Distinct Patterns of Hyperpnea During Cheyne-Stokes Respiration: Implication for Cardiac Function in Patients With Heart Failure.

STUDY OBJECTIVES: In heart failure (HF), we observed two patterns of hyperpnea during Cheyne-Stokes respiration with central sleep apnea (CSR-CSA): a positive pattern where end-expiratory lung volume remains at or above functional residual capacity, and a negative pattern where it falls below functional residual capacity. We hypothesized the negative pattern is associated with worse HF. METHODS: Patients with HF underwent polysomnography. During CSR-CSA, hyperpnea, apnea-hyperpnea cycle, and lung to finger circulation times (LFCT) were measured. Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration and left ventricular ejection fraction (LVEF) were assessed. RESULTS: Of 33 patients with CSR-CSA (31 men, mean age 68 years), 9 had a negative hyperpnea pattern. There was no difference in age, body mass index, and apnea-hypopnea index between groups. Patients with a negative pattern had longer hyperpnea time (39.5 ± 6.4 versus 25.8 ± 5.9 seconds, P < .01), longer cycle time (67.8 ± 15.9 versus 51.7 ± 9.9 seconds, P < .01), higher NT-proBNP concentrations (2740 [6769] versus 570 [864] pg/ml, P = .01), and worse New York Heart Association class (P = .02) than those with a positive pattern. LFCT and LVEF did not differ between groups. CONCLUSIONS: Patients with HF and a negative CSR-CSA pattern have evidence of worse cardiac function than those with a positive pattern. Greater positive expiratory pressure during hyperpnea is likely generated during the negative pattern and might support stroke volume in patients with worse cardiac function. COMMENTARY: A commentary on this article appears in this issue on page 1227. CLINICAL TRIAL REGISTRATION: The trial is registered with Current Controlled Trials (www.controlled-trials.com; ISRCTN67500535) and Clinical Trials (www.clinicaltrials.gov; NCT01128816).

Design of the effect of adaptive servo-ventilation on survival and cardiovascular hospital admissions in patients with heart failure and sleep apnoea: the ADVENT-HF trial.

INTRODUCTION: Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. AIM: ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. METHODS: ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea-hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. CONCLUSION: The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

Mechanisms of sleep-disordered breathing: causes and consequences.

Obstructive sleep apnea (OSA) is very common in the general population and is characterized by ineffective inspiratory efforts against a collapsed upper airway during sleep. Collapse occurs mainly at the level of the velopharynx and oropharynx due to a combination of predisposing anatomy and the withdrawal of pharyngeal dilator activity during sleep. Central sleep apnea (CSA) is a manifestation of chemoreflex control instability, leading to periods of inadequate respiratory drive sufficient to trigger breathing, usually alternating with periods of hyperventilation. While both forms of apnea are the result of differing pathophysiology, it has become increasingly clear that OSA and CSA often coexist in the same patient, the existence of one can predispose to the other, and that the two are not as distinct as previously thought. Both OSA and CSA exert a number of acute deleterious effects including intermittent hypoxia, arousals from sleep, and swings in negative intrathoracic pressure, which in turn lead to chronic physiologic consequences such as autonomic dysregulation, endothelial dysfunction, and cardiac remodeling. These underlying pathophysiological mechanisms provide a framework for understanding why OSA and CSA may predispose to cardiovascular diseases like ischemic heart disease and stroke.

Sleep-disordered breathing: autonomic mechanisms and arrhythmias.

Obstructive sleep apnea (OSA) is present in at least 2% to 4% of the general population. Central sleep apnea (CSA), though less common, is highly prevalent in patients with heart failure. Both forms of sleep apnea exert strong modulatory effects on the autonomic nervous system at night through a number of mechanisms including central respiratory-cardiac coupling in the brainstem, chemoreflex stimulation, baroreflexes, and reflexes relating to lung inflation. Arousals also contribute to the autonomic disturbance. Although sleep is normally a time when parasympathetic modulation of the heart predominates and myocardial electrical stability is enhanced, OSA and CSA disturb this quiescence, creating an autonomic profile in which both profound vagal activity leading to bradyarrhythmias, and sympatho-excitation favoring ventricular ectopy are observed. The resulting tendency toward cardiac arrhythmia may directly contribute to sudden cardiac death and premature mortality in patients with sleep apnea. Therapy consists largely of treatment with continuous positive airway pressure, which has been shown to improve autonomic profile and reduce nocturnal arrhythmias.

Continuous positive airway pressure increases heart rate variability in heart failure patients with obstructive sleep apnoea.

Patients with heart failure or OSA (obstructive sleep apnoea) have reduced HF-HRV (high-frequency heart rate variability), indicating reduced cardiac vagal modulation, a marker of poor prognosis. CPAP (continuous positive airway pressure) abolishes OSA in patients with heart failure, but effects on daytime HF-HRV have not been determined. We hypothesized that, in patients with heart failure, treatment of coexisting OSA by CPAP would increase morning HF-HRV. In 19 patients with heart failure (left ventricular ejection fraction <45%) and OSA (>/=20 apnoeas and hypopnoeas/h of sleep), HF-HRV was quantified before and 1 month after randomization to a control or CPAP-treated group. In the control group (n=7), there were no changes in HF-HRV over the 1 month study during wakefulness in the morning. In the CPAP-treated group (n=12) HF-HRV increased significantly during wakefulness in the morning [from 2.43+/-0.55 to 2.82+/-0.50 log(ms(2)/Hz); P=0.002] due to an increase in transfer function between changes in lung volume and changes in HF-HRV (92.37+/-96.03 to 219.07+/-177.14 ms/l; P=0.01). In conclusion, treatment of coexisting OSA by nocturnal CPAP in patients with heart failure increases HF-HRV during morning wakefulness, indicating improved vagal modulation of heart rate. This may contribute to improved prognosis.

Respiratory modulation of the autonomic nervous system during Cheyne-Stokes respiration.

Cheyne-Stokes respiration (CSR) is associated with increased mortality among patients with heart failure. However, the specific link between CSR and mortality remains unclear. One possibility is that CSR results in excitation of the sympathetic nervous system. This review relates evidence that CSR exerts acute effects on the autonomic nervous system during sleep, and thereby influences a number of cardiovascular phenomena, including heart rate, blood pressure, atrioventricular conduction, and ventricular ectopy. In patients in sinus rhythm, heart rate and blood pressure oscillate during CSR in association with respiratory oscillations, such that both peak heart rate and blood pressure occur during the hyperpneic phase. Inhalation of CO2 abolishes both CSR and the associated oscillations in heart rate and blood pressure. In contrast, O2 inhalation sufficient to eliminate hypoxic dips has no significant effect on CSR, heart rate, or blood pressure. In patients with atrial fibrillation, ventricular rate oscillates in association with CSR despite the absence of within-breath respiratory arrhythmia. The comparison of RR intervals between the apneic and hyperpneic phases of CSR indicates that this breathing disorder exerts its effect on ventricular rate by inducing cyclical changes in atrioventricular node conduction properties. In patients with frequent ventricular premature beats (VPBs), VPBs occur more frequently during the hyperpneic phase than the apneic phase of CSR. VPB frequency is also higher during periods of CSR than during periods of regular breathing, with or without correction of hypoxia. In summary, CSR exerts multiple effects on the cardiovascular system that are likely manifestations of respiratory modulation of autonomic activity. It is speculated that the rhythmic oscillations in autonomic tone brought about by CSR may ultimately contribute to the sympatho-excitation and increased mortality long observed in patients with heart failure and CSR.

Influence of Cheyne-Stokes respiration on ventricular response to atrial fibrillation in heart failure.

In subjects with sinus rhythm, respiration has a profound effect on heart rate variability (HRV) at high frequencies (HF). Because this HF respiratory arrhythmia is lost in atrial fibrillation (AF), it has been assumed that respiration does not influence the ventricular response. However, previous investigations have not considered the possibility that respiration might influence HRV at lower frequencies. We hypothesized that Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) would entrain HRV at very low frequency (VLF) in AF by modulating atrioventricular (AV) nodal refractory period and concealed conduction. Power spectral analysis of R-wave-to-R-wave (R-R) intervals and respiration during sleep were performed in 13 subjects with AF and CSR-CSA. As anticipated, no modulation of HRV was detected at HF during regular breathing. In contrast, VLF HRV was entrained by CSR-CSA [coherence between respiration and HRV of 0.69 (SD 0.22) at VLF during CSR-CSA vs. 0.20 (SD 0.19) at HF during regular breathing, P < 0.001]. Comparison of R-R intervals during CSR-CSA demonstrated a shorter AV node refractory period during hyperpnea than apnea [minimum R-R of 684 (SD 126) vs. 735 ms (SD 147), P < 0.001] and a lesser degree of concealed conduction [scatter of 178 (SD 56) vs. 246 ms (SD 72), P = 0.001]. We conclude that CSR-CSA entrains the ventricular response to AF, even in the absence of HF respiratory arrhythmia, by inducing rhythmic oscillations in AV node refractoriness and the degree of concealed conduction that may be a function of autonomic modulation of the AV node.

Association between atrial fibrillation and central sleep apnea.

BACKGROUND: We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. METHODS AND RESULTS: We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. CONCLUSIONS: We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.

Provocation of ventricular ectopy by cheyne-stokes respiration in patients with heart failure.

STUDY OBJECTIVES: Previous reports have suggested an association between Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) and ventricular ectopy, but there has been relatively little evidence of a cause-effect relationship. The objective of this study was to determine whether CSR-CSA directly provokes ventricular ectopy and, if so, whether it is associated with any particular phase of the CSR-CSA breathing cycle. DESIGN: We compared the frequency of ventricular premature beats (1) between the apneic and hyperpneic phases of CSR-CSA, (2) between periods of CSR-CSA and periods of regular breathing during sleep, and (3) in response to the elimination of CSR-CSA by administration of a low concentration of inhaled CO2. SETTING: Hospital-based cardiopulmonary sleep laboratory. PATIENTS: Twenty-three patients with heart failure and CSR-CSA. MEASUREMENTS AND RESULTS: Ventricular premature beats were found to occur 40% more frequently during the hyperpneic phase than the apneic phase of CSR-CSA (mean+/-SD, 7.0+/-7.4 versus 4.9+/-5.7 ventricular premature beats per minute, P = .003). Ventricular premature beat frequency was also found to be higher during periods of CSR-CSA than during periods of regular breathing occurring either spontaneously (median [25th, 75th percentile], 2.2 [1.2, 6.5] versus 1.1 [0.8, 2.0] ventricular premature beats per minute, P = .027), or induced through inhalation of CO2 (from 4.7+/-3.8 to 3.3+/-4.0 ventricular premature beats per minute, P = .048). CONCLUSIONS: CSR-CSA provokes ventricular ectopy that is most pronounced during the hyperpneic phase. Such an increase in ventricular premature beats might contribute to the higher mortality rates reported in heart failure patients with CSR-CSA.

Influence of Cheyne-Stokes respiration on cardiovascular oscillations in heart failure.

In patients with congestive heart failure, Cheyne-Stokes respiration is accompanied by oscillations in blood pressure and heart rate at a very low frequency. It is not known whether these cardiovascular oscillations are primarily related to oscillations in ventilation or oxyhemoglobin saturation. We hypothesized that abolition of the ventilatory oscillations of Cheyne-Stokes respiration by CO2 inhalation would eliminate accompanying oscillations in blood pressure and heart rate but that elimination of hypoxic dips by supplemental O2 would not. We studied 10 subjects with heart failure and Cheyne-Stokes respiration during sleep using frequency spectral analysis. During Cheyne-Stokes respiration, heart rate and blood pressure oscillated in association with respiratory oscillations at very low frequency. Inhalation of CO2 abolished Cheyne-Stokes respiration and associated oscillations in both blood pressure and heart rate. In contrast, inhalation of O2 sufficient to eliminate hypoxic dips had no significant effect on Cheyne-Stokes respiration, blood pressure (n = 6), or heart rate (n = 5). We conclude that ventilatory oscillations during Cheyne-Stokes respiration rather than oscillations in oxygenation per se powerfully induce heart rate and blood pressure oscillations. Cheyne-Stokes respiration is therefore one of the mechanisms that contributes to the very low-frequency oscillations in heart rate and blood pressure observed in patients with heart failure.

Avoidance of the left lateral decubitus position during sleep in patients with heart failure: relationship to cardiac size and function.

OBJECTIVES: We sought to determine whether patients with congestive heart failure (CHF) avoid the left lateral decubitus (LLD) position during sleep and, if so, whether this avoidance would be more pronounced in those with greater degrees of cardiomegaly. BACKGROUND: Anecdotal reports suggest that, in patients with CHF, the LLD position is associated with discomfort due to the enlarged apical heart beat and greater degree of dyspnea (trepopnea) than other positions. It has also been suggested that the LLD position is associated with increased sympathetic nervous activity. METHODS: A total of 75 patients with CHF and 75 control subjects underwent nocturnal polysomnography with monitoring of body position. Echocardiography was performed in all patients with CHF to determine left ventricular end-diastolic diameter (LVEDD). A total of 40 patients underwent cardiac catheterization from which pulmonary capillary wedge pressure (PCWP) and cardiac output (CO) were obtained. RESULTS: Patients with CHF spent significantly less time in the LLD position than in the right lateral decubitus position. No such difference was observed among control subjects. Among patients with CHF, those with larger LVEDD, higher PCWP, and lower CO spent less time in the LLD position. CONCLUSIONS: Patients with CHF avoid the LLD position spontaneously during sleep. This may be a protective strategy to avoid discomfort from the enlarged apical heart beat or further hemodynamic or autonomic compromise.

Respiratory modulation of heart rate and blood pressure during Cheyne-Stokes respiration.

Cheyne-Stokes respiration (CSR) is a form of periodic breathing associated with oscillations in heart rate (HR) and blood pressure (BP), which have previously been attributed to the effects of intermittent hypoxia and arousals from sleep. We herein review the major findings from a series of experiments, in which we explored the possibility that the ventilatory oscillations of CSR can independently modulate HR and BP. Using frequency spectral analysis, we showed that CSR in patients with heart failure causes oscillations in HR and BP that are eliminated by abolition of ventilatory oscillations, but persist during administration of supplemental O2 sufficient to prevent hypoxia. Analysis of the effects of arousals showed they have little or no effect on HR or BP independent of associated changes in ventilation. Finally, we showed that during simulated CSR, healthy awake patients were able to cause HR and BP oscillations in the absence of hypoxia or arousals. We conclude that ventilatory oscillations during Cheyne-Stokes respiration can modulate HR and BP independent of the effects of hypoxia and arousals from sleep.