Pulse Wave Amplitude Drops Index: A Biomarker of Cardiovascular Risk in Obstructive Sleep Apnea.

Rationale: It is currently unclear which patients with obstructive sleep apnea (OSA) are at increased cardiovascular risk. Objective: To investigate the value of pulse wave amplitude drops (PWADs), reflecting sympathetic activations and vasoreactivity, as a biomarker of cardiovascular risk in OSA. Methods: PWADs were derived from pulse oximetry-based photoplethysmography signals in three prospective cohorts: HypnoLaus (N = 1,941), the Pays-de-la-Loire Sleep Cohort (PLSC; N = 6,367), and "Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome. Effect of intervention with CPAP" (ISAACC) (N = 692). The PWAD index was the number of PWADs (>30%) per hour during sleep. All participants were divided into subgroups according to the presence or absence of OSA (defined as ⩾15 or more events per hour or <15/h, respectively, on the apnea-hypopnea index) and the median PWAD index. Primary outcome was the incidence of composite cardiovascular events. Measurements and Main Results: Using Cox models adjusted for cardiovascular risk factors (hazard ratio; HR [95% confidence interval]), patients with a low PWAD index and OSA had a higher incidence of cardiovascular events compared with the high-PWAD and OSA group and those without OSA in the HypnoLaus cohort (HR, 2.16 [1.07-4.34], P = 0.031; and 2.35 [1.12-4.93], P = 0.024) and in the PLSC (1.36 [1.13-1.63], P = 0.001; and 1.44 [1.06-1.94], P = 0.019), respectively. In the ISAACC cohort, the low-PWAD and OSA untreated group had a higher cardiovascular event recurrence rate than that of the no-OSA group (2.03 [1.08-3.81], P = 0.028). In the PLSC and HypnoLaus cohorts, every increase of 10 events per hour in the continuous PWAD index was negatively associated with incident cardiovascular events exclusively in patients with OSA (HR, 0.85 [0.73-0.99], P = 0.031; and HR, 0.91 [0.86-0.96], P < 0.001, respectively). This association was not significant in the no-OSA group and the ISAACC cohort. Conclusions: In patients with OSA, a low PWAD index reflecting poor autonomic and vascular reactivity was independently associated with a higher cardiovascular risk.

Sleep Apnea and Incident Unprovoked Venous Thromboembolism: Data from the Pays de la Loire Sleep Cohort.

BACKGROUND: Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA. MATERIAL AND METHODS: Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment. RESULTS: After a median [interquartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01-1.02]; p = 0.02). The CPAP treatment has no significant impact on VTE incidence. CONCLUSION: Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

Positive Airway Pressure Adherence, Mortality, and Cardiovascular Events in Patients with Sleep Apnea.

Rationale: Randomized controlled trials showed no effect of positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) on cardiovascular (CV) risk. However, patient selection and low PAP adherence preclude the generalization of their data to clinical samples. Objectives: To evaluate the association between hours of PAP use, mortality, and CV morbidity in real-life conditions. Methods: Data from the Pays de la Loire Cohort were linked to health administrative data to identify incident major adverse cardiovascular events (MACEs; a composite outcome of mortality, stroke, and cardiac diseases) in patients with OSA who were prescribed PAP. Cox proportional hazards analyses were conducted to evaluate the association between MACEs and quartiles of average daily PAP use over the study period. Measurements and Main Results: After a median follow-up of 6.6 years, 961 of 5,138 patients experienced MACEs. Considering nonadherent patients (0-4 h/night) as the reference group, adjusted hazard ratios (95% confidence intervals) for MACEs were 0.87 (0.73-1.04) for the 4-6 h/night group, 0.75 (0.62-0.92) for the 6-7 h/night group, and 0.78 (0.65-0.93) for the ⩾7 h/night group (P = 0.0130). Sensitivity analyses using causal inference approaches confirmed the association of PAP use with MACEs. The association was stronger in male patients (P value for interaction = 0.0004), patients without overt CV disease at diagnosis (P < 0.0001), and those belonging to the excessively sleepy symptom subtype (P = 0.060). Conclusions: These real-life clinical data demonstrate a dose-response relationship between PAP adherence and incident MACEs in OSA. Patient support programs may help improve PAP adherence and CV outcomes in patients with OSA.

Overnight pulse rate variability and risk of major neurocognitive disorder in older patients with obstructive sleep apnea.

BACKGROUND: Increasing evidence links obstructive sleep apnea (OSA) to cognitive decline. Autonomic dysfunction assessed by heart rate variability is a promising early biomarker of cognitive impairment in populations without major neurocognitive disorder (MND). We aimed to determine whether nocturnal pulse rate variability (PRV) extracted from oximetry signal and OSA severity could predict MND onset among older OSA patients. METHODS: This study relied on data collected within the multicenter longitudinal Pays de la Loire Sleep Cohort, linked to health administrative data to identify new-onset MND. We included patients ≥60 years with newly diagnosed OSA, and no history of MND or atrial fibrillation. Cox proportional-hazards models were used to evaluate the association of MND with indices of PRV and OSA severity generated from sleep recordings. RESULTS: After a median follow-up of 6.8 [4.7-9.4] years, 70 of 3283 patients (2.1%) had been diagnosed with MND. In multivariable Cox models, MND incidence was associated with age (p < 0.0001), depression (p = 0.013), and PRV assessed by the root mean square of the successive normal-to-normal (NN) beat interval differences (RMSSD; p = 0.008) and standard deviation of NN beat intervals (SDNN; p = 0.02). Patients with the highest quartile of RMSSD had a 2.3-fold [95%CI 1.11-4.92] higher risk of being diagnosed with MND. Indices of OSA and nocturnal hypoxia severity were not associated with MND. CONCLUSIONS: Within a large clinic-based cohort of older patients with OSA, we found an association between oximetry-based indices of PRV and the onset of MND. Nocturnal oximetry-derived PRV indices could allow the early identification of OSA patients at higher risk of MND.

Sleep Apnea-Specific Hypoxic Burden, Symptom Subtypes, and Risk of Cardiovascular Events and All-Cause Mortality.

Rationale: Data from population-based cohorts suggest that symptom subtypes and obstructive sleep apnea (OSA)-specific hypoxic burden (HB) could help to better identify patients with OSA at high cardiovascular (CV) risk. Objectives: We aimed to evaluate whether those new markers are associated with the risk of major adverse CV events (MACE) in clinical setting. Methods: Data from the Pays de la Loire cohort were linked to health administrative data to identify the occurrence of MACE (a composite outcome including all-cause mortality, acute myocardial infarction, stroke, and unplanned coronary revascularization) in patients with newly diagnosed OSA and no overt CV disease. Latent class analysis was used to identify subtypes based on eight clinically relevant variables. HB was defined as the total area under the respiratory event-related desaturation curve. Cox proportional hazards models were used to evaluate the association of symptom subtypes and HB with MACE. Measurements and Main Results: Four symptom subtypes were identified (minimally symptomatic [22.0%], disturbed sleep [17.5%], excessively sleepy [49.8%], and moderately sleepy [10.6%]). After a median follow-up of 78 months (interquartile range, 52-109), 592 (11.05%) of 5,358 patients experienced MACE. In a fully adjusted model, HB and overall nocturnal hypoxemia assessed by sleep time with oxygen saturation <90% were the only predictors of MACE (hazard ratio, 1.21; 95% confidence interval, 1.07-1.38; and hazard ratio, 1.34; 95% confidence interval, 1.16-1.55, respectively). The association appeared stronger toward younger patients and women. Conclusion: In clinical setting, patients with OSA who demonstrate elevated OSA-specific HB are at higher risk of a CV event and all-cause mortality. Symptom subtypes were not associated with MACE after adjustment for confounders.

Quantifying the effects of sleep loss: relative effect sizes of the psychomotor vigilance test, multiple sleep latency test, and maintenance of wakefulness test.

The psychomotor vigilance test (PVT) is a widely-used, minimally invasive, inexpensive, portable, and easy to administer behavioral measure of vigilance that is sensitive to sleep loss. We conducted analyses to determine the relative sensitivity of the PVT vs. the multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) during acute total sleep deprivation (TSD) and multiple days of sleep restriction (SR) in studies of healthy adults. Twenty-four studies met the criteria for inclusion. Since sleepiness countermeasures were administered in some of these studies, the relative sensitivity of the three measures to these interventions was also assessed. The difference in weighted effect size (eta-squared) was computed for each pair of sleepiness measures based on available raw test data (such as average PVT reaction time). Analyses revealed that the sleep measures were differentially sensitive to various types of sleep loss over time, with MSLT and MWT more sensitive to TSD than the PVT. However, sensitivity to SR was comparable for all three measures. The PVT and MSLT were found to be differentially sensitive to the administration of sleepiness countermeasures (drugs, sleep loss, etc.), but PVT and MWT were found to be comparably sensitive to these interventions. These findings suggest the potential utility of the PVT as a component of next-generation fatigue risk management systems.

Cardiovascular risk and mortality prediction in patients suspected of sleep apnea: a model based on an artificial intelligence system.

Objective. Cardiovascular disease (CVD) is one of the leading causes of death worldwide. There are many CVD risk estimators but very few take into account sleep features. Moreover, they are rarely tested on patients investigated for obstructive sleep apnea (OSA). However, numerous studies have demonstrated that OSA index or sleep features are associated with CVD and mortality. The aim of this study is to propose a new simple CVD and mortality risk estimator for use in routine sleep testing.Approach. Data from a large multicenter cohort of CVD-free patients investigated for OSA were linked to the French Health System to identify new-onset CVD. Clinical features were collected and sleep features were extracted from sleep recordings. A machine-learning model based on trees, AdaBoost, was applied to estimate the CVD and mortality risk score.Main results. After a median [inter-quartile range] follow-up of 6.0 [3.5-8.5] years, 685 of 5234 patients had received a diagnosis of CVD or had died. Following a selection of features, from the original 30 features, 9 were selected, including five clinical and four sleep oximetry features. The final model included age, gender, hypertension, diabetes, systolic blood pressure, oxygen saturation and pulse rate variability (PRV) features. An area under the receiver operating characteristic curve (AUC) of 0.78 was reached.Significance. AdaBoost, an interpretable machine-learning model, was applied to predict 6 year CVD and mortality in patients investigated for clinical suspicion of OSA. A mixed set of simple clinical features, nocturnal hypoxemia and PRV features derived from single channel pulse oximetry were used.

Association of Nocturnal Hypoxemia and Pulse Rate Variability with Incident Atrial Fibrillation in Patients Investigated for Obstructive Sleep Apnea.

Rationale: Nocturnal hypoxemia and sympathetic/parasympathetic imbalance might contribute to the occurrence or atrial fibrillation (AF) in patients with obstructive sleep apnea (OSA). During sleep recordings, pulse rate variability (PRV) derived from oximetry might provide an accurate estimation of heart rate variability, which reflects the autonomic cardiovascular control. Objectives: We aimed to evaluate whether indices of oxygen desaturation and PRV derived from nocturnal oximetry were associated with AF incidence in patients investigated for OSA. Methods: Data from a large multicenter cohort of AF-free patients investigated for OSA between May 15, 2007, and December 31, 2017, were linked to health administrative data to identify hospitalized and nonhospitalized patients with new-onset AF. Cox proportional hazards models were used to evaluate the association between AF incidence and oximetry-derived indices automatically generated from sleep recordings. Results: After a median (interquartile range) follow-up of 5.34 (3.3-8.0) years, 181 of 7,205 patients developed AF (130 were hospitalized for AF). After adjusting for confounders, including anthropomorphic data, alcohol intake, cardiac, metabolic and respiratory diseases, ß blocker/calcium channel blocker medications, type of sleep study, study site, and positive airway pressure adherence, AF risk was associated with increasing nocturnal hypoxemia (P trend = 0.004 for quartiles of percentage of recording time with oxygen saturation <90%) and PRV (P trend < 0.0001 for quartiles of root mean square of the successive normal-normal beat interval differences), and decreasing sympathetic/parasympathetic tone (P trend = 0.0006 for quartiles of low-frequency power/high-frequency power ratio). The highest risk of AF was observed in patients with the highest quartiles of both the percentage of recording time with oxygen saturation <90% and the root mean square of the successive normal-normal beat interval differences compared with those with neither of these conditions (adjusted hazard ratio, 3.61; 95% confidence interval, 2.10-6.22). Similar associations were observed when the analyses were restricted to hospitalized AF. Conclusions: In patients investigated for OSA, nocturnal hypoxemia and PRV indices derived from single-channel pulse oximetry were independent predictors of AF incidence. Patients with both marked nocturnal hypoxemia and high PRV were at higher risk of AF. Oximetry may be used to identify patients with OSA at greatest risk of developing AF.

Positional obstructive sleep apnea within a large multicenter French cohort: prevalence, characteristics, and treatment outcomes.

STUDY OBJECTIVES: To assess, in a large cohort of patients with obstructive sleep apnea, the factors that are independently associated with positional obstructive sleep apnea (POSA) and exclusive POSA (e-POSA) and determine their prevalence. The secondary objective was to evaluate the outcome of positive airway pressure (PAP) therapy for patients with POSA and e-POSA. METHODS: This retrospective study included 6,437 patients with typical mild-to-severe OSA from the Pays de la Loire sleep cohort. Patients with POSA and e-POSA were compared to those with non-POSA for clinical and polysomnographic characteristics. In a subgroup of patients (n = 3,000) included in a PAP follow-up analysis, we determined whether POSA and e-POSA phenotypes were associated with treatment outcomes at 6 months. RESULTS: POSA and e-POSA had a prevalence of 53.5% and 20.1%, respectively, and were independently associated with time in supine position, male sex, younger age, lower apnea-hypopnea index and lower body mass index. After adjustment for confounding factors, patients with POSA and e-POSA had a significantly lower likelihood of treatment adherence (PAP daily use ≥ 4 h) at 6 months and were at higher risk of PAP treatment withdrawal compared to those with non-POSA. CONCLUSIONS: The prevalence and independent predictors of POSA and e-POSA were determined in this large clinical population. Patients with POSA and e-POSA have lower PAP therapy adherence, and this choice of treatment may not be optimal. Thus, there is a need to offer these patients an alternative therapy.

Association Between Nocturnal Hypoxemia and Cancer Incidence in Patients Investigated for OSA: Data From a Large Multicenter French Cohort.

BACKGROUND: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans. RESEARCH QUESTION: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA? STUDY DESIGN AND METHODS: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia. RESULTS: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies. INTERPRETATION: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.