Mandibular width as a novel anthropometric measure for assessing obstructive sleep apnea risk.

Craniofacial abnormalities are a known obstructive sleep apnea (OSA) risk factor, but still need to be better characterized. This study investigates the relationship between mandibular width and the risk of developing OSA.We retrospectively analyzed 3D reconstructions of head and neck computed tomography (CT) scans at our institution for mandibular width, neck circumference, neck fat volume (NFV), airway volume (AWV), and NFV:AWV ratio. Age, gender, and BMI were also documented. Patients were contacted to complete a STOP-BANG survey to assess OSA risk. Only patients with reconstructable scans and completed STOP-BANG questionnaires were included in the study. Survey results were analyzed to assess the correlation between mandible width and STOP-BANG. Mandible association was also compared to the associations of the other known risk factors.The final analysis included 427 patients with a mean age of 58.98 years (standard deviation = 16.77), 56% of whom were male. Mandibular width was found to positively correlate with STOP-BANG score (r = .416, P < .001). Statistically significant differences between mandible size for each risk group was seen (P < .001). After controlling for age and sex, mandible size was significantly different only for the low risk vs. high risk groups (odds ratio = 1.11; 95% confidence interval = 1.03-1.20; P = .007). Furthermore, when stratified according to mandible size, the small mandible group (<77.50 mm) predominantly consisted of low risk patients; the medium size mandible group (77.50-84.40 mm) was predominated by intermediate risk patients, and large mandible (>84.40 mm) was predominantly seen in high risk patients. Mandible width expressed a stronger association than NFV:AWV ratio, but neck circumference and NFV had stronger associations than did mandible width.In addition to previously documented OSA risk factors, mandibular width is positively correlated with OSA as an independent risk factor. Observation of a wide mandible (jaw) should raise awareness of OSA risk and increase screening methods when appropriate.

Paraoxonase 1 Gene L55M Polymorphism and Paraoxonase 1 Activity in Obstructive Sleep Apnea Patients.

The antioxidant enzyme paraoxonase-1 (PON1) may limit oxidative stress in the development of cardiovascular diseases (CVD) and obstructive sleep apnea (OSA). The aim of the study was to determine PON1 gene L55M polymorphism in OSA-positive and OSA-negative subjects, along with paraoxonase activity of the enzyme (PON1-act). Caucasians aged 25-75, with BMI 19.0-53.0 kg/m2 and no acute or severe chronic disorder underwent polysomnography, and OSA-negative (n = 44) and OSA-positive (n = 57) groups were established. The following parameters were assessed: arterial blood pressure and serum glucose, lipids, C-reactive protein, and homocysteine. Genomic DNA was extracted and amplified, and automatic sequencing was used to confirm the LL, LM, MM genotypes. PON1-act was measured spectrophotometrically using paraoxon as a substrate. We found that frequency of polymorphisms differed significantly between the OSA-negative and OSA-positive patients (p < 0.05). Increased PON1-act was observed in the LL-genotype versus the LM + MM-genotype in the study population (p < 0.05). PON1-act was higher in the OSA-negative compared with OSA-positive patients (p < 0.001); in general and in the subgroups presenting the LL or LM genotype. In addition, there was an inverse relationship between PON1-act and LDL-cholesterol in the entire study population. The OSA-positive group presented an inverse relationship between PON1-act and fasting glucose. We conclude that patients could benefit from the LL genotype related with higher activity of PON1. OSA pathology might decrease the enzyme activity, despite the presence of L allele.

Gamma-glutamyl transferase activity as a predictive marker for severity of obstructive sleep apnea syndrome and concomitant hypertension.

BACKGROUND: Chronic intermittent hypia, inflammation and oxidative stress are involved in resultant obstructive sleep apnea syndrome (OSAS), which may affect numerous regulatory mechanisms that play a role in the regulation of blood pressure. Gamma-glutamyl transferase (GGT) is a novel marker in the prediction of cardiovascular risk. OBJECTIVE: The objective of this study was to investigate the correlation of serum levels of GGT with hypertension and the degree of the upper airway obstruction in subjects with OSAS. METHODS: A total of 270 subjects that met the inclusion criteria were enrolled in the study. The subjects were divided into four separate groups according to the apnea-hypopnea index (AHI) scores as the control group (AHI < 5), mild OSAS group (AHI 5-15), moderate OSAS group (AHI 16-30) and severe OSAS group (AHI >30). A further classification of the OSAS subjects was made in two groups based on the presence of hypertension. RESULTS: The study included 43 control individuals and 59 subjects with mild, 54 subjects with moderate and 114 subjects with severe OSAS. The serum levels of GGT were found to be significantly correlated with OSAS severity (control group: 18 ± 3.3, mild OSAS: 23.6 ± 7.3, moderate OSAS: 26.4 ± 7.5 and severe OSAS: 39.8 ± 12). Serum levels of GGT were found to be significantly higher in OSAS subjects with concomitant hypertension than in the group without associated hypertension (P < .05). The results showed that the adjusted mean GGT under OSA without hypertension (Madj  = 28.76, SE = 0.71) was significantly lower than in cases with OSA with hypertension (Madj  = 42.79, SE = 1.19). CONCLUSION: The present study indicated a strong correlation between high serum levels of GGT and concomitant hypertension in subjects with obstructive sleep apnea. This biomarker may be helpful in grading the severity of obstructive sleep apnea and correlated with hypertension in this population.

Association between obstructive sleep apnea and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

The relationship between obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) has been an issue of great concern. The primary purpose of this study was to determine the influence of OSA on the levels of liver enzymes including alanine transaminase (ALT) and aspartate transaminase (AST). The secondary purpose was to estimate the effect of OSA on the histological lesions of NAFLD, such as steatosis, lobular inflammation, ballooning degeneration, fibrosis, as well as NAFLD activity score (NAS). A systematic literature review using PubMed, Cochrane Library, Embase, and Ovid technologies from January 2007 to April 2017 was performed, and 9 studies (2272 participants) that met the selection criteria were evaluated. The present study demonstrated that OSA was related to ALT levels, but no significant correlation was found with AST levels. The subgroup analysis showed that the severity of OSA was associated with ALT levels, not with AST levels. The meta-regression analysis showed that age, sex, homeostasis model assessment, diabetes mellitus, body mass index, and waist circumference did not have a significant effect on the levels of ALT and AST. OSA was also found to be significantly correlated with steatosis, lobular inflammation, ballooning degeneration, and fibrosis, but was not correlated with NAS. OSA was independently related to the development and progression of NAFLD in terms of liver enzyme level and histological alterations. Future studies should investigate the possible relevant mechanisms, thereby guiding the exploration of potential therapeutic implications to prevent the progression of disease.

Serum heparanase levels are associated with endothelial dysfunction in patients with obstructive sleep apnea.

BACKGROUND AND AIM: Obstructive sleep apnea syndrome (OSAS) is well-known to be associated with high risk for cardiovascular (CV) diseases. Heparanase has been recently shown to be related to increased inflammation and vulnerability of the atherosclerotic plaques. Herein we aimed to investigate the relationships between OSAS, heparanase and endothelial dysfunction. MATERIALS AND METHODS: A total of 120 patients with varying severity of OSAS and 31 controls without OSAS were enrolled. Flow-mediated dilatation (FMD) was measured as an indicator of endothelial dysfunction. Serum heparanase levels were measured with ELISA. RESULTS: Serum heparanase levels increased in a stepwise fashion from controls to patients with more severe OSAS. When FMD was compared with controls and various degrees of severity of OSAS, a stepwise decrease in FMD was observed. Serum heparanase levels were found to be significantly associated with apnea hypopnea index (AHI) (r = .57, P < .001) and FMD (r= -.37, P < .001) in patients with OSAS. Serum heparanase levels were significantly associated with hemoglobin-A1c and body mass index in patients with OSAS. Serum heparanase and uric acid levels were independent predictors of FMD in linear regression analysis (R2 = .506, P < .001; P < .001 and P = .001 respectively). CONCLUSIONS: Serum heparanase levels were significantly increased in patients with OSAS and associated with the severity of OSAS (AHI) and endothelial dysfunction (FMD). Increased heparanase activity in OSAS may be related to increased cardiovascular risk in patients with OSAS.

Treatment of obstructive sleep apnoea-hypopnea syndrome by mandible advanced device reduced neuron apoptosis in frontal cortex of rabbits.

Objective: To investigate effects of mandible advanced device (MAD) therapy for obstructive sleep apnoea-hypopnea syndrome (OSAHS) on the neuron apoptosis and acetylcholine esterase activity in frontal cortex. Materials and methods: Thirty male New Zealand white rabbits were randomly divided into three groups (n = 10 in each group): group OSAHS, group MAD, and control group. Hydrophilic polyacrylamide gel was injected into soft palate of the animals to induce OSAHS in group OSAHS and group MAD. The group MAD animals wore MAD to relief the obstructiveness. The control group was not given any treatment. Computed tomography (CT) examination of the upper airway and polysomnography (PSG) recordings were performed in supine position. All rabbits were induced to sleep in a supine position for 4 to 6 hours every day and were observed for consecutive 8 weeks. The frontal cortices of three groups were dissected and the neuron apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry. Acetylcholine esterase (AchE) activity in the frontal cortex was measured by spectrophotometry. Results: The group OSAHS exhibited high neuron apoptosis rate and low AchE activity than those of group MAD and control group. The blood oxygen saturation was negatively correlated with neuronal apoptosis rate and positively correlated with AchE activity. Applying MAD in OSAHS animals significantly improve the neuronal damage and function deficits by apnoea-hypoxia caused by narrowed upper airway. Conclusion: This study provided evidence that MAD therapy for OSAHS can significantly decrease neuronal apoptosis and increase AchE activity in the frontal cortex.

Effect of continuous positive airway pressure on liver enzymes in obstructive sleep apnea: A meta-analysis.

BACKGROUND: Previous studies have suggested that obstructive sleep apnea (OSA) was associated with nonalcoholic fatty liver disease (NAFLD). However, the impact of OSA treatment using continuous positive airway pressure (CPAP) on liver enzymes remained controversial. This meta-analysis was conducted to determine whether CPAP therapy could reduce liver enzyme levels. METHODS: Two reviewers independently searched PubMed, Cochrane library, Embase and Web of Science before December 2015. Information on characteristics of subjects, study design and pre- and post-CPAP treatment of serum ALT and AST was extracted for analysis. A total of five studies with seven cohorts that included 192 patients were pooled into meta-analysis. RESULTS: CPAP was associated with a statistically significant decrease on both ALT and AST levels in OSA patients (WMD = 8.036, 95% CI = 2.788-13.285, z = 3.00, P = .003 and WMD = 4.612, 95% CI = 0.817-8.407, z = 2.38, P = .017, respectively). Subgroup analyses indicated that CPAP therapy was more effective in OSA patients with treatment duration > 3 mo (WMD = 12.374, 95% CI = 2.727-22.020, z = 2.51, P = .012 for ALT and WMD = 7.576, 95% CI = 1.781-13.370, z =2.56, P = .010 for AST). CONCLUSION: This meta-analysis suggested that CPAP was associated with a statistically significant decrease on liver enzymes in OSA patients. Further large-scale well-designed RCTs with long-term follow-up are required to clarify this issue.

Non-muscular myosin light chain kinase triggers intermittent hypoxia-induced interleukin-6 release, endothelial dysfunction and permeability.

Obstructive sleep apnea is characterized by intermittent hypoxia (IH) which alters endothelial function, induces inflammation and accelerates atherosclerosis-induced cardiovascular diseases. The non-muscular myosin light chain kinase (nmMLCK) isoform contributes to endothelial cell-cell junction opening. Deletion of nmMLCK protects mice from death in septic shock models and prevents atherosclerosis in high-fat diet-fed mice. The aim of the study was to analyze the implication of nmMLCK in IH-induced vascular inflammation. Human aortic endothelial cells were exposed to 6 hours of IH in absence or presence of nmMLCK inhibitors, ML-7 (5 µM) or PIK (150 µM). IH increased reactive oxygen species (ROS) and nitric oxide (NO) production, p65-NFκB activation and IL-6 secretion. While nmMLCK inhibition did not prevent IH-induced ROS production and p65-NFκB activation, it decreased NO production and partially prevented IL-6 secretion. IH-induced IL-6 secretion and vesicle-associated membrane protein-associated vesicles re-organization were inhibited in presence of the inhibitor of protein secretion, brefeldin A, or ML-7. IH increased monocytes transendothelial migration that was partially prevented by ML-7. Finally, IH reduced endothelium-dependent relaxation to acetylcholine of aortas from wild-type but not those taken from nmMLCK-deficient mice. These results suggest that nmMLCK participates to IH-induced endothelial dysfunction resulting from cytokines secretion and endothelial permeability.

Prolyl 4-Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea-Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial-to-Mesenchymal Transition.

BACKGROUND: Intermittent hypoxia (IH) induced by obstructive sleep apnea is the key factor involved in cardiovascular fibrosis. Under persistent hypoxia condition, endothelial cells respond by endothelial-to-mesenchymal transition (EndMT), which is associated with cardiovascular fibrosis. Prolyl 4-hydroxylase domain protein 3 (PHD3) is a cellular oxygen sensor and its expression increased in hypoxia. However, its role in obstructive sleep apnea-induced EndMT and cardiovascular fibrosis is still uncertain. We investigated the potential mechanism of obstructive sleep apnea-induced cardiac perivascular fibrosis and the role of PHD3 in it. METHODS AND RESULTS: In vivo, C56BL/6 mice were exposed to IH for 12 weeks. PHD3 expression was changed by lentivirus-mediated short-hairpin PHD3 and lentivirus carrying PHD3 cDNA. EndMT related protein levels, histological and functional parameters were detected after 12 weeks. In vitro, human umbilical vein endothelial cells were treated with IH/short-hairpin PHD3/lentivirus carrying PHD3 cDNA to explore the mechanism of PHD3 in altered function of human umbilical vein endothelial cells. We found that chronic intermittent hypoxia increase PHD3 expression and EndMT. In vivo, IH accelerate cardiac dysfunction and aggravate collagen deposition via the process of EndMT. And, when PHD3 were overexpressed, cardiac dysfunction and collagen excessive deposition were improved. In vitro, IH induced EndMT, which endow human umbilical vein endothelial cells spindle morphology and an enhanced ability to migration and collagen secretion. PHD3 overexpression in cultured human umbilical vein endothelial cells ameliorated IH-induced EndMT through inactivating hypoxia-inducible factor 1 alpha and small mothers against decapentaplegic 2 and 3. CONCLUSIONS: Obstructive sleep apnea-induced cardiac perivascular fibrosis is associated with EndMT, and PHD3 overexpression might be beneficial in the prevention of it by inhibiting EndMT. PHD3 overexpression might have therapeutic potential in the treatment of the disease.

Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Elevated Lipoprotein-Associated Phospholipase A2 Plasma Activity Levels.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent condition, especially in obese children, and has been associated with increased risk for endothelial dysfunction and dislipidemia, which are precursors of atherosclerosis. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is recognized as an independent risk factor for cardiovascular risk and atheromatous plaque activity. We hypothesized that Lp-PLA2 levels would be elevated in children with OSA, particularly among obese children who also manifest evidence of endothelial dysfunction. METHODS AND RESULTS: One hundred sixty children (mean age 7.1±2.3 years), either nonobese with (n=40) and without OSA (n=40) or obese with (n=40) and without OSA (n=40) underwent overnight polysomnographic and postocclusive reperfusion evaluation and a fasting blood draw the morning after the sleep study. In addition to lipid profile, Lp-PLA2 plasma activity was assessed using a commercial kit. Obese children and OSA children had significantly elevated plasma Lp-PLA2 activity levels compared to controls. Furthermore, when both obesity and OSA were concurrently present or when endothelial function was present, Lp-PLA2 activity was higher. Treatment of OSA by adenotonsillectomy resulted in reductions of Lp-PLA2 activity (n=37; P<0.001). CONCLUSIONS: Lp-PLA2 plasma activity is increased in pediatric OSA and obesity, particularly when endothelial dysfunction is present, and exhibits decreases on OSA treatment. The short-term and long-term significance of these findings in relation to cardiovascular risk remain undefined.

Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia.

Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb /J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

The Relationship Among Oxidative and Anti-Oxidative Parameters and Myeloperoxidase in Subjects With Obstructive Sleep Apnea Syndrome.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder in sleep. It is characterized by intermittent hypoxia leading to hypoxemia, hypercapnia, sleep fragmentation, and increased respiratory efforts. We evaluated the relationship between OSA and myeloperoxidase activity, the oxidative stress index (OSI), total anti-oxidative capacity (TAC), and total oxidative capacity (TOC). METHODS: A total of 70 consecutive subjects (mean age ± SD: 51.7 ± 11.7 y) were diagnosed with OSA after a night polysomnography recording between January 2014 and June 2014 consecutively. The subjects in the OSA group were divided according to the severity of the disease into three subgroups, consisting of 11 mild, 17 moderate OSA, and 22 severe OSA subjects. Twenty subjects with simple snoring were considered as the control group. RESULTS: We included a total of 70 subjects: 50 with OSA (11 subjects 6.9% mild, 17 subjects 24.7% moderate, and 22 subjects 68.5% severe) and 20 subjects with simple snoring as control cases. The mean age of the mild OSA subjects was 44.5 ± 11.7 y, moderate OSA subjects' mean age was 52.5 ± 11.9 y, and severe OSA subjects' mean age was 52.1 ± 10.1 y; 54.2% were male. There were statistically significant differences among the 4 groups' OSI, TAC, and TOC levels, but there was no statistically significant difference between the other values. The mean myeloperoxidase, TOC, OSI, and TAC levels were 55 ± 12, 61.2 ± 21.1, 3.04 ± 1.04, and 2.03 ± 0.4 in the mild OSA group; 58.7 ± 17.2, 60 ± 18.9, 3.05 ± 1, and 2 ± 0.33 in the moderate OSA group; 56.6 ± 17.9, 52.1 ± 17.9, 2.7 ± 0.76, and 1.94 ± 0.24 in the severe OSA group; and 49.8 ± 12.5, 54.3 ± 16.4, 3.08 ± 0.88, and 1.78 ± 0.26 in the control group, respectively. CONCLUSIONS: In our study, there were no differences in studied parameters between control and OSA groups. Furthermore, our low number of cases was a restrictive factor. Further studies should be undertaken to clarify this relation.

Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/re­oxygenation, may impair the cerebral system. Although mitogen­activated protein kinase (MAPK) signaling was observed to have a key role in hypoxia­induced brain injury, the intracellular events and their underlying mechanisms for intermittent hypoxia/re­oxygenation-associated damage to hippocamal MAPKs, including extracellular signal­regulated kinase (ERK)1/2, P38MAPK and c­Jun N­terminal kinase (JNK) remain to be elucidated and require further investigation. A total of five rats in each sub­group were exposed to intermittent hypoxia or continued hypoxia for 2, 4, 6 or 8 weeks. Histological, immunohistochemical and biological analyses were performed to assess nerve cell injury in the hippocampus. Surviving CA1 pyramidal cells were identified by hematoxylin and eosin staining. The levels of phosphorylated ERK1/2, P38MAPK and JNK were detected by western blotting. B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein (Bax) in neural cells were examined by immunohistochemistry. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities were measured by thiobarbituric acid and xanthine oxidation methods, respectively. Under continued hypoxia, the levels of phospho­ERK1/2 peaked at the fourth week and then declined, whereas phospho­P38MAPK and JNK were detected only in the late stages. By contrast, under intermittent hypoxia, ERK1/2, P38MAPK and JNK were activated at all time-points assessed (2, 4, 6 and 8 weeks). The levels of phospho­ERK1/2, P38MAPK and JNK were all higher in the intermittent hypoxia groups than those in the corresponding continued hypoxia groups. Bcl­2 was mainly increased and reached the highest level at six weeks in the continued hypoxia group. Of note, Bcl­2 rapidly increased to the peak level at four weeks, followed by a decrease to the lowest level at the eighth week in the intermittent hypoxia group. Bax was generally increased at the late stages under continued hypoxia, but increased at all time-points under the intermittent hypoxia conditions. The two types of hypoxia induced an increase in the MDA content, but a decrease in SOD activity. Marked changes in these two parameters coupled with markedly reduced surviving cells in the hippocampus in a time­dependent manner were observed in the intermittent hypoxia group in comparison with the continued hypoxia group. OSAS­induced intermittent hypoxia markedly activated the MAPK signaling pathways, which were triggered by oxidative stress, leading to abnormal expression of downstream Bcl­2 and Bax, and a severe loss of neural cells in the hippocampus.

[The meaning of serum myeloperoxidase in obstructive sleep apnea hypopnea syndrome].

Objective:To investigate the clinical significance of detecting peripheral blood myeloperoxidase in OSAHS patients. Method:Sixty cases of OSAHS patients in our hospital was selected as OSAHS group, which was subdivided into light, medium and heavy groups according to the PSG, each with 20 cases, and 20 cases of healthy persons were selected as control group; ELISA method was used to detect the MPO level of peripheral blood. 20 cases of severe OSAHS patients detect MPO level again three months after the fist detection, and analyze the correlation between serum MPO level and indicators of sleep respiratory related events. Result:①The level of peripheral serum MPO level positively correlated with the severity of the patients' condition. The control group, light, medium and heavy groups' serum MPO levels were (7.93±2.44), (10.58±3.31), (18.91±8.37), (29.03±10.06)ng/mg, respectively (F=19.102, P<0.05). ②OSAHS patients' peripheral blood MPO concentration had no correlation with gender, age and BMI, but was positively correlated with AHI and negatively correlated with LSaO2 (P<0.05). ③Twenty cases of severe MPO and AHI patients with OSAHS were decreased and LSaO2 increased, the difference was statistically significant (P<0.05). Conclusion:The detection of serum MPO in patients with OSAHS has important significance in judging the severity of the disease, evaluating the treatment effect and predicting the risk of cardiovascular disease in patients with severe OSAHS.

Elevated Serum Liver Enzymes in Patients with Obstructive Sleep Apnea-hypopnea Syndrome.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAS) is associated with elevated liver enzymes and fatty liver. The purpose of this study was to measure serum liver enzyme levels in patients evaluated by polysomnography (PSG) and the factors associated with liver injury in OSAS patients. METHODS: All patients referred to PSG for evaluation of sleep apnea symptoms between June 2011 and November 2014 were included in this study. Demographic data and PSG parameters were recorded. Serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were systematically measured. OSAS patients were divided into mild, moderate, and severe groups according to the apnea-hypopnea index (AHI) values of 5-14 events/h, 15-29 events/h, and ≥30 events/h. RESULTS: A total of 540 patients were enrolled in this study; among these patients, 386 were male. Elevated liver enzymes were present in 42.3% of OSAS patients (32.4% in mild/moderate group; 51.0% in severe group) and 28.1% patients without OSAS. Patients with OSAS had higher body mass index (BMI) (P < 0.01). In the bivariate correlation, the liver enzymes level was negatively correlated with age and the lowest arterial oxygen saturation (SaO 2 ), and was positively correlated with BMI, oxygen desaturation index, percent of total time with oxygen saturation level <90% (TS90%), AHI, total cholesterol (TC), and triglyceride (TG). In logistic regression analysis, Age, BMI, TS90%, TC, and TG were included in the regression equation. CONCLUSIONS: Our data suggest that OSAS is a risk factor for elevated liver enzymes. The severity of OSAS is correlated with liver enzyme levels; we hypothesize that hypoxia is one of main causes of liver damage in patients with OSAS.

Lack of association of matrix metalloproteinase-9 promoter gene polymorphism in obstructive sleep apnea syndrome.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) is a public health problem. There is an effort to establish the genetic contributions to the development of OSAS. One is matrix metalloproteinases, extracellular matrix degrading enzymes related to systemic inflammation. However, the impact of matrix metalloproteinase-9 (MMP-9) genotypes on the development of OSAS is unknown. Our aim was to determine whether MMP-9 single nucleotide polymorphism (SNP) (MMP-9 -1562C > T) is related to susceptibility to OSAS. MATERIAL AND METHODS: A total of 106 patients with a history of sleep apnea and 88 controls without a history of sleep apnea were enrolled in this study. Genotypes were determined by restriction fragment length polymorphism analyses after polymerase chain reaction. RESULTS: Genotypes and allele frequencies of the MMP-9 -1562C > T SNP was not statistically different between the patient and control groups (p > 0.05). There was a statistical association between apnea-hypopnea index (AHI) and body mass index (BMI), and also between AHI and neck circumference (p < 0.001). There was no association among the genotypes and AHI, neck circumference, or BMI (p > 0.05). CONCLUSIONS: We found no association between MMP-9 -1562C > T SNP and OSAS. Studies to investigate the role of other polymorphisms and expression of MMP-9 gene will provide more information.

Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis. DESIGN: Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia. SETTING: The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School. MEASUREMENTS AND RESULTS: In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion. CONCLUSIONS: The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease.

Increased Carbonic Anhydrase Activity is Associated with Sleep Apnea Severity and Related Hypoxemia.

STUDY OBJECTIVES: The catalytic function of the enzyme carbonic anhydrase (CA) plays a fundamental role in carbon dioxide (CO2), proton (H(+)), and bicarbonate (HCO3(-)) homeostasis. Hypoxia and tissue acidosis have been proposed to increase physiological CA activity in various compartments of the body. We hypothesized that CA activity in blood is upregulated in patients with obstructive sleep apnea (OSA). DESIGN: Cross-sectional analysis of a sleep clinic cohort. SETTINGS: Sleep laboratory at a university hospital. PARTICIPANTS: Seventy referred patients with suspected OSA (48 males, age 54 ± 13 y, apnea-hypopnea index (AHI) median [interquartile range] 21 [8-41] n/h). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In-laboratory cardiorespiratory polygraphy was used to assess OSA. CA activity was determined by an in vitro assay that quantifies the pH change reflecting the conversion of CO2 and H2O to HCO3(-) and H(+). CA activity was positively associated with AHI and 4% oxygen desaturation index (ODI4) (Spearman correlation r = 0.44 and 0.47, both P < 0.001). The associations (CA activity versus logAHI and CA versus logODI4) were independent of sex, age, body mass index, presleep oxygen saturation, nocturnal oxygen saturation, hypertension status, and use of diuretic medication in two generalized linear models (P = 0.007 and 0.011, respectively). Sitting diastolic blood pressure was associated with CA activity after adjustment of sex, age, body mass index, mean oxygen saturation, and AHI (P = 0.046). CONCLUSIONS: Carbonic anhydrase (CA) activity increased with apnea-hypopnea index and related nocturnal hypoxemia measures in patients with obstructive sleep apnea (OSA). Altered CA activity may constitute a component that modulates respiratory control and hemodynamic regulation in patients with OSA.

Gamma glutamyl transferase and oxidative stress in obstructive sleep apnea: a study in 1744 patients.

OBJECTIVE: We analyze a large population of patients to determine whether gamma glutamyl transferase (GGT) levels are increased in sleep apnea-hypopnea syndrome (OSA) and whether these levels are related to clinical characteristics or polygraphic indexes. METHODS: A cross-sectional study in a population of 1744 patients referred for OSA suspicion was conducted. The following variables were determined: glucose, cholesterol, triglycerides, aspartate aminotransferase (GOT), alanine aminotransferase (GPT), GGT, body mass index, waist-hip ratio (WHR), and overnight sleep study. RESULTS: The 483 patients with GGT ≥40 IU/l were younger and more obese, and had a pattern of more centrally distributed fat than the 1261 with GGT <40 IU/l. Patients with high levels of GGT also consumed more alcohol, had a poorer biochemical profile, and had more respiratory and oximetric alterations during sleep. GGT levels were significantly correlated with AHI, DI, and CT90. In the binary regression test, WHR, glucose, cholesterol, triglycerides, and grams of alcohol consumed per day predicted GGT levels ≥40 IU/l, while none of the polygraphic variables had predictive value. CONCLUSIONS: High GGT levels were associated with the severity of OSA. However, this relationship seems to be due to the coexistence of other associated factors, mainly central obesity, rather than to the respiratory disorders found in this disease.

Do salivary and serum collagenases have a role in an association between obstructive sleep apnea syndrome and periodontal disease? A preliminary case-control study.

OBJECTIVES: Despite increasing evidence for an association of obstructive sleep apnea syndrome (OSAS) and periodontal disease, the pathophysiological linking mechanisms remain unclear. This study aims to evaluate the salivary and serum matrix metalloproteinase-2, -8, -9 (MMP-2, -8, -9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), myeloperoxidase (MPO), neutrophil elastase (NE), neutrophil gelatinase-associated lipocalin (NGAL), as well as degree of activation of MMP-2, -9 of patients with and without OSAS. DESIGN: A total of 50 individuals were included in the study. There were 13, 17 and 20 individuals, respectively in the control (non-OSAS) group, mild-to-moderate OSAS and severe OSAS groups. Saliva, serum samples and clinical periodontal parameters were collected. Biofluid samples were analysed by immunofluorometric assay (IFMA), enzyme-linked immunosorbent assay (ELISA), western immunoblotting and gelatine zymography. Statistical analyses were performed using D'Agostino-Pearson omnibus normality test, Kruskal-Wallis test and Spearman rho rank correlation analysis. RESULTS: There were no statistically significant differences in clinical periodontal parameters between the study groups. Salivary NE and proMMP-2 levels were significantly lower in the OSAS groups than the control group (p<0.05). Serum proMMP-9 concentration and the degree of MMP-9 activation in saliva were significantly lower in the severe OSAS group than the control group (p<0.05). There were significant correlations between salivary and serum proMMP-9 and -2 concentrations (p<0.05). Serum proMMP-2, NE and salivary proMMP-9 and -2 negatively correlated with indicators of OSAS severity (p<0.05). CONCLUSIONS: The present findings do not support a pathophysiological link between the severity of OSAS and clinical periodontal status via neutrophil enzymes or MMPs.