Treatment of sleep apnoea early after myocardial infarction with adaptive servo-ventilation - a proof-of-concept randomised controlled trial.

INTRODUCTION: Sleep-disordered breathing has been associated with less myocardial salvage and smaller infarct size reduction after acute myocardial infarction (AMI). The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation (TEAM-ASV I) trial investigated the effects of adding adaptive servo-ventilation (ASV) for sleep-disordered breathing (SDB) to standard therapy on myocardial salvage index (MSI) and change in infarct size within 12 weeks after AMI. METHODS: In this multicentre, randomised, open-label trial, patients with AMI and successful percutaneous coronary intervention within 24 h after symptom onset plus SDB (apnoea-hypopnoea index ≥15/h) were randomised to standard medical therapy alone (control) or plus ASV (starting 3.6±1.4 days post-AMI). The primary outcome was MSI at 12 weeks post-AMI. Cardiac magnetic resonance (CMR) imaging was performed at ≤5 days and 12 weeks after AMI. RESULTS: Seventy-six individuals were enrolled from February 2014 to August 2020; 39 had complete CMR data for analysis of the primary endpoint. MSI was significantly higher in the ASV versus control group (difference 14.6% of left ventricular mass [LVM]; 95% confidence interval 0.14-29.1; p=0.048). At 12 weeks, absolute [interquartile range] (6.6 [4.8-8.5] versus 2.8 [0.9-4.8] %LVM; p=0.003) and relative (44 [30-57] versus 21 [6-35] % of baseline; p=0.013) reductions in infarct size were greater in the ASV versus control group. No serious treatment-related adverse events occurred. CONCLUSIONS: Early treatment of SDB with ASV improved the MSI and decreased the infarct size at 12 weeks after AMI. Larger randomised trials are required to confirm these findings.

Measurement of peripheral arterial tone to detect sleep-disordered breathing in patients with heart failure.

PURPOSE: Sleep-disordered breathing is highly prevalent in patients with heart failure and is related to increased mortality and morbidity. The gold standard for sleep diagnostic is polysomnography in a sleep laboratory. Measurement of peripheral arterial tone with a wrist-worn diagnostic device is a promising method to detect sleep-disordered breathing without major technical effort. METHODS: We prospectively enrolled patients with heart failure with reduced ejection fraction for measurement of the peripheral arterial tone and polysomnography simultaneously during one night in the sleep laboratory. Raw data of polysomnography was analyzed blindly by sleep core lab personnel and compared with automatic algorithm-based sleep results of measurement of the peripheral arterial tone. RESULTS: A total of 25 patients provided comparable sleep results. All patients had sleep-disordered breathing and were identified by measurement of the peripheral arterial tone. The comparison of apnea-hypopnea index between peripheral arterial tone 38.8 ± 17.4/h and polysomnography 44.5 ± 17.9/h revealed a bias of - 5.7 ± 9.8/h with limits of agreement of ± 19.2/h in Bland-Altman analysis but showed high and significant Pearson correlation (r = 0.848, p < 0.001). CONCLUSION: The findings suggest that measurement of the peripheral arterial tone may be useful to identify sleep-disordered breathing in patients with heart failure with reduced ejection fraction.

Early identification of heart failure deterioration through respiratory monitoring with adaptive servo-ventilation.

Cardiac decompensation is associated with worse prognosis in patients with heart failure. Reliable methods to predict cardiac decompensation events are not yet available. Sleep-disordered breathing (SDB) is a frequent comorbidity in heart failure, and it has been shown to correlate with heart failure severity. This prospective observational trial investigated SDB characteristics in patients with heart failure with the aim to identify patterns that may predict early cardiac decompensation. Patients with heart failure with diagnosed SDB and hospitalised for cardiac decompensation were prospectively enrolled and treated with adaptive servo-ventilation (ASV). SDB characteristics, daily body weight and clinical cardiac decompensation events were collected over a 1-year follow-up. Clinical events were categorised by an independent clinical event committee. A total of 43 patients were enrolled (81% male, mean [SD] age 71 [11] years, body mass index 30 kg/m2 , 95% New York Heart Association function class III or IV, mean [SD] left ventricular ejection fraction 37% [11%], median apnea-hypopnoea index [AHI] of 37 events/h). A total of 48 cardiac decompensation events were recorded during the 1-year study period. Respiratory rate was found to be significantly lower in patients with cardiac decompensation. The AHI and applied inspiratory pressure ASV-device support were significantly increased 10 days before a clinical cardiac decompensation event. Device usage was also found to be significantly decreased 2 nights before cardiac decompensation. Device-derived respiratory data in ASV therapy devices for SDB may therefore serve as a monitoring tool to predict early clinical cardiac decompensation events. Prediction and avoidance of cardiac decompensation, in turn, may attenuate serious health consequences in patients with heart failure.

APAP therapy does not improve impaired sleep quality and sympatho-vagal balance: a randomized trial in patients with obstructive sleep apnea and systolic heart failure.

PURPOSE: In heart failure with reduced ejection fraction (HFrEF), the effects of automatic positive airway pressure therapy (APAP) for obstructive sleep apnea (OSA) on sleep quality and sympatho-vagal balance (SVB) are unknown. METHODS: In this randomized controlled trial (6 months of APAP vs. nasal strips as control), sleep quality and SVB in patients with HFrEF and OSA were monitored. The distinction was made between different breathing conditions (5-min segments of OSA or normal breathing [NB] during stable N2 sleep) at baseline (T0), APAP initiation (T1), and 6 months of successful APAP treatment (T2). RESULTS: Of 75 patients enrolled, 61 were men with average age of 65 ± 12 years and LVEF of 31 ± 9%; 37 patients were randomized into the APAP and 38 into the control (nasal strips only) group. At T0, OSA was associated with a 17% increase in the low-frequency/high-frequency component ratio of heart rate variability (LF/HF) versus baseline, suggesting an increase in sympathetic drive (SVB) with OSA compared with normal breathing. Respiratory indices and oxygen saturation all significantly improved at both T1 and T2, but at 6 months, APAP had no clinically relevant effect on objective sleep quality versus control. In fact, in patients with HFrEF (n = 23 with data suitable for HRV analysis), there was even a trend (p = 0.097) towards an additional 17% increase in LF/HF at T2 in the therapy group, suggesting (undesired) increased SVB in the APAP group. CONCLUSION: Treatment of OSA in patients with systolic HF improves respiratory indices but does not have a favorable effect on sleep quality. While OSA per se was associated with an increase in sympathetic drive, APAP treatment was not associated with a reduction in sympathetic drive. After 6 months of treatment, there was even a trend towards additional increases in sympathetic drive in the APAP group.

Treatment of sleep-disordered breathing in heart failure impacts cardiac remodeling: Insights from the CAT-HF Trial.

BACKGROUND: Sleep-disordered breathing (SDB), including central and obstructive sleep apnea, is a marker of poor prognosis in heart failure (HF) and may worsen cardiac dysfunction over time. Treatment of SDB with adaptive servoventilation (ASV) may reverse pathologic cardiac remodeling in HF patients. METHODS: The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) trial randomized patients with acute decompensated HF and confirmed SDB to either optimal medical therapy (OMT) or treatment with ASV and OMT. Patients with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) were included. Echocardiograms, performed at baseline and 6 months, assessed cardiac size and function and evaluated cardiac remodeling over time. The CAT-HF trial was stopped early in response to the SERVE-HF trial, which found increased mortality among HFrEF patients with central sleep apnea treated with ASV. RESULTS: Of the 126 patients enrolled prior to trial cessation, 95 had both baseline and 6-month echocardiograms (77 HFrEF and 18 HFpEF). Among HFrEF patients, both treatment arms demonstrated a significant increase in EF: +4.3% in the ASV group (.0004) and +4.6% in OMT alone (P = .007) and a significant decrease in LV end-systolic volume index: -9.4 mL/m2 in the ASV group (P = .01) and -8.6 mL/m2 in OMT alone (P = .003). Reductions in left atrial (LA) volume and E/e' were greater in the ASV arm, whereas patients receiving OMT alone demonstrated more improvement in right ventricular function. HFpEF patients treated with ASV also had a decrease in LA size that was greater than those receiving OMT alone. Although there were significant intragroup changes within the ASV + OMT and OMT-alone groups, there were no significant intergroup differences at 6 months. CONCLUSIONS: Significant reverse LV remodeling was seen among HFrEF patients with SDB regardless of treatment allocation. Substantial reductions in LA volume among HFrEF and HFpEF patients receiving ASV suggest that ASV treatment may also improve diastolic function and warrant further investigation.

Sleep-disordered breathing in hospitalized patients with congestive heart failure: a concise review and proposed algorithm.

Congestive heart failure (CHF) is the most common cause of hospital admission in the USA costing the taxpayers billions of dollars. Sleep-disordered breathing (SDB) is a common co-morbid condition associated with CHF with prevalence estimated to be 60-70%. Despite substantial evidence supporting the negative impact of SDB on CHF, the condition is underrecognized and undertreated. Patients admitted to the hospital with CHF and SDB are prime candidates for intervention with positive airway pressure (PAP) therapy as they form a "captive audience," and timely intervention and education may mitigate sub-optimal outcomes. In conclusion, this review explores emerging data on the cost effectiveness and outcome of early intervention with PAP in hospitalized CHF patients.

Cycle length identifies obstructive sleep apnea and central sleep apnea in heart failure with reduced ejection fraction.

AIM: To clarify whether unmasking of central sleep apnea during continuous positive airway pressure (CPAP) initiation can be identified from initial diagnostic polysomnography (PSG) in patients with heart failure with reduced ejection fraction (HFREF) and obstructive sleep apnea (OSA) MATERIALS AND METHODS: Forty-three consecutive patients with obstructive sleep apnea and central sleep apnea (OSA/CSA) in HFREF were matched with 43 HFREF patients with OSA and successful CPAP initiation. Obstructive apneas during diagnostic PSG were then analyzed for cycle length (CL), ventilation length (VL), apnea length (AL), time to peak ventilation (TTPV), and circulatory delay (CD). We calculated duty ratio (DR) as the ratio of VL/CL and mathematic loop gain (LG). RESULTS: While AL was similar, CL, VL, TTPV, CD, and DR was significantly longer in patients with OSA/CSA compared to those with OSA, and LG was significantly higher. Receiver operator curves identified optimal cutoff values of 50.2 s for CL (area under the curve (AUC) 0.85, 29.2 s for VL (AUC 0.92), 11.5 s for TTPV (AUC 0.82), 26.4 s for CD (AUC 0.79), and 3.96 (AUC 0.78)) respectively for LG to identify OSA/CSA. CONCLUSION: OSA/CSA in HFREF can be identified by longer CL, VL, TTPV, and CD from obstructive events in initial diagnostic PSG. The underlying mechanisms seem to be the presence of an increased LG.

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.

Impact of sleep-disordered breathing in patients with acute myocardial infarction: a retrospective analysis.

Sleep-disordered breathing (SDB) is associated with an increased risk of cardiovascular events. Previous studies showed that severe SDB has a negative impact on myocardial salvage and progression of left ventricular dysfunction after acute myocardial infarction (AMI). This study investigated the frequency of SDB and the effects of SDB on left ventricular function after AMI. This retrospective study enrolled all patients with AMI who had undergone cardiorespiratory polygraphy for SDB diagnosis. The apnea-hypopnea index was used as a standard metric of SDB severity. SDB was classified as mild (apnea-hypopnea index >5 to <15 per h), moderate (≥15 to <30 per h) or severe (apnea-hypopnea index ≥30 per h). According to the majority of events, SDB was classified as predominant obstructive sleep apnea, central sleep apnea or mixed sleep apnea (mixed SDB). A total of 223 patients with AMI (112 with ST elevation and 111 without ST elevation; 63.2 ± 11.2 years, 82% male, left ventricular ejection fraction 49 ± 12%) were enrolled. SDB was present in 85.6%, and was moderate-to-severe in 63.2%; 40.8% had obstructive sleep apnea, 41.7% had central sleep apnea and 3.1% had mixed SDB. Left ventricular ejection fraction was lower in patients with AMI with severe SDB (45 ± 14%) versus those without SDB (57 ± 7%; P < 0.005). In addition, lower left ventricular ejection fraction (≤45%) was associated with increased frequency (apnea-hypopnea index ≥5 per h in 96%) and severity (apnea-hypopnea index ≥30 per h in 48%) of SDB in general and a higher percentage of central sleep apnea (57%) in particular. SDB is highly frequent in patients with AMI. SDB severity appeared to be linked to impaired left ventricular function, especially in patients with central sleep apnea.

Resolution of Cheyne-Stokes Respiration after Treatment of Heart Failure with Sacubitril/Valsartan: A First Case Report.

Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF), and is known to be associated with a worse prognosis. The severity of central sleep apnea is thought to mirror cardiac dysfunction. The novel angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril has been shown to improve HF, but a relationship between treatment with ARNi and the severity of SDB has not yet been investigated. We report the case of a 71-year-old male with HF and SDB. Treatment with sacubitril/valsartan was associated with improved cardiac function, as shown by a reduction in the level of N-terminal prohormone of brain natriuretic peptide from 3,249 to 1,720 pg/mL, and an improvement in left-ventricular ejection fraction from 30 to 35%. This was accompanied by a marked reduction in the apnea-hypopnea index (from 41 to 19/h). To the best of our knowledge, this is the first case to document parallel improvements in HF and SDB after the initiation of ARNi treatment.

Long-Term Experience with First-Generation Implantable Neurostimulation Device in Central Sleep Apnea Treatment.

BACKGROUND: Sleep-disordered breathing (SDB) and Cheyne-Stokes respiration (CSR) are associated with shorter survival in patients with heart failure. A novel treatment method for this patient group is unilateral phrenic nerve stimulation by the remede® system (Respicardia Inc., Minnetonka, MN, USA), a transvenously implantable neurostimulation device, which has recently been studied in a large randomized, controlled trial. Previous literature has shown efficacy and safety of the treatment with this first-generation device, but hardly any data are available on long-term clinical parameters, the remede® device's battery lifetime, device exchangeability, lead position stability, surgical accessibility, and manageability. METHODS: We performed remede® device replacements in consecutive patients for battery depletion, and documented clinical parameters, longevity, operation procedure, complications, and difficulties. RESULTS: All patients were on neurostimulation treatment by phrenic nerve neurostimulation when device replacement became necessary. Apnea-hypopnea index (from 45 ± 4/h to 9 ± 4/h), oxygen-desaturation index (from 35 ± 7/h to 7 ± 6/h), and time spent with oxygen saturation of <90% (T < 90% from 5 ± 7% to 0 ± 0%) were improved and improvements remained constant throughout the 4-year follow-up. Mean battery life was 4.2 ± 0.2 years and mean replacement procedure time was 25 ± 5.1 minutes. Apart from conventional X-ray documentation of stable lead positions in a long-term setting, no radiation or contrast dye usage was needed and no major complications occurred. In addition, clinical exercise capacity and sleepiness symptoms improved. CONCLUSIONS: Novel remede® device shows sustained therapy efficacy and safety in terms of stable lead positions over 4 years. Long-term phrenic nerve neurostimulation therapy for central SDB/CSR appears feasible in a clinical routine setting.

Sleep duration and quality in heart failure patients.

PURPOSE: Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure and reduced left ventricular ejection fraction (HF-REF). SDB is classified as predominant obstructive (OSA) or central (CSA) and may alter sleep duration, sleep quality, and quality of life. This study describes sleep quality and duration in well-characterized cohorts of these patients. METHODS: Two hundred fifty consecutive patients with HF-REF (NYHA class ≥II, ejection fraction ≤45%) underwent cardiac and pulmonary examination, plus full attended in-hospital overnight polysomnography (PSG). PSG recordings were performed according to current recommendations and underwent independent, blinded analysis at a core laboratory. RESULTS: Patients with HF-REF and CSA were older and had more impaired cardiac function compared to those with OSA. With respect to sleep parameters, patients with CSA spent more time in bed than those with OSA (468 ± 52 vs 454 ± 46 min, p = 0.021) while sleep efficiency was lower (67 ± 14 vs 72 ± 13% of total sleep time (TST), p = 0.008). In addition, CSA patients spent more time awake after sleep onset (101 ± 61 vs 71 ± 46 min, p = 0.001) and had more stage N1 (light) sleep (33 ± 19 vs 28 ± 16% of TST, p = 0.017). Overall, the proportion of sleep spent in N3 (slow-wave/deep) sleep in HF-REF patients with SDB was low (4.1 ± 6.3% of TST) compared with healthy adults. CONCLUSIONS: HF-REF patients with CSA compared to OSA have worse sleep efficiency and quality. This could result in less restorative sleep, changes in sympathovagal balance, and impaired resetting of important reflexes, which might contribute to worse cardiovascular outcomes in HF-REF patients with SDB.

Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients.

AIM: This study investigated the prognostic value of sleep-disordered breathing (SDB) in a large cohort of patients with heart failure with reduced left ventricular function (HF-REF), with focus on the role of nocturnal hypoxaemia. METHODS: This single-centre prospective cohort study enrolled patients with chronic stable HF-REF (NYHA ≥II) receiving guideline-based treatment. Unattended in-hospital polygraphy was performed to determine the apnoea-hypopnoea index (AHI). Pulse oximetry was used to determine hypoxaemic burden [time with oxygen saturation <90% (T90)], and all-cause mortality was recorded. RESULTS: Complete data were available for 963 of 1249 patients. At baseline, 58% of patients had moderate-to-severe SDB. The median follow-up was 7.35 years; 480 of 963 (49.8%) patients died. Mortality rate (per 100 person-years) was 8.1 [95% confidence interval (CI) 7.0-9.4] in patients with no or mild SDB, but 12.2 (95% CI 10.9-13.7) in moderate-to-severe SDB. Apnoea-hypopnoea index was significantly associated with time to death from any cause in a simple Cox model [hazard ratio (HR) 1.011, P < 0.001], but was no longer significant after adjustment for confounding factors (HR 1.005, P = 0.085). T90 was significantly (P < 0.001) associated with time to death from any cause even after adjustment for confounding factors. The risk of death increased by 16.1% (95% CI 8.6-24.2) per hour of T90. Five-year survival probabilities for patients in T90 quartiles 1, 2, 3, and 4 were 70, 63, 60, and 50%, respectively. CONCLUSION: Hypoxaemic burden was a robust and independent predictor of all-cause mortality in chronic stable HF-REF patients. Whether or not targeting nocturnal hypoxaemia is associated with beneficial effects on mortality in HF-REF patients remains to be determined.

Heterogenous haemodynamic effects of adaptive servoventilation therapy in sleeping patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers.

This study investigated the haemodynamic effects of adaptive servoventilation (ASV) in heart failure (HF) patients with Cheyne-Stokes respiration (CSR) versus healthy controls. Twenty-seven HF patients with CSR and 15 volunteers were ventilated for 1 h using a new ASV device (PaceWave™). Haemodynamics were continuously and non-invasively recorded at baseline, during ASV and after ventilation. Prior to the actual study, a small validation study was performed to validate non-invasive measurement of Stroke volume index (SVI). Non-invasive measurement of SVI showed a marginal overall difference of -0.03 ± 0.41 L/min/m(2) compared to the current gold standard (Thermodilution-based measurement). Stroke volume index (SVI) increased during ASV in HF patients (29.7 ± 5 to 30.4 ± 6 to 28.7 ± 5 mL/m(2), p < 0.05) and decreased slightly in volunteers (50.7 ± 12 to 48.6 ± 11 to 47.9 ± 12 mL/m(2)). Simultaneously, 1 h of ASV was associated with a trend towards an increase in parasympathetic nervous activity (PNA) in HF patients and a trend towards an increase in sympathetic nervous activity (SNA) in healthy volunteers. Blood pressure (BP) and total peripheral resistance response increased significantly in both groups, despite marked inter-individual variation. Effects were independent of vigilance. Predictors of increased SVI during ASV in HF patients included preserved right ventricular function, normal resting BP, non-ischaemic HF aetiology, mitral regurgitation and increased left ventricular filling pressures. This study confirms favourable haemodynamic effects of ASV in HF patients with CSR presenting with mitral regurgitation and/or increased left ventricular filling pressures, but also identified a number of new predictors. This might be mediated by a shift towards more parasympathetic nervous activity in those patients.

Acute improvement of pulmonary hemodynamics does not alleviate Cheyne-Stokes respiration in chronic heart failure-a randomized, controlled, double-blind, crossover trial.

OBJECTIVES: This randomized, controlled trial aimed to investigate whether acute improvement of pulmonary congestion would reduce the severity of Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF). METHODS: Twenty-one consecutive patients with CHF and CSR (apnea-hypopnea index [AHI] ≥15/h) underwent right heart catheterization with titration of intravenous (IV) glyceryltrinitrate (GTN) to a maximum tolerable dosage and inhalation of iloprost 10 µg/mL after a washout phase. Maximum tolerable dosages of GTN and iloprost were randomly applied during full cardiorespiratory polysomnography within two split-night procedures and compared with IV or inhaled sodium chloride (NaCl) 0.9 %, respectively. RESULTS: GTN (6.2 ± 1.5 mg/h) and iloprost significantly lowered \mean pulmonary artery pressure (20.1 ± 9.0 to 11.6 ± 4.2 mmHg, p < 0.001 and 16.9 ± 7.9 to 14.2 ± 6.4 mmHg, p < 0.01, respectively). Pulmonary capillary wedge pressure was only reduced by GTN (14.0 ± 5.6 to 7.2 ± 3.9 mmHg, p < 0.001), and there was no significant change in the cardiac index. Sleep studies revealed no significant improvement in markers of CSR severity, including AHI, central apnea index, and CSR cycle length following GTN or iloprost treatment. Significant decreases in blood pressure, mean oxygen saturation, and S3 sleep were documented during GTN infusion. CONCLUSIONS: Acute improvement of pulmonary congestion by GTN had no immediate impact on CSR severity. Future investigations must therefore include longer treatment periods and treatment regimens that have positive, rather than negative, additional effects on peripheral and central chemoreceptors and sleep structure. TRIAL REGISTRATION: German Clinical Trial Registry-ID:DRKS00000467 ( www.germanctr.de ).

Respiratory effects of adaptive servoventilation therapy in patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers.

BACKGROUND: Nocturnal adaptive servoventilation (ASV) therapy is now frequently used to treat Cheyne-Stokes respiration (CSR), which is highly prevalent in patients with moderate-to-severe heart failure (HF) and characterized by periodical breathing (hyperventilation). OBJECTIVES: This study analyzed and compared the acute effects of a novel ASV device on carbon dioxide pressure (pCO2) and oxygen saturation (SaO2) in HF patients with CSR and healthy volunteers. The influence of being asleep or awake on the ASV algorithm was also determined. METHODS: All subjects underwent ASV (PaceWave™, ResMed) for 1 h. Transcutaneous pCO2 (PtcCO2) and SaO2 were assessed transcutaneously, while wakefulness was analyzed using EEG recordings. Assessments were made 30 min before and after ASV, and during 1 h of ASV. RESULTS: Twenty HF patients (19 male; age 79 ± 12 years) and 15 volunteers (13 male, age 25 ± 4 years) were included. When awake, ASV was associated with a trend towards a decrease in PtcCO2 and an increase in SaO2 versus baseline in HF patients (34.4 ± 3.2 to 33.7 ± 3.8 mm Hg and 93.8 ± 2.6 to 94.9 ± 2.6%, respectively) and volunteers (39.5 ± 3.0 to 38.2 ± 3.8 mm Hg and 96.9 ± 1.3 to 97.8 ± 0.9%). While asleep during ASV, PtcCO2 increased to 36.3 ± 3.8 mm Hg and SaO2 decreased to 93.8 ± 2.6% in HF patients, with similar changes in volunteers (PtcCO2 41.7 ± 3.0 mm Hg, SaO2 97.1 ± 1.2). All comparisons were statistically significant (p ≤ 0.05, except the PtcCO2 decrease in both groups when awake). CONCLUSIONS: ASV therapy might result in hyperventilation when subjects are awake, but while asleep, PtcCO2 increased to mid-normal values, effects that would be favorable in HF patients with CSR.

Performance of conventional and enhanced adaptive servoventilation (ASV) in heart failure patients with central sleep apnea who have adapted to conventional ASV.

PURPOSE: Adaptive servo-ventilation (ASV) is a positive pressure ventilator support system to normalize ventilation in patients with Cheyne-Stokes respiration (CSR). The latest generation enhanced ASV device (PaceWave; ResMed) has a new feature--auto-adjustment of EPAP. This study tested the hypothesis that enhanced ASV with auto-adjustment of EPAP (PaceWave) is non-inferior to conventional ASV (AutoSetCS). METHODS: This prospective, randomized, crossover, single-center study enrolled adult patients with stable heart failure (HF) and moderate-to-severe sleep-disordered breathing (SDB) who had been receiving conventional ASV therapy for at least 4 weeks. Patients received conventional ASV for one night and enhanced ASV on another night. Support settings for the two ASV devices were similar, with fixed expiratory positive airway pressure (EPAP) set to between 4 and 10 cm H2O and variable EPAP set to between 4 and 15 cm H2O. Full polysomnography was performed during ASV therapy on both nights. Endpoints were the number of nocturnal respiratory events and oxygen desaturations, and changes in blood pressure (BP). RESULTS: Levels of EPAP were comparable during the use of enhanced and conventional ASV, but minimum and maximum inspiratory pressure support values were significantly higher with the PaceWave device. All measures of apnea and hypopnea, and oxygen saturation, were significantly improved during ASV therapy with either device. There were no significant changes in BP or heart rate. CONCLUSIONS: Enhanced ASV is non-inferior to ASV with fixed EPAP in patients with chronic HF and CSR, with a trend towards better control of respiratory events.

Implications of revised AASM rules on scoring apneic and hypopneic respiratory events in patients with heart failure with nocturnal Cheyne-Stokes respiration.

STUDY OBJECTIVES: This study investigated the implications of the revised scoring rules of the American Academy of Sleep Medicine (AASM) in patients with heart failure (HF) with Cheyne-Stokes respiration (CSR). METHODS: Ninety-one patients (NYHA ≥II, LVEF ≤45 %; age 73.6 ± 11.3 years old; 81 male subjects) with documented CSR underwent 8 h of cardiorespiratory polygraphy recordings. Those were analyzed by a single scorer strictly applying the 2007 recommended, 2007 alternative, and the 2012 scoring rules. RESULTS: Compared with the AASM 2007 recommended rules, apnea-hypopnea index (AHI) and hypopnea index (HI) increased significantly when the 2007 alternative and 2012 rules were applied (AHI 34.1 ± 13.5/h vs 37.6 ± 13.2/h vs 38.3 ± 13.2/h, respectively; HI 10.2 ± 9.4/h vs 13.7 ± 10.7/h vs 14.4 ± 11.0/h, respectively; all p < 0.001). Duration of CSR increased significantly with the alternate versus recommended 2007 rules (182.2 ± 117.0 vs 170.1 ± 115.0 min; p ≤ 0.001); there was a significant decrease in CSR duration for the 2012 versus 2007 alternative rules (182.2 ± 117.0 vs 166.7 ± 115.4 min; p ≤ 0.001). CONCLUSION: AHI was higher using the AASM 2012 scoring rules due to a less strict definition of hypopnea. Data on the prognostic effects of CSR in patients with HF and the benefits of treatment are mostly based on the AASM 2007 recommended rules, so differences between these and the newer version need to be taken into account.

Determining the prevalence and predictors of sleep disordered breathing in patients with chronic heart failure: rationale and design of the SCHLA-HF registry.

BACKGROUND: The objective of the SCHLA-HF registry is to investigate the prevalence of sleep-disordered breathing (SDB) in patients with chronic heart failure with reduced left ventricular systolic function (HF-REF) and to determine predictors of SDB in such patients. METHODS: Cardiologists in private practices and in hospitals in Germany are asked to document patients with HF-REF into the prospective SCHLA-HF registry if they meet predefined inclusion and exclusion criteria. Screening was started in October 2007 and enrolment was completed at the end of May 2013. After enrolment in the registry, patients are screened for SDB. SDB screening is mainly undertaken using the validated 2-channel ApneaLink™ device (nasal flow and pulse oximetry; ResMed Ltd., Sydney, Australia). Patients with a significant number of apneas and hypopneas per hour recording time (AHI ≥15/h) and/or clinical symptoms suspicious of SDB will be referred to a cooperating sleep clinic for an attended in-lab polysomnography with certified scoring where the definite diagnosis and, if applicable, the differentiation between obstructive and central sleep apnea will be made. Suggested treatment will be documented. DISCUSSION: Registries play an important role in facilitating advances in the understanding and management of cardiovascular disease. The SCHLA-HF registry will provide consistent data on a large group of patients with HF-REF that will help to answer questions on the prevalence, risk factors, gender differences and stability of SDB in these patients by cross-sectional analyses. Further insight into the development of SDB will be gained by extension of the registry to include longitudinal data.

C-reactive protein is elevated in heart failure patients with central sleep apnea and Cheyne-Stokes respiration.

BACKGROUND: Manifestation of central sleep apnea (CSA) with Cheyne-Stokes respiration is of major prognostic impact in chronic heart failure (CHF). Inflammatory processes have been linked to a progression of cardiovascular diseases, including heart failure. While an association of C-reactive protein (CRP) levels to obstructive sleep apnea has been documented before, there is a lack of information regarding variation of CRP levels in patients with CSA. OBJECTIVES: The objective of this study was to investigate a potential association of CRP levels to CSA severity in CHF patients. METHODS: High sensitivity CRP levels were analyzed in 966 patients with CHF (BMI 26.3 ± 4.6, New York Heart Association class 2.6 ± 0.5, left ventricular ejection fraction 29.4 ± 7.9%, N-terminal pro-brain natriuretic peptide, NT-proBNP, level 2,209 ± 3,315 pg/ml) without sleep-disordered breathing (SDB; Apnea-Hypopnea Index, AHI, <5/h) or various degrees of CSA, documented by in-hospital cardiorespiratory polygraphy or polysomnography. RESULTS: The CRP concentration in CHF patients was 0.550 ± 0.794 mg/dl in patients without SDB (AHI 0-4/h, n = 403) versus 0.488 ± 0.708 mg/dl in patients with mild CSA (AHI 5-14/h, n = 123, p = n.s.) and 0.660 ± 0.963 mg/dl in patients with moderate CSA (AHI 15-29/h, n = 160, p = n.s.). In patients with severe CSA (AHI ≥ 30/h, n = 280), significantly higher CRP concentrations were documented (0.893 ± 1.384 mg/dl, p < 0.05). Stepwise regression analysis revealed AHI, NT-proBNP and heart rate to be independently associated with elevated CRP levels. CONCLUSION: Severe CSA in CHF patients is associated with elevated levels of CRP, a systemic marker of inflammation and cardiovascular risk. This might explain in part the negative prognostic impact of CSA in these patients.