Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease. Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed. Patients with OSA (n = 189; 84% men; age 66 ± 8 years, BMI 28 ± 3.5 kg/m², AHI 41 ± 23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n = 91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n = 98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes. Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA. National Institutes of Health/National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.

Rationale: Coronavirus disease (COVID-19) is an ongoing pandemic, in which obesity, hypertension, and diabetes have been linked to poor outcomes. Obstructive sleep apnea (OSA) is associated with these conditions and may influence the prognosis of adults with COVID-19. Objectives: To determine the effect of OSA on clinical outcomes in patients with COVID-19. Methods: The current prospective observational study was conducted in three hospitals in Istanbul, Turkey from March 10 to June 22, 2020. The participants were categorized as high-risk or low-risk OSA according to the Berlin questionnaire that was administered in the out-patient clinic, in hospital, or shortly after discharge from hospital blinded to the clinical outcomes. A modified high-risk (mHR)–OSA score based on the snoring patterns (intensity and/or frequency), breathing pauses, and morning/daytime sleepiness, without taking obesity and hypertension into account, were used in the regression models. Results: The primary outcome was the clinical improvement defined as a decline of two categories from admission on a 7-category ordinal scale that ranges from 1 (discharged with normal activity) to 7 (death) on Days 7, 14, 21, and 28, respectively. Secondary outcomes included clinical worsening (an increase of 1 category), need for hospitalization, supplemental oxygen, and intensive care. In total, 320 eligible patients (median [interquartile range] age, 53.2 [41.3–63.0] yr; 45.9% female) were enrolled. In all, 121 (37.8%) were categorized as known (n = 3) or high-risk OSA (n = 118). According to the modified scoring, 70 (21.9%) had mHR-OSA. Among 242 patients requiring hospitalization, clinical improvement within 2 weeks occurred in 75.4% of the mHR-OSA group compared with 88.4% of the modified low-risk–OSA group (P = 0.014). In multivariate regression analyses, mHR-OSA (adjusted odds ratio [OR], 0.42; 95% confidence interval [CI], 0.19–0.92) and male sex (OR, 0.39; 95% CI, 0.17–0.86) predicted the delayed clinical improvement. In the entire study population (n = 320), including the nonhospitalized patients, mHR-OSA was associated with clinical worsening (adjusted hazard ratio, 1.55; 95% CI, 1.00–2.39) and with the need for supplemental oxygen (OR, 1.95; 95% CI, 1.06–3.59). Snoring patterns, especially louder snoring, significantly predicted delayed clinical improvement, worsening, need for hospitalization, supplemental oxygen, and intensive care. Conclusions: Adults with mHR-OSA in our COVID-19 cohort had poorer clinical outcomes than those with modified low-risk OSA independent of age, sex, and comorbidities. Clinical trial registered with www.clinicaltrials.gov (NCT04363333).

Rationale: Recent randomized controlled trials did not show cardiovascular benefits of continuous positive airway pressure (CPAP) in adults with coronary artery disease (CAD) and obstructive sleep apnea (OSA) in intention-to-treat analyses. It has been argued that exclusion of patients with OSA with excessive daytime sleepiness (EDS), who may be most likely to benefit from CPAP treatment, may be a reason for the null results. Objectives: We addressed 1) the effect of concomitant EDS on adverse outcomes in patients with CAD and OSA; and 2) whether the cardiovascular benefit of CPAP adherence differs between individuals with versus without EDS. Methods: This was a secondary analysis of the RICCADSA (Randomized Intervention with CPAP in CAD and Obstructive Sleep Apnea) trial, conducted in Sweden between 2005 and 2013. Data were analyzed from 155 patients with CAD with OSA (apnea–hypopnea index ⩾ 15/h) and EDS (Epworth Sleepiness Scale score ⩾ 10), who were allocated to CPAP and 244 patients without EDS (ESS < 10), who were randomized to CPAP or no CPAP. Patients who were allocated to no CPAP or were nonadherent (CPAP usage < 4 h/night) were compared with adherent patients (CPAP usage ⩾ 4 h/night) at 1-year follow-up. Inverse probability of treatment weighting was applied to mimic randomization of EDS. The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Results: The median follow-up was 52.2 months. The incidence of the primary endpoint did not differ significantly between the EDS versus no-EDS groups in the entire cohort. Within the adherent group, patients without EDS had a significantly decreased risk compared with patients with EDS (adjusted hazard ratio, 0.41; 95% confidence interval, 0.20–0.85; P = 0.02). Conclusions: Adverse cardiovascular outcomes did not differ by degrees of EDS for patients with CAD with OSA who were untreated or nonadherent to treatment. CPAP use, at least 4 h/night, was associated with reduced adverse outcomes in participants without EDS. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).

The Apnea-Hypopnea Index (AHI), the standard measure of obstructive sleep apnea (OSA), has limitations in reflecting disease severity. Is high hypoxic burden (HB) more strongly associated with major cardiovascular and cerebrovascular adverse events (MACCEs) than AHI≥ 30/h? This secondary analysis of the RICCADSA observational cohort included 368 adults with OSA (AHI≥15/h), with (n=155) and without (n=244) excessive daytime sleepiness, defined as an Epworth Sleepiness Scale≥10. HB was calculated as the total area under respiratory event-related desaturations divided by total sleep time. Patients were classified as high or low HB based on the median (60.7%min/h). The primary outcome was the incident of the first MACCE. Cox proportional hazard models assessed associations in the full cohort and by CPAP allocation/adherence (nonadherent or no-PAP group: n=262; adherent [adjusted PAP usage≥ 4 h/night/all nights at 1-year follow-up]: n=106). In an exploratory analysis, participants were grouped into four categories based on median AHI and HB (low/low, low/high, high/low, high/high). Over a median follow-up of 4.7 years, high HB was associated with MACCEs (adjusted hazard ratio [HR] 1.87; 95% CI 1.17-2.98; p=0.009), particularly among untreated or non-adherent patients and those with baseline EDS. AHI ≥30/h was not significantly associated with MACCEs (p=0.366). When modelled continuously, HB and AHI were each associated with MACCEs, respectively; however, compared to low AHI/low HB, only high HB, irrespective of AHI level, was linked to increased risk. In contrast, high AHI/low HB was not associated with MACCEs. High hypoxic burden, but not AHI ≥ 30/h, was associated with MACCEs in adults with moderate to severe OSA. Although AHI was associated with outcomes when modelled continuously, elevated risk appeared to be driven primarily by high hypoxic burden.

Postoperative atrial fibrillation (POAF) occurs in 20–50% of patients with coronary artery disease (CAD) after coronary artery bypass grafting (CABG). Obstructive sleep apnea (OSA) is also common in adults with CAD, and may contribute to POAF as well to the reoccurrence of AF in patients at long-term. In the current secondary analysis of the Randomized Intervention with Continuous Positive Airway Pressure (CPAP) in Coronary Artery Disease and Obstructive Sleep Apnea (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT 00519597), we included 147 patients with CABG, who underwent a home sleep apnea testing, in average 73 ± 30 days after the surgical intervention. POAF was defined as a new-onset AF occurring within the 30 days following the CABG. POAF was observed among 48 (32.7%) patients, occurring within the first week among 45 of those cases. The distribution of the apnea-hypopnea-index (AHI) categories < 5.0 events/h (no-OSA); 5.0–14.9 events/h (mild OSA); 15.0–29.9 events/h (moderate OSA); and ≥30 events/h (severe OSA), was 4.2%, 14.6%, 35.4%, and 45.8%, in the POAF group, and 16.2%, 17.2%, 39.4%, and 27.3%, respectively, in the no-POAF group. In a multivariate logistic regression model, there was a significant risk increase for POAF across the AHI categories, with the highest odds ratio (OR) for severe OSA (OR 6.82, 95% confidence interval 1.31–35.50; p = 0.023) vs. no-OSA, independent of age, sex, and body-mass-index. In the entire cohort, 90% were on β-blockers according to the clinical routines, they all had sinus rhythm on the electrocardiogram at baseline before the study start, and 28 out of 40 patients with moderate to severe OSA (70%) were allocated to CPAP. During a median follow-up period of 67 months, two patients (none with POAF) were hospitalized due to AF. To conclude, severe OSA was significantly associated with POAF in patients with CAD undergoing CABG. However, none of those individuals had an AF-reoccurrence at long term, and whether CPAP should be considered as an add-on treatment to β-blockers in secondary prevention models for OSA patients presenting POAF after CABG requires further studies in larger cohorts.