Julien V. Brugniaux

Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans

RATIONALE Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. OBJECTIVES To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR. METHODS After two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia for 6 hours per day. MEASUREMENTS AND MAIN RESULTS AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring alpha-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and alpha-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002). CONCLUSIONS Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Cardiovascular and cerebrovascular responses to acute hypoxia following exposure to intermittent hypoxia in healthy humans

Intermittent hypoxia (IH) is thought to be responsible for many of the long‐term cardiovascular consequences associated with obstructive sleep apnoea (OSA). Experimental human models of IH can aid in investigating the pathophysiology of these cardiovascular complications. The purpose of this study was to determine the effects of IH on the cardiovascular and cerebrovascular response to acute hypoxia and hypercapnia in an experimental human model that simulates the hypoxaemia experienced by OSA patients. We exposed 10 healthy, male subjects to IH for 4 consecutive days. The IH profile involved 2 min of hypoxia (nadir = 45.0 mmHg) alternating with 2 min of normoxia (peak = 88.0 mmHg) for 6 h. The cerebral blood flow response and the pressor responses to hypoxia and hypercapnia were assessed after 2 days of sham exposure, after each day of IH, and 4 days following the discontinuation of IH. Nitric oxide derivatives were measured at baseline and following the last exposure to IH. After 4 days of IH, mean arterial pressure increased by 4 mmHg (P < 0.01), nitric oxide derivatives were reduced by 55% (P < 0.05), the pressor response to acute hypoxia increased (P < 0.01), and the cerebral vascular resistance response to hypoxia increased (P < 0.01). IH alters blood pressure and cerebrovascular regulation, which is likely to contribute to the pathogenesis of cardiovascular and cerebrovascular disease in patients with OSA.

Cerebrovascular responses to altitude.

The regulation of cerebral blood flow (CBF) is a complex process that is altered significantly with altitude exposure. Acute exposure produces a marked increase in CBF, in proportion to the severity of the hypoxia and mitigated by hyperventilation-induced hypocapnia when CO(2) is uncontrolled. A number of mediators contribute to the hypoxia-induced cerebral vasodilation, including adenosine, potassium channels, substance P, prostaglandins, and NO. Upon acclimatization to altitude, CBF returns towards normal sea-level values in subsequent days and weeks, mediated by a progressive increase in PO2, first through hyperventilation followed by erythropoiesis. With long-term altitude exposure, a number of mechanisms play a role in regulating CBF, including acid-base balance, hematological modifications, and angiogenesis. Finally, several cerebrovascular disorders are associated with altitude exposure. Existing gaps in our knowledge of CBF and altitude, and areas of future investigation include effects of longer exposures, intermittent hypoxia, and gender differences in the CBF responses to altitude.

Elevated Aerobic Fitness Sustained Throughout the Adult Lifespan Is Associated With Improved Cerebral Hemodynamics

Background and Purpose— Age-related impairments in cerebral blood flow and cerebrovascular reactivity to carbon dioxide (CVRCO2) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan. Methods— Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ⩽30 years versus old, ≥60 years) and lifetime physical activity levels (trained, ≥150 minutes recreational aerobic activity/week versus sedentary, no activity). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and end-tidal partial pressure of carbon dioxide (PETCO2, capnography) were recorded during normocapnia and 3 mins of iso-oxic hypercapnea (5% CO2). Cerebrovascular resistance/conductance indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP, respectively, and CVRCO2 as the percentage increase in MCAv from baseline per millimeter of mercury (mm Hg) increase in PETCO2. Maximal oxygen consumption ( O2MAX, online respiratory gas analysis) was determined during cycling ergometry. Results— By design, older participants were active for longer (49±5 versus 6±4 years, P<0.05). Physical activity attenuated the age-related declines in O2MAX, MCAv, CVCi, and CVRCO2 and increase in CVRi (P<0.05 versus sedentary). Linear relationships were observed between O2MAX and both MCAv and CVRCO2 (r=0.58–0.77, P<0.05). Conclusions— These findings highlight the importance of maintaining aerobic fitness throughout the lifespan given its capacity to improve cerebral hemodynamics in later-life.

Impaired cerebral haemodynamic function associated with chronic traumatic brain injury in professional boxers

The present study examined to what extent professional boxing compromises cerebral haemodynamic function and its association with CTBI (chronic traumatic brain injury). A total of 12 male professional boxers were compared with 12 age-, gender- and physical fitness-matched non-boxing controls. We assessed dCA (dynamic cerebral autoregulation; thigh-cuff technique and transfer function analysis), CVRCO₂ (cerebrovascular reactivity to changes in CO₂: 5% CO₂ and controlled hyperventilation), orthostatic tolerance (supine to standing) and neurocognitive function (psychometric tests). Blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasound), mean arterial blood pressure (finger photoplethysmography), end-tidal CO₂ (capnography) and cortical oxyhaemoglobin concentration (near-IR spectroscopy) were continuously measured. Boxers were characterized by fronto-temporal neurocognitive dysfunction and impaired dCA as indicated by a lower rate of regulation and autoregulatory index (P<0.05 compared with controls). Likewise, CVRCO₂ was also reduced resulting in a lower CVRCO₂ range (P<0.05 compared with controls). The latter was most marked in boxers with the highest CTBI scores and correlated against the volume and intensity of sparring during training (r=-0.84, P<0.05). These impairments coincided with more marked orthostatic hypotension, cerebral hypoperfusion and corresponding cortical de-oxygenation during orthostatic stress (P<0.05 compared with controls). In conclusion, these findings provide the first comprehensive evidence for chronically impaired cerebral haemodynamic function in active boxers due to the mechanical trauma incurred by repetitive, sub-concussive head impact incurred during sparring training. This may help explain why CTBI is a progressive disease that manifests beyond the active boxing career.

Interchangeability between heart rate and photoplethysmography variabilities during sympathetic stimulations

Photoplethysmography variability (PPGV) is currently considered to be a good surrogate to heart rate variability (HRV) measurements using the time between two pulse waves instead of RR intervals. Nevertheless, the interchangeability between HRV and PPGV has never been evaluated in situations with severe alterations in the autonomic nervous system (ANS). We aimed to identify the conditions for a correct utilization of PPGV in evaluating the consequences of sympathetic stimulations. Nine subjects performed three tests: active orthostatic test, slow walk and moderate and exhaustive cycling exercises in the supine position. Pulse waves at the fingertip and RR intervals were recorded at the same time. We used correlations and the Bland and Altman method to compare and evaluate interchangeability between several HRV indices. Bland and Altman analysis highlighted small discrepancies between PPGV and HRV for all HRV indices in the supine position and for LF(ms)(2), HF(ms)(2), LF(peak) and RMSSD in the upright position. During the slow walk, it was impossible to detect properly PPG peaks. We observed large differences between the two methods during the cycling exercise. In conclusion, PPGV can be used instead of HRV without reserve in the supine position but only for some HRV indices in the upright position and not during slow walk and cycling exercise.

Counterpoint: Hypobaric hypoxia does not induce different responses from normobaric hypoxia

Studies on hypoxia are performed by lowering ambient oxygen partial pressure (Po2) either by reducing the barometric pressure (hypobaric hypoxia) or by lowering the O2 fraction [normobaric hypoxia at the prevailing barometric pressure (PB)]. Upon reflection we can see that many landmark studies

Polar Activity Watch 200: a new device to accurately assess energy expenditure

Objectives Energy expenditure (EE) based on movement detection is calculated by a new device, the Activity Watch 200 (AW200). The aim of this study was to validate EE measured by this device against indirect calorimetry (IC) and to assess the reproducibility of AW200 measurements. Design EE was assessed during a 9.7 km hike. 10 men and 10 women in the age range 35–45 years, and 5 men and 6 women in the age range 50–55 years were tested. One in five participants of each age- and sex-matched group was equipped with a portable metabograph (Oxycon Mobil) for IC measurements. Data were collected every 30 min during the hike, and IC was extrapolated for the remaining four other participants of the group. Results During the total hike, there was a high correlation between EE obtained from the AW200 and the IC calculation (r = 0.987, p<0.001). Identical values of EE were calculated by both methods during the first 90 min of the hike. However, EE calculated by the AW200 at 120 min and at the end of the hike was lower (p<0.05). Bland–Altman analysis showed limits of agreements between 105 and 279 kJ after 30 and 120 min, respectively. EE measured by the AW200 was well correlated with IC measurements, and limits of agreement between devices were below 10% of the measured values for hike durations longer than 60 min. Conclusion The AW200 appears to be a very useful and accurate device for measuring EE during exercise in recreational hikers and provides a useful tool for keeping track of personal EE.

Effects of intermittent hypoxia on erythropoietin, soluble erythropoietin receptor and ventilation in humans

Erythropoietin (EPO) and soluble EPO receptors (sEPOR) have been proposed to play a central role in the ventilatory acclimatisation to continuous hypoxia in mice. In this study, we demonstrated for the first time in humans (n = 9) that sEPOR is downregulated upon daytime exposure to 4 days of intermittent hypoxia (IH; 6 h·day−1, cycles of 2 min of hypoxia followed by 2 min of reoxygenation; peak end-tidal oxygen tension (PET,O2) 88 Torr, nadir PET,O2 45 Torr), thereby allowing EPO concentration to rise. We also determined the strength of the association between these haematological adaptations and alterations in the acute hypoxic ventilatory response (AHVR). We observed a nadir in sEPOR on day 2 (-70%), concomitant with the peak in EPO concentration (+50%). Following exposure to IH, tidal volume (VT) increased, respiratory frequency remained unchanged, and minute ventilation (V′E) was increased. There was a negative correlation between EPO and sEPOR (r = -0.261; p = 0.05), and between sEPOR and VT (r = -0.331; p = 0.02). EPO was positively correlated with V′E (r = 0.458; p = 0.001). In conclusion, the downregulation of sEPOR by IH modulates the subsequent EPO response. Furthermore, the alterations in AHVR and breathing pattern following IH appear to be mediated, at least in part, by the increase in EPO.

Effects of the 'live high-train low' method on prooxidant/antioxidant balance on elite athletes.

Background/Objectives:We previously demonstrated that acute exposure to hypoxia (3 h at 3000 m) increased oxidative stress markers. Thus, by using the ‘living high–training low’ (LHTL) method, we further hypothesized that intermittent hypoxia associated with endurance training alters the prooxidant/antioxidant balance.Subjects/Methods:Twelve elite athletes from the Athletic French Federation were subjected to 18-day endurance training. They were divided into two groups: one group (control group) trained at 1200 m and lived in hypoxia (2500–3000 m simulated altitude) and the second group trained and lived at 1200 m. The subjects performed an acute hypoxic test (10 min at 4800 m) before and immediately after the training. Plasma levels of advanced oxidation protein products (AOPP), malondialdehydes (MDA), ferric-reducing antioxidant power (FRAP), lipid-soluble antioxidants normalized for triacylglycerols, and cholesterol and retinol were measured before and after the 4800 m tests.Results:After the training, MDA and AOPP concentrations were decreased in response to the 4800 m test only for the control group. Eighteen days of LHTL induced a significant decrease of all antioxidant markers (FRAP, P=0.01; α-tocopherol, P=0.04; β-carotene, P=0.01 and lycopene, P=0.02) for the runners. This imbalance between antioxidant and prooxidant might result from insufficient intakes in vitamins A and E.Conclusions:The LHTL model characterized by the association of aerobic exercises and intermittent resting hypoxia exposures decreased the antioxidant status whereas the normoxic endurance training induced preconditioning mechanisms in response to the 4800 m test.