Sleep-Disordered Breathing and Chronic Heart Failure: Changing Position May be Important

During the past decade, non-cardiac co-morbidities in chronic heart failure (HF) have gained increasing attention. Many of these co-morbidities (e.g. anaemia, iron deficiency, renal failure) are associated with impaired quality of life, high health-care utilisation and poor prognosis.1-3 Consequently, co-morbidities have gained greater prominence in both European and American HF management guidelines.4, 5 Importantly, some co-morbidities might constitute a therapeutic target,6 where interventions tackling the co-morbidity might improve the outcome for the patient. This would be particularly desirable for co-morbidities with a high prevalence. One such target co-morbidity might be sleep-disordered breathing (SDB). Sleep-disordered breathing is common in heart failure, with a prevalence of up to 70%. The severity of obstructive sleep apnoea (OSA) is conventionally expressed as the apnoea–hypopnoea index (AHI). An apnoea is defined as a total cessation of breathing for ≥10 s, whereas an hypopnoea is present when there is a ≥30% reduction in respiratory flow for ≥10 s, including a ≥4% decrease in oxygen saturation. Another measure of the severity of SDB is the oxygen desaturation index, the number of times per hour that blood oxygen level drops by ≥3 percentage points from baseline. Two major subtypes of SDB can be distinguished, although both types can occur in the same patient, and the phenotype may change somewhat from one night to another, and during the course of one night. Obstructive sleep apnoea, is characterized by loss of muscle tone in the upper airway and consequent upper airway collapse (partial or complete) during sleep. During such upper airway collapse, ventilation is compromised, resulting in oxygen desaturation and arousal from sleep. To overcome the collapse, respiratory effort increases, creating a more negative intrathoracic pressure. Right ventricular venous return increases, and the interventricular septum shifts to the left, hampering left ventricular filling and diminishing preload. In addition, the negative intrathoracic pressure leads to an increase in left ventricular transmural pressure and thus afterload. The increased afterload and decreased preload reduce left ventricular stroke volume.7, 8 A key feature of OSA is an increased sympathetic tone, enhanced adrenergic activity because of hypercapnia and hypoxia, and frequent arousals from sleep. In addition, parasympathetic tone appears to be significantly reduced when OSA is present. These neurohumoral abnormalities also persist during the day and may accelerate further deterioration in cardiac function, and increase the risk of arrhythmia.8 Intermittent hypoxaemia caused by obstructive episodes may also promote cardiac myocyte apoptosis and necrosis.7, 8 Oxidative stress, release of pro-inflammatory mediators (e.g. C-reactive protein, tumour necrosis factor-α), and subsequent endothelial dysfunction have been linked to oscillatory partial pressure of arterial oxygen (PaO2).7 Observational studies have shown a twofold increase in all-cause mortality in HF patients with untreated moderate OSA compared with mild or no OSA.7 It is still debated whether OSA is a true independent risk factor for all-cause mortality in patients with HF or whether it is merely a marker of more severe HF. Major risk factors for OSA in heart failure are obesity (for men only), male sex, and age (for women only).9 Heart failure (HF) itself may have an influence on the pathophysiology of OSA, for example owing to mucosal oedema in the upper airways (increasing the susceptibility to upper airway collapse particularly with nocturnal rostral fluid shifts), or concomitant Cheyne–Stokes respiration, which may decrease upper airway muscle tone and thereby increase the propensity for airway obstruction.7, 8 The diagnosis of OSA in HF patients is challenging, as excessive daytime sleepiness is often absent, possibly because of higher sympathetic tone.7 Although (loud) snoring and obesity can suggest OSA in the general population, this is most likely not true for HF patients. A recent study by De Vries et al.10 showed that known clinical risk factor profile for SDB [i.e. age, sex, body mass index, left ventricular ejection fraction (LVEF), atrial fibrillation, use of diuretics, and Epworth Sleepiness Scale) explained only 17% of the variance of SDB in a stable HF population. The second type of SDB, central sleep apnoea (CSA), is largely confined to (and is considered a consequence) of HF. Cheyne–Stokes respiration (CSR), a waxing-and-waning cyclical breathing pattern, is a particular form of CSA. In the majority of HF patients, chronic hyperventilation is observed, most likely owing to pulmonary congestion triggering a pulmonary irritant reflex.7 In addition, HF patients exhibit an increase in both central and peripheral chemosensitivity.7, 11 Both features may lead to chronic hypocapnia, and central apnoeic/hypopnoeic events occur when the partial pressure of arterial carbon dioxide (PaCO2) drops below the apnoeic threshold.7 Just as in OSA, CSA is associated with hypoxaemic–normoxaemic cycles and an increase in sympathetic tone, although the swings in intrathoracic pressure are less than in OSA.7, 11 Similarly to OSA, there is an association with all-cause mortality in HF patients. Traditionally, CSA is considered a maladaptive response to the underlying cardiac dysfunction, although more recently it has been suggested that CSR may be a protective phenomenon,12 by hyperventilation-related increases in end-expiratory lung volume, intrinsic positive airway pressure, assistance to stroke volume, attenuation of excessive sympathetic activity, avoidance of hypercapnic acidosis, and periodic rest to fatigue-prone respiratory pump muscles. Although risk factors for the presence of CSA are clear (male sex, older age, presence of atrial fibrillation, and poorer left ventricular systolic function) symptoms cannot reliably distinguish HF patients with CSA from those who do not have CSA. Recently, the surprising results of SERVE-HF (Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure) trial were published.13 In this randomized, parallel-group, event-driven study, 1,325 symptomatic HF patients with reduced LVEF (≤45%) and at least moderate central sleep apnoea (i.e. AHI ≥15/h with predominantly central apnoeic events) were assigned to either adaptive servo-ventilation (ASV) therapy with standard guideline-based care, or standard guideline-based care only. Despite significant and substantial improvement in respiratory indices in the ASV group {AHI from 31.2 [interquartile range (IQR) 10.3–115.3] at baseline to 6.6 [0.0–50.8] at 12 months follow-up}, a statistically significant increase in both all-cause and cardiovascular mortality was observed in the treatment arm [hazard ratio (HR) 1.28, 95% confidence intervals (CI) 1.06–1.55, P = 0.01; and HR 1.34, 95% CI 1.09–1.65, P = 0.006], respectively].13 There are two possible explanations for these unexpected results, over and above chance. First, positive airway pressure therapy might have detrimental effects on cardiac function in certain HF patients, particularly when pulmonary wedge pressure is low, and where left ventricular systolic function is very poor.13 However, there was no increase in the risk of HF hospitalization or death from pump failure in SERVE-HF; neither was the excess mortality confined to the first few months of therapy. The second explanation may be that CSA (and more specifically, CSR) might be part of a compensatory mechanism in chronic HF, and therefore reducing CSR events may be harmful, presumably by affecting the autonomic balance and/or cellular and organ electrophysiological properties. The increased risk of death in SERVE-HF appears to be largely confined to patients who died without a preceding hospitalization, suggesting sudden death (and presumably an arrhythmic mechanism). In the light of the unexpected results of the SERVE-HF trial, other treatment modalities for SDB in chronic HF might constitute an interesting alternative. The positive influence of body position on the severity of SDB in the general population has been recognized for some time.14, 15 However, positional effects on SDB have not been subject to detailed study in HF patients, other than the potential impact of rostral fluid shift on the severity of SDB.16 In the present issue of this journal, Pinna et al.17 publish data on the effect of sleeping position on the severity of SDB in patients with chronic HF in a prospective, observational study. In total, 267 stable, symptomatic HF patients with reduced LVEF were screened for the presence of SDB using outpatient polysomnography. Patients were eligible for the study when clinically significant SDB was present (AHI ≥15). Ultimately, 120 HF patients with moderate to severe SDB were included in the study. For all analyses, patients were subdivided based on their SDB phenotype (i.e. predominantly CSA or predominantly OSA). The two subgroups were comparable with respect to demographics, clinical characteristics and respiratory indices but predominant CSA was found in 76% of those with SDB. ‘Positional’ SDB, defined as a greater than 50% reduction in AHI when in the lateral position compared with the supine position (measured using a validated body position sensor) was present in 53% and 76% of patients with CSA and OSA, respectively. For those with such a positional effect in CSA, the AHI dropped from 47.4 (IQR 37.6–56.0) to 19.3 (IQR 11.9–33.3), and for those with OSA, the AHI dropped from 50.3 (IQR 36.9–67.6) to 10.4 (IQR 7.0–18.5) (both P < 0.0001). The effect of sleeping position on AHI was more pronounced in the OSA group compared than in the CSA group (P = 0.027), presumably because of the positional effect on the likelihood of the upper airway collapsing. Moreover, the authors state that the degree of positional effects was negatively correlated with the severity of SDB (i.e. less marked effect of positional change in patients with more severe SDB). The authors conclude that the lateral sleeping position has favourable effects on the severity of SDB, especially in patients with OSA, and that positional therapy can be considered in HF patients with positional SDB (given the high prevalence of this type of SDB in patients with chronic HF). Indeed, positional therapy seems to be at least equivalent to continuous positive airway pressure therapy regarding improvement in AHI, sleep quality, and oxygen desaturation in otherwise healthy subjects with positional OSA.18 To date, there has only been one small non-randomized study of the effect of positional therapy in HF patients with SDB, in 25 patients (predominantly men) with a reduced LVEF and CSA.19 In this study by Joho et al.,19 ultimately seven patients having position-dependent CSA received a one-night treatment of positional therapy using the ‘tennis ball technique’. This therapy consisted of the patient wearing a chest belt with a tennis ball sewn into the belt to reduce the likelihood of the patient sleeping in the supine position.20 Patients showed a significant decrease in AHI (i.e. from 23 ± 16 at baseline to 13 ± 11 after the treatment night, P < 0.05) and a trend towards lower plasma BNP levels (P = 0.07). More long-term, randomized studies using larger HF patients cohorts are definitely warranted to elaborate the effect of this inexpensive and straightforward positional therapy, given the beneficial effects of this approach in typical OSA.18 Possible explanations for the significant effect of position change on SDB severity are partly different for the two main SDB phenotypes. In general, for both CSA and OSA, an increased instability of ventilatory control (i.e. increased loop gain) has been observed, increasing the propensity to develop (sleep-)disordered breathing.21, 22 For CSA, the decrease in functional residual capacity observed when moving to the supine position might thereby worsen SDB.23 Gravitational differences between the lateral and supine position regarding the degree of fluid shift towards and in the lungs are most likely irrelevant. The AHI changes almost immediately after changing body position; rostral fluid redistribution cannot take place in such a short time-frame.24 In patients with OSA, upper airway collapsibility is likely to vary when body position changes, which is mainly explained by gravitational effects on pharyngeal tissue.25 Although the SERVE-HF study demonstrated an adverse effect of ASV on all-cause and cardiovascular mortality in chronic HF patients with reduced LVEF, the results of this landmark study should not be extrapolated directly to other populations. First, the prognostic consequences of positive airway therapy in HF patients with preserved ejection fraction (HFpEF) and SDB are unclear. For example, only one small, prospective, randomized trial with 36 symptomatic HF patients with a LVEF >50% and significant SDB has published results on the effect of ASV therapy. After a follow-up of 6 months, ASV therapy significantly improved surrogate endpoints such as New York Heart Association (NYHA) functional class, cardiac diastolic function Doppler echocardiographic indices, arterial stiffness, and plasma BNP levels. Adaptive servo-ventilation therapy was the only independent predictor of cardiac events (HR 0.58, 95% CI 0.18–0.80, P = 0.016).26 Larger studies are necessary to determine the true effect on outcome for such patients. Second, the effects of ASV therapy in predominantly OSA in systolic HF needs to be elucidated, particularly as in milder HF OSA is the predominant subtype of SDB.27 This patient group is currently being enrolled in the Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure trial (ADVENT-HF, NCT01128816), along with a smaller group of patients with predominantly CSA. In addition, this study is using a different ASV algorithm than that used in SERVE-HF. The results of the SERVE-HF trial clearly demonstrated, that improvement in patient outcome along with safety should always be a high-priority issue for any intervention in HF, whether device or drug, and over-reliance on surrogate endpoints should be avoided. SERVE-HF suggests that we do not understand the relevance of CSA in patients with systolic HF and further research is needed. The effect of implantable technologies that at least partially treat CSR (such as phrenic nerve stimulation therapy)28 will be interesting, particularly as it treats CSR by pacing the diaphragm rather than applying positive airway pressure. However, the effect on respiratory parameters cannot be safely extrapolated to harder endpoints, such as death. In addition to device therapy, pharmacological approaches are the subject of study in HF patients with CSA. For example, acetazolamide (a mild diuretic with respiratory-stimulating effects) has been shown to reduce CSR and improve oxygen saturation in 12 HF patients.29 A small (n = 85) randomized study addressing the effect of acetazolamide on the severity of SDB in HF is currently being conducted [Predicting Successful Sleep Apnoea Treatment with Acetazolamide in Heart Failure Patients (HF-ACZ), NCT01377987]. This is an exciting time for the clinical and scientific community studying SDB in HF. Given the substantial burden of SDB in HF, we should be encouraged by recent studies to further assess a range of treatment options (both pharmacological and non-pharmacological) in larger, long-term randomized studies. In addition a better understanding of the role of CSR is needed – is this a maladaptive response by a body in crisis, or is it something that is at least partially adaptive and that should not be treated? As the study of Pinna et al.17 clearly shows, the simple concept of body position during sleep has significant effects on the severity of SDB in patients with HF. Strange as it may seem, in selected patients positional therapy might be a cheap, easy to use alternative or supplementary technique for the treatment of SDB in patients with HF. More research is urgently needed in this field.