical investigation and blood analyses were performed on 182 (93 females and 89 males) elderly participants (mean age: 75.83 ± 1.22). Health status of participants were classified. Sex differences in endothelial function, blood viscosity, high density lipoprotein (HDL), hematocrit, and red blood cell (RBC) aggregation were assessed. CVD prevalence was higher in males (27.0%) than in females (5.4%) (p < 0.001). Females had higher vasoreactivity (p = 0.014) and HDL (p < 0.001) level than males. Blood viscosity was higher in males than in females at any shear rate (p < 0.001). Hematocrit was greater in males than in females (p < 0.001) while RBC aggregation did not differ between the two populations. To conclude, females have less CVD than age-matched males that might be due to their greater vascular function and lower blood viscosity.

Introduction The prevalence of acute mountain sickness (AMS) is increasing with altitude (i.e., 10-25% at 2,500 m and 50-85% at ~ 5,000 m; Bärtsch & Swenson, 2013). While there is no error-free test to predict its occurrence, several risk factors and tests have been proposed. For example, the hypoxic ventilatory response (HVR) measures the ratio between the increase in ventilation (VE) and the decrease in pulse saturation (SpO2) during hypoxic exposure. Some studies reported an increased (Lhuissier et al., 2012), no difference (Pokorski and Marczak, 2003), or a decreased HVR (Kronenberg and Drage, 1973) with age. The effect of sex remains also debated since women have been reported to have a higher (Richalet et al., 2012) or lower (Schneider et al. 2002; Vardy et al., 2006) AMS prevalence. Therefore, we aimed to compare measurements of HVR, VE and SpO2 between pre- (PreM) and post-menopausal (postM) women and to investigate if they are related to AMS. We hypothesized differences in hypoxic tolerance between age groups. Methods We screened pre-menopausal women (PreM; n = 13; age = 31.7 ± 7.8yr; weight = 63.5 ±9.6 kg; height = 167 ±10 cm) during three phases (early follicular, Fol1; late follicular, Fol2; luteal, Lut3) of their menstrual cycle and post-menopausal women (PostM; n = 15; age = 62.8 ±2.3 yr; weight = 56.1 ±8.3 kg; height 163 ±5 cm) on one occasion. They were evaluated with a pure nitrogen breathing test (N2T; Solaiman et al., 2014) for HVR and with a cycling exercise (5 min of rest followed by 5 min of cycling at 1.5 W/kg) in hypoxia (FiO2 = 14%; simulated altitude of 3,500 m) with measurement of SpO2 and VE. They were then exposed to one night in real altitude (3,375 m) with AMS assessment (Lake Louise Score; Roach et al., 2018). Results PreM had a higher resting VE in normoxia (9.95-10.07 vs 8.50 L/min; P < 0.05) and increased VE (7.49-8.78 vs 5.41 L/min; P < 0.05) during the N2T at the three measurements points than PostM. Moreover, only at Fol2, HVR (-0.43 vs -0.27 L/min/%; P = 0.023), VEpeak (18.9 vs 15.0 L/min; P = 0.025) during N2T and resting SpO2 in normoxia (95.9 vs 94.9, P = 0.093) were higher in PreM. The prevalence of AMS was similar between PreM and PostM (30.8 vs 40.0%). When AMS positive and AMS negative subgroups were compared, no difference in HVR was found while there were differences in SpO2 and VE. Discussion/Conclusion The main finding of the present study is that HVR was higher in PreM than in PostM only during the late follicular phase of the former. Since estrogen is known to have a stimulatory effect on both pulmonary ventilation and blood vessel vasodilation and peaks during this phase, this suggests that it is the main trigger of the observed differences in HVR. The prevalence of AMS was in line with the literature for a similar altitude (34% at 3,650m; Maggiorini et al., 1990). Contrary to Richalet et al. (2012), HVR did not diagnose AMS in any group nor was lower in the older age group. No other parameter showed to be a solid predictive metric for AMS. Given conflicting results in this study (i.e., HVR and AMS) and in the literature, there is no clear evidence of an effect of age on hypoxic tolerance and on AMS prediction. References Bärtsch, P., & Swenson, E. R. (2013). Acute high-altitude illnesses. New England Journal of Medicine, 368(24), 2294-2302. https://doi.org/10.1056/NEJMcp1214870 Kronenberg, R. S., & Drage, C. W. (1973). Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. The Journal of Clinical Investigation, 52(8), 1812-1819. https://doi.org/10.1172/JCI107363 Lhuissier, F. J., Canouï‐Poitrine, F., & Richalet, J. P. (2012). Ageing and cardiorespiratory response to hypoxia. The Journal of Physiology, 590(21), 5461-5474. https://doi.org/10.1113/jphysiol.2012.238527 Maggiorini, M., Bühler, B., Walter, M., & Oelz, O. (1990). Prevalence of acute mountain sickness in the Swiss Alps. British Medical Journal, 301(6756), 853-855. https://doi.org/10.1136/bmj.301.6756.853 Pokorski, M., & Marczak, M. (2003). Ventilatory response to hypoxia in elderly women. Annals of Human Biology, 30(1), 53-64. https://doi.org/10.1080/03014460210162000 Richalet, J. P., Larmignat, P., Poitrine, E., Letournel, M., & Canouï-Poitrine, F. (2012). Physiological risk factors for severe high-altitude illness: A prospective cohort study. American Journal of Respiratory and Critical Care Medicine, 185(2), 192-198. https://doi.org/10.1164/rccm.201108-1396OC Roach, R. C., Hackett, P. H., Oelz, O., Bärtsch, P., Luks, A. M., MacInnis, M. J., ... & Lake Louise AMS Score Consensus Committee. (2018). The 2018 Lake Louise acute mountain sickness score. High Altitude Medicine & Biology, 19(1), 4-6. https://doi.org/10.1089/ham.2017.0164 Schneider, M., Bernasch, D., Weymann, J., Holle, R., & Bärtsch, P. (2002). Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate. Medicine & Science in Sports & Exercise, 34(12), 1886-1891. Solaiman, A. Z., Feehan, R. P., Chabitnoy, A. M., Leuenberger, U. A., & Monahan, K. D. (2014). Ventilatory responses to chemoreflex stimulation are not enhanced by angiotensin II in healthy humans. Autonomic Neuroscience, 183, 72-79. https://doi.org/10.1016/j.autneu.2014.01.010 Vardy, J., Vardy, J., & Judge, K. (2006). Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya. Aviation, Space, and Environmental Medicine, 77(7), 742-744.

Introduction Repeated sprints exercise (RSE) performed in hypoxia (RSH) induce greater performance improvement than in normoxia (Brocherie et al., 2017). It has been previously argued that RSH efficiency depend on the oxidative-glycolytic balance which is influenced by sprint duration and exercise-to-rest-ratio (E:R). Indeed, we recently showed that long sprint duration (e.g. 20 s vs 10 s or 5 s) blunts the additional impact of hypoxia on RSH with a constant large E:R of 1:22. However, E:R also influence acute response to RSH. Therefore, this study aims to compare acute responses during RSE to exhaustion with a short E:R (1:6) in normoxia (RSN) and hypoxia (FiO2 = 0.13) and the same sprint durations (5, 10 or 20 s) previously used. Methods On separate visits, 10 active participants completed in random order three RSH and three RSN sessions to exhaustion on a cycle-ergometer (Excalibur Sport, Lode) with three sprint durations and a constant short E:R of 1:6 (5:30; 10:60 and 20:120). Vastus lateralis muscle de-reoxygenation (Oxymon, Artinis Medical Systems) and power output were continuously recorded. Lower limb and breathing discomfort, blood lactate, and ratings of perceived exertion were evaluated immediately after exhaustion. Results Number of sprints and peak power output were higher while blood lactate was lower (all p < 0.001) during 5:30 compared to 10:60 or 20:120. No condition or interaction effects were reported for blood lactate and exercise-related sensation. Blood lactate and muscle deoxyhemoglobin increase (p < 0.001) and total hemoglobin decrease (p = 0.002) during sprint were more pronounced when sprint duration increased (no hypoxia effect). Discussion Similar deoxygenation changes during recovery were reported in hypoxia compared to normoxia suggesting that 1:6 ratio and the associated long recovery period seemed to allow myoglobin O2 store restauration, even with a FiO2 = 13%. Sprint effort should be interspersed by incomplete recovery making impossible the full O2 reloading myoglobin and PCr resynthesis. The increase in blood lactate and the concomitant decrease in muscle oxygenation during sprint with longer duration confirmed a switch in the oxidative-glycolytic balance for energy supply. Since short exercise-to-rest ratio blunt hypoxic effect during RSH due to too long recovery period, hypoxia did not participate to the switch from oxidative to glycolytic energy supply. Conclusion During RSE to exhaustion, a short exercise-to-rest ratio (i.e., 1:6) blunts the specific psychophysiological responses induced by hypoxia, probably due to too long of recovery period. Manipulating effort duration rather than hypoxic exposure is preferable to alter both anaerobic energy system solicitation and power produced during repeated cycling sprints to exhaustion using a short exercise-to-rest ratio. References Brocherie, F., Girard, O., Faiss, R., & Millet, G. P. (2017). Effects of repeated-sprint training in hypoxia on sea-level performance: A meta-analysis. Sports Medicine, 47, 1651-1660. https://doi.org/10.1007/s40279-017-0685-3

Exercise-induced hypoxemia (EIH) is well-described in endurance-trained athletes during both maximal and submaximal exercise intensities. Despite the drop in oxygen (O2) saturation and provided that training volumes are similar, athletes who experience EIH nevertheless produce the same endurance performance in normoxia as athletes without EIH. This lack of a difference prompted trainers to consider that the phenomenon was not relevant to performance but also suggested that a specific adaptation to exercise is present in EIH athletes. Even though the causes of EIH have been extensively studied, its consequences have not been fully characterized. With the development of endurance outdoor activities and altitude/hypoxia training, athletes often train and/or compete in this stressful environment with a decrease in the partial pressure of inspired O2 (due to the drop in barometric pressure). Thus, one can reasonably hypothesize that EIH athletes can specifically adapt to hypoxemic episodes during exercise at altitude. Although our knowledge of the interactions between EIH and acute exposure to hypoxia has improved over the last 10 years, many questions have yet to be addressed. Firstly, endurance performance during acute exposure to altitude appears to be more impaired in EIH vs. non-EIH athletes but the corresponding physiological mechanisms are not fully understood. Secondly, we lack information on the consequences of EIH during chronic exposure to altitude. Here, we (i) review research on the consequences of EIH under acute hypoxic conditions, (ii) highlight unresolved questions about EIH and chronic hypoxic exposure, and (iii) suggest perspectives for improving endurance training.

This study examined to what extent athletes exhibiting exercise-induced hypoxemia (EIH) possess an altered redox status at rest, in response to exercise at sea level (SL) and during moderate altitude exposure. EIH was defined as a fall in arterial O2 saturation of at least 4% during exercise. Nine endurance athletes with EIH and ten without (NEIH) performed a maximal incremental test under three conditions: SL, one (H1) and five (H2) days after arrival to 2400 m. Gas exchange and peripheral capillary oxygen saturation (SpO2) were continuously monitored. Blood was sampled before exercise and after exercise cessation. Advanced oxidation protein products (AOPP), catalase, ferric-reducing antioxidant power, glutathione peroxidase, superoxide dismutase (SOD) and nitric oxide metabolites (NOx) were measured in plasma by spectrophotometry. EIH athletes had higher AOPP and NOx concentrations at pre- and post-exercise stages compared to NEIH at SL, H2 but not at H1. Only the EIH group experienced increased SOD activity between pre- and post-exercise exercise at SL and H2 but not at H1. EIH athletes had exacerbated oxidative stress compared to the NEIH athletes at SL and H2. These differences were blunted at H1. Oxidative stress did not alter the EIH groups’ aerobic performance and could lead to higher minute ventilation at H2. These results suggest that higher oxidative stress response EIH athletes could be involved in improved aerobic muscle functionality and a greater ventilatory acclimatization during prolonged hypoxia.