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.

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.

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.

Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea: A Pooled Cohort Analysis.

STUDY OBJECTIVES: Early evidence with transvenous phrenic nerve stimulation (PNS) demonstrates improved disease severity and quality of life (QOL) in patients with central sleep apnea (CSA). The goal of this analysis is to evaluate the complete prospective experience with PNS in order to better characterize its efficacy and safety, including in patients with concomitant heart failure (HF). METHODS: Using pooled individual data from the pilot (n = 57) and pivotal (n = 151) studies of the remede System in patients with predominant moderate to severe CSA, we evaluated 12-month safety and 6- and 12-month effectiveness based on polysomnography data, QOL, and cardiac function. RESULTS: Among 208 combined patients (June 2010 to May 2015), a remede device implant was successful in 197 patients (95%), 50/57 pilot study patients (88%) and 147/151 pivotal trial patients (97%). The pooled cohort included patients with CSA of various etiologies, and 141 (68%) had concomitant HF. PNS reduced apnea-hypopnea index (AHI) at 6 months by a median of -22.6 episodes/h (25th and 75th percentile; -38.6 and -8.4, respectively) (median 58% reduction from baseline, P < .001). Improvement in sleep variables was maintained through 12 months of follow-up. In patients with HF and ejection fraction ≤ 45%, PNS was associated with improvement in systolic function from 27.0% (23.3, 36.0) to 31.1% (24.0, 41.5) at 12 months (P = .003). In the entire cohort, improvement in QOL was concordant with amelioration of sleep measures. CONCLUSIONS: Transvenous PNS significantly improves CSA severity, sleep quality, ventricular function, and QOL regardless of HF status. Improvements, which are independent of patient compliance, are sustained at 1 year and are associated with acceptable safety.

Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod.

The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability.