Nocturnal Intermittent Hypoxia Research Articles

Adenotonsillectomy can decrease enuresis and sympathetic nervous activity in children with obstructive sleep apnea syndrome

The nocturnal intermittent hypoxia caused by obstructive sleep apnea syndrome (OSAS) can provoke the sympathetic nervous activity (SNA). Salivary alpha-amylase (sAA) is a sensitive, non-invasive biomarker for reflecting the SNA, and a useful marker for pediatric OSAS subjects. Adenotonsillar hypertrophy (ATH) is the most commonly identified risk factor in OSAS childhood, therefore, several studies showed that the adenotonsillectomy (T&A) may alleviate nocturnal enuresis (NE) in children with OSAS. The present study was to investigate the effect of T&A on NE, the change of sAA value in ATH and OSAS children, with/without NE, and with/without the operation. 37 children (Group A) were admitted for ATH and NE. The saliva samples were taken before and after polysomnography for the measure of sAA. After the T&A, the children were followed-up for 1 year. 35 OSAS children with NE but no T&A were as a NE watchful-waiting group (Group B), 32 subjects without OSAS or NE were as non-OSAS control (Group C), 42 cases who underwent T&A but did not have NE were admitted to evaluate the SNA (Group D). Follow-up included evaluations for NE, sAA and urinary catecholamine after the T&A or at the equivalent time points. The observational results in the present study showed a significant rate of the disappearance of NE 1 month after the T&A and had an almost complete resolution 1 year later. OSAS may irritate oxidative stress and increase SNA in pediatric subjects, which reflected by increased levels of sAA and urinary catecholamine, while the T&A can decrease enuresis and the SNA in children with OSAS (Figure). Little research has previously focused on the relationship between childhood OSAS and the SNA. No data are currently available regarding comparisons of sAA levels before and after the T&A in children with OSAS and enuresis. Our findings in this present study showed that there was a resolution or decrease in enuresis events and drops in sAA levels following T&A, which were consistent with earlier study. However, there was no significant difference in the urinary catecholamine levels was found between OSAS groups with or without NE. Furthermore, there was no correlation between the urinary catecholamine and polysomnography parameters. T&A has a favorable therapeutic effect on NE and may decrease SNA in children with OSAS. sAA might be associated with instability of ANS by OSAS and have a consistent relationship with the apnea-hypopnea index. Our studying aims had been met.

Nocturnal intermittent hypoxia and short sleep duration are independently associated with elevated C-reactive protein levels in patients with coronary artery disease

BackgroundSleep-disordered breathing (SDB) or short sleep duration and coronary artery disease (CAD) are related, yet, the prevalence of SDB and short sleep duration as well as their mechanism remain unknown. Enhanced vascular inflammation is also implicated as one of the pathophysiologic mechanisms in CAD. The aims of this study were to evaluate the prevalence of patients with SDB and short sleep duration, and to examine their relationship with serum C-reactive protein (CRP) level in CAD patients. Methods and resultsWe evaluated 161 CAD patients who underwent percutaneous coronary intervention, using nocturnal pulse oximetry, a non-invasive screening method for nocturnal intermittent hypoxia. Based on three percent oxygen desaturation index (3% ODI), the patients were divided into nocturnal intermittent hypoxia (3% ODI ≥ 15; n = 45) and control groups (3% ODI < 15, n = 116). The nocturnal intermittent hypoxia group had higher body mass index and serum CRP level compared with the control group. Short sleep duration (<6 h, n = 45) was also associated with increased CRP level compared with the control group (≥6 h, n = 116). In multiple regression analysis, nocturnal intermittent hypoxia (β = 0.332, 95% confidence interval [CI] 0.102–0.562, P = 0.005) and short sleep duration (β = 0.311, 95% CI 0.097–0.526, P = 0.005) were both independent determinants for log serum CRP level. ConclusionsNocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that both SDB and sleep shortage are associated with enhanced inflammation in CAD patients. SDB and sleep duration may be important modifiable factors in the clinical management of patients with CAD.

Independent Association between Sleep Fragmentation and Dyslipidemia in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is independently associated with dyslipidemia. Previous studies have demonstrated that sleep fragmentation can impair lipid metabolism. The present study aimed to identify whether sleep fragmentation is independently associated with dyslipidemia, in a large-scale, clinic-based consecutive OSA sample. This cross-sectional study was conducted among 2,686 patients who underwent polysomnography (PSG) for suspicion of OSA from January 2008 to January 2013 at the sleep laboratory. Multivariate regression analyses were performed to evaluate the independent associations between the microarousal index (MAI) and lipid profiles adjusting for potential confounders, including metabolic syndrome components and nocturnal intermittent hypoxia. The adjusted odds ratios (ORs) for various types of dyslipidemia according to MAI quartiles, as determined by logistic regression were also evaluated. MAI was found positively associated with low-density lipoprotein cholesterol (LDL-c) but not with total cholesterol (TC), triglyceride (TG) or high-density lipoprotein cholesterol (HDL-c). Furthermore, the adjusted ORs (95% confidence interval) for hyper-LDL cholesterolemia increased across MAI quartiles, as follows: 1 (reference), 1.3 (1.1–1.7), 1.6 (1.2–2.0), and 1.6 (1.2–2.1) (p = 0.001, linear trend). Sleep fragmentation in OSA is independently associated with hyper-LDL cholesterolemia, which may predispose patients with OSA to a higher risk of cardiovascular disease.

Relaxin in Obstructive Sleep Apnea: Relationship with Blood Pressure and Inflammatory Mediators

Background: Obstructive sleep apnea (OSA) is associated with nocturnal intermittent hypoxia, which may be responsible for increased circulating levels of vascular endothelial growth factor (VEGF) and inflammatory mediators, such as metalloproteinases (MMPs), and which contributes to the pathogenesis of systemic hypertension. Why some OSA patients remain normotensive is poorly understood. Relaxin-2, a pregnancy hormone, may sometimes circulate in men and could increase in hypoxic conditions. It exerts a vasodilatory activity and can modulate the release of molecules, such as MMPs and VEGF. Objectives: The objective of this study was to explore if circulating relaxin-2 in male OSA subjects may be related to OSA severity, to circulating levels of MMPs, of their inhibitors (tissue inhibitors of metalloproteinases; TIMPs), and of VEGF, and if it may protect from hypertension. Patients andMethods: Fifty untreated male subjects with suspected OSA were recruited. After nocturnal polysomnography, a morning venous blood sample was withdrawn. Then, 24-hour ambulatory blood pressure (BP) monitoring was performed. Results: The respiratory disturbance index in the sample was 30.4 [interquartile range (IQR) 15.6-55.2]. Relaxin-2 was detectable in 20 subjects. These subjects did not differ in OSA severity or diurnal and nocturnal BP from subjects with undetectable relaxin-2, but they showed lower TIMP-1 (126.8 ± 29.1 vs. 156.9 ± 41.7 pg/ml, respectively; p = 0.007) and a marginally higher MMP-9/TIMP-1 molar ratio [0.58 (IQR 0.23-1.35) vs. 0.25 (IQR 0.15-0.56); p = 0.052]. Conclusions: Relaxin-2 in male subjects was not related to OSA severity, but it was associated with lower TIMP-1. As it was often undetectable, even when BP values were normal, it is unlikely that it plays a role as a major factor protecting from hypertension in OSA.

Role of Oxidative Stress in the Neurocognitive Dysfunction of Obstructive Sleep Apnea Syndrome

Obstructive sleep apnea syndrome (OSAS) is characterized by chronic nocturnal intermittent hypoxia and sleep fragmentations. Neurocognitive dysfunction, a significant and extraordinary complication of OSAS, influences patients' career, family, and social life and reduces quality of life to some extent. Previous researches revealed that repetitive hypoxia and reoxygenation caused mitochondria and endoplasmic reticulum dysfunction, overactivated NADPH oxidase, xanthine oxidase, and uncoupling nitric oxide synthase, induced an imbalance between prooxidants and antioxidants, and then got rise to a series of oxidative stress (OS) responses, such as protein oxidation, lipid peroxidation, and DNA oxidation along with inflammatory reaction. OS in brain could trigger neuron injury especially in the hippocampus and cerebral cortex regions. Those two regions are fairly susceptible to hypoxia and oxidative stress production which could consequently result in cognitive dysfunction. Apart from continuous positive airway pressure (CPAP), antioxidant may be a promising therapeutic method to improve partially reversible neurocognitive function. Understanding the role that OS played in the cognitive deficits is crucial for future research and therapeutic strategy development. In this paper, recent important literature concerning the relationship between oxidative stress and cognitive impairment in OSAS will be summarized and the results can provide a rewarding overview for future breakthrough in this field.

Abstract 17077: Nocturnal Intermittent Hypoxia and Short Sleep Duration were Independently Associated With Elevated C-reactive Protein Level in Patients With Coronary Artery Disease

Introduction: There is growing evidence of a relationship between sleep disorders and cardiovascular diseases including coronary artery disease (CAD). However, the mechanism of these association is not well established. Enhanced vascular inflammation is implicated as a pathophysiologic mechanism in CAD. The aim of this study was to evaluate the relationship among sleep-disordered breathing (SDB), sleep duration, and serum C-reactive protein (CRP) level in patients with CAD. Methods and Results: Consecutive 225 patients with CAD who underwent percutaneous coronary intervention were evaluated. We used a nocturnal pulse oximetry as a non-invasive screening method for nocturnal intermittent hypoxia, a surrogate marker of SDB. Nocturnal intermittent hypoxia was evaluated using 3% oxygen desaturation index (3% ODI) which was the number of oxygen desaturation measurement ≤ 3% per hour, and we divided the patients into nocturnal intermittent hypoxia group (3% ODI≥15; n=64) and control group (3% ODI&lt;15; n=161). Sleep quality was assessed using validated questionnaires (Pittsburgh Sleep Quality Index [PSQI]; 5.3±3.4, sleep duration; 385±83 minutes). Nocturnal intermittent hypoxia group had significantly higher BMI compared with control group, but age, gender, other coronary risk factors, sleep disturbance (PSQI≥8), sleep duration, and angiographic findings did not differ between two groups. Laboratory data showed that serum CRP level was significantly higher in patients with nocturnal intermittent hypoxia (0.15 [0.09-0.33] vs 0.06 [0.02-0.21] mg/dl, p=0.003). Short sleep duration (&lt;6 hours) was also associated with increased CRP level (0.22 [0.04-0.40] vs 0.07 [0.03-0.14] mg/dl, p=0.036). In multiple regression analysis adjusted by age, gender, BMI, and acute coronary syndrome, 3% ODI (β=0.25; p=0.016; 95% CI, 0.153 to 1.475) and short sleep duration (β=0.20; p=0.04; 95% CI, 0.022 to 1.299) were independent determinants for log serum CRP level. Conclusions: Nocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that SDB and sleep duration could be important modifiable factors for the clinical management of patients with CAD.

Abstract 14835: The Prevalence of Sleep Disturbance and Its Strong Impact on Depression Symptom in Patients Hospitalized With Cardiovascular Diseases

Introduction: There is increasing evidence that sleep disturbance significantly contribute to the development of heart disease. However, sleep disturbance often remains unrecognized and untreated because of barrier to its assessment. The aims of this study were to assess the prevalence of sleep disturbance in cardiovascular patients, and examine its related factors including mental status. Methods and Results: A total of 1087 patients (mean age, 65±15 years; 29% female) hospitalized for a spectrum of cardiovascular diseases in Keio University Hospital were enrolled (coronary artery disease n=348, arrhythmia n=459, heart failure n=81, valvular heart disease n=119, and other n=80). We assessed sleep disturbance using the Pittsburgh Sleep Quality Index (PSQI; mean 5.6±3.3). The sleep disturbance was defined as PSQI&gt;7 (n=256 [24%]). We screened sleep-disordered breathing (SDB) using nocturnal pulse oximetry, a non-invasive method for detecting nocturnal intermittent hypoxia. The prevalence of SDB (3% oxygenation desaturation index&gt;15/hour) was higher in patients with sleep disturbance (33% vs 26%, p=0.02). Sleep disturbance was associated with older age, higher BNP and CRP level, and lower eGFR and albumin level (all p&lt;0.05). Sex, BMI, and the prevalence of hypertension or diabetics mellitus did not differ between patients with sleep disturbances and those without. The patients with sleep disturbance had significantly higher depression (Hospital Anxiety and Depression Scale [HADS]-Depression score; 6.4±3.7 vs 3.7±3.2, p&lt;0.001, PHQ-9; 6.8±4.5 vs 2.7±2.9, p&lt;0.001) and anxiety (HADS-anxiety score; 6.2±3.8 vs 3.6±2.9, p&lt;0.001) symptoms. After adjustment for age, sex, and psychological disturbance, sleep disturbance was associated with heart failure (OR=1.81; P=0.027; 95% CI, 1.06-3.06). Multiple regression analysis revealed that depressive symptom was the most powerful factor related to sleep disturbance (OR=1.2; P&lt;0.0001; 95% CI, 1.12-1.33). Conclusions: Given the high prevalence of sleep disturbances and their strong impact on psychological disturbance, increased efforts should be undertaken for their identification and treatment in patients with cardiovascular diseases, especially in the field of heart failure.

Nocturnal Intermittent Hypoxia Is Associated With Left Ventricular Hypertrophy in Middle-Aged Men With Hypertension and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) and left ventricular (LV) hypertrophy are considered to be closely associated. However, the relationship has not yet been fully demonstrated and is hence still controversial. The purpose of this study was to assess in hypertensive male patients the relationship between OSA and cardiac structure using a new index, namely, integrated area of desaturation (IAD), in addition to the apnea-hypopnea index (AHI) that is currently the most frequently used index of sleep-disordered breathing. In our cross-sectional study, 223 hypertensive men younger than 65 years with sleep apnea and normal cardiac function were enrolled. All subjects were evaluated by fully attended polysomnography. Cardiac structure and function were evaluated by echocardiography. LV mass index significantly correlated with IAD (r = 0.203, P < 0.05), but not with AHI. Multivariate linear regression analyses showed that IAD, brain natriuretic peptide (BNP), and age are independent variables affecting the LV mass index (β = 0.262, 0.237, and 0.173, respectively, P < 0.05). IAD was the one and only determinant among the indices of sleep-disordered breathing. Nocturnal intermittent hypoxia defined by IAD may be associated with LV hypertrophy in men with well-controlled hypertension and obstructive sleep apnea.

Audiologic profile of OSAS and simple snoring patients: the effect of chronic nocturnal intermittent hypoxia on auditory function.

The objective of this work was to study the effect of nocturnal intermittent hypoxia on auditory function of simple snoring patients and subjects affected by OSAS; we compared the audiologic profile with the severity of OSAS to detect early signs of cochlear damage. One hundred-sixty patients underwent overnight polysomnography, micro-otoscopy, multi-frequency audiometry, acufenometry, TEOAE recording and d-ROMs test. All subjects were divided in four groups, based on presence/absence of AHI (simple snoring without OSAS, mild OSAS, moderate OSAS, severe OSAS). Sixty (37.5%) patients were not affected by OSAS, 58 (36.25%) presented a mild OSAS, 18 (11.25%) a moderate OSAS and 24 (15%) a severe OSAS; the 57.14% of moderate to severe OSAS suffered from tinnitus with respect to the 31.03% of mild OSAS (P=0.024). A higher percentage (41.66%) of hearing loss was found among individuals with moderate to severe degree of OSAS (P<0.0001). All groups were characterized by a mean hearing threshold<25dB HL for 0.25-3kHz frequencies and a progressive decrease in hearing sensitivity, particularly for 6-16kHz frequencies (P<0.05). The analysis of otoacoustic emissions SNR mean values evidenced a significant difference between simple snoring and severe OSAS individuals for 3 and 4kHz frequencies (P<0.05). d-ROM levels resulted higher in patients with severe OSAS with respect to simple snoring subjects (P=0.004). Our data underline the key role of chronic nocturnal intermittent hypoxia in the development of an early cochlear damage and a more marked high-frequency hearing loss in case of severe OSAS (P<0.05).

Sleep apnea syndrome in endocrine clinics.

Obstructive sleep apnea syndrome (OSAS) is a chronic condition with a high prevalence (up to 7 % of the general population) characterized by frequent episodes of upper airway collapse while sleeping. Left untreated, OSAS can cause severe complications, including systemic hypertension, cardiovascular disease, stroke, and abnormal glucose metabolism. This review aims to summarize the close links between OSAS, endocrinology, and metabolism. In patients with metabolic syndrome, OSAS is an independent risk factor for the onset of type 2 diabetes and a worsening glycemic control. The accumulation of adipose tissue in the neck and limited chest wall dynamics, hypoxia, and local micro-inflammation link visceral obesity closely with OSAS. There is now an abundance of convincing data indicating that promoting lifestyle changes, improving sleep hygiene, and adjusting diet can ameliorate both metabolic syndrome and OSAS, especially in obese patients. The incidence of OSAS in acromegaly is high, though GH treatments seem to be unrelated to the onset of apnea in GH-deficient individuals. Prospective studies have suggested an association between hypertension and OSAS because intermittent nocturnal hypoxia prompts an increase in sympathetic tone, endothelial dysfunction, and vascular inflammation: aldosterone excess may have a pathophysiological role, and some authors have reported that treating OSAS leads to a modest, but significant, reduction in blood pressure.

Neurogenic mechanisms underlying the rapid onset of sympathetic responses to intermittent hypoxia.

Sleep apnea (SA) leads to metabolic abnormalities and cardiovascular dysfunction. Rodent models of nocturnal intermittent hypoxia (IH) are used to mimic arterial hypoxemias that occur during SA. This mini-review focuses on our work examining central nervous system (CNS) mechanisms whereby nocturnal IH results in increased sympathetic nerve discharge (SND) and hypertension (HTN) that persist throughout the 24-h diurnal period. Within the first 1-2 days of IH, arterial pressure (AP) increases even during non-IH periods of the day. Exposure to IH for 7 days biases nucleus tractus solitarius (NTS) neurons receiving arterial chemoreceptor inputs toward increased discharge, providing a substrate for persistent activation of sympathetic outflow. IH HTN is blunted by manipulations that reduce angiotensin II (ANG II) signaling within the forebrain lamina terminalis suggesting that central ANG II supports persistent IH HTN. Inhibition of the hypothalamic paraventricular nucleus (PVN) reduces ongoing SND and acutely lowers AP in IH-conditioned animals. These findings support a role for the PVN, which integrates information ascending from NTS and descending from the lamina terminalis, in sustaining IH HTN. In summary, our findings indicate that IH rapidly and persistently activates a central circuit that includes the NTS, forebrain lamina terminalis, and the PVN. Our working model holds that NTS neuromodulation increases transmission of arterial chemoreceptor inputs, increasing SND via connections with PVN and rostral ventrolateral medulla. Increased circulating ANG II sensed by the lamina terminalis generates yet another excitatory drive to PVN. Together with adaptations intrinsic to the PVN, these responses to IH support rapid onset neurogenic HTN.

Withstanding the obstructive sleep apnea syndrome at the expense of arousal instability, altered cerebral autoregulation and neurocognitive decline.

The present review attempts to put together the available evidence and potential research paradigms at the interface of obstructive sleep apnea syndrome (OSAS), sleep micro- and macrostructure, cerebral vasoreactivity and cognitive neuroscience. Besides the significant health-related consequences of OSAS including hypertension, increased risk of cardio- and cerebrovascular events, notable neurocognitive lapses and excessive daytime somnolence are considered as potential burdens. The intermittent nocturnal hypoxia and hypercapnia which occur in OSAS are known to affect cerebral circulation and result in brain hypoperfusion. Arousal instability is then resulted from altered cyclic alternating patterns (CAPs) reflected in sleep EEG. In chronic state, some pathological loss of gray matter may be resulted from obstructive sleep apnea. This is proposed to be related to an upregulated proinflammatory state which may potentially result in apoptotic cell loss in the brain. On this basis, a pragmatic framework of the possible neural mechanisms which underpin obstructive sleep apnea-related neurocognitive decline has been discussed in this review. In addition, the impact of OSAS on cerebral autoregulation and sleep microstructure has been articulated.

Effect of Nocturnal Intermittent Hypoxia on Left Atrial Appendage Flow Velocity in Atrial Fibrillation

BackgroundThe mechanism underlying the associations of sleep-disordered breathing (SDB) with stroke and atrial fibrillation (AF) is not well established. We explored the relationship between nocturnal intermittent hypoxia, a marker of SDB, and left atrial (LA)/LA appendage (LAA) function among AF patients. MethodsWe evaluated 134 consecutive AF candidates for catheter ablation (age, 59.6 ± 9.4 years; body mass index [BMI], 24.8 ± 3.2; Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc) score, 1.2 ± 1.1, paroxysmal AF, n = 83) using nocturnal pulse oximetry, a noninvasive screening method for nocturnal intermittent hypoxia. Based on 3% oxygen desaturation index (3% ODI), patients were divided into nocturnal intermittent hypoxia (3% ODI > 15; n = 32) and control groups (3% ODI ≤ 15; n = 102). ResultsThe nocturnal intermittent hypoxia group demonstrated significantly higher weight, BMI, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) and CHA2DS2-VASc scores, serum hemoglobin A1c and plasma brain natriuretic peptide levels, LA size, and prevalence of hypertension, vascular disease, and sick sinus syndrome. Echocardiographically, nocturnal intermittent hypoxia was associated with a higher grade of spontaneous echo contrast and low LAA flow velocity. Multiple regression analysis adjusted for type of AF, CHA2DS2-VASc score, BMI, plasma brain natriuretic peptide level, LA size, and rhythm on echocardiography revealed that 3% ODI was a factor independently associated with LAA flow velocity (β = −0.184; 95% confidence interval, −0.818 to −0.006). ConclusionsNocturnal intermittent hypoxia was an independent determinant for low LAA flow velocity in patients with AF, suggesting that the connection between SDB and LAA function might underlie the association of AF with stroke.

The Japanese Government&amp;rsquo;s &amp;ldquo;Good Sleep&amp;rdquo; Challenge: Sleep Guidelines for Health Promotion 2014

Sleep is one of the most important components of lifestyles that are associated with risk of non-communicable diseases (NCDs). For example, it is well known that both short and long durations of sleep are associated with increased risk of cardiovascular disease.1 Some studies have shown that irregular sleep rhythms (eg, those resulting from shift work) is associated with increased risk of cardiovascular disease2 and cancer.3 Poor quality of sleep due to apnea and nocturnal intermittent hypoxia is also recognized as a risk factor for cardiovascular disease.4,5 Therefore, it is crucial to have “good sleep” for the prevention and control of NCDs; however, we have few guidelines for sleep, unlike other lifestyles, such as diet and physical activity. In fact, there is no description related to sleep in the global action plan for the prevention and control of NCDs for 2013–2020.6 At the end of March 2014, the Japanese Heath Service Bureau published “Sleep Guidelines for Health Promotion 2014”7 after thorough discussion by an expert committee for the revision of previous guidelines. First, the expert committee concluded that evidence exists, especially from epidemiological studies with large sample sizes of free-living populations over the last decade, that allows us to understand the effect of sleep on risk of NCDs and focusing on “good sleep” for health. The new guideline has 12 messages on how to improve sleep for health, such as how sleep can reduce risk of NCDs as well as accidents. Although previous guidelines used the phrase “comfortable sleep”, the expert committee concluded that “comfortable sleep” was too subjective an expression and decided not to use this phrase in the new guideline. The present guidelines have messages for three generations (ie, the young, middle-aged, and elderly). For the young generation, such as schoolchildren, the guidelines recommend not staying up late, as this may result in a short duration of sleep.8 The use of smartphones is also likely to delay the time of falling asleep and reduce sleep duration. We warned young persons and their parents, as well as health professionals, of these and other current major causes for inadequate sleep duration. For the working middle-aged generation, the guidelines recommend that workers sleep as long as they can, because persons in the working generation are likely to receive inadequate sleep and justify it as being for work.9 To help workers improve their sleep, we also mention several tips for falling asleep and sleeping deeply. Persons in the elderly generation were encouraged not to make an effort to extend sleep duration if they cannot sleep. Some elderly people get enough sleep but are obsessed with the idea that they could not sleep well, which leads to difficulty falling asleep.10 This message encourages them to have “good sleep” by reducing their obsession. The Japanese Health Service Bureau published the new guideline to be used by health professionals in community workplaces and clinics, but it will also be made available to all residents through the government’s health promotion measures as well as commercial tools. We also requested that all users review their own sleep and use the guidance to improve specific individual sleep issues, because the adequate range of duration and suitable methods vary widely between individuals and generations. The Government of Japan has started a new challenge for health promotion through “good sleep” for the prevention and control of NCDs. In this challenge, we encourage all residents to assess and improve their sleep though “Sleep Guidelines for Health Promotion 2014”.

Obstructive Sleep Apnea, Oxidative Stress, and Cardiovascular Disease: Evidence from Human Studies.

Obstructive sleep apnea (OSA) is a frequent disease mainly affecting obese people and caused by repetitive collapse of the upper airways during sleep. The increased morbidity and mortality of OSA are mainly thought to be the consequence of its adverse effects on cardiovascular (CV) health. In this context, oxidative stress induced by nocturnal intermittent hypoxia has been identified to play a major role. This is suggested by biomarker studies in OSA patients showing excessively generated reactive oxygen species from leukocytes, reduced plasma levels of nitrite and nitrate, increased lipid peroxidation, and reduced antioxidant capacity. Biopsy studies complement these findings by demonstrating reduced endothelial nitric oxide synthase expression and increased nitrotyrosine immunofluorescence in the vasculature of these patients. Furthermore, oxidative stress in OSA correlates with surrogate markers of CV disease such as endothelial function, intima-media thickness, and high blood pressure. Continuous positive airway pressure therapy reverses oxidative stress in OSA. The same may be true for antioxidants; however, more studies are needed to clarify this issue.

Association between inflammation and cognitive function and effects of continuous positive airway pressure treatment in obstructive sleep apnea hypopnea syndrome

To explore the association between serum inflammation levels and cognitive function in patients with obstructive sleep apnea-hypopnea syndromes (OSAHS) and evaluate the effects of continuous positive airway pressure treatment (CPAP) on serum inflammation levels and cognitive function. A total of 139 eligible patients were monitored by overnight polysomnography (PSG) at Sleep Center, Second Affiliated Hospital, Soochow University from June 2011 to April 2013. Based on the results of apnea-hypopnea index (AHI), they were divided into 4 groups of primary snoring (n = 18), mild OSAHS(n = 23), moderate OSAHS (n = 29) and severe OSAHS (n = 69). The questionnaires of Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE) and Epworth Sleepiness Scale (ESS) were administered to assess cognitive function and daytime sleepiness. The serum levels of high-sensitivity C-reactive protein (Hs-CRP), leptin and tumor necrosis factor alpha (TNF-α) were detected to evaluate systemic inflammation. The questionnaire scores, serum levels of Hs-CRP, leptin and TNF-α and PSG parameters were compared among 4 groups. Thirty-three patients in severe OSAHS group (treatment group) with good adherence were evaluated at baseline and after long-time CPAP treatment. Compared to primary snoring group, the serum Hs-CRP ((1.77 ± 1.19) vs (0.92 ± 0.82) mg/L), leptin ((15.21 ± 13.26) vs (6.35 ± 4.51) mmol/L) and TNF-α ((21.04 ± 7.78) vs (10.30 ± 5.23) pmol/L) levels increased significantly in severe OSAHS group (P < 0.05). After adjusting for body mass index (BMI), age and education years, MoCA scores showed negative correlations with serum TNF-α, AHI, oxygen reduction index (ODI) and TS90% (r = -0.266, -0.236, -0.201, -0.18 respectively, all P < 0.05) and positive correlations with minimum oxygen saturation (LSaO(2)) (r = 0.224, P < 0.05). The evaluations of MoCA subdomains further revealed selective reductions in visual space, executive function, attention and delayed memory function. The treatment group with good adherence to > 6-month continuous positive airway pressure (CPAP) treatment and after CPAP treatment, the serum levels of Hs-CRP, TNF-α and leptin improved markedly ((1.20 ± 0.88) vs (2.03 ± 1.58) mg/L, (14.12 ± 4.34) vs (22.74 ± 6.72) pmol/L and (7.37 ± 5.30) vs (13.69 ± 7.17) mmol/L respectively). The scores of MoCA and ESS also improved (27.79 ± 1.69 vs 24.76 ± 2.57, 4.33 ± 3.14 vs 12.61 ± 5.80 respectively) (all P < 0.01). The score of all MoCA subdomains improved after treatment. Cognitive dysfunction and inflammatory reaction are common in OSAHS patients. MoCA scores are correlated significantly with serum level of TNF-α and nocturnal intermittent hypoxia. Systemic inflammation may play an important role in cognitive dysfunction of OSAHS patients. And long-time CPAP treatment can improve systemic inflammatory response and cognitive impairment.

The impact of sleep and hypoxia on the brain: potential mechanisms for the effects of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a chronic, highly prevalent, multisystem disease, which is still largely underdiagnosed. Its most prominent risk factors, obesity and older age, are on the rise, and its prevalence is expected to grow further. The last few years have seen an exponential increase in studies to determine the impact of OSA on the central nervous system. OSA-induced brain injury is now a recognized clinical entity, although its possible dual relationship with several other neuropsychiatric and neurodegenerative disorders is debated. The putative neuromechanisms behind some of the effects of OSA on the central nervous system are discussed in this review, focusing on the nocturnal intermittent hypoxia and sleep fragmentation. Recent preclinical and clinical findings suggest that neurogenic ischemic preconditioning occurs in some OSA patients, and that it may partly explain variability in clinical findings to date. However, the distinct parameters of the interplay between ischemic preconditioning, neuroinflammation, sleep fragmentation and cerebrovascular changes in OSA-induced brain injury are still largely unclear, and more research is required. Early diagnosis and intervention in patients with OSA is of paramount importance. Future clinical studies should utilize multimodal investigative approaches to enable more reliable referencing for the acuity of the pathological process, as well as its reversibility following the treatment.

Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model.

Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses.

Nocturnal Intermittent Hypoxia: Utility for the Evaluation of Severity Sleep Apnea and Cardiovascular Comorbidity

Nocturnal Intermittent Hypoxia: Utility for the Evaluation of Severity Sleep Apnea and Cardiovascular Comorbidity

Relationships between nocturnal intermittent hypoxia, arterial stiffness and cardiovascular risk factors in a community-based population: the Toon health study.

Nocturnal intermittent hypoxia (NIH), a primary marker of obstructive sleep apnea, has increasingly been linked with cardiovascular morbidity and mortality. The purpose of this study was to investigate the association between NIH and arterial stiffness as measured according to the cardio-ankle vascular index (CAVI) based on cardiovascular risk factors in a Japanese community-dwelling population. We conducted a cross-sectional study in Toon city among 684 men and 1,241 women 30-79 years of age. The severity of NIH was defined as mild or moderate-to-severe according to five or 15 events/hour on the 3% oxygen desaturation index (ODI), respectively. Increased arterial stiffness was diagnosed according to a CAVI of ≥9. The number of subjects with no, mild and moderate-to-severe NIH was 1,348 (70%), 451 (23%) and 126 (7%), respectively. Increased arterial stiffness was detected in 21.9% of the participants. The multivariable-adjusted odds ratio (95% CI) of severe NIH related to an increased CAVI in comparison with a 3% ODI of <5 was 1.36 (0.82-2.23). The stratified logistic regression analysis showed that the multivariable-adjusted OR of severe NIH for an increased CAVI was remarkably increased in the individuals with a BMI of ≥25 (OR=2.53, 1.08-5.96; p=0.03). An interaction test showed a trend for an overweight status to be a modifier of the association between OSA and increased arterial stiffness (p=0.05). NIH has a tendency to promote increased arterial stiffness as measured according to the CAVI, especially in overweight subjects.