ABSTRACT
Background and objective
In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death‐1 (PD‐1) receptor ...and its ligand (PD‐L1). Because the risk of OSA‐related cancer depends on age, we assessed PD‐L1/PD‐1 expression in middle‐aged and older patients with OSA as well as in a murine model.
Methods
PD‐L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD‐L1 expression on monocytes and plasma PD‐L1 protein levels. Moreover, we analysed PD‐L1 expression on an in vivo IH model with old and young mice.
Results
In subjects up to 55 years of age, severe OSA increased PD‐L1 surface protein and mRNA level expression on monocytes and soluble‐PD‐L1 protein concentration in plasma compared to HV. PD‐L1 and hypoxia‐induced factor (HIF)‐1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD‐L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF‐1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD‐L1 expression in monocytes was related to HIF‐1α expression in young patients with OSA.
Conclusion
PD‐L1 upregulation in patients with OSA as a consequence of HIF‐1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.
Hypoxia‐induced upregulation of the programmed cell death‐1 receptor and its ligand (PD‐L1) may explain associations between sleep apnoea and cancer. This link may be age‐dependent but, contrary to expectations, this study shows that PD‐L1 upregulation in sleep apnoea occurs mainly in younger patients.
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Introduction
Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. ...Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy.
Methods
The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using
in vitro
models. In addition, PSGL-1 impact on T-cells function was evaluated by
ex vivo
models.
Results
Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia.
Discussion
In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.
Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-β) plays a crucial role ...in the development and progression of atherosclerosis. In this context, the central regulator of TGF-β pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.
Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea ...suppression on DKD progression is unclear.
To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA.
In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (
= 93) or usual care alone (
= 92).
UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% 95% confidence interval, -19.06 to -2.06;
= 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life.
In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).
/Objective: Sleep-disordered breathing (SDB) may change from the acute to stable phase of some cardiovascular disorders, but little is known whether these dynamic changes also exist in pulmonary ...embolism (PE). This study aimed to analyze the changes in the apnea-hypopnea index (AHI) from the acute to stable phase of PE as well as the factors associated.
We conducted a prospective, longitudinal and multicenter study of consecutive adults requiring hospitalization for non-hypotensive acute PE, with a protocol including clinical, imaging (transthoracic echocardiography TTE and computed tomography), blood tests and a sleep study within 48 h of diagnosis of PE. After 3 months of follow-up, the sleep study was repeated. Right ventricular (RV) dysfunction was defined according to TTE criteria.
One hundred and eleven patients (mean age SD: 63 15 years; body mass index: 28.4 4.7 kg/m2) were included. The initial AHI was 24.4 (21.8) events/h (AHI≥5: 82.8 %; AHI≥30: 33.3 %). Seventy-seven patients (69.4 %) had RV dysfunction. In the overall cohort, the AHI decreased by 8.7 events/h from the acute to stable phase (24.4/h vs. 15.7/h; p=0.013). Patients with RV dysfunction showed a greater decrease in AHI (mean decrease 12.3/h vs. 0.43/h). In the multivariable analysis a drop of an AHI≥5 events/hour was independently associated with the presence of initial RV dysfunction (hazard ratio 3.9; 95%CI 1.3 to 12.1).
In hemodynamically stable patients with acute PE, there is a transient but clinically significant decrease in the AHI from the acute to stable phase, particularly when initially presenting with RV dysfunction.
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•Obstructive sleep-disordered breathing (SDB) events are highly prevalent in patients with acute pulmonary embolism (PE).•The number of obstructive SDB events temporarily increase during the acute phase of PE with concomitant right ventricular dysfunction (RVD).•Clinicians are recommended to perform a sleep study within a stable phase when there is suspicion of obstructive sleep apnea in patients with acute PE and RVD.
Our aim was to assess the effect of continuous positive airway pressure (CPAP) on the nocturnal evolution of peripheral chemosensitivity, renin-angiotensin-aldosterone system activity, sympathetic ...tone and endothelial biomarkers in obstructive sleep apnoea (OSA) patients with isolated nocturnal hypertension (INH) or day-night sustained hypertension (D-NSH).In a crossover randomised trial, 32 OSA patients newly diagnosed with hypertension and without antihypertensive treatment were randomly assigned to 12 weeks of CPAP or sham CPAP. Peripheral chemosensitivity was evaluated before and after sleep using the hypoxic withdrawal test (%Δ
).At baseline, D-NSH patients showed higher %Δ
before sleep and higher levels of aldosterone and diurnal catecholamines. CPAP only reduced the nocturnal increase of %Δ
in INH patients (6.9%, 95% CI 1.0-12.8%; p=0.026). CPAP-induced change from baseline in %Δ
after sleep was 7.5% (95% CI 2.6-12.2%, p=0.005) in the INH group and 5.7% (95% CI 2.2-9.3%, p=0.004) in the D-NSH group. In contrast, %Δ
before sleep only decreased with CPAP in the D-NSH patients (3.0%, 95% CI 0.5-5.6%; p=0.023).In conclusion, CPAP reduces the nocturnal increase of peripheral chemosensitivity experienced by INH patients and corrects the high daytime sensitivity of patients with D-NSH. Differences in response to CPAP between these patients can help better understand the mechanisms of perpetuation of hypertension in sleep apnoea.
Obstructive sleep apnea (OSA) has been associated with cardiovascular events (CVEs), although recent randomized controlled trials have not demonstrated that long-term continuous positive airway ...pressure (CPAP) prevents CVEs. Our objective was to determine the effect of CPAP on older adults with moderate OSA regarding CVE reduction.
An observational and multicenter study of a cohort of older adults (> 70 years of age) diagnosed with moderate OSA (apnea-hypopnea index 15.0-29.9 events/h) was conducted. Two groups were formed: (1) CPAP treatment and (2) standard of care. The primary endpoint was CVE occurrence after OSA diagnosis. Association with CPAP treatment was assessed by propensity score matching and inverse weighting probability. Secondary endpoints were incidence of CVE separately and time to first CVE.
A total of 614 patients were included. After matching, 236 older adults (111 men, mean age 75.9 ± 4.7 years) with a follow-up of 47 months (interquartile range: 29.6-64.0 months) were considered for primary and secondary endpoint evaluations. Forty-one patients presented at least 1 CVE (17.4%): 20 were in the standard-of-care group (16.9%) and 21 were in the CPAP group (17.8%), with a relative risk of 1.05 (95% confidence interval CI, 0.60-1.83;
= .43) for CPAP treatment. Inverse probability weighting of the initial 614 patients determined an adjusted relative risk of 1.24 (95% CI, 0.79-1.96;
= .35) for CPAP treatment. No statistical differences were found in secondary endpoint analyses.
CPAP should not be prescribed to reduce CVE probability in older adults with moderate OSA.
López-Padilla D, Terán-Tinedo J, Cerezo-Lajas A, et al. Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study).
. 2022;18(2):553-561.
Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19).
What is the incidence of VTE and bleeding among ...hospitalized patients with COVID-19?
In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language. Incidence estimates were pooled by using random effects meta-analyses. Heterogeneity was evaluated by using the I
statistic, and publication bias was assessed by using the Begg and Egger tests.
The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding. In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs. The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%).
Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies. Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection. Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes.
PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/.
Noninvasive ventilation (NIV) prolongs survival and quality of life in amyotrophic lateral sclerosis (ALS); however, its benefits depend upon the optimisation of both ventilation and adherence. We ...aimed to identify factors associated with effective initiation and ongoing use of NIV in ALS to develop evidence-based guidance and identify areas for further research.
We searched 11 electronic databases (January 1998 to May 2018) for all types of quantitative and qualitative studies. Supplementary grey literature searches were conducted. Records were screened against eligibility criteria, data were extracted from included studies and risk of bias was assessed. We present findings using a narrative synthesis.
We screened 2430 unique records and included 52 quantitative and six qualitative papers. Factors reported to be associated with NIV optimisation included coordinated multidisciplinary care, place of initiation, selection of interfaces, ventilator modes and settings appropriate for the individual patient, and adequate secretion management. The literature indicated that patients with significant bulbar dysfunction can still derive considerable benefit from NIV if their needs are met. Research emphasises that obstructive airway events, mask leak and uncontrolled secretions should be addressed by adjustments to the interface and machine settings, and the concomitant use of cough augmentation.
This review highlights that NIV optimisation requires an individualised approach to respiratory management tailored to the differing needs of each patient. Ultimately, this should lead to improved survival and quality of life. This review expands on recommendations in current international guidelines for NIV use in ALS and identifies areas for future research.
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