Clinical and financial impact of sleep disordered breathing on heart failure admissions.

BACKGROUND: The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. METHODS: A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. RESULTS: The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. INTERPRETATION: Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

The Utility of Home Sleep Apnea Testing in the Advanced Heart Failure Populations.

Untreated sleep disorders form a risk of coronary artery disease, hypertension, obesity, and diabetes mellitus. Access to polysomnography is limited, especially during the COVID-19 pandemic, with home sleep apnea testing (HSAT) being a potentially viable alternative. We describe an HSAT protocol in patients with advanced heart failure (HF). In a single-center, observational analysis between 2019 and 2021 in patients with advanced HF and heart transplant (HT), 135 screened positive on the STOP-Bang sleep survey and underwent a validated HSAT (WatchPAT, ZOLL-Itamar). HSAT was successful in 123 patients (97.6%), of whom 112 (91.1%; 84 HF and 28 HT) tested positive for sleep apnea. A total of 91% of sleep apnea cases were obstructive, and 63% were moderate to severe. Multivariable linear regression showed that the apnea hypopnea index was 34% lower in the HT group than in the HF group (p = 0.046) after adjusting for gender, and that this effect persisted in White patients but not among African-Americans. Patient characteristics were similar between groups, with coronary artery disease, diabetes mellitus, and hypertension as the most prevalent co-morbidities. In conclusion, sleep apnea remains prevalent in patients with HF with a high co-morbidity burden. HSAT is a feasible and effective tool for screening and diagnosis in this population.

Design of the remede System Therapy (reST) study: A prospective non-randomized post-market study collecting clinical data on safety and effectiveness of the remede system for the treatment of central sleep apnea.

BACKGROUND: Central sleep apnea (CSA) is a disorder defined by lack of respiratory drive from the brain stem on breathing efforts. There is a lack of established therapies for CSA and most available therapies are limited by poor patient adherence, limited randomized controlled studies, and potentially adverse cardiovascular effects. The remede System (ZOLL Respicardia, Inc., Minnetonka, Minnesota) uses transvenous phrenic nerve stimulation to stimulate the diaphragm, thereby restoring a more normal breathing pattern throughout the sleep period. METHODS: The remede System Therapy (reST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remede System in the post-market setting. Up to 500 adult patients with moderate to severe CSA will be enrolled and followed up to 5 years at approximately 50 sites in the United States and Europe. Safety objectives include evaluation of adverse events related to the implant procedure, device or delivered therapy, death, and hospitalizations. Effectiveness endpoints include assessment of changes in sleep-disordered breathing metrics from polysomnograms and home sleep tests, changes in daytime sleepiness using the Epworth Sleepiness Scale, and changes in QoL using the PROMIS-29 and Patient Global Assessment questionnaires. The subgroup of patients with heart failure will undergo additional assessments including echocardiography to assess cardiac reverse remodeling, 6-min walk distance, QoL assessment by Kansas City Cardiomyopathy Questionnaire and measurement of biomarkers. CONCLUSION: This will be the largest prospective study evaluating long-term safety and effectiveness of transvenous phrenic nerve stimulation for the treatment of moderate to severe CSA in adult patients.

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.

Improving Nocturnal Hypoxemic Burden with Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea.

Nocturnal hypoxemic burden is established as a robust prognostic metric of sleep-disordered breathing (SDB) to predict mortality and treating hypoxemic burden may improve prognosis. The aim of this study was to evaluate improvements in nocturnal hypoxemic burden using transvenous phrenic nerve stimulation (TPNS) to treat patients with central sleep apnea (CSA). The remede System Pivotal Trial population was examined for nocturnal hypoxemic burden. The minutes of sleep with oxygen saturation < 90% significantly improved in Treatment compared with control (p < .001), with the median improving from 33 min at baseline to 14 min at 6 months. Statistically significant improvements were also observed for average oxygen saturation and lowest oxygen saturation. Hypoxemic burden has been demonstrated to be more predictive for mortality than apnea-hypopnea index (AHI) and should be considered a key metric for therapies used to treat CSA. Transvenous phrenic nerve stimulation is capable of delivering meaningful improvements in nocturnal hypoxemic burden. There is increasing interest in endpoints other than apnea-hypopnea index in sleep-disordered breathing. Nocturnal hypoxemia burden may be more predictive for mortality than apnea-hypopnea index in patients with poor cardiac function. Transvenous phrenic nerve stimulation is capable of improving nocturnal hypoxemic burden. Graphical Abstract.

Central sleep apnea and atrial fibrillation: A review on pathophysiological mechanisms and therapeutic implications.

Precipitating factors and chronic diseases associated with atrial fibrillation (AF) are detailed in the literature. Emerging evidence over the last several decades suggests a potential causal relationship between central sleep apnea (CSA) and AF. Mechanisms including apnea-induced hypoxia with intermittent arousal, fluctuating levels of carbon dioxide, enhanced sympathetic/neurohormonal activation and oxidative stress causing inflammation have been implicated as etiologic causes of AF within this subpopulation. CSA affects the efficacy of pharmacologic and catheter-based antiarrhythmic treatments, which is why treating CSA prior to these interventions may lead to lower rates of AF. Subsequently, a reduction in the AF burden with transvenous phrenic nerve stimulation (TPNS) has become a topic of interest. The present review describes the relationship between these conditions, pathophysiologic mechanisms implicating the role of CSA in development of AF, and emerging therapeutic interventions.

Transvenous phrenic nerve stimulation for central sleep apnea is safe and effective in patients with concomitant cardiac devices.

BACKGROUND: Central sleep apnea is common in heart failure patients. Transvenous phrenic nerve stimulation (TPNS) requires placing a lead to stimulate the phrenic nerve and activate the diaphragm. Data are lacking concerning the safety and efficacy of TPNS in patients with concomitant cardiovascular implantable electronic devices (CIEDs). OBJECTIVE: To report the safety and efficacy of TPNS in patients with concomitant CIEDs. METHODS: In the remede System Pivotal Trial, 151 patients underwent TPNS device implant. This analysis compared patients with concomitant CIEDs to those without with respect to safety, implant metrics, and efficacy of TPNS. Safety was assessed using incidence of adverse events and device-device interactions. A detailed interaction protocol was followed. Implant metrics included overall TPNS implantation success. Efficacy endpoints included changes in the apnea-hypopnea index (AHI) and quality of life. RESULTS: Of 151 patients, 64 (42%) had a concomitant CIED. There were no significant differences between the groups with respect to safety. There were 4 CIED oversensing events in 3 patients leading to 1 inappropriate defibrillator shock and delivery of antitachycardia pacing. There was no difference in efficacy between the CIED and non-CIED subgroups receiving TPNS, with both having similar percentages of patients who achieved ≥50% reduction in AHI and quality-of-life improvement. CONCLUSION: Concomitant CIED and TPNS therapy is safe. The presence of a concomitant CIED did not seem to impact implant metrics, implantation success, and TPNS efficacy. A detailed interaction protocol should be followed to minimize the incidence of device-device interaction.

Meta-Analysis Comparing Outcomes of Therapies for Patients With Central Sleep Apnea and Heart Failure With Reduced Ejection Fraction.

Patients with heart failure with reduced ejection fraction and predominant central sleep apnea pose treatment challenges. A system review and meta-analysis of randomized controlled trials (RCTs) were undertaken. Electronic searches of digital repositories, journals, specialty society and manufacturer websites, manual searches of reference sections of RCTs, and published clinical guidelines were performed. Studies were graded for bias. Meta-analytic random effects models were used. Outcomes of interest included: sleep, cardiovascular, mortality, and quality of life (QoL). Grading of recommendations assessment, development and evaluation was performed. Nineteen randomized studies were identified that met the inclusion criteria of apnea hypopnea index (AHI) ≥10, predominant central sleep apnea (CSA), and heart failure with reduced ejection fraction (HFrEF) ≤50%. Most trials examined adaptive servo ventilation (ASV) (8 studies) and continuous positive airway pressure (CPAP) (9 studies). Bias existed in that: 15 of 19 (79%) of the trials lacked blinding, 10 of 19 were manufacturer funded, and with attrition in 8 of 19 studies. In meta-analysis, ASV performed better than control on sleep but not on QoL or cardiovascular outcomes, including mortality. CPAP demonstrated positive short-term outcomes on sleep, cardiovascular, and QoL (3 months). Longer-term cardiovascular and mortality data did not show benefit. Drug therapies demonstrated a positive clinical effect short term on sleep outcomes only. Transvenous phrenic nerve stimulation (TPNS) demonstrated positive treatment outcomes on sleep and QoL at 6 months. Evidence suggests improvement in cardiovascular outcomes with TPNS. In conclusion, ASV and CPAP therapies improve sleep, but long-term QoL or cardiovascular benefit was lacking. TPNS exhibited positive outcomes on sleep and QoL at 6 months with positive trends in CV outcomes.

Novel phrenic nerve stimulator treats Cheyne-Stokes respiration: polysomnographic insights.

None: A symptomatic patient with atrial fibrillation and Cheyne-Stokes respiration (CSR) was implanted with a transvenous phrenic nerve stimulation (TPNS) device-the remede System-that is indicated for adult patients with moderate to severe central sleep apnea. Sleep recordings demonstrated that TPNS eliminated periodic breathing by activating the diaphragm and stabilizing respiratory patterns. These recordings of preprogrammed periods on versus off TPNS illustrate prompt (1) stabilization of tidal airflow, respiratory effort, and oxygenation as stimulation amplitude increased stepwise and (2) recurrence of CSR immediately after TPNS deactivated. Despite differences in respiratory patterns, minute ventilation was comparable during periods on and off TPNS. These findings suggest that diaphragmatic pacing entrains ventilation without disrupting sleep, accounting for observed improvements in periodic breathing, gas exchange, sleep architecture, and quality of life. Effective means to relieve CSR could potentially mitigate nocturnal cardiovascular stress and disease progression.

Phrenic nerve stimulation in patients with central sleep apnea: a single­center experience from pilot and pivotal trials evaluating the remede System.

BACKGROUND: Patients with central sleep apnea (CSA) have recently been shown to have improved sleep metrics and quality of life (QoL) with phrenic nerve stimulation (PNS). AIMS: The aim of this study was to report the results of a partnership between cardiology, sleep medicine, and electrophysiology in a single clinical center as well as the enrollment, implantation, and follow­up experience demonstrating both the safety and efficacy of PNS. METHODS: This analysis included data from the pilot and pivotal trials investigating the effect of PNS using an implantable transvenous system in patients with CSA. We present our experience and data on the enrollment processes, implantation feasibility and safety, sleep indices, and QoL at 6 and 12 months of follow­up. RESULTS: Between June 2010 and May 2015, cardiology patients were prescreened and 588 of them were sent for in­home sleep test. Ninety­six patients were referred for polysomnographic studies, and 33 were enrolled and had an implant attempt, with 31 successfully receiving an implant. The apnea-hypopnea index was reduced in the pilot trial (mean [SD] of 48.7 [15.5] events/h to 22.5 [13.2] events/h; P <0.001) and in the pivotal trial (mean [SD] of 48.3 [18.8] events/h to 26.0 [21.9] events/h; P <0.001). Improvement in QoL was also observed. CONCLUSIONS: We showed that PNS improved sleep metrics and QoL in patients with CSA, which is a result of multiple factors, including a comprehensive coordination between cardiology, sleep medicine, and electrophysiology. This ensures appropriate patient identification leading to safe implantation and full patient compliance during follow­up visits.

In patients with heart failure the burden of central sleep apnea increases in the late sleep hours.

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.

Identification and Treatment of Central Sleep Apnoea: Beyond SERVE-HF.

Central sleep apnoea (CSA) occurs in a large proportion of HF patients. CSA has clear detrimental effects, resulting in intermittent hypoxia and sympathetic activation, and is associated with significant morbidity and mortality. Treatment options are limited following the results of a recent trial in which adaptive servo-ventilation resulted in an increase in cardiovascular mortality. Ongoing studies utilising other forms of positive airway pressure may provide additional insight into the results of this trial. A new neurostimulation therapy, phrenic nerve stimulation, has offered a new physiological approach to the treatment of CSA. This therapy has resulted in improvements in the severity of disease and quality of life.

Non-Mask-based Therapies for Central Sleep Apnea in Patients with Heart Failure.

Central sleep apnea is common in heart failure and contributes to morbidity and mortality. Symptoms are often similar to those associated with heart failure and a high index of suspicion is needed. Testing is typically done in the sleep laboratory, but home testing equipment can distinguish between central and obstructive events. Treatments are limited. Mask-based therapies have been the primary treatment. Oxygen has some data but lacks long-term studies. Neurostimulation of the phrenic nerve is a new technology that has demonstrated improvement. Coordination of care between sleep specialists and cardiologists is important as the field of central sleep apnea continues to develop.

Novel Therapies for the Treatment of Central Sleep Apnea.

Neurophysiologically, central apnea is due to a temporary cessation of respiratory rhythmogenesis in medullary respiratory networks. Central apneas occur in several disorders and result in pathophysiological consequences, including arousals and desaturation. The 2 most common causes in adults are congestive heart failure and chronic use of opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea may improve quality of life, morbidity, and mortality. This article discusses recent developments in the treatment of central sleep apnea in heart failure and opioids use.

Sleep-disordered breathing and cardiovascular disease.

Sleep-disordered breathing (SDB) is a common comorbidity in a number of cardiovascular diseases, and mounting clinical evidence demonstrates that it has important implications in the long-term outcomes of patients with cardiovascular disease (CVD). While recognition among clinicians of the role of SDB in CVD is increasing, it too often remains neglected in the routine care of patients with CVD, and therefore remains widely undiagnosed and untreated. In this article, we provide an overview of SDB and its relationship to CVD, with the goal of helping cardiovascular clinicians better recognize and treat this important comorbidity in their patients. We will describe the two major types of SDB and discuss the pathophysiologic, diagnostic, and therapeutic considerations of SDB in patients with CVD.

A novel therapeutic approach for the treatment of central sleep apnea: The remede® system.

Central sleep apnea (CSA) occurs primarily in cardiovascular patients and is associated with high morbidity and mortality. The disorder often is unrecognized due to the overlap of symptoms with those of the underlying cardiac disease. CSA can be easily diagnosed with a sleep study. Following optimization of all co-morbidities, the therapeutic approach available currently focuses on mask-based therapies which suffer from poor patient adherence. A new therapy, the remede® System, has been developed; it utilizes a transvenous, fully implantable system providing phrenic nerve stimulation intended to restore a more normal breathing pattern. The therapy demonstrated promising results based on an initial chronic study and a randomized trial is underway to further evaluate safety and efficacy of this novel system in patients with CSA.

Sleep disordered breathing in patients with heart failure.

Sleep disordered breathing (SDB) is a common co-morbidity in patients with heart failure (HF). Both its forms - central and obstructive sleep apnea - are highly prevalent in this population. SDB fragments sleep, impairs life quality, worsens exercise tolerance, worsens HF and is an independent predictor of poor prognosis. Still, SDB remains largely undiagnosed. Therefore, early detection of SDB seems to be of primary importance, especially in the presence of new diagnostic and therapeutic methods. Treatment with continuous positive airway pressure (CPAP) increases left ventricular ejection fraction and stroke volume in virtually all HF patients with obstructive and in 50% with central sleep apnea. For those in whom central sleep apnea is not suppressed by CPAP, a trial of adaptive servoventilation is recommended. Although no randomized, controlled trials have shown improvement in mortality, several observational studies have shown that effective treatment of both forms of sleep apnea with various positive airway pressure devices improves survival of HF patients. Currently, 2 large trials with newer masked based therapies with adaptive servoventilation are in progress. This article is a brief overview of present knowledge, the pathophysiology, diagnostic approach and therapy of SDB.

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.