Gender Differences in Outcomes of Ambulatory and Hospitalized Patients With Obesity Hypoventilation Syndrome.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is associated with high morbidity and mortality. There are few data on whether there are gender differences in outcomes. RESEARCH QUESTION: Is female gender associated with worse outcomes in ambulatory and hospitalized patients with OHS? STUDY DESIGN AND METHODS: Post hoc analyses were performed on 2 separate OHS cohorts: (1) stable ambulatory patients from the 2 Pickwick randomized controlled trials; and (2) hospitalized patients with acute-on-chronic hypercapnic respiratory failure from a retrospective international cohort. We first conducted bivariate analyses of baseline characteristics and therapeutics between genders. Variables of interest from these analyses were then grouped into linear mixed effects models, Cox proportional hazards models, or logistic regression models to assess the association of gender on various clinical outcomes. RESULTS: The ambulatory prospective cohort included 300 patients (64% female), and the hospitalized retrospective cohort included 1,162 patients (58% female). For both cohorts, women were significantly older and more obese than men. Compared with men, baseline Paco2 was similar in ambulatory patients but higher in hospitalized women. In the ambulatory cohort, in unadjusted analysis, women had increased risk of emergency department visits. However, gender was not associated with the composite outcome of emergency department visit, hospitalization, or all-cause mortality in the fully adjusted model. In the hospitalized cohort, prescription of positive airway pressure was less prevalent in women at discharge. In unadjusted analysis, hospitalized women had a higher mortality at 3, 6, and 12 months following hospital discharge compared with men. However, after adjusting for age, gender was not associated with mortality. INTERPRETATION: Although the diagnosis of OHS is established at a more advanced age in women, gender is not independently associated with worse clinical outcomes after adjusting for age. Future studies are needed to examine gender-related health disparities in diagnosis and treatment of OHS.

Treatment of OSA and its Impact on Cardiovascular Disease, Part 2: JACC State-of-the-Art Review.

Many studies have shown an association of obstructive sleep apnea (OSA) with incident cardiovascular diseases, particularly when comorbid with insomnia, excessive sleepiness, obesity hypoventilation syndrome, and chronic obstructive pulmonary disease. Randomized controlled trials (RCTs) have demonstrated that treatment of OSA with positive airway pressure devices (CPAP) improves systemic hypertension, particularly in those with resistant hypertension who are adherent to CPAP. However, large RCTs have not shown long-term benefits of CPAP on hard cardiovascular outcomes, but post hoc analyses of these RCTs have demonstrated improved hard outcomes in those who use CPAP adequately. In theory, low CPAP adherence and patient selection may have contributed to neutral results in intention-to-treat analyses. Only by further research into clinical, translational, and basic underlying mechanisms is major progress likely to continue. This review highlights the various treatment approaches for sleep disorders, particularly OSA comorbid with various other disorders, the potential reasons for null results of RCTs treating OSA with CPAP, and suggested approaches for future trials.

Interactions of Obstructive Sleep Apnea With the Pathophysiology of Cardiovascular Disease, Part 1: JACC State-of-the-Art Review.

The American Heart Association considers sleep health an essential component of cardiovascular health, and sleep is generally a time of cardiovascular quiescence, such that any deviation from normal sleep may be associated with adverse cardiovascular consequences. Many studies have shown that both impaired quantity and quality of sleep, particularly with obstructive sleep apnea (OSA) and comorbid sleep disorders, are associated with incident cardiometabolic consequences. OSA is associated with repetitive episodes of altered blood gases, arousals, large negative swings in intrathoracic pressures, and increased sympathetic activity. Recent studies show that OSA is also associated with altered gut microbiota, which could contribute to increased risk of cardiovascular disease. OSA has been associated with hypertension, atrial fibrillation, heart failure, coronary artery disease, stroke, and excess cardiovascular mortality. Association of OSA with chronic obstructive lung disease (overlap syndrome) and morbid obesity (obesity hypoventilation syndrome) increases the odds of mortality.

The impact of neck circumference on hypoglossal nerve stimulator therapy outcomes.

STUDY OBJECTIVES: Hypoglossal nerve stimulation (HGNS) therapy has historically had strict eligibility requirements including a body mass index (BMI) < 32 kg/m2. However, recent Food and Drug Administration approval expanded indications to a BMI < 40 kg/m2. There is a wide variability in body fat distribution. This study sought to determine whether neck circumference (NC) is a better surrogate predictive variable for HGNS outcomes than BMI. METHODS: A retrospective chart review was conducted at a tertiary care center on adults who underwent HGNS implantation by a single surgeon from March 2017 to October 2021. Baseline demographic data including NC, diagnostic sleep studies, and postimplantation HGNS titration studies were collected. Linear regression and Spearman's correlation coefficient analysis were used to compare NC, percentage of predicted NC, and BMI with the apnea-hypopnea index at effective voltage. RESULTS: This study included 43 patients who were middle-aged (61.1 years), predominantly male (76.7%), with severe obstructive sleep apnea (median apnea-hypopnea index, 35 events/h) and mean NC of 15.3 inches. Using the NC and percentage of predicted NC, positive correlations with apnea-hypopnea index at effective voltage were observed (P = .0033, Spearman's correlation coefficient = .438 and P = .0029, Spearman's correlation coefficient = .444). While controlling for BMI, a 1-inch increase in NC was associated with a 35% increase in apnea-hypopnea index at effective voltage (P = .0411). CONCLUSIONS: A larger NC was independently associated with worse HGNS outcomes. Further research is needed to support and confirm these findings, particularly across sexes. CITATION: Hutz MJ, Plata DM, LoSavio P, Herdegen J, Zhang Y, Mokhlesi B. The impact of neck circumference on hypoglossal nerve stimulator therapy outcomes. J Clin Sleep Med. 2024;20(11):1755-1761.

Obstructive Sleep Apnea, Obesity Hypoventilation Syndrome, and Pulmonary Hypertension: A State-of-the-Art Review.

The pathophysiological interplay between sleep-disordered breathing (SDB) and pulmonary hypertension (PH) is complex and can involve a variety of mechanisms by which SDB can worsen PH. These mechanistic pathways include wide swings in intrathoracic pressure while breathing against an occluded upper airway, intermittent and/or sustained hypoxemia, acute and/or chronic hypercapnia, and obesity. In this review, we discuss how the downstream consequences of SDB can adversely impact PH, the challenges in accurately diagnosing and classifying PH in the severely obese, and review the limited literature assessing the effect of treating obesity, obstructive sleep apnea, and obesity hypoventilation syndrome on PH.

Dysregulation of the Long Noncoding RNA X-Inactive-Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with female sex as a significant risk factor. Increased expression of the long noncoding RNA X-inactive-specific transcript (Xist), as induced by an intersectin-1s protein fragment with proliferative potential (EHITSN), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes. Herein, increased Xist expression was detected in a subset of ECs and lung tissue samples of male patients with PAH. The role of different Xist expression levels in ECs of male patients with PAH (ECPAH) was studied in several lines of male ECPAH in conjunction with molecular, biochemical, morphologic, and functional approaches. Male ECPAH showed on average 10.3-fold increase in high Xist versus low Xist, a significant association between Xist levels and their proliferative potential, and a heterogeneous methylation of the Xist/XIST antisense RNA (Tsix) locus. Interestingly, Xist up-regulation in male ECPAH decreased the expression of Krueppel-like factor 2 (Klf2), via EHITSN interaction with enhancer of zeste polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of the polycomb repressive complex 2. Moreover, the studies demonstrate that EHITSN-triggered p38/ETS domain-containing protein Elk1/AP-1 transcription factor subunit (c-Fos) signaling is a pathologic mechanism central to ECPAH proliferation and the dynamic crosstalk with cell cycle regulatory proteins cyclin A1/cyclin D2 and Xist-EZH2-Klf2 interaction participate directly and differentially in establishing the proliferative profile of male ECPAH.

The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Home Oxygen After Hospitalization for COVID-19: Results From the Multi-Center OXFORD Study.

BACKGROUND: In the first months of the pandemic, prior to the introduction of proven-effective treatments, 15-37% of patients hospitalized with COVID-19 were discharged on home oxygen. After proven-effective treatments for acute COVID-19 were established by evidence-based guidelines, little remains known about home oxygen requirements following hospitalization for COVID-19. METHODS: This was a retrospective, multi-center cohort study of subjects hospitalized for COVID-19 between October 2020-September 2021 at 3 academic health centers. Information was abstracted from electronic health records at the index hospitalization and for 60 d after discharge. The World Health Organization COVID-19 Clinical Progression Scale score was used to identify patients with severe COVID-19. RESULTS: Of 517 subjects (mean age 58 y, 47% female, 42% Black, 36% Hispanic, 22% with severe COVID-19), 81% were treated with systemic corticosteroids, 61% with remdesivir, and 2.5% with tocilizumab. About one quarter of subjects were discharged on home oxygen (26% [95% CI 22-29]). Older age (adjusted odds ratio [aOR] 1.02 per 5 y [95% CI 1.02-1.02]), higher body mass index (aOR 1.02 per kg/m2 [1.00-1.04]), diabetes (yes vs no, aOR 1.73 [1.46-2.02]), severe COVID-19 (vs moderate, aOR 3.19 [2.19-4.64]), and treatment with systemic corticosteroids (yes vs no, aOR 30.63 [4.51-208.17]) were associated with an increased odds of discharge on home oxygen. Comorbid hypertension (yes vs no, aOR 0.71 [0.66-0.77) was associated with a decreased odds of home oxygen. Within 60 d of hospital discharge, 50% had documentation of pulse oximetry; in this group, home oxygen was discontinued in 46%. CONCLUSIONS: About one in 4 subjects were prescribed home oxygen after hospitalization for COVID-19, even after guidelines established proven-effective treatments for acute illness. Evidence-based strategies to reduce the requirement for home oxygen in patients hospitalized for COVID-19 are needed.

Association of preadmission insomnia symptoms with objective in-hospital sleep and clinical outcomes among hospitalized patients.

STUDY OBJECTIVES: To determine the prevalence of preadmission insomnia symptoms among hospitalized patients and assess the association of insomnia symptoms with objective in-hospital sleep and clinical outcomes. METHODS: We conducted a prospective cohort study of medicine inpatients (age ≥ 50, no previously diagnosed sleep disorders). Participants answered the Insomnia Severity Index (ISI) questionnaire to assess for preadmission insomnia symptoms (scored 0-28; higher scores suggest more insomnia symptoms). Sleep duration and efficiency were measured with actigraphy. Participants self-reported 30-day postdischarge readmissions and emergency department and/or urgent care visits. RESULTS: Of 568 participants, 49% had ISI scores suggestive of possible undiagnosed insomnia (ISI ≥ 8). Higher ISI scores were associated with shorter sleep duration [ß = -2.6, 95% confidence interval (CI) -4.1 to -1.1, P = .001] and lower sleep efficiency (ß = -0.39, 95% CI -0.63 to -0.15, P = .001). When adjusted for age, sex, body mass index, and comorbidities, higher ISI scores were associated with longer length of stay (incidence rate ratio 1.01, 95% CI 1.00-1.02, P = .011), increased risk of 30-day readmission (odds ratio 1.04, 95% CI 1.01-1.07, P = .018), and increased risk of 30-day emergency department or urgent care visit (odds ratio 1.04, 95% CI 1.00-1.07, P = .043). CONCLUSIONS: Among medicine inpatients, there was a high prevalence of preadmission insomnia symptoms suggestive of possible undiagnosed insomnia. Participants with higher ISI scores slept less with lower sleep efficiency during hospitalization. Higher ISI scores were associated with longer length of stay, increased risk of a 30-day postdischarge readmission, and increased risk of a 30-day postdischarge emergency department or urgent care visit. CITATION: Neborak JM, Press VG, Parker WF, et al. Association of preadmission insomnia symptoms with objective in-hospital sleep and clinical outcomes among hospitalized patients. J Clin Sleep Med. 2024;20(5):681-687.

A new index, Respiratory Insufficiency index and Modified Early Warning Scores predict extubation failure.

Background: Extubation failure occurs in 5%-20% of patients and is associated with poor clinical outcomes. The primary aim of this project was to determine the predictive ability of the Respiratory Insufficiency (RI) index, Respiratory Oxygenation (ROX) index and Modified Early Warning Score (MEWS) in identifying extubation failure. Methods: This was a secondary analysis of a prior cross-sectional retrospective study conducted from February 2018 through December 2018 among adult subjects who received mechanical ventilation for more than 24 h. Extubation failure was defined as the need for reintubation or rescue non-invasive ventilation (NIV) within 48 h after planned extubation. Univariate analysis and logistic regression were used to identify the predictors and final model was validated using 10-fold cross validation. Nomogram was constructed based on the final model. Results: Of 216 enrolled subjects, 46 (21.3%) experienced extubation failure. The median RI index 1-h post extubation was 20 [interquartile range [IQR] 16.33-24.24] for success group and 27.02 [IQR 22.42-33.83] for the failure group (P<0.001). The median ROX index 1-h post extubation was 16.66 [IQR 12.57-19.84] for success group and 11.11 [IQR 8.09-14.67] for failure group (P<0.001). The median MEWS 1-h post extubation was 2 [IQR 1-3] for the success group and 4 [IQR 3-5] for the failure group (P<0.001). In multivariable analysis, age >60 years [OR 3.89 (95% CI 1.56-9.73); P=0.004], MEWS >4 [OR 4.01 (95% CI (1.59-10.14); P=0.003] and, RI index >20 [OR 4.50 (95% CI 1.43-14.21); P=0.010] were independently associated with extubation failure. Conclusion: In the present study, RI index and MEWS were independently associated with predicting extubation failure within 1 h of extubation. A prospective validation study is warranted to establish the role of these indices in predicting extubation outcome.

Leptin-mediated neural targets in obesity hypoventilation syndrome.

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Taking to "heart" the proposed legislation for permanent daylight saving time.

In March 2022, the US Senate passed the Sunshine Protection Act that would abolish the biannual change in clocks each fall and spring and permanently adopt daylight saving time that aligns with the "spring forward" time change each March. A number of scientific and medical societies have endorsed the abolishment of the biannual clock change, but oppose the permanent adoption of daylight saving time. Instead, leading organizations such as the American Academy of Sleep Medicine (AASM) and the Society for Research on Biological Rhythms (SRBR) position statements highlight peer-reviewed evidence in favor of a permanent shift to standard time. The present perspectives will summarize some of the key AASM and SRBR recommendations, with a particular focus on the potential cardiovascular implications of a legislative change that would result in a permanent switch to either standard time or daylight saving time. Collectively, although there is building scientific consensus that abolishing the biannual time change has several sleep and circadian health benefits, the preponderance of evidence is opposite to the current legislation and instead suggests a permanent switch to standard time may offer the maximum health and safety benefits. This scientific evidence should be considered as the United States House of Representatives considers the Sunshine Protection Act.

Effectiveness of CPAP vs. Noninvasive Ventilation Based on Disease Severity in Obesity Hypoventilation Syndrome and Concomitant Severe Obstructive Sleep Apnea.

RATIONALE: Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity. OBJECTIVE: To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups. METHODS: Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI)≥30events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45-49.9 or ≥50mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model. RESULTS: 204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups. CONCLUSION: In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2.

The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed.