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European Journal of Heart Failure 2007 9(3):243-250; doi:10.1016/j.ejheart.2006.08.001
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© 2007 European Society of Cardiology

A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction

A. Vazira,b,*, P.C. Hastingsa, M. Dayerb, H.F. McIntyrec, M.Y. Heneinb, P.A. Poole-Wilsonb, M.R. Cowieb, M.J. Morrella and A.K. Simondsa

a Academic Unit of Sleep and Breathing, The Royal Brompton Hospital, National Heart and Lung Institute Imperial College, Sydney Street, London, United Kingdom
b Department of Cardiac Medicine, The Royal Brompton Hospital, National Heart and Lung Institute Imperial College, Sydney Street, London, United Kingdom
c Department of Cardiology, The Conquest Hospital The Ridge, Hastings, East Sussex, United Kingdom

* Corresponding author. Academic Unit of Sleep and Breathing and Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, Sydney Street, London SW3 6NP. Tel.: +44 20 7351 8027; fax: +44 20 7351 8911. E-mail address: alivazir{at}doctors.org.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Sleep disordered breathing (SDB) is common in severe chronic heart failure (CHF) and is associated with increased morbidity and mortality. The prevalence of SDB in mild symptomatic CHF is unknown.

Aim: The aim of this study was to determine the prevalence and characteristics of SDB in male patients with NYHA class II symptoms of CHF.

Methods and results: 55 male patients with mild symptomatic CHF underwent assessment of quality of life, echocardiography, cardiopulmonary exercise, chemoreflex testing and polysomnography. 53% of the patients had SDB. 38% had central sleep apnoea (CSA) and 15% had obstructive sleep apnoea. SDB patients had steeper VE/VCO2 slope [median (inter-quartile range) 31.1 (28–37) vs. 28.1 (27–30) respectively; p=0.04], enhanced chemoreflexes to carbon dioxide during wakefulness [mean±sd: 2.4±1.6 vs. 1.5±0.7%VE Max/mmHg CO2 respectively; p=0.03], and significantly higher levels of brain natriuretic peptide and endothelin-1 compared to patients without SDB. No differences in left ventricular ejection fraction, percent predicted peak oxygen uptake, or symptoms of SDB were observed.

Conclusions: A high prevalence of SDB was found in men with mild symptomatic CHF. Patients with SDB could not be differentiated by symptoms or by routine cardiac assessment making clinical diagnosis of SDB in CHF difficult.

Key Words: Chronic Heart Failure • Obstructive Sleep Apnoea • Central Sleep Apnoea

Received November 11, 2005; Revised June 14, 2006; Accepted August 15, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure (CHF) is a common condition, affecting 1-2% of the population of developed countries [1], and is associated with reduced longevity and quality of life. For the year 2006 the estimated cost of heart failure in the United States was $29.6 (23.6) billion [2].

Up to 70% of patients with CHF secondary to left ventricular (LV) systolic dysfunction have mild symptoms of heart failure, i.e. New York Heart Association (NYHA) functional class II symptoms [3]. In this population it is important to identify the presence of coexisting conditions, which may accelerate the progression of heart failure. One such condition is sleep disordered breathing (SDB).

Studies of the prevalence of SDB have shown that it occurs in 50-60% of patients with systolic dysfunction and varying severity of symptoms of heart failure [4,5]. The prevalence and characteristics of SDB in mild symptomatic CHF are unknown. In a study by Javaheri et al, 81 male CHF patients were recruited from primary and secondary care [4], of these 70% were either asymptomatic or had mild symptoms (NYHA I-II) with the remaining 30% having moderate to severe symptoms of CHF (NYHA III-IV). The authors found that the predominant type of SDB was central sleep apnoea (CSA) with a significant proportion having obstructive sleep apnoea (OSA). Patients with SDB had significantly lower left ventricular ejection fraction and also lower PaCO2. The prevalence and characteristics of SDB in the mild symptomatic CHF patients was not reported by Javaheri et al. In another study of SDB in CHF, Sin et al [5] assessed risk factors for SDB in 450 patients with CHF. In their series they found that the predominant type of SDB was CSA, and the presence of atrial fibrillation, male sex, age above 60 years and hypocapnia were the main risk factors predisposing to CSA. However the interpretation of these results is limited as their study was retrospective and CHF patients with suspected SDB (e.g. because of daytime sleepiness) referred to a sleep centre over a period of 10 years were studied.

The management of CHF has evolved with the widespread use of beta-blockers and in selected patients the use of aldosterone antagonists. These newer interventions have significantly improved the quality of life and survival of patients with CHF. However, the impact of these new interventions on the prevalence of SDB in patients with CHF has not yet been evaluated. Furthermore, detailed evaluation of cardiac function to include full physiological and biochemical assessment were not performed in previous studies of the prevalence of SDB in patients with CHF.

The aims of this study were to investigate the prevalence and type of SDB in a cohort of male patients with mild symptomatic CHF secondary to LV systolic dysfunction on maximal medical therapy, and to identify the mechanisms that may contribute to the development of SDB in this group.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patient selection
We prospectively recruited and studied consecutive male patients from cardiology clinics between October 2002 and May 2004. Eligibility for participation included: male patients with mild stable CHF (NYHA class II) secondary to LV systolic dysfunction (left ventricular ejection fraction (LVEF) <45%) of at least 6 months duration, due to idiopathic dilated cardiomyopathy or ischaemic cardiomyopathy. Stable CHF was defined as no changes in medication or symptoms for 4 weeks prior to the sleep study and no hospitalisation within the preceding 8 weeks. All patients were on optimal medical therapy, with percent predicted FEV1/FVC ratio >70%. Exclusion criteria included the presence of unstable angina, primary valvular or congenital heart disease, or a history of chronic respiratory or neurological disease. We excluded patients with biventricular pacing systems, as the impact of cardiac resynchronization therapy on SDB was unknown at the time, and also patients taking hypnotic agents e.g. benzodiazepines or those taking theophylline or opiates.

The total population of clinic patients was 517; 310 patients had LV systolic dysfunction, and of these 170 met the study criteria. These patients were invited to participate in the study, 55 (32%) agreed to take part. The main reason for refusal to participate was unwillingness to travel long distances into central London or to stay overnight for the sleep study. There were no significant differences between the patients studied and those not studied for age (61±12 versus 66±9 years respectively; p=0.08) or LVEF [30.1 (27-40) versus 32.3 (22.5-39.6)% respectively, p=0.14]. The study was approved by the Royal Brompton and Harefield Trust ethics committee and all patients gave written informed consent.

2.2. Study protocol
On entry to the study, patients underwent a clinical examination, and quality of life was assessed using the Minnesota Living with Heart Failure [6] and the Short Form-36 (SF-36) questionnaires [7]. Subjective sleepiness was assessed using the Epworth Sleepiness Scale [8]. This was followed by measurements of spirometry, venous blood sampling, 2D echocardiography, cardiopulmonary exercise test, 12 lead ECG, earlobe arterialised blood gas sampling, chemoreflex testing and nocturnal polysomnography. Patients were asked to avoid caffeinated drinks during the day and night of their study. Patients with OSA were referred for treatment with CPAP therapy, but all others (those with CSA or without SDB) were followed up for 12 months from their date of recruitment, and the number of cardiovascular hospitalisations noted.

2.3. Measurements
2.3.1. Venous blood sample
A venous blood sample was taken in the late morning for full blood count, renal function tests, brain natriuretic peptide (BNP) and endothelin-1 levels.

2.3.2. Cardiac assessment
A complete 2D and Doppler echocardiography study was performed for each patient. LV chamber size was assessed from the left parasternal long axis view at the level of the tips of the mitral valve using M-mode echocardiography. LVEF was assessed by the single plane Simpson's method [9]. Patients underwent ergometric cardiopulmonary exercise test (Oxycon, Jaeger Ltd) from which peak oxygen uptake (peak VO2) and the slope of ventilation in relation to carbon dioxide production (VE/VCO2 slope) were calculated. The percent predicted peak VO2 was also calculated [10].

2.3.3. Chemoreflex testing
The steady state constant technique [11] was used to assess chemoreflexes to carbon dioxide under normoxia. The hypercapnic ventilatory response (HCVR) was calculated from the slope of the regression line between the mean values for minute ventilation and end tidal carbon dioxide (PETCO2) for 3 increasing loads of carbon dioxide. The HCVR was further corrected for FEV1 and for age [12].

2.3.4. Sleep study
Full polysomnography was performed (Jaeger Sleeplab 1000p, Wurzburg, Germany). Sleep was monitored using three electroencephalograms (C4-A1, C3-A2, O1-A2), two electroculograms, and a submental electromyogram. Leg electromyogram was also used to determine periodic leg movements. Airflow was assessed using a pneumotachograph (4700 series, Hans Rudolph, USA) attached to a facemask, the deadspace of which was 210 ml. Arterial oxygen saturation was measured with a finger pulse-oximeter (200-E, Nellcor). Chest and abdominal excursions were monitored using pneumatic effort bands.

2.4. Analysis of sleep study
Sleep stages, EEG arousals and periodic leg movements were scored manually using standard criteria [13-15] by a single scorer trained in analysing polysomnography. Arousals were deemed as respiratory, spontaneous or associated with periodic limb movements if the arousal occurred within 3 s of such events.

Respiratory events were defined as follows: an obstructive apnoea- complete cessation of airflow with continued paradoxical chest and abdominal excursion for >10 s; central apnoea-complete cessation of airflow and complete cessation of chest and abdominal excursion for >10 s; Mixed apnoea-cessation of airflow for >10 s with complete cessation of both abdominal and chest movement in at least the first half of the apnoea (first 5 s) followed by paradoxical chest and abdominal excursion in the latter half of the apnoea; Hypopnoea — a reduction of airflow of >50% from baseline for >10 s in association with a 4% desaturation or EEG arousal. Hypopnoeas were classed as obstructive if there was continued but paradoxical chest and abdominal excursion or central if accompanied by reduced chest and abdominal excursion.

The patients with SDB were further classified into either CSA or OSA, if more than 50% of their apnoeas-hypopnoeas were central (central and mixed respiratory events) or obstructive in origin, respectively. This is in keeping with the criteria used in several other studies [5,16,17].

Sleep studies were also scored to assess the time spent in classic Cheyne-Stokes respiration (CSR) during sleep, using previously defined criteria [18]. Using this criterion hypopnoeas were defined as a reduction in airflow of >50% from the baseline, with or without an oxygen desaturation.

2.5. Statistical analysis
Values are expressed as mean and standard deviation for data that were normally distributed, or as median and interquartile range for data that were not normally distributed. For comparison between two groups the unpaired Student's t-test and the Mann-Whitney rank sum test were used when data were normally and non-normally distributed, respectively. Frequency variables between the two groups were assessed by z-test. Pearson's correlation coefficient was used to assess the relationship between two continuous variables. A Kaplan-Meier curve was constructed to assess event free survival. Results were analysed using Sigmastat version 3.0 (SPSS Inc. Chicago, USA); P values of <0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
The characteristics of the 55 male patients studied are given in Table 1. All patients had LV systolic dysfunction and exercise limitation, and were optimally treated with modern medical therapy for heart failure. 98% were either treated with ACE inhibitors or Angiotensin II receptor blockers and 80% were taking a beta-blocker. Over 90% were receiving diuretics.


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  		Table 1 Baseline characteristics of 55 male CHF patients

 
3.2. Prevalence of SDB
The prevalence of SDB in our population of male patients with mild symptomatic heart failure is shown in Fig. 1. Using apnoea-hypopnoea index (AHI) thresholds of ≥5, ≥15 and ≥30 events/h the percentage of patients with SDB were: 80% (4/55), 53% (29/55), and 22% (12/55), respectively.


Figure 01
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  		Fig. 1 Prevalence of sleep disordered breathing within a population of male patients with mild symptomatic chronic heart failure secondary to left ventricular systolic dysfunction.

 
3.3. Characteristics of patients with SDB (AHI >15 events/ h)
The demographic and physiological characteristics for the patients with SDB versus no SDB are given in Tables 2 and 3. There were no demographic differences between patients with SDB compared with those with no SDB. Patients with SDB had a significantly enhanced ventilatory response to exercise [VE/VCO2 slope: 31.3 (28-37) v 28.1 (27-30); p=0.04], despite no difference in percent-predicted peak VO2 [74.6 (55-83) v 68.3 (60-75)%; p=0.39], compared to patients with no SDB. Patients with SDB had enhanced chemoreflexes compared to patients with no SDB [hypercapnic ventilatory response: 2.4±1.6 v 1.5±0.7 l/min/mmHg CO2; p=0.03]. In addition patients with SDB had significantly higher levels of BNP [14.3 (7.4-50.8) vs. 6.7 (3.0-15.7) pg/ml; p=0.04] and endothelin-1 [1.6 (1.1-2.1) vs. 1.0 (0.9-1.8) pmol/l; p=0.04] compared to those without SDB (Table 3).


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  		Table 2 Demographic characteristics of male heart failure patients with sleep disordered breathing (SDB) versus those without SDB (No SDB), and those with central sleep apnoea (CSA) versus those with obstructive sleep apnoea (OSA)

 


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  		Table 3 Physiological characteristics of male chronic heart failure patients with sleep disordered breathing (SDB) versus those without SDB (No SDB), and those with central sleep apnoea (CSA) versus those with obstructive sleep apnoea (OSA)

 
No differences were found for LVEF [30±10 v 32±10%; p=0.52], or other echocardiographic measurements between patients with SDB compared to those without. Both groups were found to be hypocapnic during resting wakefulness.

Respiratory and sleep architecture parameters according to the presence or absence of SDB are given in Table 4. The majority of respiratory events were hypopnoeas. Patients with SDB had significantly more light sleep with arousals that were more often respiratory in origin. In the "no SDB" group arousals were more often spontaneous. No differences in total sleep time, sleep efficiency, the amounts of deep or REM sleep were found between the two groups.


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  		Table 4 Respiratory parameters and sleep architecture of male chronic heart failure patients with sleep disordered breathing (SDB) versus those without SDB (No SDB), and for those with central sleep apnoea (CSA) versus those withobstructive sleep apnoea (OSA)

 
3.4. Comparison of CHF patients with CSA versus those with OSA
Patients with SDB (N=29) were subdivided into patients with CSA (N=21) and those with OSA (N=8). The demographic, physiological and respiratory parameters with sleep characteristics of the two groups are given in Tables 2, 3 and 4 respectively. CSA patients were significantly older and reported more physical symptoms as assessed by the SF-36 questionnaire compared to patients with OSA. Of note, patients with CSA had a similar body mass index when compared to OSA patients. CSA patients had significantly greater left atrial diameter than OSA patients.

At 12 months, the CHF patients with CSA (N=21) had 8 cardiovascular hospitalisations compared to 3 in the no SDB group (N=26), (p=0.03).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We found the prevalence of SDB to be 53% in stable, optimally treated male patients with mild symptomatic CHF secondary to LV systolic dysfunction. The SDB found in this population was mainly central in origin, but a significant proportion had OSA. The patients with SDB had significantly greater chemosensitivity to CO2 and enhanced ventilatory response to exercise, greater levels of BNP and endothelin-1, than the no SDB patients. SDB in mild symptomatic CHF is not associated with a poorer ejection fraction or a more limited exercise capacity, which could have helped to differentiate them from patients without SDB. Furthermore the majority of patients with SDB did not report excessive daytime sleepiness, suggesting that identification of CHF patients with SDB is likely to be difficult if based on subjective sleepiness symptoms alone.

4.1. Identification of OSA in CHF
In our study, 15% of the patients had OSA using similar criteria to previous studies [5,17]. CHF patients with OSA were referred for treatment with CPAP therapy, as the presence of OSA in CHF patients results in adverse mechanical and haemodynamic insults to the failing heart [19]. In OSA, recurrent hypoxaemia, hypercapnia [20] and baroreflex inhibition [21] contribute to elevated sympathetic nerve activity, which is known to be cardiotoxic in heart failure [22]. Hypoxaemia may also independently lead to oxidative vascular wall injury [23] and contribute to the development of systemic hypertension [24], which is a precursor of CHF [25]. Randomised controlled trials of CPAP have shown that it reverses the mechanical and haemodynamic effects of OSA and results in a significant improvement in LVEF, and reduces sympathetic activation together with a reduction in daytime resting heart rate and blood pressure [26,27]. Taken together, these studies indicate that identifying OSA in patients with CHF and referring these patients for treatment is beneficial.

4.2. Identification of patients with CSA
In our study we found that 38% of mildly symptomatic CHF patients had CSA, and they had significantly more cardiovascular hospitalisations than those without SDB, despite similar underlying cardiac function. In common with a previous study in a more severe symptomatic CHF population, our patients with mild symptomatic CHF with CSA had an enhanced ventilatory response to exercise [28] and also enhanced chemoreflexes [29]. Furthermore, patients with CSA had significantly greater levels of BNP and endothelin-1, in keeping with previous studies [30,31]; however, whether the higher levels of these peptides are related to the presence of central apnoea or oxygen desaturation is unclear from this study.

Enhanced ventilatory response to exercise, elevated BNP and endothelin-1 levels are independent markers of poor outcome for CHF, and are thought to be better predictors of overall outcome than peak VO2, NYHA class, or LVEF [32-34]. Thus CHF patients with CSA are likely to have a poorer prognosis compared to those without SDB.

The presence of enhanced chemosensitivity to CO2 is thought to be an important mechanism in the development of CSA, especially by interacting with hypocapnia, which was also present in our patients. Enhanced chemosensitivity to CO2 can lower arterial PaCO2, principally in the presence of hypocapnia, below the apnoeic threshold resulting in central apnoea. Furthermore, enhanced chemosensitivity to CO2 may independently over stimulate the sympathetic nervous system, by playing a central role in a vicious cycle involving the depression of the baroreceptor reflex [35]. The latter may lead to increased sympathetic nerve activity further enhancing chemosensitivity to CO2. This vicious cycle acts indirectly with other factors associated with sleep apnoea, such as recurrent hypoxia and autonomic arousals [36], to contribute to over stimulation of the sympathetic nervous system, therefore putting CHF patients with CSA at risk of lethal arrhythmias [37], cardiotoxicity [22], and to accelerated progression of heart failure with a poorer cardiovascular outcome. These combined mechanisms highlight the need to establish an optimum treatment for CSA, which at the present time remains unclear.

4.3. Controversies in classifying sleep disordered breathing
In our study, the CHF patients with SDB were classified into CSA or OSA using criteria from previous studies [5,17]. However the majority of these patients with SDB had coexisting central and obstructive events, Table 3. In light of the lack of an optimal treatment for CSA, whether CHF patients with CSA and significant coexisting obstructive respiratory events should be considered for CPAP or managed in the same way as patients with pure CSA remains unclear. Therefore the current criterion to classify SDB seems to be controversial and requires further examination as it has significant implications for treatment.

4.4. Limitations of the study
We acknowledge the relatively small number of patients who participated in our study. The sample size is very similar to that in other recent studies looking at the prevalence of SDB within a single functional group [37,38]. The study by Sin et al [5] involved a much larger number of patients; however, it should not be directly compared to our study as it was retrospective and was based on a population of CHF patients who were referred to sleep clinics on clinical suspicion of SDB and thus may not be representative of the CHF patients within cardiology clinics.

A major limitation of our study is that our finding cannot be extrapolated to females. We did not include females in our study, as we had difficulty recruiting women with NYHA class II symptoms with left ventricular systolic dysfunction and without significant co-morbidity. Furthermore, we did not study patients with common co-morbidities such as chronic obstructive pulmonary disease, as one of the aims of the study was to assess chemoreflexes in the absence of pulmonary disease. Nevertheless, we believe that our findings in a population of relatively young male CHF patients, who lacked significant co-morbidities, are translatable to mild symptomatic male CHF patients who attend cardiology clinics.

By using the pneumotachograph to measure airflow we may have underestimated the prevalence of central sleep apnoea, as this method introduces 210 ml of deadspace that could have alleviated some central respiratory events. However, contrary to this, both groups of patients were found to be hypocapnic. Our method of measuring airflow is more accurate than using a pressure cannula to assess oro-nasal flow and is the gold standard technique [18].

4.5. Clinical implications
We conclude that there is a high prevalence of SDB in male patients with mild symptoms of heart failure. Identifying patients with SDB is difficult, if based on symptoms specific to SDB alone or on standard cardiac assessment e.g. echocardiography or peak VO2.

Our study raises the question of whether routine screening for SDB should be performed in patients with CHF, in particular screening for OSA, as CPAP is a well established mode of treatment. The gold standard sleep study is polysomnography but this is not widely available. Screening with ambulatory cardio-respiratory monitors has recently been shown to be useful in diagnosing SDB in a heart failure population [39]. However simpler and less expensive modes of screening, e.g. with heart rate variation [40] alone or combined with pulse oximetry after prospective validation, may also be useful and more feasible in detecting SDB in the heart failure population.


   Acknowledgements
 
The study was supported by grants from the British Heart Foundation (AV, PCH, MJM, AKS), the Wellcome Trust (MJM) and the ResMed Foundation (PCH, AKS). We would like to thank Mr R. Minnion for the technical support in polysomnography, and also Dr M. Jones who carried out the pilot work for this study. Conflicts of Interests Disclosure. AKS has received a project grant from Resmed UK. PCH has been in part funded by ResMed UK. AV, MJM, MD, MYH, HFM, MRC and PAPW have "no conflicts of interest".


   References
Top
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 1. Introduction
 2. Methods
 3. Results
 4. Discussion
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