Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

BACKGROUND: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP). METHODS: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level. RESULTS: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship. CONCLUSION: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

Obstructive sleep apnoea is related to melanoma aggressiveness through paraspeckle protein-1 upregulation.

BACKGROUND: In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-ß signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the in vitro effects of soluble PSPC1 and intermittent hypoxia on melanoma cell aggressiveness mechanisms were assessed. METHODS: In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-ß were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions. RESULTS: PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-ß expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics. CONCLUSION: In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness.

Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation.

Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non-OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81-61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells.

The Effect of Sleep Apnea on Cardiovascular Events in Different Acute Coronary Syndrome Phenotypes.

Rationale: Obstructive sleep apnea (OSA) is associated with increased cardiovascular disease (CVD) risk. Conversely, OSA has not been shown to increase recurrent cardiovascular events in patients with acute coronary syndrome (ACS). This lack of homogeneity could suggest that the deleterious effect of OSA and its contribution to CVD could depend on specific patient profiles.Objectives: To evaluate the effect of OSA on cardiovascular risk for patients with different ACS phenotypes.Methods:Post hoc analysis of the ISAACC (Continuous Positive Airway Pressure in Patients with ACS and OSA) study, including 1,701 patients admitted for ACS (NCT01335087). To evaluate the presence of OSA (apnea-hypopnea index ≥ 15 events · h-1), all patients underwent polygraphy. Patients were followed up for a minimum period of 1 year. We performed nonsupervised clustering using latent class analysis to identify subgroups of patients on the basis of 12 clinical factors associated with cardiovascular risk. The effect of OSA on recurrent cardiovascular event risk was evaluated for each phenotype identified.Measurements and Main Results: Two phenotypes were identified: patients without previous heart disease and without previous ACS ("no-previous-CVD" phenotype; 81%) and patients with previous heart disease and previous ACS ("previous-CVD" phenotype; 19%). The median (interquartile range) at follow-up was 2.67 (3.8) years. For the no-previous-CVD phenotype, the effect of OSA showed an adjusted hazard ratio (95% confidence interval) of 1.54 (1.06-2.24; P value = 0.02), whereas for the previous-CVD phenotype, the effect of OSA showed an adjusted hazard ratio of 0.69 (0.46-1.04; P value = 0.08).Conclusions: For patients with ACS and a specific phenotype, OSA is associated with an increased risk of recurrent cardiovascular events. These patients are mainly characterized by no previous heart disease and admission for a first ACS occurrence.

SleepPos App: An Automated Smartphone Application for Angle Based High Resolution Sleep Position Monitoring and Treatment.

Poor sleep quality or disturbed sleep is associated with multiple health conditions. Sleep position affects the severity and occurrence of these complications, and positional therapy is one of the less invasive treatments to deal with them. Sleep positions can be self-reported, which is unreliable, or determined by using specific devices, such as polysomnography, polygraphy or cameras, that can be expensive and difficult to employ at home. The aim of this study is to determine how smartphones could be used to monitor and treat sleep position at home. We divided our research into three tasks: (1) develop an Android smartphone application ('SleepPos' app) which monitors angle-based high-resolution sleep position and allows to simultaneously apply positional treatment; (2) test the smartphone application at home coupled with a pulse oximeter; and (3) explore the potential of this tool to detect the positional occurrence of desaturation events. The results show how the 'SleepPos' app successfully determined the sleep position and revealed positional patterns of occurrence of desaturation events. The 'SleepPos' app also succeeded in applying positional therapy and preventing the subjects from sleeping in the supine sleep position. This study demonstrates how smartphones are capable of reliably monitoring high-resolution sleep position and provide useful clinical information about the positional occurrence of desaturation events.

Enhanced Monitoring of Sleep Position in Sleep Apnea Patients: Smartphone Triaxial Accelerometry Compared with Video-Validated Position from Polysomnography.

Poor sleep quality is a risk factor for multiple mental, cardiovascular, and cerebrovascular diseases. Certain sleep positions or excessive position changes can be related to some diseases and poor sleep quality. Nevertheless, sleep position is usually classified into four discrete values: supine, prone, left and right. An increase in sleep position resolution is necessary to better assess sleep position dynamics and to interpret more accurately intermediate sleep positions. This research aims to study the feasibility of smartphones as sleep position monitors by (1) developing algorithms to retrieve the sleep position angle from smartphone accelerometry; (2) monitoring the sleep position angle in patients with obstructive sleep apnea (OSA); (3) comparing the discretized sleep angle versus the four classic sleep positions obtained by the video-validated polysomnography (PSG); and (4) analyzing the presence of positional OSA (pOSA) related to its sleep angle of occurrence. Results from 19 OSA patients reveal that a higher resolution sleep position would help to better diagnose and treat patients with position-dependent diseases such as pOSA. They also show that smartphones are promising mHealth tools for enhanced position monitoring at hospitals and home, as they can provide sleep position with higher resolution than the gold-standard video-validated PSG.

Soluble PD-L1 is a potential biomarker of cutaneous melanoma aggressiveness and metastasis in obstructive sleep apnoea patients.

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects.

Good long-term adherence to continuous positive airway pressure therapy in patients with resistant hypertension and sleep apnea.

Although adequate adherence is paramount in achieving the beneficial effects of continuous positive airway pressure therapy in patients with obstructive sleep apnea, long-term adherence and the variables involved in continuous positive airway pressure compliance in patients with resistant hypertension and obstructive sleep apnea are yet unknown. We conducted a prospective, multicentre, observational study in 177 patients recruited from hypertensive units with resistant hypertension confirmed by means of 24-hr blood pressure monitoring (blood pressure ≥ 130 and/or ≥ 80 mmHg, despite taking at least three antihypertensive drugs or < 130/80 mmHg with > 3 drugs) and obstructive sleep apnea (apnea-hypopnea index ≥ 5 in a respiratory polygraph) who were prescribed continuous positive airway pressure treatment. Good adherence was defined as an average cumulative continuous positive airway pressure use of ≥ 4 hr per night at the end of the follow-up. A multivariate Cox regression analysis was performed to identify independent predictors of continuous positive airway pressure adherence. Patients were followed for a median of 57.6 (42-72) months after initiating continuous positive airway pressure therapy. At the end of the follow-up, the median continuous positive airway pressure use was 5.7 (inter-quartile range 3.9-6.6) hr per night, and 132 patients (74.5%) showed good continuous positive airway pressure adherence. The only baseline variable associated with poor adherence was the presence of previous stroke (hazard ratio 4.00, 95% confidence interval 1.92-8.31). Adequate adherence at 1 month also predicted good adherence at the end of the follow-up (hazard ratio 14.4, 95% confidence interval 4.94-56). Both variables also predicted adherence at a threshold of 6 hr per night. Our results show that good continuous positive airway pressure adherence is an achievable and feasible goal in patients with resistant hypertension and obstructive sleep apnea. Previous stroke and short-term adherence predicted long-term adherence.

A randomized controlled trial: branched-chain amino acid levels and glucose metabolism in patients with obesity and sleep apnea.

There is evidence that changes in branched-chain amino acid (BCAA) levels may correlate with the efficacy of therapeutic interventions for affecting improvement in metabolic control. The objective of this study was to evaluate whether serum concentrations of BCAAs (leucine, isoleucine, valine) could mediate in insulin sensitivity and glucose tolerance after continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnea (OSA). A prospective randomized controlled trial of OSA patients with morbid obesity was conducted. Eighty patients were randomized into two groups: 38 received conservative treatment and 42 received CPAP treatment for 12 weeks. Plasma levels of BCAA, glucose tolerance and insulin resistance were evaluated at baseline and after treatment. After treatment, significant decreases of leucine levels were observed in both groups when compared with baseline levels (P < 0.005). With respect to patients with normal glucose tolerance (NGT), patients with impaired glucose tolerance (IGT) had higher baseline levels of isoleucine (78 ± 16 versus 70 ± 13 µmol L-1 , P = 0.014) and valine (286 ± 36 versus 268 ± 41 µmol L-1 , P = 0.049), respectively. Changes in levels of leucine and isoleucine after treatment were related negatively to changes in fasting plasma glucose and glycosylated haemoglobin values only in the conservative group (P < 0.05). In summary, we found that the treatment with CPAP for 12 weeks caused similar changes in circulating BCAAs concentrations to conservative treatment and a differential metabolic response of CPAP and conservative treatment was observed between the relationship of BCAAs and glucose homeostasis. Additional studies are needed to determine the interplay between branched-chain amino acids and glucose metabolism in patients with sleep apnea.

Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study.

AIMS: The role of high-intensity exercise and other emerging risk factors in lone atrial fibrillation (Ln-AF) epidemiology is still under debate. The aim of this study was to analyse the contribution of each of the emerging risk factors and the impact of physical activity dose in patients with Ln-AF. METHODS AND RESULTS: Patients with Ln-AF and age- and sex-matched healthy controls were included in a 2:1 prospective case-control study. We obtained clinical and anthropometric data transthoracic echocardiography, lifetime physical activity questionnaire, 24-h ambulatory blood pressure monitoring, Berlin questionnaire score, and, in patients at high risk for obstructive sleep apnoea (OSA) syndrome, a polysomnography. A total of 115 cases and 57 controls were enrolled. Conditional logistic regression analysis associated height [odds ratio (OR) 1.06 [1.01-1.11]], waist circumference (OR 1.06 [1.02-1.11]), OSA (OR 5.04 [1.44-17.45]), and 2000 or more hours of cumulative high-intensity endurance training to a higher AF risk. Our data indicated a U-shaped association between the extent of high-intensity training and AF risk. The risk of AF increased with an accumulated lifetime endurance sport activity ≥ 2,000 h compared with sedentary individuals (OR 3.88 [1.55-9.73]). Nevertheless, a history of <2000 h of high-intensity training protected against AF when compared with sedentary individuals (OR 0.38 [0.12-0.98]). CONCLUSION: A history of ≥ 2,000 h of vigorous endurance training, tall stature, abdominal obesity, and OSA are frequently encountered as risk factors in patients with Ln-AF. Fewer than 2000 total hours of high-intensity endurance training associates with reduced Ln-AF risk.

Obstructive sleep apnoea in the elderly: role of continuous positive airway pressure treatment.

Almost all the information about the effect of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnoea (OSA) comes from clinical trials involving only middle-aged patients. The objective of this study was to assess the effect of CPAP treatment in elderly patients with severe OSA on clinical, quality-of-life and neurocognitive spheres. We performed an open-label, randomised, multicentre clinical trial in a consecutive clinical cohort of 224 elderly (≥70 years old) patients with confirmed severe OSA (apnoea-hypopnea index ≥30) randomised to receive CPAP (n=115) or no CPAP (n=109) for 3 months. A sleep study was performed by either full polysomnography or respiratory polygraphy. CPAP titration was performed by an autoCPAP device. The primary endpoint was quality of life (Quebec Sleep Questionnaire) and secondary endpoints included sleep-related symptoms, presence of anxiety/depression, office-based blood pressure and some neurocognitive tests. The mean±sd age was 75.5±3.9 years. The CPAP group achieved a greater improvement in all quality-of-life domains (p<0.001; effect size: 0.41-0.98), sleep-related symptoms (p<0.001; effect size 0.31-0.91) as well as anxiety (p=0.016; effect size 0.51) and depression (p<0.001; effect size: 0.28) indexes and some neurocognitive tests (digit symbol test (p=0.047; effect size: 0.20) and Trail Making Test A (p=0.029; effect size: 0.44)) in an intention-to-treat analysis. In conclusion, CPAP treatment resulted in an improvement in quality of life, sleep-related symptoms, anxiety and depression indexes and some neurocognitive aspects in elderly people with severe OSA.

Association between sleep disordered breathing and aggressiveness markers of malignant cutaneous melanoma.

Some recent studies have shown an association between sleep disordered breathing (SDB) and cancer mortality and incidence but no study has focused on a specific type of cancer. The objective of this study was to analyse the relationship between the severity of SDB and factors related to cutaneous malignant melanoma (CMM) aggressiveness. We performed a multicentre observational study in 82 consecutive patients diagnosed with CMM. 56 patients in whom melanoma measurements were available were finally included in the study. Melanoma measurements of aggressiveness included: tumour mitotic rate, Breslow index, presence of ulceration, stage of disease and growth rate of melanoma. A sleep study was performed in all the included patients. Multivariate analyses were used to examine the independent relationship between SDB severity (apnoea-hypopnea index (AHI) and nocturnal oxygen desaturation indexes (ODI3% and ODI4%)) and measures of CMM aggressiveness. 60.7% of patients had SDB (AHI ≥ 5) and 14.3% severe obstructive sleep apnoea (AHI ≥ 30). In fully adjusted multivariate analyses, AHI (OR 1.08, 95% CI 1.02-1.14), ODI3% (OR 1.08, 95% CI 1.02-1.11) and ODI4% (OR 1.1, 95% CI 1.02-1.2) were independently associated with an increased melanoma growth rate. Furthermore, AHI, ODI4% and ODI3% were significantly correlated with other aggressiveness factors of CMM, such as Breslow index, presence of ulceration and mitotic index. SDB severity markers are associated with some aggressiveness markers of CMM.

Unraveling the Molecular Mechanisms of OSA-Related Cardiovascular Event Recurrence: A Post Hoc Analysis From the ISAACC Study.

RATIONALE: Although obstructive sleep apnea (OSA) is a prevalent condition among patients with acute coronary syndrome (ACS), the impact of OSA on cardiovascular event (CVE) recurrence is not homogeneous. We previously defined a specific phenotype of first-ACS patients without previous cardiovascular disease who are at increased risk of OSA-related CVE recurrence. However, the pathobiological mechanisms whereby OSA leads to adverse cardiovascular outcomes in this singular ACS phenotype remain to be investigated. OBJECTIVE: To characterize the molecular pathways that relate OSA with CVE recurrence. METHODS: This post hoc analysis of the ISAACC study (NCT01335087) included subjects without previous cardiovascular disease who were hospitalized for a first ACS and developed a recurrent CVE during the follow-up. Patients underwent respiratory polygraphy and fasting blood extraction during hospitalization. Two study groups were established on the basis of the apnea-hypopnea index (AHI): untreated severe OSA (AHI≥30events/h) and non-OSA (AHI<15events/h) groups. Proteomic profiling analysis included 276 cardiovascular and inflammatory-related plasma proteins via Olink® technology. RESULTS: Proteomics was performed in 58 patients (77.6% male, median [p25;p75] age 58.0 [51.2;65.8] years, and median BMI 28.6 [25.8;31.2]kg/m2). Thirty patients had severe OSA, and 28 subjects were considered non-OSA controls. A total of 24 plasma proteins were differentially expressed between the groups. Among these proteins, 18 were significantly associated with OSA severity parameters derived from respiratory polygraphy. Further bioinformatic analyses of OSA-related proteins revealed their involvement in several molecular pathways, mostly related to immune function, cell signaling, and inflammatory processes. CONCLUSION: A specific proteomic profile related to OSA presence and severity was identified in the plasma of ACS patients who developed recurrent CVEs. This analysis suggests the activation of key OSA-mediated molecular pathways with potential implications for cardiovascular prognosis.

Vitamin D status and parathyroid hormone levels in patients with obstructive sleep apnea.

BACKGROUND: Vitamin D insufficiency and high levels of parathyroid hormone (PTH) appear to be emerging risk factors for metabolic syndrome (MS), diabetes and cardiovascular disease, conditions that occur frequently in patients with obstructive sleep apnea syndrome (OSAS). OBJECTIVES: This study examined whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] and PTH were associated with the presence of MS, diabetes and hypertension among an OSAS population. METHODS: A total of 826 patients (635 men and 191 women) with newly diagnosed OSAS were studied. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III clinical criteria. Serum levels of 25(OH)D, PTH, glucose, triglycerides, cholesterol, HDL cholesterol, creatinine and uric acid were determined. RESULTS: In 55.3% of the men and in 63.2% of the women, the serum 25(OH)D level was less than 30 ng/ml (insufficient status). After adjusting for age, sex and seasonality, there was a significant trend of decreasing odds for diabetes [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.33-0.94, ptrend = 0.038] and MS (OR 0.34, 95% CI 0.21-0.56, ptrend < 0.001) with increasing vitamin D levels. Higher PTH levels were associated with a higher prevalence of obesity (OR 2.05, 95% CI 1.06-3.09, ptrend < 0.001) and hypertension (OR 1.83, 95% CI 1.01-3.05, ptrend = 0.049). CONCLUSIONS: These data suggest an inverse association of 25(OH)D with diabetes and MS and a positive association of PTH with obesity and hypertension among patients with OSAS. Based on our observational study, the causative nature of the associations cannot be established. These findings require further examination in prospective studies including clinical trials.

Cardiovascular mortality in obstructive sleep apnea in the elderly: role of long-term continuous positive airway pressure treatment: a prospective observational study.

RATIONALE: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular death in middle-aged subjects, but it is not known whether it is also a risk factor in the elderly. OBJECTIVES: To investigate whether OSA is a risk factor for cardiovascular death and to assess whether continuous positive airway pressure (CPAP) treatment is associated with a change in risk in the elderly. METHODS: Prospective, observational study of a consecutive cohort of elderly patients (≥65 yr) studied for suspicion of OSA between 1998 and 2007. Patients with an apnea-hypopnea index (AHI) less than 15 were the control group. OSA was defined as mild to moderate (AHI, 15-29) or severe (AHI, ≥30). Patients with OSA were classified as CPAP-treated (adherence ≥ 4 h/d) or untreated (adherence < 4 h/d or not prescribed). Participants were monitored until December 2009. The end point was cardiovascular death. A multivariate Cox survival analysis was used to determine the independent impact of OSA and CPAP treatment on cardiovascular mortality. MEASUREMENTS AND MAIN RESULTS: A total of 939 elderly were studied (median follow-up, 69 mo). Compared with the control group, the fully adjusted hazard ratios for cardiovascular mortality were 2.25 (confidence interval [CI], 1.41 to 3.61) for the untreated severe OSA group, 0.93 (CI, 0.46 to 1.89) for the CPAP-treated group, and 1.38 (CI, 0.73 to 2.64) for the untreated mild to moderate OSA group. CONCLUSIONS: Severe OSA not treated with CPAP is associated with cardiovascular death in the elderly, and adequate CPAP treatment may reduce this risk.

Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial.

IMPORTANCE: More than 70% of patients with resistant hypertension have obstructive sleep apnea (OSA). However, there is little evidence about the effect of continuous positive airway pressure (CPAP) treatment on blood pressure in patients with resistant hypertension. OBJECTIVE: To assess the effect of CPAP treatment on blood pressure values and nocturnal blood pressure patterns in patients with resistant hypertension and OSA. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized, multicenter clinical trial of parallel groups with blinded end point design conducted in 24 teaching hospitals in Spain involving 194 patients with resistant hypertension and an apnea-hypopnea index (AHI) of 15 or higher. Data were collected from June 2009 to October 2011. INTERVENTIONS: CPAP or no therapy while maintaining usual blood pressure control medication. MAIN OUTCOMES AND MEASURES: The primary end point was the change in 24-hour mean blood pressure after 12 weeks. Secondary end points included changes in other blood pressure values and changes in nocturnal blood pressure patterns. Both intention-to-treat (ITT) and per-protocol analyses were performed. RESULTS: A total of 194 patients were randomly assigned to receive CPAP (n = 98) or no CPAP (control; n = 96). The mean AHI was 40.4 (SD, 18.9) and an average of 3.8 antihypertensive drugs were taken per patient. Baseline 24-hour mean blood pressure was 103.4 mm Hg; systolic blood pressure (SBP), 144.2 mm Hg; and diastolic blood pressure (DBP), 83 mm Hg. At baseline, 25.8% of patients displayed a dipper pattern (a decrease of at least 10% in the average nighttime blood pressure compared with the average daytime blood pressure). The percentage of patients using CPAP for 4 or more hours per day was 72.4%. When the changes in blood pressure over the study period were compared between groups by ITT, the CPAP group achieved a greater decrease in 24-hour mean blood pressure (3.1 mm Hg [95% CI, 0.6 to 5.6]; P = .02) and 24-hour DBP (3.2 mm Hg [95% CI, 1.0 to 5.4]; P = .005), but not in 24-hour SBP (3.1 mm Hg [95% CI, -0.6 to 6.7]; P = .10) compared with the control group. Moreover, the percentage of patients displaying a nocturnal blood pressure dipper pattern at the 12-week follow-up was greater in the CPAP group than in the control group (35.9% vs 21.6%; adjusted odds ratio [OR], 2.4 [95% CI, 1.2 to 5.1]; P = .02). There was a significant positive correlation between hours of CPAP use and the decrease in 24-hour mean blood pressure (r = 0.29, P = .006), SBP (r = 0.25; P = .02), and DBP (r = 0.30, P = .005). CONCLUSIONS AND RELEVANCE: Among patients with OSA and resistant hypertension, CPAP treatment for 12 weeks compared with control resulted in a decrease in 24-hour mean and diastolic blood pressure and an improvement in the nocturnal blood pressure pattern. Further research is warranted to assess longer-term health outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00616265.

Montjuïc Hill (Barcelona): A Hotspot for Plant Invasions in a Mediterranean City.

Cities are often hotspots for biological invasions, showing much higher percentages of alien species than non-urbanized settings. The reasons are multiple and are mostly related to two main factors: their heterogeneous, highly disturbed habitats and their many gateways that allow alien species introduction (e.g., airports, roads, train stations, or gardens). In addition to being a sink of biological invasions, cities can also be a source of the spread of alien species into surrounding landscapes, which adds further complexity to this issue. Herein, we are presenting the results of a five-year survey of the alien flora of Montjuïc, the largest urban hill in Barcelona (Spain). In just about 3.4 km2, we recorded up to 247 alien plant taxa, a figure much higher than those of many other Mediterranean cities and which clearly points to the role of Montjuïc as a hotspot for alien plants. The comparison with the alien flora of its surrounding region (coastal Catalonia) suggests that the alien flora of Montjuïc would have become enriched through many immigration episodes from close geographic areas. The hill, however, would have also acted as a source of the spread of alien plants, and indeed, some species have not been detected yet beyond the confines of Montjuïc. This study aims to be a key tool to ensure early detection and also to develop appropriate management and/or eradication actions.

Proteomic profiling for prediction of recurrent cardiovascular event in patients with acute coronary syndrome and obstructive sleep apnea: A post-hoc analysis from the ISAACC study.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with a recurrent cardiovascular event (CVE) risk in patients with a first acute coronary syndrome (ACS). However, the pathological pathways by which OSA promotes this deleterious role are unknown. We aim to explore the proteomic profile associated with OSA that promote the recurrent CVE risk in severe OSA patients with ACS without previous cardiovascular diseases. METHODS: This post-hoc analysis from the ISAACC study (NCT01335087) included 86 patients admitted for ACS. Patients underwent respiratory polygraphy for the first 24-72 h to OSA diagnosis. We analyzed of 276 cardiovascular and inflammatory related proteins in baseline fasting plasma samples using proximity expression assay technology (Olink®, Sweden). Protein levels were compared between severe OSA patients with/without recurrent CVEs during follow-up. Random forest was conducted to select relevant proteins and generate a predictive model of recurrent CVE. RESULTS: We included 86 patients (median age: 61 years, median BMI: 29.4 kg/m2 and 86 % males) admitted for ACS with severe OSA (56 without recurrent CVE/30 with recurrent CVE). The plasma levels of 38 proteins were differentially expressed between groups. Additionally, 12 proteins had a significant association with respiratory polygraphy parameters. Three proteins discriminate with an AUC of 0.81 (95 % CI of 0.71-0.9) between severe OSA patients with and without recurrent CVE. These proteins were implicated in cell proliferation, communication and apoptosis, and regulation/response to the inflammatory and immune systems. CONCLUSION: In ACS patients with severe OSA, a proteomic profile was associated with recurrent CVEs. This proteomic profile was correlated with specific OSA parameters from respiratory polygraphy. Proteomic profiling may provide an new direction for patient risk stratification and clinical management.

Role of Sleep Apnea and Long-Term CPAP Treatment in the Prognosis of Patients With Melanoma: A Prospective Multicenter Study of 443 Patients.

BACKGROUND: OSA has been associated with increased incidence and aggressiveness of melanoma. However, the long-term impact of OSA and CPAP treatment on the prognosis of melanoma remains unexplored. RESEARCH QUESTION: Are OSA and CPAP treatment associated independently with a poor prognosis for cutaneous melanoma? STUDY DESIGN AND METHODS: Four hundred forty-three patients with a diagnosis of cutaneous melanoma (2012-2015) underwent a sleep study within 6 months of diagnosis. The main 5-year outcome of the study was a composite of melanoma recurrence, metastasis, or mortality. Patients were divided into four groups: baseline apnea-hypopnea index (AHI) of fewer than 10 events/h (no OSA; control group), OSA treated with CPAP and good adherence, untreated or poor CPAP adherence in moderate (AHI, 10-29 events/h), and severe OSA (AHI, ≥ 30 events/h). Survival analysis was used to determine the independent role of OSA and CPAP treatment on melanoma composite outcome. RESULTS: Three hundred ninety-one patients (88.2%) were available for analysis at 5-year follow-up (mean age, 65.1 ± 15.2 years; 49% male; Breslow index, 1.7 ± 2.5 mm). One hundred thirty-nine patients had AHI of fewer than 10 events/h (control group); 78 patients with OSA were adherent to CPAP; and 124 and 50 patients had moderate and severe OSA, respectively, without CPAP treatment. Median follow-up was 60 months (interquartile range, 51-74 months). During follow-up, 32 relapses, 53 metastases, and 52 deaths occurred (116 patients showed at least one of the main composite outcomes). After adjusting for age, sex, sentinel lymph nodes affected at diagnosis, BMI, diabetes, nighttime with an oxygen saturation below 90%, Breslow index, Epworth sleepiness scale scores, and melanoma treatment, moderate (hazard ratio [HR], 2.45; 95% CI, 1.09-5.49) and severe OSA (HR, 2.96; 95% CI, 1.36-6.42) were associated with poorer prognosis of melanoma compared with the control group. However, good adherence to CPAP avoided this excess risk (HR, 1.66; 95% CI, 0.71-3.90). INTERPRETATION: Moderate to severe untreated OSA is an independent risk factor for poor prognosis of melanoma. Treatment with CPAP is associated with improved melanoma outcomes compared with untreated moderate to severe OSA.

The influence of obesity and obstructive sleep apnea on metabolic hormones.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by excessive daytime sleepiness and repetitive upper airway obstruction episodes during sleep. Clinically, obesity is a major risk factor for developing OSAS. However, OSAS has been associated with hormonal and metabolic alterations that could predispose patients to obesity. The aim of this study was to investigate the independent role of apneas and obesity on plasma levels of metabolic hormones (adiponectin, ghrelin, and leptin) in patients with OSAS. METHODS: We have studied patients with OSAS and controls with and without obesity. All patients were male, had an apnea-hypopnea index of 20/h or greater, and were eligible for nasal continuous positive airway pressure (nCPAP) treatment. Patients were considered obese (n = 28) when their BMI was higher than 30 kg/m(2) and non-obese (n = 21) when it was lower than 27 kg/m(2). Non-obese control subjects (n = 20) were non-snorers with a normal cardiorespiratory sleep study, while obese control subjects (n = 10) were recruited from those obese subjects who were visited in our sleep unit and for whom OSAS was excluded by full polysomnography. A single blood sample was obtained from an antecubital vein in all participants after the completion of the nocturnal sleep laboratory recording. Plasma leptin, adiponectin, and ghrelin levels were determined by radioimmunoassay. RESULTS: The adiponectin, ghrelin, and leptin plasma levels were similar in both patients and controls. There were differences in leptin and adiponectin plasma levels between the obese and non-obese in both patient and control groups. In the case of ghrelin, differences between obese and non-obese subjects were only seen in patients. There were no significant differences in hormone levels between the obese controls and obese patients or between non-obese controls and non-obese patients. After 3 months of nCPAP treatment, adiponectin levels decreased significantly both in obese and non-obese patients, and leptin levels decreased in obese patients. Finally, nCPAP did not reduce ghrelin in either obese or non-obese patients. CONCLUSIONS: The basal levels of leptin, adiponectin, and ghrelin were mostly associated with obesity. We found that sleep apnea was not a determinant factor in leptin, adiponectin, and ghrelin hormonal levels. Interestingly, nCPAP treatment diminishes leptin in obese OSA patients and adiponectin levels in obese and non-obese patients with OSAS.