The Role of Sleep in Cardiovascular Disease.

PURPOSE OF REVIEW: Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD. RECENT FINDINGS: Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health. There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.

Impact of PAP on the gut microbiome in OSA: A pilot study.

OBJECTIVE/BACKGROUND: Microbes within the gastrointestinal tract have emerged as modulators of the host's health. Obstructive sleep apnea (OSA) is characterized by intermittent partial, or complete, airway closure during sleep and is associated with increased risk of non-communicable diseases as well as dysbiosis of the gut microbiome. Thus, we investigated if improving nocturnal airway patency via positive airway pressure (PAP) therapy improves gut microbial diversity in recently diagnosed patients with moderate-to-severe OSA (apnea-hypopnea index ≥15.0 events/hr). PATIENTS/METHODS: Eight subjects (3 F, 56±9yrs, 33.5 ± 7.7 kg/m2, 45.0 ± 38.4 events/hr) provided stool samples before, and two months after, PAP therapy (mean adherence of 95 ± 6%, residual apnea-hypopnea index of 4.7 ± 4.6 events/hr). RESULTS: While the Shannon diversity index tended to increase following PAP (3.96 ± 0.52 to 4.18 ± 0.56, p = 0.08), there were no changes in the Observed (1,088 ± 237 to 1,136 ± 289, p = 0.28) nor Inverse-Simpson (22.4 ± 12.99 to 26.6 ± 18.23, p = 0.28) alpha diversity indices. There were also no changes in beta diversity assessed using the Bray-Curtis (p = 0.98), Jaccard (p = 0.99), WUniFrac (p = 0.98), GUniFrac (p = 0.98), or UniFrac (p = 0.98) methods. No changes in differential abundance taxa were found using a false discovery rate threshold of <0.20. CONCLUSIONS: Our data are the first to report that PAP therapy may not offset, or reverse, gut dysbiosis in patients with OSA. Accordingly, interventions which improve gut microbial health should be explored as potential adjunctive treatment options in patients with OSA to reduce their risk of developing non-communicable diseases.

Effect of Active Workstations on Neurocognitive Performance and Typing Skills: A Randomized Clinical Trial.

BACKGROUND: Extended sedentary behavior is a risk factor for chronic disease and mortality, even among those who exercise regularly. Given the time constraints of incorporating physical activity into daily schedules, and the high likelihood of sitting during office work, this environment may serve as a potentially feasible setting for interventions to reduce sedentary behavior. METHODS AND RESULTS: A randomized cross-over clinical trial was conducted at an employee wellness center. Four office settings were evaluated on 4 consecutive days: stationary or sitting station on day 1 (referent), and 3 subsequent active workstations (standing, walking, or stepper) in randomized order. Neurocognitive function (Selective Attention, Grammatical Reasoning, Odd One Out, Object Reasoning, Visuospatial Intelligence, Limited-Hold Memory, Paired Associates Learning, and Digit Span) and fine motor skills (typing speed and accuracy) were tested using validated tools. Average scores were compared among stations using linear regression with generalized estimating equations to adjust standard errors. Bonferroni method adjusted for multiple comparisons. Healthy subjects were enrolled (n=44), 28 (64%) women, mean±SD age 35±11 years, weight 75.5±17.1 kg, height 168.5±10.0 cm, and body mass index 26.5±5.2 kg/m2. When comparing active stations to sitting, neurocognitive test either improved or remained unchanged, while typing speed decreased without affecting typing errors. Overall results improved after day 1, suggesting habituation. We observed no major differences across active stations, except decrease in average typing speed 42.5 versus 39.7 words per minute with standing versus stepping (P=0.003). CONCLUSIONS: Active workstations improved cognitive performance, suggesting that these workstations can help decrease sedentary time without work performance impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06240286.

Characteristics and Outcomes of Hospitalized Patients with Heart Failure and Sarcoidosis: A Propensity-Matched Analysis of the Nationwide Readmissions Database 2010-2019.

BACKGROUND: Sarcoidosis is associated with a poor prognosis. There is a lack of data examining the outcomes and readmission rates of sarcoidosis patients with heart failure (SwHF) and without heart failure (SwoHF). We aimed to compare the impact of non-ischemic heart failure on outcomes and readmissions in these two groups. METHODS: The US Nationwide Readmission Database was queried from 2010 to 2019 for SwHF and SwoHF patients identified using the International Classification of Diseases, 9th and 10th Editions. Those with ischemic heart disease were excluded, and both cohorts were propensity matched for age, gender, and Charlson Comorbidity Index (CCI). Clinical characteristics, length of stay, adjusted healthcare-associated costs, 90-day readmission and mortality were analyzed. RESULTS: We identified 97,961 hospitalized patients (median age 63 years, 37.9% male) with a diagnosis of sarcoidosis (35.9% SwHF vs 64.1% SwoHF). On index admission, heart failure patients had higher prevalences of atrioventricular block (3.3% vs 1.4%, P < .0001), ventricular tachycardia (6.5% vs 1.3%, P < .0001), ventricular fibrillation (0.4% vs 0.1%, P < .0001) and atrial fibrillation (22.1% vs 7.5%, P < .0001). SwHF patients were more likely to be readmitted (hazard ratio 1.28, P < .0001), had higher length of hospital stay (5 vs 4 days, P < .0001), adjusted healthcare-associated costs ($9,667.0 vs $9,087.1, P < .0001) and mortality rates on readmission (5.1% vs 3.8%, P < .0001). Predictors of mortality included heart failure, increasing age, male sex, higher CCI, and liver disease. CONCLUSION: SwHF is associated with higher rates of arrhythmia at index admission, as well as greater hospital cost, readmission and mortality rates compared to those without heart failure.

Trends and Disparities in Treatment and Control of Atherosclerotic Cardiovascular Disease in US Adults, 1999 to 2018.

BACKGROUND: Although cardiovascular mortality continued declining from 2000 to 2019, the rate of this decrease decelerated. We aimed to assess the trends and disparities in risk factor control and treatment among US adults with atherosclerotic cardiovascular disease to find potential causes of the deceleration. METHODS AND RESULTS: A total of 55 ,021 participants, aged ≥20 years, from the 1999 to 2018 National Health and Nutrition Examination Survey were included, of which 5717 were with atherosclerotic cardiovascular disease. Risk factor control was defined as hemoglobin A1c <7%, blood pressure <140/90 mm Hg, and non-high-density lipoprotein cholesterol <100 mg/dL. The prevalence of atherosclerotic cardiovascular disease oscillated between 7.3% and 8.9% from 1999 to 2018. A significant increasing trend was observed in the prevalence of diabetes, obesity, heavy alcohol consumption, and self-reported hypertension within the population with atherosclerotic cardiovascular disease (Ptrend≤0.001). Non-high-density lipoprotein cholesterol <100 mg/dL increased from 7.1% in 1999 to 2002 to 15.7% in 2003 to 2006, before plateauing. Blood pressure control (<140/90 mm Hg) increased until 2011 to 2014, but declined to 70.1% in 2015 to 2018 (Ptrend<0.001, Pjoinpoint=0.14). Similarly, the proportion of participants achieving hemoglobin A1c control began to decrease after 2006 (Pjoinpoint=0.05, Ptrend=0.001). The percentage of participants achieving all 3 targets increased significantly from 4.5% to 18.6% across 1999 to 2018 (Ptrend=0.02), but the increasing trend decelerated after 2005 to 2006 (Pjoinpoint<0.001). Striking disparities in risk factor control and medication use persisted between sexes, and between different racial and ethnic populations. CONCLUSIONS: Worsened control of glycemia, blood pressure, obesity, and alcohol consumption, leveled lipid control, and persistent socioeconomic disparities may be contributing factors to the observed deceleration in decreasing cardiovascular mortality trends.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota.

OBJECTIVE: To contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. PATIENTS AND METHODS: A validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. RESULTS: Two hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. CONCLUSION: The incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

Association of sleep duration with atrial fibrillation/flutter mortality in the United States: a cross-sectional analysis.

BACKGROUND: The association between sleep duration and atrial fibrillation risk is poorly understood, with inconsistent findings reported by several studies. We sought to assess the association between long sleep duration and mortality due to atrial fibrillation/atrial flutter (AF/AFL). METHODS: The 2016-2020 Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research dataset was used to identify death records secondary to AF/AFL in the United States population. We used the 2018 Behavioral Risk Factor Surveillance System (BRFSS) dataset of sleep duration at the county level. All counties were grouped into quartiles based on the percentage of their population with long sleep duration (i.e., ≥ 7 h), Q1 being the lowest and Q4 the highest quartile. Age-adjusted mortality rates (AAMR) were calculated for each quartile. County Health Rankings for Texas were used to adjust the AAMR for comorbidities using linear regression. RESULTS: Overall, the AAMR for AF/AFL were highest in Q4 (65.9 [95% CI, 65.5-66.2] per 100,000 person-years) and lowest in Q1 (52.3 [95% CI, 52.1-52.5] per 100,000 person-years). The AAMR for AF/AFL increased stepwise from the lowest to highest quartiles of the percentage population with long sleep duration. After adjustment for the county health ranks of Texas, long sleep duration remained associated with a significantly higher AAMR (coefficient 220.6 (95% CI, 21.53-419.72, p-value = 0.03). CONCLUSIONS: Long sleep duration was associated with higher AF/AFL mortality. Increased focus on risk reduction for AF, public awareness about the importance of optimal sleep duration, and further research to elucidate a potential causal relationship between sleep duration and AF are warranted.

Novel metrics of sleep-disordered breathing are associated with outcome after ischemic stroke.

OBJECTIVE/BACKGROUND: Standard measures of sleep-disordered breathing (SDB) that rely on count data may not sufficiently capture SDB severity or reflect downstream consequences of SDB. We hypothesized that novel metrics derived from pulse rate, oxygen saturation, and nasal pressure would be associated with stroke outcomes. PATIENTS/METHODS: Shortly after ischemic stroke, participants in a population-based study were offered ApneaLink Plus testing. Signal analysis was used to generate 166 metrics from the nasal pressure cannula and finger probe, categorized as: autonomic (based on pulse rate variability), oximetry-derived, nasal pressure-derived, and mixed oxygen and nasal pressure-derived measures. Three-month outcome assessments included functional and cognitive outcomes and stroke recurrence. Tobit regression and Cox proportional hazards models were used to examine associations between each sleep apnea metric and the three outcomes, unadjusted and adjusted for multiple potential confounders. Models were adjusted for multiple comparisons. RESULTS: Of the 530 participants, the median age was 65 (IQR: 57, 73), 49 % were female, and 64 % were Mexican American. Without covariate adjustment, 23 of 166 variables were associated with functional outcome, 43 were associated with cognitive outcome, and 1 was associated with stroke recurrence. After adjustment, 7 mixed, oximetry, or nasal pressure-based metrics and 1 autonomic metric were associated with functional outcome, but none was associated with cognitive outcome or stroke recurrence. CONCLUSIONS: Many novel metrics of SDB were associated with important stroke outcomes, and 8 novel metrics were associated with functional outcome in adjusted models. This raises hypotheses about pathways by which SDB may negatively impact stroke outcomes.

Cardiovascular Disease Burden, Mortality, and Sudden Death Risk in Epilepsy: A UK Biobank Study.

BACKGROUND: Sudden death is the leading cause of mortality in medically refractory epilepsy. Middle-aged persons with epilepsy (PWE) are under investigated regarding their mortality risk and burden of cardiovascular disease (CVD). METHODS: Using UK Biobank, we identified 7786 (1.6%) participants with diagnoses of epilepsy and 6,171,803 person-years of follow-up (mean 12.30 years, standard deviation 1.74); 566 patients with previous histories of stroke were excluded. The 7220 PWE comprised the study cohort with the remaining 494,676 without epilepsy as the comparator group. Prevalence of CVD was determined using validated diagnostic codes. Cox proportional hazards regression was used to assess all-cause mortality and sudden death risk. RESULTS: Hypertension, coronary artery disease, heart failure, valvular heart disease, and congenital heart disease were more prevalent in PWE. Arrhythmias including atrial fibrillation/flutter (12.2% vs 6.9%; P < 0.01), bradyarrhythmias (7.7% vs 3.5%; P < 0.01), conduction defects (6.1% vs 2.6%; P < 0.01), and ventricular arrhythmias (2.3% vs 1.0%; P < 0.01), as well as cardiac implantable electric devices (4.6% vs 2.0%; P < 0.01) were more prevalent in PWE. PWE had higher adjusted all-cause mortality (hazard ratio [HR], 3.9; 95% confidence interval [CI], 3.01-3.39), and sudden death-specific mortality (HR, 6.65; 95% CI, 4.53-9.77); and were almost 2 years younger at death (68.1 vs 69.8; P < 0.001). CONCLUSIONS: Middle-aged PWE have increased all-cause and sudden death-specific mortality and higher burden of CVD including arrhythmias and heart failure. Further work is required to elucidate mechanisms underlying all-cause mortality and sudden death risk in PWE of middle age, to identify prognostic biomarkers and develop preventative therapies in PWE.

Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults.

Background: The reduced effectiveness of standard-dose influenza vaccines in persons ≥65 years of age led to the preferential recommendation to use high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) vaccines for this age group. Sleep is an important modulator of immune responses to vaccines and poor sleep health is common in older adults. However, potential effects of poor sleep health on immune responses to influenza vaccination in older adults remain largely unknown. Methods: We conducted a cohort study of 210 healthy participants age ≥65 years, who received either seasonal high-dose (HDFlu) or MF59-adjuvanted (MF59Flu) influenza vaccine. We assessed sleep characteristics in this cohort by standardized questionnaires and measured the antibody titer against influenza A/H3N2 virus in serum of study participants by hemagglutination inhibition assay on the day of immunization and 28 days thereafter. We then assessed the association between sleep characteristics and antibody titers. Results: Our results demonstrated that male, but not female, study participants with excessive daytime sleepiness had an impaired influenza A/H3N2-specific antibody response at Day 28 post-vaccination. No other associations were found between antibody titer and other sleep characteristics, including sleep quality and obstructive sleep apnea. Conclusion: Our results provide an additional and easily measured variable explaining poor vaccine effectiveness in older adults. Our results support that gaining sufficient sleep is a simple non-vaccine interventional approach to improve influenza immune responses in older adults. Our findings extend the literature on the negative influence of excessive daytime sleepiness on immune responses to influenza vaccination in older male adults.

Predictors of morbidity and in-hospital mortality following procedure-related cardiac tamponade.

Background: Cardiac tamponade (CT) can be a complication following invasive cardiac procedures. We assessed CT following common cardiac electrophysiology (EP) procedures to facilitate risk prediction of associated morbidity and in-hospital mortality. Methods: Patients who underwent various EP procedures in the cardiac catheterization lab (ablations and device implantations) were identified using the International Classification of Diseases, Ninth and Tenth Edition, Clinical Modification (ICD-9-CM and ICD-10-CM, respectively) from the Nationwide Inpatient Sample (NIS) database. Patient demographics, presence of comorbidities, CT-related events, and in-hospital death were also abstracted from the NIS database. Results: The frequency of CT-related events in patients with EP intervention from 2010 to 2017 ranged from 3.4% to 7.0%. In-hospital mortality related to CT-related events was found to be 2.2%. Increasing age was the only predictor of higher mortality in atrial fibrillation (AF) ablation and cardiac resynchronization therapy (CRT) groups (OR [95% CI]: AF ablation = 11.15 [1.70-73.34], p = .01; CRT = 1.41 [1.05-1.90], p = .02). Conclusions: In the real-world setting, CT-related events in EP procedures were found to be 3.4%-7.0% with in-hospital mortality of 2.2%. Older patients undergoing AF ablation were found to have higher mortality.

Performance of the ACC/AHA Pooled Cohort Cardiovascular Risk Equations in Clinical Practice.

BACKGROUND: The performance of the American College of Cardiology/American Heart Association pooled cohort equation (PCE) for atherosclerotic cardiovascular disease (ASCVD) in real-world clinical practice has not been evaluated extensively. OBJECTIVES: The goal of this study was to test the performance of PCE to predict ASCVD risk in the community, and determine if including individuals with values outside the PCE range (ie, age, blood pressure, cholesterol) or statin therapy initiation over follow-up would significantly affect PCE predictive capabilities. METHODS: The PCE was validated in a community-based cohort of consecutive patients who sought primary care in Olmsted County, Minnesota, between 1997 and 2000, followed-up through 2016. Inclusion criteria were similar to those of PCE derivation. Patient information was ascertained by using the record linkage system of the Rochester Epidemiology Project. ASCVD events (nonfatal and fatal myocardial infarction and ischemic stroke) were validated in duplicate. Calculated and observed ASCVD risk and c-statistics were compared across predefined groups. RESULTS: This study included 30,042 adults, with a mean age of 48.5 ± 12.2 years; 46% were male. Median follow-up was 16.5 years, truncated at 10 years for this analysis. Mean ASCVD risk was 5.6% ± 8.73%. There were 1,555 ASCVD events (5.2%). The PCE revealed good performance overall (c-statistic 0.78) and in sex and race subgroups; it was highest among non-White female subjects (c-statistic 0.81) and lowest in White male subjects (c-statistic 0.77). Out-of-range values and initiation of statin medication did not affect model performance. CONCLUSIONS: The PCE performed well in a community cohort representing real-world clinical practice. Values outside PCE ranges and initiation of statin medication did not affect performance. These results have implications for the applicability of current strategies for the prevention of ASCVD.

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank.

BACKGROUND: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population. OBJECTIVES: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank. METHODS: Using whole exome sequencing data, variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). RESULTS: Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (HR: 1.13 [95% CI: 1.01-1.25]; P = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR: 5.75 [95% CI: 4.58-7.23]; P < 0.0001), and elevated risk for composite outcome (HR: 1.29 [95% CI: 1.20-1.39]; P < 0.0001) than CMP-G- individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups. CONCLUSIONS: Adults with predicted deleterious variants in cardiomyopathy-associated genes exhibited a slightly higher risk of mortality and a significantly increased risk of developing cardiomyopathy, and cardiomyopathy-related composite outcomes, in comparison with genotype-negative controls.

Sex Differences in Neurovascular Control: Implications for Obstructive Sleep Apnea.

Patients with obstructive sleep apnea (OSA) have a heightened risk of developing cardiovascular diseases, namely hypertension. While seminal evidence indicates a causal role for sympathetic nerve activity in the hypertensive phenotype commonly observed in patients with OSA, no studies have investigated potential sex differences in the sympathetic regulation of blood pressure in this population. Supporting this exploration are large-scale observational data, as well as controlled interventional studies in healthy adults, indicating that sleep disruption increases blood pressure to a greater extent in females relative to males. Furthermore, females with severe OSA demonstrate a more pronounced hypoxic burden (i.e., disease severity) during rapid eye movement sleep when sympathetic nerve activity is greatest. These findings would suggest that females are at greater risk for the hemodynamic consequences of OSA and related sleep disruption. Accordingly, the purpose of this review is three-fold: (1) to review the literature linking sympathetic nerve activity to hypertension in OSA, (2) to highlight recent experimental data supporting the hypothesis of sex differences in the regulation of sympathetic nerve activity in OSA, and (3) to discuss the potential sex differences in peripheral adrenergic signaling that may contribute to, or offset, cardiovascular risk in patients with OSA.

The need to promote sleep health in public health agendas across the globe.

Healthy sleep is essential for physical and mental health, and social wellbeing; however, across the globe, and particularly in developing countries, national public health agendas rarely consider sleep health. Sleep should be promoted as an essential pillar of health, equivalent to nutrition and physical activity. To improve sleep health across the globe, a focus on education and awareness, research, and targeted public health policies are needed. We recommend developing sleep health educational programmes and awareness campaigns; increasing, standardising, and centralising data on sleep quantity and quality in every country across the globe; and developing and implementing sleep health policies across sectors of society. Efforts are needed to ensure equity and inclusivity for all people, particularly those who are most socially and economically vulnerable, and historically excluded.

Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea.

Objective: Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA. Methods: Newly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness (N = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality. Results: In cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69-0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05-1.31) and women (OR 1.26, 95% CI 1.10-1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5-8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05-1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality. Conclusion: The implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized.