Model Of Obstructive Sleep Apnea Research Articles

Cardiac Sympathetic Denervation Suppresses Atrial Fibrillation and Blood Pressure in a Chronic Intermittent Hypoxia Rat Model of Obstructive Sleep Apnea.

BackgroundChronic intermittent hypoxia (CIH) is a distinct pathological mechanism of obstructive sleep apnea (OSA), which is recognized as an independent risk factor for cardiovascular diseases. The aims of this study were to ascertain whether CIH induces atrial fibrillation (AF), to determine whether cardiac sympathetic denervation (CSD) can prevent it and suppress blood pressure, and to explore the potential molecular mechanisms involved.Methods and ResultsSixty Sprague‐Dawley male rats were randomly divided into 4 groups: sham, CSD, CIH, CIH+CSD. The rats were exposed either to CIH 8 hours daily or normoxia for 6 weeks. Cardiac pathology and structure were analyzed by hematoxylin and eosin staining and echocardiogram. ECG, blood pressure, body weight, and blood gas were recorded. Connexin 43 and tyrosine hydroxylase were detected by western blot, immunohistochemistry, and immunofluorescence. CIH induced atrial remodeling, and increased AF inducibility. CSD treatment reduced postapneic blood pressure rises and AF susceptibility, which could attenuate CIH‐associated structural atrial arrhythmogenic remodeling. In addition, CIH‐induced sympathetic nerve hyperinnervation and CSD treatment reduced sympathetic innervation, which may affect CIH‐induced AF‐associated sympathovagal imbalance. Connexin 43 was specifically downregulated in CIH, whereas CSD treatment increased its expression.ConclusionsThese results suggested CIH induces atrial remodeling, increases AF inducibility, results in sympathetic nerve hyperinnervation, and decreases connexin 43 expression, but CSD treatment reduces AF susceptibility, postapneic blood pressure increase, sympathetic innervation, and the alteration of Cx43, which may be a key point in the genesis of CIH‐induced AF.

Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea.

Disruption of the gut microbiota, termed gut dysbiosis, has been described in animal models of hypertension and hypertensive patients. We have shown that gut dysbiosis plays a causal role in the development of hypertension in a rat model of obstructive sleep apnea (OSA). Functional analysis of the dysbiotic microbiota in OSA demonstrates a loss of short chain fatty acid-producing bacteria. However, measurements of short chain fatty acid concentrations and testing of their role in blood pressure regulation are lacking. We hypothesized that reduced short chain fatty acids in the gut are responsible for OSA-induced hypertension. OSA significantly increased systolic blood pressure at 7 and 14 days ( P<0.05), an effect that was abolished by the probiotic Clostridium butyricum or the prebiotic Hylon VII. The 16S rRNA analysis identified several short chain fatty acid-producing bacteria that were significantly increased by Cbutyricum and Hylon treatment. Acetate concentration in the cecum was decreased by 48% after OSA ( P<0.05), an effect that was prevented by Cbutyricum and Hylon. Cbutyricum and Hylon reduced OSA-induced dysbiosis, epithelial goblet cell loss, mucus barrier thinning, and activation of brain microglia ( P<0.05 for each). To examine the role of acetate in OSA-induced hypertension, we chronically infused acetate into the cecum during 2 weeks of sham or OSA. Restoring cecal acetate concentration prevented OSA-induced gut inflammation and hypertension ( P<0.05). These studies identify acetate as a key player in OSA-induced hypertension. We demonstrate that various methods to increase cecal acetate concentrations are protective from the adverse effects of OSA on the microbiota, gut, brain, and blood pressure.

A6032 Carotid body enhanced chemosensory discharge is essential for the hypertension induced by intermittent hypoxia in a model of obstructive sleep apnea

A6032 Carotid body enhanced chemosensory discharge is essential for the hypertension induced by intermittent hypoxia in a model of obstructive sleep apnea

Simplifying the Screening of Obstructive Sleep Apnea With a 2-Item Model, No-Apnea: A Cross-Sectional Study

To develop and validate a practical model for obstructive sleep apnea (OSA) screening in adults based on objectively assessed criteria, and then compare it with two widely used tools, namely STOP-BANG and NoSAS. This is a retrospective study of an existing database of consecutive outpatients who were referred for polysomnography for suspected sleep-disordered breathing by their primary care physicians. Area under the curve (AUC) and 2 × 2 contingency tables were employed to obtain the performance of the new instrument. A total of 4,072 subjects were randomly allocated into two independent cohorts: one for derivation (n = 2,037) and one for validation (n = 2,035). A mnemonic model, named No-Apnea, with two variables (neck circumference and age) was developed (total score: 0-9 points). We used the cutoff ≥ 3 to classify patients at high risk of having OSA. OSA severity was categorized by apnea-hypopnea index (AHI): any OSA (AHI 5 ≥ events/h; OSA-5), moderate/ severe OSA (AHI 15 ≥ events/h; OSA-15); and severe OSA (AHI 30 ≥ events/h; OSA-30). In the derivation cohort, the AUCs for screening of OSA-5, OSA-15, and OSA-30 were: 0.784, 0.758, and 0.754; respectively. The rate of subjects correctly screened was 78.1%, 68.8%, and 54.4%, respectively for OSA-5, OSA-15, and OSA-30. Subsequently, the model was validated confirming its reproducibility. In both cohorts, No-Apnea discrimination was similar to STOP-BANG or NoSAS. The No-Apnea, a 2-item model, appears to be a useful and practical tool for OSA screening, mainly when limited resources constrain referral evaluation. Despite its simplicity when compared to previously validated tools (STOP-BANG and NoSAS), the instrument exhibits similar performance characteristics.

Cognitive Deficits Are Attenuated in Neuroglobin Overexpressing Mice Exposed to a Model of Obstructive Sleep Apnea.

Background: Obstructive sleep apnea (OSA) is a highly prevalent disease manifesting as intermittent hypoxia during sleep (IH) and is increasingly recognized as being independently associated with neurobehavioral deficits. These deficits may be due to increased apoptosis in the hippocampus and cerebral cortex, as well as increased oxidative stress and inflammation. It has been reported that neuroglobin (Ngb) is upregulated in response to hypoxia-ischemia insults and exhibits a protective role in ischemia-reperfusion brain injury. We hypothesized that transgenic overexpression of Ngb would attenuate spatial learning deficits in a murine model of OSA.Methods:Wild-type mice and Ngb overexpressing male mice (Ngb-TG) were randomly assigned to either IH or room air (RA) exposures. The effects of IH during the light period on performance in a water maze spatial task were assessed, as well as anxiety and depressive-like behaviors using elevated plus maze (EPM) and forced swim tests. Cortical tissues from all the mice were extracted for biochemical studies for lipid peroxidation.Results:Ngb TG mice exhibited increased Ngb immunoreactivity in brain tissues and IH did not elicit significant changes in Ngb expression in either Ngb-TG mice or WT mice. On a standard place training task in the water maze, Ngb-TG mice displayed preserved spatial learning, and were protected from the reduced spatial learning performances observed in WT mice exposed to IH. Furthermore, anxiety and depression levels were enhanced in WT mice exposed to IH as compared to RA controls, while alterations emerged in Ngb-TG mice exposed to IH. Furthermore, WT mice, but not Ngb-TG mice had significantly elevated levels of malondialdehyde in cortical lysates following IH exposures.Conclusions:In a murine model of OSA, oxidative stress responses and neurocognitive and behavioral impairments induced by IH during sleep are attenuated by the neuroprotective effects of Ngb.

0333 A Novel Rat Model of Obstructive Sleep Apnea

0333 A Novel Rat Model of Obstructive Sleep Apnea

Examining the Role of Gut Dysbiosis in Neuroinflammation and Hypertension in a Model of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA), characterized by repeated closure of the upper airway during sleep, is a significant clinical problem and an independent risk factor for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We have previously demonstrated that gut dysbiosis is associated with the development of hypertension in a rat model of OSA. Transplanting the dysbiotic microbiota from a hypertensive OSA rat into a normotensive rat induces hypertension, demonstrating a causal relationship between gut dysbiosis and hypertension. The mechanisms linking gut dysbiosis to hypertension are unknown. We tested the hypothesis that OSA‐induced gut dysbiosis impairs gut barrier function, causing systemic inflammation and neuroinflammation, which is linked to hypertension. Using an in vivo model of OSA, we exposed high fat fed rats to 2 weeks of sham or OSA (60 apneas/hr). Relative to sham rats, OSA led to a significant increase in TNFα mRNA expression in the cecum wall as well as decreased goblet cells/crypt in the cecum and colon (n=6, p&lt;0.05). OSA resulted in a 3‐fold increase in gut permeability (n=6, p&lt;0.05). Consistent with impaired gut barrier function and bacterial translocation, we observed increased bacterial 16S rRNA signatures in the mesenteric lymph node and visceral adipose tissue following OSA (n=4–7, p&lt;0.05). Flow cytometric analysis using whole brain revealed a significant increase in the number of activated microglia following OSA (n=4–6, p&lt;0.05). Short chain fatty acids play a key role in maintaining gut barrier integrity and regulating immune responses. We found that OSA significantly reduced the acetate concentraction in the cecum (n=5, p&lt;0.05). To increase short chain fatty acid production in the gut, rats were treated with a prebiotic (diet enriched with 20% resistant starch), or probiotic (Clostridium butyricum; 109 CFU by gavage every three days) during the 2 weeks of sham or OSA. Pre‐ and probiotics each prevented OSA‐induced decrease in cecal acetate concentration, prevented OSA‐induced loss of goblet cells, and prevented increased TNFα expression in the cecum of OSA rats (n=5–6, p&lt;0.05 for each). Additionally, pre‐ and probiotics prevented OSA‐induced activation of microglia in brain (n=6–8, p&lt;0.05). Importantly, both the pre‐ and probiotic successfully prevented the development of hypertension in OSA rats. To test the direct effects of acetate, we chronically infused 20μmol/(kg‐min) acetate into the cecum during the 2 weeks of sham or OSA. Cecal acetate infusion prevented OSA‐induced hypertension. These data demonstrate a causal role for gut dysbiosis in the development of hypertension, which involves reduced acetate production, gut barrier disruption, bacterial translocation, and neuroinflammation. Our data suggest that manipulation of the gut microbiota may serve as a novel therapy in the prevention of hypertension.Support or Funding InformationThis project was funded by NINDS R01NS080531 (RMB), AHA 16SDG29970000 (DJD), and by Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center (DJD).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Norepinephrine modulation of parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) during normoxia and chronic intermittent hypoxia

The PVN is important for eliciting the cardiorespiratory reflex responses to a variety of stimuli and stressors. This is accomplished, in part, via reciprocal connections to several nuclei, including the ventrolateral medulla (VLM) and nucleus tractus solitarii (nTS). The PVN receives dense norepinephrine (NE) projections from the VLM and nTS. The α‐1 and α‐2 adrenergic receptors (aAR) are present in PVN, and stimulation of α‐ARs increase blood pressure and sympathetic outflow. Hypoxia is a stressor stimulus that activates PVN, VLM and nTS neurons, including catecholaminergic VLM and nTS neurons. CIH is a model for obstructive sleep apnea (OSA), and like OSA, elevates respiration, induces sympathoexcitation and hypertension and increases circulating NE. The contribution of the PVN, and the role of NE in the PVN, in CIH remains elusive. We determined the electrophysiological properties of PVN parvocellular neurons in response to NE in normoxia and CIH. Male Sprague‐Dawley rats (110–150 g) were exposed to either 10 days normoxia (Norm, FiO2 = 21%, n = 8) or CIH (alternating FiO2 = 21% and 6%, 8 hr/day, n = 5). PVN slices (~280 μm) were generated and cell capacitance (Cm), initial input resistance, holding currents (Ihold) and spontaneous excitatory postsynaptic currents (sEPSCs) were examined by whole cell patch clamp. Ihold and sEPSCs were recorded under aCSF baseline, and following 10 or 100 mM NE (5 min) and/or the α‐1 AR antagonist prazocin (10 mM). Norm and CIH neurons were of similar size [Cm; Norm, 17.7 ± 2.8 pF (n=19) vs CIH, 17.1 ± 1.8 pF (n=15)], but CIH decreased initial input resistance [Rin; Norm, 2.2 ± 0.4 GΩ (n=19) vs CIH, 1.0 ± 0.4 GΩ (n=15)]. Between Norm (n=19) and CIH (n=15), baseline sEPSC frequency (15.9 ± 1.5 vs 13.5 ± 2.5 Hz) and amplitude (11.9 ± 1.4 vs 15.2 ± 2.2 pA) were similar. In Norm cells, 10 mM NE increased, but not significantly, sEPSC frequency (9.1 ± 2.4 to 19.4 ± 4.5 Hz) but did not alter amplitude. Increasing NE to 100 mM significantly increased sEPSC frequency (19.7 ± 0.7 to 32.0 ± 3.4 Hz) and amplitude (8.2 ± 0.5 to 10.3 ± 1.1 pA). Block of the α‐1‐AR with prazosin did not alter sEPSC frequency (aCSF, 17.2 ± 2.9 vs α‐1‐AR block, 17.3 ± 3.2 Hz) or amplitude (aCSF, 9.8 ± 1.3 pA vs α‐1‐AR block, 11.0 ± 1.9 pA). NE (100 mM) in the presence of α‐1‐AR antagonist blocked the increase in sEPSC frequency (14.8 ± 2.9 Hz) and amplitude (7.7 ± 0.7 pA). In contrast to Norm, CIH sEPSC frequency and amplitude were not altered by NE at 10 mM (e.g., 4.7 ± 1.1 to 6.3 ± 1.4 Hz, n=4) or 100 mM (e.g., 19.5 ± 3.1 to 19.0 ± 4.4 Hz, n=5). Prazocin alone did not alter CIH sEPSC frequency or amplitude (e.g., 14.4 ± 4.7 to 15.4 ± 4.6 Hz, n=6). Neither NE nor prazocin altered Norm or CIH Ihold measured 5 min after their application. These results demonstrate that under Norm conditions PVN parvocellular neurons are significantly influenced by NE and α‐1 AR activation. Following CIH, NE responsiveness is reduced, likely as a compensatory mechanism caused by sympathetic hyperactivity. Catecholaminergic activity therefore is likely important in cardiorespiratory reflex modulation under physiological and pathophysiological conditions.Support or Funding InformationHL 098602 and HL128454This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

P798Application of intermittent negative upper airway pressure as a novel rat model for obstructive sleep apnea and atrial fibrillation

P798Application of intermittent negative upper airway pressure as a novel rat model for obstructive sleep apnea and atrial fibrillation

Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea

BackgroundRecently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated.MethodsC57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1α using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments.ResultsCompared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-α and IL-6 mRNA levels and the NF-κB P65 protein level. HIF-1α protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses.ConclusionsThese results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH-induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations.

Intermittent hypoxia causes histological kidney damage and increases growth factor expression in a mouse model of obstructive sleep apnea.

Epidemiological studies demonstrate an association between obstructive sleep apnea (OSA) and accelerated loss of kidney function. It is unclear whether the decline in function is due to OSA per se or to other confounding factors such as obesity. In addition, the structural kidney abnormalities associated with OSA are unclear. The objective of this study was to determine whether intermittent hypoxia (IH), a key pathological feature of OSA, induces renal histopathological damage using a mouse model. Ten 8-week old wild-type male CB57BL/6 mice were randomly assigned to receive either IH or intermittent air (IA) for 60 days. After euthanasia, one kidney per animal was paraformaldehyde-fixed and then sectioned for histopathological and immunohistochemical analysis. Measurements of glomerular hypertrophy and mesangial matrix expansion were made in periodic acid–Schiff stained kidney sections, while glomerular transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and vascular endothelial growth factor-A (VEGF-A) proteins were semi-quantified by immunohistochemistry. The antigen-antibody reaction was detected by 3,3′-diaminobenzidine chromogen where the color intensity semi-quantified glomerular protein expression. To enhance the accuracy of protein semi-quantification, the percentage of only highly-positive staining was used for analysis. Levels of TGF-β, CTGF and VEGF-A proteins in the kidney cortex were further quantified by western blotting. Cellular apoptosis was also investigated by measuring cortical antiapoptotic B-cell lymphoma 2 (Bcl-2) and apoptotic Bcl-2-associated X (Bax) proteins by western blotting. Further investigation of cellular apoptosis was carried out by fluorometric terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining. Finally, the levels of serum creatinine and 24-hour urinary albumin were measured as a general index of renal function. Our results indicate that mice exposed to IH have an increased glomerular area (by 1.13 fold, p< 0.001) and expansion of mesangial matrix (by 1.8 fold, p< 0.01). Moreover, the glomerular expressions of TGF-β1, CTGF and VEGF-A proteins were 2.7, 2.2 and 3.8-fold higher in mice exposed to IH (p< 0.05 for all). Furthermore, western blotting protein analysis demonstrates that IH-exposed mice express higher levels of TGF-β1, CTGF and VEGF-A proteins by 1.9, 4.0 and 1.6-fold (p< 0.05 for all) respectively. Renal cellular apoptosis was greater in the IH group as shown by an increased cortical Bax/Bcl-2 protein ratio (p< 0.01) and higher fluorometric TUNEL staining (p< 0.001). Finally, 24-hr urinary albumin levels were higher in mice exposed to IH (43.4 μg vs 9.7 μg, p< 0.01), while there were no differences in serum creatinine levels between the two groups. We conclude that IH causes kidney injury that is accompanied by glomerular hypertrophy, mesangial matrix expansion, increased expression of glomerular growth factors and an increased cellular apoptosis.

EFFECTS OF IMATINIB ON PULMONARY VASCULATURE IN AN ANIMAL MODEL OF OBSTRUCTIVE SLEEP APNEA

RespirologyVolume 22, Issue S3 p. 143-144 APSR Poster Abstracts EFFECTS OF IMATINIB ON PULMONARY VASCULATURE IN AN ANIMAL MODEL OF OBSTRUCTIVE SLEEP APNEA First published: 23 November 2017 https://doi.org/10.1111/resp.13207_160Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume22, IssueS3Supplement: 22nd Congress of the Asian Pacific Society of Respirology, International Convention Centre, Sydney, Australia, 23–26 November 2017November 2017Pages 143-144 RelatedInformation

Activation of the Integrated Stress Response and Metabolic Dysfunction in a Murine Model of Sleep Apnea.

Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2α), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week-old CHOP/GADD34-/- (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2α:total eIF2α, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34-/- and PERK+/- mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6chigh) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea.

Effects of chronic intermittent hypoxia on left ventricular myocardial contractibility in a rabbit model of obstructive sleep apnea

Objective: To explore the effects of chronic intermittent hypoxia (CIH) on left ventricular myocardial contractibility in a rabbit model of obstructive sleep apnea (OSA). Methods: Based on random number table, twenty-four rabbits were randomly divided into three groups: operation, sham, and control groups, each with 8 rabbits. The rabbit model for OSA in operation group was established by repeatedly closing the airway and then reopening it. Upper airway obstructions were conducted on rabbits every day, which were alternately closed for 15 s and then reopened for 75 s in a 90 s-long cycle, for 8 h each day over 3 months. The sham rabbits were subjected to the same surgical procedure but no airway obstructions were applied. The control animals were subjected to no intervention. The blood pressure, left ventricular function parameters were assessed before and after the experiment. And the relative expressions of myosin heavy chain α/β (α-MHC and β-MHC) mRNAs in myocardium were observed for all rabbits by real time fluorescent quantitative polymerase chain reaction 3 months later. Results: After 3 months, all rabbits in the operation group manifested sleepiness and the blood pressure rose gradually [(114.25±4.20) vs (93.88±2.10) mmHg, P<0.01]. Compared with the sham operation and the control groups, the left ventricular end-systolic volume [(6.05±1.62) vs (2.83±0.49) and (2.74±0.32) ml, P<0.001] and the left ventricular end-diastolic volume [(1.61±0.78) vs (0.83±0.13) and (0.82±0.10) ml] in operation group were obviously higher, the left ventricular ejection fraction [(63.9±4.2) % vs (74.3±2.5) % and (75.8±3.8) %], left ventricular fractional shortening [(32.2±2.1) % vs (41.8±1.8) % and (42.1±1.8) %] and stroke volume [(1.46±0.13) vs (1.93±0.21) and (1.98±0.24) ml/s] were decreased (all P<0.001). Besides, the maximal rate of the increase of left ventricular pressure [(4 154±360) vs (6 802±492) and (6 759±206) mmHg/s], the maximal rate of the decrease of left ventricular pressure [(4 994±621) vs (6 330±314) and (6 591±225) mmHg/s] in the operation group decreased markedly, left ventricular end diastolic pressure (LVEDP) increased [(6.5±1.6) vs (3.3±0.8) and (3.2±0.9) mmHg] (all P<0.001). The relative expression of α-MHC mRNA in left ventricular myocardial tissue was lower and the relative expression of β-MHC mRNA was higher in operation group than those in the sham operation and the control groups (P<0.05). There were no significant difference in the relevant indicators of cardiac function, and in the relative expressions of α-MHC mRNA and the β-MHC mRNA between the control group and the sham operation group (P>0.05). Conclusions: Repeated intermittent hypoxia can induce hypertension and myocardial contractibility damage in OSA model rabbit simulating upper airway obstruction.

Benefits of oxytocin administration in obstructive sleep apnea.

Activation of oxytocin receptors has shown benefits in animal models of obstructive sleep apnea (OSA). We tested if nocturnal oxytocin administration could have beneficial effects in OSA patients. Eight patients diagnosed with OSA were administered intranasal oxytocin (40 IU). Changes in cardiorespiratory events during sleep, including apnea and hypopnea durations and frequency, risk of event-associated arousals, and heart rate variability, were assessed. Oxytocin significantly increased indexes of parasympathetic activity, including heart rate variability, total sleep time, and the postpolysommogram sleep assessment score, an index of self-reported sleep satisfaction. Although the apnea-hypopnea index was not significantly changed with oxytocin administration, when apnea and hypopnea events were compared independently, the frequency of hypopneas, but not apneas, was significantly (P ≤ 0.005) decreased with oxytocin treatment. Both apneas and hypopneas were significantly shortened in duration with oxytocin treatment. Oxytocin treatment significantly decreased the percent of apnea and hypopnea events that were accompanied with an arousal. Oxytocin administration has the potential to restore cardiorespiratory homeostasis and reduce some clinically important (objective and patient-reported) adverse events that occur with OSA. Additional studies are needed to further understand the mechanisms by which oxytocin promotes these changes in cardiorespiratory and autonomic function in OSA patients.

Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia.

Mounting evidence has revealed a causative role of intermittent hypoxia (IH) in cancer progression in mouse models of obstructive sleep apnea (OSA), but most studies have focused on the effects of IH following tumor implantation using an exposure to single IH frequency. Thus, we aimed to investigate 1) the potential effect of IH on the initial tumor growth in patients with OSA without an interaction with other mechanisms induced by IH in mice and 2) the influence of the IH frequency on tumor growth, which were tested using pre-conditioning with IH (Pre-IH) and 2 different IH frequencies, respectively. Pre-IH was achieved by alternatively maintaining melanoma cells between normoxia (10 min, 21% O2) and hypoxia (50 min, 1% O2) for 7 days (12 cycles per day) before administering them to mice. The conditions for IH-1 and IH-2 were 90 s of 12% FiO2 followed by 270s of 21% FiO2 (10 cycles/h), and 90 s of 12% FiO2 and 90 s of 21% FiO2 (20 cycles/h), respectively, for 8 h per day. Tumor growth was significantly higher in the Pre-IH group than in the normoxia group. In addition, the IH-2 group showed more accelerated tumor growth compared to the normoxia and IH-1 groups. Immunohistochemistry and gene-expression results consistently showed the up-regulation of molecules associated with HIF-1α-dependent hypoxic adaptation in tumors of the Pre-IH and IH-2 groups. Our findings reveal that IH increased tumor progression in a frequency-dependent manner, regardless of whether it was introduced before or after in vivo tumor cell implantation.

A novel adjustable automated system for inducing chronic intermittent hypoxia in mice.

BackgroundSleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer’s Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders.New methodAn automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8) and control mice (no hypoxia, n = 7) were handled in the same manner and their hippocampal brain regions compared by histology.ResultsThe chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1) P <0.001; cornu ammonis 3 (CA3) P <0.001; and dentate gyrus (DG) P = 0.023). In both, control and hypoxic conditions, there was a significantly higher number of apoptotic neurons in the DG compared to the CA1 and CA3 subfields (P <0.001).ConclusionThe new design of a hypoxic chamber provides a fast, adjustable and reliable model of obstructive sleep apnea, which was validated by apoptosis of hippocampal neurons.

Ultrasonographic Detection of Airway Obstruction in a Model of Obstructive Sleep Apnea.

Purpose Obstructive sleep apnea (OSA) is a common clinical disorder characterized by repetitive airway obstruction during sleep. The gold standard for diagnosis of OSA, polysomnogram (PSG), cannot anatomically localize obstruction. Precise identification of obstruction has potential to improve outcomes following surgery. Current diagnostic modalities that provide this information require anesthesia, involve ionizing radiation or disrupt sleep. To mitigate these problems, we conceived that ultrasound (US) technology may be adapted (i) to detect, quantify and localize airway obstruction and (ii) for translational application to home-based testing for OSA. Materials and Methods Segmental airway collapse was induced in 4 fresh cadavers by application of negative pressure. Following visualization of airway obstruction, a rotary US probe was used to acquire transcervical images of the airway before and after induction of obstruction. These images (n=800) were analyzed offline using image processing algorithms. Results Our results show that the non-obstructed airway consistently demonstrated the presence of a US air-tissue interface. Importantly, automated detection of the air-tissue interface strongly correlated with manual measurements. The algorithm correctly detected an air-tissue interface in 90% of the US images while incorrectly detecting it in 20% (area under the curve=0.91). Conclusion The non-invasive detection of airway obstruction using US represents a major step in expanding OSA diagnostics beyond PSG. The preliminary data obtained from our model could spur further research in non-invasive localization of obstruction. US offers the benefit of precise localization of the site of obstruction, with potential for improving outcomes in surgical management.

Aorta macrophage inflammatory and epigenetic changes in a murine model of obstructive sleep apnea: Potential role of CD36

Obstructive sleep apnea (OSA) affects 8–10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Transcriptomic and MeDIP-seq approaches identified activation of pro-atherogenic pathways involving a complex interplay of histone modifications in functionally-relevant biological pathways, such as inflammation and oxidative stress in aorta macrophages. Discontinuation of CIH did not elicit significant improvements in aorta wall macrophage phenotype. However, CIH-induced aorta changes were absent in CD36 knockout mice, Our results provide mechanistic insights showing that CIH exposures during sleep in absence of concurrent pro-atherogenic settings (i.e., genetic propensity or dietary manipulation) lead to the recruitment of CD36(+)high macrophages to the aortic wall and trigger atherogenesis. Furthermore, long-term CIH-induced changes may not be reversible with usual OSA treatment.

A predictive model for obstructive sleep apnea and Down syndrome.

Obstructive sleep apnea (OSA) occurs frequently in people with Down syndrome (DS) with reported prevalences ranging between 55% and 97%, compared to 1-4% in the neurotypical pediatric population. Sleep studies are often uncomfortable, costly, and poorly tolerated by individuals with DS. The objective of this study was to construct a tool to identify individuals with DS unlikely to have moderate or severe sleep OSA and in whom sleep studies might offer little benefit. An observational, prospective cohort study was performed in an outpatient clinic and overnight sleep study center with 130 DS patients, ages 3-24 years. Exclusion criteria included previous adenoid and/or tonsil removal, a sleep study within the past 6 months, or being treated for apnea with continuous positive airway pressure. This study involved a physical examination/medical history, lateral cephalogram, 3D photograph, validated sleep questionnaires, an overnight polysomnogram, and urine samples. The main outcome measure was the apnea-hypopnea index. Using a Logic Learning Machine, the best model had a cross-validated negative predictive value of 73% for mild obstructive sleep apnea and 90% for moderate or severe obstructive sleep apnea; positive predictive values were 55% and 25%, respectively. The model included variables from survey questions, medication history, anthropometric measurements, vital signs, patient's age, and physical examination findings. With simple procedures that can be collected at minimal cost, the proposed model could predict which patients with DS were unlikely to have moderate to severe obstructive sleep apnea and thus may not need a diagnostic sleep study.