Defining Extreme Phenotypes of OSA Across International Sleep Centers.

BACKGROUND: Extreme phenotypes of OSA have not been systematically defined. RESEARCH QUESTION: This study developed objective definitions of extreme phenotypes of OSA by using a multivariate approach. The utility of these definitions for identifying characteristics that confer predisposition toward or protection against OSA is shown in a new prospective sample. STUDY DESIGN AND METHODS: In a large international sample, race-specific liability scores were calculated from a weighted logistic regression that included age, sex, and BMI. Extreme cases were defined as individuals with an apnea-hypopnea index (AHI) ≥ 30 events/hour but low likelihood of OSA based on age, sex, and BMI (liability scores > 90th percentile). Similarly, extreme controls were individuals with an AHI < 5 events/hour but high likelihood of OSA (liability scores < 10th percentile). Definitions were applied to a prospective sample from the Sleep Apnea Global Interdisciplinary Consortium, and differences in photography-based craniofacial and intraoral phenotypes were evaluated. RESULTS: This study included retrospective data from 81,338 individuals. A total of 4,168 extreme cases and 1,432 extreme controls were identified by using liability scores. Extreme cases were younger (43.1 ± 14.7 years), overweight (28.6 ± 6.8 kg/m2), and predominantly female (71.1%). Extreme controls were older (53.8 ± 14.1 years), obese (34.0 ± 8.1 kg/m2), and predominantly male (65.8%). These objective definitions identified 29 extreme cases and 87 extreme controls among 1,424 Sleep Apnea Global Interdisciplinary Consortium participants with photography-based phenotyping. Comparisons suggest that a greater cervicomental angle increases risk for OSA in the absence of clinical risk factors, and smaller facial widths are protective in the presence of clinical risk factors. INTERPRETATION: This objective definition can be applied in sleep centers throughout the world to consistently define OSA extreme phenotypes for future studies on genetic, anatomic, and physiologic pathways to OSA.

High-throughput sleep phenotyping produces robust and heritable traits in Diversity Outbred mice and their founder strains.

STUDY OBJECTIVES: This study describes high-throughput phenotyping strategies for sleep and circadian behavior in mice, including examinations of robustness, reliability, and heritability among Diversity Outbred (DO) mice and their eight founder strains. METHODS: We performed high-throughput sleep and circadian phenotyping in male mice from the DO population (n = 338) and their eight founder strains: A/J (n = 6), C57BL/6J (n = 14), 129S1/SvlmJ (n = 6), NOD/LtJ (n = 6), NZO/H1LtJ (n = 6), CAST/EiJ (n = 8), PWK/PhJ (n = 8), and WSB/EiJ (n = 6). Using infrared beam break systems, we defined sleep as at least 40 s of continuous inactivity and quantified sleep-wake amounts and bout characteristics. We developed assays to measure sleep latency in a new environment and during a modified Murine Multiple Sleep Latency Test, and estimated circadian period from wheel-running experiments. For each trait, broad-sense heritability (proportion of variability explained by all genetic factors) was derived in founder strains, while narrow-sense heritability (proportion of variability explained by additive genetic effects) was calculated in DO mice. RESULTS: Phenotypes were robust to different inactivity durations to define sleep. Differences across founder strains and moderate/high broad-sense heritability were observed for most traits. There was large phenotypic variability among DO mice, and phenotypes were reliable, although estimates of heritability were lower than in founder mice. This likely reflects important nonadditive genetic effects. CONCLUSIONS: A high-throughput phenotyping strategy in mice, based primarily on monitoring of activity patterns, provides reliable and heritable estimates of sleep and circadian traits. This approach is suitable for discovery analyses in DO mice, where genetic factors explain some proportion of phenotypic variation.

Candidate gene analysis in the São Paulo Epidemiologic Sleep Study (EPISONO) shows an association of variant in PDE4D and sleepiness.

INTRODUCTION: Sleepiness and cardiovascular disease share common molecular pathways; thus, genetic risk factors for sleepiness may also predict cardiovascular disease risk. This study explored the associations between subjective sleepiness and single-nucleotide polymorphisms (SNPs) in candidate genes within oxidative stress, inflammatory, and neuronal pathways, which may contribute to sleepiness and downstream cardiovascular disease risk: Cytochrome B-245, Alpha Polypeptide (CYBA), Cytochrome B-245, Beta Polypeptide (CYBB), Neutrophil Cytosolic Factor (NCF2), Tumor Necrosis Factor-Alpha (TNFA), and Phosphodiesterase 4D (PDE4D). METHODS: Adults (N = 918) from the general population who were a part of the São Paulo Epidemiologic Sleep Study (EPISONO) in São Paulo, Brazil, were genotyped using Human Omni Express BeadChip array. The average age was 42 ± 14.5 years, subjects had a mean body mass index (BMI) of 26.9 ± 5.4 kg/m2, and 44% were male. Based on the Epworth Sleepiness Scale (ESS), subjects were classified as having sleepiness (ESS ≥ 10) or no sleepiness (ESS < 10). Logistic regression models were used to examine the associations with SNPs within candidate genes and sleepiness, adjusting for age, gender, BMI, Apnea-Hypopnea Index (AHI), total sleep time, and ancestry informative principal components (PCs). Complementary analyses using linear regression to assess the relationship between SNPs and continuous ESS were performed. RESULTS: We observed a novel association between the C allele of the rs12522161 SNP on PDE4D and a decreased likelihood of sleepiness, controlling for covariates and ancestry [OR (95% CI) = 0.64 (0.50, 0.81); p = 0.0002]. CONCLUSION: We present data for a novel genetic association with sleepiness for an SNP on the PDE4D gene, rs12522161.

Anatomic predictors of response and mechanism of action of upper airway stimulation therapy in patients with obstructive sleep apnea.

Study Objectives: Upper airway stimulation has been shown to be an effective treatment for some patients with obstructive sleep apnea. However, the mechanism by which hypoglossal nerve stimulation increases upper airway caliber is not clear. Therefore, the objective of this study was to identify the mechanism of action of upper airway stimulation. We hypothesized that, with upper airway stimulation, responders would show greater airway opening in the retroglossal (base of the tongue) region, greater hyoid movement toward the mandible, and greater anterior motion in the posterior, inferior region of the tongue compared with nonresponders. Methods: Seven participants with obstructive sleep apnea who had been successfully treated with upper airway stimulation (responders) and six participants who were not successfully treated (nonresponders) underwent computed tomography imaging during wakefulness with and without hypoglossal nerve stimulation. Responders reduced their apnea-hypopnea index (AHI) by 22.63 ± 6.54 events per hour, whereas nonresponders had no change in their AHI (0.17 ± 14.04 events per hour). We examined differences in upper airway caliber, the volume of the upper airway soft tissue structures, craniofacial relationships, and centroid tongue and soft palate movement between responders and nonresponders with and without hypoglossal nerve stimulation. Results: Our data indicate that compared with nonresponders, responders had a smaller baseline soft palate volume and, with stimulation, had (1) a greater increase in retroglossal airway size; (2) increased shortening of the mandible-hyoid distance; and (3) greater anterior displacement of the tongue. Conclusions: These results suggest that smaller soft palate volumes at baseline and greater tongue movement anteriorly with stimulation improve the response to upper airway stimulation.

Recognizable clinical subtypes of obstructive sleep apnea across international sleep centers: a cluster analysis.

Study Objectives: A recent study of patients with moderate-severe obstructive sleep apnea (OSA) in Iceland identified three clinical clusters based on symptoms and comorbidities. We sought to verify this finding in a new cohort in Iceland and examine the generalizability of OSA clusters in an international ethnically diverse cohort. Methods: Using data on 972 patients with moderate-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events per hour) recruited from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC), we performed a latent class analysis of 18 self-reported symptom variables, hypertension, cardiovascular disease, and diabetes. Results: The original OSA clusters of disturbed sleep, minimally symptomatic, and excessively sleepy replicated among 215 SAGIC patients from Iceland. These clusters also generalized to 757 patients from five other countries. The three clusters had similar average AHI values in both Iceland and the international samples, suggesting clusters are not driven by OSA severity; differences in age, gender, and body mass index were also generally small. Within the international sample, the three original clusters were expanded to five optimal clusters: three were similar to those in Iceland (labeled disturbed sleep, minimal symptoms, and upper airway symptoms with sleepiness) and two were new, less symptomatic clusters (labeled upper airway symptoms dominant and sleepiness dominant). The five clusters showed differences in demographics and AHI, although all were middle-aged (44.6-54.5 years), obese (30.6-35.9 kg/m2), and had severe OSA (42.0-51.4 events per hour) on average. Conclusions: Results confirm and extend previously identified clinical clusters in OSA. These clusters provide an opportunity for a more personalized approach to the management of OSA.

Carotid Artery Wall Thickness in Obese and Nonobese Adults With Obstructive Sleep Apnea Before and Following Positive Airway Pressure Treatment.

Study objectives: Debate persists as to whether obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The purpose of this study was to compare carotid intima-media thickness (IMT), an early sign of atherosclerosis, in obese and nonobese adults with OSA before and following positive airway pressure (PAP) treatment. Methods: A total of 206 adults newly diagnosed with OSA with an apnea-hypopnea index (AHI) of 15-75 events/hour and 53 controls with AHI <10 were studied. Waist circumference was used to classify participants as obese and nonobese. Bilateral common carotid artery B-mode ultrasound was performed at baseline to assess IMT, arterial diameter, arterial-wall mass, and circumferential wall stress. Measurements were repeated in 118 participants with OSA who completed a 4-month PAP treatment and had an average daily use over that period of ≥4 hours/day. Results: No significant differences in carotid IMT, diameter, or arterial-wall mass were present at baseline between participants with OSA and controls stratified by waist circumference, after adjusting for other cardiovascular risk factors. In participants with OSA, who had adequate PAP adherence over the 4-month treatment, carotid artery diameter significantly increased (mean change [95% confidence interval] = 0.13 [0.06, 0.20] mm; p = .0004), but no significant changes in carotid IMT, arterial-wall mass, and circumferential stress were observed in obese and nonobese participants. Conclusions: Regardless of obesity status, carotid IMT is not increased in adults with moderate to severe OSA versus controls and does not change following 4 months of PAP treatment.

Heritability of Heart Rate Response to Arousals in Twins.

Objectives: To determine if the large and highly reproducible interindividual differences in arousal intensity and heart rate response to arousal (ΔHR) during non-REM sleep are heritable. Methods: Polysomnograms of 55 monozygotic (14 male and 41 female pairs) and 36 dizygotic (15 male and 21 female pairs) same-sex twin pairs were analyzed. Arousals were scored using the 2012 American Academy of Sleep Medicine criteria. Arousal intensity was scaled (between 0 and 9) using an automatic algorithm based on the change in electroencephalogram time and frequency characteristics. The ΔHR was determined at each arousal. We calculated average arousal duration, average arousal intensity, average overall ΔHR, average ΔHR at a given arousal intensity, slope of ΔHR per arousal intensity, and arousal intensity threshold of ΔHR. Results: The intraclass correlations among monozygotic and dizygotic twin pairs were 0.663 and 0.146, respectively, for average arousal intensity, and 0.449 and 0, respectively, for arousal intensity threshold of ΔHR controlling for age, sex, and race. These values imply large broad sense heritability (H2) for these traits. This evidence was confirmed by a robust maximum likelihood-based variance components estimation approach, with an additive genetic heritability of 0.64 (95% confidence interval: 0.48 to 0.80) for average arousal intensity and a combined additive and dominance genetic heritability and of 0.46 (0.25 to 0.68) for arousal intensity threshold of ΔHR. Results also suggested significant additive genetic effects for average arousal duration, ΔHR at arousal intensity scale 4 and the overall average ΔHR. Conclusion: Genetic factors explain a significant fraction of the phenotypic variability for average arousal intensity and arousal intensity threshold of ΔHR. Results suggest that the duration of arousals and specific average ΔHR values may also be heritable traits. Clinical trial registration: NCT02827461.

Symptomless Multi-Variable Apnea Prediction Index Assesses Obstructive Sleep Apnea Risk and Adverse Outcomes in Elective Surgery.

Study Objective: To validate that the symptomless Multi-Variable Apnea Prediction index (sMVAP) is associated with Obstructive Sleep Apnea (OSA) diagnosis and assess the relationship between sMVAP and adverse outcomes in patients having elective surgery. We also compare associations between Bariatric surgery, where preoperative screening for OSA risk is mandatory, and non-Bariatric surgery groups who are not screened routinely for OSA. Methods: Using data from 40 432 elective inpatient surgeries, we used logistic regression to determine the relationship between sMVAP and previous OSA, current hypertension, and postoperative complications: extended length of stay (ELOS), intensive-care-unit-stay (ICU-stay), and respiratory complications (pulmonary embolism, acute respiratory distress syndrome, and/or aspiration pneumonia). Results: Higher sMVAP was associated with increased likelihood of previous OSA, hypertension and all postoperative complications (p < .0001). The top sMVAP quintile had increased odds of postoperative complications compared to the bottom quintile. For ELOS, ICU-stay, and respiratory complications, respective odds ratios (95% CI) were: 1.83 (1.62, 2.07), 1.44 (1.32, 1.58), and 1.85 (1.37, 2.49). Compared against age-, gender- and BMI-matched patients having Bariatric surgery, sMVAP was more strongly associated with postoperative complications in non-Bariatric surgical groups, including: (1) ELOS (Orthopedics [p < .0001], Gastrointestinal [p = .024], Neurosurgery [p = .016], Spine [p = .016]); (2) ICU-stay (Orthopedics [p = .0004], Gastrointestinal [p < .0001], and Otorhinolaryngology [p = .0102]); and (3) respiratory complications (Orthopedics [p =.037] and Otorhinolaryngology [p =.011]). Conclusions: OSA risk measured by sMVAP correlates with higher risk for select postoperative complications. Associations are stronger for non-Bariatric surgeries, where preoperative screening for OSA is not routinely performed. Thus, preoperative screening may reduce OSA-related risk for adverse postoperative outcomes.

Glutamate Is a Wake-Active Neurotransmitter in Drosophila melanogaster.

Introduction: In mammals, there is evidence that glutamate has a role as a wake-active neurotransmitter. So using video-based analysis of Drosophila behavior, we undertook a study to examine if glutamate, which has been previously shown to have an excitatory role in neuromuscular junctions in Drosophila, may have a conserved wake-active role in the adult brain. Aims and Methods: Using 6- to 9-day-old female flies, we examined the effect of perturbations of the glutamatergic signaling on total wakefulness and wake bout architecture. We increased and decreased neuronal activity of glutamatergic neurons in the brains of adult flies using Upstream Activating Sequence (UAS) NaChBac and UAS EKO, respectively. We blocked neurotransmission from glutamatergic neurons in adult flies using the UAS-driven temperature-sensitive dynamin mutation shibirets. We examined the behavior of flies with loss of function mutations of individual subunits of brain-specific ionotropic glutamate receptors. Results: Increasing the activity of glutamatergic neurons in the adult brain led to a significant increase in wakefulness compared to the control groups both in the daytime and nighttime and decreasing the activity of these same neurons reduced wakefulness in the nighttime. Blocking neurotransmitter release in glutamatergic neurons significantly reduced wake in the nighttime. The ionotropic receptor mutants had significantly less wake in the nighttime than their respective genetic background controls. Conclusion: The results show the following: glutamate is indeed a wake-active neurotransmitter in Drosophila; there is a major time of day effect associated with loss of glutamatergic neurotransmission; and it is a major wake-active neurotransmitter in the nighttime.

Diagnosis and treatment of sleep disordered breathing in hospitalized cardiac patients: a reduction in 30-day hospital readmission rates.

BACKGROUND: Sleep disordered breathing (SDB) is associated with significant cardiovascular sequelae and positive airway pressure (PAP) has been shown to improve heart failure and prevent the recurrence of atrial fibrillation in cardiac patients with sleep apnea. Patients who are hospitalized with cardiac conditions frequently have witnessed symptoms of SDB but often do not have a diagnosis of sleep apnea. We implemented a clinical paradigm to perform unattended sleep studies and initiate treatment with PAP in hospitalized cardiac patients with symptoms consistent with SDB. We hypothesized that PAP adherence in cardiac patients with SDB would reduce readmission rates 30 days after discharge. METHODS: 106 consecutive cardiac patients hospitalized for heart failure, arrhythmias, and myocardial infarction and who reported symptoms of SDB were evaluated. Patients underwent a type III portable sleep study and those patients diagnosed with sleep apnea were started on PAP. Demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits were collected. RESULTS: Of 106 patients, 104 had conclusive diagnostic studies using portable monitoring systems. Seventy-eight percent of patients (81/104) had SDB (AHI ≥ 5 events/h). Eighty percent (65/81) had predominantly obstructive sleep apnea, and 20% (16/81) had predominantly central sleep apnea. None of 19 patients (0%) with adequate PAP adherence, 6 of 20 (30%) with partial PAP use, and 5 of 17 (29%) of patients who did not use PAP were readmitted to the hospital or visited the emergency department (ED) for a cardiac issue within 30 days from discharge (p = 0.025). CONCLUSIONS: Performing diagnostic unattended sleep studies and initiating PAP treatment in hospitalized cardiac patients was feasible and provided important clinical information. Our data indicate that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhered to PAP treatment than those who were not adherent. COMMENTARY: A commentary on this article appears in this issue on page 1067.

Heritability of craniofacial structures in normal subjects and patients with sleep apnea.

OBJECTIVES: Accumulating evidence has shown that there is a genetic contribution to obstructive sleep apnea (OSA).The objectives were to use magnetic resonance imaging (MRI) cephalometry to (1) confirm heritability of craniofacial risk factors for OSA previously shown by cephalometrics; and (2) examine the heritability of new craniofacial structures that are measurable with MRI. DESIGN: A sib pair "quad" design examining apneics, apneic siblings, controls, and control siblings. The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for differences in age, sex, ethnicity, height, and weight. SETTING: Academic medical center. PATIENTS: We examined 55 apneic probands (apnea-hypopnea index [AHI]: 46.8 ± 33.5 events/h), 55 proband siblings (AHI: 11.1 ± 15.9 events/h), 55 controls (AHI: 2.2 ± 1.7 events/h), and 55 control siblings (AHI: 4.1 ± 4.0 events/h). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Five independent domains reflecting different aspects of the craniofacial structure were examined. We confirmed heritability of sella-nasion-subspinale (38%, P = 0.002), saddle angle (55%, P < 0.0001), mandibular length (24%, P = 0.02) and lower facial height (33%, P = 0.006) previously measured by cephalometry. In addition, the current study added new insights by demonstrating significant heritability of mandibular width (30%, P = 0.005), maxillary width (47%, P < 0.0001), distance from the hyoid bone to the retropogonion (36%, P = 0.0018) and size of the oropharyngeal space (31%, P = 0.004). Finally, our data indicate that heritability of the craniofacial structures is similar in normal patients and those with apnea. CONCLUSIONS: The data support our a priori hypothesis that the craniofacial structures that have been associated with obstructive sleep apnea (OSA) are heritable. We have demonstrated heritability for several intermediate craniofacial phenotypes for OSA. Thus, we believe that future studies should be able to identify genes associated with these intermediate craniofacial phenotypes.

Tongue fat and its relationship to obstructive sleep apnea.

STUDY OBJECTIVES: The objective of this study was to determine whether tongue fat is increased in obese sleep apneics compared to obese subjects without sleep apnea. We hypothesized that excess fat is deposited in the tongue in obese patients with sleep apnea. DESIGN: Case-control design. SETTING: Academic medical center. PATIENTS: We examined tongue fat in 31 obese controls (apnea-hypopnea index, 4.1 ± 2.7 events/h) and 90 obese apneics (apnea-hypopnea index, 43.2 ± 27.3 events/h). Analyses were repeated in a subsample of 18 gender-, race-, age-, and BMI-matched case-control pairs. INTERVENTIONS: All subjects underwent a MRI with three-point Dixon magnetic resonance imaging. We used sophisticated volumetric reconstruction algorithms to study the size and distribution of upper airway fat deposits in the tongue and masseter muscles within apneics and obese controls. MEASUREMENTS AND RESULTS: The data supported our a priori hypotheses that after adjustment for age, BMI, gender, and race, the tongue in apneics was significantly larger (P = 0.001) and had an increased amount of fat (P = 0.002) compared to controls. Similar results were seen in our matched sample. Our data also demonstrate that within the apneic and normal tongue, there are regional differences in fat distribution, with larger fat deposits at the base of the tongue. CONCLUSIONS: There is increased tongue volume and deposition of fat at the base of tongue in apneics compared to controls. Increased tongue fat may begin to explain the relationship between obesity and obstructive sleep apnea.