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European Journal of Heart Failure 2006 8(3):227-236; doi:10.1016/j.ejheart.2005.07.013
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© 2005 European Society of Cardiology

Heart failure and sleep apnoea: To sleep perchance to dream

Susana Ferreira, João Winck, Paulo Bettencourt* and Francico Rocha-Goncalves

Faculdade Medicina do Porto Portugal

* Corresponding author.pbettfer{at}esoterica.pt


   Abstract
Top
 Abstract
1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
Heart failure and sleep apnoea are major health problems with an increasingly recognized association; evidence suggests that sleep apnoea may play a role in the progression of heart failure. However, confounding factors such as obesity, hypertension and coronary heart disease make this relationship uncertain and an independent correlation remains unproven.

Diagnosis of sleep apnoea is suboptimal, as it is often asymptomatic and polysomnography is expensive and time-consuming. A simple and reliable screening protocol is required. All heart failure patients should be considered to be at high risk of sleep apnoea, as this association might be linked to adverse outcome. Continuous positive airway pressure has shown some beneficial effects, but long-term outcome and improvement in survival remains to be demonstrated.

Despite recent advances in the understanding of the complex relationship between heart failure and sleep apnoea, there are a number of areas requiring further investigation, which may have important implications for the management and prognosis of a significant number of patients.

Key Words: Heart failure • Sleep apnoea • Prognosis • Continuous positive airway pressure

Received December 22, 2004; Revised May 12, 2005; Accepted July 26, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
Sleep apnoea (SA) affects 2-5% of the general population [1,2], places a huge burden on health services and is responsible for daytime sleepiness, cognitive dysfunction, lower quality of life and increased risk of motor vehicle and occupational accidents [1-8]. Diagnosis of SA is suboptimal because it is often (50%) asymptomatic [2,5,6,9]. Overnight polysomnography is the diagnostic gold-standard [9], however, it requires significant expertise, is expensive and is often not widely available [3,4,9]. Continuous positive airway pressure (CPAP) is the treatment of choice [10-12], especially in symptomatic and/or severe cases [10-14].

SA is associated with increased cardiovascular risk and mortality [15-37]. Few studies have evaluated the association between SA and heart failure (HF), but a high prevalence has been reported (11-45%) [38-50]. Clinical data support the role of SA in the deterioration of ventricular function but whether this is an independent mechanism or mediated by hypertension, coronary heart disease or obesity is unclear. Whether treatment of SA leads to clinical improvement and reverses or slows ventricular dysfunction in patients with heart failure requires further investigation. The high prevalence of SA in HF populations, and its association with adverse outcome [47-49] raises the question of whether routine screening for SA should be performed in HF patients and highlights the need for a simple and reliable diagnostic protocol [38].

In this review we update the available evidence linking SA and HF, exploring pathophysiological relationships, diagnostic and treatment possibilities as well as prognosis.


   2. Definition of sleep apnoea
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
There are two major forms of SA-obstructive and central-with different pathophysiology, mainly distinguished by the presence or absence of respiratory effort [3-5,9]. Obstructive sleep apnoea (OSA) is characterized by repetitive partial and/or complete obstruction of the upper airway during sleep, despite ongoing respiratory effort [9]. It may result in oxygen desaturation, hypercapnia and arousals from sleep. Diagnosis and severity is based on clinical evaluation and polysomnography. There are specific questionnaires and scales (for example: the Sleep Disorder Questionnaire and the Epworth Sleepiness Scale) which evaluate symptoms like excessive daytime sleepiness, choking or gasping during sleep, recurrent awakenings, unrefreshing sleep, daytime fatigue and impaired concentration [51,52]. Overnight monitoring determines the number of obstructive breathing events during sleep (apnoea, hypopnoea and respiratory effort-related arousals (RERA) of 10 s or longer), defining the apnoea-hypopnoea index (AHI), i.e., the number of obstructive breathing events/hour of sleep [9]. If the AHI is greater than 5, SA is present and can be classified as mild [5-15], moderate [15-30] or severe (>30) [9]. Symptomatic patients are classified as having the syndrome of SA [9].

Central sleep apnoea (CSA) is characterized by recurrent apnoeic episodes in the absence of upper airway obstruction and respiratory effort [9]. It can be hypercapnic as in hypoventilation syndromes, or it can be normo/hypocapnic resulting from an increased ventilatory response to carbon dioxide (CO2) as is the case in HF [9]. Cheyne-Stokes respiration, characterized by periodic changes in tidal volume resulting in cycles of hyperventilation alternating with hypoventilation/apnoea in a crescendo-decrescendo pattern, is particularly associated with cardiac and neurological dysfunction [9].


   3. Epidemiology
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
In the Wisconsin Sleep Cohort Study, a prospective study of the cardiopulmonary disorders of sleep which enrolled 3513 participants, SA (AHI>5) was found in 24% of men and 9% of women and was symptomatic in 4% and 2%, respectively [1]. Snoring was reported in 40-60% and was associated with SA severity. Males and obese subjects were at higher risk of SA [1]. This study highlighted the prevalence of undiagnosed sleep-disordered breathing among adults, with a wide range of severity and the relevance of obesity as a potential modifiable risk factor.

Other studies have confirmed this observation and reported an even higher proportion of undiagnosed cases (75-80%), mainly in females who are also less likely to be evaluated and treated early [53]. The prevalence of SA increases with age, with a 2- to 3-fold higher prevalence in patients aged over 65 years [53]. Some data suggest that in older patients SA is more often of the central type [53].

Few studies have evaluated SA in HF patients, although the reported prevalence is between 11-45% [38-50]. This wide variability is probably due to the small number of patients in the different studies, the predominant inclusion of males, the quite different risk factors for SA, as well as the occurrence of other conditions that may affect breathing (for example: pulmonary disease, obesity) [38-40]. Also, the severity of ventricular dysfunction and the inclusion of patients with unstable HF may contribute to the huge differences in the reported prevalence of SA [38-40]. In HF patients, CSA is more frequent (40%), has been long recognized as a consequence rather than a cause of HF [15,19,38,39,46] and is associated with a poor prognosis [47-49]. However, the prevalence of OSA is also high (20%) [38,40-42]. Coexistence of both types and an overnight shift from obstructive to central apnoea has been reported [50], suggesting sequential stages related to HF severity [19,38,50]. A comparison between the characteristics of the two types of SA in HF is shown in Table 1.


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  		Table 1 Comparison between obstructive and central sleep apnoea in patients with heart failure

 
Javaheri and colleagues determined the prevalence and effects of SA in 42 ambulatory patients with stable HF [40]. In this population, the severity of left ventricular dysfunction was an independent risk factor for SA which was commonly occult and severe [45% had AHI>26) [40]. A higher prevalence of ventricular arrhythmia was also found in patients with HF and SA, mainly of the central type [40]. More recently, the same group prospectively evaluated a larger sample of HF patients (81 male), and found a prevalence of SA of 51% (with an average AHI of 44/h) [41]. These patients had a higher prevalence of atrial fibrillation (4 times higher) and ventricular arrhythmias and had significantly lower ejection fraction (22±8% vs 27±9%, p=0.01) [41]. Central type was more common (40% vs 11%) but there were no significant differences between these two groups, namely in relation to the severity of ventricular dysfunction [41]. The authors suggested that the interaction between SA and left ventricular dysfunction could result in a vicious cycle, further increasing morbidity and mortality in patients with HF. Non-diagnosis of SA in this population might be related to the predominance of CSA, which is more frequently asymptomatic [41].

In a large epidemiological study, the Sleep Heart Health Study, (N=6424), 16% of the participants had one or more manifestations of cardiovascular disorders [23,24]. Patients with SA were found to have a 2.38 increased risk of HF, exceeding the risk of other cardiovascular diseases including hypertension [24]. CSA accounted for a small proportion of cases and the association between the AHI and HF was not attenuated after excluding CSA patients [24].

Sin et al. evaluated 450 patients with HF (382 men) and found a high prevalence of SA-CSA 32.9%, OSA — 37.3% [42]. In this sample, men were more commonly affected by both types of SA [42]. Risk factors for CSA were: atrial fibrillation (OR 4.13, 95% CI 1.53-11.14), age>60 years (OR 2.37, 95% CI 1.35-4.10) and hypocapnia (pCO2<38 mmHg — OR 4.33, 95% CI 2.50-7.52) [42]. Risk factors for OSA differed according to sex: obesity was the greatest risk factor in men (mean body-mass index (BMI)>35 kg/m2 — OR 6.10, 95% CI 2.86-13.00) and aging in women (age>60 years — OR 6.04, 95% CI 1.75-20) [42].

The prevalence of SA in HF patients with isolated diastolic dysfunction has only been evaluated in a small study and was reported to be 55%, mainly OSA (64%) [43]. This HF sample had a high prevalence of hypertension (85%) and obesity (BMI 28±3.2 kg/m2) [43] however, there were no differences between patients with or without SA, suggesting that these two factors were unlikely to account for the differences in sleep disorders [43]. Patients with SA had a more prolonged deceleration time (282±31 ms vs 236±40 ms, p<0.05), while isovolumic relaxation time (IVRT) and E/A ratio did not differ significantly [43]. Furthermore, a lower minimum percentage of oxygen saturation but not AHI was associated with a lower E/A ratio and a prolonged IVRT, also indicating more severe diastolic dysfunction in patients with SA [43].


   4. HF and SA: potential pathophysiological links
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
Most pathophysiological studies of HF have focused on the awake patient, presupposing that the harmful effects of HF are quiescent during sleep [38]. However, SA disrupts this cardiovascular rest state and may play a role in the development and/or progression of HF [38,54]. The pathophysiology remains uncertain but an independent effect from hypertension seems to be present and several mechanisms have been suggested based in animal models [55-57] and human studies [26,27] (Table 2).


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  		Table 2 Potential mechanisms for development and/or progression of heart failure in patients with sleep apnoea

 
Patients with SA have activation of neurohumoral and inflammatory systems that are also activated in HF. In SA, several factors (hypoxia, hypercapnia, arousals) activate the sympathetic nervous system (SNS), especially in HF patients [58-61]. This sympathetic activation leads to hypertension, decreased heart rate variability, vasoconstriction, myocardial hypertrophy and injury, even in the absence of high blood pressure [19,20,38,58,60-64]. Intermittent hypoxia may directly impair cardiac contractility [65], further activate the SNS [66], leading to myocardial ischaemia and arrhythmias [38] and might increase the production of reactive oxygen species with subsequent ischaemia-reperfusion lesions [67,68].

Increased levels of atrial natriuretic peptide (ANP) have been observed in SA patients, suggesting an increase in atrial tension [69]. There are conflicting results about changes in levels of B-type natriuretic peptide (BNP) and whether it has a precise role or just reflects blood pressure variations [70,71]. In this group of patients, inflammatory markers, C-reactive protein (CRP) [72], interleukin-6 (IL-6) and tumour necrosis factor-P (TNF-P) [73,74] are also increased. Moreover, increased levels of ICAM-1 and VCAM-1 [75] and decreased nitric oxide [75-77] have been reported, suggesting endothelial injury [75,78] and a state of increase oxidative stress [20,67]. There is also evidence that SA leads to a prothrombotic state with increased levels of fibrinogen, plasminogen activator inhibitor and enhanced platelet activity and aggregation [20].

Left ventricle wall thickness has been shown to be increased in normotensive patients with OSA compared to normotensive control subjects, suggesting that OSA by itself can lead to left ventricular hypertrophy independently of the effect on blood pressure [79]. Repeated negative intrathoracic pressure swings during obstructive apnoeas lead to increased wall tension and subsequent increase in left ventricle (LV) afterload. Overdistention of the right ventricle leads to a decrease in preload caused by a leftward shift of the intraventricular septum [80-86]. The net effect is a reduction in stroke volume and cardiac output which is more pronounced in patients with HF [86]. In a canine model, OSA was associated with sustained decrease in LV systolic performance in previously healthy animals [55]. These results suggest that OSA may be involved in the initiation of the HF process.

SA can cause pulmonary hypertension (PH) leading to cor pulmonale and right ventricular dysfunction [87-89]. The potential mechanisms involved are increased pulmonary vascular tone secondary to hypoxic pulmonary vasoconstriction, hypoxia-induced endothelial dysfunction and pulmonary vascular remodelling [87-93]. PH is found in 27% to 39% of patients with OSA, tends to be mild and its presence is associated with a lower daytime PaO2 and oxygen desaturation during sleep [90]. In animal models, intermittent hypoxic episodes like those mimicking SA, lead to pulmonary artery remodelling and PH [92]. A small study found a strong association between PH and SA in obese patients with HF. This suggests that SA should be considered in HF patients with severe PH [93]. Moreover, treatment with CPAP tends to reduce PH in OSA [94,95].

There are pathophysiological links between HF and SA, suggesting HF can induce SA. Breathing is normally controlled by a negative-feedback system in which an increase in CO2 stimulates breathing and a decrease inhibits it. A prolonged circulation time proportionally related to dysfunction severity and recumbent position can lead to pulmonary congestion, increase sensitivity of chemoreceptors, hyperventilation, hypocapnia, supression of the respiratory drive and subsequent CSA [39,78,96-98]. Patients with HF may have increased sensitivity to CO2 which elicits a large ventilatory response when its partial pressure rises [78]. The consequent hyperventilation, by driving CO2 below the apnoeic threshold, results in CSA [78]. As a result, CO2 rises again which leads to an increase in ventilation [78]. In this way, cycles of central apnoea and hyperventilation recur during sleep — Cheyne-Stokes respiration [78].

An accumulation of fluid in pharyngeal tissues and decreased drive to the pharyngeal dilator muscle can predispose to OSA in patients with HF [38]. Tkacova et al. suggested that the deleterious effects of repeated obstructive apnoeas can cause deterioration of ventricular function and an overnight shift to central apnoea [50].

All these observations suggest that SA leads to activation of different systems implicated in the genesis of cardiovascular disease. Whether SA could be an independent risk factor for HF is not clarified yet.


   5. Diagnosis
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
6. Treatment
 7. Prognosis
 8. Conclusion
 References
 
Polysomnography is the gold-standard diagnostic test for SA, however, it requires technical expertise, is time-consuming, is not always readily accessible and has high-cost. An alternative, simpler screening protocol is therefore desirable [3,4,9]. The interest in alternative diagnostic approaches, such as the use of clinical prediction rules, overnight oximetry and portable monitors, has increased [3,9,99-107] but evidence is still insufficient in patients with HF.

A standard polysomnography consists of an overnight study with at least two channels of electroencephalogram and electro-oculogram, submental (and eventually tibialis) electromyogram, respiratory airflow, respiratory effort recording (thoracic and abdominal breathing movements), oximetry and electrocardiography [9]. Body position and snoring are also frequently monitored [9,99]. For patients with high pre-test probability of SA, an alternative approach can be used-the "split-night" study-where the first part of the night is used to establish the diagnosis and the latter part for titration of CPAP [101].

Combination of clinical variables such as risk factors for SA, suggestive symptoms, BMI, neck circumference, thyro-mental distance and pharyngeal grade, have a high sensitivity to predict SA (78-95%) but a low specificity (41-63%) [101]. The Epworth Sleepiness Scale (ESS) is a simple, self-administered questionnaire that helps to define the clinical severity [51]. Home oximetry has a high sensitivity (98%) but a low specificity (48%), which can be increased (88%) by automated analysis of a digitized oximetry signal [100-103]. A negative oximetry is helpful in ruling out the diagnosis of SA in patients clinically suspected of having the syndrome, reducing the probability from 54% to 3% [100-103]. Nevertheless, this method only detects apnoeic events with desaturation and, in some cases, repeated arousals and sleep fragmentation can be the only consequences of SA [101].

Gurubhagavatula et al. retrospectively compared the accuracy of a two-stage risk stratification algorithm for SA in a population without known HF, using a questionnaire plus nocturnal pulse oximetry, against using polysomnography [104]. The model identified cases of SA with 95% sensitivity and severe apnoea with 97% specificity [104]. This strategy has the potential to identify patients with low risk for SA for whom polysomnography is not warranted and the subset of patients with risk for severe SA who should be prioritized for early testing and treatment. In a more recent study, the same authors demonstrated that this two-stage strategy was also a reliable screening test in commercial drivers [107].

Domiciliary sleep studies are reliable diagnostic procedures that are easier and cheaper than in-laboratory polysomnography [108], but are not yet fully validated in patients with HF. However, in a recent study involving 75 patients with stable systolic HF, home respiratory polygraphy was found to have a high diagnostic accuracy (78.9-84%) when compared with the gold-standard, with high sensitivity (68.4-82.5%) and specificity (88.6-97.8%) [109]. Moreover, it was also able to correctly identify both types of SA. These data suggest that domiciliary studies may be a useful screening tool for SA in HF patients, but further investigation is needed.

A clinical decision rule based on risk factors for SA, symptoms and anthropometric measurements with or without overnight oximetry may help to select the patients in whom polysomnography should be performed and those who should be treated. A higher level of awareness should be maintained in patients with comorbidities such as HF, as they are at increased risk and may lack conventional symptoms. Until other methods, such as home ambulatory monitoring, are validated in this setting, in-laboratory polysomnography remains the diagnostic gold-standard.


   6. Treatment
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
7. Prognosis
 8. Conclusion
 References
 
Despite advances in pharmacological therapy, morbidity, mortality and rates of hospitalisation for HF remain high [110,111]. Identification of all treatable comorbidities including SA is important.

In SA patients, conservative measures include a lateral sleeping position, avoidance of alcohol and sedatives and weight loss.

CPAP is the treatment of choice for SA [12]. It has been evaluated in patients with stable HF with both types of SA and it has been shown to improve functional capacity (NYHA class, 6 min walk-test), quality of life and cardiac function [112-121] and to reverse most of the above mentioned pathogenic mechanisms [122-136]. It provides non-invasive mechanical assistance to the failing heart by several mechanisms: increasing intrathoracic pressure and reducing LV transmural pressure [122] which reduces LV afterload [127], augmenting preload, stroke volume and cardiac output [126]; reducing mitral regurgitation and ANP levels [69], possibly through reverse remodelling; decreasing sympathetic tone [130,131] and improving nocturnal baroreflex sensitivity [129]; assisting inspiratory muscles and increasing end expiratory lung volume [126]. The successful treatment of OSA has also been shown to improve blood pressure control [133-136]. In patients with SA, compliance with CPAP treatment is between 50% to 80% and the average duration of use ranges from 3.4 to 4.5 h per night [113].

6.1. Obstructive sleep apnoea
Malone et al. reported a significant improvement in LVEF after 1 month of CPAP [114]. However, this study was not randomized, lacked a control group, included only patients with non-ischaemic dilated cardiomyopathy and did not assess other cardiovascular variables. The same group later carried a larger randomized study (N=24) and found similar results [113]. Patients treated with 1 month of CPAP had a 9% improvement in ejection fraction (p<0.001) which was significantly greater than in the control group (p=0.009) [113]. They also had a significant reduction in daytime systolic blood pressure. The presence of OSA was not associated with daytime sleepiness, indicating that patients with HF, despite having no symptoms related to SA, can have benefits from CPAP [113]. This observation raises the issue of screening for SA in HF patients.

Mansfield et al. confirmed and extended these findings in a similar study of 55 patients with moderately impaired left ventricular systolic dysfunction and mild to moderate OSA [115]. Patients were randomized to 3 months of CPAP vs usual care [115]. Among the 40 patients who completed the study, there was a significant (5%) improvement in ejection fraction in the CPAP group (p=0.04) [115]. The smaller improvement in ventricular function observed in this study (5% compared with 9% reported by Kaneko et al. [113]) may have been due to the less severe OSA (AHI 26 vs 42/h) and higher baseline LV ejection fraction (EF) (35% vs 28%). CPAP reduced overnight urinary norepinephrine levels and improved general and disease-specific quality of life but improvement in dyspnoea scores or exercise capacity was not observed [115]. Awake blood pressure was unchanged, in contrast with the previous reported study, suggesting that hypertension control is not the most important mechanism in improving systolic function.

These studies, evaluating patients on optimal therapy for HF, suggest that CPAP can improve cardiac function in HF patients with systolic dysfunction. However, there are some limitations as the studies only included a small number of patients (N=8-55), who were predominantly male, only moderate to severe cases of SA and only patients with systolic dysfunction, there was no placebo group (sham CPAP) [137] and long-tem effects and mortality were not evaluated.

Selection of treatment should be based on AHI but should also consider the severity of symptoms and coexisting illnesses. An accurate diagnosis and a lower threshold for treatment is needed in patients with cardiovascular disease [3]. Whether "nonsleepy sleep apnoeics" should be treated is not clear but, if SA is demonstrated to be a new cardiovascular risk factor, then CPAP might be a successful preventive measure and treatment indications may be expanded to include asymptomatic patients, at least in higher risk populations like HF [23]. Larger randomized trials are warranted to evaluate the long-term outcome after CPAP in patients with HF and SA.

Oral appliances such as mandibular and tongue advancements can be useful but they are less effective than CPAP [3]. They should be considered for patients who refuse or fail to tolerate CPAP and for the mildest cases. They have been proven effective in a group of patients with HF and SA [138].

Surgical procedures for OSA include uvulopalatopharyngoplasty, laser-assisted uvulopalatopharyngoplasty, tonsillectomy, partial resection or ablation of the tongue, major reconstruction of the mandible or maxillae and tracheostomy [3]. Tracheostomy is effective in almost all cases, but is seldom used due to the efficacy of nasal CPAP. Uvulopalatopharyngoplasty is probably the most frequent surgical procedure in OSA, although it is useful in less than 50% of cases [3]. The most recent laser-assisted uvulopalatoplasty has also shown lack of effectiveness [139]. Maxillomandibular advancement has the best results [140] but is a radical and high risk surgery in which long-term outcomes are still lacking [141]. To our knowledge, these procedures have never been evaluated in patients with concomitant HF.

6.2. Central sleep apnoea
The best treatment for CSA remains controversial [39,117-119,138,142-153], optimization of HF therapy can be effective and should be the first approach in these patients [39]. However, evidence suggests CSA can also have adverse cardiovascular consequences and specific treatment can be beneficial [117-119,138,142-153]. Treatments can be divided into those which stimulate ventilation and override the periodic breathing pattern and those directed towards improving underlying cardiac function [121]. Inhaled carbon dioxide [142,143], inhaled oxygen [142,143] and theophyline [146] reduce the severity of CSA over a short period, but a long-term effect has not been demonstrated. Agents that improve cardiac function have had greater success in the management of CSA, captopril reduced the severity of CSA by 50% over a 4 week period in an observational study of 8 patients [147].

Treatment with CPAP was shown to significantly improve LVEF and quality of life in patients with HF and CSA [117-119]. A significant reduction in the relative risk of long-term mortality-cardiac transplantation was demonstrated [117]. Other studies have shown conflicting results [148,154]. In the CANPAP trial, 258 patients with HF and CSA were randomized to treatment with CPAP (N=128) or standard medical therapy. The trial was stopped prematurely (mean follow-up of 2 years) because there was no significant difference in clinical events — death or hospitalisation (p=0.54). However, the CPAP group had larger decreases in AHI (18.6 vs 39.7/h, p<0.001) and norepinephrine (3 vs 2.1 pmol/L, p=0.014) and higher ejection fraction (27.3% vs 24.8%, p<0.05) [154].

Other types of ventilatory support have been tested in patients with HF but they require further investigation [149-153]. Nonivasive volume/pressure preset ventilation (NVPV/NPPV) has been shown to abolish CSA and reduce AHI and sleep fragmentation, leading to an improvement in symptoms and cardiac function [149,150]. It is suggested that NPPV attenuates fluctuations in oxygen and CO2 tension in arterial blood by supporting ventilation during the apnoea portion of the Cheyne-Stokes cycle, thereby preventing oscillations of arterial CO2 above and below the apnoea threshold [150]. It has been proposed as an alternative therapy in those patients who do not respond or fail to tolerate CPAP [149,150].

Bilevel ventilation (BiPAP) has potential advantages over CPAP in the treatment of CSA, as it is able to ventilate a patient even in the absence of respiratory effort [151]. In a study of 14 patients with HF and CSA, the AHI was significantly reduced by CPAP and BiPAP (from 26.7±10.7 to 7.7±5.6 and 6.5±6.6, respectively) and there were significant and equal improvements in sleep quality, daytime fatigue and NYHA class [151].

A novel method of ventilatory support has been especially designed for Cheyne-Stokes respiration in HF [152,153]. Adaptive servo-ventilation (ASV) provides a baseline degree of ventilatory support, maintaining ventilation even if the patient ceases all central respiratory effort [152]. Teschler et al. compared the acute effects of ASV with other treatments [152]. Fourteen patients with HF and Cheyne-Stokes respiration were tested untreated and on four different treatments which were given in random order: nasal oxygen (2 L/min), CPAP, BiPAP or ASV. AHI declined from 44.5±3.4/h at baseline to 28.2±3.4/h on oxygen, 26.8±4.6/h on CPAP, 14.8±2.3/h on BiPAP and 6.3±0.9/h on ASV (p<0.001 vs BiPAP). ASV provided a further 83% reduction in the central apnoea index compared with CPAP, yielded better improvement in sleep quality and was preferred by most patients [152]. Pepperell et al. prospectively evaluated 30 patients with HF and Cheyne-Stokes respiration, randomized to treatment with either therapeutic or subtherapeutic (controls) ASV, for 1 month [153]. They found a significant reduction in daytime sleepiness and neurohumoral activation (BNP and catecholamine levels) in treated patients, suggesting not only a symptomatic improvement but also a potential benefit in prognosis [153]. These findings suggest ASV has potential advantages and may be a new promising therapy in this setting. However, there are only a small number of studies, samples are small and long-term effects have not been evaluated.

Cardiac pacing has also been proposed as a potential effective therapy. Garrigue et al. evaluated 15 patients with a dual-chamber pacemaker for symptomatic sinus-node dysfunction and a diagnosis of SA, by polysomnography [155,156]. A reduction of more than 50% in the number of episodes of apnoea and hypopnoea was achieved in most patients (87%), irrespective of the type of SA, and these variables returned to baseline when the pacemaker was turned-off [156]. However, more recently, the same group reported conflicting results [157].


   7. Prognosis
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
8. Conclusion
 References
 
SA is associated with systemic and pulmonary hypertension, sleep fragmentation, cardiac arrhythmias, nocturnal angina and impaired quality of life [3,7,9]. Patients with an AHI>10 had a 6-fold increased risk for having a traffic accident and this association is independent of potential confounders like alcohol consumption [8]. Early diagnosis is warranted since the morbidity and mortality of SA is high (12.5% and 35%, respectively) but it can be diminished by effective treatment [5].

Despite improvement in survival over recent years, HF mortality remains high (20-30% at 1-year and 50% at 5-years) and it is one of the most common causes of hospitalisation [110,111]. Prognostic factors in HF include haemodynamic, neurohumoral, electrophysiological and treatment variables. There is increasing evidence that sleep-disordered breathing is also a prognostic factor [38,39,47-49]. The presence of CSA in patients with HF is associated with a significantly increased risk for death and cardiac transplantation [48]. Lanfranchi et al. studied 62 patients with HF and CSA for 28±13 months and found a higher value of AHI in the nonsurvivors (p<0.03) [49]. In other study, patients with HF and CSA had shorter survival than those with just HF or SA or neither disorder (HR 1.66, p=0.012) [158]. More recently, OSA has been also recognized in HF and thought to have impact on outcome [47].

CPAP improves symptoms and morbidity and it is expected to improve survival as it reduces LV afterload and increases stroke volume, improves left ventricular function and inspiratory muscle strength and reduces sympathetic tone. Further studies are needed to demonstrate the long-term effects on outcome in order to offer a potential benefit for patients with HF.


   8. Conclusion
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
References
 
SA (central and obstructive) is common and frequently undiagnosed in patients with HF. Whether SA is an expression of the severity of HF or contributes to its development and/or progression is still not known. As it is a treatable condition, there is an urgent need to clarify this issue and to develop a simple screening protocol in this high risk population.

A better understanding of the underlying pathophysiological mechanisms involved and the magnitude of the potential benefit from therapy is needed, in order to establish recommendations for screening and treatment of SA in the HF population.

The evaluation and management of patients with HF may therefore be modified and an improvement in prognosis may be achieved. Further studies are required to test diagnostic algorithms and therapies and determine the optimal approach.


   References
Top
 Abstract
 1. Introduction
 2. Definition of sleep...
 3. Epidemiology
 4. HF and SA:...
 5. Diagnosis
 6. Treatment
 7. Prognosis
 8. Conclusion
 References
 

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