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Abstract Study Objective: Intermittent hypoxia (IH) is associated with increased risk of cardiovascular disease. Exosomes are secreted by most cell types and released in biological fluids, including plasma, and play a role in modifying the functional phenotype of target cells. Using an experimental human model of IH, we investigated potential exosome-derived biomarkers of IH-induced vascular dysfunction. Methods: Ten male volunteers were exposed to room air (D0), IH (6 h/day) for 4 days (D4) and allowed to recover for 4 days (D8). Circulating plasma exosomes were isolated and incubated with human endothelial monolayer cultures for impedance measurements and RNA extracted and processed with messenger RNA (mRNA) arrays to identify gene targets. In addition, immunofluorescent assessments of endothelial nitric oxide synthase (eNOS) mRNA expression, ICAM-1 cellular distribution were conducted. Results: Plasma exosomal micro RNAs (miRNAs) were profiled. D4 exosomes, primarily from endothelial sources, disrupted impedance levels compared to D0 and D8. ICAM-1 expression was markedly upregulated in endothelial cells exposed to D4 exosomes along with significant reductions in eNOS expression. Microarray approaches identified a restricted and further validated signature of exosomal miRNAs in D4 exosomes, and mRNA arrays revealed putative endothelial gene target pathways. Conclusions: In humans, intermittent hypoxia alters exosome cargo in the circulation which promotes increased permeability and dysfunction of endothelial cells in vitro. A select number of circulating exosomal miRNAs may play important roles in the cardiovascular dysfunction associated with OSA by targeting specific effector pathways.

Introduction: This study aimed to validate the ability of a prototype sport watch (Polar Electro Oy, FI) to recognize wake and sleep states in two trials with and without an interval training session (IT) 6 h prior to bedtime. Methods: Thirty-six participants completed this study. Participants performed a maximal aerobic test and three polysomnography (PSG) assessments. The first night served as a device familiarization night and to screen for sleep apnea. The second and third in-home PSG assessments were counterbalanced with/without IT. Accuracy and agreement in detecting sleep stages were calculated between PSG and the prototype. Results: Accuracy for the different sleep stages (REM, N1 and N2, N3, and awake) as a true positive for the nights without exercise was 84 ± 5%, 64 ± 6%, 81 ± 6%, and 91 ± 6%, respectively, and for the nights with exercise was 83 ± 7%, 63 ± 8%, 80 ± 7%, and 92 ± 6%, respectively. The agreement for the sleep night without exercise was 60.1 ± 8.1%, k = 0.39 ± 0.1, and with exercise was 59.2 ± 9.8%, k = 0.36 ± 0.1. No significant differences were observed between nights or between the sexes. Conclusion: The prototype showed better or similar accuracy and agreement to wrist-worn consumer products on the market for the detection of sleep stages with healthy adults. However, further investigations will need to be conducted with other populations.

Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response to angiotensin II (AngII), which reflects RAS activity. Twenty normotensive, nondiabetic, newly diagnosed OSA subjects (15 men, 5 women, 50 ± 2 yr, respiratory disturbance index [RDI] > 15 h(-1)) with nocturnal hypoxemia (SaO2 < 90% for >12% of the night) were studied in high-salt balance pre- and post-CPAP therapy (>4 h CPAP use/night for 1 mo). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) (a surrogate marker for intraglomerular pressure) were measured pre- and post-CPAP using inulin and para-aminohippurate clearance techniques at baseline and in response to graded AngII infusion (3 ng/kg/min × 30 min and 6 ng/kg/min × 30 min, respectively). CPAP corrected OSA and hypoxemia (RDI: 42 ± 4 vs. 4 ± 1 h(-1), P < 0.001; duration SaO2 < 90%: 36% ± 5% vs. 6 ± 2%, P < 0.001). CPAP reduced GFR (124 ± 8 ml/min vs. 110 ± 6 ml/min, P = 0.014), increased RPF (692 ± 36 ml/min vs. 749 ± 40 ml/min, P = 0.059), and reduced baseline FF (18.9 ± 1.6% vs. 15.3 ± 1.0%, P = 0.004). Post-CPAP demonstrated a blunted GFR response (-9 ± 3 ml/min vs. -2 ± 2 ml/min, P = 0.033) and augmented RPF response (-182 ± 22 ml/min vs. -219 ± 25 ml/min, P = 0.024) to AngII. FF response was maintained (P = 0.4). CPAP reduced baseline mean arterial pressure (94 ± 2 vs. 89 ± 2 mm Hg, P = 0.002), plasma aldosterone (149 ± 18 vs. 109 ± 10 pmol/L, P = 0.003), and urinary protein excretion (61 [39-341] mg/day vs. 56 [22-204] mg/d, P = 0.003). CPAP therapy was associated with improved renal hemodynamics and down-regulation of renal RAS activity, suggesting a potential therapeutic benefit for kidney function.

This study aimed to quantify the effect of two consecutive prolonged, intermittent exposures to high and very high altitudes on oxygen saturation (SpO 2 ) and acute mountain sickness (AMS). For this, healthy lowlanders (N = 21), aged 18–30 years, underwent two 7-day sojourns at the ALMA observatory, Chile (6 h/day at 5050 m, 18 h/day at 2900 m), separated by 1-week at 520 m. SpO 2 (pulse oximetry) and AMS severity (AMSc, Environmental Symptom Questionnaire cerebral score) diagnosing AMS (AMSc ≥ 0.7) were assessed daily at both altitudes. The study was registered at www.ClinicalTrials.gov: NCT02730143. SpO 2 at 2900 m and 5050 m on arrival was mean ± SD 93.6 ± 0.5% and 79.9 ± 1.0% ( P  < 0.05 between altitudes), whereas the AMSc scores were 0.43 ± 0.08 and 0.97 ± 0.11 ( P  < 0.05 between altitudes), respectively. At 2900 m during a 7-day intermittent hypoxic exposure, SpO 2 increased by a mean (95% CI) 0.3 %/day (0.1;0.4) and by 0.9 %/day (0.4;1.3) at 5050 m. Similarly, AMSc decreased by 0.05 points/day (0.01;0.08) at 2900 m and by 0.16 points/day (0.11;0.21) at 5050 m. During the second sojourn (vs. 1st sojourn), day 1, SpO 2 at 2900 m was unchanged but higher at 5050 m by 2.9% (0.6;5.3). AMSc was lower at 2900 m and 5050 m by 0.37 (0.16;0.59) and 0.37 (0.11;0.63) ( P  < 0.05 both comparisons vs 1st sojourn), respectively. Acclimatization with the 2nd sojourn increased SpO 2 at 2900 m by 0.3%/day (0.1;0.4) and 5050 m by 0.5%/day (0.1;0.8). AMSc remained unchanged with acclimatization at 2900 m but decreased at 5050 m by 0.08 points/day (0.04;0.11). In conclusion, in healthy lowlanders, a 7-day intermittent hypobaric hypoxic exposure improved SpO 2 and AMS severity at 2900 m, with larger improvements at 5050 m. During a second identical sojourn, initial AMS severity was reduced despite comparable SpO 2 at 2900 m compared to the 1st sojourn. No further acclimatization effects were observed in SpO 2 but in AMS symptoms at 2900 m. In contrast, re-exposure to 5050 m showed higher initial SpO 2 and lower AMSc values with further improvement with intermittent re-exposures. These findings highlight altitude-dependent acclimatization patterns and confirm pre-conditioning’s effectiveness in preventing AMS.

Carbon dioxide is a potent cerebral vasodilator. We have identified a significant source of low-frequency variation in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal at 3 T arising from spontaneous fluctuations in arterial carbon dioxide level in volunteers at rest. Fluctuations in the partial pressure of end-tidal carbon dioxide (P et CO 2 ) of ±1.1 mm Hg in the frequency range 0–0.05 Hz were observed in a cohort of nine volunteers. Correlating with these fluctuations were significant generalized grey and white matter BOLD signal fluctuations. We observed a mean (±standard error) regression coefficient across the group of 0.110 ± 0.033% BOLD signal change per mm Hg CO 2 for grey matter and 0.049 ± 0.022% per mm Hg in white matter. P et CO 2 -related BOLD signal fluctuations showed regional differences across the grey matter, suggesting variability of the responsiveness to carbon dioxide at rest. Functional magnetic resonance imaging (fMRI) results were corroborated by transcranial Doppler (TCD) ultrasound measurements of the middle cerebral artery (MCA) blood velocity in a cohort of four volunteers. Significant P et CO 2 -correlated fluctuations in MCA blood velocity were observed with a lag of 6.3 ± 1.2 s (mean ± standard error) with respect to P et CO 2 changes. This haemodynamic lag was adopted in the analysis of the BOLD signal. Doppler ultrasound suggests that a component of low-frequency BOLD signal fluctuations is mediated by CO 2-induced changes in cerebral blood flow (CBF). These fluctuations are a source of physiological noise and a potentially important confounding factor in fMRI paradigms that modify breathing. However, they can also be used for mapping regional vascular responsiveness to CO 2.

Obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with chronic kidney disease and up-regulation of the renin-angiotensin system (RAS), which is deleterious to renal function. The extent to which the magnitude of RAS activation is influenced by the severity of nocturnal hypoxemia and comorbid obesity has not been determined. To determine the association between the severity of nocturnal hypoxemia and RAS activity and whether this is independent of obesity in patients with OSA. Effective renal plasma flow (ERPF) response to angiotensin II (AngII) challenge, a marker of renal RAS activity, was measured by paraaminohippurate clearance technique in 31 OSA subjects (respiratory disturbance index, 51 ± 25 h(-1)), stratified according to nocturnal hypoxemia status (mean nocturnal SaO2, ≥90% [moderate hypoxemia] or <90% [severe hypoxemia]) and 13 obese control subjects. Compared with control subjects, OSA subjects demonstrated decreased renovascular sensitivity (ERPF, -153 ± 79 vs. -283 ± 31 ml/min; P = 0.004) (filtration fraction, 5.4 ± 3.8 vs. 7.1 ± 2.6%; P = 0.0025) in response to 60 minutes of AngII challenge (mean ± SD; all P values OSA vs. control). The fall in ERPF in response to AngII was less in patients with severe hypoxemia compared with those with moderate hypoxemia (P = 0.001) and obese control subjects after 30 minutes (P < 0.001) and 60 minutes (P < 0.001) of AngII challenge, reflecting more augmented renal RAS activity. Severity of hypoxemia was not associated with the blood pressure or the systemic circulating RAS component response to AngII. The severity of nocturnal hypoxemia influences the magnitude of renal, but not the systemic, RAS activation independently of obesity in patients with OSA.

Abstract 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 α-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 α-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.

BackgroundObservational studies have suggested that various nutrients, dietary supplements, and vitamins may delay the onset of age-associated cognitive decline and dementia. We systematically reviewed recent randomized controlled trials investigating the effect of nutritional interventions on cognitive performance in older non-demented adults.MethodsWe searched MEDLINE, CINAHL, Embase, and the Cochrane Library for articles published between 2003 and 2013. We included randomized trials of ≥ 3 months’ duration that examined the cognitive effects of a nutritional intervention in non-demented adults > 40 years of age. Meta-analyses were done when sufficient trials were available.ResultsTwenty-four trials met inclusion criteria (six omega-3 fatty acids, seven B vitamins, three vitamin E, eight other interventions). In the meta-analyses, omega-3 fatty acids showed no significant effect on Mini-Mental State Examination (MMSE) scores (four trials, mean difference 0.06, 95% CI -0.08 – 0.19) or digit span forward (three trials, mean difference -0.02, 95% CI -0.30 – 0.25), while B vitamins showed no significant effect on MMSE scores (three trials, mean difference 0.02, 95% CI -0.22 – 0.25). None of the vitamin E studies reported significant effects on cognitive outcomes. Among the other nutritional interventions, statistically significant differences between the intervention and control groups on at least one cognitive domain were found in single studies of green tea extract, Concord grape juice, chromium picolinate, betacarotene, two different combinations of multiple vitamins, and a dietary approach developed for the control of hypertension.ConclusionsOmega-3 fatty acids, B vitamins, and vitamin E supplementation did not affect cognition in non-demented middle-aged and older adults. Other nutritional interventions require further evaluation before their use can be advocated for the prevention of age-associated cognitive decline and dementia.

Background: Effects of hypobaric hypoxia at altitude on exercise performance of lowlanders with chronic obstructive pulmonary disease (COPD) have not been studied in detail. Objectives: To quantify changes in exercise performance and associated physiologic responses in lowlanders with COPD travelling to moderate altitude. Methods: A total of 31 COPD patients with a median age (quartiles) of 66 years (59; 69) and FEV 1 of 56% predicted (49; 69) living below 800 m performed a constant-load bicycle exercise to exhaustion at 60% of the maximal work rate at 490 m (Zurich) and at an identical work rate at 2,590 m (Davos) in randomized order. Pulmonary gas exchange, pulse oximetry (SpO 2 ), cerebral tissue oxygenation (CTO; near-infrared spectroscopy), and middle cerebral artery peak blood flow velocity (MCAv) by Doppler ultrasound during 30 s at end exercise were compared between altitudes. Results: With ascent from 490 to 2,590 m, the median endurance time (quartiles) was reduced from 500 s (256; 795) to 205 s (139; 297) by a median (95% CI) of 303 s (150–420) (p < 0.001). End exercise SpO 2 decreased from 92% (89; 94) to 81% (77; 84) and CTO from 62% (56; 66) to 55% (50; 60); end exercise minute ventilation increased from 40.6 L/min (35.5; 47.8) to 47.2 L/min (39.6; 58.7) (p < 0.05; all comparisons 2,590 vs. 490 m). MCAv increased similarly from rest to end exercise at 490 m (+25% [17; 36]) and at 2,590 m (+21% [14; 30]). However, the ratio of MCAv increase to SpO 2 drop during exercise decreased from +6%/% (3; 12) at 490 m to +3%/% (2; 5) at 2,590 m (p < 0.05). Conclusions: In lowlanders with COPD travelling to 2,590 m, exercise endurance is reduced by more than half compared to 490 m in association with reductions in systemic and cerebral oxygen availability.

Cerebral autoregulation (CA) is impaired during acute high-altitude (HA) exposure, however, effects of temporarily living high and working higher on CA require further investigation. In 18 healthy lowlanders (11 women), we hypothesized that the cerebral autoregulation index (ARI) assessed by the percentage change in middle cerebral artery peak blood velocity (Δ%MCAv)/percentage change in mean arterial blood pressure (Δ%MAP) induced by a sit-to-stand maneuver, is (i) reduced on Day1 at 5050 m compared to 520 m, (ii) is improved after 6 days at 5050 m, and (iii) is less impaired during re-exposure to 5050 m after 7 days at 520 m compared to Cycle1. Participants spent 4-8 h/day at 5050 m and slept at 2900 m similar to real-life working shifts. High/low ARI indicate impaired/intact CA, respectively. With the sit-to-stand at 520 m, mean (95% CI) in ΔMAP and ΔMCAv were − 26% (− 41 to − 10) and − 13% (− 19 to − 7), P  < 0.001 both comparisons; mean ± SD in ARI was 0.58 ± 2.44Δ%/Δ%, respectively. On Day1 at 5050 m, ARI worsened compared to 520 m (3.29 ± 2.42Δ%/Δ%), P  = 0.006 but improved with acclimatization (1.44 ± 2.43Δ%/Δ%, P  = 0.039). ARI was less affected during re-exposure to 5050 m (1.22 ± 2.52Δ%/Δ%, P  = 0.027 altitude-induced change between sojourns). This study showed that CA (i) is impaired during acute HA exposure, (ii) improves with living high, working higher and (iii) is ameliorated during re-exposure to HA.