ABSTRACT
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 if neck circumference 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 neck circumference, diagnostic sleep studies and post-implantation HGNS titration studies were collected. Linear regression and Spearman's Correlation Coefficient (SCC) analysis were utilized to compare neck circumference (NC), percentage of predicted neck circumference (PPNC) and BMI with the apnea-hypopnea index at effective voltage (AHI-v). RESULTS: This study included 43 patients who were middle aged (61.1 years), predominantly male (76.7%), with severe obstructive sleep apnea (median AHI 35) and mean neck circumference of 15.3 inches. Utilizing the NC and PPNC, positive correlations with AHI-v were observed (p = 0.0033, SCC = .438, and p = 0.0029, SCC = .444). While controlling for BMI, a 1-inch increase in neck circumference was associated with a 35% increase in AHI-v (p = 0.0411). CONCLUSIONS: A larger neck circumference was independently associated with worse HGNS outcomes. Further research is needed to support and confirm these findings, particularly across sexes.
ABSTRACT
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.
Subject(s)
Pulmonary Arterial Hypertension , RNA, Long Noncoding , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Male , Humans , Pulmonary Arterial Hypertension/genetics , Pulmonary Arterial Hypertension/metabolism , Pulmonary Arterial Hypertension/pathology , Female , Endothelial Cells/metabolism , Cell Proliferation/genetics , Middle Aged , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , ets-Domain Protein Elk-1/metabolism , ets-Domain Protein Elk-1/genetics , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Gene Expression Regulation , Enhancer of Zeste Homolog 2 Protein/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , AdultABSTRACT
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.
Subject(s)
Hypertension, Pulmonary , Obesity Hypoventilation Syndrome , Sleep Apnea, Obstructive , Humans , Obesity Hypoventilation Syndrome/therapy , Obesity Hypoventilation Syndrome/physiopathology , Obesity Hypoventilation Syndrome/diagnosis , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/therapy , Hypertension, Pulmonary/diagnosis , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/therapy , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/diagnosisABSTRACT
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.
Subject(s)
Blood Glucose , Circadian Rhythm , Diabetes Mellitus, Type 2 , Glycemic Control , Self Report , Sleep , Humans , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/complications , Male , Female , Young Adult , Blood Glucose/metabolism , Adult , Sleep Quality , Glycated Hemoglobin/metabolism , Diabetes Complications/physiopathology , Diabetes Complications/blood , Time Factors , Adolescent , Risk Factors , Biomarkers/bloodABSTRACT
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.
Subject(s)
COVID-19 , Humans , Female , Middle Aged , Male , COVID-19/therapy , SARS-CoV-2 , Retrospective Studies , Cohort Studies , Hospitalization , Oxygen , Adrenal Cortex HormonesABSTRACT
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.
Subject(s)
Hospitalization , Inpatients , Sleep Initiation and Maintenance Disorders , Humans , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Initiation and Maintenance Disorders/complications , Male , Female , Prospective Studies , Middle Aged , Hospitalization/statistics & numerical data , Inpatients/statistics & numerical data , Patient Readmission/statistics & numerical data , Aged , Surveys and Questionnaires , Prevalence , Actigraphy/statistics & numerical data , Severity of Illness Index , Cohort StudiesABSTRACT
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.
ABSTRACT
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.
Subject(s)
Obesity Hypoventilation Syndrome , Humans , Hypercapnia/complications , Hypoventilation/complications , Leptin/metabolism , Obesity/complications , Obesity Hypoventilation Syndrome/complications , Obesity Hypoventilation Syndrome/therapyABSTRACT
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.
Subject(s)
Cardiovascular System , Sleep , Circadian Rhythm , Heart , Seasons , Time Factors , United StatesABSTRACT
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.
ABSTRACT
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.
Subject(s)
Pulmonary Arterial Hypertension , RNA, Long Noncoding , Female , Humans , Pulmonary Arterial Hypertension/genetics , Pulmonary Artery , Sex Characteristics , Sex Chromosomes/geneticsABSTRACT
STUDY OBJECTIVES: Pulmonary hypertension (PH) is prevalent in obesity hypoventilation syndrome (OHS). However, there is a paucity of data assessing pathogenic factors associated with PH. Our objective is to assess risk factors that may be involved in the pathogenesis of PH in untreated OHS. METHODS: In a post hoc analysis of the Pickwick trial, we performed a bivariate analysis of baseline characteristics between patients with and without PH. Variables with a P value ≤ .10 were defined as potential risk factors and were grouped by theoretical pathogenic mechanisms in several adjusted models. Similar analysis was carried out for the 2 OHS phenotypes, with and without severe concomitant obstructive sleep apnea. RESULTS: Of 246 patients with OHS, 122 (50%) had echocardiographic evidence of PH defined as systolic pulmonary artery pressure ≥ 40 mm Hg. Lower levels of awake PaO2 and higher body mass index were independent risk factors in the multivariate model, with a negative and positive adjusted linear association, respectively (adjusted odds ratio 0.96; 95% confidence interval 0.93 to 0.98; P = .003 for PaO2, and 1.07; 95% confidence interval 1.03 to 1.12; P = .001 for body mass index). In separate analyses, body mass index and PaO2 were independent risk factors in the severe obstructive sleep apnea phenotype, whereas body mass index and peak in-flow velocity in early/late diastole ratio were independent risk factors in the nonsevere obstructive sleep apnea phenotype. CONCLUSIONS: This study identifies obesity per se as a major independent risk factor for PH, regardless of OHS phenotype. Therapeutic interventions targeting weight loss may play a critical role in improving PH in this patient population. CLINICAL TRIAL REGISTRATION: Registry: Clinicaltrial.gov; Name: Alternative of Treatment in Obesity Hypoventilation Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT01405976; Identifier: NCT01405976. CITATION: Masa JF, Benítez ID, Javaheri S, et al. Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome. J Clin Sleep Med. 2022;18(4):983-992.