Model Of Obstructive Sleep Apnea Research Articles

The Cardiovascular and Metabolic Effects of Chronic Hypoxia in Animal Models: A Mini-Review.

Animal models are useful to understand the myriad physiological effects of hypoxia. Such models attempt to recapitulate the hypoxemia of human disease in various ways. In this mini-review, we consider the various animal models which have been deployed to understand the effects of chronic hypoxia on pulmonary and systemic blood pressure, glucose and lipid metabolism, atherosclerosis, and stroke. Chronic sustained hypoxia (CSH)—a model of chronic lung or heart diseases in which hypoxemia may be longstanding and persistent, or of high altitude, in which effective atmospheric oxygen concentration is low—reliably induces pulmonary hypertension in rodents, and appears to have protective effects on glucose metabolism. Chronic intermittent hypoxia (CIH) has long been used as a model of obstructive sleep apnea (OSA), in which recurrent airway occlusion results in intermittent reductions in oxyhemoglobin saturations throughout the night. CIH was first shown to increase systemic blood pressure, but has also been associated with other maladaptive physiological changes, including glucose dysregulation, atherosclerosis, progression of nonalcoholic fatty liver disease, and endothelial dysfunction. However, models of CIH have generally been implemented so as to mimic severe human OSA, with comparatively less focus on milder hypoxic regimens. Here we discuss CSH and CIH conceptually, the effects of these stimuli, and limitations of the available data.

Enhanced Ocular Surface and Intraoral Nociception via a Transient Receptor Potential Vanilloid 1 Mechanism in a Rat Model of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA), characterized by low arterial oxygen saturation during sleep, is associated with an increased risk of orofacial pain. In this study, we simulated chronic intermittent hypoxia (CIH) during the sleep/rest phase (light phase) to determine the role of transient receptor potential vanilloid 1 (TRPV1) in mediating enhanced orofacial nocifensive behavior and trigeminal spinal subnucleus caudalis (Vc) neuronal responses to capsaicin (a TRPV1 agonist) stimulation in a rat model of OSA. Rats were subjected to CIH (nadir O2, 5%) during the light phase for 8 or 16 consecutive days. CIH yielded enhanced behavioral responses to capsaicin after application to the ocular surface and intraoral mucosa, which was reversed under normoxic conditions. The percentage of TRPV1-immunoreactive trigeminal ganglion neurons was greater in CIH rats than in normoxic rats and recovered under normoxic conditions after CIH. The ratio of large-sized TRPV1-immunoreactive trigeminal ganglion neurons increased in CIH rats. The density of TRPV1 positive primary afferent terminals in the superficial laminae of Vc was higher in CIH rats. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells intermingled with the central terminal of TRPV1-positive afferents in the Vc. The number of pERK-immunoreactive cells following low-dose capsaicin (0.33 µM) application to the tongue was significantly greater in the middle portion of the Vc of CIH rats than of normoxic rats and recovered under normoxic conditions after CIH. These data suggest that CIH during the sleep (light) phase is sufficient to transiently enhance pain on the ocular surface and intraoral mucosa via TRPV1-dependent mechanisms.

Novel screening model of obstructive sleep apnea for snorers with suspected NAFLD undergoing liver sonography

Background/aimsGiven the increased incidence of obstructive sleep apnea (OSA) among patients with nonalcoholic fatty liver disease (NAFLD), noninvasive screening methods are urgently needed to screen for OSA risk in these patients when conducting an office-based assessment of hepatic steatosis. Therefore, we investigated the controlled attenuation parameter (CAP) and hepatic steatosis index (HSI) in patients with and without OSA and developed screening models to detect OSA.MethodsWe retrospectively reviewed the medical records of all adult snorers with suspected NAFLD undergoing liver sonography between June 2017 and June 2020. Records encompassed CAP and HSI data as well as data collected during in-hospital full-night polysomnography. The multivariate logistic regression models were constructed to explore the predictors of OSA risk. Furthermore, model validation was performed based on the medical records corresponding to the July 2020–June 2021 period.ResultsA total of 59 patients were included: 81.4% (48/59) were men, and the mean body mass index (BMI) was 26.4 kg/m2. Among the patients, 62.7% (37/59) and 74.6% (44/59) (detected by the HSI and CAP, respectively) had NAFLD, and 78% (46/59) were diagnosed with OSA on the basis of polysomnography. Three screening models based on multivariate analysis were established. The model combining male sex, a BMI of > 24.8, and an HSI of > 38.3 screened for OSA risk the most accurately, with an area under the receiver operating characteristic curve of 0.81 (sensitivity: 78%; specificity: 85%; and positive and negative predictive values: 95% and 52%, respectively) in the modeling cohort. An accuracy of 70.0% was achieved in the validation group.ConclusionsThe combination screening models proposed herein provide a convenient, noninvasive, and rapid screening tool for OSA risk and can be employed while patients receive routine hepatic check-ups. These models can assist physicians in identifying at-risk OSA patients and thus facilitate earlier detection and timely treatment initiation.

Prediction Models of Obstructive Sleep Apnea in Pregnancy: A Systematic Review and Meta-Analysis of Model Performance.

Background: Gestational obstructive sleep apnea (OSA) is associated with adverse maternal and fetal outcomes. Timely diagnosis and treatment are crucial to improve pregnancy outcomes. Conventional OSA screening questionnaires are less accurate, and various prediction models have been studied specifically during pregnancy. Methods: A systematic review and meta-analysis were performed for multivariable prediction models of both development and validation involving diagnosis of OSA during pregnancy. Results: Of 1262 articles, only 6 studies (3713 participants) met the inclusion criteria and were included for review. All studies showed high risk of bias for the construct of models. The pooled C-statistics (95%CI) for development prediction models was 0.817 (0.783, 0850), I2 = 97.81 and 0.855 (0.822, 0.887), I2 = 98.06 for the first and second–third trimesters, respectively. Only multivariable apnea prediction (MVAP), and Facco models were externally validated with pooled C-statistics (95%CI) of 0.743 (0.688, 0.798), I2 = 95.84, and 0.791 (0.767, 0.815), I2 = 77.34, respectively. The most common predictors in the models were body mass index, age, and snoring, none included hypersomnolence. Conclusions: Prediction models for gestational OSA showed good performance during early and late trimesters. A high level of heterogeneity and few external validations were found indicating limitation for generalizability and the need for further studies.

A model for obstructive sleep apnea detection using a multi-layer feed-forward neural network based on electrocardiogram, pulse oxygen saturation, and body mass index.

To develop and evaluate a model for obstructive sleep apnea (OSA) detection using an artificial neural network (ANN) based on the combined features of body mass index (BMI), electrocardiogram (ECG), and pulse oxygen saturation (SpO2). Polysomnography (PSG) data for 148 patients withOSA and 33 unaffected individuals were included. A multi-layer feed-forward neural network (FNN) was used based on the features obtained from ECG, SpO2, and BMI. The receiver operating characteristic (ROC) curve and the metrics of accuracy, sensitivity, and specificity were used to evaluate the performance of the overall classification. Some other machine learning methods including linear discriminant, linear Support Vector Machine (SVM), Complex Tree, RUSBoosted Trees, and Logistic Regression were also used to compare their performance with the FNN. The accuracy, sensitivity, and specificity of the proposed multi-layer FNN were 97.8%, 98.6%, and 93.9%, respectively, and the area under the ROC curve was 97.0%. Compared with the other machine learning methods mentioned above, the FNN achieved the highest performance. The satisfactory performance of the proposed FNN model for OSA detection indicated that it is reliable to screen potential patients withOSA using the combined channels of ECG and SpO2 and also taking into account BMI. This strategy might be a viable alternative method for OSA diagnosis.

Angiopoietin-like proteins 8 knockout reduces intermittent hypoxia-induced vascular remodeling in a murine model of obstructive sleep apnea

ObjectiveObstructive sleep apnea (OSA) is a major risk factor for cardiovascular mortality. Apnea-induced chronic intermittent hypoxia (CIH) is a primary pathophysiological manifestation of OSA that promotes various cardiovascular alterations, such as aortic vascular remodeling. In this study, we investigated the association between angiopoietin-like proteins 8 (ANGPTL8) and CIH-induced aortic vascular remodeling in mice. MethodsC57BL/6J male mice were divided into four groups: Normoxia group, ANGPTL8−/− group, CIH group, CIH + ANGPTL8−/− group. Mice in the normoxia group and ANGPTL8−/− group received no treatment, while mice in the CIH and CIH + ANGPTL8−/− group were subjected to CIH (21%–5% O2, 180 s/cycle, 10 h/day) for 6 weeks. At the end of the experiments, intima-media thickness (IMT), elastin disorganization, and aortic wall collagen abundance were assessed in vivo. Immunohistochemistry and Western-blot were used to detect endoplasmic reticulum stress (ERS) and aortic vascular smooth muscle cell proliferation. ANGPTL8 shRNA and ANGPL8 overexpression were used in aortic vascular smooth muscle cells to investigate the mechanism of ANGPTL8 in CIH. ResultsCompared to the control group, CIH exposure significantly increased intima-media thickness (IMT), elastic fibers disorganization, and aortic wall collagen abundance. CIH also significantly increased blood pressure, induced hyperlipidemia, as well as the expression of ERS protein activating transcription factor-6 (ATF6) and aortic vascular smooth muscle cell proliferation. Contrary, ANGPTL8−/− significantly mitigated the CIH-induced vascular remodeling; ANGPTL8−/− decreased CIH-induced hypertension and hyperlipidemia, inhibited the protein expression of ATF6, and aortic vascular smooth muscle cell proliferation. Moreover, our in vitro study suggested that CIH could induce ANGPTL8 expression via hypoxia-inducible factor (HIF-1α); ANGPTL8 induced proliferation of aortic vascular smooth muscle cells via the ERS pathway. ConclusionANGPTL8−/− can prevent CIH-induced aortic vascular remodeling, probably through the inhibition of the ERS pathway. Therefore, ANGPTL8 might be a potential target in CIH-induced aortic vascular remodeling.

A novel mouse model of obstructive sleep apnea by bulking agent-induced tongue enlargement results in left ventricular contractile dysfunction.

Obstructive sleep apnea (OSA) is a widespread disease with high global socio-economic impact. However, detailed pathomechanisms are still unclear, partly because current animal models of OSA do not simulate spontaneous airway obstruction. We tested whether polytetrafluoroethylene (PTFE) injection into the tongue induces spontaneous obstructive apneas. PTFE (100 μl) was injected into the tongue of 31 male C57BL/6 mice and 28 mice were used as control. Spontaneous apneas and inspiratory flow limitations were recorded by whole-body plethysmography and mRNA expression of the hypoxia marker KDM6A was quantified by qPCR. Left ventricular function was assessed by echocardiography and ventricular CaMKII expression was measured by Western blotting. After PTFE injection, mice showed features of OSA such as significantly increased tongue diameters that were associated with significantly and sustained increased frequencies of inspiratory flow limitations and apneas. Decreased KDM6A mRNA levels indicated chronic hypoxemia. 8 weeks after surgery, PTFE-treated mice showed a significantly reduced left ventricular ejection fraction. Moreover, the severity of diastolic dysfunction (measured as E/e') correlated significantly with the frequency of apneas. Accordingly, CaMKII expression was significantly increased in PTFE mice and correlated significantly with the frequency of apneas. We describe here the first mouse model of spontaneous inspiratory flow limitations, obstructive apneas, and hypoxia by tongue enlargement due to PTFE injection. These mice develop systolic and diastolic dysfunction and increased CaMKII expression. This mouse model offers great opportunities to investigate the effects of obstructive apneas.

Pharmacological inhibition of acetylcholine-regulated potassium current (IK,ACh) and associated A1- and M2-pathways prevent atrial arrhythmogenic changes in a rat model for obstructive sleep apnea

Abstract Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone and adenosine release, potentially resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation by A1-receptor and M2-receptor activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg), M2-receptor inhibitor (atropine; 1μg/kg), A1-receptor inhibitor (Rolofylline; 1μg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP) and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results Independent of IK,Ach-inhibition, single INAP applications prolonged transiently atrial activation times (Control: INAP vs. pre-INAP p=0.034; XAF-1407: INAP vs. pre-INAP p=0.039). In control-rats, seventy minutes of repetitive INAP decreased AERP by 15.45±0.06% (vs. baseline p=0.0015), which was reversible upon 1 hour of recovery. AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r=−0.773; p=0.025). Whilst only XAF-1407 and atropine increased baseline AERP, all drug interventions, XAF-1407, atropine and Rolofylline could prevent INAP-associated AERP shortening (end INAP-protocol vs. respective baseline XAF-1407 p=0.994; atropine p=0.984; Rolofylline p=0.951). Drops in oxygen saturation and applied INAP were comparable in all groups. Conclusion Short-term simulated OSA is associated with progressive AERP shortening, which was determined by the cumulative negative airway pressure applied. This potentially represents an important insight in future OSA treatment. Pharmacological IK,ACh inhibition prevented INAP-associated AERP-shortening suggesting an involvement in acute atrial arrhythmogenesis in OSA. However, if IK,Ach and its potential upstream activating A1- and M2-pathway pose a pharmacological treatment target for OSA-patients with AF, requires further investigation. Funding Acknowledgement Type of funding source: None

Alpha adrenergic receptor signaling in the hypothalamic paraventricular nucleus is diminished by the chronic intermittent hypoxia model of sleep apnea

Chronic intermittent hypoxia (CIH) is a model for obstructive sleep apnea. The paraventricular nucleus (PVN) of the hypothalamus has been suggested to contribute to CIH-induced exaggerated cardiorespiratory reflexes, sympathoexcitation and hypertension. This may occur, in part, via activation of the dense catecholaminergic projections to the PVN that originate in the brainstem. However, the contribution of norepinephrine (NE) and activation of its alpha-adrenergic receptors (α-ARs) in the PVN after CIH exposure is unknown. We hypothesized CIH would increase the contribution of catecholaminergic input. To test this notion, we determined the expression of α-AR subtypes, catecholamine terminal density, and synaptic properties of PVN parvocellular neurons in response to α-AR activation in male Sprague-Dawley normoxic (Norm) and CIH exposed rats. CIH decreased mRNA for α1d and α2b AR. Dopamine-β-hydroxylase (DβH) terminals in the PVN were similar between groups. NE and the α1-AR agonist phenylephrine (PE) increased sEPSC frequency after Norm but not CIH. Block of α1-ARs with prazosin alone did not alter sEPSCs after either Norm or CIH but did prevent agonist augmentation of sEPSC frequency following normoxia. These responses to NE were mimicked by PE during action potential block suggesting presynaptic terminal alterations in CIH. Altogether, these results demonstrate that α1-AR activation participates in neuronal responses in Norm, but are attenuated after CIH. These results may provide insight into the cardiovascular, respiratory and autonomic nervous systems alterations in obstructive sleep apnea.

Hypoglossal nerve stimulation in a rabbit model of obstructive sleep apnea reduces apneas and improves oxygenation

Based on a prior anesthetized model, we developed an unanesthetized model to evaluate the effects of hypoglossal nerve stimulation (HNS) during sleep. We prepared three rabbits with injections of hyaluronic acid in the base of tongue to produce upper airway obstruction followed by HNS implant. Two rabbits were saline controls, and one, a passive control. Measures were sleep, airflow, effort, oxygen saturation, and heart rate. HNS with electrodes around the right hypoglossal nerve were adjusted to a level without behaviorally disturbing the animal. During HNS stimulation in the tongue-base injected rabbits, obstructive apneas and hypopneas of intermediate (3 to 7 cycles of respiratory effort) or longer (≥8 cycles) duration were largely eliminated while less clinically relevant shorter events (<3) were unaffected, and oxygen saturation was improved. Control animals exhibited no intermediate or long events. In this model HNS can relieve induced sleep apnea, without disturbing the animal: however, despite being non-canine and of substantial size, the model has its challenges.NEW & NOTEWORTHY This report describes a rabbit model for testing the impact of hypoglossal nerve stimulation (HNS) on obstructive apneas. Obstructive sleep apnea (OSA) is induced by injecting hyaluronic acid (as a filler) into the base of the tongue. HNS reduced the length and rate of obstructions and improved oxygenation during sleep. Our efforts with this model advanced understanding of the complexities of this OSA preclinical model for neurostimulation reversal of sleep-disordered breathing.

Intranasal oxytocin increases respiratory rate and reduces obstructive event duration and oxygen desaturation in obstructive sleep apnea patients: a randomized double blinded placebo controlled study

BackgroundActivation of the oxytocin network has shown benefits in animal models of Obstructive Sleep Apnea (OSA) as well as other cardiorespiratory diseases. We sought to determine if nocturnal intranasal oxytocin administration could have beneficial effects in reducing the duration and/or frequency of obstructive events in obstructive sleep apnea subjects. MethodsTwo sequential standard “in-lab” polysomnogram (PSG) sleep studies were performed in patients diagnosed with OSA that were randomly assigned to initially receive either placebo or oxytocin (40 i.u.) administered intranasally in this double blinded randomized placebo controlled study. Changes in cardiorespiratory events during sleep, including apnea and hypopnea durations and frequency, risk of event-associated bradycardias, arterial oxygen desaturation and respiratory rate were assessed in 2 h epochs following sleep onset. Oxytocin significantly decreased the duration of obstructive events, as well as the oxygen desaturations and incidence of bradycardia that were associated with these events. Notably, oxytocin increased respiratory rate during non-obstructive periods. There were no significant changes in sleep architecture and no adverse effects were reported. ConclusionsOxytocin administration can benefit OSA subjects by reducing the duration and adverse consequences of obstructive events. Oxytocin could also be beneficial in situations involving respiratory depression as oxytocin increased respiratory rate. Additional studies are needed to further understand the mechanisms by which oxytocin promotes these changes in cardiorespiratory function. The long-term efficacy and optimal dose of intranasal oxytocin treatment should also be determined in OSA subjects.ClinicalTrials.gov NCT03148899.

741Pharmacological inhibition of the acetylcholine-regulated potassium channel (IK,ACh) prevents atrial arrhythmogenic changes in a rat model for obstructive sleep apnea

Abstract Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone, resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP), inducible atrial fibrillation (AF)-durations and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results During single INAP applications atrial activation times prolonged transiently in both groups (Control: INAP vs. pre-INAP p = 0.034; XAF-1407: INAP vs. pre-INAP p = 0.039). In control-rats, seventy minutes of repetitive INAP prolonged P-wave duration (+10.8 ± 2.7% vs. baseline, p = 0.008) and decreased AERP by 14.6 ± 3.1% (vs. baseline p = 0.001). AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r= -0.773; p= 0.025). XAF-1407 could prevent P-wave prolongation and AERP shortening. Inducible AF-durations (CTR 0.94 ± 0.34s vs. XAF-1407 0.1 ± 0.09s p = 0.049) were shorter in XAF-1407 treated rats. Drops in oxygen saturation or applied INAP were comparable in control and XAF-1407 rats. Conclusion Short-term simulated OSA is associated with AF-related arrhythmogenic changes, which could be prevented by pharmacological IK,ACh inhibition. Moreover, the cumulative negative airway pressure applied determined aERP shortening and may represent a target for OSA treatment. These findings have important implications for the antiarrhythmic management of AF patients with OSA.

Feasibility study of determining a risk assessment model for obstructive sleep apnea in children based on local findings and clinical indicators

ObjectiveTo test a feasible and reliable model for diagnosing obstructive sleep apnea (OSA) in children, based on the clinically relevant parameters, in comparison to a polysomnography. MethodsA total of 94 children with the suspected underlying OSA were included in the analyses. An association between clinical parameters (modified Mallampati score, tonsil size, adenoid size, age, gender, and body mass index) and apnea-hypopnea index (AHI) obtained following an overnight polysomnography was assessed, and significant variables were incorporated in the logistic regression model. Also, the sensitivity and specificity calculations of the model with the inclusion of ROC curve analysis were performed. ResultsAll tee local clinical parameters were significantly associated with AHI (P < 0.001). The most significant correlation with AHI was shown with the modified Mallampati score (r = 0.723), following with tonsil size (r = 0.673), and adenoid size (r = 0.502). The sensitivity of the tested model was 84%, and specificity was 74%. ConclusionThis study derived a model based on the local clinical findings that significantly overlapped with the results of an overnight polysomnography, in diagnosing OSA in children.

Loss of excitatory amino acid transporter restraint following chronic intermittent hypoxia contributes to synaptic alterations in nucleus tractus solitarii.

Peripheral viscerosensory afferent signals are transmitted to the nucleus tractus solitarii (nTS) via release of glutamate. Following release, glutamate is removed from the extrasynaptic and synaptic cleft via excitatory amino acid transporters (EAATs), thus limiting glutamate receptor activation or over activation, and maintaining its working range. We have shown that EAAT block with the antagonist threo-β-benzyloxyaspartic acid (TBOA) depolarized nTS neurons and increased spontaneous excitatory postsynaptic current (sEPSC) frequency yet reduced the amplitude of afferent (TS)-evoked EPSCs (TS-EPSCs). Interestingly, chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea (OSA), produces similar synaptic responses as EAAT block. We hypothesized EAAT expression or function are downregulated after CIH, and this reduction in glutamate removal contributes to the observed neurophysiological responses. To test this hypothesis, we used brain slice electrophysiology and imaging of glutamate release and TS-afferent Ca2+ to compare nTS properties of rats exposed to 10 days of normoxia (Norm; 21%O2) or CIH. Results show that EAAT blockade with (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]-amino]phenyl]methoxy]-l-aspartic acid (TFB-TBOA) in Norm caused neuronal depolarization, generation of an inward current, and increased spontaneous synaptic activity. The latter augmentation was eliminated by inclusion of tetrodotoxin in the perfusate. TS stimulation during TFB-TBOA also elevated extracellular glutamate and decreased presynaptic Ca2+ and TS-EPSC amplitude. In CIH, the effects of EAAT block are eliminated or attenuated. CIH reduced EAAT expression in nTS, which may contribute to the attenuated function seen in this condition. Therefore, CIH reduces EAAT influence on synaptic and neuronal activity, which may lead to the physiological consequences seen in OSA and CIH.NEW & NOTEWORTHY Removal of excitatory amino acid transporter (EAAT) restraint increases spontaneous synaptic activity yet decreases afferent [tractus solitarius (TS)]-driven excitatory postsynaptic current (EPSC) amplitude. In the chronic intermittent hypoxia model of obstructive sleep apnea, this restraint is lost due to reduction in EAAT expression and function. Thus EAATs are important in controlling elevated glutamatergic signaling, and loss of such control results in maladaptive synaptic signaling.

Obesity, sleep apnea, and cancer.

The interest on a potential association between cancer and sleep-disordered breathing (SDB) has clearly gained substantial traction over the last several years. This novel relationship was initially explored in experimental models of obstructive sleep apnea (OSA) and showed that both intermittent hypoxia and sleep fragmentation, the two main hallmarks of OSA, promoted alterations in both tumorigenesis and tumor malignant properties. In parallel, an intriguing role of obesity as a major interactive player in the relationship between cancer and OSA was postulated in the following contextual settings: (1) obesity (with or without OSA) is associated with increased risk of some types of cancer (both incidence and aggressiveness), whereas obesity could be protective for others ("obesity paradox"); (2) OSA has been associated with increased risk for some types of cancer (independent of obesity), but not with others; (3) More than 80% of adult patients with OSA are overweight and >50% are obese; (4) both OSA and obesity exhibit oscillations in tissue oxygen tensions in peripheral organs such as adipose tissues. Further understanding these complex relationships become all the more important considering that the prevalence of obesity, cancer and OSA are all increasing worldwide. In parallel, experimental models of OSA provide biological plausibility constructs to the clinical and epidemiological findings, suggesting that the metabolic and inflammatory changes induced by chronic intermittent hypoxia and sleep fragmentation may foster or exacerbate immune and biomechanical alterations of the tumor microenvironment, including the expression of extracellular matrix components facilitating tumor progression.

Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1β expression via HIF1 transcriptional activity.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed to examine the effects of long noncoding RNA CPS1 intronic transcript 1 (CPS1-IT) on PAH in rat models of obstructive sleep apnea (OSA) through regulating interleukin (IL)-1β expression. The OSA models were induced in rats, for determination of the CPS1-IT expression. The binding of CPS1-IT and hypoxia-inducible factor 1 (HIF1) was verified. To analyze the effects of CPS1-IT on PAH, the overexpression vector of CPS1-IT and HIF1, shRNA against IL-1β and pyrrolidine dithiocarbamate (PDTC, inhibitor of the NF-κB signaling pathway) were injected into rat models, respectively. The blood pressure and activity of biochemical indicators including nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), and lipid peroxide (LPO) were assessed. The expression of IL-1β, HIF1, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and fibronectin (FN) was determined. The relationship of CPS1-IT to IL-1β and NF-κB was evaluated. CPS1-IT was downregulated in the OSA rat model. Overexpressed CPS1-IT increased the activity of NO, NOS, and SOD as well as α-SMA expression, whereas decreasing LPO activity and expression of PCNA and FN, whereby PAH was suppressed. Notably, overexpressed CPS1-IT reduced IL-1β expression through NF-κB signaling pathway via inhibiting the HIF1 transcriptional activity, suggesting a mechanism affecting PAH. To conclude, overexpressed CPS1-IT alleviated PAH in OSA by reducing IL-1β expression, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway.

0259 Reduction of the Apnea-Hypopnea Duration Ameliorates Endothelial Dysfunction, Vascular Inflammation, and Systemic Hypertension in a Rat Model of Obstructive Sleep Apnea

0259 Reduction of the Apnea-Hypopnea Duration Ameliorates Endothelial Dysfunction, Vascular Inflammation, and Systemic Hypertension in a Rat Model of Obstructive Sleep Apnea

Clinical Prediction Model for Obstructive Sleep Apnea among Adult Patients with Habitual Snoring.

To identify standard clinical parameters that may predict the presence and severity of obstructive sleep apnea/hypopnea syndrome (OSA). Case series with chart review. Tertiary academic medical center. A total of 325 adult patients (274 men and 51 women; mean age, 44.2 years) with habitual snoring completed comprehensive polysomnography and anthropometric measurements, including modified Mallampati grade (also known as updated Friedman's tongue position [uFTP]), tonsil size grading, uvular length, neck circumference, waist circumference, hip circumference, and body mass index (BMI). When the aforementioned physical parameters were correlated singly with the apnea/hypopnea index (AHI), we found that sex, uFTP, tonsil size grading, neck circumference, waist circumference, hip circumference, thyroid-mental distance, and BMI grade were reliable predictors of OSA. When all important factors were considered in a multiple stepwise regression analysis, an estimated AHI can be formulated by factoring sex, uFTP, tonsil size grading, and BMI grade as follows: -43.0 + 14.1 × sex + 12.8 × uFTP + 5.0 × tonsil size + 8.9 × BMI grade. Severity of OSA can be predicted with a receiver operating characteristic curve. Predictors of OSA can be further obtained by the "OSA score." This study has distinguished the correlations between sex, uFTP, tonsil size, and BMI grade and the presence and severity of OSA. An OSA score might be beneficial in identifying patients who should have a full sleep evaluation.

Role of Alpha‐1 Adrenergic Receptors (α1AR) and Norepinephrine Transporter in Parvocellular Neurons of the Hypothalamic Paraventricular Nucleus (PVN) After Chronic Intermittent Hypoxia Exposure

The Paraventricular nucleus (PVN) of the hypothalamus is critical for autonomic homeostasis and cardiorespiratory reflex responses to a variety of stimuli and stressors. This is accomplished, in part, via dense catecholaminergic and norepinephrine (NE) projections from nucleus tractus solitarii (nTS) and ventrolateral medulla (VLM). NE signaling is balanced by the uptake of NE by transporters (NET's) and the activation of one or more adrenergic receptor (AR). Within the PVN, stimulation of aAR's increases the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), decreases the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and depolarizes resting membrane potential (RMP) which elevates blood pressure (BP) and sympathetic outflow. Chronic intermittent hypoxia (CIH) is a model for obstructive sleep apnea (OSA) that elevates respiration, BP, sympathoexcitation and circulating NE levels. CIH activates not only PVN neurons but also the catecholaminergic neurons in the VLM and nTS. However, the contribution of aAR and NET in PVN neurons after CIH exposure remains elusive. In the present work, we determined the electrophysiological properties of PVN parvocellular neurons in response to a1AR activation and NET inhibition after normoxia (Norm) and CIH. Male Sprague‐Dawley rats (110–150g) were exposed to either 10 days normoxia (Norm, FiO2 = 21%) or CIH (alternating FiO2 = 21% and 6%, 8 hr/day). PVN slices (~280 μm) were generated and cell capacitance (Cm), initial input resistance (Rin), and sEPSCs were examined by whole cell patch clamp. sEPSCs were recorded under aCSF baseline or in the presence of one or more of the following: NE (10–100 μM, general AR agonist), phenylephrine (Phe, a1AR agonist, 100 μM), prazosin (a1AR antagonist, 10 μM), or NET inhibitor (desipramine, 100 μM). The Cm of Norm neurons was smaller than CIH, but CIH decreased Rin. Between Norm and CIH, baseline sEPSC frequency and amplitude were similar. Phe and NE significantly increased sEPSC frequency in Norm but not in CIH. Block of the a1AR with prazosin alone did not alter sEPSC frequency or amplitude in Norm (n=10) or CIH (n=6). NE in the presence of prazosin (n=7) prevented the increase in sEPSC frequency in Norm. In Norm (n=5) and CIH (n=6), NET block with desipramine increased sEPSC frequency but did not alter amplitude. However, the magnitude of increase in sEPSC frequency was comparable. These results demonstrate that a1AR activation participate of neuronal responses in Norm, but are minimized in CIH. NET function may be elevated after CIH exposure. The latter may contribute to reduced neuronal responses evoked by Phe after CIH, as well as compensatory mechanism caused by over sympathetic activity.Support or Funding InformationHL 098602 and HL128454This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.