TRPC5 channel participates in myocardial injury in chronic intermittent hypoxia.

OBJECTIVE: The purpose of this study is to develop an animal model of Chronic Intermittent Hypoxia (CIH) and investigate the role of the TRPC5 channel in cardiac damage in OSAHS rats. METHODS: Twelve male Sprague Dawley rats were randomly divided into the CIH group and the Normoxic Control (NC) group. Changes in structure, function, and pathology of heart tissue were observed through echocardiography, transmission electron microscopy, HE-staining, and TUNEL staining. RESULTS: The Interventricular Septum thickness at diastole (IVSd) and End-Diastolic Volume (EDV) of rats in the CIH group significantly increased, whereas the LV ejection fraction and LV fraction shortening significantly decreased. TEM showed that the myofilaments in the CIH group were loosely arranged, the sarcomere length varied, the cell matrix dissolved, the mitochondrial cristae were partly flocculent, the mitochondrial outer membrane dissolved and disappeared, and some mitochondria were swollen and vacuolated. The histopathological examination showed that the cardiomyocytes in the CIH group were swollen with granular degeneration, some of the myocardial fibers were broken and disorganized, and most of the nuclei were vacuolar and hypochromic. CONCLUSION: CIH promoted oxidative stress, the influx of Ca2+, and the activation of the CaN/NFATc signaling pathway, which led to pathological changes in the morphology and ultrastructure of cardiomyocytes, the increase of myocardial apoptosis, and the decrease of myocardial contractility. These changes may be associated with the upregulation of TRPC5.

Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

TRPC5 channel participates in myocardial injury in chronic intermittent hypoxia

Abstract Objective The purpose of this study is to develop an animal model of Chronic Intermittent Hypoxia (CIH) and investigate the role of the TRPC5 channel in cardiac damage in OSAHS rats. Methods Twelve male Sprague Dawley rats were randomly divided into the CIH group and the Normoxic Control (NC) group. Changes in structure, function, and pathology of heart tissue were observed through echocardiography, transmission electron microscopy, HE-staining, and TUNEL staining. Results The Interventricular Septum thickness at diastole (IVSd) and End-Diastolic Volume (EDV) of rats in the CIH group significantly increased, whereas the LV ejection fraction and LV fraction shortening significantly decreased. TEM showed that the myofilaments in the CIH group were loosely arranged, the sarcomere length varied, the cell matrix dissolved, the mitochondrial cristae were partly flocculent, the mitochondrial outer membrane dissolved and disappeared, and some mitochondria were swollen and vacuolated. The histopathological examination showed that the cardiomyocytes in the CIH group were swollen with granular degeneration, some of the myocardial fibers were broken and disorganized, and most of the nuclei were vacuolar and hypochromic. Conclusion CIH promoted oxidative stress, the influx of Ca2+, and the activation of the CaN/NFATc signaling pathway, which led to pathological changes in the morphology and ultrastructure of cardiomyocytes, the increase of myocardial apoptosis, and the decrease of myocardial contractility. These changes may be associated with the upregulation of TRPC5.

Chemogenetic inhibition of NTS astrocytes normalizes cardiac autonomic control and ameliorate hypertension during chronic intermittent hypoxia.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by recurrent episodes of chronic intermittent hypoxia (CIH), which has been linked to the development of sympathoexcitation and hypertension. Furthermore, it has been shown that CIH induced inflammation and neuronal hyperactivation in the nucleus of the solitary tract (NTS), a key brainstem region involved in sympathetic and cardiovascular regulation. Since several studies have proposed that NTS astrocytes may mediate neuroinflammation, we aimed to determine the potential contribution of NTS-astrocytes on the pathogenesis of CIH-induced hypertension. RESULTS: Twenty-one days of CIH induced autonomic imbalance and hypertension in rats. Notably, acute chemogenetic inhibition (CNO) of medullary NTS astrocytes using Designer Receptors Exclusively Activated by Designers Drugs (DREADD) restored normal cardiac variability (LF/HF: 1.1 ± 0.2 vs. 2.4 ± 0.2 vs. 1.4 ± 0.3, Sham vs. CIH vs. CIH + CNO, respectively) and markedly reduced arterial blood pressure in rats exposed to CIH (MABP: 82.7 ± 1.2 vs. 104.8 ± 4.4 vs. 89.6 ± 0.9 mmHg, Sham vs. CIH vs. CIH + CNO, respectively). In addition, the potentiated sympathoexcitation elicit by acute hypoxic chemoreflex activation in rats exposed to CIH was also completely abolished by chemogenetic inhibition of NTS astrocytes using DREADDs. CONCLUSION: Our results support a role for NTS astrocytes in the maintenance of heightened sympathetic drive and hypertension during chronic exposure to intermittent hypoxia mimicking OSA.

Evidences That Sympathetic Overactivity and Neurogenic Hypertension Correlate with Changes in the Respiratory Pattern in Rodent Models of Experimental Hypoxia.

The main question of this chapter is as follows: What is the contribution of changes in the sympathetic-respiratory coupling to the hypertension observed in some experimental models of hypoxia? Although there is evidence supporting the concept that sympathetic-respiratory coupling is increased in different models of experimental hypoxia [chronic intermittent hypoxia (CIH) and sustained hypoxia (SH)], it was also observed that in some strains of rats and in mice, these experimental models of hypoxia do not affect the sympathetic-respiratory coupling and the baseline arterial pressure. The data from studies performed in rats (different strains, male and female, and in the natural sleep cycle) and mice submitted to chronic CIH or SH are critically discussed. The main message from these studies performed in freely moving rodents and in the in situ working heart-brainstem preparation is that experimental hypoxia changes the respiratory pattern, which correlates with increased sympathetic activity and may explain the hypertension observed in male and female rats previously submitted to CIH or SH.

The Beneficial Effect of the Blockade of Stim-Activated TRPC-ORAI Channels on Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia Is Independent of Oxidative Stress.

Obstructive sleep apnea (OSA), a sleep breathing disorder featured by chronic intermittent hypoxia (CIH), is associated with pulmonary hypertension (PH). Rats exposed to CIH develop systemic and lung oxidative stress, pulmonary vascular remodeling, and PH and overexpress Stim-activated TRPC-ORAI channels (STOC) in the lung. Previously, we demonstrated that 2-aminoethyl-diphenylborinate (2-APB)-treatment, a STOC-blocker, prevents PH and the overexpression of STOC induced by CIH. However, 2-APB did not prevent systemic and pulmonary oxidative stress. Accordingly, we hypothesize that the contribution of STOC in the development of PH induced by CIH is independent of oxidative stress. We measured the correlation between right ventricular systolic pressure (RVSP) and lung malondialdehyde (MDA) with the gene expression of STOC and morphological parameters in the lung from control, CIH-treated, and 2-APB-treated rats. We found correlations between RVSP and increased medial layer and STOC pulmonary levels. 2-APB-treated rats showed a correlation between RVSP and the medial layer thickness, α-actin-ir, and STOC, whereas RVSP did not correlate with MDA levels in CIH and 2-APB-treated rats. CIH rats showed correlations between lung MDA levels and the gene expression of TRPC1 and TRPC4. These results suggest that STOC channels play a key role in developing CIH-induced PH that is independent from lung oxidative stress.

Chronic intermittent hypobaric hypoxia induces cardiovascular dysfunction in a high-altitude working shift model.

AIMS: Chronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 × 4 or 7 × 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x low-altitude (760 m) working shifts. MAIN METHODS: We analyzed in vivo cardiac function through echocardiography, ex vivo vascular reactivity by wire myography, and in vitro cardiac morphology by histology and protein expression and immunolocalization by molecular biology and immunohistochemistry techniques in 12 rats, 6 exposed to CIHH in the hypoxic chamber, and respective normobaric normoxic controls (n = 6). KEY FINDINGS: CIHH induced cardiac dysfunction with left and right ventricle remodeling, associated with an increased collagen content in the right ventricle. In addition, CIHH increased HIF-1α levels in both ventricles. These changes are associated with decreased antioxidant capacity in cardiac tissue. Conversely, CIHH decreased contractile capacity with a marked decreased in nitric oxide-dependent vasodilation in both, carotid and femoral arteries. SIGNIFICANCE: These data suggest that CIHH induces cardiac and vascular dysfunction by ventricular remodeling and impaired vascular vasodilator function. Our findings highlight the impact of CIHH in cardiovascular function and the importance of a periodic cardiovascular evaluation in high-altitude workers.

Carotid body contribution to the physio-pathological consequences of intermittent hypoxia: role of nitro-oxidative stress and inflammation.

Obstructive sleep apnoea (OSA), characterized by chronic intermittent hypoxia (CIH), is considered to be an independent risk for hypertension. The pathological cardiorespiratory consequences of OSA have been attributed to systemic oxidative stress, inflammation and sympathetic overflow induced by CIH, but an emerging body of evidence indicates that a nitro-oxidative and pro-inflammatory milieu within the carotid body (CB) is involved in the potentiation of CB chemosensory responses to hypoxia, which contribute to enhance the sympathetic activity. Accordingly, autonomic and cardiovascular alterations induced by CIH are critically dependent on an abnormally heightened CB chemosensory input to the nucleus of tractus solitarius (NTS), where second-order neurons project onto the rostral ventrolateral medulla (RVLM), activating pre-sympathetic neurons that control pre-ganglionic sympathetic neurons. CIH produces oxidative stress and neuroinflammation in the NTS and RVLM, which may contribute to the long-term irreversibility of the CIH-induced alterations. This brief review is mainly focused on the contribution of nitro-oxidative stress and pro-inflammatory molecules on the hyperactivation of the hypoxic chemoreflex pathway including the CB and the brainstem centres, and whether the persistence of autonomic and cardiorespiratory alterations may depend on the glial-related neuroinflammation induced by the enhanced CB chemosensory afferent input.

Sympathetic dysregulation induced by postnatal intermittent hypoxia.

STUDY OBJECTIVES: Exposure to postnatal chronic intermittent hypoxia (pCIH), as experienced in sleep-disordered breathing, is a risk factor for developing cardiorespiratory diseases in adulthood. pCIH causes respiratory instability and motor dysfunction that persist until adult life. In this study, we investigated the impact of pCIH on the sympathetic control of arterial pressure in rats. METHODS AND RESULTS: Neonate male Holtzman rats (P0-1) were exposed to pCIH (6% O2 for 30 seconds, every 10 minutes, 8 h/day) during their first 10-15 days of life, while control animals were maintained under normoxia. In early adult life (P25-40), freely behaving pCIH animals (n = 13) showed higher baseline arterial pressure levels linked to augmented sympathetic-mediated variability than control animals (n = 12, p < 0.05). Using decerebrated in situ preparations, we found that juvenile pCIH rats exhibited a twofold increase in thoracic sympathetic nerve activity (n = 14) and elevated firing frequency of ventromedullary presympathetic neurons (n = 7) compared to control rats (n = 6-7, p < 0.05). This pCIH-induced sympathetic dysregulation was associated with increased HIF-1α (hypoxia-inducible factor 1 alpha) mRNA expression in catecholaminergic presympathetic neurons (n = 5, p < 0.05). At older age (P90-99), pCIH rats displayed higher arterial pressure levels and larger depressor responses to ganglionic blockade (n = 6-8, p < 0.05), confirming the sympathetic overactivity state. CONCLUSIONS: pCIH facilitates the vasoconstrictor sympathetic drive by mechanisms associated with enhanced firing activity and HIF-1α expression in ventromedullary presympathetic neurons. This excessive sympathetic activity persists until adulthood resulting in high blood pressure levels and variability, which contribute to developing cardiovascular diseases.

Duration and Consequences of Periodic Breathing in Infants Born Preterm Before and After Hospital Discharge.

OBJECTIVE: To investigate the amount of time spent in periodic breathing and its consequences in infants born preterm before and after hospital discharge. METHODS: Infants born preterm between 28-32 weeks of gestational age were studied during daytime sleep in the supine position at 32-36 weeks of postmenstrual age (PMA), 36-40 weeks of PMA, and 3 months and 6 months of corrected age. The percentage of total sleep time spent in periodic breathing (% total sleep time periodic breathing) was calculated and infants were grouped into below and above the median (8.5% total sleep time periodic breathing) at 32-36 weeks and compared with 36-40 weeks, 3 and 6 months. RESULTS: Percent total sleep time periodic breathing was not different between 32-36 weeks of PMA (8.5%; 1.5, 15.0) (median, IQR) and 36-40 weeks of PMA (6.6%; 0.9, 15.1) but decreased at 3 (0.4%; 0.0, 2.0) and 6 months of corrected age 0% (0.0, 1.1). Infants who spent above the median % total sleep time periodic breathing at 32-36 weeks of PMA spent more % total sleep time periodic breathing at 36-40 weeks of PMA (18.1%; 7.7, 23.9 vs 2.1%; 0.6, 6.4) and 6 months of corrected age 0.9% (0.0, 3.3) vs 0.0% (0.0, 0.0). CONCLUSIONS: Percentage sleep time spent in periodic breathing did not decrease as infants born preterm approached term corrected age, when they were to be discharged home. High amounts of periodic breathing at 32-36 weeks of PMA was associated with high amounts of periodic breathing at term corrected age (36-40 weeks of PMA), and persistence of periodic breathing at 6 months of corrected age.

The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.

Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia.

More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1ß, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

Cardiac Autonomic Modulation and Response to Sub-Maximal Exercise in Chilean Hypertensive Miners.

Cardiac autonomic modulation in workers exposed to chronic intermittent hypoxia (CIH) has been poorly studied, especially considering hypertensive ones. Heart rate variability (HRV) has been proven as valuable tool to assess cardiac autonomic modulation under different conditions. The aim of this study is to investigate the cardiac autonomic response related to submaximal exercise (i.e., six-minute walk test, 6MWT) in hypertensive (HT, n = 9) and non-hypertensive (NT, n = 10) workers exposed for > 2 years to CIH. Participants worked on 7-on 7-off days shift between high altitude (HA: > 4.200 m asl) and sea level (SL: < 500 m asl). Data were recorded with electrocardiography (ECG) at morning upon awakening (10 min supine, baseline), then at rest before and after (5 min sitting, pre and post) the 6MWT, performed respectively on the first day of their work shift at HA, and after the second day of SL sojourn. Heart rate was higher at HA in both groups for each measurement (p < 0.01). Parasympathetic indices of HRV were lower in both groups at HA, either in time domain (RMSSD, p < 0.01) and in frequency domain (log HF, p < 0.01), independently from measurement's time. HRV indices in non-linear domain supported the decrease of vagal tone at HA and showed a reduced signal's complexity. ECG derived respiration frequency (EDR) was higher at HA in both groups (p < 0.01) with interaction group x altitude (p = 0.012), i.e., higher EDR in HT with respect to NT. No significant difference was found in 6MWT distance regarding altitude for both groups, whereas HT covered a shorter 6MWT distance compared to NT (p < 0.05), both at HA and SL. Besides, conventional arm-cuff blood pressure and oxygen blood saturation values (recorded before, at the end and after 5-min recovery from 6MWT), reported differences related to HA only. HA is the main factor affecting cardiac autonomic modulation, independently from hypertension. However, presence of hypertension was associated with a reduced physical performance independently from altitude, and with higher respiratory frequency at HA.

Crucial Role of Stromal Interaction Molecule-Activated TRPC-ORAI Channels in Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia.

Obstructive sleep apnea (OSA), a sleep breathing disorder featured by chronic intermittent hypoxia (CIH), is associate with pulmonary hypertension. Rats exposed to CIH develop lung vascular remodeling and pulmonary hypertension, which paralleled the upregulation of stromal interaction molecule (STIM)-activated TRPC-ORAI Ca2+ channels (STOC) in the lung, suggesting that STOC participate in the pulmonary vascular alterations. Accordingly, to evaluate the role played by STOC in pulmonary hypertension we studied whether the STOC blocker 2-aminoethoxydiphenyl borate (2-APB) may prevent the vascular remodeling and the pulmonary hypertension induced by CIH in a rat model of OSA. We assessed the effects of 2-APB on right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, α-actin and proliferation marker Ki-67 levels in pulmonary arterial smooth muscle cells (PASMC), mRNA levels of STOC subunits, and systemic and pulmonary oxidative stress (TBARS) in male Sprague-Dawley (200 g) rats exposed to CIH (5% O2, 12 times/h for 8h) for 28 days. At 14 days of CIH, osmotic pumps containing 2-APB (10 mg/kg/day) or its vehicle were implanted and rats were kept for 2 more weeks in CIH. Exposure to CIH for 28 days raised RVSP > 35 mm Hg, increased the medial layer thickness and the levels of α-actin and Ki-67 in PASMC, and increased the gene expression of TRPC1, TRPC4, TRPC6 and ORAI1 subunits. Treatment with 2-APB prevented the raise in RVSP and the increment of the medial layer thickness, as well as the increased levels of α-actin and Ki-67 in PASMC, and the increased gene expression of STOC subunits. In addition, 2-APB did not reduced the lung and systemic oxidative stress, suggesting that the effects of 2-APB on vascular remodeling and pulmonary hypertension are independent on the reduction of the oxidative stress. Thus, our results supported that STIM-activated TRPC-ORAI Ca2+ channels contributes to the lung vascular remodeling and pulmonary hypertension induced by CIH.

Contribution of STIM-Activated TRPC-ORAI Channels in Pulmonary Hypertension Induced by Chronic Sustained and Intermittent Hypoxia.

Sustained and intermittent hypoxia produce vasoconstriction, arterial remodeling, and hypertension in the lung. Stromal interaction molecule (STIM)-activated transient receptor potential channels (TRPC) and calcium release-activated calcium channel protein (ORAI) channels (STOC) play key roles in the progression of pulmonary hypertension in pre-clinical models of animals subjected to sustained and intermittent hypoxia. The available evidence supports the theory that oxidative stress and hypoxic inducible factors upregulate and activate STIM-activated TRPC-ORAI Ca2+ channels, contributing to the pulmonary remodeling and hypertension induced by sustained hypoxia. However, less is known about the effects of oxidative stress and hypoxic inducible factors on the modulation of STIM-activated TRPC-ORAI channels following chronic intermittent hypoxia. In this review, we examined the emerging evidence supporting the theory that oxidative stress and hypoxic inducible factors induced by intermittent hypoxia upregulate and activate STIM-activated TRPC-ORAI Ca2+ channels. In addition, we used bioinformatics tools to search public databases for the genes involved in the upregulation of STIMactivated TRPC-ORAI Ca2+ channels and compare the differential gene expression and biological processes induced by intermittent and sustained hypoxia in lung cells.

Intermittent hypoxia and respiratory patterns during sleep of preterm infants aged 3 to 18 months residing at high altitude.

STUDY OBJECTIVES: The aim of this study was to determine the impact of apneas on oxygen saturation and the presence of intermittent hypoxia, during sleep of preterm infants (PTIs) born at high altitudes and compare with full-term infants (FTIs) at the same altitude. METHODS: PTIs and FTIs from 3 to 18 months were included. They were divided into three age groups: 3-4 months (Group 1); 6-7 months (Group 2), and 10-18 months (Group 3). Polysomnography parameters and oxygenation indices were evaluated. Intermittent hypoxia was defined as brief, repetitive cycles of decreased oxygen saturation. Kruskal-Wallis test for multiple comparisons, t-test or Mann-Whitney U-test were used. RESULTS: 127 PTI and 175 FTI were included. Total apnea-hypopnea index (AHI) was higher in PTI that FTI in all age groups (Group 1: 33.5/h vs. 12.8/h, p = 0.042; Group 2: 27.0/h vs. 7.4/h, p < 0.001; and Group 3: 11.6/h vs. 3.1/h, p < 0.001). In Group 3, central-AHI (8.0/h vs. 2.3/h, p < 0.001) and obstructive-AHI (1.8/h vs. 0.6/h, p < 0.008) were higher in PTI than FTI. T90 (7.0% vs. 0.5, p < 0.001), oxygen desaturation index (39.8/h vs. 11.3, p < 0.001) were higher in PTI than FTI, nadir SpO2 (70.0% vs. 80.0, p<0.001) was lower in PTI. CONCLUSION: At high altitude, compared to FTI, PTI have a higher rate of respiratory events, greater desaturation, and a delayed resolution of these conditions, suggesting the persistence of intermittent hypoxia during the first 18 months of life. This indicates the need for follow-up of these infants for timely diagnosis and treatment of respiratory disturbances during sleep.

Perinatal inflammation and gestational intermittent hypoxia disturbs respiratory rhythm generation and long-term facilitation in vitro: Partial protection by acute minocycline.

Perinatal inflammation triggers breathing disturbances early in life and affects the respiratory adaptations to challenging conditions, including the generation of amplitude long-term facilitation (LTF) by acute intermittent hypoxia (AIH). Some of these effects can be avoided by anti-inflammatory treatments like minocycline. Since little is known about the effects of perinatal inflammation on the inspiratory rhythm generator, located in the preBötzinger complex (preBötC), we tested the impact of acute lipopolysaccharide (LPS) systemic administration (sLPS), as well as gestational LPS (gLPS) and gestational chronic IH (gCIH), on respiratory rhythm generation and its long-term response to AIH in a brainstem slice preparation from neonatal mice. We also evaluated whether acute minocycline administration could influence these effects. We found that perinatal inflammation induced by sLPS or gLPS, as well as gCIH, modulate the frequency, signal-to-noise ratio and/or amplitude (and their regularity) of the respiratory rhythm recorded from the preBötC in the brainstem slice. Moreover, all these perinatal conditions inhibited frequency LTF and amplitude long-term depression (LTD); gCIH even induced frequency LTD of the respiratory rhythm after AIH. Some of these alterations were not observed in slices pre-treated in vitro with minocycline, when compared with slices obtained from naïve pups, suggesting that ongoing inflammatory conditions affect respiratory rhythm generation and its plasticity. Thus, it is likely that alterations in the inspiratory rhythm generator and its adaptive responses could contribute to the respiratory disturbances observed in neonates that suffered from perinatal inflammatory challenges.

Health Effects of Chronic Intermittent Hypoxia at a High Altitude among Chilean Miners: Rationale, Design, and Baseline Results of a Longitudinal Study.

OBJECTIVES: This study aims to assess the health effects on mining workers of exposure to chronic intermittent hypoxia (CIH) at high- and very high-altitude mining compared with similar work at lower altitudes in Chile, and it also aims to constitute the baseline of a 5-year follow-up study. METHODS: We designed a cross-sectional study to assess health conditions in 483 miners working at 2 levels of altitude exposure: 336 working at a very high or high altitude (HA; 247 above 3900-4400 m, and 89 at 3000-3900 m), and 147 below 2400 m. Subjects were randomly selected in two stages. First, a selection of mines from a census of mines in each altitude stratum was made. Secondly, workers with less than 2 years of employment at each of the selected mines were recruited. The main outcomes measured at the baseline were mountain sickness, sleep alterations, hypertension, body mass index, and neurocognitive functions. RESULTS: Prevalence of acute mountain sickness (AMS) was 28.4% in the very high-altitude stratum (P = 0.0001 compared with the low stratum), and 71.7% experienced sleep disturbance (P = 0.02). The adjusted odds ratio for AMS was 9.2 (95% confidence interval: 5.2-16.3) when compared with the very high- and low-altitude groups. Motor processing speed and spatial working memory score were lower for the high-altitude group. Hypertension was lower in the highest-altitude subjects, which may be attributed to preoccupational screening even though this was not statistically significant. CONCLUSIONS: Despite longer periods of acclimatization to CIH, subjects continue to present AMS and sleep disturbance. Compromise of executive functions was detected, including working memory at HA. Further rigorous research is warranted to understand long-term health impacts of high-altitude mining, and to provide evidence-based policy recommendations.

Blood Pressure Response in Miners Exposed to Chronic Intermittent Hypoxia in Chile.

Introduction: Limited information is available on blood pressure (BP) behavior in workers exposed to chronic intermittent hypoxia (CIH), and even less is known regarding effects of CIH on 24-h ambulatory BP in those affected by arterial hypertension at sea level (SL). The aims of this study were to assess clinic and 24-h ambulatory BP at SL and at high altitude (HA; 3,870 m above SL) in workers exposed to CIH, and to compare BP response to HA exposure between normotensive and hypertensive workers. Methods: Nineteen normotensive and 18 pharmacologically treated hypertensive miners acclimatized to CIH were included, whose work was organized according to a "7 days-on-7 days-off" shift pattern between SL and HA. All measurements were performed on the second and seventh day of their HA shift and after the second day of SL sojourn. Results: Compared to SL, 24-h systolic BP (SBP) and diastolic BP (DBP) increased at HA [+14.7 ± 12.6 mmHg (p < 0.001) and +8.7 ± 7.2 mmHg (p < 0.001), respectively], and SBP nocturnal fall decreased consistently (-4.1 ± 9.8%; p < 0.05) in all participants, with hypertensives showing higher nocturnal DBP than normotensives (p < 0.05) despite the current therapy. Also, heart rate (HR) nocturnal fall tended to be reduced at HA. In addition, the 24-h SBP/DBP hypertension threshold of ≥130/80 mmHg was exceeded by 39% of workers at SL and by 89% at HA. Clinic HR, SBP, and DBP were significantly higher on the second day of work at HA compared with SL, the increase being more pronounced for SBP in hypertensives (p < 0.05) and accompanied by, on average, mild altitude sickness in both groups. These symptoms and the values of all cardiovascular variables decreased on the seventh day at HA (p < 0.05) regardless of CIH exposure duration. Conclusion: Long history of work at HA according to scheduled CIH did not prevent the occurrence of acute cardiovascular changes at HA during the first days of exposure. The BP response to HA tended to be more pronounced in hypertensive than in normotensive workers despite being already treated; the BP changes were more evident for 24-h ambulatory BP. Twenty-four-hour ABP monitoring is a useful tool for an appropriate evaluation of BP in CIH workers.

Chronic intermittent hypoxia alters main olfactory bulb activity and olfaction.

Olfactory dysfunction is commonly observed in patients with obstructive sleep apnea (OSA), which is related to chronic intermittent hypoxia (CIH). OSA patients exhibit alterations in discrimination, identification and odor detection threshold. These olfactory functions strongly rely on neuronal processing within the main olfactory bulb (MOB). However, a direct evaluation of the effects of controlled CIH on olfaction and MOB network activity has not been performed. Here, we used electrophysiological field recordings in vivo to evaluate the effects of 21-day-long CIH on MOB network activity and its response to odors. In addition, we assessed animals´ olfaction with the buried food and habituation/dishabituation tests. We found that mice exposed to CIH show alterations in MOB spontaneous activity in vivo, consisting of a reduction in beta and gamma frequency bands power along with an increase in the theta band power. Likewise, the MOB was less responsive to odor stimulation, since the proportional increase of the power of its population activity in response to four different odorants was smaller than the one observed in control animals. These CIH-induced MOB functional alterations correlate with a reduction in the ability to detect, habituate and discriminate olfactory stimuli. Our findings indicate that CIH generates alterations in the MOB neural network, which could be involved in the olfactory deterioration in patients with OSA.