Objective: Pulse transit time (PTT) is a promising tool for the non-invasive identification and characterization of obstructive and central apneas in sleep apnea syndrome (SAS). However, a lack of standardized and physiologically explainable features extracted from PTT limits its interpretability and the possibility to perform this classification automatically. Methods: Features were extracted from PTT and its oscillations ($\Delta$PTT) to characterize their variation during obstructive and central apneas, on a database of 26 patients from the HYPNOS clinical study. They were used to train a random forest classifier and obtain a ranking of feature importance. The most significant features were studied using a Morris sensitivity analysis of a novel integrated model of cardio-respiratory interactions simulating the PTT, to understand the main physiological mechanisms modulating them. Results: An AUC of 0.83$\pm$0.12 was obtained for the classification. The most significant features were related to $\Delta$PTT and its changes during the apnea compared to the baseline. They were sensitive to model parameters affecting its sensitivity to blood CO$_{2}$. Conclusion and significance: A new integrated model of PTT in sleep apnea was proposed, and allowed for the physiological interpretation of novel informative PTT features for the classification of obstructive and central apneas.

STUDY OBJECTIVES:The association between obstructive sleep apnea (OSA) and liver fibrosis has been primarily evaluated using noninvasive tools or in selected populations (bariatric surgery). The aim of the study was to determine whether OSA is associated with liver fibrosis in patients with suspected nonalcoholic fatty liver disease (NAFLD) referred for liver biopsy (LB). METHODS:Patients who underwent percutaneous LB for suspected NAFLD were prospectively included and investigated by in-lab polysomnography. Liver lesions were evaluated using the NASH-CRN scoring system and advanced fibrosis was defined as F ≥ 3. Moderate to severe OSA was defined by an apnea-hypopnea index (AHI) ≥15 events/h. RESULTS:Among the 97 patients included in the study, 40 exhibited advanced fibrosis, while 63 demonstrated moderate to severe OSA. The prevalence of moderate to severe OSA in patients with advanced fibrosis was 82% versus 52% in patients with F0-2 fibrosis stage (p < .0037). The association between moderate to severe OSA and advanced fibrosis remained significant after adjustment for sex, age, diabetes and obesity with an OR of 3.48 (CI = 1.03% to 11.83%; p = .045). Similar association was found with nocturnal hypoxia markers (oxygen desaturation index and the time spent under 90% of saturation). No association was observed between moderate to severe OSA and steatosis or nonalcoholic steatohepatitis. CONCLUSIONS:Utilizing the gold-standard tools for OSA and NAFLD diagnosis in a multicentric cohort of biopsy-proven NAFLD patients, an independent association between OSA and liver fibrosis was confirmed. Statement of Significance This study provides the strongest evidence to date that obstructive sleep apnea (OSA) is independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. Unlike prior studies based on indirect measures or bariatric populations, this work used gold-standard diagnostics-full polysomnography and liver histology-in a general NAFLD cohort. The high prevalence of OSA among patients with advanced fibrosis suggests systematic screening may be warranted. These findings identify OSA as a potential modifiable risk factor for liver disease progression.

RATIONALE:Obstructive sleep apnea (OSA) and hypertension are common comorbidities and are associated with poor prognosis. Blood pressure (BP) trajectories using home BP monitoring after initiation of continuous positive airway pressure (CPAP) therapy for OSA are poorly documented. OBJECTIVES:To describe BP trajectories in the first 6 months after CPAP therapy initiation based on repeated longitudinal measurements of home BP, to evaluate the impact of CPAP on morning and evening home BP, and to identify predictors of home BP evolution during CPAP. METHODS:This prospective cohort study enrolled patients with OSA. Home BP monitoring was used to assess morning and evening home BP values over a 7-day period at baseline and over the first 6 months after starting CPAP therapy. RESULTS:A total of 98 patients were enrolled, and 36,600 home BP measurements were available for analysis. Morning and evening systolic/diastolic home BP decreased significantly during the first 6 months of CPAP therapy (P < 0.05 vs. baseline). Morning home BP was significantly higher than evening home BP throughout the study (P < 0.01). After adjustment for OSA severity at baseline and CPAP adherence, factors associated with limited home BP response to CPAP were older age, weight gain during CPAP therapy, current smoking, and previous hypertension. CONCLUSIONS:CPAP improved home BP trajectories during the first 6 months, but the response was heterogeneous and less marked for morning BP values. Based on the predictors of BP response during CPAP therapy, weight control appears key to the effective management of patients with OSA and hypertension.Clinical trial registered with www. CLINICALTRIALS:gov (NCT04963192 and NCT04054180).

STUDY OBJECTIVES:High ambient temperatures are associated with negative health outcomes, including heat stress, injuries and accidents, and poor mental health. Sleep loss may contribute to these adverse impacts. However, robust supporting evidence is lacking. METHODS:Data from a global sample of sleep tracker users (N = 317 758; Withings Sleep Analyzer [WSA]: n = 116 879; Withings ScanWatch: n = 200 879) between January 2020 and September 2023 (~165 million nights) were analyzed. Ambient temperatures (24 hour average) were extracted from a climate model for each nightly observation based on the users' location. We used the case-time-series design with participant-year-week intercept and spline functions to derive exposure-response curves between temperature and short sleep (<6 hours/night) prevalence, adjusting for other time-varying factors and meteorological variables. RESULTS:High temperatures (99th vs 50th percentile of the observed global distribution; 27.3°C vs 12.2°C) were associated with (mean [95%CI]) -15.2 [-15.6, -14.9] and -16.9 [-17.4, -16.4] minute sleep loss in the users of the smartwatch and under-mattress sensors, respectively. Similarly, high temperatures were associated with an approximately 40% relative increase in the probability of short sleep on the same night (WSA: Risk Ratio: RR [95%CI]; 1.40 [1.38, 1.41]; ScanWatch: 1.43 [1.41, 1.44]). Estimates ranged between 10% and 75% depending on the country. Sleep loss to high temperatures was higher in participants residing in Europe and countries with lower national gross domestic product per capita. CONCLUSIONS:High temperatures negatively impact sleep duration and increase the probability of short sleep globally. Our findings suggest that rising temperatures may increase the health impacts of short sleep. Statement of Significance High ambient temperatures are linked to negative health outcomes, with sleep loss potentially contributing to these effects. This study analyzed data from 317 758 global sleep tracker users to examine the relationship between temperature and short sleep. Results showed an approximately 40% relative increase in the probability of short sleep at high temperatures (99th vs 50th percentile; 27.3°C vs 12.2°C) globally. Sleep loss to high temperatures was higher in participants residing in countries with lower national gross domestic product per capita and older adults. These results suggest that sleep inadequacy from rising temperature due to climate change may further amplify global inequalities. Our findings also highlight the urgent need for targeted strategies to mitigate temperature-induced sleep loss.

Objectif Déterminer la relation dose-réponse entre le niveau de protrusion mandibulaire et l’effort respiratoire résiduel chez les patients atteints du syndrome d’apnées obstructives du sommeil (SAOS) et traités par orthèse. Méthodes Étude prospective sur 93 patients avec SAOS traités par orthèse (NOA, OrthoApnea, Espagne). La titration est réalisée progressivement selon la persistance ou l’aggravation des symptômes. Des tests de sommeil à domicile, basés sur l’analyse des mouvements mandibulaires (MJM) (Sunrise, Belgique), sont effectués à 3 niveaux de protrusion : minimal, intermédiaire et optimal. L’efficacité du traitement a été évaluée par l’indice d’apnée-hypopnée (IAH) et REMOV, représentant le pourcentage du temps total de sommeil (TTS) en effort respiratoire élevé, soit la durée cumulée des évènements obstructifs. Les réponses optimales pour l’IAH et REMOV sont définies comme une réduction de l’IAH>50 % et REMOV<14 % du TTS. Résultats IAH et REMOV ont montré une réduction progressive avec l’augmentation de la protrusion (Fig. 1). Aux points de titration initial, intermédiaire et optimal, l’IAH a diminué de –10,3, –12,7 et –13,0/h, respectivement, par rapport au niveau de base, tandis que REMOV a diminué de 14,5, 16,8 et 18,6 % du TTS. Cependant, ces indices suivent des trajectoires de réponse différentes : 15,1 % des patients montrent une réponse optimale en REMOV mais pas en IAH en fin de titration, et 5,4 % l’inverse. Le groupe avec une réponse optimale des deux indices présente un IAH médian de 2,2/h, contre un IAH médian de 11,3/h chez celui avec une réponse optimale uniquement en IAH. Conclusion Il existe une relation dose-réponse entre la protrusion mandibulaire et l’effort respiratoire résiduel. Une réponse optimale en IAH et REMOV montre une meilleure efficacité dans la réduction des événements obstructifs, tandis qu’un IAH ou REMOV élevé suggère respectivement des apnées centrales ou de l’effort respiratoire marqué de micro-éveils (MELER). Ces résultats montrent l’intérêt de l’analyse des MJM à domicile pour suivre ces deux indicateurs dans la gestion du traitement par orthèse.

Objectif Le syndrome d’apnées obstructives du sommeil (SAOS) est une maladie chronique fréquente associée aux pathologies cardiovasculaires dont la sténose calcifiée de la valve aortique (SCVA). Les processus physiopathologiques mécanistiques de la SCVA impliquent l’autophagie, l’inflammation, le stress oxydant et la calcification. Le but de ce travail est d’évaluer l’impact du SAOS et de l’hypoxie sur ces mécanismes du fait de l’association forte de ces deux pathologies. Méthodes Les patients programmés pour un remplacement valvulaire chirurgical ont été inclus de manière prospective dans la base de données « Multimorbidity Apnea Respiratory failure Sleep », après signature d’un consentement écrit. Des 31 patients phénotypés par polysomnographie, 18 présentaient un SAOS avec un IAH≥15/h. Les valves aortiques natives ont été collectées au décours de l’opération et séparées en trois parties selon leur aspect morphologique macroscopique (saine, intermédiaire et calcifiée). La quantification de l’expression des gènes et protéines a été réalisée respectivement par RT-qPCR et Western Blot. Une analyse multivariée a été réalisée en prenant en compte les facteurs associés aux expressions transcriptionnelles et traductionnelles. Résultats Sur les parties saines valvulaires, la baisse de l’expression génique de Beclin-1 dans le groupe SaO2 minimale<88 % (p<0,05) traduit une altération de l’autophagie sous hypoxie sévère à la phase précoce de la SCVA. En revanche, aux stades plus avancés intermédiaire et calcifié, une expression protéique de P62 diminuée chez les SAOS sévères (p=0,03) traduit une augmentation de l’autophagie chez ces patients. Dans les parties calcifiées, l’expression génique de Beclin-1 est abaissée pour l’ensemble de la population (p<0,001), suggérant une dérégulation de l’autophagie. L’état pro-calcifiant des patients SAOS était visible à l’échelle morphologique et transcriptionnelle par l’augmentation de l’expression génique de l’ostéocalcine associée à l’index de désaturations (p=0,02). Il n’y avait pas d’impact du SAOS sur l’inflammation et le stress oxydant. Conclusion Il s’agit de la première étude évaluant l’impact du SAOS sur les mécanismes d’athérosclérose valvulaire humaine. Le SAOS, par sa composante hypoxique sévère, est associé à une baisse de l’autophagie et à une action pro-calcifiante. Ce travail permet d’ouvrir des perspectives thérapeutiques de modulation de l’autophagie afin de limiter les dommages valvulaires chez les patients SAOS.

Objectif Les apnées du sommeil (AS) affectent plus de deux tiers des adultes avec une trisomie 21 (T21) et sont associées à une aggravation de leurs comorbidités. Toutefois, les phénotypes ventilatoires d’AS et leur impact sur la fragmentation du sommeil des patients avec T21 est peu décrite à ce jour. L’objectif était de décrire les phénotypes des AS et leurs répercussions sur la fragmentation du sommeil chez les adultes avec T21. Méthodes Étude rétrospective. Trente-cinq adultes T21 (30,3±7,2 ans ; 49,7 % de femmes) et 35 témoins adressés pour suspicion d’AS (43,7±13,4 ans ; 49,7 % femmes), appariés pour le sexe et la sévérité des AS, évaluée par l’IAH (31,4±22,7 vs 28,5±21,2/h, p=0,157) et diagnostiquée par polysomnographie ont été inclus. Les patients présentant une AS modérée-sévère (IAH≥15/h) ont été séparés en deux groupes : AS obstructives (IAH central/IAH total<20 %), et AS coexistantes et centrales (IAH central/IAH total≥20 %). L’index de perturbation respiratoire (IPR : IAH+limitation inspiratoire de débit), les stades de sommeil (en % du temps de sommeil total), l’index de micro-éveils respiratoires et les changements de stade du sommeil ont été quantifiés. Des analyses de covariances ou tests de permutations ajustés pour l’âge et l’IMC ont été réalisés, ainsi qu’une régression linéaire bidirectionnelle pour identifier les facteurs associés à l’index de micro-éveil respiratoire. Résultats Trente-trois (94,3 %) adultes T21 présentaient une forme d’AS : 8 (22,9 %) légère, 7 (20 %) modérée et 18 (51,4 %) sévère. L’ensemble du groupe T21 avait un index d’apnées obstructives plus élevé (7,2±10,5 vs 3,3±5,3/h ; p=0,048) et prolongées (14,6±7,3 vs 9,3±9,9s ; p=0,013), un IPR accru (38,6±22,4 vs 32,9±21,7/h ; p=0,045). La prévalence d’AS modérés-sévères coexistantes ou centrales atteignait 31,4 % dans la T21. Le groupe T21 présentait un index de micro-éveils respiratoires plus élevé (29,4±19,3 vs 21,8±17,0/h ; p=0,022) et plus de changements de stade (159,6±58,4 vs 102,7±38,7 ; p<0,001). La T21 et l’IAH étaient significativement associés à un index de micro-éveils respiratoires plus élevé. Conclusion Pour une sévérité donnée d’AS, les adultes avec T21 présentaient un phénotype spécifique d’AS avec un impact distinct sur l’architecture et la fragmentation du sommeil. La prévalence d’AS centrale est probablement sous-estimée dans cette population.

Excessive daytime sleepiness is a consistent and common symptom in sleep medicine. It represents a major public health problem due to its association with significant impairments in quality of life, work productivity, and driving ability. Objective clinical tests for assessing excessive daytime sleepiness follow the universal American academy of sleep medicine scoring classification, which overlooks short intrusions of sleep during wake states, known as microsleep episodes. This narrative review provides a comprehensive summary of the existing literature concerning microsleep episodes, highlighting their significance and potential additional value in the context of sleepiness assessment. Moreover, due to the related attention lapses they cause, microsleep episodes may have significant implications for cognitive performance and road traffic accidents. These are discussed along with potential effective countermeasures. This review concludes by proposing an innovative framework for enriching excessive daytime sleepiness evaluation by integrating the assessment of microsleep episodes into routine clinical tests. Such an approach promises to provide valuable insights into the dynamics of sleepiness and could significantly enhance excessive daytime sleepiness assessment and management through personalized medicine.

RATIONALE:Chronic obstructive pulmonary disease (COPD) is the most common indication for domiciliary non-invasive ventilation (NIV), but long-term outcomes data are limited. OBJECTIVE:This multistate model analysis estimated the impact of NIV therapy continuation versus cessation on transitions between three different disease states. METHODS:Model data came from the French national health insurance reimbursement system database for individuals aged ≥40 years with COPD and ≥1 NIV reimbursement in 2015-2019. MEASUREMENT AND MAIN RESULTS:Data from 49 503 patients started on NIV were included (median age 70 years, 51.2% male, median 1 exacerbation in the previous year). There were 80 361 severe exacerbations and 18 125 deaths (including 7805 in severe exacerbation). In multistate models, NIV continuation was associated with a significant reduction in transition to death, from severe exacerbation (HR 0.84, 95% CI 0.79 to 0.91) and without exacerbation (HR 0.88, 95% CI 0.83 to 0.93). NIV continuation versus cessation had no significant effect on transition between without exacerbation to severe exacerbation (HR 0.98, 95% CI 0.95 to 1.00) but was significantly associated with slower transition from severe exacerbation to without exacerbation (HR 0.87, 95% CI 0.84 to 0.89). CONCLUSION:This multistate model analysis found that the long-term use of domiciliary NIV was associated with a lower risk of transitions to death, but was not associated with a reduction in recovery time after severe exacerbation. These data highlight the potential mortality benefits of long-term domiciliary NIV in COPD and can be used as one piece of evidence to support evidence-based guideline recommendations.

BACKGROUND:Data regarding the effect of positive airway pressure (PAP) therapy for obstructive sleep apnoea (OSA) on all-cause mortality are inconsistent. We aimed to conduct a systematic review and meta-analysis to test the hypothesis that PAP therapy is associated with reduced all-cause and cardiovascular mortality in people with OSA. METHODS:For this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials, from database inception to Aug 22, 2023 (updated Sept 9, 2024), with no language or geographical restrictions. Reference lists of eligible studies and recent conference abstracts (2022-23) were also reviewed. We included outpatient studies (randomised controlled trials [RCTs] or confounder-adjusted, non-randomised controlled studies [NRCSs]) assessing the incidence of all-cause mortality, cardiovascular mortality, or both in adults (aged ≥18 years) with OSA who were treated versus not treated with PAP; other study types and studies that evaluated only PAP adherence were excluded. Abstracts of all retrieved publications were independently screened by two of three researchers (BS, SRB, and KCW), with disagreements resolved by adjudication from another researcher (SHM). The AutoLit feature of the Nested Knowledge platform was used for the review and data-extraction phases. We analysed each log-transformed hazard ratio (HR) and SE using a linear random-effects model to estimate overall HRs and 95% CIs. To evaluate the risk of bias, we used the Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa Scale for NRCSs. This study was registered with PROSPERO, CRD42023456627. FINDINGS:Of 5484 records identified by our search, 435 were assessed for eligibility and 30 studies were included in the systematic review and meta-analysis (ten RCTs and 20 NRCSs). These studies included 1 175 615 participants, of whom 905 224 (77%) were male and 270 391 (23%) were female (SE 1·9), with a mean age of 59·5 (SE 1·4) years and a mean follow-up of 5·1 (0·5) years. The risk of bias was low to moderate. The risk of all-cause mortality (HR 0·63, 95% CI 0·56-0·72; p<0·0001) and cardiovascular mortality (0·45, 0·29-0·72; p<0·0001) was significantly lower in the PAP group than in the no-PAP group, and the clinically relevant benefit of PAP therapy increased with use. INTERPRETATION:Our results are consistent with a potentially beneficial effect of PAP therapy on all-cause and cardiovascular mortality in patients with OSA. Patients should be made aware of this effect of their treatment, which could result in greater acceptance of treatment initiation and greater adherence, leading to a higher likelihood of improved outcomes. FUNDING:ResMed.

PURPOSE:Obstructive sleep apnea (OSA) is typically treated with continuous positive airway pressure (CPAP) therapy. Some patients experience residual excessive daytime sleepiness (EDS) under CPAP. Pitolisant demonstrated effectiveness in reducing EDS. An individual patient meta-analysis was conducted assessing the efficacy and safety of pitolisant 20 mg and 40 mg versus placebo to treat EDS in patients with OSA using CPAP. METHODS:A study-patient, hierarchical, random-effects model was used. Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance test (OSLER) were co-primary endpoints. Secondary endpoints included EDS-Z scores, fatigue, clinical global impression, and quality of life (QoL). RESULTS:The searches identified three randomized controlled trials. Individual patient data were derived from 423 patients (placebo: n = 120, pitolisant 20 mg: n = 183, pitolisant 40 mg: n = 120). Treatment effects on ESS were -3.20 (95 % confidence interval [CI]: 4.37, -2.00; P < 0.001) and -3.57 (95 % CI: 4.87, -2.80); P < 0.001) for the 20 mg and 40 mg doses, with corresponding standardized mean differences (SMD) of -0.71 (95 % CI: 0.45, -0.97) and -0.79 (95 % CI: 0.51, -1.08). Treatment effects in minutes for OSLER were 1.24 (95 % CI: 0.60, 1.10, SMD = 0.61; P = 0.001) and 1.21 (95 % CI: 0.06, 1.38, SMD = 0.51; P = 0.006). Pitolisant 40 mg was superior to the 20-mg dose for older age (≥50 years) and higher baseline apnea-hypopnea index values (≥15). No significant differences were observed for safety outcomes. CONCLUSION:Pitolisant 20 mg and 40 mg were significantly therapeutically superior to placebo in treating residual EDS in patients with OSA who received CPAP on the outcomes for ESS, OSLER, and QoL.

BACKGROUND:OSA is associated with coronary artery disease (CAD) risk. This study examined the impact of positive airway pressure (PAP) therapy adherence on health care resource use (HCRU) in patients with CAD and newly diagnosed OSA. RESEARCH QUESTION:Is adherence to PAP therapy associated with reduced HCRU in patients with CAD and OSA? STUDY DESIGN AND METHODS:This retrospective analysis linked administrative claims to objective PAP use data (ResMed AirView) for adults (≥ 18 years of age) with CAD who received a new diagnosis of OSA. Two-year adherence was defined by the number of 90-day time frames in which adherence criteria were met. Inverse probability of treatment weighting was applied to assess primary outcomes of emergency room (ER) visits and hospitalizations 1 and 2 years after the index date. RESULTS:Thirty-two thousand nine hundred eleven patients were included (34.9% female; mean age, 60.9 years). Compared with adherent patients, nonadherent patients were slightly younger, more commonly female, and had higher prevalence of severe obesity and comorbidities. Compared with nonadherent patients, adherent patients made significantly fewer ER visits (-26% and -24%; P < .001) and all-cause hospitalizations (-35% and -39%; P < .001) in years 1 and 2, respectively. HCRU for intermediately adherent patients fell between that of adherent and nonadherent patients. After risk adjustment, the threshold for minimum nightly PAP use to derive a significant HCRU benefit was < 3 h/night for all outcomes and periods. A 4.7% to 5.9% reduction in HCRU rates with each additional hour per night of PAP use was noted. INTERPRETATION:In real-world patients with CAD and newly diagnosed OSA, PAP therapy adherence was associated with lower HCRU. These findings strongly support the importance of diagnosing and treating OSA in these patients.

BACKGROUND:Insomnia and OSA, together known as comorbid insomnia and OSA (COMISA), are highly prevalent sleep disorders, each of which has the potential to impair treatment efficacy for the other. RESEARCH QUESTION:Is adherence to positive airway pressure (PAP) therapy, the first-line treatment for OSA, associated with reduced health care resource use in patients with COMISA? STUDY DESIGN AND METHODS:We linked de-identified payer-sourced medical claims and objective PAP use data for patients with insomnia and newly diagnosed with OSA. Inverse probability of treatment weighting was used to create covariate-balanced groups of patients who either were adherent, intermediately adherent, or nonadherent to PAP therapy to compare rates of hospitalizations and emergency room (ER) visits. A contextual analysis was conducted among those with OSA without insomnia. RESULTS:From a sample of 27,071 patients with COMISA (average age, 53.6 years; 53% female), 72% were at least intermediately adherent to PAP over 2 years. During the first year, PAP adherence was associated significantly with fewer ER visits (mean [SD]: adherent, 0.50 [1.39] vs intermediate, 0.59 [1.36] [P < .001]; vs nonadherent, 0.68 [1.74] [P < .001]) and all-cause hospitalizations (mean [SD]: adherent, 0.10 [0.53] vs intermediate, 0.15 [0.60] [P < .001]; vs nonadherent, 0.14 [0.57] [P < .001]). Results were similar in the second year of PAP use. When viewed in the context of patients with OSA without insomnia, patients with COMISA showed lower PAP use and higher rates of resource use both before and after the index date, but showed similar relative reductions in ER visits and hospitalizations with PAP adherence. INTERPRETATION:These results provide additional evidence from a large, diverse sample to support the treatment of OSA in patients with COMISA and encourage development of COMISA-specific strategies to improve acceptance of PAP therapy.

Introduction Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity and systemic insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction. Objective We hypothesize that sympathetic hyperactivity and metabolic alterations induced by IH participate in the aggravation of ischemic cardiomyopathy via activation of G protein-coupled receptors kinase (GRK2), known to be involved in adrenergic desensitization. To investigate the detrimental role of GRK2, we used paroxetine, described as a specific GRK2 inhibitor. Method MI is induced in C57bl6 mice by permanent ligation of the left coronary artery. Mice are then randomized to IH (21–5% FiO2, 60 s cycle, 8h/day) or normoxia (N) for up to 6 weeks. After two weeks exposure, mice are treated with a GRK2 inhibitor, paroxetine (5mg/kg/d), or 25% DMSO (Alzet® pumps). Longitudinal follow-up of mice includes evaluation of sympathetic activity (spectral analysis of heart rate variability (HRV), systemic insulin sensitivity (dynamic insulin tolerance test) and determination of cardiac function/remodeling (echocardiography). At the end of the protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining). Assessment of insulin signaling pathway is performed by Western blot 15min after injection of NaCl or insulin (0,5UI/kg). Results Compared to N condition, IH worsens post-MI contractile dysfunction (i.e. ejection fraction), which is prevented by paroxetine treatment. Whereas IH does not induce cardiomyocyte hypertrophy, it results in increased cardiac interstitial fibrosis and apoptosis, which are limited by paroxetine. Our results evidence an IH-induced sympathetic overactivity in MI mice [i.e. increase in LF (Low Frequencies), derived from HRV analysis]. Paroxetine abolishes the increase in LF in MI-IH condition and restores mRNA expression of β1 and β2 adrenergic receptors. Finally, IH induces post-MI systemic insulin resistance compared to MI-N condition, which is prevented by paroxetine. This beneficial effect of paroxetine could result from improvement of insulin signaling in liver and muscle of MI-IH mice (pIRβ & pAKT). Conclusion Inhibition of GRK2 by paroxetine limits IH-induced worsening of ischemic cardiomyopathy, by limiting both cardiac sympathetic hyperactivity and systemic insulin resistance.

Chronic conditions such as cardiovascular disease, diabetes, and chronic obstructive pulmonary disease are associated with obstructive sleep apnea (OSA). These conditions are more prevalent in older adults, who may be at heightened risk for OSA. Studies on OSA prevalence have primarily focused on individuals aged up to 70 years, leaving a significant gap in data regarding the population >70 years. Therefore, it is crucial to assess the prevalence of OSA in this group. We aimed to estimate the prevalence of OSA among older adults across the United States through 2050. A dynamic open-cohort Markov model was constructed to simulate changes in population structure from 2020 to 2050. Parameters for population growth, the progression of OSA, body mass index (BMI) trajectories, all-cause mortality, and mortality linked to OSA and BMI were based on estimates from existing literature and were modeled across various subgroups categorized by age, sex, and BMI trends, updated every five years. OSA prevalence was adjusted according to age, sex, and BMI subgroups. The projection of OSA prevalence (defined as AHI >5) was focused on individuals aged 70-85 years. From 2020 to 2050, the prevalence of OSA in older adults is projected to increase substantially. The overall prevalence of OSA with AHI ≥ 5 is expected to rise by 136%, from 11.9 (33%) million cases in 2020 to 28.2 (53.7%) million cases in 2050. For older females, the prevalence of OSA (AHI ≥ 5) will see an increase of 159%, from 4.7 million (23% of females 70-85 years) cases in 2020 to 12.1 million (45.0%) cases in 2050. For older males, the increase will be more moderate than for females, with a rise of 121%, from 7.3 million (45.7%) cases in 2020 to 16.1 million (63.4%) cases in 2050. The prevalence of OSA in older adults is expected to rise significantly through 2050, with the most pronounced increase among older females. The potential clinical implications of these findings highlight the need for targeted healthcare strategies in the United States to address the anticipated growth in OSA burden in the aging population. ResMed

The global obesity pandemic contributes to an increase in the prevalence of obesity hypoventilation syndrome (OHS). OHS is associated with poor prognosis and early mortality. Definitions of OHS and disease severity classifications differ between international guidelines, and consideration of polysomnographic features is often lacking. To address this, the European Respiratory Society has proposed a severity classification approach. It is also important to consider the possibility that patients with OHS might have multiple factors contributing to hypercapnia, including obesity-related changes in the respiratory system, alterations in central respiratory drive, and different sleep-disordered breathing (SDB) abnormalities. There are also multiple health trajectories that occur before an OHS diagnosis. Positive airway pressures such as continuous positive airway pressure or non-invasive ventilation are the mainstay of OHS treatment. The choice of therapy needs to be guided by appropriate SDB phenotyping and daytime hypercapnia severity. Comorbidities are common in patients with OHS and these trigger and increase the risk of acute on chronic respiratory failure. Appropriate management of comorbidities, and weight loss management, are essential (including behavioral interventions, physical activity, pharmacotherapy, and metabolic/bariatric procedures, as appropriate for each individual). Newer pharmacological treatments such as glucagon-like peptide-1 receptor agonists, recombinant human leptin, and orexin receptor antagonists are promising, but have not yet been specifically investigated in OHS populations. Overall, there is a need for a significant redesign in assessment and care to facilitate the evidence-based management of the complex and diverse OHS presentations in clinical practice.

Daridorexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia disorder in adults. Approximately 30%-35% of patients with insomnia disorder also have obstructive sleep apnoea (OSA) of any severity. It is unclear whether sleep medications provide safe and effective treatment for insomnia in these patients. This post hoc analysis evaluated the efficacy and safety of daridorexant 25 and 50 mg on objective and self-reported insomnia variables and self-reported daytime functioning in patients with untreated mild OSA and comorbid insomnia disorder (COMISA). This analysis included participants with insomnia disorder enrolled in the Phase 3 study assessing either daridorexant 25 or 50 mg with an apnoea/hypopnoea index 5-< 15 events/h ('mild OSA'). Wake after sleep onset (WASO), latency to persistent sleep (LPS), self-reported total sleep time (sTST) and the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) were assessed at Months 1 and 3. Safety endpoints were treatment-emergent adverse events, daytime somnolence and next-morning residual effects. In participants with mild OSA, daridorexant improved WASO, LPS, sTST and IDSIQ total score over time. The average treatment effect size for all efficacy parameters was numerically greater with daridorexant 50 mg than with daridorexant 25 mg; daridorexant 25 mg was not always greater than placebo. No safety concerns were reported for daridorexant 50 or 25 mg. In participants with comorbid insomnia and untreated mild OSA, daridorexant 50 mg versus placebo improved all sleep parameters over time and was well tolerated. Daridorexant warrants further investigation in COMISA. Trial Registration: ClinicalTrials.gov identifier: NCT03545191.

STUDY OBJECTIVES:Despite the well-established benefits of positive airway pressure therapy in obstructive sleep apnea, adoption and persistence rates vary widely. Self-efficacy, motivation, and social support may be important behavioral determinants of positive airway pressure usage, but few studies have examined the role of these factors in real-world populations. METHODS:This retrospective analysis examined the association between behavioral survey data and objectively measured positive airway pressure usage data among positive airway pressure therapy users with obstructive sleep apnea. A feature selection process helped to identify key behavioral predictors of positive airway pressure usage, and Firth's logistic regression estimated the association between selected behavioral determinants and short- (90 days) and long-term (360 days) positive airway pressure therapy usage. Regressions controlled for demographic and clinical factors, positive airway pressure device type, and length of therapy use. RESULTS:A total of 11 228 respondents were included in the 90-day assessment and 3605 were included in the 360-day assessment. Confidence to stay on therapy, identification of a motivator, and involvement of a health care provider were significantly associated with greater odds of both short- and long-term positive airway pressure usage. In males and females, confidence was a significant determinant of greater odds of positive airway pressure usage, but there were gender differences by the type of motivation and the importance of social support. CONCLUSIONS:Confidence, motivation, and healthcare provider involvement may play an important role in achieving both short- and long-term positive airway pressure therapy usage. These insights, alongside the observed differences in behavioral drivers by gender, suggest an opportunity to better understand and tailor positive airway pressure follow-up strategies that leverage behavior change determinants. Statement of Significance Despite the well-established benefit of positive airway pressure (PAP) therapy for the treatment of obstructive sleep apnea (OSA), patient usage can vary widely. This study is one of the largest real-world investigations of behavioral factors associated with PAP usage, including patient self-efficacy, motivation, and social support. Our findings underscore the importance of confidence, motivational factors, and healthcare provider involvement in achieving short- and long-term PAP therapy usage. Notably, we also identified key gender differences, reinforcing the importance of personalized approaches. Our study provides actionable strategies for PAP adherence interventions, with implications for improving long-term OSA management.