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Sleep-disordered breathing and chronic heart failure: changing position may be important
Haye H. van der Wala, Martin R. Cowieb, Peter van der Meera
Word count: 2,394
From the a Department of Cardiology, University Medical Center Groningen, University of
Groningen, Groningen, the Netherlands; bImperial College London (Royal Brompton Hospital),
London, United Kingdom
Corresponding author: Peter van der Meer, MD, PhD, Department of Cardiology, Thorax Center,
University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, The
Netherlands. E-mail: [email protected].
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 healthcare 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
target6, 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).
SDB is common in heart failure, with a prevalence of up to 70%. The severity of OSA is
conventionally expressed as the apnoea-hypopnoea index (AHI). An apnoea is defined as a total
cessation of breathing for ≥10 seconds, whereas an hypopnoea is present when there is a ≥30%
reduction in respiratory flow for ≥10 seconds, 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 (OSA), is characterised 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. Additionally, 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 due to
hypercapnia and hypoxia and frequent arousals from sleep. In addition, parasympathetic tone
appears to be significantly reduced when OSA is present. These neurohumoral abnormalities
persist during the day also, and may accelerate further deterioration in cardiac function, and
increase the risk of arrhythmia.8 Additionally, intermittent hypoxaemia caused by obstructive
episodes may 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 PaO2.7 Observational studies have shown
a two-fold increase in all-cause mortality in HF patients with untreated moderate OSA compared
to 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 comprise obesity (for men only), male sex,
and age (for women only).9 HF itself may have an influence on the pathophysiology of OSA, for
example due 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 due to 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. showed that known clinical risk factor profile for
SDB (i.e. age, sex, body mass index, left ventricular ejection fraction [LVEF], atrial fibrillation,
diuretic use, and Epworth Sleepiness Scale) explained only 17% of the variance of SDB in a
stable HF population.10
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 due to pulmonary congestion triggering a pulmonary irritant reflex.7
Additionally, 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 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 allcause 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 phenomenon12, 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 LV systolic function) symptoms cannot
reliably distinguish HF patients with CSA from those who do not have this.
Recently, the surprising results of SERVE-HF (Treatment of Sleep-Disordered Breathing with
Predominant Central Sleep Apnea 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 apnea (i.e. AHI
≥15/hour with predominantly central apnoeic events) were assigned to either adaptive servoventilation (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 [IQR 10.3 – 115.3] at baseline to 6.6 [0.0 – 50.8] at twelve months follow-up), a
statistically significant increase in both all-cause and cardiovascular mortality was observed in
the treatment arm (HR: 1.28 [95% 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. Firstly, 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 hospitalisation or death from pump failure in SERVE-HF, nor 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 hospitalisation,
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 current issue of this
journal, Pinna et al. publish data on the effect of sleeping position on the severity of SDB in
patients with chronic HF in a prospective, observational study.17 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 to 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
(11.9 – 33.3), and for those with OSA, the AHI dropped from 50.3 (36.9 – 67.6) to 10.4 (7.0 –
18.5) (both P<0.0001). The effect of sleeping position on AHI was more pronounced in the OSA
group compared to the CSA group (P=0.027), presumably due to the positional effect on the
likelihood of the upper airway collapsing. Moreover, the authors state that the degree of
positional effects was negatively correlated to 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., 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. Firstly, 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
the effect of ASV therapy. After a follow-up of six months, ASV therapy significantly improved
surrogate endpoints such as NYHA functional class, cardiac diastolic function Doppler
echocardiographic indices, arterial stiffness, and plasma BNP levels. ASV 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. Secondly, 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 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 therapy28) 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.
Besides 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 twelve 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 Apnea 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. 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, easyto-use alternative or supplementary technique for the treatment of SDB in patients with HF.
More research is urgently needed in this field.
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