Cerebral blood flow regulation in hypobaric hypoxia: role of haemoconcentration.

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl-1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min-1; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia.

Mechanisms underpinning sympathoexcitation in hypoxia.

Sympathoexcitation is a hallmark of hypoxic exposure, occurring acutely, as well as persisting in acclimatised lowland populations and with generational exposure in highland native populations of the Andean and Tibetan plateaus. The mechanisms mediating altitude sympathoexcitation are multifactorial, involving alterations in both peripheral autonomic reflexes and central neural pathways, and are dependent on the duration of exposure. Initially, hypoxia-induced sympathoexcitation appears to be an adaptive response, primarily mediated by regulatory reflex mechanisms concerned with preserving systemic and cerebral tissue O2 delivery and maintaining arterial blood pressure. However, as exposure continues, sympathoexcitation is further augmented above that observed with acute exposure, despite acclimatisation processes that restore arterial oxygen content ( C a O 2 ${C_{{\mathrm{a}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ). Under these conditions, sympathoexcitation may become maladaptive, giving rise to reduced vascular reactivity and mildly elevated blood pressure. Importantly, current evidence indicates the peripheral chemoreflex does not play a significant role in the augmentation of sympathoexcitation during altitude acclimatisation, although methodological limitations may underestimate its true contribution. Instead, processes that provide no obvious survival benefit in hypoxia appear to contribute, including elevated pulmonary arterial pressure. Nocturnal periodic breathing is also a potential mechanism contributing to altitude sympathoexcitation, although experimental studies are required. Despite recent advancements within the field, several areas remain unexplored, including the mechanisms responsible for the apparent normalisation of muscle sympathetic nerve activity during intermediate hypoxic exposures, the mechanisms accounting for persistent sympathoexcitation following descent from altitude and consideration of whether there are sex-based differences in sympathetic regulation at altitude.

Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO2.

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

BACKGROUND: An increasing number of hypertensive persons travel to high altitude while using antihypertensive medications such as betablockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, ß-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). METHODS: In seven healthy male lowlanders, pulmonary artery pressure was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a three-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release maneuvers were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. RESULTS: At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11dyn*s*cm-5 (21 and 57% increase, p=0.01 and p<0.0001). The PVR response to PROP was amplified at HA to 76% (p<0.0001, p[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (p<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2%*mmHg-1 with PROP+GLYC (p=0.01). CONCLUSIONS: Our data show that ß-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that ß-adrenergic blockade exaggerates HPV for the management of mountaineers using ß-blockers for prevention or treatment of cardiovascular conditions.

Determinants and reference values for blood volume and total hemoglobin mass in women and men.

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m2 ) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hbmass ), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kgBM ) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kgLBM ). Hbmass /BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kgBM ) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kgLBM )/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R2 = .72, p < .001) and Hbmass (R2 = .81, p < .001). These data may only be valid for BV/Hbmass when assessed by CO re-breathing. Hbmass /LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis.

Regulation of haemoglobin concentration at high altitude.

Lowlanders sojourning for more than 1 day at high altitude (HA) experience a reduction in plasma volume (PV) that increases haemoglobin concentration and thus restores arterial oxygen content. If the sojourn extends over weeks, an expansion of total red cell volume (RCV) occurs and contributes to the haemoconcentration. While the reduction in PV was classically attributed to an increased diuretic fluid loss, recent studies support fluid redistribution, rather than loss, as the underlying mechanism. The fluid redistribution is presumably driven by a disappearance of proteins from the circulation and the resulting reduction in oncotic pressure exerted by the plasma, although the fate of the disappearing proteins remains unclear. The RCV expansion is the result of an accelerated erythropoietic activity secondary to enhanced renal erythropoietin release, but a contribution of other mechanisms cannot be excluded. After return from HA, intravascular volumes return to normal values and the normalisation of RCV might involve selective destruction of newly formed erythrocytes, although this explanation has been strongly challenged by recent studies. In contrast to acclimatised lowlanders, native highlanders originating from the Tibetan and the Ethiopian plateaus present with a normal or only mildly elevated haemoglobin concentration. Genetic adaptations blunting the erythropoietic response to HA exposure have been proposed as an explanation for the absence of more pronounced haemoconcentration in these populations, but new evidence also supports a contribution of a larger than expected PV. The functional significance of the relatively low haemoglobin concentration in Tibetan and Ethiopian highlanders is incompletely understood and warrants further investigation.

Effects of Hypobaric Hypoxia on Coagulation in Healthy Subjects Exposed to 3,500 m Altitude.

Kammerer, Tobias, Anna Walzl, Thomas Müller, Philipp Groene, Giulia Roveri, Rachel Turner, Johanna Roche, Hannes Gatterer, Christoph Siebenmann, and Simon T. Schäfer. Effects of hypobaric hypoxia on coagulation in healthy subjects exposed to 3,500 m altitude. High Alt Med Biol. 24:94-103, 2023. Background: Hypoxia is discussed as a trigger for prothrombotic changes both in intensive care and high altitude medicine. This research study aimed to evaluate the effect of isolated hypobaric hypoxia (HH) on coagulation in females in a highly standardized setting. Methods: Twelve healthy female subjects were studied under HH (equivalent to 3,500 m) and normoxia (NX) during two 4-day sojourns, in a strictly controlled crossover design. Nutrition, fluid intake, hormonal status (i.e., menstrual cycle variation), and physical stress were standardized. Functional coagulation and blood lysis were measured by viscoelastometry and compared between HH and NX. In addition, plasma-based coagulation tests (PBCTs), namely prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII coagulation activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), and von Willebrand factor ristocetin cofactor activity (vWF:RCo) were measured. Results: Neither for Viscoelastic Haemostatic Assays nor for PBCTs significant changes were found for HH compared with NX (all p > 0.05). Specifically, the lysis ability, as well as clotting time, clot formation, clot amplitude, and maximum clot firmness unchanged were similar between HH and NX. This also applied to all other variables. Conclusion: We demonstrate that moderate HH per se has no influence on blood coagulation in healthy females.

Changes in body mass, appetite-related hormones, and appetite sensation in women during 4 days of hypobaric hypoxic exposure equivalent to 3,500-m altitude.

Altitude exposure may suppress appetite and hence provide a viable weight-loss strategy. While changes in food intake and availability as well as physical activity may contribute to altered appetite at altitude, herein we aimed to investigate the isolated effects of hypobaric hypoxia on appetite regulation and sensation. Twelve healthy women (age: 24.0 ± 4.2 years, body mass: 60.6 ± 7.0 kg) completed two 4-day sojourns in a hypobaric chamber, one in normoxia [PB = 761 mmHg, 262 m (NX)] and one in hypobaric hypoxia [PB = 493 mmHg (HH)] equivalent to 3,500-m altitude. Energy intake was standardized 4 days prior and throughout both sojourns. Plasma concentrations of leptin, acylated ghrelin, cholecystokinin (CCK), and cytokine growth differentiation factor 15 (GDF15) were determined every morning. Before and after breakfast, lunch, and dinner, appetite was assessed using visual analog scales. Body mass was significantly decreased following HH but not NX (-0.71 ± 0.32 kg vs. -0.05 ± 0.54 kg, condition: P < 0.001). Compared to NX, acylated ghrelin decreased throughout the HH sojourn (condition × time: P = 0.020), while leptin was higher throughout the entire HH sojourn (condition: P < 0.001). No differences were observed in CCK and GDF15 between the sojourns. Feelings of satiety and fullness were higher (condition: P < 0.001 and P = 0.013, respectively), whereas prospective food consumption was lower in HH than in NX (condition: P < 0.001). Our findings suggest that hypoxia exerts an anorexigenic effect on appetite-regulating hormones, suppresses subjective appetite sensation, and can induce weight loss in young healthy women. Among the investigated hormones, acylated ghrelin and leptin most likely explain the observed HH-induced appetite suppression.NEW & NOTEWORTHY This study investigated the effects of hypoxia on appetite regulation in women while strictly controlling for diet, physical activity, menstrual cycle, and environmental conditions. In young women, 4 days of altitude exposure (3,500 m) decreases body weight and circulating acylated ghrelin levels while preserving leptin concentrations. In line with the hormonal changes, altitude exposure induces alterations in appetite sensation, consisting of a decreased feeling of hunger and prospective food intake and an increased feeling of fullness and satiety.

Hypoxia briefly increases diuresis but reduces plasma volume by fluid redistribution in women.

We have recently reported that hypobaric hypoxia (HH) reduces plasma volume (PV) in men by decreasing total circulating plasma protein (TCPP). Here, we investigated whether this applies to women and whether an inflammatory response and/or endothelial glycocalyx shedding could facilitate the TCCP reduction. We further investigated whether acute HH induces a short-lived diuretic response that was overlooked in our recent study, where only 24-h urine volumes were evaluated. In a strictly controlled crossover protocol, 12 women underwent two 4-day sojourns in a hypobaric chamber: one in normoxia (NX) and one in HH equivalent to 3,500-m altitude. PV, urine output, TCPP, and markers for inflammation and glycocalyx shedding were repeatedly measured. Total body water (TBW) was determined pre- and postsojourns by deuterium dilution. PV was reduced after 12 h of HH and thereafter remained 230-330 mL lower than in NX (P < 0.0001). Urine flow was 45% higher in HH than in NX throughout the first 6 h (P = 0.01) but lower during the second half of the first day (P < 0.001). Twenty-four-hour urine volumes (P ≥ 0.37) and TBW (P ≥ 0.14) were not different between the sojourns. TCPP was lower in HH than in NX at the same time points as PV (P < 0.001), but inflammatory or glycocalyx shedding markers were not consistently increased. As in men, and despite initially increased diuresis, HH-induced PV contraction in women is driven by a loss of TCPP and ensuing fluid redistribution, rather than by fluid loss. The mechanism underlying the TCPP reduction remains unclear but does not seem to involve inflammation or glycocalyx shedding.NEW & NOTEWORTHY This study is the first to investigate the mechanisms underlying plasma volume (PV) contraction in response to hypoxia in women while strictly controlling for confounders. PV contraction in women has a similar time course and magnitude as in men and is driven by the same mechanism, namely, oncotically driven redistribution rather than loss of fluid. We further report that hypoxia facilitates an increase in diuresis, that is, however, short-lived and of little relevance for PV regulation.

Hypobaric hypoxia and cardiac baroreflex sensitivity in young women.

We sought to determine the effects of prolonged moderate hypobaric hypoxia (HH) on cardiac baroreflex sensitivity (cBRS) in young women and whether these effects are a consequence of the reduced arterial oxygen (O2) tension and/or increased pulmonary ventilation in HH. We hypothesized that HH would reduce cBRS and that this effect would be counteracted by acute restoration of the inspiratory partial pressure of O2 ([Formula: see text]) and/or voluntary attenuation of pulmonary ventilation. Twelve healthy women (24.0 ± 4.2 yr) were studied before (day 0) and twice during a sojourn in a hypobaric chamber (∼8 h, day 1; 4 days, day 4) where barometric pressure corresponded to ∼3,500-m altitude. Minute ventilation (V̇e; pneumotachometer), heart rate (electrocardiogram), and arterial pressure (finger volume clamp method) were recorded. cBRS was calculated using transfer function analysis between systolic pressure and RR interval. Assessments were made during 1) spontaneous breathing and (in HH only), 2) controlled breathing (reducing V̇e by ∼1 to 2 L/min), and 3) breathing a hyperoxic gas mixture that normalized [Formula: see text]. During spontaneous breathing, HH decreased cBRS (12.5 ± 7.1, 8.9 ± 4.4, and 7.4 ± 3.0 ms/mmHg on days 0, 1, and 4, respectively; P = 0.018). The normalization of [Formula: see text] increased cBRS (10.6 ± 3.3 and 10.7 ± 6.1 ms/mmHg on days 1 and 4) in HH compared with values observed during spontaneous breathing (P < 0.001), whereas controlled breathing had no effect on cBRS (P = 0.708). These findings indicate that ongoing arterial chemoreflex activation by the reduced arterial O2 tension, independently of the hypoxic ventilatory response, reduces cBRS in young women exposed to extended HH.NEW & NOTEWORTHY We examined the effects of prolonged hypobaric hypoxia (corresponding to ∼3,500-m altitude) on cardiac baroreflex sensitivity (cBRS) in young women and investigated underlying mechanisms. We found that cBRS was reduced in hypoxia and that this reduction was attenuated by acute restoration of inspiratory oxygen partial pressure but not by volitional restraint of pulmonary ventilation. These findings help to elucidate the role of arterial chemoreflex mechanisms in the control of cBRS during hypobaric hypoxia in young women.

Marked improvements in cardiac function in postmenopausal women exposed to blood withdrawal plus endurance training.

The cardiac phenotype of a substantial fraction of the population, i.e., mature women, is mainly unresponsive to endurance training (ET), the most effective intervention to improve cardiorespiratory fitness. This study assessed whether a novel intervention comprising additional haemodynamic stimuli may overcome the generalized limitations to modify the cardiac phenotype of middle-aged and older women. Fifteen healthy postmenopausal women (52-75 yr) were recruited. Transthoracic echocardiography and central haemodynamics were assessed during incremental cycle ergometry (i) in baseline conditions, (ii) after standard (10%) blood withdrawal and (iii) subsequent 8-week ET. Main outcomes such as left ventricular (LV) function and structure and blood volume (BV) were determined. Phlebotomy induced a 0.5 ± 0.1 l reduction of BV, which was re-established after ET. Decrements in LV end-systolic volume (-27%) and increments in LV ejection fraction (+8%) during exercise as well as improved E/A ratio were detected after ET compared with baseline. In parallel, ET induced a 10% increment in LV mass without a concomitant increase in LV size. In conclusion, postmenopausal women exhibit large improvements in cardiac systolic and diastolic functions along with LV concentric remodelling in response to the sequenced combination of blood withdrawal and ET.

Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

Cerebral lactate uptake during exercise is driven by the increased arterial lactate concentration.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood-brain barrier. However, nonspecific ß-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting ß-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesized that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercises to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account, we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (P < 0.05), reaching 14 ± 3 and 11 ± 3 mmol·l-1 during maximal exercise without and with propranolol, respectively. Although AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a ß-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.NEW & NOTEWORTHY During exercise the brain consumes lactate as a substitute for glucose. Propranolol has previously attenuated this cerebral lactate uptake, suggesting a ß-adrenergic transport mechanism. However, in the present study, we demonstrate that the fractional extraction of arterial lactate by the brain is unaffected by propranolol throughout incremental exercise to exhaustion. We conclude that cerebral lactate uptake during exercise is passively driven by the increasing arterial concentration, rather than by a ß-adrenergic mechanism within the brain.

Blood Oxygen Carrying Capacity Determines Cardiorespiratory Fitness in Middle-Age and Older Women and Men.

PURPOSE: Whether blood oxygen (O2)-carrying capacity plays a substantial role in determining cardiorespiratory fitness, a strong predictor of mortality, remains uncertain in women and elderly individuals because of the scarcity of experimental investigations. This study experimentally assessed the role of blood O2-carrying capacity on cardiorespiratory fitness in middle-age and older individuals. METHODS: Healthy women and men (n = 31, 35-76 yr) matched by age and fitness were recruited. Transthoracic echocardiography, central hemodynamics, and O2 uptake were assessed throughout incremental exercise in (i) control conditions and (ii) after a 10% reduction of blood O2-carrying capacity via carbon monoxide administration, in a blinded manner. Effects on cardiac function, blood pressure, peak O2 uptake, and effective hemoglobin (Hb) were determined with established methods. RESULTS: Blood O2-carrying capacity, represented by effective Hb, was similarly reduced in women (11.8 ± 0.6 vs 10.7 ± 0.6 g·dL-1, P < 0.001) and men (13.0 ± 0.9 vs 11.7 ± 0.6 g·dL-1, P < 0.001) (P for sex effect = 0.580). Reduced O2-carrying capacity did not induce major effects on cardiac function and hemodynamics during exercise, except for a 10%-15% decrement in peak systolic blood pressure in both sexes (P ≤ 0.034). Peak O2 uptake decreased from 35 ± 6 to 31 ± 6 mL·min-1·kg-1, P < 0.001) in women and from 35 ± 9 to 32 ± 9 mL·min-1·kg-1 (P = 0.024) in men in approximate proportion to the reduction of O2-carrying capacity, an effect that did not differ between sexes (P = 0.778). CONCLUSIONS: Blood O2-carrying capacity stands out as a major determinant of cardiorespiratory fitness in healthy mature women and men, with no differential effect of sex.

The middle cerebral artery blood velocity response to acute normobaric hypoxia occurs independently of changes in ventilation in humans.

NEW FINDINGS: What is the central question of this study? Does the ventilatory response to moderate acute hypoxia increase cerebral perfusion independently of changes in arterial oxygen tension in humans? What is the main finding and its importance? The ventilatory response does not increase middle cerebral artery mean blood velocity during moderate isocapnic acute hypoxia beyond that elicited by reduced oxygen saturation. ABSTRACT: Hypoxia induces ventilatory, cardiovascular and cerebrovascular adjustments to defend against reductions in systemic oxygen delivery. We aimed to determine whether the ventilatory response to moderate acute hypoxia increases cerebral perfusion independently of changes in arterial oxygenation. Eleven young healthy individuals were exposed to four 15 min experimental conditions: (1) normoxia (partial pressure of end-tidal oxygen, PETO2  = 100 mmHg), (2) hypoxia ( PETO2  = 50 mmHg), (3) normoxia with breathing volitionally matched to levels observed during hypoxia (hyperpnoea; PETO2  = 100 mmHg) and (4) hypoxia ( PETO2  = 50 mmHg) with respiratory frequency and tidal volume volitionally matched to levels observed during normoxia (i.e., restricted breathing (RB)). Isocapnia was maintained in all conditions. Middle cerebral artery mean blood velocity (MCA Vmean ), assessed by transcranial Doppler ultrasound, was increased during hypoxia (58 ± 12 cm/s, P = 0.04) and hypoxia + RB (61 ± 14 cm/s, P < 0.001) compared to normoxia (55 ± 11 cm/s), while it was unchanged during hyperpnoea (52 ± 13 cm/s, P = 0.08). MCA Vmean was not different between hypoxia and hypoxia + RB (P > 0.05). These findings suggest that the hypoxic ventilatory response does not increase cerebral perfusion, indexed using MCA Vmean , during moderate isocapnic acute hypoxia beyond that elicited by reduced oxygen saturation.

Plasma volume contraction reduces atrial natriuretic peptide after four days of hypobaric hypoxia exposure.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L (P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL (P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 (P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 (P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L (P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.

The interaction between metformin and physical activity on postprandial glucose and glucose kinetics: a randomised, clinical trial.

AIMS/HYPOTHESIS: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. METHODS: Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA1c of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m2) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Wattmax for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student's t tests. RESULTS: Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: -0.7 [95% CI -1.4, 0.0] mmol/l, p = 0.05 and ∆MET: -0.7 [-1.5, -0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O2peak increased 15% (4.6 [3.3, 5.9] ml kg-1 min-1, p < 0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively). CONCLUSIONS/INTERPRETATION: Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities. FUNDING: The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03316690). Graphical abstract.

Regulation of plasma volume in male lowlanders during 4 days of exposure to hypobaric hypoxia equivalent to 3500 m altitude.

KEY POINTS: Acclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O2 content. Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled. We examined the mechanisms underlying the PV contraction evoked by 4 days of exposure to hypobaric hypoxia (HH) in 11 healthy lowlanders, while strictly controlling water intake, diet, temperature and physical activity. Exposure to HH-induced an ∼10% PV contraction that was accompanied by a reduction in total circulating protein mass, whereas diuretic fluid loss and total body water remained unchanged. Our data support an oncotically driven fluid redistribution from the intra- to the extravascular space, rather than fluid loss, as the mechanism underlying HH-induced PV contraction. ABSTRACT: Extended hypoxic exposure reduces plasma volume (PV). The mechanisms underlying this effect are controversial, possibly as previous studies have been confounded by inconsistent experimental conditions. Here, we investigated the effect of hypobaric hypoxia (HH) on PV in a cross-over study that strictly controlled for diet, water intake, physical activity and temperature. Eleven males completed two 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in HH equivalent to 3500 m altitude. PV, urine output, volume-regulating hormones and plasma protein concentration were determined daily. Total body water (TBW) was determined at the end of both sojourns by deuterium dilution. Although PV was 8.1 ± 5.8% lower in HH than in NX after 24 h and remained ∼10% lower thereafter (all P < 0.002), no differences were detected in TBW (P = 0.17) or in 24 h urine volumes (all P > 0.23). Plasma renin activity and circulating aldosterone were suppressed in HH during the first half of the sojourn (all P < 0.05) but thereafter similar to NX, whereas no differences were detected for copeptin between sojourns (all P > 0.05). Markers for atrial natriuretic peptide were higher in HH than NX after 30 min (P = 0.001) but lower during the last 2 days (P < 0.001). While plasma protein concentration was similar between sojourns, total circulating protein mass (TCP) was reduced in HH at the same time points as PV (all P < 0.03). Despite transient hormonal changes favouring increased diuresis, HH did not enhance urine output. Instead, the maintained TBW and reduced TCP support an oncotically driven fluid redistribution into the extravascular compartment as the mechanism underlying PV contraction.

Endothelial function and shear stress in hypobaric hypoxia: time course and impact of plasma volume expansion in men.

High-altitude exposure typically reduces endothelial function, and this is modulated by hemoconcentration resulting from plasma volume contraction. However, the specific impact of hypobaric hypoxia independent of external factors (e.g., cold, varying altitudes, exercise, diet, and dehydration) on endothelial function is unknown. We examined the temporal changes in blood viscosity, shear stress, and endothelial function and the impact of plasma volume expansion (PVX) during exposure to hypobaric hypoxia while controlling for external factors. Eleven healthy men (25 ± 4 yr, mean ± SD) completed two 4-day chamber visits [normoxia (NX) and hypobaric hypoxia (HH; equivalent altitude, 3,500 m)] in a crossover design. Endothelial function was assessed via flow-mediated dilation in response to transient (reactive hyperemia; RH-FMD) and sustained (progressive handgrip exercise; SS-FMD) increases in shear stress before entering and after 1, 6, 12, 48, and 96 h in the chamber. During HH, endothelial function was also measured on the last day after PVX to preexposure levels (1,140 ± 320 mL balanced crystalloid solution). Blood viscosity and arterial shear stress increased on the first day during HH compared with NX and remained elevated at 48 and 96 h (P < 0.005). RH-FMD did not differ during HH compared with NX and was unaffected by PVX despite reductions in blood viscosity (P < 0.05). The stimulus-response slope of increases in shear stress to vasodilation during SS-FMD was preserved in HH and increased by 44 ± 73% following PVX (P = 0.023). These findings suggest that endothelial function is maintained in HH when other stressors are absent and that PVX improves endothelial function in a shear-stress stimulus-specific manner.NEW & NOTEWORTHY Using a normoxic crossover study design, we examined the impact of hypobaric hypoxia (4 days; altitude equivalent, 3,500 m) and hemoconcentration on blood viscosity, shear stress, and endothelial function. Blood viscosity increased during the hypoxic exposure and was accompanied by elevated resting and exercising arterial shear stress. Flow-mediated dilation stimulated by reactive hyperemia and handgrip exercise was preserved throughout the hypoxic exposure. Plasma volume expansion reversed the hypoxia-associated hemoconcentration and selectively increased handgrip exercise flow-mediated dilation.