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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., Competing Interests: Funding Support and Author Disclosures No funding was received for this study. Dr Shahrokh Javaheri is funded by the National Institutes of Health (NIH) for an oxygen trial; has received income related to medical education from Jazz and Idorsia Pharmaceutical; and has served as a consultant to ZOLL Respicardia. Dr Sogol Javaheri has received grant funding from Zoll, the Massachusetts Technology Collaborative, and an internal health equity grant from Harvard Medical School. Dr Somers is funded by the National Heart, Lung, and Blood Institute (HL65176 and HL160619); has served as a consultant for Bayer, Jazz Pharmaceuticals, Huxley, Apnimed, ResMed, Lilly, Wesper, and ZOLL; and is on the Sleep Number Scientific Advisory Board. Dr Gozal is funded by the NIH for research on sleep apnea, mineralocorticoid receptors, and Alzheimer disease, University of Missouri grants, and the Leda J. Sears Foundation. Dr Mehra is supported by American Academy of Sleep Medicine and American Heart Association grants; has received honorarium from the American Academy of Sleep Medicine for speaking; and has received royalties from UpToDate. Dr Zee is funded by the NIH; has served as a consultant to Eisai, Idorsia, Jazz, Harmony, and Sanofi; and reports grants to Northwestern University from Vanda. Dr Cistulli has an appointment to an endowed academic Chair at the University of Sydney that was established from ResMed funding; has received research support from ResMed and SomnoMed; is a consultant to ResMed, SomnoMed, Signifier Medical Technologies, Bayer, and Sunrise Medical; and has a pecuniary interest in SomnoMed related to a role in research and development (2004). Dr Malhotra is funded by the NIH; has received income related to medical education from Jazz, LivaNova, Eli Lilly, and Zoll; and ResMed provided a philanthropic donation to UC San Diego. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Funding Support and Author Disclosures ResMed provided a philanthropic donation to UC San Diego. Dr Shahrokh Javaheri has received income related to medical education from Res Med, Jazz, Idorsia, Eli Lilly, and Avadel Pharmaceutical; and is a consultant to Zoll-Respicardia. Dr Sogol Javaheri has received grant funding from Zoll and the Massachusetts Technology Collaborative; and is supported by an internal health equity grant from Harvard Medical School. Dr Mehra has received an honorarium from the American Academy of Sleep Medicine; has received funds for service on the American Board of Internal Medicine writing group; has received NIH funding; and has received royalties from Up to Date. Dr Somers is supported by National Institutes of Health (NIH) grant HL65176; has served as a consultant for Bayer, Jazz Pharmaceuticals, Huxley, Apnimed, ResMed, Lilly, and Respicardia; and is on the Sleep Number Scientific Advisory Board. Dr Zee is a consultant to Eisai, Idorsia, Jazz, and Harmony; and has received institutional grants from Vanda and Sleep Number. Dr Cistulli has an appointment to an endowed academic Chair at the University of Sydney that was established from ResMed funding; has received research support from ResMed and SomnoMed; is a consultant to ResMed, SomnoMed, Signifier Medical Technologies, Bayer, and Sunrise Medical; and has a pecuniary interest in SomnoMed related to a role in research and development (2004). Dr Malhotra is funded by the NIH; and has received income related to medical education from Powell Mansfield, Livanova, Eli Lilly, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Observational and retrospective studies suggest that people with narcolepsy may have an increased prevalence of cardiovascular and cardiometabolic comorbidities and may be at greater risk for future cardiovascular events. An expert consensus panel was formed to establish agreement on the risk of hypertension and cardiovascular/cardiometabolic disease in people with narcolepsy and to develop strategies to mitigate these risks., Methods and Results: Experts in sleep medicine and cardiology were selected to participate in the panel. After reviewing the relevant literature, the experts identified key elements, drafted recommendation statements, and developed discussion points to provide supporting evidence for the recommendations. The draft and final recommendations were rated on a scale from 0 (not at all agree) to 4 (very much agree). All experts had an agreement rating of 4.0 for all 14 revised recommendation statements for patients with narcolepsy. These statements comprised 3 themes: (1) recognize the risk of hypertension and cardiovascular/cardiometabolic disease, (2) reduce the risk of hypertension and cardiovascular/cardiometabolic disease, and (3) reduce sodium intake to lower the risk of hypertension and cardiovascular disease., Conclusions: These consensus recommendations are intended to increase awareness of potential cardiovascular/cardiometabolic risks in patients with narcolepsy for all clinicians. Early monitoring for, and prevention of, cardiovascular risks in this population are of great importance, especially as narcolepsy usually develops in adolescents and young adults, who will be exposed to adverse effects of the disease for decades. Prospective systematic studies are needed to determine association and causation of narcolepsy with cardiovascular/cardiometabolic disorders.

Medication-induced central sleep apnea (CSA) is one of the eight categories of causes of CSA but in the absence of awareness and careful history may be misclassified as primary CSA. While opioids are a well-known cause of respiratory depression and CSA, non-opioid medications including sodium oxybate, baclofen, valproic acid, gabapentin, and ticagrelor are less well-recognized. Opioids-induced respiratory depression and CSA are mediated primarily by µ-opioid receptors, which are abundant in the pontomedullary centers involved in breathing. The non-opioid medications, sodium oxybate, baclofen, valproic acid, and gabapentin, act upon brainstem gamma-aminobutyric acid (GABA) receptors, which co-colonize with µ-opioid receptors and mediate CSA. The pattern of ataxic breathing associated with these medications is like that induced by opioids on polysomnogram. Finally, ticagrelor also causes periodic breathing and CSA by increasing central chemosensitivity and ventilatory response to carbon dioxide. Given the potential consequences of CSA and the association between some of these medications with mortality, it is critical to recognize these adverse drug reactions, particularly because discontinuation of the offending agents has been shown to eliminate CSA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Objectives: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI] ≥3%Only ) vs events with arousals but no desaturation (AHI ArOnly ) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts., Methods: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI ≥3%Only and AHI ArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease., Results: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI ≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHI ArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years ( P < .0001)., Conclusions: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea., Citation: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med . 2023;19(8):1475-1484., (© 2023 American Academy of Sleep Medicine.)

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases., (© 2023 European Society of Cardiology.)

Rationale: Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) is prevalent in some patients with heart failure with reduced ejection fraction (HFrEF). Theoretical models of Hunter-Cheyne-Stokes breathing predict that a low metabolic rate (MR) predisposes one to CSA. Objectives: In this study, we examined the role of MR in the pathogenesis of CSA. Methods: A physiological study was conducted in a sleep laboratory at a U.S. Department of Veterans Affairs medical center. Patients were 28 consecutive male Veterans with stable HFrEF. After an adaptation night, polysomnography, left ventricular ejection fraction, pulmonary function tests, carbon dioxide production ([Formula: see text]), and arterial blood samples were obtained under strict standardized conditions. Physiological variables were then entered into regression models to examine the association with CSA. Results: Body mass index varied from 20 to 40 kg/m 2 , and [Formula: see text] ranged from 167 to 434 ml/min. In the final regression model, low [Formula: see text] and low body mass index were associated with CSA index. [Formula: see text] had the strongest association (95% confidence interval, -0.36 to -0.06; P  = 0.007). Conclusions: In patients with HFrEF, a low MR and related low [Formula: see text], but not low oxygen consumption, were associated with CSA. Mechanistically, in the face of low MR and [Formula: see text], a given change in ventilation results in large swings in partial pressure of CO 2 , thus promoting CSA. To our knowledge, this is the first study in humans that shows this association.

Among sleep-related disordered breathing events, hypopneas are the most frequent. Like obstructive and central apneas, hypopneas may be obstructive or central (reduced drive) in origin. Nevertheless, unlike apneas, categorizing hypopneas as either "obstructive" or "central" is often difficult or ambiguous. It has been suggested that hypopneas could be categorized as obstructive when associated with snoring, inspiratory flow limitation, or paradoxical thoraco-abdominal excursions. This approach, however, has not been extensively tested and misclassification of hypopneas is unavoidable. Yet, much rides on the accurate distinction of these events to guide therapy with medical devices or pharmacological therapy in each patient. Additionally, accurate hypopnea classification is critical for design of clinical trials, because therapeutic responses differ depending on the subtype of hypopnea. Correctly classifying hypopneas can also allay concerns about obtaining coverage for therapies that specifically target either central or obstructive sleep-disordered breathing events. The present paper expands on the current criteria for differentiating obstructive from central hypopneas and provides illustrative tracings that can help classify these events., Citation: Javaheri S, Rapoport DM, Schwartz AR. Distinguishing central from obstructive hypopneas on a clinical polysomnogram. J Clin Sleep Med . 2023;19(4):823-834., (© 2023 American Academy of Sleep Medicine.)

Central sleep apnea is not a single disorder; it can present as an isolated disorder or as a part of other clinical syndromes. In some conditions, such as heart failure, central apneic events are due to transient inhibition of ventilatory motor output during sleep, owing to the overlapping influences of sleep and hypocapnia. Specifically, the sleep state is associated with removal of wakefulness drive to breathe; thus, rendering ventilatory motor output dependent on the metabolic ventilatory control system, principally PaCO2. Accordingly, central apnea occurs when PaCO2 is reduced below the "apneic threshold". Our understanding of the pathophysiology of central sleep apnea has evolved appreciably over the past decade; accordingly, in disorders such as heart failure, central apnea is viewed as a form of breathing instability, manifesting as recurrent cycles of apnea/hypopnea, alternating with hyperpnea. In other words, ventilatory control operates as a negative-feedback closed-loop system to maintain homeostasis of blood gas tensions within a relatively narrow physiologic range, principally PaCO2. Therefore, many authors have adopted the engineering concept of "loop gain" (LG) as a measure of ventilatory instability and susceptibility to central apnea. Increased LG promotes breathing instabilities in a number of medical disorders. In some other conditions, such as with use of opioids, central apnea occurs due to inhibition of rhythm generation within the brainstem. This review will address the pathogenesis, pathophysiologic classification, and the multitude of clinical conditions that are associated with central apnea, and highlight areas of uncertainty., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Opioid medications are considered a significant component in the multidisciplinary management of chronic pain. In the past two decades, the use of opioid medications has dramatically risen in part because of an increased awareness by health care providers to treat chronic pain more effectively. In addition, patients are encouraged to seek treatment. The release of a sentinel joint statement in 1997 by the American Academy of Pain Medicine and the American Pain Society in a national effort to increase awareness and support the treatment of chronic pain has undoubtedly contributed to the opioid crisis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era., Objectives: This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments., Methods: Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization., Results: A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05)., Conclusions: In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes., Competing Interests: Funding Support and Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Obstructive sleep apnea (OSA) is highly prevalent among patients with asymptomatic left ventricular systolic and diastolic dysfunction and congestive heart failure, and if untreated may contribute to the clinical progression of heart failure (HF). Given the health and economic burden of HF, identifying potential modifiable risk factors such as OSA and whether appropriate treatment improves outcomes is of critical importance. Identifying the subgroups of patients with OSA and HF who would benefit most from OSA treatment is another important point. This focused review surveys current knowledge of OSA and HF in order to provide: (1) a better understanding of the pathophysiologic mechanisms that may increase morbidity among individuals with HF and comorbid OSA, (2) a summary of current observational data and small randomized trials, (3) an understanding of the limitations of current larger randomized controlled trials, and (4) future needs to more accurately determine the efficacy of OSA treatment among individuals with HF.

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 PaO 2 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 PaO 2 , and 1.07; 95% confidence interval 1.03 to 1.12; P = .001 for body mass index). In separate analyses, body mass index and PaO 2 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., (© 2022 American Academy of Sleep Medicine.)

When considered separately from cardiovascular disease, stroke is the third leading cause of death in the U.S. and is the leading cause of long-term disability in adults. New approaches that can be offered to the majority of ischemic stroke patients, can be continued throughout post-stroke care, can limit stroke severity, and can complement or even enhance rehabilitation, would transform ischemic stroke recovery. The treatment of obstructive sleep apnea (OSA) in patients with acute ischemic stroke may represent one such approach. This manuscript reviews the epidemiologic studies of the bidirectional association between OSA and stroke, and the mechanisms and molecular signatures of OSA leading to transient ischemic attack and stroke as well as the randomized controlled trials and observational cohort studies examining continuous positive airway treatment efficacy on the impact of stroke outcomes. Finally, the insights these studies provide on future research are also discussed., Competing Interests: Conflicts of interest All authors declare no conflict of interest related to the current work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sleep disorders are prevalent in heart failure and include insomnia, poor sleep architecture, periodic limb movements and periodic breathing, and encompass both obstructive (OSA) and central sleep apnea (CSA). Polysomnographic studies show excess light sleep and poor sleep efficiency particularly in those with heart failure. Multiple studies of consecutive patients with heart failure show that about 50% of patients suffer from either OSA or CSA. While asleep, acute pathological consequences of apneas and hypopneas include altered blood gases, sleep fragmentation, and large negative swings in intrathoracic pressure. These pathological consequences are qualitatively similar in both types of sleep apnea, though worse in OSA than CSA. Sleep apnea results in oxidative stress, inflammation, and endothelial dysfunction, best documented in OSA. Multiple studies show that both OSA and CSA are associated with excess hospital readmissions and premature mortality. However, no randomized controlled trial (RCT) has been reported for OSA, but sensitivity analysis of two randomized controlled trials has concluded that use of positive airway pressure devices is associated with excess mortality in patients with heart failure and CSA. Phrenic nerve stimulation has shown improvement in sleep apnea events and daytime sleepiness; however, no randomized controlled trials have demonstrated improvement in survival in patients with heart failure. The correct identification and treatment of heart failure patients with sleep and breathing disorders could affect the long-term outcomes of these patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Study Objectives: Patients with congestive heart failure (CHF) frequently exhibit an elevated ratio of minute ventilation over CO 2 output (VE/VCO 2 slope) while undergoing exercise tests. One of the factors contributing to this elevated slope is an increased chemosensitivity to CO 2 in that this slope significantly correlates with the slope of the ventilatory response to CO 2 rebreathing at rest. A previous study in patients with CHF and central sleep apnea showed that the highest VE/VCO 2 slope during exercise was associated with the most severe central sleep apnea. In the current study, we tested the hypothesis that in patients with CHF and obstructive sleep apnea (OSA), the highest VE/VCO 2 slope is also associated with the most severe OSA. If the hypothesis is correct, then it implies that in CHF, augmented instability in the negative feedback system controlling breathing predisposes to both OSA and central sleep apnea., Methods: This preliminary study involved 70 patients with stable CHF and a spectrum of OSA severity who underwent full-night polysomnography, echocardiography, and cardiopulmonary exercise testing. Peak oxygen consumption and the VE/VCO 2 slope were calculated., Results: There was significant positive correlation between the apnea-hypopnea index and the VE/VCO 2 slope ( r = .359; P = .002). In the regression model, involving the relevant variables of age, body mass index, sex, VE/VCO 2 slope, peak oxygen consumption, and left ventricular ejection fraction, the apnea-hypopnea index retained significance with VE/VCO 2 ., Conclusions: In patients with CHF, the VE/VCO 2 slope obtained during exercise correlates significantly to the severity of OSA, suggesting that an elevated CO 2 response should increase suspicion for the presence of severe OSA, a treatable disorder that is potentially associated with excess mortality., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Comparison Between Exercise Training and CPAP Treatment for Patients With Heart Failure and Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/record/NCT01538069; Identifier: NCT01538069., Citation: Bittencourt L, Javaheri S, Servantes DM, Pelissari Kravchychyn AC, Almeida DR, Tufik S. In patients with heart failure, enhanced ventilatory response to exercise is associated with severe obstructive sleep apnea. J Clin Sleep Med. 2021;17(X):1875-1880., (© 2021 American Academy of Sleep Medicine.)

Background: The remedē System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remedē System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant., Methods: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis., Results: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years., Conclusion: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01816776., Competing Interests: Dr Maria Rosa Costanzo report grants, personal fees from Respicardia, during the conduct of the study; Dr Shahrokh Javaheri report personal fees from Respicardia, during the conduct of the study; Dr Piotr Ponikowski report personal fees from Respicardia, during the conduct of the study; personal fees from Vifor Pharma, personal fees from Amgen, personal fees from Servier, personal fees from Novartis, personal fees from Berlin Chemie, personal fees from Bayer, personal fees from Pfizer, personal fees from Cibiem, personal fees from Coridea, personal fees from Impulse Dynamics, personal fees from Renal Guard Solutions, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from BMS, personal fees from AbbottVascular, personal fees from Radcliffe Group, personal fees from Ono Pharmaceutical, outside the submitted work; Dr Ralph Augostini report personal fees from Respicardia, outside the submitted work; Dr Lee R Goldberg report grants, personal fees from Respicardia, during the conduct of the study; personal fees from Abbott, outside the submitted work; Dr Christoph Stellbrink report grants from Respicardia, during the conduct of the study; Dr Alan R Schwartz report grants from NIH, personal fees from Respicardia, during the conduct of the study; personal fees from Respicardia, outside the submitted work; Mr Scott McKane and Dr Timothy E. Meyer are employees of Respicardia so receive salary and have ownership in the company during the conduct of the study. Dr William T Abraham report personal fees from Respicardia, during the conduct of the study; Dr Costanzo (study principal investigator for remedē® System Pivotal Trial). The authors report no other conflicts of interest in this work., (© 2021 Costanzo et al.)

Background: Central sleep apnea (CSA) is common among patients with heart failure and has been strongly linked to adverse outcomes. However, progress toward improving outcomes for such patients has been limited. The purpose of this official statement from the American Thoracic Society is to identify key areas to prioritize for future research regarding CSA in heart failure. Methods: An international multidisciplinary group with expertise in sleep medicine, pulmonary medicine, heart failure, clinical research, and health outcomes was convened. The group met at the American Thoracic Society 2019 International Conference to determine research priority areas. A statement summarizing the findings of the group was subsequently authored using input from all members. Results : The workgroup identified 11 specific research priorities in several key areas: 1 ) control of breathing and pathophysiology leading to CSA, 2 ) variability across individuals and over time, 3 ) techniques to examine CSA pathogenesis and outcomes, 4 ) impact of device and pharmacological treatment, and 5 ) implementing CSA treatment for all individuals Conclusions: Advancing care for patients with CSA in the context of heart failure will require progress in the arenas of translational (basic through clinical), epidemiological, and patient-centered outcome research. Given the increasing prevalence of heart failure and its associated substantial burden to individuals, society, and the healthcare system, targeted research to improve knowledge of CSA pathogenesis and treatment is a priority.

Study Objectives: Idiopathic central sleep apnea (ICSA) is a rare disorder diagnosed when known causes of central sleep apnea are excluded. No established treatments exist for ICSA, and long-term studies are lacking. We assessed the long-term effectiveness and safety of transvenous phrenic nerve stimulation in patients with ICSA., Methods: In the remedē System Pivotal Trial, 16/151 (11%) participants with central sleep apnea were diagnosed as having ICSA. Patients were implanted and followed through 18 months of active therapy. Polysomnograms obtained at baseline and at 6, 12, and 18 months were scored by a central laboratory. Sleep metrics and patient-reported quality of life outcomes were assessed., Results: Patients experienced moderate-severe central sleep apnea. The baseline AHI, central apnea index, and arousal index were 40, 25, and 32 events/h of sleep, respectively. These metrics improved at 6, 12, and 18 months of therapy: the AHI decreased by 25, 25, and 23 events/h (P < .001 at each visit), the central apnea index by 22, 23, and 22 events/h (P < .001 at each visit), and the arousal index by 12 (P = .005), 11 (P = .035), and 13 events/h (P < .001). Quality of life instruments showed clinically meaningful improvements in daytime somnolence, fatigue, general and mental health, and social functioning. The only related serious adverse event was lead component failure in 1 patient., Conclusions: This is the longest prospective study for the treatment of ICSA. Transvenous phrenic nerve stimulation significantly decreased sleep-disordered breathing metrics with consequent improvement in quality of life at 6 months, and all benefits were sustained through 18 months., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Respicardia, Inc. Pivotal Trial of the remedē System; URL: https://clinicaltrials.gov/ct2/show/NCT01816776; Identifier: NCT01816776., (© 2020 American Academy of Sleep Medicine.)

Background: Therapy options for OSA and central sleep apnea (CSA) are limited, thus many patients remain untreated. Clinically, acetazolamide is sometimes used for CSA; however, given overlapping pathophysiologic properties of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs, and languages, thus including few studies (typically ≤3) limiting insights., Research Question: How efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose?, Study Design and Methods: We queried MEDLINE, EMBASE, and ClinicalTrials.gov from inception until March 11, 2019. Any study in which adults with OSA/CSA received oral acetazolamide vs no acetazolamide (control) that reported sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and oxygen saturation nadir. Quality of evidence (QoE) was rated with the use of Grades of Recommendation Assessment, Development and Evaluation methods., Results: We included 28 studies (13 OSA/15 CSA; N Subjects,Acetazolamide  = 542; N Subjects,Control  = 553) that enabled meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36 to 1000 mg/d and treatment duration from 1 to 90 d (median, 6 d). Overall, acetazolamide vs control lowered the AHI by -0.7 effect sizes (95% CI, -0.83 to -0.58; I 2  = 0%; moderate QoE) that corresponded to a reduction of 37.7% (95% CI, -44.7 to -31.3) or 13.8/h (95% CI, -16.3 to -11.4; AHI Control  = 36.5/h). The AHI reduction was similar in OSA vs CSA, but significantly greater with higher doses (at least up to 500 mg/d). Furthermore, acetazolamide improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5; I 2  = 63%; no evidence of effect modification; very low QoE) and several secondary outcomes that included sleep quality measures and BP (mostly low QoE)., Interpretation: Short-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow up are warranted to assess Acetazolamide's value for the chronic treatment of patients with sleep apnea., Clinical Trial Registration: PROSPERO (CRD42019147504)., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Obstructive sleep apnea (OSA) is associated with increased mortality and readmissions in patients with heart failure (HF). The effect of in-hospital diagnosis and treatment of OSA during decompensated HF episodes remains unknown., Methods and Results: A single-site, randomized, controlled trial of hospitalized patients with decompensated HF (n = 150) who were diagnosed with OSA during the hospitalization was undertaken. All participants received guideline-directed therapy for HF decompensation. Participants were randomized to an intervention arm which received positive airway pressure (PAP) therapy during the hospitalization (n = 75) and a control arm (n = 75). The primary outcome was discharge left ventricular ejection fraction (LVEF). The LVEF changed in the PAP arm from 25.5 ± 10.4 at baseline to 27.3 ± 11.9 at discharge. In the control group, LVEF was 27.3 ± 11.7 at baseline and 28.8 ± 10.5 at conclusion. There was no significant effect on LVEF of in-hospital PAP compared with controls (P = .84) in the intention-to-treat analysis. The on-treatment analysis in the intervention arm showed a significant increase in LVEF in participants who used PAP for ≥3 hours per night (n = 36, 48%) compared with those who used it less (P = .01). There was a dose effect with higher hours of use associated with more improvement in LVEF. Follow-up of readmissions at 6 months after discharge revealed a >60% decrease in readmissions for patients who used PAP ≥3 h/night compared with those who used it <3 h/night (P < .02) and compared with controls (P < .04)., Conclusions: In-hospital treatment with PAP was safe but did not significantly improve discharge LVEF in patients with decompensated HF and newly diagnosed OSA. An exploratory analysis showed that adequate use of PAP was associated with higher discharge LVEF and decreased 6 months readmissions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

OSA is a highly prevalent sleep disorder, and subjective excessive daytime sleepiness (EDS) is the cardinal symptom for which many individuals seek medical advice. Positive airway pressure (PAP) devices, first-line treatment for OSA, eliminates EDS in most patients. However, a subset of patients suffers from persistent EDS despite adherence to therapy. Multiple conditions, some reversible, could account for the residual sleepiness and need to be explored, requiring detailed history, review of PAP data from the smart card, and sometimes additional testing. When all known causes of EDS are excluded, in adequately treated subjects, the purported mechanisms could relate to long-term exposure to the OSA-related sleep fragmentation, sleep deprivation, and hypoxic injury to the arousal system, shifts in melatonin secretion, or altered microbiome. Independent of the mechanism, in well-treated OSA, pharmacological therapy with approved drugs can be considered. Modafinil is commonly prescribed to combat residual EDS, but more recently two drugs, solriamfetol, a dual dopamine-norepinephrine reuptake inhibitor, and pitolisant, a histamine H3 receptor inverse agonist, were approved for EDS. Solriamfetol has undergone randomized controlled trials for treatment of EDS associated with both OSA and narcolepsy, exhibiting robust efficacy. Solriamfetol is renally excreted, with no known drug interactions. Pitolisant, which is nonscheduled, has undergone multiple RCTs in narcolepsy, showing improvement in subjective and objective EDS and one OSA trial showing improvement in subjective EDS., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Central sleep apnea/Hunter-Cheyne-Stokes breathing (CSA/HCSB) is prevalent in patients with heart failure with reduced ejection fraction (HFrEF). The acute pathobiologic consequences of CSA/HSCB eventually lead to sustained sympathetic overactivity, repeated hospitalization, and premature mortality. A few randomized controlled trials (RCTs) have shown statistically significant and clinically important reduction in sympathetic activity when CSA/HCSB is attenuated by oxygen or PAP therapy. Yet, the two largest PAP RCTs in patients with HFrEF, one with CPAP and the other with adaptive servoventilation (ASV), were negative with respect to their primary outcomes, and both were associated with excess mortality. However, both trials suffered from significant deficiencies, casting doubt on their results. A second RCT evaluating an ASV device with an advanced algorithm is ongoing. A new modality of therapy, unilateral phrenic nerve stimulation, has undergone an RCT that demonstrated an improvement in CSA that was associated with a reduction in arousals, improvement in sleepiness, and improvement in quality of life. However, a long-term mortality trial has not been performed with this modality. Most recently, the National Institutes of Health has funded a long-term, phase 3 RCT of low-flow oxygen vs sham for the treatment of CSA/HCSB in HFrEF. The composite primary outcome includes all-cause mortality and hospitalization for worsening HF. In this article, we focus on various therapeutic options for the treatment of CSA/HCSB and, when appropriate, emphasize the importance of identifying CSA/HCSB phenotypes to tailor treatment., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Sleep-disordered breathing (SDB), including OSA and central sleep apnea, is highly prevalent in patients with heart failure (HF). Multiple studies have reported this high prevalence in asymptomatic as well as symptomatic patients with reduced left ventricular ejection fraction (HFrEF), as well as in those with HF with preserved ejection fraction. The acute pathobiologic consequences of OSA, including exaggerated sympathetic activity, oxidative stress, and inflammation, eventually could lead to progressive left ventricular dysfunction, repeated hospitalization, and excessive mortality. Large numbers of observational studies and a few small randomized controlled trials have shown improvement in various cardiovascular consequences of SDB with treatment. There are no long-term randomized controlled trials to show improved survival of patients with HF and treatment of OSA. One trial of positive airway pressure treatment of OSA included patients with HF and showed no improvement in clinical outcomes. However, any conclusions derived from this trial must take into account several important pitfalls that have been extensively discussed in the literature. With the role of positive airway pressure as the sole therapy for SDB in HF increasingly questioned, a critical examination of long-accepted concepts in this field is needed. The objective of this review was to incorporate recent advances in the field into a phenotype-based approach to the management of OSA in HF., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objective: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy., Methods: Patients in the remedē System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided., Results: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remedē System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months., Conclusion: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns., Trial Registration: NCT01816776., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Citation: Javaheri S, Gay PC. To die, to sleep - to sleep, perchance to dream…without hypertension: dreams of the visionary Christian Guilleminault revisited. J Clin Sleep Med. 2019;15(9):1189-1190., (© 2019 American Academy of Sleep Medicine.)

Purpose: The purpose of this review is to discuss the pathogenesis, clinical manifestations, diagnosis and treatment, including areas of controversy and uncertainty., Recent Findings: Central apnea may be due to hypoventilation or to hypocapnia following hyperventilation. The occurrence of central apnea initiates a cascade of events that perpetuates breathing instability, recurrent central apnea and upper airway narrowing. In fact, breathing instability and upper airway narrowing are key elements of central and obstructive apnea. Clinically, central apnea is noted in association with obstructive sleep apnea, heart failure, atrial fibrillation, cerebrovascular accidents tetraplegia, and chronic opioid use.Management strategy for central apnea aim to eliminate abnormal respiratory events, stabilize sleep and alleviate the underlying clinical condition. Positive pressure therapy (PAP) remains a standard therapy for central as well as obstructive apnea. Other treatment options include adaptive-servo ventilation (ASV), supplemental oxygen, phrenic nerve stimulation, and pharmacologic therapy. However, ASV is contraindicated in patients with central sleep apnea who had heart failure with reduced ejection fraction, owing to increased mortality in this population., Summary: There are several therapeutic options for central apnea. Randomized controlled studies are needed to ascertain the long-term effectiveness of individual, or combination, treatment modalities in different types of central apnea., Competing Interests: Conflict of Interest Shahrokh Javaheri reports fees from Respicardia as a constulant. M. Safwan Badr declares no conflict of interest.

Study Objectives: Periodic breathing with central sleep apnea (CSA) is common in patients with left ventricular systolic dysfunction. Based on the pathophysiological mechanisms underlying CSA, we hypothesized that the frequency of CSA episodes would increase in the late hours of non-rapid eye movement (NREM) of sleep., Methods: Forty-one patients with left ventricular ejection fraction <40% underwent full-night-attended polysomnography scored by a central core lab. Because central apneas occur primarily in NREM sleep, total NREM sleep time for each patient was divided into 8 equal duration segments. Segment event counts were normalized to an events/hour index based on sleep segment duration., Results: Central apnea index (CAI) varied among sleep segments (p = 0.001). As expected CAI was higher in segment 1 compared to segments 2 and 3, increasing during later segments. The minimum CAI occurred in segment 2 with mean ± SD of 21 ± 3 events/hour and maximum CAI was in segment 8 with 37 ± 4 events/hour. We also determined central apnea duration which varied among segments (p = 0.005), with longer durations later in the night (segment 1: 22 ± 1 seconds; segment 8: 26 ± 1 seconds, p < 0.001). Data were also analyzed including rapid eye movement (REM) sleep, with similar results. Further, comparison of CAI between the first and second half of the night showed a significant increase in the index. Circulation time did not change across the segments (p = 0.073)., Conclusions: In patients with left ventricular dysfunction and CSA, central apnea burden (number and duration) increases during later hours of sleep. These findings have pathophysiological and therapeutic implications., Clinical Trial Registration: NCT01124370.

Aims: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics., Methods and Results: All patients randomized in the remedē System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by -6.8 ± 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system., Conclusions: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life., (© 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Exercise and CPAP improve OSA. This study examined the effects of exercise in patients with heart failure (HF) and OSA., Methods: Patients with HF and OSA were randomized to the following study groups: control, exercise, CPAP, and exercise + CPAP., Results: Sixty-five participants completed the protocol. Comparing baseline vs 3 months, the mean apnea-hypopnea index (AHI) did not change significantly (in events per hour) in the control group, decreased moderately in the exercise group (28 ± 17 to 18 ± 12; P < .03), and decreased significantly more in the CPAP group (32 ± 25 to 8 ± 11; P < .007) and in the exercise + CPAP group (25 ± 15 to 10 ± 16; P < .007). Peak oxygen consumption, muscle strength, and endurance improved only with exercise. Both exercise and CPAP improved subjective excessive daytime sleepiness, quality of life, and the New York Heart Association functional class. However, compared with the control group, changes in scores on the 36-item Medical Outcomes Study Short Form Survey and Minnesota Living with Heart Failure Questionnaire were only significant in the exercise groups., Conclusions: In patients with HF and OSA, our preliminary results showed that exercise alone attenuated OSA and improved quality of life more than CPAP. In the landscape treatment of OSA in patients with HF, this analysis is the only randomized trial showing any treatment (in this case, exercise) that improved all the studied parameters. The results highlight the important therapeutic benefits of exercise, particularly because adherence to CPAP is low., (Copyright © 2018. Published by Elsevier Inc.)

Transvenous phrenic nerve stimulation improved sleep metrics and quality of life after 6 months versus control in the remedē System Pivotal Trial. This analysis explored the effectiveness of phrenic nerve stimulation in patients with central sleep apnea after 12 months of therapy. Reproducibility of treatment effect was assessed in the former control group in whom the implanted device was initially inactive for the sixth month and subsequently activated when the randomized control assessments were complete. Patients with moderate-to-severe central sleep apnea implanted with the remedē System were randomized to therapy activation at 1 month (treatment) or after 6 months (control). Sleep indices were assessed from baseline to 12 months in the treatment group and from 6 to 12 months in former controls. In the treatment group, a ≥50% reduction in apnea-hypopnea index occurred in 60% of patients at 6 months (95% confidence interval [CI] 47% to 64%) and 67% (95% CI 53% to 78%) at 12 months. After 6 months of therapy, 55% of former controls (95% CI 43% to 67%) achieved ≥50%reduction in apnea-hypopnea index. Patient Global Assessment was markedly ormoderately improved at 6 and 12 months in 60% of treatment patients.Improvements persisted at 12 months. A serious adverse event within 12 months occurred in 13 patients (9%). Phrenic nerve stimulation produced sustained improvements in sleep indices and quality of life to at least 12 months in patients with central sleep apnea. The similar improvement of former controls after 6 months of active therapy confirms benefits are reproducible and reliable., (Copyright © 2018 Respicardia, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic use of opioids negatively affects sleep on 2 levels: sleep architecture and breathing. Patients suffer from a variety of daytime sequelae. There may be a bidirectional relationship between poor sleep quality, sleep-disordered breathing, and daytime function. Opioids are a potential cause of incident depression. The best therapeutic option is withdrawal of opioids, which proves difficult. Positive airway pressure devices are considered first-line treatment for sleep-related breathing disorders. New generation positive pressure servo ventilators are increasingly popular as a treatment option for opioid-induced sleep-disordered breathing. Treatments to improve sleep quality, sleep-related breathing disorders, and quality of life in patients who use opioids chronically are discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Questionnaires indicate that patients with liver disease have disturbed sleep. However, polysomnographic studies to quantify sleep architecture and sleep disorders in this population are lacking. The current study compared polysomnographic findings of two groups of patients with clinically stable but severe end-stage pathology of the liver and heart., Methods: This was a prospective study of consecutive patients with end-stage liver disease or severe heart failure (HF)., Measurements and Results: Patients underwent full-night, attended polysomnography along with a number of laboratory tests. Polysomnograms were scored blindly. Compared to HF patients, patients with cirrhosis suffered from severe periodic limb movements during sleep (PLMS), with an index of 39/hour associated with excessive arousals. In patients with cirrhosis, serum iron and ferritin levels were either at the upper normal limit or elevated. There were significant correlations between severity of PLMS versus blood levels of bilirubin (r = 0.73, p = 0.004) and ammonia (r = 0.74, p = 0.017)., Conclusions: This was the first polysomnographic study of patients with stable cirrhosis demonstrating severely disturbed sleep infrastructure and presence of excessive PLMS with arousals. The pathobiochemical mechanisms of these findings remain to be established. Independent of the mechanisms, these polysomnographic findings confirmed the subjective reports of poor sleep by patients with cirrhosis. Further, a subset of patients with cirrhosis acquired a syndrome similar to idiopathic Parkinson's disease, which per se was frequently associated with PLMS; the current results were consistent with this notion. Future studies are needed to determine if PLMS of cirrhosis is an early indication of incident Parkinsonian syndrome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Objectives: Subjective versus objective sleepiness in heart failure (HF) remains understudied; therefore, we sought to examine the association of these measures and interrelationships with biochemical markers., Methods: Participants with stable systolic HF recruited from a clinic-based program underwent attended polysomnography, Multiple Sleep Latency Testing, questionnaire data collection including Epworth Sleepiness Scale (ESS), and morning phlebotomy for biochemical markers. Linear regression was used to assess the association of mean sleep latency (MSL) and ESS (and other reported outcomes) with adjustment of age or body mass index or left ventricular ejection fraction (LVEF) (beta coefficients, 95% confidence interval) and also with biochemical markers (beta coefficients, 95% confidence interval)., Results: The final analytic sample comprised 26 participants: 52 ± 14 years with apnea-hypopnea index (AHI): 34 ± 27, LVEF: 34 ± 12%, MSL: 7 ± 5 minutes and ESS: 7 (5, 10). There was no significant association of MSL and ESS (-0.36, -0.81 to 0.09, P = .11), AHI, or other questionnaire-based outcomes in adjusted analyses. Although statistically significant associations of ESS and biomarkers were not observed, there were associations of MSL and cortisol (μg/dL) [-0.05: -0.08, -0.01, P = .012] and interleukin-6 (pg/mL) [-0.11: -0.18, -0.04, P = .006], which persisted in adjusted models., Conclusions: In systolic HF, although overall objective sleepiness was observed, this was not associated with subjective sleepiness (ie, a discordance was identified). Differential upregulation of systemic inflammation in objective sleepiness was observed, findings not observed with subjective sleepiness. These findings suggest that underlying mechanistic pathways of inflammation may provide the explanation for dissonance of objective and subjective sleepiness symptoms in HF, thus potentially informing targeted diagnostic and therapeutic approaches., Commentary: A commentary on this article appears in this issue on page 1369., (© 2017 American Academy of Sleep Medicine)

Since the introduction of continuous positive airway pressure (PAP) for the treatment of obstructive sleep apnea (OSA) in 1981, PAP technology has diversified exponentially. Compact and quiet fixed continuous PAP flow generators, autotitrating PAP devices, and bilevel PAP devices that can treat multiple sleep-disordered breathing phenotypes including OSA, central sleep apnea (CSA), combinations of OSA and CSA, and hypoventilation are available. Adaptive servo-ventilators can suppress Hunter-Cheyne-Stokes breathing and CSA and treat coexisting obstructive events. Volume-assured pressure support PAP apparatus purports to provide a targeted degree of ventilatory assistance while also treating cooccurring OSA and/or CSA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Opioid-induced sleep disordered breathing presents a therapeutic predicament with the increasing incidence of prescription opioid use for noncancer chronic pain in the United States. Central sleep apnea with a Biot or cluster breathing pattern is characteristic of polysomnography studies; however, long-term clinical outcomes and the impact of therapy remain unknown. Novel ampakine-based therapies are being investigated. Randomized controlled trials with therapies that target the underlying pathophysiologic mechanisms of opioid-induced sleep disordered breathing are required., (Published by Elsevier Inc.)

Central sleep apnea (CSA) and Hunter-Cheyne-Stokes breathing (HCSB) are caused by failure of the pontomedullary pacemaker generating breathing rhythm. CSA/HCSB may complicate several disorders causing recurrent arousals and desaturations. Common causes of CSA in adults are congestive heart failure, stroke, and chronic use of opioids; opioids have hypoventilatory effects. Diagnosis and treatment of hyperventilatory CSA may improve quality of life, and, when associated with heart failure or cerebrovascular disease, reduce morbidity and perhaps mortality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The obesity hypoventilation syndrome (OHS) is associated with significant morbidity and increased mortality compared with simple obesity and eucapnic obstructive sleep apnea. Accurate diagnosis and commencement of early and appropriate management is fundamental in reducing the significant personal and societal burdens this disorder poses. Sleep disordered breathing is a major contributor to the developmental of sleep and awake hypercapnia, which characterizes OHS, and is effectively addressed through the use of positive airway pressure (PAP) therapy. This article reviews the current evidence supporting different modes of PAP currently used in managing these individuals., (Copyright © 2017 Elsevier Inc. All rights reserved.)