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Review: Sleep-Disordered Breathing in Heart Failure

Simon G Pearse and Martin R Cowie

Imperial College London and Royal Brompton Hospital, London, UK.

Key-words: heart failure; sleep disordered breathing; diagnosis; treatment

Address for correspondence:

Professor Martin R Cowie MD MSc FRCP FRCP (Ed) FESC

Professor of Cardiology

Imperial College London (Royal Brompton Hospital)

Dovehouse Street

London SW3 6LY

T: +442073518856

F: +442073518148

E: m.cowie@imperial.ac.uk

Acknowledgement: MRC’s salary is supported by the NIHR Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital, London.

Declaration of interests: MRC is the co-Principal Investigator of the SERVE-HF Study, funded by ResMed, and has received research grants and honoraria for speaking on sleep disordered breathing from ResMed, and consultancy fees from Respicardia and Sorin. SGP’s salary is funded by Boston Scientific.

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Abstract: 241 words

Abstract

Sleep-disordered breathing - comprising obstructive sleep apnoea (OSA), central sleep apnoea (CSA), or a combination of the two - is found in over half of heart failure (HF) patients and may have harmful effects on cardiac function, with swings in intra-thoracic pressure (and therefore preload and afterload), blood pressure, and sympathetic activity, and repetitive hypoxaemia. It is associated with reduced health-related quality of life, higher health care utilisation, and a poor prognosis. Whilst continuous positive airways pressure (CPAP) is the treatment of choice for patients with daytime sleepiness due to OSA, the optimal management of CSA remains uncertain. There is much circumstantial evidence that the treatment of OSA in HF patients with CPAP can improve symptoms, cardiac function, biomarkers of cardiovascular disease, and quality of life, but the quality of evidence for an improvement in mortality is weak. For systolic HF patients with CSA, the CANPAP trial did not demonstrate an overall survival or hospitalisation advantage for CPAP. A minute-ventilation targeted PAP therapy, adaptive servo-ventilation (ASV), can control CSA and improves several surrogate markers of cardiovascular outcome, but in the recently-published SERVE-HF randomised trial, ASV was associated with significantly increased mortality and no improvement in HF hospitalisation or quality of life. Further research is needed to clarify the therapeutic rationale for the treatment of CSA in HF. Cardiologists should have a high index of suspicion for SDB in those with HF and work closely with sleep physicians to optimise patient management.

Introduction

Heart failure (HF) affects around 2% of the adult population in developed countries; a figure that rises to 10% in those over 70 years (1). Despite advances in therapy, HF continues to confer a poor prognosis and more than half of patients hospitalised for HF die within 5 years (2).

Sleep-disordered breathing (SDB) is increasingly recognised as a marker of poor prognosis in patients with HF and a disease process that may accelerate the downward spiral of cardiac dysfunction. Over 50% of patients with HF (with either preserved or reduced ejection fraction) have SDB, which is around ten times the rate in the general population (3–5). In current clinical practice, many patients remain undiagnosed. Older age, male gender, increased body mass index, lower ejection fraction and the presence of atrial fibrillation are independent predictors for the presence of SDB (6).

Despite increasing evidence of the impact of SDB, the European Society of Cardiology guidelines on heart failure mention it only as a potential co-morbidity and suggest that treatment “might be considered” (7). This review describes the aetiology and pathophysiological effects of SDB, the current approach to diagnosis, and the treatment options available.

Aetiology and classification of sleep-disordered breathing

SDB includes obstructive sleep apnoea (OSA), central sleep apnoea (CSA), or a combination of both. In OSA, there is collapse of the pharynx during sleep with consequent upper airway obstruction, often with snoring. Predisposing factors include obesity, a short neck and retrognathism. In HF, rostral shift of fluid during sleep leads to pharyngeal oedema, which may exacerbate the tendency to obstruction (8). In CSA, the underlying abnormality is in the regulation of breathing in the respiratory centres of the brainstem. In normal physiology, minute ventilation during sleep is primarily regulated by chemoreceptors in the brainstem and carotid bodies which trigger an increase in respiratory drive in response to a rise in arterial carbon dioxide (PaCO2), thus maintaining PaCO2 within a narrow range. Patients with HF and CSA tend to have an exaggerated respiratory response to carbon dioxide, associated with excess sympathetic nervous activity, so that modest rises in PaCO2 that may occur during sleep result in inappropriate hyperventilation (9,10). This drives the PaCO2 below the “apnoeic threshold”, at which point the neural drive to respire is too low to stimulate effective inspiration and an apnoea (complete pause in breathing) or hypopnoea (partial reduction in airflow) ensues. PaCO2 subsequently rises and the cycle is repeated. This overshoot of the homeostatic feedback loop is exacerbated by the prolonged circulation time between the alveoli and the brainstem seen in more severe HF, so that the PaCO2 sensed in the brainstem may not accurately reflect the PaCO2 at the lung. CSA is associated with increased sympathetic nervous activity, more severe cardiac dysfunction, and lower resting PaCO2 (11). The more prolonged the circulation time, the longer the duration of the hyperpnoeic phase of CSA (12). In addition, pulmonary congestion and oedema lead to stimulation of J receptors in the lungs, triggering reflex hyperventilation. A tendency to progress from OSA to CSA over the course of the night has been observed, thought to be secondary to progressive pulmonary congestion and deteriorating haemodynamics, which may itself be exacerbated by the SDB (11). Typically cyclical ‘waxing and waning’ CSA is termed Cheyne-Stokes respiration.

Apnoea is currently defined as a reduction in airflow by at least 90% of pre-event baseline for at least 10 seconds; hypopnoea as a reduction in airflow by at least 30% from baseline for at least 10 seconds, associated with a fall in arterial oxygen saturation of at least 3%, or an arousal from sleep (13). In OSA, there is evidence of on-going respiratory effort throughout the apnoeic-hypopnoeic event, often with paradoxical movement of the chest and abdomen as breathing against a closed airway is attempted. In contrast, apnoeas and hypopnoeas in CSA are accompanied by a marked reduction or cessation of respiratory effort. (Figure 1). The average number of apnoeic and hypopnoeic events per hour of sleep is termed the ‘apnoea-hypopnoea index’ (AHI). Up to 5 events/hour is defined as ‘normal’, 5-15/hour ‘mild’, 15-30 ‘moderate’ and >30/hour ‘severe’ SDB. Those in whom >50% of events are obstructive are labelled as ‘predominantly’ OSA, and if >50% of events are central such a patient is labelled as ‘predominantly’ CSA.

Pathophysiological consequences of sleep-disordered breathing in heart failure

OSA may accelerate the progression of HF in several ways (Figure 2). The negative intrathoracic pressure generated by the respiratory muscles trying to inspire against a closed airway increases venous return to the right heart, increasing pre-load and causing the septum to shift to the left which may compromise left ventricular (LV) function. The ability of the failing LV to cope with enhanced pre-load is further impaired by the increased trans-mural pressure during episodes of negative intrathoracic pressure, which increases the afterload. Apnoea and hypopnoea activate the sympathetic nervous system – serum catecholamines and muscle sympathetic nerve activity are higher in those with OSA and HF than matched controls with HF only (10,14). Patients with OSA experience swings in blood pressure and heart rate, which affects shear stress on the vascular endothelium and, in combination with recurrent hypoxaemia, may lead to endothelial dysfunction - increased expression of the vasoconstrictor endothelin-1 and a blunted response to cholinergic vasodilators have been reported (15). The consequent vasoconstriction, hypertension and changes in protein regulation and fibrosis in the myocardium may adversely affect left ventricular diastolic function (16). Other changes associated with OSA are an increase in circulating C-reactive protein concentration and enhanced platelet aggregation (17,18).

In contrast to OSA, CSA is typically considered a consequence rather than a cause of HF (19). However, while those with CSA do not experience such marked episodes of negative intrathoracic pressure as seen in OSA, diurnal sympathetic activation is higher in those with HF and CSA than matched controls with HF only (10). Just as in OSA, episodes of apnoea or hypopnoea in CSA are associated with oscillations in heart rate, blood pressure, hypoxaemia and possibly endothelial stress. C-reactive protein concentrations, known to be associated with vascular events, are also elevated in those with CSA (20).

Both forms of SDB appear to be associated with an increase in sympathetic activity and this is likely to be harmful – leading to additional peripheral vasoconstriction, tachycardia and renin-angiotensin-aldosterone system stimulation with salt and water retention. In the neurohormonal model of heart failure, damping of this response is considered vital to improving the longer-term prognosis. Therefore SDB may be a new therapeutic target in heart failure – additional to the effects of neurohormonal modulators such as beta-blockers, angiotensin converting enzyme inhibitors and aldosterone antagonists.

Patients with SDB are at increased risk of malignant ventricular arrhythmia (21). Those with OSA are most likely to receive ICD therapies at night (hazard ratio (HR) for appropriate overnight ICD therapies 3.0 [CI 1.28-7.06, p=0.03] for those with moderate to severe OSA relative to daytime risk), whilst those with CSA or no SDB are more likely to experience appropriate ICD therapies during the day (22). Enhanced sympathetic activity, alongside changes in intrathoracic pressure and haemodynamic disturbances, are thought to contribute to this.

The effect of SDB on clinical outcomes in HF

Given the pathophysiological consequences of SDB, it is perhaps unsurprising that SDB is linked to poor outcomes in those with HF and in the general population. The Sleep Heart Health study followed 4422 patients free of heart disease at baseline for almost 9 years (23). Those with severe OSA had more than twice the all-cause mortality during follow-up. However, severe OSA was found to be associated with an increased risk of coronary events only in men less than 70 years of age. OSA was also associated with a 58% increase in risk of developing HF de novo in men, but not women. In another study, only those with OSA and HF of ischaemic aetiology were at increased risk of death over a mean follow up of 32 months (HR 3.03, CI 1.04-8.84, p=0.043), possibly related to the vascular stress induced by OSA (24). Hypertension is also common amongst those with OSA, with absent nocturnal dipping a frequent feature. Despite this, the high prevalence of confounding factors such as obesity and metabolic syndrome in those with OSA has made proving a causal relationship difficult (25).

CSA is also a marker of poor prognosis in HF – in one study mean survival for those with at least moderate systolic dysfunction and CSA (mean AHI 34/hr) was 45 months vs. 90 months for those without CSA (AHI 12.5 events per hour or a high pre-test probability based on clinical history (Figure 3).

In the past 10 years, there has been increasing interest in whether pacemaker algorithms could be developed to accurately detect and quantify SDB (41). It is possible to continually measure thoracic impedance between the right ventricular lead tip and the generator. On inspiration, the increased volume of air in the chest increases thoracic impedance with the inverse occurring on expiration, with consequent proportional changes in detected potential difference. SDB diagnostic algorithms are now commercially available in certain pacemakers. The DREAM study reported a sensitivity of 88.9% and specificity of 84.6% for the diagnosis of moderate to severe SDB (42). Studies on other device platforms are currently underway (including NCT02204865). With the additional facility to download implanted device data remotely, it is hoped that changes in SDB severity may be useful as an early marker of HF decompensation, providing a window of opportunity to optimise treatment. Further research is required.

Treatment options for patients with SDB and heart failure

Obstructive Sleep Apnoea

Continuous positive airway pressure (CPAP) is well-established in clinical guidelines for the treatment of symptomatic OSA in the non-heart failure population (43). CPAP provides continuous pressure (typically 5-10cmH20) throughout the respiratory cycle. The resultant positive pressure prevents the pharynx from collapsing and thus reduces apnoea and hypopnoea. It may have additional benefits in HF, as positive end-expiratory pressure prevents alveoli collapsing secondary to pulmonary oedema and maintains alveoli at a greater diameter, thus reducing the work of breathing. It also increases alveolar recruitment, improves gas exchange and reduces right to left intrapulmonary shunting of blood. The positive intrathoracic pressure reduces venous return (pre-load) and LV trans-mural pressure (afterload) and may therefore benefit cardiac function in some patients.

There have been many studies of CPAP for OSA, with some studies examining HF specifically. CPAP improves daytime somnolence, some measures of quality of life and physical vitality scores (44). In a randomised control trial of 55 patients with HF and OSA, nocturnal CPAP for 3 months improved LV ejection fraction (by 5.0±1.0% vs. 1.0±1.4%, p=0.04) and reduced urinary noradrenalin excretion (45). Kaneko and colleagues demonstrated that even one night of CPAP lowers systolic blood pressure (126±6 to 116±5mmHg, p=0.02), reduces heart rate (68±3 to 64±3/min, p=0.007) and improves LV end-systolic diameter (54.5±1.8 to 51.7±1.2mm, p=0.009) in those with OSA and HF, compared to standard medical therapy (46). Another study with echocardiographic and cardiac magnetic resonance follow-up demonstrated that CPAP improves right ventricular function, left ventricular mass and pulmonary hypertension after 3 months of treatment. These improvements persisted at 1 year (47). An observational study (88 patients) of CPAP versus medical therapy for those with HF and moderate to severe OSA demonstrated a significantly higher rate of hospitalisation or death in the non-CPAP group (HR 2.03, CI 1.07 to 3.68, p=0.03) compared to those treated with CPAP (48). Patients who were not compliant with CPAP also had a higher risk of the composite endpoint. Two other large registry studies found similar results (49,50). Perhaps because of the lack of appropriately-sized randomised outcome studies, no international heart failure guidelines yet exist for the use of CPAP in patients with HF and OSA in the absence of daytime somnolence. The effect of CPAP on hypertension, stroke and myocardial infarction risk is debated and beyond the scope of this review.

Therapy with continuous nocturnal oxygen has been used in those intolerant of CPAP. A meta-analysis of 14 studies concluded that oxygen therapy does reduce overnight desaturations, but prolongs apnoeas and hypopnoeas (51). CPAP was shown to be superior to oxygen in reducing AHI in OSA and the effect of oxygen on prognosis in OSA is not known.

More generally, optimisation of HF therapy improves cardiac output and reduces peripheral oedema, presumably minimising rostral fluid shift and pharyngeal oedema. The impact on AHI is unknown. Weight loss significantly reduces AHI in obese patients with OSA. Meta-analysis of seven randomised controlled trials shows that weight loss programmes result in a mean reduction in AHI of 6.04 events/h (CI -11.18 to -0.90) (52). However, patients with HF and OSA are less likely to be obese and the impact in this group is not known. In patients with retrognathism, mandibular advancement devices may also significantly improve AHI in OSA (53).

Central Sleep Apnoea

The optimal management of CSA in HF is less well determined than OSA. Medical therapy with acetazolamide has been reported to reduce AHI, which may be due its respiratory stimulating properties as well as a diuretic action (54). Whether furosemide achieves the same effect is unknown, although reduction in pulmonary congestion might be expected to lessen CSA by reducing pulmonary J-receptor stimulation. Cardiac resynchronisation therapy (CRT) significantly reduces AHI in CSA with HF (55). Meta-analysis of trials investigating the effect of CRT on CSA reports a mean reduction in AHI of 13.05/h (CI −16.74 to −9.36; p ................
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