[Show abstract][Hide abstract]ABSTRACT: Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance.
[Show abstract][Hide abstract]ABSTRACT: The aim of the present study was to investigate the effects of manipulating hematocrit by different methods (acute exercise, training or isovolumic hemodilution) on blood viscosity in high-level aerobic endurance athletes. We hypothesized than increasing hematocrit does not always cause a rise in blood viscosity.
Sixteen endurance athletes underwent maximal exercise before and after 4 weeks of training with (LHTL; n = 10) or without (placebo; n = 6) Live High-Train Low modalities. Total hemoglobin mass was measured before and after training by a carbon monoxide rebreathing technique. After training, subjects performed two maximal exercise bouts separated by isovolumic hemodilution (phlebotomy and/or plasma volume expander) to readjust red blood cell volume and plasma volume to baseline values. Blood samples were obtained before and after exercise to assess hematocrit and blood and plasma viscosity.
Training session (LHTL and placebo) increased hematocrit (Hct) in all subjects but without any significant change in blood viscosity. The decrease in plasma viscosity in all groups may explain this result. Isovolumic hemodilution caused a drop of Hct without any significant change in blood viscosity at rest. Maximal exercise increased Hct, blood and plasma viscosities in both groups, regardless of isovolumic hemodilution. However, peak hemorheological values after exercise were lower after isovolumic hemodilution.
In conclusion, while acute increase in Hct during exercise caused an increase of blood viscosity, the chronic increase of Hct induced by training session did not result in a rise in blood viscosity. The lowering of plasma viscosity during training may compensate for the increase of Hct, hence limiting its impact on blood viscosity.
Full-text Article · Jan 2016 · Clinical hemorheology and microcirculation
[Show abstract][Hide abstract]ABSTRACT: This work presents an analytical method for the simultaneous analysis in human urine of 38 pharmacologically active compounds (19 benzodiazepine-like substances, 7 selective serotonin reuptake inhibitors, 4 azole antifungal drugs, 5 inhibitors of the phosphodiesterases type 4 and 3 inhibitors of the phosphodiesterase type 5) by liquid-chromatography coupled with tandem mass spectrometry. The above substances classes include both the most common "non banned" drugs used by the athletes (based on the information reported on the "doping control form") and those drugs who are suspected to be performance enhancing and/or act as masking agents in particular conditions. The chromatographic separation was performed by a reverse-phase octadecyl column using as mobile phases acetonitrile and ultra-purified water, both with 0.1% formic acid. The detection was carried out using a triple quadrupole mass spectrometric analyser, positive electro-spray as ionization source and selected reaction monitoring as acquisition mode. Sample pre-treatment consisted in an enzymatic hydrolysis followed by a liquid-liquid extraction in neutral field using tert-butyl methyl-ether. The analytical procedure, once developed, was validated in terms of sensitivity (lower limits of detection in the range of 1-50ngmL(-1)), specificity (no interferences were detected at the retention time of all the analytes under investigation), recovery (≥60% with a satisfactory repeatability, CV % lower than 10), matrix effect (lower than 30%) and reproducibility of retention times (CV% lower than 0.1) and of relative abundances (CV% lower than 15). The performance and the applicability of the method was evaluated by analyzing real samples containing benzodiazepines (alprazolam, diazepam, zolpidem or zoplicone) or inhibitors of the phosphodiesterases type 5 (sildenafil or vardenafil) and samples obtained incubating two of the phosphodiesterases type 4 studied (cilomilast or roflumilast) with pooled human liver microsomes. All the parent compounds, together with their main phase I metabolites, were clearly detected using the analytical procedures here developed.
Full-text Article · Sep 2015 · Journal of pharmaceutical and biomedical analysis
[Show abstract][Hide abstract]ABSTRACT: It is investigated if recombinant human erythropoietin (rHuEPO) treatment for 15 weeks (n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H+, and K+ during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume and composition by hemodilution preceded an additional incremental test. Group averages were calculated for an exercise intensity ∼80% of pre-rHuEPO peak power output. After rHuEPO treatment, leg lactate release to the plasma compartment was similar to before (4.3 ± 1.6 vs 3.9 ± 2.5 mmol/min) and remained similar after hemodilution. Venous lactate concentration was higher (P < 0.05) after rHuEPO treatment (7.1 ± 1.6 vs 5.2 ± 2.1 mM). Leg H+ release to the plasma compartment after rHuEPO was similar to before (19.6 ± 5.4 vs 17.6 ± 6.0 mmol/min) and remained similar after hemodilution. Nevertheless, venous pH was lower (P < 0.05) after rHuEPO treatment (7.18 ± 0.04 vs 7.22 ± 0.05). Leg K+ release to the plasma compartment after rHuEPO treatment was similar to before (0.8 ± 0.5 vs 0.7 ± 0.7 mmol/min) and remained similar after hemodilution. Additionally, venous K+ concentrations were similar after vs before rHuEPO (5.3 ± 0.3 vs 5.1 ± 0.4 mM). In conclusion, rHuEPO does not reduce plasma accumulation of lactate, H+, and K+ at work rates corresponding to ∼80% of peak power output.
Full-text Article · Jan 2015 · Scandinavian Journal of Medicine and Science in Sports
[Show abstract][Hide abstract]ABSTRACT: Aims:
To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia.
The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot.
At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence.
Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP.
[Show abstract][Hide abstract]ABSTRACT: The effects of hypoxic training on exercise performance remain controversial. Here we tested the hypotheses that i) hypoxic training possesses ergogenic effects at sea-level and altitude, and ii) the benefits are primarily mediated by improved mitochondrial function of skeletal muscle.
We determined aerobic performance (incremental test to exhaustion and time trial for a set amount of work) in moderately-trained subjects undergoing six weeks of endurance training (3-4 times/week, 60 min/session) in normoxia (placebo, n=8) or normobaric hypoxia (FIO2=0.15; n=9) using a double blind and randomized design. Exercise tests were performed in normoxia and acute hypoxia (FIO2=0.15). Skeletal muscle mitochondrial respiratory capacities and electron coupling efficiencies were measured via high-resolution respirometry. Total hemoglobin mass (Hbmass) was assessed by carbon-monoxide rebreathing.
Skeletal muscle respiratory capacity was not altered by training or hypoxia, however electron coupling control respective to fat oxidation slightly diminished with hypoxic training. Hypoxic training did increase Hbmass more than placebo (8.4 vs 3.3%, p=0.02). In normoxia, hypoxic training had no additive effect on maximal measures of oxygen uptake (VO2peak) or time trial performance. In acute hypoxia, hypoxic training conferred no advantage on VO2peak, but tended to enhance time trial performance more than normoxic training (52 versus 32%, p=0.09).
Our data suggest that, in moderately-trained subjects, six weeks of hypoxic training possess no ergogenic effect at sea-level. It is not excluded that hypoxic training might facilitate endurance capacity at moderate altitude, however this issue is still open and needs to be further examined.
Article · Mar 2014 · Medicine and science in sports and exercise
[Show abstract][Hide abstract]ABSTRACT: With this study we tested the hypothesis that six weeks of endurance training increases maximal cardiac output (Qmax) relatively more by elevating blood volume (BV) than by inducing structural and functional changes within the heart. Nine healthy but untrained volunteers (VO2max 47 ± 5 ml.min(-1).kg(-1)) underwent supervised training (60 min; 4 times weekly at 65% VO2max for six weeks) and Qmax was determined by inert gas re-breathing during cycle ergometer exercise before and after the training period. After the training period, blood volume (determined in duplicates by CO re-breathing) was re-established to pre-training values by phlebotomy and Qmax was quantified again. Resting echography revealed no structural heart adaptations as a consequence of the training intervention. Following the training period, plasma volume (PV), red blood cell volume (RBCV) and BV increased (p<0.05) by 147 ± 168 (5 ± 5 %), 235 ± 64 (10 ± 3 %) and 382 ± 204 ml (7 ± 4 %), respectively. VO2max was augmented (p<0.05) by 10 ± 7 % following the training period and decreased (p<0.05) by 8 ± 7 % with phlebotomy. Concomitantly, Qmax was increased (p<0.05) from 18.9 ± 2.1 to 20.4 ± 2.3 l.min(-1) (9 ± 6 %) as a consequence of the training intervention, and following normalization of BV by phlebotomy Qmax returned to pre training values (18.1 ± 2.5 l.min(-1); 12 ± 5 % reversal). Thus, the exercise training induced increase in BV is the main mechanism increasing Qmax following six weeks of endurance training in previously untrained subjects.
Full-text Article · Mar 2014 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract]ABSTRACT: This study investigated the changes in cerebral near-infrared spectroscopy (NIRS) signals, cerebrovascular and ventilatory responses to hypoxia and CO2 during altitude exposure. At sea level (SL), after 24 hours and 5 days at 4,350 m, 11 healthy subjects were exposed to normoxia, isocapnic hypoxia, hypercapnia, and hypocapnia. The following parameters were measured: prefrontal tissue oxygenation index (TOI), oxy- (HbO2), deoxy- and total hemoglobin (HbTot) concentrations with NIRS, blood velocity in the middle cerebral artery (MCAv) with transcranial Doppler and ventilation. Smaller prefrontal deoxygenation and larger ΔHbTot in response to hypoxia were observed at altitude compared with SL (day 5: ΔHbO2-0.6±1.1 versus -1.8±1.3 μmol/cmper mm Hg and ΔHbTot 1.4±1.3 versus 0.7±1.1 μmol/cm per mm Hg). The hypoxic MCAv and ventilatory responses were enhanced at altitude. Prefrontal oxygenation increased less in response to hypercapnia at altitude compared with SL (day 5: ΔTOI 0.3±0.2 versus 0.5±0.3% mm Hg). The hypercapnic MCAv and ventilatory responses were decreased and increased, respectively, at altitude. Hemodynamic responses to hypocapnia did not change at altitude. Short-term altitude exposure improves cerebral oxygenation in response to hypoxia but decreases it during hypercapnia. Although these changes may be relevant for conditions such as exercise or sleep at altitude, they were not associated with symptoms of acute mountain sickness.Journal of Cerebral Blood Flow & Metabolism advance online publication, 25 September 2013; doi:10.1038/jcbfm.2013.167.
Full-text Article · Sep 2013 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Hemoglobin mass (Hbmass) is commonly assessed using the CO re-breathing method with the subject in the seated position. This may lead to an underestimation of Hbmass as blood in lower extremity veins while seated may not be tagged with carbon monoxide (CO) during the re-breathing period.
To test this hypothesis, CO re-breathing was performed on four occasions in nine male subjects, twice in the seated position and twice in combination with light cycle ergometer exercise (1 W/kg body-weight) intending to accelerate blood circulation and thereby potentially allowing for a better distribution of CO throughout the circulation as compared to in the seated position. Blood samples were drawn from an antecubital vein and the saphenous magna vein following the re-breathing procedure.
In the seated position, CO re-breathing increased the percent carboxyhemoglobin (%HbCO) in the antecubital vein to 8.9 % (7.8-10.7) [median (min-max)], but less (P = 0.017) in the saphenous magna vein [7.8 % (5.0-9.9)]. With exercise, no differences in %HbCO were observed between sampling sites. As a result, CO re-breathing in combination with exercise revealed a ~3 % higher (P = 0.008) Hbmass, i.e., 936 g (757-1,018) as compared to 908 g (718-940) at seated rest.
This study suggests an uneven distribution of CO in the circulation if the CO re-breathing procedure is performed at rest in the seated position and therefore can underestimate Hbmass.
[Show abstract][Hide abstract]ABSTRACT: Inhibition of hepcidin expression by erythropoietic signals is of great physiological importance, however the inhibitory pathways remain poorly understood. To investigate i) the direct effect of erythropoietin (Epo) and ii) the contribution of putative mediators on hepcidin repression, healthy volunteers were injected with a single dose of Epo, either low (63 IU/kg, n=8) or high (400 IU/kg, n=6). Low-dose Epo provoked hepcidin down-modulation within 24 hours; the effect was not immediate since hepcidin circadian variations were still present following injection. High-dose Epo induced no additional effect on the hepcidin response, i.e. hepcidin diurnal fluctuations were not abolished in spite of extremely high Epo levels. We did not find significant changes in putative mediators of hepcidin repression, such as transferrin saturation, soluble transferrin receptor, or growth differentiation factor 15. Furthermore, the potential hepcidin inhibitor, soluble hemojuvelin, was found unaltered by Epo stimulation. This finding was consistent with the absence of signs of iron deficiency observed at the level of skeletal muscle tissue. Our data suggest that hepcidin repression by erythropoietic signals in humans may not be controlled directly by Epo but mediated by a still undefined factor. This article is protected by copyright. All rights reserved.
Full-text Article · Apr 2013 · European Journal Of Haematology
[Show abstract][Hide abstract]ABSTRACT: Changes in cerebral perfusion and CO(2) cerebrovascular reactivity during and immediately after a sojourn at high altitude remain unclear but may be critical for acclimatization. The aim of the present study was to assess the effects of 6days at 4,350m on cerebral perfusion and cerebrovascular reactivity (CVR) to CO(2) by arterial spin labeling (ASL) magnetic resonance imaging at sea level and to compare it with transcranial Doppler (TCD) results at altitude. Eleven healthy male subjects, non-acclimatized to altitude, stayed for 6days at 4,350m (Observatoire Vallot, massif du Mont-Blanc). Prior to the stay and within 6h after returning to sea level, subjects were investigated using pseudo-continuous ASL at 3T during a block-design inhalation paradigm to measure basal cerebral blood flow (CBF) and CO(2) CVR. End-tidal CO(2) (PetCO(2)), respiratory rate, heart rate and oxygen saturation were recorded during the exam. Subjects were also examined using TCD prior to and on day 5 of the stay at altitude to measure blood velocity in the middle cerebral artery (MCAv) and CO(2) CVR. CO(2) CVR was expressed as percent change in ASL CBF or TCD MCAv per mmHg change in PetCO(2). PetCO(2) was significantly decreased during and after altitude. Significant increases in TCD MCAv compared to before altitude measurements were observed on day 5 at altitude (+20.5±15.5 %). Interestingly, ASL CBF remained increased in the MCA and anterior vascular territories (+22.0±24.1 % and 20.5±20.3 %, respectively) after altitude under normoxic conditions. TCD CVR tended to decrease on day 5 at 4,350m (-12.3±54.5 % in the MCA) while the ASL CVR was significantly decreased after altitude (-29.5±19.8 % in the MCA). No correlation was observed between cerebral hemodynamic changes and symptoms of acute mountain sickness at high altitude. In conclusion, prolonged exposure to high altitude significantly increases blood flow during the altitude stay and within 6h after returning to sea level. Decreased CO(2) CVR after prolonged altitude exposure was also observed using ASL. Changes in cerebral hemodynamics with altitude exposure probably involve other mechanisms than the vasodilatory effect of hypoxia only, since it persists under normoxia several hours following the descent.
[Show abstract][Hide abstract]ABSTRACT: Running a marathon or a long-distance triathlon [1–3] induces transient ventricular dysfunctions associated in some subjects with an increase in cardiac troponin I (cTnI), a biomarker of myocardial damages [1,2,4]. Ultra-long duration exercise (ULDE, i.e. N24 h) is getting more and more popular. However, little information is available about the potential cardiovascular alterations induced by such race. The present study described for the first time ULDE-induced acute cardiovascular perturbations through simultaneous 2D-strain echocardiography, cTnI and blood and plasma volume evaluations. Twenty-one experienced ultramarathon male runners (age: 40±8 yr) participated in the Ultra-Trail du Mont-Blanc (UTMB®), a 166-km race with 9600 m of positive altitude change across France, Italy and Switzer-land (race duration: 38 ± 5 h). The protocol was part of a larger experiment [5,6] and was approved by the local Ethics Committee. All subjects gave written informed consent. Heart rate (HR) was continuously monitored during the race (Garmin Forerunner-310XT, Olathe, USA). Before and after the race, left and right ventricular (LV and RV, respectively) evaluations included standard echocardiography, tissue Doppler imaging and 2D-strain echocardiogra-phy (Vivid Q, GE-Healthcare, Horten, Norway) as previously described . RV longitudinal strains (S) and strain rates (SR) were assessed on the free wall, from an apical 4-chambers view. CTnI were analyzed from peripheral venous blood samples before and immediately after the race . The conventional upper cutoff level of normal and acute myocardial infarction risk (i.e. 0.03 μg/L)  was used to identify subjects with elevated cTnI. Blood (BV) and plasma (PV) volumes were assessed by a carbon monoxide re-breathing method . Data were analyzed using one-way repeated measures analysis of variance. In athletes with elevated cTnI (n=7), Wilcoxon signed rank tests were used to compare pre and post values. Regression analysis between finishing time and pre-post changes for echocardiographic and biochemical data were examined using Pearson correlations. Data are expressed as mean±standard deviation and statistical significance was assumed if Pb 0.05. HR decreased regularly during the race so that first and second half of the race were run respectively at 59% and 39% of the reserve HR (mean : 117 ± 7 bpm). After the race, cTnI were significantly increased (from 0.010 ±0.001 to 0.038 ± 0.055 μg/L pre-post race) and seven of the twenty-one athletes (including the fastest runners of the study) had increased cTnI above the cutoff level of myocardial infarction risk. PV and BV were higher after the ULDE (+20% and +12%, respectively) , but no significant correlations were found with changes in LV and RV functional parameters. LV global diastolic (i.e. Peak E and Peak A velocities) and systolic functions (i.e. ejection fraction) were respectively enhanced and unchanged after the race (Table 1). LV S did not change post-race, except radial apical S which was increased. LV longitudinal and apical radial systolic and diastolic SR were higher post-race. Similar results were obtained on all parameters of the LV on the seven athletes with elevated cTnI. Concerning RV data (Table 2), RV annular end-diastolic diameter, RA end-diastolic area and peak E m recorded at the free wall level were increased post-race. The increase in RA end-diastolic area was positively correlated with finishing times (P b 0.05), the fastest participants demonstrating the highest increases. Longitudinal S and systolic and diastolic SR were unchanged post-race and fractional area shortening (FAC) tended to decrease. Interestingly, when considering only the athletes with elevated cTnI, results indicated higher RV basal
Full-text Article · Sep 2012 · International journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: It remains unclear by which mechanism 'live high-train low' (LHTL) altitude training increases exercise performance. Haematological and skeletal muscle adaptations have both been proposed. To test the hypotheses that (i) LHTL improves maximal oxygen uptake (VO(2)max) and (ii) this improvement is related to hypoxia-induced increases in total haemoglobin mass (Hb(mass)) and not to improved maximal oxidative capacity of skeletal muscle, we determined VO(2)max before LHTL and after LHTL, before and after the altitude-induced increases in Hb(mass) (measured by carbon-monoxide rebreathing) had been abolished by isovolumic haemodilution. We obtained skeletal muscle biopsies to quantify mitochondrial oxidative capacity and efficiency. Sixteen endurance-trained athletes were assigned (double-blinded, placebo controlled) to ≥16 h/day over 4 weeks to normoxia (placebo, n=6) or normobaric hypoxia equivalent to 3000 m altitude (LHTL, n=10). Four-week LHTL did not increase VO(2)max, irrespective of treatment (LHTL: 1.5%; placebo: 2.0%). Hb(mass) was slightly increased (4.6%) in 5 (of 10) LHTL subjects but this was not accompanied by a concurrent increase in VO(2)max. In the subjects demonstrating an increase in Hb(mass), isovolumic haemodilution elicited a 5.8% decrease in VO(2)max. Cycling efficiency was altered neither with time nor by LHTL. Neither maximal capacity of oxidative phosphorylation nor mitochondrial efficiency was modified by time or LHTL. The present results suggest that LHTL has no positive effect on VO(2)max in endurance-trained athletes because (i) muscle maximal oxidative capacity is not improved following LHTL and (ii) erythrocyte volume expansion after LHTL, if any, is too small to alter O(2) transport.
Full-text Article · Jul 2012 · British Journal of Sports Medicine
[Show abstract][Hide abstract]ABSTRACT: Hypoxia-stimulated erythropoiesis, such as that observed when red blood cell volume (RCV) increases in response to high-altitude exposure, is well understood while the physiological importance is not. Maximal exercise tests are often performed in hypoxic conditions following some form of RCV manipulation in an attempt to elucidate oxygen transport limitations at moderate to high altitudes. Such attempts, however, have not made clear the extent to which RCV is of benefit to exercise at such elevations. Changes in RCV at sea level clearly have a direct influence on maximal exercise capacity. Nonetheless, at elevations above 3000 m, the evidence is not that clear. Certain studies demonstrate either a direct benefit or decrement to exercise capacity in response to an increase or decrease, respectively, in RCV whereas other studies report negligible effects of RCV manipulation on exercise capacity. Adding to the uncertainty regarding the importance of RCV at high altitude is the observation that Andean and Tibetan high-altitude natives exhibit similar exercise capacities at high altitude (3900 m) even though Andean natives often present with a higher percent haematocrit (Hct) when compared with both lowland natives and Tibetans. The current review summarizes past literature that has examined the effect of RCV changes on maximal exercise capacity at moderate to high altitudes, and discusses the explanation elucidating these seemingly paradoxical observations.