Heart failure is the only cardiovascular disease with increasing incidence and mortality.1 Approximately five million Americans have heart failure, with an annual incidence of 10 per 1,000 in individuals over 65 years of age, an already rising demographic segment of society. Heart failure is the most frequent Medicare diagnosis, with most of its cost related to hospitalizations.1,2 Identification and treatment of highly prevalent comorbidities with known detrimental effects, such as sleep-disordered breathing (SDB), carries a high potential for positive impact.3 SDB is broadly divided into two main syndromes: obstructive sleep apnea (OSA) and central sleep apnea (CSA). Both syndromes of SDB are increasingly recognized as contributors to cardiovascular morbidity and mortality. OSA is a cause of hypertension and a risk factor for coronary artery disease, arrhythmia, and cardiovascular mortality.4 Thus, OSA is highly prevalent in patients with end-stage heart disease.5 A rare form of SDB in the general population, CSA is a consequence of respiratory control instability in patients with severe heart failure, and it worsens the prognosis of the underlying heart failure.6–8 SDB in both obstructive and central forms is present in over 60% of patients with heart failure and is largely undiagnosed.5,9,10 Treatment of both CSA and OSA is safe, effective, and well tolerated, and can improve the underlying heart failure as well as quality of life.11,12
Before proceeding with this review, it is critical to clarify the nomenclature that has evolved over the past 200 years to describe the manifestation of respiratory control instability in heart failure. An oscillatory pattern of respiration was first described in patients with heart failure, along with stroke and morbid obesity, well over two centuries ago by Cheyne, followed by Stokes. Cheyne-Stokes respiration (CSR) is an oscillatory breathing pattern characterized by recurring 60–90-second cycles of gradually increasing ventilation (crescendo). This is followed by a gradual decrease in ventilation (decrescendo) that culminates in a visually recognizable prolonged apnea or hypopnea (see Figure 1). CSR is a morphological pattern of ventilation that can occur during restful wakefulness and exercise in patients with heart failure6,13 as well as during sleep. As polygraphic recording of sleep (polysomnography) was developed in the 1960s, the first polysomnographic description of CSR was made in 1965.14
The diagnosis of CSA is made based on clinical polysomnography (sleep study) and takes into account only the presence of central apnea or hypopnea and not necessarily the presence of the oscillatory pattern of ventilation. Generally, patients with heart failure and CSA will have the CSR pattern with central apneas, and the disorder is sometimes termed CSA-CSR. For purposes of clarity, CSA is the polysomnographically diagnosed SDB with predominantly central apneas, while CSR is the oscillatory breathing pattern that is visually recognized and can be present during sleep as well as wakefulness. When CSR occurs during restful wakefulness or exercise, it obviously cannot be termed central ‘sleep’ apnea and is referred to as CSR only. Therefore, both terms describe the same underlying respiratory control instability.
It is imperative at this point to note that at the end of a central apnea, a decrease in upper airway tone occurs.15 Thus, obstruction of the upper airway is part of the mechanism of central apnea. One patient can manifest mixed, central, and obstructive events during a single night. It is therefore sometimes overly and inappropriately simplistic to consider a particular patient’s respiratory sleep disorder as one or the other and not a combined central and OSA disorder.
Mechanism of Central Sleep Apnea
As cardiac systolic function deteriorates, several pathophysiological conditions develop and contribute to both respiratory control instability and reduced upper airway patency, subsequently promoting both obstructive and central respiratory events during sleep. The following discussion of the mechanism of CSA is brief and will focus on recent developments. The topic has been fully reviewed recently.16,17
Respiratory Control Instability in Heart Failure
During sleep, the organism’s metabolic rate is slow and stable, and CO2 production is subsequently at a steady sate. Behavioral control of breathing is abolished by the sleep state, and the arterial carbon dioxide level (PaCO2) becomes the main stimulus for ventilation. As such, respiration ceases if PaCO2 falls below a tightly regulated level called the apnea threshold. Patients with heart failure have a pattern of chronic hyperventilation characterized by close proximity between their baseline sleep (eupneic) level of PaCO2 (steady-state level of ventilation) and their apnea threshold.18 The mechanism of this chronic hyperventilation in patients with heart failure is thought to be related to pulmonary interstitial congestion.19,20 In animal models, respiratory control instability and central apnea were induced in response to increased left atrial pressure.21 This is a typical condition in patients with systolic dysfunction, and is more likely when they assume the supine position during sleep.22
Any slight increase in ventilation during sleep, as occurs with arousal or changes in sleep stage, will result in a drop in PaCO2 below the apnea threshold, precipitating apneic events.23 Given the inertia in the respiratory control system,24 breathing does not resume until an excessive chemical stimulus (hypercapnea) has accumulated, producing an ‘overshoot’ of ventilation that is likely to drop PaCO2 below the apnea threshold again and propagate periodic breathing and CSR. The chemoreceptor’s response to hypercapnea is increased in patients with heart failure and CSA25 and their eupeic PaCO2 is close to their apnea threshold, making this mechanism likely.18,26
Changes in cerebral perfusion (cerebrovascular reactivity) in response to changes in PaCO2 play an important role in the ventilatory response of the central chemoreceptors. Normally, an increase in PaCO2 (i.e. during apnea) produces cerebrovascular dilation, while a decrease in PaCO2 (i.e. post-apnea hyperventilation) produces cerebrovascular constriction. The normal decrease in cerebral perfusion with hypocapnea (which occurs during the hyperventilation phase of CSR) allows for greater accumulation of CO2 at the level of central chemoreceptors. This subsequently allows for continued stimulus to breathe and possibly decreases the potential for or duration of apnea.
Similarly, the cerebrovascular dilation that occurs with hypercapnea can produce a ‘wash-out’ effect at the level of the central chemoreceptors. This decreases the accumulation of CO2 following an apnea and prevents the expected ventilatory overshoot, therefore decreasing the likelihood that an apnea will ensue.27 Patients with heart failure have a reduced cerebrovascular response to changes in PaCO2. This reduces the ability of the respiratory control center to dampen the overshoot and undershoot in the ventilatory response to CO2.28
Central Sleep Apnea, Mixed Sleep-disordered Breathing, and Systolic Heart Failure
The role of increased filling pressure in the pathogenesis of SDB in patients with heart failure is intriguing and only minimally understood. Increased pulmonary vascular congestion is thought to contribute to hyperventilation and increased respiratory control instability, leading to CSA.17,19 Studies also suggest that cervical venous congestion may equally destabilize the upper airway and potentially produce obstructive events as well.29 It is known that CSA may result from upper airway instability30 and that upper airway obstruction may follow central apnea.15 Worsening of heart failure may therefore lead to both increased central and obstructive apneas.
Consequences of Central Sleep Apnea in Heart Failure
CSA is a manifestation of respiratory control instability in patients with severe systolic dysfunction. Once present, however, CSA is associated with a set of neurocirculatory responses that are detrimental for the failing heart. The recurrence of central respiratory events followed by a recovery phase induces a cyclical pattern of intermittent hypoxia–reoxygenation. Evidence from experimental human and animal studies has demonstrated that intermittent hypoxia is the critical lesion accounting for this cascade of the neurocirculatory response to SDB. Figure 2 summarizes the mechanisms discussed in this section.
Intermittent Hypoxia and Sympathetic Activation in Central Sleep Apnea
Following every apnea or hypopnea, the resulting hypoxia stimulates the chemoreceptors,31 which mediate an increase in sympathetic activity.32 This sympathetic activation produces peripheral vasoconstriction and a subsequent surge in blood pressure,33,34 increasing the afterload for a failing heart. With the recurrence of apnea–recovery and the associated hypoxia–reoxygenation, a cyclical pattern of sympathetic activation and blood pressure surges recurs throughout the sleep period, resulting in increased cardiac muscle workload.35 Furthermore, the increase in sympathetic activity and blood pressure persists during the daytime after a night in intermittent hypoxia.36,37 This carryover effect36 results in increased sympathetic tone in patients with CSA well into the daytime. The negative role of increased sympathetic tone is well established in heart failure.38 Patients with heart failure and CSA have increased urinary and daytime plasma levels of norepinephrine compared with those with heart failure and no CSA.39 Elimination of central apnea events by positive airway pressure results in decreased norepinephrine levels in those patients with heart failure.39,40 Cessation of the rhythmic sympathoinhibitory feedback that normally accompanies eupneic breathing does not contribute importantly to sympathetic excitation during apnea.41
Sympathetic activation-mediated vasoconstriction may induce long-lasting structural changes in the resistance of microcirculatory vessels that contribute to the pathogenesis and persistence of hypertension.42 Animal models of intermittent hypoxia demonstrate early structural and functional changes,43 along with impaired vasodilator response to hypoxia.44 Moreover, intermittent hypoxia contributes to platelet activation and thrombogenesis.45,46 The role of these microcirculatory endothelial changes has, however, not been evaluated in patients with heart failure and CSA.
Aside from vasoconstriction and increased afterload, increased sympathetic tone can contribute to ventricular irritability and arrhythmogenecity in patients with heart failure. Patients with heart failure and CSA have increased ventricular irritability,47 which decreases with treatment.48 In one series of patients with heart failure, a relationship between atrial fibrillation and having CSA was reported.49
Oxidative signaling mediates the response of the chemoreceptors to intermittent hypoxia.50,51 This ventilatory response outlasts the intermittent hypoxia and may be responsible for the persistence in sympathetic excitation in patients with SDB.36,52 Oxidative stress is a consequence of intermittent hypoxia53–55 and is well established in patients with OSA,56,57 but has not been evaluated in patients with CSA. A direct impact of intermittent hypoxia, possibly independent of sympathetic activation, on the myocardium or the peripheral vascular system must also be considered. In an animal model of intermittent hypoxia, investigators induced oxidative-stress-mediated left ventricular dysfunction.53
Hypoxia, as well as inducing systemic vasoconstriction, can induce pulmonary vasoconstriction58 and subsequently increase the right ventricular afterload.59 The impact of CSA on right ventricular function and load is another area that has not been evaluated in patients with existing systolic dysfunction and CSA. Sympathetic excitation is likely to be the mechanism of increase in arrhythmogenesis reported in patients with heart failure and CSA.60
The Role of Respiratory Effort in Cardiovascular Consequences of Central Sleep Apnea
The mechanical perturbations associated with respiratory effort are less profound in CSA than OSA and probably have less severe implications for patients with heart failure. When an obstructive apnea or hypopnea occurs, the resulting hypoxia stimulates the respiratory centers, which generate a repetitive vigorous inspiratory effort in an attempt to overcome the collapsed airway. Subsequently, the pressure inside the thoracic cavity becomes increasingly negative, reaching several times the normal inspiratory negative pressure. This can have serious effects on the heart via several mechanisms. In central apnea, large breaths occur during the recovery phase after an arousal terminates the apnea, usually without major accompanying upper airway obstruction and, therefore, with less profound negative swings in the intrathoracic pressure. Changes in the venous return and transmural cardiac pressure, however, may still occur.
One cannot discount the impact of this vigorous respiratory effort in a patient with systolic heart failure. In one study, improvement in respiratory muscle workload in patients with heart failure and CSA was associated with improvement in left ventricular ejection fraction.39 The sympathetic activation associated with CSA appears to be more important in mediating the cardiovascular effects of CSA than these less profound pressure changes.32
Impact of Central Sleep Apnea on Mortality in Patients with Heart Failure
While CSA is associated with significant perturbations in the neuro-humoral system, its clinical impact on outcomes of patients with heart failure is incompletely understood. Several small studies have demonstrated a link between CSA and poor outcome in patients with heart failure, including an effect on mortality.7,8 These findings were further duplicated in a more recent report by Javeheri et al.61 Other studies suggested that the presence of periodic breathing or CSR respiration during exercise was an even more important negative prognostic factor than sleep-related CSR (i.e. CSA).6,62 Debate, however, persists as to the applicability of these findings to the larger population of heart failure patients.63,64 Some investigators feel that CSA is largely a consequence of severe systolic heart failure and it improves or resolves with improvement in heart failure.63,64 From a clinical perspective, it is likely that the clinician will encounter CSA in patients with more severe systolic dysfunction. In these patients, the low cardiac output state would have persisted despite optimal management of the underlying heart failure. These are precisely the patients who have poor prognosis but who are also likely to derive symptomatic benefit from identification and treatment of the concomitant CSA. The impact of treatment of CSA on survival will require large, randomized controlled trials.
Prevalence and Presentation of Central Sleep Apnea in Patients with Heart Failure
Studies of the prevalence and distribution of SDB in heart failure yielded widely varying estimates depending on the population studied. Earlier studies evaluated only65 or predominantly49 elderly males with severe systolic dysfunction. These studies reported a prevalence of CSA ranging from 40 to 50% of patients studied. Recent studies with more representative populations of heart failure patients that included women demonstrated a lower prevalence of CSA, ranging from 18 to 25%.9,10,66 Other studies have suggested that the decline in prevalence of CSA may be due to the standard use of beta-blockers in patients with heart failure.67
These changes in the management of chronic heart failure, along with the increasing obesity in the general adult population,68 may explain the increasing prevalence of OSA in these recent prevalence studies.5,9,10,66 OSA is highly prevalent in middle-aged individuals,69 is a consequence of rising obesity and aging,70 and has a strong relation with cardiovascular disease.4,71–73 Overall, the prevalence of SDB ranged from 6 to 80% of patients with heart failure, with more OSA than CSA.
It is likely that patients with heart failure and CSA will report sleepiness.74 The overlap between symptoms of SDB-related sleepiness and heart-failure- related fatigue creates difficulty in identifying SDB in patients with chronic heart failure based on history alone. Fatigue, sleepiness, reduced physical activity level, and impaired cognitive function may be due to either CSA or heart failure. The symptoms therefore do not aid in determining which patients to screen for SDB. As such, it is imperative to maintain a very high index of suspicion for this diagnosis. In patients with heart failure, risk factors for CSA include lower left ventricular ejection fraction, more dilated myocardium, and male age.5,49 Other investigators reported that atrial fibrillation is a risk factor for CSA in patients with heart failure.49
Management of Central Sleep Apnea and Its Impact on Cardiac Function
Optimal Treatment of the Underlying Heart Failure
CSA is most likely to be a consequence of severe systolic dysfunction. The severity of CSA is correlated with severity of the underlying systolic dysfunction.5,75 Optimal treatment of the heart failure is therefore of foremost importance in the management of CSA. Heart failure medications, such as angiotensin-converting enzyme (ACE) inhibitors, have been reported to improve CSA.76 Additionally, beta-blocker treatment is also associated with decreased CSA events.67 The mechanism of effect of these medications may be mediated by decreased preload or improved cerebral perfusion and responsiveness at the level of the central chemoreceptors.28 In clinical practice, optimal medical management of heart failure with ACE inhibitors and beta-blockers is already a target in all patients, regardless of underlying SDB. When a heart failure patient is diagnosed with CSA, it is likely that the patient will already be on optimal treatment and will require additional treatment targeted to CSA.
Improvement in CSA was reported with atrial overdrive pacing,77 likely due to the associated increase in cardiac output. Similarly, improvement in CSA occurs with cardiac resynchronization,78,79 probably due to improved underlying cardiac output.80 These reports further support the pathophysiological relation between systolic dysfunction and CSA. They confirm that optimal treatment, whether pharmacological or electromechanical, of underling heart failure will improve the associated CSA.
Continuous Positive Airway Pressure in the Treatment of Central Sleep Apnea
Continuous positive airway pressure (CPAP) acts as an ‘air splint’ for the upper airway, preventing collapse and episodes of obstructive apnea and hypopnea. Thus, CPAP is the standard treatment for OSA in the general population. CPAP and other forms of positive airway pressure exert additional effects on cardiovascular function in patients with heart failure, including decreased respiratory and cardiac muscle workload,39 improved myocardiac contractile efficiency,81 and increased left ventricular ejection fraction.82,83 The positive effects of CPAP on the heart include improved autonomic tone and decreased preload.84,85
Given the association between CSA and upper airway instability,15 and the salutary effects of CPAP on cardiac function, CPAP has been used for the treatment of CSA. Earlier underpowered trials suggested that CPAP was beneficial in this setting. In small trials of CPAP versus control in patients with heart failure and CSA, CPAP improved sympathetic activity39 and gas exchange.86 CPAP in patients with heart failure–CSA produced unloading of respiratory muscles, along with increased left ventricular ejection fraction87 and cardiac work index.39 In another pilot trial, the same investigators reproduced this improvement in left ventricular ejection fraction with CPAP in patients with systolic dysfunction and CSA.88 These studies were so encouraging that a large, adequately powered multicenter trial commenced. The results of this trial, however, were negative and there was no survival benefit for treatment with CPAP in patients with systolic dysfunction and CSA.40 A post-hoc analysis suggested that a subgroup of patients who experienced a profound reduction in their respiratory events with CPAP may still benefit from treatment.89
Given the co-existence of obstructive and central SDB in patients with heart failure, however, it is likely that those patients who had profound improvement in their respiratory events with CPAP actually had a more obstructive than central disorder to begin with. At this time, CPAP is not an acceptable treatment for patients with heart failure and predominantly CSA rather than OSA.
Adaptive Pressure Support Servo Ventilation
This is a new modality of ventilatory support that delivers baseline-positive airway pressure along with machine-generated breaths during central apneas. These devices are equipped with sensitive sensors that can detect central apneas. They deliver several breaths, a tidal volume, and respriratory rate previously determined to match the patient’s minute ventilation during stable breathing. Therefore, the mechanism of effect of this modality is by preventing the increase in PaCO2 during the apnea and subsequently preventing the hyperventilation that follows the apnea, in effect breaking the periodic breathing cycle. Several small trials have demonstrated significant benefit of adaptive pressure support servo ventilation (ASV) in eliminating central events, increasing left ventricular ejection fraction, and improving quality of life.12,90 These studies are promising but will require confirmation with an adequately powered randomized controlled trial.
Bilevel-positive airway pressure has also been used effectively in small trials to treat CSA. In this setting, bilevel-positive airway pressure was administered with a back-up rate effectively as a form of ventilation with predetermined minute ventilation that corresponds to the patient’s minute ventilation during stable breathing.91 ASV is a very promising treatment modality for CSA and is rapidly becoming widely used.
Given that the primary lesion in CSA responsible for the cardiovascular consequences is intermittent hypoxia, it is logical to expect that nocturnal oxygen may be an effective treatment in preventing sympathetic activation. Moreover, supplemental oxygen will improve the oxygen store in patients with heart failure, subsequently dampening the ventilatory response to the increase in PaCO2 during apnea.
Another possible mechanism of action would be a direct effect on the peripheral chemoreceptors, decreasing their background chemosensitivity (to PaCO2), and dampening the ventilatory overshoot following apnea-induced hypercapnea.92–94 Indeed, nocturnal oxygen was effective in decreasing the number of central events in several small trials.92,95 Moreover, a beneficial effect was also noted on left ventricular ejection fraction95,96 and sympathetic tone.97 Other longer-term trials have also supported the beneficial role of nocturnal oxygen in the treatment of CSA in heart failure patients.98,99 A major concern regarding nocturnal oxygen compared with positive airway pressure is its inability to eliminate the upper airway obstruction that co-exists with central apneas.100
Similar to ASV, nocturnal oxygen is a promising therapy but has not yet been sufficiently studied in adequately-powered, randomized controlled trials for the treatment of CSA in patients with heart failure. Subsequently, oxygen therapy is not the standard of care for these patients.
Experimental (Phase I and II) Therapeutics for Central Sleep Apnea
These are modalities that target different components of the pathophysiology of CSA. The effectiveness of these modalities was demonstrated in small human trials, but safety and efficacy have not yet been evaluated in randomized controlled trials. These approaches, therefore, are not all part of current clinical practice.
Respiratory stimulants such as theophylline have been suggested for the treatment of CSA in heart failure. Proposed mechanisms include increased ventilatory responsiveness below eupnea, resulting in increased proximity between eupneic PaCO2 and the apnea threshold. Other potential mechanisms include a stimulatory effect on cardiac function, which is a concern. This has limited the use of theophylline in clinical practice. Only one double-blinded crossover study has examined the short-term effects of theophylline on CSA in 15 patients with stable heart failure. Compared with placebo, theophylline decreased the central events and the severity of oxygen desaturation, but without improvement in left ventricular ejection fraction.101 Overall, the cardiac-stimulatory effects of theophylline limit its use in clinical practice until adequately powered studies can demonstrate its safety and efficacy.
Acetazolamide induces metabolic acidosis and has a stimulatory effect on ventilation, increasing the proximity between the eupneic PaCO2 and the apnea threshold.102 In a recent short-term (six-night) placebo-controlled, cross-over trial, Javaheri found a decrease in respiratory events and severity of nocturnal desaturation with acetazolamide compared with placebo, with an improvement in subjective sleep quality.103 There were no changes in objective measures of sleep quality and left ventricular ejection fraction with acetazolamide. The potential for urinary potassium wasting leading to hypokalemia and increased arrhythmia risk with acetazolamide remains a serious concern. The role of acetazolamide in the long-term treatment of CSA has yet to be determined.
Administration of small doses of exogenous CO2 directly or indirectly by increased dead space is another intriguing treatment modality for CSA. CO2 is a respiratory stimulator that can stabilize the breathing pattern. Again, long-term adequately powered trials are lacking and preclude consideration of this modality. Furthermore, the practicalities of delivery and safety remain cardinal concerns with this treatment option.104,105
Hypnotics, such as benzodiazepines, have been studied in patients with CSA. The mechanism of action was presumed to be a decrease in arousal-related ventilatory overshoot. Early pilot reports showed a decrease in the number of nocturnal arousals, but no change in the severity of respiratory events or nocturnal oxygen desaturation was found.106,107
The distinction between central and obstructive disorders in patients with heart failure may be difficult due to the complex physiological interaction between the mechanisms leading to either disorder. A mixed pattern of SDB is present in many patients with heart failure, resulting in central, obstructive, and mixed apneas and hypopneas during the course of one night. Patients with heart failure benefit from the identification and treatment of underlying SDB in its two main forms: CSA and OSA. The clinician caring for patients with heart failure must therefore be cognizant of this overlap and maintain a comprehensive approach to the management of SDB in this complicated setting. Combined sleep and heart failure programs are one way to achieve this comprehensive approach. There is adequate evidence to support the notion that CSA is harmful for the failing heart, but no large epidemiological studies of the impact on survival have been carried out. While there is no widely accepted treatment for CSA, several treatment modalities are available and promising.