RESUMEN
La apnea obstructiva del sueño (AOS) y el síndrome hipoventilación-obesidad (SHO) son patologías que se encuentran estrechamente asociadas a la obesidad como principal factor de riesgo, hasta un 70% de los pacientes con AOS son obesos. Ambas patologías comparten procesos fisiopatológicos comunes, donde destaca la inflamación sistémica, lo que, sumado a la hipoxia crónica intermitente y la fragmentación del sueño característicos de la AOS, aumenta considerablemente el riesgo de presentar comorbilidades metabólicas como síndrome metabólico, alteraciones en el metabolismo de la glucosa (resistencia a la insulina y diabetes mellitus tipo 2), y hígado graso metabólico. En esta revisión narrativa, se describirán los mecanismos identificados en estas asociaciones, así como la prevalencia y la evidencia sobre el tratamiento de la AOS y del SHO
Obstructive sleep apnea (OSA) and obesity-hypoventilation syndrome (OHS) are pathologies that are closely associated with obesity as the main risk factor, up to 70% of patients with OSA are obese. Both pathologies share common pathophysiological processes, where systemic inflammation stands out, which, added to the intermittent chronic hypoxia and sleep fragmentation characteristic of OSA, considerably increases the risk of presenting metabolic comorbidities such as metabolic syndrome, alterations in the metabolism of the glucose (insulin resistance and type 2 diabetes mellitus), and metabolic fatty liver. In this narrative review, the mechanisms identified in these associations will be described, as well as the prevalence and evidence on the treatment of OSA and OHS
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/epidemiología , Síndrome de Hipoventilación por Obesidad/metabolismo , Síndrome de Hipoventilación por Obesidad/epidemiología , Factores de Riesgo , Apnea Obstructiva del Sueño/terapia , Síndrome Metabólico , Hipoxia/fisiopatologíaRESUMEN
Intermittent hypoxia (IH) is a feature of obstructive sleep apnea (OSA), a condition highly associated with hypertension-related cardiovascular diseases. Repeated episodes of IH contribute to imbalance of angiogenic growth factors in the hypertrophic heart, which is key in the progression of cardiovascular complications. In particular, the interaction between vascular endothelial growth factor (VEGF) and the kallikrein-kinin system (KKS) is essential for promoting angiogenesis. However, researchers have yet to investigate experimental models of IH that reproduce OSA, myocardial angiogenesis, and expression of KKS components. We examined temporal changes in cardiac angiogenesis in a mouse IH model. Adult male C57BI/6 J mice were implanted with Matrigel plugs and subjected to IH for 1-5 weeks with subsequent weekly histological evaluation of vascularization. Expression of VEGF and KKS components was also evaluated. After 3 weeks, in vivo myocardial angiogenesis and capillary density were decreased, accompanied by a late increase of VEGF and its type 2 receptor. Furthermore, IH increased left ventricular myocardium expression of the B2 bradykinin receptor, while reducing mRNA levels of B1 receptor. These results suggest that in IH, an unexpected response of the VEGF and KKS systems could explain the reduced capillary density and impaired angiogenesis in the hypoxic heart, with potential implications in hypertrophic heart malfunction.
Asunto(s)
Cardiomegalia/metabolismo , Hipoxia/metabolismo , Cininas/metabolismo , Miocardio/metabolismo , Neovascularización Fisiológica , Apnea Obstructiva del Sueño/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Capilares/metabolismo , Capilares/fisiología , Cardiomegalia/complicaciones , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiología , Hipoxia/complicaciones , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Bradiquinina/genética , Receptores de Bradiquinina/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Moderate and severe obstructive sleep apnea (OSA) have been independently associated with dyslipidemia. The results of metabolic improvement with continuous positive airway pressure (CPAP) have been controversial. Less evidence exists regarding this issue in mild OSA. A current treatment for mild OSA is mandibular advancement device (MAD) therapy, but its effectiveness on the metabolic profile needs to be compared with CPAP. The purpose of this study was to compare MAD vs CPAP vs no treatment on the metabolic profile during 6 and 12 months of follow-up in patients with mild OSA. METHODS: The inclusion criteria were patients with mild OSA, both genders, ages 18 to 65 years, and body mass index (BMI) of < 35 Kg/m2. Patients were randomized in 3 groups (CPAP, MAD, and control). The evaluations included physical examination, metabolic profile, and full polysomnography at baseline, 6 months, and 12 months of follow-up. RESULTS: Seventy-nine patients with mild OSA were randomized in three treatment groups, with mean age (± SD) of 47 ± 9 years, 54% men, and AHI 9.5 ± 2.9 events/h. MAD and CPAP reduced AHI at 6 and 12 months compared to the control group. MAD adherence was higher than CPAP at 6 and 12 months. Despite lower adherence compared to MAD, CPAP was more effective in reducing total cholesterol over 12 months (baseline 189.3 ± 60.2 mg/dl to 173.4 ± 74.3 mg/dl) and low-density lipoprotein cholesterol (LDL-c, baseline 112.8 ± 54.9 mg/dl to 94.5 ± 67.4 mg/dl). CONCLUSIONS: After 1 year of treatment, CPAP was superior to MAD in reducing total cholesterol and LDL-c in patients with mild OSA.
Asunto(s)
Presión de las Vías Aéreas Positiva Contínua , Avance Mandibular , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/terapia , Adolescente , Adulto , Anciano , Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Ferulas Oclusales , Gravedad del Paciente , Polisomnografía , Resultado del Tratamiento , Adulto JovenRESUMEN
Obstructive sleep apnea (OSA) is a common clinical condition associated with increased cardiovascular morbidity and mortality. Recent evidence from clinical studies and animal models suggest that OSA can promote cardiovascular disease by inducing autonomic, hemodynamic, inflammatory and metabolic dysregulation. However, most of the evidence addressing hard endpoints in humans is derived from observational studies. Several challenges have been noted in the pursuit of a comprehensive knowledge base about the impact of OSA including: 1) the precise mechanisms by which OSA causes metabolic and cardiovascular consequences are not clear, which limits our current ability to address potential targets in OSA; 2) several patients with OSA, even with severe forms, present with no or mild daytime symptoms. Beyond the obvious challenges for obtaining good adherence for conventional OSA treatments, there is evidence that symptomatic vs. asymptomatic patients with OSA do not necessarily have the same metabolic and cardiovascular outcomes; and 3) the cardiovascular response to OSA treatment may vary even in those patients with good adherence. In this scenario, there is an obvious need to develop biomarkers in the OSA research area. This review focuses on describing the advances that have occurred so far in exploring potential OSA biomarkers with clear emphasis for the cardiovascular risk. Particular attention will be devoted to discuss molecular biomarkers including the potential role of microRNAs, proteomics and metabolomics. We also discuss the major challenges and perspectives in this growing research field.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Metaboloma , Proteoma , Apnea Obstructiva del Sueño/complicaciones , Transcriptoma , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Perfilación de la Expresión Génica , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Metabolómica , Valor Predictivo de las Pruebas , Proteómica , Medición de Riesgo , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/metabolismoRESUMEN
BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated to intermittent hypoxia (IH) and is an aggravating factor of non-alcoholic fatty liver disease (NAFLD). We investigated the effects of hypoxia in both in vitro and in vivo models of NAFLD. METHODS: Primary rat hepatocytes treated with free fatty acids (FFA) were subjected to chemically induced hypoxia (CH) using the hypoxia-inducible factor-1 alpha (HIF-1α) stabilizer cobalt chloride (CoCl2). Triglyceride (TG) content, mitochondrial superoxide production, cell death rates, cytokine and inflammasome components gene expression and protein levels of cleaved caspase-1 were assessed. Also, Kupffer cells (KC) were treated with conditioned medium (CM) and extracellular vehicles (EVs) from hypoxic fat-laden hepatic cells. The choline deficient L-amino acid defined (CDAA)-feeding model used to assess the effects of IH on experimental NAFLD in vivo. RESULTS: Hypoxia induced HIF-1α in cells and animals. Hepatocytes exposed to FFA and CoCl2 exhibited increased TG content and higher cell death rates as well as increased mitochondrial superoxide production and mRNA levels of pro-inflammatory cytokines and of inflammasome-components interleukin-1ß, NLRP3 and ASC. Protein levels of cleaved caspase-1 increased in CH-exposed hepatocytes. CM and EVs from hypoxic fat-laden hepatic cells evoked a pro-inflammatory phenotype in KC. Livers from CDAA-fed mice exposed to IH exhibited increased mRNA levels of pro-inflammatory and inflammasome genes and increased levels of cleaved caspase-1. CONCLUSION: Hypoxia promotes inflammatory signals including inflammasome/caspase-1 activation in fat-laden hepatocytes and contributes to cellular crosstalk with KC by release of EVs. These mechanisms may underlie the aggravating effect of OSAS on NAFLD. [Abstract word count: 257].
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hipoxia/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Apnea Obstructiva del Sueño/genética , Animales , Caspasa 1/genética , Deficiencia de Colina/genética , Deficiencia de Colina/metabolismo , Deficiencia de Colina/patología , Cobalto/toxicidad , Modelos Animales de Enfermedad , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Ácidos Grasos no Esterificados/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hipoxia/inducido químicamente , Hipoxia/metabolismo , Hipoxia/patología , Inflamasomas/genética , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/genética , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Ratas , Apnea Obstructiva del Sueño/etiología , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/patología , Triglicéridos/genéticaRESUMEN
PURPOSE: Obstructive sleep apnea (OSA) is a common condition characterized by repetitive collapse of the upper airways and intermittent oxygen desaturation, which may lead to airway inflammation. Here, we explored whether fractional exhaled nitric oxide (FeNO) levels provide a non-invasive screening tool of OSA. METHODS: Over a 3-month period, FeNO levels were measured in consecutive non-smoking patients referred for a sleep laboratory. All patients underwent full polysomnography. OSA severity was classified based on the apnea/hypopnea index: ≥ 5.0/h as any OSA, ≥ 15.0/h as moderate/severe OSA, and ≥ 30.0/h as severe OSA. FeNO was measured by a portable device (NIOX-MINO®; Aerocrine AB, Solna, Sweden) and expressed as parts per billion (ppb). Discrimination by area under the curve (AUC) and binary logistic regression were performed. RESULTS: A total of 229 subjects were evaluated. Mean FeNO values were similar among subjects without OSA or with OSA: 16.9 ± 10.6 ppb versus 20.2 ± 14.5 ppb, p = 0.221; respectively. FeNO was not an inclusionary parameter to predict any OSA, moderate/severe OSA, and severe OSA: odds ratio (OR) 1.023 (95% confidence interval [CI]: 0.986-1.062); OR 1.012 (95% CI: 0.991-1.034); and OR 0.999 (95% CI: 0.980-1.018), respectively. The AUC values for FeNO in the diagnosis of any OSA, moderate/severe OSA, and severe OSA showed no discriminatory properties: AUC: 0.567 (95% CI: 0.464-0.670), AUC: 0.541 (95% CI: 0.465-0.618), and AUC: 0.535 (95% CI: 0.459-0.610); respectively. CONCLUSIONS: In a sleep-lab setting, our findings suggest that FeNO measurements are inconsequential in the screening of OSA in adults.
Asunto(s)
Pruebas Respiratorias , Espiración , Pulmón/metabolismo , Óxido Nítrico/metabolismo , Apnea Obstructiva del Sueño/diagnóstico , Adulto , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
This study aimed to explore lipoprotein metabolism in obstructive sleep apnea (OSA) and the effects of continuous positive airway pressure (CPAP). We studied 15 men with severe OSA [apnea-hypopnea index (AHI) ≥30 events/hour] and 12 age-, BMI-, and waist circumference-matched volunteers without OSA (AHI <5 events/hour). Carotid intima-media thickness (CIMT) was determined by a blind examiner. After 12 h fasting, a triglyceride-rich chylomicron-like emulsion, labeled with [14C]cholesteryl oleate and [3H]triolein, was injected intravenously followed by blood sample collection at preestablished times. Fractional clearance rate (FCR) of the radiolabeled lipids was estimated by compartmental analysis of radioisotope decay curves. Compared with controls, patients with OSA showed a significant delay in both cholesteryl ester FCR (0.0126 ± 0.0187 vs. 0.0015 ± 0.0025 min-1; P = 0.0313) and triglycerides FCR (0.0334 ± 0.0390 vs. 0.0051 ± 0.0074 min-1; P = 0.0001). CIMT was higher in the OSA group: 620 ± 17 vs. 725 ± 29 µm; P = 0.004. Cholesteryl ester FCRs were inversely related to total sleep time <90% (r = -0.463; P = 0.029) and CIMT (r = -0.601; P = 0.022). The triglyceride FCR was inversely correlated with AHI (r = -0.537; P = 0.04). In a subgroup of patients treated with CPAP for 3 months (n = 7), triglyceride FCR increased 5-fold (P = 0.025), but the cholesteryl ester FCR was unchanged. In conclusion, severe OSA decreased lipolysis of triglyceride-rich lipoproteins and delayed removal of remnants. CPAP treatment may be effective to restore the lipolysis rates.
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Presión de las Vías Aéreas Positiva Contínua , Lipoproteínas/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/terapia , Triglicéridos/metabolismo , Adulto , Femenino , Humanos , Lipólisis , Lipoproteínas/sangre , Masculino , Sueño , Apnea Obstructiva del Sueño/sangre , Triglicéridos/sangreRESUMEN
ABSTRACT Objective To investigate the applicability of predictive equations for resting energy expenditure (REE) in obese individuals with obstructive sleep apnea (OSA) and the effects of OSA severity on REE. Materials and methods Twenty-nine obese men, 41.5 ± 7 years old, with moderate and severe OSA were recruited. All subjects were submitted to a clinical polysomnography, body composition, and indirect calorimetry measurements. REE was also predicted by three different equations: Harris and Benedict (1919), Cunningham (1990), and DRI (2002). Results No effects of OSA severity on REE were found. The measured REE (2416.0 ± 447.1 kcal/day) and the REE predicted by equations were different from each other (F = 2713.88; p < 0.05): Harris and Benedict (2128.0 ± 245.8 kcal/day), Cunningham (1789.1 ± 167.8 kcal/day) and DRI (2011.1 ± 181.4 kcal/day). Pearson correlations showed a moderate positive correlation between the REE measured and predicted by all equations. Conclusion Our findings suggest that predictive equations for REE underestimate the energy expenditure in obese patients with sleep apnea. Also, no effects of OSA severity on REE were found.
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Humanos , Masculino , Adulto , Persona de Mediana Edad , Descanso/fisiología , Algoritmos , Apnea Obstructiva del Sueño/metabolismo , Metabolismo Energético/fisiología , Obesidad/fisiopatología , Obesidad/metabolismo , Valores de Referencia , Factores de Tiempo , Índice de Severidad de la Enfermedad , Composición Corporal/fisiología , Calorimetría Indirecta/métodos , Antropometría , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Análisis de Varianza , Polisomnografía , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
OBJECTIVE: To investigate the applicability of predictive equations for resting energy expenditure (REE) in obese individuals with obstructive sleep apnea (OSA) and the effects of OSA severity on REE. MATERIALS AND METHODS: Twenty-nine obese men, 41.5 ± 7 years old, with moderate and severe OSA were recruited. All subjects were submitted to a clinical polysomnography, body composition, and indirect calorimetry measurements. REE was also predicted by three different equations: Harris and Benedict (1919), Cunningham (1990), and DRI (2002). RESULTS: No effects of OSA severity on REE were found. The measured REE (2416.0 ± 447.1 kcal/day) and the REE predicted by equations were different from each other (F = 2713.88; p < 0.05): Harris and Benedict (2128.0 ± 245.8 kcal/day), Cunningham (1789.1 ± 167.8 kcal/day) and DRI (2011.1 ± 181.4 kcal/day). Pearson correlations showed a moderate positive correlation between the REE measured and predicted by all equations. CONCLUSION: Our findings suggest that predictive equations for REE underestimate the energy expenditure in obese patients with sleep apnea. Also, no effects of OSA severity on REE were found.
Asunto(s)
Algoritmos , Metabolismo Energético/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Descanso/fisiología , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Análisis de Varianza , Antropometría , Composición Corporal/fisiología , Calorimetría Indirecta/métodos , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Valor Predictivo de las Pruebas , Valores de Referencia , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
ABSTRACT INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.
Resumo Introdução: A relação complexa entre os distúrbios do sono e os hormônios pode levar a alterações na produção de cortisol e testosterona em pacientes com Apneia obstrutiva do sono (AOS). Objetivo: O objetivo deste estudo foi determinar as curvas diurnas de testosterona e cortisol livres na saliva e sua proporção (razão T/C). Método: Dez indivíduos recém-diagnosticados com AOS com base na avaliação por polissonografia noturna e sonolência diurna excessiva e sete controles pareados foram recrutados, consecutivamente. Cortisol e testosterona foram medidos em amostras de saliva coletadas ao acordar, ao meio-dia e à noite. A avaliação psicométrica dos distúrbios de ansiedade/depressão e função sexual mencionados foi realizada para detectar a presença de comorbidades neuropsicológicas. Resultados: O achado principal foi que os indivíduos com AOS apresentam hipocortisolismo ao acordar e uma redução significante na concentração de testosterona à noite, em comparação com o grupo controle, que manteve a variação fisiológica diurna de testosterona e cortisol com concentrações hormonais mais elevadas pela manhã e concentrações mais baixas durante a noite. O uso de dados de várias mensurações diurnas, em vez de uma única mensuração, permitiu detectar as alterações na razão T/C de sinais opostos no início e no final do dia: os indivíduos com AOS apresentaram razão T/C maior que os controles na parte da manhã, enquanto que a razão T/C foi significantemente inferior à dos controles durante a noite. Conclusão: Os desequilíbrios no balanço anabólico-catabólico diurno sugerem que a AOS está associada a uma desregulação dos eixos hipotálamo-hipófise-adrenal e hipotálamo-hipófise-gonadal, potencialmente a causa subjacente de algumas das comorbidades neuropsicológicas observadas em pacientes com AOS.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Saliva/química , Testosterona/metabolismo , Hidrocortisona/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Ansiedad/fisiopatología , Ansiedad/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Sistema Hipófiso-Suprarrenal/metabolismo , Índice de Severidad de la Enfermedad , Estudios de Casos y Controles , Estudios Prospectivos , Ritmo Circadiano , Polisomnografía , Apnea Obstructiva del Sueño/fisiopatología , Depresión/fisiopatología , Depresión/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipotálamo-Hipofisario/metabolismo , Disfunción Eréctil/fisiopatología , Disfunción Eréctil/metabolismoRESUMEN
The expression of glucocorticoid receptor-α and -ß (GR-α and GR-ß) in the tonsil tissues of children with and without obstructive sleep apnea hypopnea syndrome (OSAHS) was evaluated. A total of 30 children with OSAHS who underwent tonsillectomy in the Navy General Hospital from June 2012 to June 2014 were enrolled as the experimental group, and 30 non-OSAHS children were enrolled as the control group. The diagnosis of OSAHS was confirmed by preoperative sleep monitoring. The expression of GR-α and GR-ß in tonsil tissues was detected using western blot and immunohistochemical analyses. GR-α and GR-ß were both expressed in the tonsil tissues of OSAHS and non-OSAHS patients. The expression of GR-α in the tonsil tissues of OSAHS children was significantly lower than that in the tonsil tissues of non-OSAHS children, while the expression of GR-ß in the tonsil tissues was similar between the two groups of children. Since it has been reported that GR-α expression is correlated to glucocorticoid therapy sensitivity, the sensitivity of children with OSAHS to glucocorticoid treatment may be lower than that in children who do not have OSAHS. However, the function of GR in children with OSAHS still requires further investigation.
Asunto(s)
Tonsila Palatina/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Adolescente , Niño , Preescolar , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunohistoquímica , Masculino , Tonsila Palatina/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Apnea Obstructiva del Sueño/tratamiento farmacológicoRESUMEN
INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.
Asunto(s)
Hidrocortisona/metabolismo , Saliva/química , Apnea Obstructiva del Sueño/metabolismo , Testosterona/metabolismo , Adulto , Ansiedad/metabolismo , Ansiedad/fisiopatología , Estudios de Casos y Controles , Ritmo Circadiano , Depresión/metabolismo , Depresión/fisiopatología , Disfunción Eréctil/metabolismo , Disfunción Eréctil/fisiopatología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Polisomnografía , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
Recent data have indicated that inflammation may have an important correlation with obstructive sleep apnea (OSA). Studies have indicated a relationship between OSA and TNF-α gene polymorphisms. Zinc finger protein 36 (ZFP36) regulates TNF-α mRNAs. However, ZFP36 gene polymorphisms have not been investigated in OSA. Therefore, we conducted the present case-control study to assess whether variances in ZFP36 gene polymorphisms account for differences in TNF-α levels in patients with moderate-to-severe OSA. This case-control study aims to investigate the relationship between genetic variations in the ZFP36 gene and moderate-to-severe OSA. Three common single nucleotide polymorphisms of the ZFP36 gene (rs251864, rs3746083, and rs17879933) were evaluated in a group of patients with moderate-to-severe OSA (N = 408) and in a control group (N = 394) by using TaqMan polymerase chain reaction analysis. The moderate-to-severe OSA group and the control group exhibited significant differences in the distributions of rs251864 and rs17879933 genotypes and alleles (P < 0.05). TNF-α levels were significantly different not only among the three rs251864 genotypes but also between the II genotype and the DD + ID genotypes of rs17879933. However, no significant differences in sleep apnea parameters in the three ZFP36 gene polymorphisms were observed. Logistic regression analyses demonstrated that TNF-α and the three ZFP36 gene polymorphisms were not independently associated with OSA. ZFP36 might be involved in TNF-α regulation. However, ZFP36 gene variants were not independent risk factors for moderate-to-severe OSA.
Asunto(s)
Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , Apnea Obstructiva del Sueño/genética , Tristetraprolina/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Frecuencia de los Genes , Genotipo , Humanos , Inflamación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polisomnografía , ARN Mensajero/metabolismo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Transducción de Señal , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/patología , Tristetraprolina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Obstructive sleep apnea (OSA) has been related to elevation of inflammatory cytokines and development of insulin resistance in morbidly obese (MO) subjects. However, it is still unclear whether the systemic concentration of anti-inflammatory mediators is also affected in MO subjects directly related to the severity of OSA and level of insulin resistance. Normal weight and MO subjects were subjected to overnight polysomnography in order to establish the severity of OSA, according to the apnea-hypopnea index (AHI). Blood samples were obtained for estimation of total cholesterol and triglycerides, insulin, glucose, insulin resistance, tumor necrosis factor alpha (TNF-α), interleukin 12 (IL12), and interleukin 10 (IL-10). Serum levels of IL-10 were significantly lower in MO subjects with OSA than in MO and control individuals without OSA. Besides being inversely associated with serum TNF-α and IL-12, decreased IL-10 levels were significantly related to increased AHI, hyperinsulinemia, and insulin resistance. Serum IL-10 is significantly reduced in morbidly obese subjects with severe OSA while also showing a clear relationship with a state of hyperinsulinemia and insulin resistance probably regardless of obesity in the present sample. It may be of potential clinical interest to identify the stimulatory mechanisms of IL-10 in obese individuals with OSA.
Asunto(s)
Regulación de la Expresión Génica , Resistencia a la Insulina , Interleucina-10/sangre , Obesidad Mórbida/inmunología , Apnea Obstructiva del Sueño/metabolismo , Adulto , Antropometría , Índice de Masa Corporal , Estudios de Casos y Controles , Colesterol/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Hiperinsulinismo , Insulina/metabolismo , Interleucina-10/metabolismo , Subunidad p35 de la Interleucina-12/metabolismo , Masculino , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , Polisomnografía , Síndromes de la Apnea del Sueño/metabolismo , Encuestas y Cuestionarios , Triglicéridos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. METHODS: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. RESULTS: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic ß-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and ß-cell staining for insulin and glucagon. CONCLUSIONS: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted.
Asunto(s)
Hipoxia/metabolismo , Canales Iónicos/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas Mitocondriales/metabolismo , ARN Mensajero/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Animales , Modelos Animales de Enfermedad , Hipoxia/fisiopatología , Resistencia a la Insulina , Canales Iónicos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Mitocondriales/genética , Apnea Obstructiva del Sueño/fisiopatología , Proteína Desacopladora 2RESUMEN
Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic β-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. .
Objetivo: Investigar o efeito da hipóxia intermitente com um modelo de apneia obstrutiva do sono (AOS) sobre a expressão de uncoupling protein-2 (UCP2), assim como sobre perfis glicêmicos e lipídicos, em camundongos C57BL. Métodos: Camundongos C57BL machos foram expostos a hipóxia intermitente ou hipóxia simulada (grupo controle) 8 h/dia durante 35 dias. A condição de hipóxia intermitente envolveu a exposição dos camundongos a uma atmosfera de 92% de N e 8% de CO2 por 30 s, com redução progressiva de fração de O2 inspirado até 8 ± 1%, seguida por exposição a ar ambiente por 30 s e repetições do ciclo (480 ciclos no período experimental de 8 h). Os pâncreas foram dissecados para isolar as ilhotas. Foi realizada PCR em tempo real utilizando o método TaqMan. Resultados: A expressão do mRNA da UCP2 nas ilhotas pancreáticas foi 20% maior no grupo controle que no grupo hipóxia (p = 0,11). A insulina sérica de jejum foi maior no grupo hipóxia do que no grupo controle (p = 0,01). O modelo de avaliação da homeostase de resistência à insulina indicou que, em comparação com os camundongos controle, aqueles expostos à hipóxia intermitente apresentaram 15% menor resistência à insulina (p = 0,09) e 21% maior função das células beta (p = 0,01). A coloração das ilhotas pancreáticas por imuno-histoquímica não mostrou diferenças significativas entre os grupos em termos da área ou da intensidade das células alfa e beta, marcadas por insulina e glucagon. Conclusões: Segundo nosso conhecimento, esta é a primeira descrição do efeito da hipóxia intermitente sobre a expressão da UCP2. Nossos achados sugerem que UCP2 regula a produção de insulina na AOS. Futuras investigações sobre o papel da UCP2 no controle glicêmico em pacientes com AOS são justificadas. .
Asunto(s)
Animales , Masculino , Ratones , Hipoxia/metabolismo , Canales Iónicos/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas Mitocondriales/metabolismo , ARN Mensajero/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Hipoxia/fisiopatología , Modelos Animales de Enfermedad , Resistencia a la Insulina , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
OBJECTIVE: The purpose of this systematic review is to evaluate the diagnostic value of biological markers (exhaled breath condensate, blood, salivary and urinary) in the diagnosis of OSA in comparison to the gold standard of nocturnal PSG. METHODS: Studies that differentiated OSA from controls based on PSG results, without age restriction, were eligible for inclusion. The sample of selected studies could include studies in obese patients and with known cardiac disease. A detailed individual search strategy for each of the following bibliographic databases was developed: Cochrane, EMBASE, MEDLINE, PubMed, and LILACS. The references cited in these articles were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: After a two-step selection process, nine articles were identified and subjected to qualitative and quantitative analyses. Among them, only one study conducted in children and one in adults found biomarkers that exhibit sufficiently satisfactory diagnostic accuracy that enables application as a diagnostic method for OSA. CONCLUSION: Kallikrein-1, uromodulin, urocotin-3, and orosomucoid-1 when combined have enough accuracy to be an OSA diagnostic test in children. IL-6 and IL-10 plasma levels have potential to be good biomarkers in identifying or excluding the presence of OSA in adults.
Asunto(s)
Apnea Obstructiva del Sueño/metabolismo , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Niño , Preescolar , Femenino , Humanos , Interleucina-10/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Orosomucoide/orina , Polisomnografía , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Calicreínas de Tejido/sangre , Calicreínas de Tejido/orina , Urocortinas/sangre , Urocortinas/orina , Uromodulina/sangre , Uromodulina/orinaRESUMEN
Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular diseases such as systemic arterial hypertension, ischemic heart disease, stroke, heart failure, atrial fibrillation, and cardiac sudden death. The pathogenesis of cardiovascular disease in OSA is thought to be induced primarily by chronic intermittent hypoxia (CIH), a specific pattern of change in oxygenation during sleep. However, the underlying mechanisms of CIH-induced vasculature injury and gender differences are not well documented. The iTRAQ Quantitative Proteomic method enables analysis of a number of different proteins among several groups. Thus, we explored gender differences in protein expression in the vascular walls of mice exposed to CIH. C57BL/6J mice of each gender were exposed to CIH with a fractional inspired O2 (FiO2) nadir of 5% or control, with a treatment time of 8 h/day for 28 days. Differential proteins related to CIH-induced vascular injury between genders were identified using iTRAQ proteomic technology. A total of 163 proteins were identified, of which 34 showed significant differences between genders, which may correlate with vascular injury by CIH. Twenty up-regulated proteins and 14 downregulated proteins were observed in female mice compared with male mice. We identified different vascular proteins expressed under CIH between genders, suggesting that these proteins may be biomarkers of vascular injury by CIH.
Asunto(s)
Aorta Abdominal/metabolismo , Hipoxia/metabolismo , Proteoma , Proteómica , Animales , Aorta Abdominal/lesiones , Aorta Abdominal/patología , Biología Computacional , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Proteómica/métodos , Factores Sexuales , Apnea Obstructiva del Sueño/metabolismoRESUMEN
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.