Genetic polymorphisms and expression of Rhesus blood group RHCE are associated with 2,3-bisphosphoglycerate in humans at high altitude.

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity.

Are coagulation profiles in Andean highlanders with excessive erythrocytosis favouring hypercoagulability?

Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.

Making a virtue out of an evil: Are red blood cells from chronic mountain sickness patients eligible for transfusions?

We investigated highlanders, permanently living at an altitude of 5100 m and compared Chronic Mountain Sickness (CMS) patients with control volunteers. While we found differences in systemic parameters such as blood oxygen content, hematocrit, hemoglobin concentration, and blood viscosity, the mechanical and rheological properties of single red blood cells did not differ between the two investigated groups.

Expedition 5300: limits of human adaptations in the highest city in the world.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000-5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2  = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues.

Cardiorespiratory Fitness and Neuromuscular Function of Mechanically Ventilated ICU COVID-19 Patients.

OBJECTIVES: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration. DESIGN: Prospective nonrandomized study. SETTING: Patients hospitalized in ICU for COVID-19 infection. PATIENTS: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status. CONCLUSIONS: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.

Hypoxic high-intensity interval training in individuals with overweight and obesity.

Combining moderate-intensity exercise training with hypoxic exposure may induce larger improvement in cardiometabolic risk factors and health status compared with normoxic exercise training in obesity. Considering the greater cardiometabolic effects of high-intensity intermittent training (HIIT), we hypothesized that hypoxic high-volume HIIT (H-HIIT) would induce greater improvement in cardiorespiratory fitness and health status despite a lower absolute training workload than normoxic HIIT (N-HIIT) in overweight/obesity. Thirty-one subjects were randomized to an 8-week H-HIIT [10 male and 6 female; age: 51.0 ± 8.3 years; body mass index (BMI): 31.5 ± 4 kg·m-2] or N-HIIT (13 male and 2 female; age: 52.0 ± 7.5 years; BMI: 32.4 ± 4.8 kg·m-2) program (3 sessions/week; cycling at 80% or 100% of maximal workload for H-HIIT and N-HIIT, respectively; target arterial oxygen saturation for H-HIIT 80%, [Formula: see text] ∼0.12, i.e., ∼4,200 meters above sea level). Before and after training, the following evaluations were performed: incremental maximal and submaximal cycling tests, pulse-wave velocity, endothelial function, fasting glucose, insulin, lipid profile, and body composition. Maximal exercise (V̇o2peak: H-HIIT +14.2% ± 8.3% vs. N-HIIT +12.1 ± 8.8%) and submaximal (ventilatory thresholds) capacity and exercise metabolic responses (power output at the crossover point and at maximal fat oxidation rate) increased significantly in both groups, with no significant difference between groups and without other cardiometabolic changes. H-HIIT induced a greater peak ventilatory response (ANOVA group × time interaction F = 7.4, P = 0.016) compared with N-HIIT. In overweight/obesity, the combination of normobaric hypoxia and HIIT was not superior for improving cardiorespiratory fitness improvement compared with HIIT in normoxia, although HIIT in hypoxia was performed at a lower absolute training workload.

Changes in cardiac function following a speed ascent to the top of Europe at 4808 m.

PURPOSE: Both prolonged exercise and acute high-altitude exposure are known to induce cardiac changes. We sought to describe the cardiac responses to speed climbing at high-altitude, including left ventricular (LV) performance assessment using the myocardial work index (MWI), a new index derived from 2D speckle tracking echocardiography (STE). METHODS: Eleven elite alpinists (9 males, age: 26 ± 4 years) were evaluated before and immediately after a speed ascent of the Mont-Blanc (4808 m) by echocardiography using conventional measurements as well as STE and MWI computation with derivate parameters as global work efficiency (GWE) or global wasted work (GWW). RESULTS: Athletes performed a long-duration (8 h 58 min ± 60 min) and intense (78 ± 4% of maximal heart rate) ascent under gradual hypoxic conditions (minimal SpO2 at 4808 m: 71 ± 4%). Hypoxic exercise-induced cardiac fatigue was observed post-ascent with a change in right ventricular (RV) and LV systolic function (RV fractional area change: - 20 ± 23%, p = 0.01; LV global longitudinal strain change: - 8 ± 9%, p = 0.02), as well as LV geometry and RV-LV interaction alterations with emergence of a D-shape septum in 5/11 (46%) participants associated with RV pressure overload (mean pulmonary arterial pressure change: + 55 ± 20%, p < 0.001). Both MWI and GWE were reduced post-ascent (- 21 ± 16%, p = 0.004 and - 4 ± 4%, p = 0.007, respectively). Relative decrease in MWI and GWE were inversely correlated with increase in GWW (r = - 0.86, p = 0.003 and r = -0.97, p < 0.001, respectively). CONCLUSIONS: Prolonged high-altitude speed climbing in elite climbers is associated with RV and LV function changes with a major interaction alteration. MWI, assessing the myocardial performance, could be a new tool for evaluating LV exercise-induced cardiac fatigue.

Effect of a speed ascent to the top of Europe on cognitive function in elite climbers.

PURPOSE: The combined effects of acute hypoxia and exercise on cognition remain to be clarified. We investigated the effect of speed climbing to high altitude on reactivity and inhibitory control in elite climbers. METHODS: Eleven elite climbers performed a speed ascent of the Mont-Blanc (4810 m) and were evaluated pre- (at 1000 m) and immediately post-ascent (at 3835 m). In both conditions, a Simon task was done at rest (single-task session, ST) and during a low-intensity exercise (dual-task session, DT). Prefrontal cortex (PFC) oxygenation and middle cerebral artery velocity (MCAv) were monitored using near-infrared spectroscopy and transcranial Doppler, respectively, during the cognitive task. Self-perceived mental fatigue and difficulty to perform the cognitive tests were estimated using a visual analog scale. Heart rate and pulse oxygenation (SpO2) were monitored during the speed ascent. RESULTS: Elite climbers performed an intense (~ 50% of the time ≥ 80% of maximal heart rate) and prolonged (8h58 ± 6 min) exercise in hypoxia (minimal SpO2 at 4810 m: 78 ± 4%). Reaction time and accuracy during the Simon task were similar pre- and post-ascent (374 ± 28 ms vs. 385 ± 39 ms and 6 ± 4% vs. 5 ± 4%, respectively; p > 0.05), despite a reported higher mental fatigue and difficulty to perform the Simon task post-ascent (all p < 0.05). The magnitude of the Simon effect was unaltered (p > 0.05), suggesting a preserved cognitive control post-ascent. Pattern of PFC oxygenation and MCAv differed between pre- and post-ascent as well as between ST and DT conditions. CONCLUSIONS: Cognitive control is not altered in elite climbers after a speed ascent to high-altitude despite substantial cerebral deoxygenation and fatigue perception.

High-intensity interval training to promote cerebral oxygenation and affective valence during exercise in individuals with obesity.

Left/right prefrontal cortex (PFC) activation is linked to positive/negative affects, respectively. Besides, larger left PFC oxygenation during exercise relates to higher cardiorespiratory fitness (CRF). High-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICT) in improving CRF. The influence of training on PFC oxygenation and affects during exercise in individuals with obesity is, however, currently unknown. Twenty participants with obesity (14 males, 48 ± 8 years, body-mass index = 35 ± 6 kg·m-2) were randomised to MICT [50% peak work rate (WRpeak)] or HIIT (1-min bouts 100% WRpeak; 3 sessions/week, 8 weeks). Before/after training, participants completed an incremental ergocycle test. Near-infrared spectroscopy and the Feeling Scale assessed PFC oxygenation and affects during exercise, respectively. Improvements in CRF (e.g., WRpeak: 32 ± 14 vs 20 ± 13 W) were greater after HIIT vs MICT (p < 0.05). Only HIIT induced larger left PFC oxygenation (haemoglobin difference from 7 ± 6 to 10 ± 7 µmol) and enhanced affective valence (from 0.7 ± 2.9 to 2.2 ± 2.0; p < 0.05) at intensities ≥ second ventilatory threshold. Exercise-training induced changes in left PFC oxygenation correlated with changes in CRF [e.g., WRpeak (% predicted), r = 0.46] and post-training affective valence (r = 0.45; p < 0.05). HIIT specifically improved left PFC oxygenation and affects during exercise in individuals with obesity. Implementing HIIT in exercise programmes may therefore have relevant implications for the management of obesity, since greater affective response to exercise is thought to be associated with future commitment to physical activity.

Effects of high intensity interval training on sustained reduction in cardiometabolic risk associated with overweight/obesity. A randomized trial.

Background: Considering the potential greater cardiocirculatory effects of high intensity interval training (HIIT), we hypothesized that a 2-month supervised high volume short interval HIIT would induce greater improvements in CRF and cardiometabolic risk and increase long-term maintenance to physical activity compared to isocaloric moderate intensity continuous training (MICT) in overweight/obesity. Methods: Sixty (19 females) subjects with overweight/obesity were randomized to three training programs (3 times/week for 2 months): MICT (45 min, 50% peak power output-PPO), HIIT (22 × 1-min cycling at 100% PPO/1-min passive recovery) and HIIT-RM (RM: recovery modulation, i.e. subjects adjusted passive recovery duration between 30s and 2 min). After the intervention, participants no longer benefited from supervised physical activity and were instructed to maintain the same exercise modalities on their own. We assessed anthropometrics, body composition, CRF, fat oxidation, lipid profile, glycemic balance, low-grade inflammation, vascular function, spontaneous physical activity and motivation for eating at three time points: baseline (T0), 4 days after the end of the 2-month supervised training program (T2) and 4 months after the end of the training program (T6). Results: HIIT/HIIT-RM induced greater improvement in VO2peak (between +14% and +17%), power output at ventilatory thresholds and at maximal fat oxidation rate (+25%) and waist circumference (-1.53 cm) compared to MICT and tended to decrease insulin resistance. During the four-month follow-up period during which exercise in autonomy was prescribed, HIIT induced a greater preservation of CRF, decreases in total and abdominal fat masses and total cholesterol/HDL. Conclusion: We have shown greater short-term benefits induced by a high volume short interval (1 min) HIIT on cardiorespiratory fitness and cardiometabolic risk over an isocaloric moderate intensity continuous exercise in persons with overweight/obesity. We also showed greater long-term effects (i.e. after 4 months) of this exercise modality on the maintenance of CRF, decreases in total and abdominal fat masses and total cholesterol/HDL.

Oxygen supplementation during exercise improves leg muscle fatigue in chronic fibrotic interstitial lung disease.

BACKGROUND: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease (f-ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O2) supplementation can ameliorate these abnormalities. METHODS: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO2)). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue. RESULTS: Patients showed severe hypoxaemia (lowest O2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O2 was associated with a significant increase in muscle (HbO2), leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O2 significantly improved leg discomfort (p=0.005). CONCLUSION: O2 supplementation during exercise improves leg muscle oxygenation and fatigue in f-ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.

Impact of obstructive sleep apnoea and intermittent hypoxia on blood rheology: a translational study.

BACKGROUND: Haemorheological alterations are reported in obstructive sleep apnoea (OSA) and reversed with continuous positive airway pressure (CPAP), observations potentially explained by intermittent hypoxia (IH)-induced oxidative stress. Our objective was to investigate whether IH causes haemorheological alterations via oxidative stress. METHODS: Wistar rats were exposed to normoxia (n=7) or IH (n=8) for 14 days. 23 moderate-to-severe OSA patients were assessed at three time-points: baseline, after randomisation to either 2 weeks of nocturnal oxygen (n=13) or no treatment (n=10) and after 1 month of CPAP treatment (n=17). Furthermore, an OSA-free control group (n=13) was assessed at baseline and after time-matched follow-up. We measured haemorheological parameters (haematocrit, blood viscosity, plasma viscosity (rats only), erythrocyte aggregation and deformability (humans only)) and redox balance (superoxide dismutase (SOD), glutathione peroxidase, protein oxidation (advanced oxidation protein products (AOPPs)) and lipid peroxidation (malondialdehyde)). We also tested the haemorheological sensitivity of erythrocytes to reactive oxygen species (ROS) in our human participants using the oxidant t-butyl hydroperoxide (TBHP). RESULTS: In rats, IH increased blood viscosity by increasing haematocrit without altering the haemorheological properties of erythrocytes. IH also reduced SOD activity and increased AOPPs. In humans, baseline haemorheological properties were similar between patients and control participants, and properties were unaltered following oxygen and CPAP, except erythrocyte deformability was reduced following oxygen therapy. Redox balance was comparable between patients and control participants. At baseline, TBHP induced a greater reduction of erythrocyte deformability in patients while CPAP reduced TBHP-induced increase in aggregation strength. CONCLUSIONS: IH and OSA per se do not cause haemorheological alterations despite the presence of oxidative stress or higher sensitivity to ROS, respectively.

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure.

The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.

Cerebral haemodynamics and oxygenation during whole-body exercise over 5 days at high altitude.

NEW FINDINGS: What is the central question of this study? Impairment and subsequent improvement in cerebral oxygenation during acute and prolonged exposure to high altitude affect exercise performance. This study innovates by investigating the effect of acute and prolonged high-altitude exposure on cerebral haemodynamics during submaximal endurance exercise performed at the same relative intensity. What is the main finding and its importance? Despite exercising at the same relative intensity at sea level and high altitude, participants showed a sustained impairment in cerebral oxygenation after prolonged exposure to high altitude, which might contribute to the absence of improvement in exercise tolerance. ABSTRACT: Deterioration and subsequent improvement in cerebral oxygenation during acute and prolonged hypoxic exposure may affect whole-body exercise performance at high altitude. In this study, we investigated the effect of hypoxic exposure on cerebral haemodynamics at different cortical locations during exercise at the same relative intensity after 1 (D1) and 5 days (D5) at 4350 m. Eleven male subjects performed a submaximal bout of cycling exercise (6 min at 35% + 6 min at 55% + time-to-exhaustion at 75% of peak work rate achieved in the same conditions, i.e. normoxia or hypoxia at sea level) on D1 and D5. Transcranial Doppler and near-infrared spectroscopy were used to assess middle cerebral artery blood velocity and prefrontal and motor cortex oxygenation, respectively. Despite using the same relative intensity, the duration of exercise was reduced on D1 (22.7 ± 5.1 min) compared with sea level (32.2 ± 9.0 min; P < 0.001), with no improvement on D5 (20.9 ± 6.3 min; P > 0.05). Middle cerebral artery blood velocity during exercise was elevated on D1 (+18.2%) and D5 (+15.0%) compared with sea level (P < 0.001). However, prefrontal and motor cortex oxygenation was reduced on D1 and D5 compared with sea level (P < 0.001). This pattern was of similar magnitude between cortical locations, whereas the total haemoglobin concentration increased to a greater extent in the prefrontal versus motor cortex at exhaustion on D1 and D5. In contrast to our primary hypothesis, prefrontal and motor cortex oxygenation and exercise performance did not improve over 5 days at 4350 m. The sustained impairment in cerebral oxygenation might contribute to the absence of improvement in exercise performance after partial acclimatization to high altitude.

Diaphragm Thickening During Venoarterial Extracorporeal Membrane Oxygenation Weaning: An Observational Prospective Study.

OBJECTIVES: The respiratory workload, according to the diaphragm thickening fraction (TF) during sweep gas flow (SGF), decrease during weaning from venoarterial extracorporeal membrane oxygenation (VA ECMO) was evaluated for the present study. DESIGN: Prospective observational study. SETTING: Monocentric. PARTICIPANTS: Patients were included if they were suitable for a first VA ECMO weaning trial and were breathing spontaneously. INTERVENTIONS: SGF was set for 15 minutes when the TF was measured at 4 L/min, 2 L/min, and 1 L/min, with a 10-minute return to baseline between each step. Mechanical ventilation, when required, was set to pressure-support ventilation mode with 7 cmH2O (pressure support) and a positive end-expiratory pressure of 0 cmH2O. Diaphragm ultrasound was used to assess the TF at the end of each step. Demographics, left ventricular ejection fraction (LVEF), and outcome were collected. MEASUREMENTS AND MAIN RESULTS: Fifteen patients were included. Ten patients were extubated, and five were ventilated. TF values were 6.3% [0-10] at 4 L/min, 13.3% [10-26] at 2 L/min, and 26.7% [22-44] at 1 L/min (analysis of variance: p < 0.001 between 4 L/min and 2 L/min and p = 0.03 between 2 L/min and 1 L/min). TF did not differ whether patients were or were not ventilated or whether they were or were not weaned successfully from ECMO. TF was correlated with LVEF at 1 L/min SGF (Pearson R 0.67 [0.21-0.88]; p = 0.009) and at 2 L/min (R 0.7 [0.27-0.89]; p = 0.005) but not at 4 L/min. SGF mitigated the relationship between LVEF and TF (analysis of covariance: p < 0.005). CONCLUSIONS: Diaphragm TF was related to the SGF of the venoarterial ECMO settings and LVEF at the time of weaning.

Blood viscosity and its determinants in the highest city in the world.

KEY POINTS: Highlanders develop unique adaptative mechanisms to chronic hypoxic exposure, including substantial haemoglobin and haematocrit increases. However, a significant proportion of populations living permanently at high altitude develop maladaptive features known as chronic mountain sickness (CMS). This study aimed to assess the effects of permanent life at high altitude on clinical and haemorheological parameters (blood viscosity and red blood cell aggregation) and to compare clinical and haemorheological parameters of dwellers from the highest city in the world according to CMS severity. Blood viscosity increased with altitude, together with haemoglobin concentration and haematocrit. At 5100 m, highlanders with moderate-to-severe CMS had higher blood viscosity mainly at high shear rate and even at corrected haematocrit (40%), with a lower red blood cell aggregation. Blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit. ABSTRACT: Chronic mountain sickness (CMS) is a condition characterised by excessive erythrocytosis (EE). While EE is thought to increase blood viscosity and subsequently to trigger CMS symptoms, the exact relationship between blood viscosity and CMS symptoms remains incompletely understood. We assessed the effect of living at high altitude on haemoglobin, haematocrit and haemorheological parameters (blood viscosity and red blood cell aggregation), and investigated their relationship with CMS in highlanders living in the highest city in the world (La Rinconada, Peru, 5100 m). Ninety-three men participated in this study: 10 Caucasian lowlanders, 13 Andean highlanders living at 3800 m and 70 Andean highlanders living at 5100 m (35 asymptomatic, CMS score ≤5; 15 with mild CMS, CMS score between 6 and 10; 20 with moderate-to-severe CMS, CMS score >10). Blood viscosity was measured at native and corrected haematocrit (40%). Haemoglobin concentration and haematocrit increased with the altitude of residency. Blood viscosity also increased with altitude (at 45 s-1 : 6.7 ± 0.9 mPa s at sea level, 14.0 ± 2.0 mPa s at 3800 m and 27.1 ± 8.8 mPa s at 5100 m; P < 0.001). At 5100 m, blood viscosity at corrected haematocrit was higher in highlanders with moderate-to-severe CMS (at 45 s-1 : 18.9 ± 10.7 mPa s) than in highlanders without CMS (10.2 ± 5.9 mPa s) or with mild CMS (12.1 ± 6.1 mPa s) (P < 0.05). In conclusion, blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit.

Cardiovascular and metabolic responses to passive hypoxic conditioning in overweight and mildly obese individuals.

Although severe intermittent hypoxia (IH) is well known to induce deleterious cardiometabolic consequences, moderate IH may induce positive effects in obese individuals. The present study aimed to evaluate the effect of two hypoxic conditioning programs on cardiovascular and metabolic health status of overweight or obese individuals. In this randomized single-blind controlled study, 35 subjects (54 ± 9.3 yr, 31.7 ± 3.5 kg/m2) were randomized into three 8-wk interventions (three 1-h sessions per week): sustained hypoxia (SH), arterial oxygen saturation ([Formula: see text]) = 75%; IH, 5 min [Formula: see text] = 75% - 3 min normoxia; normoxia. Ventilation, heart rate, blood pressure, and tissue oxygenation were measured during the first and last hypoxic conditioning sessions. Vascular function, blood glucose and insulin, lipid profile, nitric oxide metabolites, and oxidative stress were evaluated before and after the interventions. Both SH and IH increased ventilation in hypoxia (+1.8 ± 2.1 and +2.3 ± 3.6 L/min, respectively; P < 0.05) and reduced normoxic diastolic blood pressure (-12 ± 15 and -13 ± 10 mmHg, respectively; P < 0.05), whereas changes in normoxic systolic blood pressure were not significant (+3 ± 9 and -6 ± 13 mmHg, respectively; P > 0.05). IH only reduced heart rate variability (e.g., root-mean-square difference of successive normal R-R intervals in normoxia -21 ± 35%; P < 0.05). Both SH and IH induced no significant change in body mass index, vascular function, blood glucose, insulin and lipid profile, nitric oxide metabolites, or oxidative stress, except for an increase in superoxide dismutase activity following SH. This study indicates that passive hypoxic conditioning in obese individuals induces some positive cardiovascular and respiratory improvements despite no change in anthropometric data and even a reduction in heart rate variability during IH exposure.

Features of Chronic Exertional Compartmental Syndrome of the Leg in Elite Nordic Skiers.

This study aimed to assess prevalence and incidence of chronic exertional compartmental syndrome as well as functional outcomes after surgery in elite Nordic skiers. An exhaustive list of 294 elite Nordic skiers from the French national teams between 1994 and 2014 was analyzed through their individual medical files in order to identify cases of chronic exertional compartmental syndrome. Eighteen athletes had confirmed diagnosis and performed a structured interview to identify factors associated with chronic exertional compartmental syndrome and surgery outcomes. The prevalence was 6.1% and the incidence 13 per 1000 skier-years. Biathletes had a higher prevalence than cross-country skiers (OR=0.40, p=0.08). Free-technique skiing and roller-skiing were the main conditions inducing symptoms. All injured athletes had bilateral surgery and 94% of them reported no more or sporadic leg pain after. Almost 90% resumed competition at the same or higher level than prior surgery. Compare to previous studies, the incidence rate of chronic exertional compartmental syndrome is higher in French elite Nordic skiers. The higher prevalence in biathletes and the trigger during free-technique skiing suggest a contribution of this technique to this disease. This study also confirmed that surgery was an efficient therapeutic solution without compromising athletes' career.

A short bout of high-intensity intermittent exercise before moderate-intensity prolonged exercise as a mean to potentiate fat oxidation ?

Moderate-intensity continuous exercise (MICE) improves fat oxidation. High-intensity intermittent exercise (HIIE) is thought to have a greater potential for fat oxidation but it might be too demanding in the long term for patients. We hypothesized that an initial bout of HIIE could maximize fat oxidation during MICE and the following passive recovery. Eighteen healthy participants performed two acute isocaloric exercise sessions at random. MICE consisted of 45-min cycling at 50% of maximal aerobic power (Pmax). COMB began with five 1-min bouts of HIIE at Pmax (interspaced with 1-min recovery periods) followed by 35-min MICE. Gas exchange allowed substrate oxidation rate assessment.Expressed as a % of energy expenditure, fat oxidation (%) increased during in the passive recovery following COMB (Recovery: 36.0 ± 19.4 vs 23.0 ± 20.3%; ES: 0.66; p < 0.0001). An initial bout of HIIE preceding a prolonged moderate-intensity exercise may potentiate fat oxidation during the following recovery. This might be relevant for health management of overweight/obese persons.

ERS statement on respiratory muscle testing at rest and during exercise.

Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.