Mireia Dalmases

Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea

Obstructive sleep apnea (OSA) has recently been associated with an increased risk of cancer incidence and mortality in humans. Experimental data in mice have also shown that intermittent hypoxia similar to that observed in OSA patients enhances tumor growth. The aim of this study was to test the hypothesis that intermittent hypoxia mimicking OSA enhances lung metastasis. A total of 75 C57BL/6J male mice (10-week-old) were subjected to either spontaneous or induced melanoma lung metastasis. Normoxic animals breathed room air and intermittent hypoxic animals were subjected to cycles of 20s of 5% O2 followed by 40s of room air for 6h/day. Spontaneous and induced lung metastases were studied after subcutaneous and intravenous injection of B16F10 melanoma cells, respectively. Compared with normoxia, intermittent hypoxia induced a significant increase in melanoma lung metastasis. These animal model results suggest that intermittent hypoxia could contribute to cancer metastasis in patients with OSA.

A Bayesian cost-effectiveness analysis of a telemedicine-based strategy for the management of sleep apnoea: a multicentre randomised controlled trial

Background Compliance with continuous positive airway pressure (CPAP) therapy is essential in patients with obstructive sleep apnoea (OSA), but adequate control is not always possible. This is clinically important because CPAP can reverse the morbidity and mortality associated with OSA. Telemedicine, with support provided via a web platform and video conferences, could represent a cost-effective alternative to standard care management. Aim To assess the telemedicine impact on treatment compliance, cost-effectiveness and improvement in quality of life (QoL) when compared with traditional face-to-face follow-up. Methods A randomised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with standard face-to-face management. Consecutive OSA patients requiring CPAP treatment, with sufficient internet skills and who agreed to participate, were enrolled. They were followed-up at 1, 3 and 6 months and answered surveys about sleep, CPAP side effects and lifestyle. We compared CPAP compliance, cost-effectiveness and QoL between the beginning and the end of the study. A Bayesian cost-effectiveness analysis with non-informative priors was performed. Results We randomised 139 patients. At 6 months, we found similar levels of CPAP compliance, and improved daytime sleepiness, QoL, side effects and degree of satisfaction in both groups. Despite requiring more visits, the telemedicine group was more cost-effective: costs were lower and differences in effectiveness were not relevant. Conclusions A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as standard hospital-based care in terms of CPAP compliance and symptom improvement, with comparable side effects and satisfaction rates. The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity (indirect costs). Trial register number NCT01716676.

Effect of CPAP on Cognition, Brain Function, and Structure Among Elderly Patients With OSA: A Randomized Pilot Study

BACKGROUND Despite the increasing aging population and the high prevalence of OSA in elderly adults, little is known about cognitive effects of OSA and the effectiveness of CPAP treatment. Therefore, this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment. METHODS This randomized, evaluator-blinded, parallel-group, single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome. Thirty-three patients were assigned to receive either conservative care (CC) or CPAP plus CC for 3 months. At baseline and 3 months after treatment, patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network (DMN) and of cortical thickness. RESULTS Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline. By contrast, after CPAP treatment, patients showed a significant improvement in episodic (between-group difference in change, 7.60; 95% CI, 1.66-13.55; P = .014) and short-term memory (between-group difference in change, 1.06; 95% CI, 0.10-2.01; P = .032) and in executive function (speed of mental processing, 5.74; 95% CI, 1.69-9.79; P = .007; mental flexibility, -47.64; 95% CI, -81.83 to -13.45; P = .008), whereas no changes were observed in the CC group. Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group. No association was seen between cognition and brain functional connectivity changes within the DMN. CONCLUSIONS Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment. Moreover, CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01826032; URL: www.clinicaltrials.gov.

Male fertility is reduced by chronic intermittent hypoxia mimicking sleep apnea in mice.

STUDY OBJECTIVES Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and oxidative stress. However, it is unknown whether intermittent hypoxia mimicking OSA modifies male fertility. We tested the hypothesis that male fertility is reduced by chronic intermittent hypoxia mimicking OSA in a mouse model. DESIGN Case-control comparison in a murine model. SETTING University research laboratory. PARTICIPANTS Eighteen F1 (C57BL/6xCBA) male mice. INTERVENTIONS Mice were subjected to a pattern of periodic hypoxia (20 sec at 5% O2 followed by 40 sec of room air) 6 h/day for 60 days or normoxia. After this period, mice performed a mating trial to determine effective fertility by assessing the number of pregnant females and fetuses. MEASUREMENTS AND RESULTS After euthanasia, oxidative stress in testes was assessed by measuring the expression of glutathione peroxidase 1 (Gpx1) and superoxide dismutase-1 (Sod1) by reverse-transcription polymerase chain reaction. Sperm motility was determined by Integrated Semen Analysis System (ISAS). Intermittent hypoxia significantly increased testicular oxidative stress, showing a reduction in the expression of Gpx1 and Sod1 by 38.9% and 34.4%, respectively, as compared with normoxia (P < 0.05). Progressive sperm motility was significantly reduced from 27.0 ± 6.4% in normoxia to 12.8 ± 1.8% in the intermittent hypoxia group (P = 0.04). The proportion of pregnant females and number of fetuses per mating was significantly lower in the intermittent hypoxia group (0.33 ± 0.10 and 2.45 ± 0.73, respectively) than in normoxic controls (0.72 ± 0.16 and 5.80 ± 1.24, respectively). CONCLUSIONS These results suggest that the intermittent hypoxia associated with obstructive sleep apnea (OSA) could induce fertility reduction in male patients with this sleep breathing disorder.

Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats.

STUDY OBJECTIVES To test the hypotheses that brain oxygen partial pressure (PtO2) in response to obstructive apneas changes with age and that it might lead to different levels of cerebral tissue oxidative stress. DESIGN Prospective controlled animal study. SETTING University laboratory. PARTICIPANTS Sixty-four male Wistar rats: 32 young (3 mo old) and 32 aged (18 mo). INTERVENTIONS Protocol 1: Twenty-four animals were subjected to obstructive apneas (50 apneas/h, lasting 15 sec each) or to sham procedure for 50 min. Protocol 2: Forty rats were subjected to obstructive apneas or sham procedure for 4 h. MEASUREMENTS AND RESULTS Protocol 1: Real-time PtO2 measurements were performed using a fast-response oxygen microelectrode. During successive apneas cerebral cortex PtO2 presented a different pattern in the two age groups; there was a fast increase in young rats, whereas it remained without significant changes between the beginning and the end of the protocol in the aged group. Protocol 2: Brain oxidative stress assessed by lipid peroxidation increased after apneas in young rats (1.34 ± 0.17 nmol/mg of protein) compared to old ones (0.63 ± 0.03 nmol/mg), where a higher expression of antioxidant enzymes was observed. CONCLUSIONS The results suggest that brain oxidative stress in aged rats is lower than in young rats in response to recurrent apneas, mimicking obstructive sleep apnea. This could be due to the different PtO2 response observed between age groups and the increased antioxidant expression in aged rats. CITATION Dalmases M, Torres M, Márquez-Kisinousky L, Almendros I, Planas AM, Embid C, Martínez-Garcia MA, Navajas D, Farré R, Montserrat JM. Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats.

Chronic intermittent hypoxia preserves bone density in a mouse model of sleep apnea.

Very recent clinical research has investigated whether obstructive sleep apnea (OSA) may modulate bone homeostasis but the few data available are conflicting. Here we report novel data obtained in a mouse study specifically designed to determine whether chronic intermittent hypoxia realistically mimicking OSA modifies bone mineral density (BMD). Normal male and female mice and orchidectomized mice (N=10 each group) were subjected to a pattern of high-frequency intermittent hypoxia (20s at 5% and 40s at 21%, 60 cycles/h) for 6h/day. Identical groups breathing room air (normoxia) were the controls. After 32 days of intermittent hypoxia/normoxia the trabecular bone mineral density (BMD) in the peripheral femora were measured by micro-CT scanning. When compared with normoxia (two-way ANOVA), intermittent hypoxia did not significantly modify BMD in the three animal groups tested. Data in this study suggest that the type of intermittent hypoxia characterizing OSA, applied as a single challenge, preserves bone homeostasis.

Early and mid-term effects of obstructive apneas in myocardial injury and inflammation

BACKGROUND Obstructive sleep apnea (OSA) is associated with cardiovascular disorders, but the different comorbidities in OSA patients make it difficult to know their specific effects on the development of cardiovascular injury. The aim of the present study was to investigate whether recurrent obstructive apneas could lead to myocardial injury. METHODS Thirty-six male Sprague-Dawley rats (300-350 g) were either acutely (3 h) or sustainably (5 h/day, for 10 days) subjected to obstructive apneas with a pattern of 15 s each, 60 apneas/h. Corresponding control groups were formed for the acute and sustained models. To assess the induction of systemic inflammation, IL1-β was measured in plasma. Ventricular tissue injury was evaluated by histological techniques (presence of inflammatory cell infiltration, eosin autofluorescence, and detection of apoptosis). RESULTS After 3h of obstructive apneas, a significant increase in IL1-β (64.9±29.6 ng/μl) were observed with respect to the controls (7.3±1.0 ng/μl), but no myocardial injury was present. Conversely to the acute model, the systemic inflammation triggered by obstructive apneas for 10 days was reduced. However, the percentage of area with enhanced eosin autofluorescence and of apoptotic cells (1.83±0.35% and 24.4±1.5%, respectively) was increased when compared to the control group (0.72±0.20% and 5.0±2.8%, respectively). CONCLUSIONS This study suggests that obstructive apneas are a potential source of early systemic and ventricular inflammation and myocardial cell injury after sustained apneas application, which could represent an initial phase in the progression of heart disease associated with OSA.

A New mHealth application to support treatment of sleep apnoea patients.

Introduction Continuous positive airway pressure (CPAP) is the first-choice treatment for obstructive sleep apnoea (OSA), but adherence is frequently suboptimal. Innovative, patient-centred interventions are, therefore, needed to enhance compliance. Due to its low cost and ubiquity, mobile health (mHealth) technology seems particularly suited for this purpose. We endeavoured to develop an mHealth application called “APPnea,” aimed at promoting patient self-monitoring of CPAP treatment. We then assessed the feasibility and acceptability of APPnea in a group of OSA patients. Methods Consecutive OSA patients used APPnea for six weeks. APPnea gave patients daily reminders to answer three questions about their OSA treatment (CPAP use, physical activity, and diet) and prompted them to upload their body weight weekly. Answers were saved to a secure server for further analysis. After completing the study, patients gave their anonymous opinions about APPnea. Results We enrolled 60 patients with OSA receiving CPAP treatment. The mean age was 56 ± 10 years and the apnoea–hypopnea index was 47 ± 25 events/hour. In total, 63% of participants completed the daily questionnaire for more than 66% of the study period. Objective CPAP compliance was generally high (5.3 ± 1.6 hours/night). In a subset of 38 patients naïve to CPAP, those who used APPnea regularly had significantly higher CPAP compliance. Satisfaction levels were high for the majority of users. Conclusion This mHealth intervention is not only feasible but also satisfactory to patients. Although larger randomized trials and cost-effectiveness studies should be performed, this study shows that APPnea could promote participation and improve compliance among patients with OSA, thereby improving outcomes.

Predictors of long-term adherence to continuous positive airway pressure in patients with obstructive sleep apnoea and acute coronary syndrome

Background Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnoea (OSA), but an evaluation of CPAP adherence is rarely carried out among patients with acute coronary syndrome (ACS). The goals of the study are to analyse long-term adherence and identify the predictors of non-compliance with CPAP treatment for patients with non-sleepy OSA and ACS. Methods This is an ancillary study of the ISAACC study, which is a multicentre, prospective, open-label, parallel, randomized, and controlled trial (NCT01335087) in patients with hospital admission for ACS. For the purpose of this study, only non-sleepy patients with moderate or severe OSA and randomized to receive CPAP treatment were analysed (n=357). Non-compliance was defined as CPAP dropout or average cumulative CPAP use of <4 hours/night. Multivariable logistic regression analysis was performed to identify predictors of CPAP adherence. Results Adherence to treatment was 35.3% at 12 months. According to the unadjusted analysis, higher apnoea-hypopnea index (AHI) (P<0.001) and oxygen desaturation index (ODI) (P=0.001) were associated with a lower risk of non-compliance. Multivariable logistic regression analysis showed that high AHI (P=0.0051), high amounts of smoking pack-year (P=0.0170), and long intensive care unit (ICU) stays (P=0.0263) were associated with lower odds of non-compliance. It also showed a significant interaction between ACS history and age (P=0.0131), such that young patients with their first ACS showed significantly lower odds of CPAP non-compliance than patients with recurrent ACS and significantly lower odds of CPAP non-compliance were associated with ageing only in patients with recurrent ACS. Conclusions Protective factors against non-compliance with CPAP treatment in non-sleepy patients with ACS were illness severity (high values of AHI or ICU stay length) or smoking amount. Patients with no previous history of ACS showed lower odds of CPAP non-compliance than patients with a recurrent ACS with younger age.

Assessing sleep health in a European population: Results of the Catalan Health Survey 2015

Objective To describe the overall sleep health of the Catalan population using data from the 2015 Catalan Health Survey and to compare the performance of two sleep health indicators: sleep duration and a 5-dimension sleep scale (SATED). Methods Multistage probability sampling representative of the non-institutionalized population aged 15 or more years, stratified by age, gender and municipality size, was used, excluding nightshift-workers. A total of 4385 surveys were included in the analyses. Associations between sleep health and the number of reported chronic diseases were assessed using non-parametric smoothed splines. Differences in the predictive ability of age-adjusted logistic regression models of self-rated health status were assessed. Multinomial logistic regression models were used to assess SATED determinants. Results Overall mean (SD) sleep duration was 7.18 (1.16) hours; and SATED score 7.91 (2.17) (range 0–10), lower (worse) scores were associated with increasing age and female sex. Alertness and efficiency were the most frequently impaired dimensions across age groups. SATED performed better than sleep duration when assessing self-rated health status (area under the curve = 0.856 vs. 0.798; p-value <0.001), and had a linear relationship with the number of reported chronic diseases, while the sleep duration relationship was u-shaped. Conclusions Sleep health in Catalonia is associated with age and gender. SATED has some advantaged compared to sleep duration assessment, as it relates linearly to health indicators, has a stronger association with self-rated health status, and provides a more comprehensive assessment of sleep health. Therefore, the inclusion of multi-dimensional sleep health assessment tools in national surveys should be considered.