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.

Respiratory Polygraphy Patterns and Risk of Recurrent Cardiovascular Events in Patients With Acute Coronary Syndrome.

Introduction: Obstructive sleep apnea (OSA) severity is based on the apnea-hypopnea index (AHI). The AHI is a simplistic measure that is inadequate for capturing disease severity and its consequences in cardiovascular diseases (CVDs). Deleterious effects of OSA have been suggested to influence the prognosis of specific endotypes of patients with acute coronary syndrome (ACS). We aim to identify respiratory polygraphy (RP) patterns that contribute to identifying the risk of recurrent cardiovascular events in patients with ACS. Methods: Post hoc analysis of the ISAACC study, including 723 patients admitted for a first ACS (NCT01335087) in which RP was performed. To identify specific RP patterns, a principal component analysis (PCA) was performed using six RP parameters: AHI, oxygen desaturation index, mean and minimum oxygen saturation (SaO2), average duration of events and percentage of time with SaO2 < 90%. An independent HypnoLaus population-based cohort was used to validate the RP components. Results: From the ISAACC study, PCA showed that two RP components accounted for 70% of the variance in the RP data. These components were validated in the HypnoLaus cohort, with two similar RP components that explained 71.3% of the variance in the RP data. The first component (component 1) was mainly characterized by low mean SaO2 and obstructive respiratory events with severe desaturation, and the second component (component 2) was characterized by high mean SaO2 and long-duration obstructive respiratory events without severe desaturation. In the ISAACC cohort, component 2 was associated with an increased risk of recurrent cardiovascular events in the third tertile with an adjusted hazard ratio (95% CI) of 2.44 (1.07 to 5.56; p-value = 0.03) compared to first tertile. For component 1, no significant association was found for the risk of recurrent cardiovascular events. Conclusion: A RP component, mainly characterized by intermittent hypoxemia, is associated with a high risk of recurrent cardiovascular events in patients without previous CVD who have suffered a first ACS.

Long-Term Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Treatment on Blood Pressure in Patients with Acute Coronary Syndrome: A Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is prevalent in patients with acute coronary syndrome (ACS) and is a cause of secondary hypertension. Objectives: To explore the long-term effects of OSA and continuous positive airway pressure (CPAP) treatment on blood pressure (BP) in patients with ACS. Methods: Post hoc analysis of the ISAACC study (Continuous Positive Airway Pressure in Patients with Acute Coronary Syndrome and Obstructive Sleep Apnea; NCT01335087) included 1,803 patients admitted for ACS. Patients with OSA (apnea-hypopnea index [AHI], ⩾15 events/h) were randomly assigned to receive either CPAP or usual care and were seen in follow-up for 1-5 years. Office BP was determined at each visit. Results: We included 596 patients without OSA, 978 patients in the usual care or poor CPAP adherence group, and 229 patients in the good CPAP adherence group. At baseline, 52% of the patients were diagnosed with hypertension. Median (25th to 75th percentile) age and body mass index were 59 (52.0 to 67.0) years and 28.2 (25.6 to 31.2) kg/m2, respectively. After a median (25th to 75th percentile) follow-up of 41.2 (18.3 to 59.6) months, BP changes were similar in the OSA and non-OSA groups. However, we observed an increase in BP in the third tertile of the AHI (AHI, >40 events/h), with a maximum difference in mean BP of +3.3 mm Hg at 30 months. Patients with OSA with good CPAP adherence (⩾4 h/night) reduced mean BP after 18 months compared with patients with usual care/poor CPAP adherence, with a maximum mean difference (95% confidence interval) of -4.7 (-6.7 to -2.7) mm Hg. In patients with severe OSA, we observed a maximum mean difference of -7.1 (-10.3 to -3.8) mm Hg. Conclusions: In patients with ACS, severe OSA is associated with a long-term increase in BP, which is reduced by good CPAP adherence. Clinical trial registered with www.clinicaltrials.gov (NCT01335087).

Effectiveness of CPAP vs. Noninvasive Ventilation Based on Disease Severity in Obesity Hypoventilation Syndrome and Concomitant Severe Obstructive Sleep Apnea.

RATIONALE: Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity. OBJECTIVE: To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups. METHODS: Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI)≥30events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45-49.9 or ≥50mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model. RESULTS: 204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups. CONCLUSION: In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2.

Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome.

STUDY OBJECTIVES: Pulmonary hypertension (PH) is prevalent in obesity hypoventilation syndrome (OHS). However, there is a paucity of data assessing pathogenic factors associated with PH. Our objective is to assess risk factors that may be involved in the pathogenesis of PH in untreated OHS. METHODS: In a post hoc analysis of the Pickwick trial, we performed a bivariate analysis of baseline characteristics between patients with and without PH. Variables with a P value ≤ .10 were defined as potential risk factors and were grouped by theoretical pathogenic mechanisms in several adjusted models. Similar analysis was carried out for the 2 OHS phenotypes, with and without severe concomitant obstructive sleep apnea. RESULTS: Of 246 patients with OHS, 122 (50%) had echocardiographic evidence of PH defined as systolic pulmonary artery pressure ≥ 40 mm Hg. Lower levels of awake PaO2 and higher body mass index were independent risk factors in the multivariate model, with a negative and positive adjusted linear association, respectively (adjusted odds ratio 0.96; 95% confidence interval 0.93 to 0.98; P = .003 for PaO2, and 1.07; 95% confidence interval 1.03 to 1.12; P = .001 for body mass index). In separate analyses, body mass index and PaO2 were independent risk factors in the severe obstructive sleep apnea phenotype, whereas body mass index and peak in-flow velocity in early/late diastole ratio were independent risk factors in the nonsevere obstructive sleep apnea phenotype. CONCLUSIONS: This study identifies obesity per se as a major independent risk factor for PH, regardless of OHS phenotype. Therapeutic interventions targeting weight loss may play a critical role in improving PH in this patient population. CLINICAL TRIAL REGISTRATION: Registry: Clinicaltrial.gov; Name: Alternative of Treatment in Obesity Hypoventilation Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT01405976; Identifier: NCT01405976. CITATION: Masa JF, Benítez ID, Javaheri S, et al. Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome. J Clin Sleep Med. 2022;18(4):983-992.

Sleep apnoea-hypopnoea syndrome in the obese and non-obese: Clinical, polysomnographical and clinical characteristics.

INTRODUCTION: Sleep apnoea-hypopnoea syndrome (SAHS) and childhood obesity are two high prevalence conditions that represent a public health challenge. OBJECTIVE: To analyse the association between both and comparing child groups that had or did not have both conditions. PATIENTS AND METHODS: A prospective study in children (3-14 years), referred to the "Multidisciplinary Sleep Unit" due to suspected SAHS, between 1 November 2015 and 1 August 2017. The following parameters were evaluated: anthropometry, symptoms, blood pressure, ear, nose, and throat examination, polysomnography (nocturnal PSG) and laboratory tests. RESULTS: A total of 67 children were evaluated (64% non-obese (NOb) and 36% obese (Ob). It was observed that the Ob were older (P < .001), slept less hours (P = .028), did less physical exercise (P = .029), ate less in the school dining room (P = .009), had la lower sleep efficiency, and had abnormal values in carbohydrate and lipid metabolism. The children with SAHS were younger (P = .010), a high percentage of daytime sleepiness (P = .001), and breathing through the mouth (P = .006), greater percentile of diastolic blood pressure (P = .019) and a lower IGF-1 (P = .003) than those that did not have SAHS. The comparison of the SAHS NOb and SAHS Ob groups, showed that the first group were younger (P = .010), snored more (P = .012), had a more severe SAHS (IAH 13.1 vs 5.4, P = .041), and a higher GOT (P < .001). In the second group, they slept less hours P = .038) and showed lower values of glucose (P = .039), insulin (P < .001), and HOMA (P < .001). CONCLUSION: The behaviour of SAHS is different in obese children and non-obese children, with differences in age, clinical characteristics, severity of SAHS, and metabolic changes. The children diagnosed with SAHS were in the higher percentile of diastolic blood pressure. Obesity was associated with worse sleep quality, and changes in carbohydrate and lipid metabolism.

Long-term Noninvasive Ventilation in Obesity Hypoventilation Syndrome Without Severe OSA: The Pickwick Randomized Controlled Trial.

BACKGROUND: Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe OSA phenotype. RESEARCH QUESTION: Is NIV effective in OHS without severe OSA phenotype? STUDY DESIGN AND METHODS: In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index < 30 events/h (ie, no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days per year. Secondary end points included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, BP, quality of life, sleepiness, and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating physicians from the routine care team were not aware of patients' enrollment in the clinical trial. The study was stopped early in its eighth year because of difficulty identifying patients with OHS without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles and by adherence subgroups. RESULTS: Forty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year ± SD was 2.60 ± 5.31 in the control group and 2.71 ± 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P = .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in Paco2, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms. INTERPRETATION: In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01405976; URL: www.clinicaltrials.gov.

Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. OBJECTIVES: We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. METHODS: Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. RESULTS: In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91-3.14) years for NIV group and 3.00 (2.92-3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. CONCLUSION: CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. TRIAL REGISTRATION NUMBER: NCT01405976.

Echocardiographic Changes with Positive Airway Pressure Therapy in Obesity Hypoventilation Syndrome. Long-Term Pickwick Randomized Controlled Clinical Trial.

Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking.Objectives: In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes.Methods: At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV.Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P < 0.0001 for longitudinal intragroup changes for both treatment arms). However, there were no significant differences between groups. NIV and CPAP therapies similarly improved left ventricular diastolic dysfunction and reduced left atrial diameter. Both NIV and CPAP improved respiratory function and dyspnea.Conclusions: In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction.Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

Metabolic biomarkers in community obese children: effect of obstructive sleep apnea and its treatment.

OBJECTIVE: Obesity and obstructive sleep apnea in children have been associated with metabolic morbidities. The present study aimed to evaluate the presence of metabolic alterations among obese children recruited from the community, with and without obstructive sleep apnea syndrome (OSAS), and the impact of treatment of OSAS on metabolic profiles. METHODS: A cross-sectional, prospective, multicenter study of Spanish children aged 3-14 years with a body mass index (BMI) ≥95th percentile for age and sex were randomly selected in the first phase. Four groups emerged for follow-up: (1) no treatment; (2) dietary intervention; (3) surgical treatment of OSA; and (4) continuous positive airway pressure (CPAP) treatment of OSA. Fasting blood tests were performed at baseline (T0) and approximately one year after the intervention (T1). RESULTS: A total of 113 obese children with a mean age of 11.3 ± 2.9 years completed T0 and T1 assessments. Their mean BMI z-score at T1 was 1.34 ± 0.59, and mean Respiratory Disturbance Index was 8.6 ± 13.0 at T0 and 3.3 ± 4.0/hour total sleep time at T1. Only glucose fasting levels differed among metabolic parameters in obese children with OSAS and without OSAS at baseline (T0) (p = 0.018). There were statistically significant differences between surgically treated OSAS (p = 0.002), and CPAP-treated OSAS (p = 0.024) versus the non-OSAS group in the glucose levels between baseline (T0) and follow-up (T1) after controlling for age and change in BMI. Significant univariate associations between BMI and C-reactive protein, insulin, and homeostasis model assessment of insulin resistance emerged at both T0 and T1. CONCLUSIONS: Concurrent obesity and OSAS could promote metabolic and inflammatory alterations, and the latter appeared to be sensitive to OSAS treatment outcomes. ClinicalTrials.gov Identifier: NCT01322763.

Reliability of home respiratory polygraphy for the diagnosis of sleep apnea in children.

OBJECTIVE: The objective of this study was to evaluate the diagnostic reliability of home respiratory polygraphy (HRP) in children with a clinical suspicion of OSA-hypopnea syndrome (OSAS). METHODS: A prospective blind evaluation was performed. Children between the ages of 2 to 14 years with clinical suspicion of OSAS who were referred to the Sleep Unit were included. An initial HRP followed by a later date, same night, in-laboratory overnight respiratory polygraphy and polysomnography (PSG) in the sleep laboratory were performed. The apnea-hypopnea index (AHI)-HRP was compared with AHI-PSG, and therapeutic decisions based on AHI-HRP and AHI-PSG were analyzed using intraclass correlation coefficients, Bland-Altman plots, and receiver operator curves (ROCs). RESULTS: Twenty-seven boys and 23 girls, with a mean age of 5.3 ± 2.5 years, were studied, and 66% were diagnosed with OSAS based on a PSG-defined obstructive respiratory disturbance index ≥ 3/h total sleep time. Based on the availability of concurrent HRP-PSG recordings, the optimal AHI-HRP corresponding to the PSG-defined OSAS criterion was established as ≥ 5.6/h The latter exhibited a sensitivity of 90.9% (95% CI, 79.6%-100%) and a specificity of 94.1% (95% CI, 80%-100%). CONCLUSIONS: HRP recordings emerge as a potentially useful and reliable approach for the diagnosis of OSAS in children. However, more research is required for the diagnosis of mild OSAS using HRP in children.

Respiratory polygraphy for follow-up of obstructive sleep apnea in children.

OBJECTIVES: (1) To evaluate the effectiveness of adenotonsillectomy for the treatment of Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) in children. (2) To evaluate the usefulness of respiratory polygraphy (RP) for controlling post-adenotonsillectomy effects. METHODS: The children studied were referred to the Burgos Sleep Unit (SU) with clinical suspicion of OSAHS before undergoing adenotonsillectomy. For all patients, a clinical history was taken and a general physical examination, as well as a specific ear, nose, and throat examination was done. RP before adenotonsillectomy, and seven months afterwards, was also done. OSAHS was diagnosed if the Apnea Hypopnea Index (AHI) was ≥ 4.6. RESULTS: Of the 100 children studied, 68 were male and 32 female, with an age of 4.17 ± 2.05 years. Using RP, 86 of them were diagnosed with OSAHS before undergoing adenotonsillectomy. There was a significant improvement in all clinical and polygraphic variables after adenotonsillectomy. The pre and post surgery AHI index was 11.9 ± 11.0 and 2.6 ± 1.5, respectively, with a significant mean difference (9.4 ± 10.9, p<0.01). The residual OSAHS was 11.6% (CI 95%: 4.3-19%). CONCLUSIONS: Respiratory polygraphy is a useful tool for monitoring the effectiveness of surgical treatment and the detection of residual OSAHS in children with adenotonsillar hypertrophy.

[Reliability of respiratory polygraphy for the diagnosis of sleep apnea-hypopnea syndrome in children]. / Fiabilidad de la poligrafía respiratoria para el diagnóstico del síndrome de apneas-hipopneas durante el sueño en niños.

OBJECTIVE: Overnight polysomnography (PSG) is the gold standard diagnostic tool for sleep apnea-hypopnea syndrome (SAHS) in children. The aim of the present study was to evaluate the usefulness of diagnostic respiratory polygraphy in children with clinically suspected SAHS referred to our sleep-disordered breathing clinic. PATIENTS AND METHODS: We studied 53 children referred with clinical suspicion of SAHS; 29 (54.7%) were boys and the mean (SD) age was 6.4 (2.9) years. After a medical history was taken and a physical examination performed, patients underwent respiratory polygraphy (Edentec) simultaneously with overnight PSG in the sleep laboratory. The 2 diagnostic tools were compared using statistical analysis. RESULTS: SAHS was defined by an obstructive apnea-hypopnea index (OAHI) of 3 or more in overnight PSG and a respiratory disturbance index (RDI) of 3 or more in respiratory polygraphy. The rate of diagnostic agreement was 84.9%. The difference between the mean OAHI and RDI values was not significant (0.7 +/- 5.4; P=.34). The intraclass correlation coefficient between the OAHI and RDI was 89.4 (95% confidence interval, 82.4-93.7; P< .001). When receiver operating characteristic curves were calculated for the OAHI cutoff points used for the diagnosis of SAHS (> or =1, > or =3, and > or =5), the best RDI cutoff for all 3 OAHI values considered was found to be 4.6. When age strata were considered, in children 6 years or older the best RDI cutoff for the 3 OAHI values was 2.1. In children younger than 6 years the best RDI cutoff was 3.35 for OAHI > or =1 and 5.85 for OAHI > or =3 and > or =5. CONCLUSIONS: Respiratory polygraphy in the sleep laboratory is a valid method for the diagnosis of SAHS in children.