Hypoxic and Autonomic Mechanisms from Sleep-Disordered Breathing Leading to Cardiopulmonary Dysfunction.

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder. Its prevalence has increased due to increasing obesity and improved screening and diagnostic strategies. OSA overlaps with cardiopulmonary diseases to promote intermittent hypoxia and autonomic dysfunction. Intermittent hypoxia increases the risk for oxidative stress and inflammation, which promotes endothelial dysfunction and predisposes to atherosclerosis and other cardiovascular complications. OSA is associated with an increased sympathetic nervous system drive resulting in autonomic dysfunction leading to worsening of cardiopulmonary diseases. Cardiovascular diseases are observed in 40% to 80% of OSA patients. Therefore, it is essential to screen and treat cardiovascular diseases.

Health-Related Quality of Life Across the Spectrum of Pulmonary Hypertension.

BACKGROUND: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH). RESEARCH QUESTION: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system? STUDY DESIGN AND METHODS: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups. RESULTS: Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3. INTERPRETATION: HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH.

Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension.

BACKGROUND: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear. OBJECTIVES: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival. METHODS: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses. RESULTS: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation. CONCLUSIONS: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).

Sleep-Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation.

Background We leverage a large clinical cohort to elucidate sleep-disordered breathing and sleep-related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep-related hypoxia and pulmonary physiology in sleep-disordered breathing and AF. Methods and Results Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation <90%, minimum and mean oxygen saturation, and maximum end-tidal carbon dioxide on incident AF adjusted for age, sex, race, body mass index, cardiopulmonary disease and risk factors, antiarrhythmic medications, and positive airway pressure. Those with spirometry were additionally adjusted for forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity. This cohort (n=42 057) was 50.7±14.1 years, 51.3% men, 74.1% White individuals, had median body mass index 33.2 kg/m2, and 1947 (4.6%) developed AF over 5 years. A 10-unit apnea hypopnea index increase was associated with 2% higher AF risk (hazard ratio [HR], 1.02 [95% CI, 1.00-1.03]). A 10-unit increase in percentage time oxygen saturation <90% and 10-unit decreases in mean and minimum oxygen saturation were associated with 6% (HR, 1.06 [95% CI, 1.04-1.08]), 30% (HR, 1.30 [95% CI, 1.18-1.42]), and 9% (HR, 1.09 [95% CI, 1.03-1.15]) higher AF risk, respectively. After adjustment for spirometry (n=9683 with available data), only hypoxia remained significantly associated with incident AF, although all coefficients were stable. Conclusions Sleep-related hypoxia was associated with incident AF in this clinical cohort, consistent across 3 measures of hypoxia, persistent after adjustment for pulmonary physiologic impairment. Findings identify a strong role for sleep-related hypoxia in AF development without pulmonary physiologic interdependence.

Comparison of clinical pathways for hypoglossal nerve stimulation management: in-laboratory titration polysomnography vs home-based efficacy sleep testing.

STUDY OBJECTIVES: We conducted this study to evaluate whether laboratory or home-based hypoglossal nerve stimulation (HNS) management would have equivalent objective and subjective obstructive sleep apnea outcomes 6 months after activation. METHODS: Patients undergoing standard-of-care HNS implantation were randomly assigned in a prospective, multicenter clinical trial to either a 3-month postactivation in-laboratory titration polysomnography (tPSG) or an efficacy home sleep study (eHST) with tPSG by exception for eHST nonresponders at 5 months. Both groups underwent an eHST 6 months postactivation. RESULTS: Sixty patients were randomly assigned. Patients experienced equivalent decreases in the apnea-hypopnea index (mean difference: -0.01 events/h [-8.75, 8.74]) across both groups with HNS; the selection of tPSG or eHST did not associate with therapy response rates (tPSG vs eHST: 63.2% vs 59.1%). The Epworth Sleepiness Scale (median of differences: 1 [-1, 3]) and device usage (median of differences: 0.0 hours [-1.3, 1.3]) outcomes were similar but did not meet a priori statistical equivalence criteria. CONCLUSIONS: This prospective, multicenter, randomized clinical trial demonstrated that patients undergoing HNS implantation experienced statistically equivalent improvements in objective obstructive sleep apnea outcomes and similar improvements in daytime sleepiness regardless of whether they underwent tPSG. HNS titration with tPSG may not be required for all postoperative patients. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Inspire Home Study: Utilization of Home Monitoring During Therapy Optimization in Patients With an Inspire Upper Airway Stimulation System (Comparison of Home Sleep Testing vs. In-lab Polysomnography Testing) (HOME); URL: https://clinicaltrials.gov/ct2/show/NCT04416542; Identifier: NCT04416542. CITATION: Kent D, Huyett P, Yu P, et al. Comparison of clinical pathways for hypoglossal nerve stimulation management: in-laboratory titration polysomnography vs home-based efficacy sleep testing. J Clin Sleep Med. 2023;19(11):1905-1912.

Machine learning polysomnographically-derived electroencephalography biomarkers predictive of epworth sleepiness scale.

Excessive daytime sleepiness (EDS) causes difficulty in concentrating and continuous fatigue during the day. In the clinical setting, the assessment and diagnosis of EDS rely mostly on subjective questionnaires and verbal reports, which compromises the reliability of clinical diagnosis and the ability to robustly discern candidacy for available therapies and track treatment response. In this study, we used a computational pipeline for the automated, rapid, high-throughput, and objective analysis of previously collected encephalography (EEG) data to identify surrogate biomarkers for EDS, thereby defining the quantitative EEG changes in individuals with high Epworth Sleepiness Scale (ESS) (n = 31), compared to a group of individuals with low ESS (n = 41) at the Cleveland Clinic. The epochs of EEG analyzed were extracted from a large overnight polysomnogram registry during the most proximate period of wakefulness. Signal processing of EEG showed significantly different EEG features in the low ESS group compared to high ESS, including enhanced power in the alpha and beta bands and attenuation in the delta and theta bands. Our machine learning (ML) algorithms trained on the binary classification of high vs. low ESS reached an accuracy of 80.2%, precision of 79.2%, recall of 73.8% and specificity of 85.3%. Moreover, we ruled out the effects of confounding clinical variables by evaluating the statistical contribution of these variables on our ML models. These results indicate that EEG data contain information in the form of rhythmic activity that could be leveraged for the quantitative assessment of EDS using ML.

The Beginning of the AI-Enabled Preventative PAP Therapy Era: A First-in-Human Proof of Concept Interventional Study.

Positive Airway Pressure (PAP) therapy is the most common and efficacious treatment for Obstructive Sleep Apnea (OSA). However, it suffers from poor patient adherence due to discomfort and may not fully alleviate all adverse consequences of OSA. Identifying abnormal respiratory events before they have occurred may allow for improved management of PAP levels, leading to improved adherence and better patient outcomes. Our previous work has resulted in the successful development of a Machine-Learning (ML) algorithm for the prediction of future apneic events using existing airflow and air pressure sensors available internally to PAP devices. Although researchers have studied the use of ML for the prediction of apneas, research to date has focused primarily on using external polysomnography sensors that add to patient discomfort and has not investigated the use of internal-to-PAP sensors such as air pressure and airflow to predict and prevent respiratory events. We hypothesized that by using our predictive software, OSA events could be proactively prevented while maintaining patients' sleep quality. An intervention protocol was developed and applied to all patients to prevent OSA events. Although the protocol's cool-down period limited the number of prevention attempts, analysis of 11 participants revealed that our system improved many sleep parameters, which included a statistically significant 31.6% reduction in Apnea-Hypopnea Index, while maintaining sleep quality. Most importantly, our findings indicate the feasibility of unobtrusive identification and unique prevention of each respiratory event as well as paving the path to future truly personalized PAP therapy by further training of ML models on individual patients.

Moving toward Equitable Care for Sleep Apnea in the United States: Positive Airway Pressure Adherence Thresholds: An Official American Thoracic Society Policy Statement.

Background: Positive airway pressure (PAP) is a highly effective treatment for obstructive sleep apnea (OSA), but adherence limits its efficacy. In addition, coverage of PAP by CMS (Centers for Medicare & Medicaid Services) and other insurers in the United States depends on adherence. This leaves many beneficiaries without PAP, disproportionally impacting non-white and low socioeconomic position patients with OSA and exacerbating sleep health disparities. Methods: An inter-professional, multidisciplinary, international committee with various stakeholders was formed. Three working groups (the historical policy origins, impact of current policy, and international PAP coverage models) met and performed literature reviews and discussions. Using surveys and an iterative discussion-based consensus process, the policy statement recommendations were created. Results: In this position paper, we advocate for policy change to CMS PAP coverage requirements to reduce inequities and align with patient-centered goals. We specifically call for eradicating repeat polysomnography, eliminating the 4-hour rule, and focusing on patient-oriented outcomes such as improved sleepiness and sleep quality. Conclusions: Modifications to the current policies for PAP insurance coverage could improve health disparities.

Sex-specific differences in diagnostic approaches of inpatient sleep testing for obstructive sleep apnea.

BACKGROUND: Few studies have investigated sex-specific disparities in inpatient sleep testing. We postulate that women are more likely to have a milder degree of obstructive sleep apnea (OSA) and lower extent of hypoxia on Type III sleep studies versus polysomnography (PSG). PATIENTS AND METHODS: The Cleveland Clinic Sleep laboratory registry was leveraged to identify all adult inpatient sleep studies performed for OSA. Demographics, comorbidities, and sleep study measures were collected and compared by sex and sleep study type. Logistic regression was used to examine sleep study type predictive of OSA (apnea hypopnea index [AHI; ≥5, ≥15 and ≥ 30]) and hypoxia, (median percentage of sleep time spent at <90% SaO2 [TST<90%,≥ 11%,] adjusted for covariates. RESULTS: The sample 778 patients had a mean age of 56.1 ± 16.1 years; 44.5% were female and 72.2% Caucasian. At an AHI≥5, women showed an increase odds of OSA (adjusted, OR = 2.04,95%; CI:1.24-3.35, p = 0.005) with Type III sleep study vs PSG compared to men. At an AHI≥15, men had less odds of OSA (adjusted OR = 0.60,95%CI:0.39-0.90,p = 0.015) with Type III sleep study vs PSG compared to women (OR = 1.15,95%CI:0.72-1.85,p = 0.56), with an interaction p-value of 0.040. These results were attenuated when the analysis was restricted using the 3% hypopnea scoring rule. Men and women had higher odds of TST <90 ≥ 11% (OR:2.60,95%CI:1.60-4.21,p=<0.001; OR:3.46,95%CI:1.97-6.05,p < 0.001) with Type III sleep study versus PSG, albeit no sex-interaction was observed. CONCLUSIONS: These results suggest that sex-specific differences in diagnostic performance of sleep testing type in the inpatient setting should be considered according to level of OSA severity, which are influenced by hypopnea-related desaturation extent.

Sleep and obstructive sleep apnea in women with infertility.

PURPOSE: Obstructive sleep apnea (OSA) is associated with polycystic ovarian syndrome (PCOS), a common cause of infertility. Understanding predictors and outcomes of OSA in women with infertility may guide treatment. METHODS: A descriptive cross-sectional survey was performed to assess OSA in women presenting to an infertility clinic using validated sleep questionnaires to assess sleep and fertility outcomes. An Infertile-C group (controls with male or tubal factors) and an Infertile-S group (unknown/other infertile causes) were analyzed to assess OSA risk and other sleep disorders (e.g., restless legs syndrome (RLS) and insomnia) with fertility outcomes (time to pregnancy, PCOS, irregular menstruation, and miscarriage). RESULTS: In 258 women, occurrences of OSA diagnosis (6%) and RLS (10%) were reported similar to women of child-bearing age in the general population. PCOS was unassociated with OSA risk. Predictors of OSA risk were BMI, insomnia symptoms, and sleep aid use. Obese women with high OSA risk were more likely to have other comorbidities (e.g., depression). In adjusted models, prior clinical OSA diagnosis was associated with miscarriage (odds ratio: 6.17 (1.24, 30.62), p = 0.026). RLS was associated with irregular menstruation (odds ratio: 3.73 (1.21, 11.53), p = 0.022). CONCLUSIONS: Similar to other populations, women with infertility and OSA risk have more health comorbidities and higher BMI and may present with insomnia symptoms. While the data are limited, this study supports the potential associations of OSA and miscarriage. Further work is needed to evaluate OSA in female infertility.

Evaluation and identification of advanced lentil interspecific derivatives resulted in the development of early maturing, high yielding, and disease-resistant cultivars under Indian agro-ecological conditions.

The genetic base revealed by pedigree records of the majority of released cultivars appears to be narrow in major pulse crops, including lentils, because of the frequent use of the same parents and their derivatives in crop improvement programs. Therefore, corrective measures are needed to widen the genetic base by involving the genetic resources of a distinct gene pool. In this direction, rigorous efforts were made to introgress wild Lens taxa, L. culinaris ssp. orientalis, and L. ervoides into the backgrounds of cultivated varieties. Subsequently, genetic materials were advanced through the single seed descent method of breeding along with a rapid generation advancement (normal and off-season) approach. Two F10:11 interspecific derivatives of lentils were evaluated in augmented block design at two locations, viz. International Centre for Agricultural Research in Dry Areas (ICARDA) and Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST), India. The analysis of variance showed remarkable variability for all target characters at both locations. The heritability estimates were high, and correlation analysis exhibited a significant association between the majority of traits assessed at ICARDA and SKUAST, India. Further, SKUAST identified the most promising lines as "Jammu Lentil 144" and "Jammu Lentil 71." These derivatives were further validated separately for their agronomic potential and resistance against major biotic stresses. The results revealed that Jammu Lentil 144 and Jammu Lentil 71 produced 16.65 and 9.40% more seed yield than local and national checks, including earliness, by 25 and 15 days, respectively. These promising interspecific derivatives were also found to be resistant to fusarium wilt, root rot, pod borer, and aphid infestations. The standard agronomy of these cultivars has also been assessed consecutively for 2 years at SKUAST. Overall, the pre-breeding efforts have resulted in the development of early maturing, high-yielding, and disease-resistant lentil cultivars for the Jammu region of India.

Obesity-associated sleep hypoventilation and increased adverse postoperative bariatric surgery outcomes in a large clinical retrospective cohort.

STUDY OBJECTIVES: Although obesity hypoventilation syndrome (OHS) is associated with increased morbidity and mortality, post-bariatric surgery OHS risk remains unclear due to often nonsystematic OHS assessments. METHODS: We leverage a clinical cohort with nocturnal CO2 monitoring during polysomnography to address the hypothesis that patients with obesity-associated sleep hypoventilation (OaSH; ie, stage II OHS) have increased adverse postoperative bariatric surgery outcomes. We retrospectively analyzed data from patients undergoing pre-bariatric surgery polysomnography at the Cleveland Clinic from 2011-2018. OaSH was defined by body mass index ≥ 30 kg/m2 and either polysomnography-based end-tidal CO2 ≥ 45 mmHg or serum bicarbonate ≥ 27 mEq/L. Outcomes considered were as follows: intensive care unit stay, intubation, tracheostomy, discharge disposition other than home or 30-day readmission individually and as a composite, and all-cause mortality. Two-sample t test or Wilcoxon rank-sum test for continuous variables and chi-square or Fisher's exact test for categorical variables were used for OaSH vs non-OaSH comparisons. All-cause mortality was compared using Kaplan-Meier estimation and Cox proportional hazards models. RESULTS: The analytic sample (n = 1,665) was aged 45.2 ± 12 years, 20.4% were male, had a body mass index of 48.7 ± 9 kg/m2, and 63.6% were White. OaSH prevalence was 68.5%. OaSH patients were older and more likely to be male with a higher BMI, apnea-hypopnea index, and glycated hemoglobin. The composite outcome was higher in OaSH vs non-OaSH patients (18.9% vs 14.3%, P = .021). Although some individual outcomes were respectively higher in OaSH vs non-OaSH patients, differences were not statistically significant: intubation (1.5% vs 1.3%, P = .81) and 30-day readmission (13.8% vs 11.3%, P = .16). Long-term mortality (median follow-up: 22.9 months) was not significantly different between groups, likely due to overall low event rate (hazard ratio = 1.39, 95% confidence interval: 0.56, 3.42). CONCLUSIONS: In this largest sample to date of systematically phenotyped OaSH in a bariatric surgery cohort, we identify increased postoperative morbidity in those with sleep-related hypoventilation in stage II OHS when a composite outcome was considered, but individual contributors of intubation, intensive care unit admission, and hospital length of stay were not increased. Further study is needed to identify whether perioperative treatment of OaSH improves post-bariatric surgery outcomes. CITATION: Chindamporn P, Wang L, Bena J, et al. Obesity-associated sleep hypoventilation and increased adverse postoperative bariatric surgery outcomes in a large clinical retrospective cohort. J Clin Sleep Med. 2022;18(12):2793-2801.

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease.

BACKGROUND: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Sleep characterization with smart wearable devices: a call for standardization and consensus recommendations.

The general public increasingly adopts smart wearable devices to quantify sleep characteristics and dedicated devices for sleep assessment. The rapid evolution of technology has outpaced the ability to implement validation approaches and demonstrate relevant clinical applicability. There are untapped opportunities to validate and refine consumer devices in partnership with scientists in academic institutions, patients, and the private sector to allow effective integration into clinical management pathways and facilitate trust in adoption once reliability and validity have been demonstrated. We call for the formation of a working group involving stakeholders from academia, clinical care and industry to develop clear professional recommendations to facilitate appropriate and optimized clinical utilization of such technologies.