Research Priorities for Patients with Heart Failure and Central Sleep Apnea. An Official American Thoracic Society Research Statement.

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 individualsConclusions: 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.

In-Hospital Management of Sleep Apnea During Heart Failure Hospitalization: A Randomized Controlled Trial.

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.

Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.

BACKGROUND: Central sleep apnoea is a serious breathing disorder associated with poor outcomes. The remedé system (Respicardia Inc, Minnetonka, MN, USA) is an implantable device which transvenously stimulates a nerve causing diaphragmatic contraction similar to normal breathing. We evaluated the safety and effectiveness of unilateral neurostimulation in patients with central sleep apnoea. METHODS: We recruited patients from 31 hospital-based centres in Germany, Poland, and the USA in this prospective, multicentre, randomised trial. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an apnoea-hypopnoea index (AHI) of at least 20 events per h, tested by a polysomnography, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness endpoint in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50% or greater AHI reduction from baseline to 6 months, measured by a full-night polysomnography assessed by masked investigators in a core laboratory. The primary safety endpoint of 12-month freedom from serious adverse events related to the procedure, system, or therapy was evaluated in all patients. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov (NCT01816776). FINDINGS: Between April 17, 2013, and May 28, 2015, we randomly assigned 151 eligible patients to the treatment (n=73) or control (n=78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51%] of 68) had an AHI reduction from baseline of 50% or greater at 6 months than had those in the control group (eight [11%] of 73; difference between groups 41%, 95% CI 25-54, p<0·0001). 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomisation period when neurostimulation was delivered to only the treatment group and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. 27 (37%) of 73 patients in the treatment group reported non-serious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients, but was unresolved in one (1%) patient. INTERPRETATION: Transvenous neurostimulation significantly reduced the severity of central sleep apnoea, including improvements in sleep metrics, and was well tolerated. The clinically meaningful effects of the therapy are supported by the concordant improvements in oxygenation and quality of life, making transvenous neurostimulation a promising therapeutic approach for central sleep apnoea. FUNDING: Respicardia Inc.

Gender differences in patients with obesity hypoventilation syndrome.

The role of gender and menopause in obstructive sleep apnoea is well known; however, no study has reported the impact of gender on the clinical presentation and the nocturnal respiratory events in patients with obesity hypoventilation syndrome. Therefore, this study prospectively evaluated differences in the clinical characteristics of women and men with obesity hypoventilation syndrome in a large cohort of patients with obstructive sleep apnoea. During the study period, a total of 1973 patients were referred to the sleep clinic with clinical suspicion of obstructive sleep apnoea. All patients underwent overnight polysomnography, during which time spirometry, arterial blood samples and thyroid tests were routinely obtained. Among 1973 consecutive patients, 1693 (617 women) were diagnosed with obstructive sleep apnoea, among whom 144 suffered from obesity hypoventilation syndrome (96 women). The prevalence of obesity hypoventilation syndrome among women and men was 15.6% and 4.5%, respectively (P < 0.001). Women with obesity hypoventilation syndrome were significantly older than men with obesity hypoventilation syndrome (61.5 ± 11.9 years versus 49.1 ± 12.5 years, P < 0.001). Although there were no significant differences between genders regarding symptoms, body mass index, spirometric data or daytime PaCO2 , women with obesity hypoventilation syndrome suffered significantly more from hypertension, diabetes and hypothyroidism. The prevalence of obesity hypoventilation syndrome was higher in post-menopausal (21%) compared with pre-menopausal (5.3%) women (P < 0001). HCO3 and duration of SpO2 <90% were the only independent predictors of obesity hypoventilation syndrome. In conclusion, this study reported that among subjects referred to the sleep disorders clinic for evaluation of obstructive sleep apnoea, obesity hypoventilation syndrome is more prevalent in women than men, and that women with obesity hypoventilation syndrome suffer from significantly more co-morbidities. Post-menopausal women with obstructive sleep apnoea have the highest prevalence of obesity hypoventilation syndrome.

Design of the remede System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea.

BACKGROUND: Central sleep apnea is common in patients with cardiovascular disease and worsens outcomes. There is a lack of established therapies for central sleep apnea, and those available are limited by poor patient adherence and potentially adverse cardiovascular effects, at least in a subset of patients. The remede System (Respicardia, Minnetonka, Minnesota) is a new physiologic treatment that uses transvenous phrenic nerve stimulation to contract the diaphragm, thereby stabilizing gas exchange and restoring normal breathing throughout the sleep period. METHODS: This is a prospective multicenter randomized trial with blinded end points evaluating the safety and efficacy of the remede System. Up to 173 patients with central sleep apnea will be randomized 1:1 to remede System therapy initiated at 1 month after implantation (treatment) or to an implanted remede System that will remain inactive for 6 months (control). Primary efficacy end point is the percentage of patients who experience a reduction in apnea-hypopnea index by a ≥ 50% at 6 months (responder analysis). Primary safety end point is freedom from serious adverse events through 12 months. Secondary end points include sleep-disordered breathing parameters, sleep architecture, Epworth Sleepiness Scale score, and Patient Global Assessment. CONCLUSIONS: This is the 1st randomized controlled trial of the safety and efficacy of the remede System for the treatment of central sleep apnea.

Adaptive servo-ventilation for the treatment of central sleep apnea in congestive heart failure: what have we learned?

PURPOSE OF REVIEW: Positive airway pressure devices for the noninvasive treatment of sleep-disordered breathing are being marketed that have substantially expanded capabilities. Most recently, adaptive servo-ventilation devices have become available that are capable of measuring patient ventilation continuously and use that information to adjust expiratory positive airway pressure and pressure support levels to abolish central and obstructive apneas and hypopneas, including central sleep-disordered breathing of the Hunter-Cheyne-Stokes variety. Patients with congestive heart failure are particularly prone to developing central sleep apnea and/or Hunter-Cheyne-Stokes breathing, and studies have shown that suppression of these abnormal breathing patterns may improve cardiac function and, ultimately, mortality. RECENT FINDINGS: Over the last approximately 18 months, increasing numbers of studies have appeared demonstrating improvement in cardiac function and other important outcomes after both acute application of adaptive servo-ventilation as well as 3 to 6 months of use in patients with congestive heart failure and central sleep apnea/Hunter-Cheyne-Stokes breathing. Several of these studies are randomized controlled trials and several include assessment of cardiac event-free survival showing an advantage to treating with adaptive servo-ventilation. SUMMARY: As an adjunct to optimal pharmacological management, adaptive servo-ventilation shows considerable promise as a means to improve outcomes in patients with congestive heart failure complicated by central sleep apnea/Hunter-Cheyne-Stokes breathing. Larger randomized controlled trials will be necessary to demonstrate the ultimate role of this therapeutic modality in such patients.

Medication-Induced Central Sleep Apnea: A Unifying Concept.

Medication-induced central sleep apnea (CSA) is one of the 8 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-opioids 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.

Sleep apnea, heart failure, and pulmonary hypertension.

Despite the emergence of sleep apnea (SA) as a significant risk factor for heart failure (HF) mortality, data indicate that SA remains under-diagnosed and under-treated. Less well established, though perhaps more emphasized, is the role of sleep apnea in pulmonary hypertension (PH). SA occurs in approximately 50 % of HF patients, and its consequences include intermittent hypoxemia, arousal, and intra-thoracic pressure swings leading to neurohormonal stimulation, oxidative stress and inflammation. While SA is also considered a cause of PH, severe PH due solely to SA is rare. Combining the results of several studies using Swan-Ganz catheters for diagnosis of PH, approximately 10 % of patients with OSA have PH. Effective treatment of SA in HF is associated with improved survival, while treatment of SA in PH is typically associated with modest hemodynamic improvement.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure.

AIMS: Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients. METHODS AND RESULTS: Thirty-one patients from six centres underwent attempted transvenous lead placement. Of these, 16 qualified to undergo two successive nights of polysomnography-one night with and one night without phrenic nerve stimulation. Comparisons were made between the two nights using the following indices: apnoea-hypopnoea index (AHI), central apnoea index (CAI), obstructive apnoea index (OAI), hypopnoea index, arousal index, and 4% oxygen desaturation index (ODI4%). Patients underwent phrenic nerve stimulation from either the right brachiocephalic vein (n = 8) or the left brachiocephalic or pericardiophrenic vein (n = 8). Therapy period was (mean ± SD) 251 ± 71 min. Stimulation resulted in significant improvement in the AHI [median (inter-quartile range); 45 (39-59) vs. 23 (12-27) events/h, P = 0.002], CAI [27 (11-38) vs. 1 (0-5) events/h, P≤ 0.001], arousal index [32 (20-42) vs. 12 (9-27) events/h, P = 0.001], and ODI4% [31 (22-36) vs. 14 (7-20) events/h, P = 0.002]. No significant changes occurred in the OAI or hypopnoea index. Two adverse events occurred (lead thrombus and episode of ventricular tachycardia), though neither was directly related to phrenic nerve stimulation therapy. CONCLUSION: Unilateral transvenous phrenic nerve stimulation significantly reduces episodes of CSA and restores a more natural breathing pattern in patients with heart failure. This approach may represent a novel therapy for CSA and warrants further study.

Central sleep apnea: pathophysiologic classification.

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 Association between Low CO2 Production and Central Sleep Apnea in Men with Heart Failure.

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/m2, 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 CO2, thus promoting CSA. To our knowledge, this is the first study in humans that shows this association.

Distinguishing central from obstructive hypopneas on a clinical polysomnogram.

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.

Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases.

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.

Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis.

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 (AHIArOnly) 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 AHIArOnly 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), AHIArOnly 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.

Sleep apnea testing and outcomes in a large cohort of Medicare beneficiaries with newly diagnosed heart failure.

RATIONALE: Previous studies have demonstrated a high prevalence of sleep apnea (SA) in patients with chronic heart failure (HF), which is associated with higher rates of morbidity, mortality, and health care use. OBJECTIVES: To investigate the reported incidence, treatment, outcomes, and economic cost of SA in new-onset HF in a large U.S. database. METHODS: This retrospective cohort study used the 2003 to 2005 Medicare Standard Analytical Files and included subjects with newly diagnosed HF from the first quarter of 2004, without prior diagnosis of SA, stratified by testing, diagnosis, and treatment status. MEASUREMENTS AND MAIN RESULTS: Among a study population of 30,719 incident subjects with HF, only 1,263 (4%) were clinically suspected to have SA. Of these, 553 (2% of the total cohort) received SA testing, and 545 received treatment. After adjustment for age, sex, and comorbidities, subjects with HF who were tested, diagnosed, and treated for SA had a better 2-year survival rate compared with subjects with HF who were not tested (hazard ratio, 0.33 [95% confidence interval, 0.21-0.51], P < 0.0001). Similarly, among subjects who were tested and diagnosed, those who were treated had a better 2-year survival rate than those who were not treated (hazard ratio, 0.49 [95% confidence interval, 0.29-0.84], P = 0.009). CONCLUSIONS: In Medicare beneficiaries with HF, comorbid SA is most often not tested and consequently subjects are underdiagnosed and not treated. Meanwhile, in the few subjects in whom a diagnosis of SA is established and treatment is executed, survival improves significantly. These results support the importance of SA testing and treatment for patients newly diagnosed with HF.

Obstructive Sleep Apnea in Heart Failure: Current Knowledge and Future Directions.

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.

Sleep and breathing disorders in heart failure.

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.