- Email: [email protected]
Epidemiology of central sleep apnoea in heart failure
IJCA-22094; No of Pages 4 International Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Epidemiology of central sleep apnoea in heart failure Matthew T. Naughton General Respiratory & Sleep Medicine, The Alfred Hospital & Monash University, Melbourne, Victoria, Australia
a r t i c l e
i n f o
Article history: Received 15 November 2015 Received in revised form 27 January 2016 Accepted 21 February 2016 Available online xxxx Keywords: Central and obstructive sleep apnoea
a b s t r a c t Central sleep apnoea occurs in about a third of patients with reduced systolic heart failure and is a marker of increased mortality. Such patients usually are older males with advanced heart failure (i.e., high pulmonary wedge pressure), often in atrial fibrillation, with evidence of hyperventilation (i.e., low PaCO2) in the absence of hypoxemia. Characteristically, ventilation waxes and wanes in a sinusoidal pattern, with mild hypoxemia, occurring in the lighter levels of sleep usually when supine. Snoring may also occur in central sleep apnoea, often at the peak of hyperventilation, sometimes contributing to the confusion or overlap with obstructive sleep apnoea. Central sleep apnoea is associated with orthopnoea, paroxysmal nocturnal dyspnoea and an oscillatory respiratory pattern with an incremental cardiopulmonary exercise study. Importantly, heart failure therapies (e.g., afterload reduction, diuresis, pacemakers, transplantation) attenuate central sleep apnoea. Night to night variability in severity of central sleep apnoea may occur with changes in patients' posture during sleep (less severe when sleeping on-side or upright). Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Whilst dyspnoea has long been known to be a cardinal feature in the heart failure (HF) syndrome, it has only been in recent times that the patterns of breathing have been studied in depth. One particular type of dyspnoea results in an oscillatory or periodic breathing pattern during sleep, and is referred to as central sleep apnoea with Cheyne Stokes respiration (CSA-CSR). Occasionally in patients with CSA-CSR, a similar periodic breathing pattern (without apnoeas) occurs during an incremental exercise study and is referred to as exertional oscillatory ventilation (EOV).
2. Clinical features Central sleep apnoea with Cheyne Stokes respiration is often associated with advanced heart failure as indicated by a reduced LVEF and exercise capacity (VO2 max and 6 min walk distance) and an elevated PCWP, BNP and sympathetic nerve activity (SNA) [1]. In such patients with CSA-CSR, an elevated VE/VCO2 slope during exercise and central and peripheral ventilatory chemoreceptor activity with hyperventilation are also observed. During sleep, CSA-CSR is associated with a prevailing hyperventilation and hypocapnia, triggered by an arousal or state change. The oscillatory pattern continues for at least 3 cycles and periods of greater than 10 min [2]. Characteristically it is observed during the transition from wake to nonREM sleep stages 1 and 2, worse when supine and E-mail address: [email protected].
alleviated when non-supine [3] or when the head of the bed is raised [4]. The ventilation pattern in patients with CSA-CSR usually normalizes during slow wave sleep and REM sleep. Patients with CSA-CSR complain of fatigue, insomnia and occasionally orthopnoea with paroxysmal nocturnal dyspnoea. The bed partner often observes apnoeas during their partner's sleep, sometimes with snoring during the peak of hyperventilation. The risk factors which should alert clinicians to the possibility of CSA-CSR are age ≥60 years, male gender, atrial fibrillation and low PaCO2 [5] in patients with unstable HF. CSA-CSR is relieved by improving the underlying cardiac function (pump, rhythm and valves) through medications, devices (pacemakers, left ventricular assist device), surgery (valve repair & transplantation) or correction of co-existent medical problems such as anaemia or OSA. 3. Pathogenesis Studies into the pathogenesis of CSA-CSR have suggested the following mechanisms: an elevated respiratory drive (due to increased SNA or increase pulmonary vagal afferent activity) [6,7], reduced lung function (i.e., reduced volume and impaired diffusing capacity [8,9]) and a delay in the chemical signal (PaCO2) required to stimulate ventilation reaching the brain from the heart (i.e., due to low cardiac output). The periodic breathing pattern relates to the prevailing PaCO2 level oscillating above and below the apnoea threshold [6]. The mean SNA (plasma and urine norepinephrine) is higher in the CSA-CSR patient group than in groups with HF and no sleep apnoea [10]. Initially, it was thought that recurring arousals and hypoxemia due to CSA-CSR were responsible for the elevated SNA. However,
http://dx.doi.org/10.1016/j.ijcard.2016.02.125 0167-5273/Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
2
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
detailed multivariate analyses indicate that the severity of HF is a more important factor responsible for the elevated SNA than is the severity of CSA (i.e., the AHI) [11]. In addition, CSA-CSR is not always associated with hypoxemia, a potent stimulus for elevated SNA. Moreover, patients without CSA-CSR frequently have arousals (due to periodic limb movements) without necessarily having high SNA. Of note beta blockers do not appear to have altered the prevalence of CSA-CSR [12,13]. Although increased vagal activity is an additional proposed mechanism supported by the elevated PCWP [14], vagally denervated patients (due to lung transplantation) still have CSA-CSR [15]. 4. Differentiation from other breathing disorders during sleep The CSA-CSR breathing disturbance should be distinguished from two other common breathing disorders during sleep. The first breathing disorder is snoring with obstructive sleep apnoea which is thought to contribute to difficult to control hypertension [16] and heart failure [17] via large negative intrathoracic pressures, swings in oxygenation and associated surges in systemic and pulmonary pressures during the supposedly “restful” and recuperative period of sleep. Upper airway collapse at the base of the tongue occurs often in the setting of obesity or craniofacial abnormalities. The second breathing disorder is central apnoea with hypoventilation and elevated PaCO2 due to conditions such as kyphoscoliosis, motor neurone disease or morbid obesity.
change, as markers of ventilation are non-linear measurements of flow. Accordingly, a 25% reduction in either nasal pressure or oronasal thermistor does not translate to a 25% reduction in ventilation. By convention, an apnoea is when ventilation is b10% and hypopnoeas b50% of preceding normal airflow flow lasting N10 s and associated with either an arousal or a drop in SpO2 of ≥3%. Nasal ventilation may cease or be overwhelmed by oral flow in cases of nasal obstruction or hyperventilation. The effect of using only nasal pressure as the single monitoring signal of ventilation may over estimate obstructive sleep apnoea. The oximeter averaging time and storage capacity can also influence the sensitivity of SpO2 readings. Fifth, the exact categorization into “obstructive” (where there is complete or partial reduction in ventilation with incremental respiratory effort) or “central” apnoea groups can be difficult to measure without accurate measures of respiratory effort (e.g., intrathoracic pressure) and total flow (i.e., with an oronasal pneumotachograph). Moreover, the type of apnoea may vary across the night from obstructive to central [25] and alter with changes in body position (rotation, head elevation and neck flexion). Finally, the severity (AHI) and type of apnoea (Obstructive vs CSACSR) may vary from night to night depending upon HF control, nasal resistance and various factors that can alter respiratory control (blood glucose level, thyroid status, medications [progesterone, aminophylline, narcotics] and social drugs [alcohol, cigarettes]).
5. Definition 6. Epidemiology CSA-CSR is defined by a frequency of apnoeas or hypopnoeas (complete or partial reductions in tidal volume) per hour sleep occurring in a cyclic nature for N3 cycles and N10 min duration, from which the apnoea hypopnoea index (AHI) is derived [1]. A less commonly used metric of CSA-CSR is the % of sleep time in which CSA-CSR occurs [1]. A third metric, recently found to be indicative of treatment response is loop gain, defined as a ratio of the response (apnoea) to the trigger (hyperpnoea) [18]. Typically the apnoea and hyperpnoea cycle length is 45–75 s in patients with advanced HF. If a shorter (b45 s) cycle length is observed, non-HF causes for CSA should be considered such as atrial fibrillation with otherwise normal cardiac function [19], stroke [20], narcotic ingestion [21], premature infancy [22] and high altitude [23]. Although the “AHI” definition of CSA-CSR that is commonly used in research papers and epidemiological studies appears straight forward, it is open to some parochial interpretation and variation for several reasons. First is that the threshold of significant CSA-CSR used by various investigators varies from ≥5 to ≥30 events per hour. Second, the AHI is a ratio of the numbers of apnoeas and hyopnoeas per hour sleep, where the denominator of the AHI should be the number of hours sleep. Sleep duration is measured by using polysomnography (monitoring of sleep [EEG, EOG and EMG], ventilation and ECG) in either an attended or unattended environment. However several research groups use polygraphy (monitoring of ventilation and ECG, i.e., not sleep) and use “recording time” as the denominator. Given that the average sleep efficiency (sleep time/recording time) of patients with HF is ~ 70% [6], the AHI based upon recoding time may underestimate the AHI based upon sleep time by ~25%. Third, although in the research studies that recorded sleep duration, it is well recognised that patients with HF have poor quality sleep characterised by fragmentation with brief (b15 s) periods of sleep, making precise sleep scoring for quality and duration with standard measures [24] difficult resulting in potential variation from one centre to another. The R + K criteria were based upon normal subjects in 1960s. Fourth, the definition of apnoea or hypopnoea is also dependent upon the method of assessing ventilation (pressure, temperature or pneumotachograph) and whether this measurement is of the nasal, oral or oronasal flow. Measurements of pressure and temperature
The Sleep Heart Health Study was a longitudinal study of 6441 community dwellers, aged N40 years in USA who had an unattended home polysomnogram in 1994 along with general and cardiovascular assessment [26]. The polysomnogram was repeated in a subgroup 4 to 8 years later with data censored in 2006 and again in 2011. The SHHS indicated that OSA occurred in about 1 in 5 subjects (46% had AHI ≥ 5; 18% had AHI ≥ 15 and 6% had AHI ≥ 30 events per hour) whereas CSA-CSR was exceptionally rare (b1%). Two large epidemiological studies of HF populations assessing apnoea prevalence have been published in 1999 [5] and 2007 [27]. In the 1999 report [5], 450 clinically defined HF patients in Toronto (85% male, mean age ~ 60 years and BMI ~ 29 kg/m2) underwent polysomnograms between 1987 and 1998 [5]. The group mean LVEF was 27% and 75% took ACEI, 67% digoxin and 76% diuretics. The % of patients with OSA and CSA-CSR with AHI ≥ 10 were 38 and 33, AHI ≥ 15 were 32 and 29% and AHI ≥ 20 events/h were 27 and 25% respectively. Risk factors for CSA-CSR were male gender, age N60, atrial fibrillation and awake PaCO2 ≤38 mm Hg. Risk factor for OSA in males was a BMI ≥ 35 kg/m2 and in women age ≥ 60 years. The same group repeated the prevalence studies after the introduction of beta blocker and spironolactone therapy (between 1996 and 2004) and found no significant difference in the prevalence of either OSA or CSA-CSR within the HF population [12]. This has been confirmed by McDonald et al. [28]. The 2007 report [27] indicated similar prevalence of OSA and CSACSR. Seven hundred prospective HF patients (LVEF b40%) attending a single health service in Germany between 2003 and 2005 underwent polygraphy in addition to cardiopulmonary exercise testing [27]. As a group, 80% were male with mean age of 65 years, BMI ~ 27 kg/m2 and were optimally managed with 94% taking ACE and/or AT-1-receptor inhibitors, 85% taking beta blockers, 84% taking diuretics, and 60% taking spironolactone. Using an AHI threshold of N5 events per hour, 40% had CSA-CSR and 36% had OSA, whereas a threshold of N 15 events per hour, 32% had CSA-CSR and 19% had OSA. Both CSA-CSR and OSA had a significantly male predominance (~ 85%). Compared with the OSA group, the CSA-CSR group had lower BMI, higher NYHA class, greater frequency of nocturia and atrial fibrillation, lower work load and reduced distance walked in 6 min despite relatively similar severities of cardiac function and medications.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
Thus based upon the large Canadian [5] and German [27] prevalence studies, (and the 4 large mortality studies below) about 1 in 3 HF patients have CSA-CSR and 1 in 4 have OSA, unaltered by the introduction of beta blockers or spironolactone [12,28]. Moreover, both these prevalences were greater than that seen in the general population [26]. The incidence of CSA-CSR (i.e., new cases) is not known. Pinna et al. [29] undertook monthly polygraphy studies over 12 months in 79 moderate to severe HF patients (mean age 59 years, 90% male, BMI = 26 kg/m2, LVEF = 29%) and observed 30% to have occasional and 50% persistent sleep apnoea (undefined as to whether OSA or CSA-CSR) and 20% with no sleep apnoea. This would suggest that in some patients, CSA-CSR may unknowingly emerge and acquiesce when HF is better controlled. The relationship between CSA-CSR and EOV has been rarely studied. Corra et al. [30] reported in the 133 patients, that CSA occurred in 46% and EOV in 21%. In 16%, both CSA-CSR and EVO were observed, 29% had CSA without EOV and 4% EOV without CSA-CSR. Of note CSA-CSR was defined as AHI ≥30 and EOV as ≥15% variation in tidal volume for ≥60% of the exercise time. The main difference between those patients with both CSA-CSR and EOV with those without either was a greater VE/VCO2 slope and reduced VO2 max in the CSA-CSR and EOV group. The cumulative survival Kaplan–Meier curve indicated a worse prognosis in those patients with CSA-CSR and worse still with combined CSA-CSR and EOV compared with EOV and no periodic breathing groups. 7. Mortality Is CSA-CSR associated with greater mortality? Initial studies suggested this to be possible [31–33] whereas other studies did not [34–36]. However these early studies were generally based upon small patient numbers and did not control for markers of HF severity or other well known risk factors of mortality (e.g., age). In the past 10 years, there have been 4 prospective studies with N100 patients per study [30,37–39] with three (30,37,38) indicating CSA-CSR to be an independent marker of increased mortality (Table 1). Corra et al. [30] identified a greater mortality, but in the subsequent studies [39] the AHI did not predict mortality when controlled for age and severity of HF. A more recent study reported a significant greater mortality (controlled for various cardiovascular markers) in 1117 patients with acute heart failure with either CSA-CSR and OSA (confirmed by polygraphy pre-hospital discharge) at the 36 month follow-up [38] Therefore, it is now generally considered that CSA-CSR is a marker of greater HF severity and probably an independent risk factor for mortality.
3
volume with the swings in intrathoracic pressure due to unobstructed hyperventilation, development of respiratory alkalosis to buffer against respiratory acidosis due to fulminant pulmonary oedema, periodic rest to the respiratory muscles and the provision of intrinsic PEEP during expiration, sympathetic nerve attenuation induced by lung stretch and bronchodilatation. Does this mean that CSA-CSR should be ignored? In this author's opinion, no. As previously stated, CSA-CSR is a signal that the HF is increasing in severity associated with hypoxemia and elevated sympathetic activity. It may also explain the symptoms of subacute pulmonary oedema. It therefore should trigger attention in increasing HF management via medication, devices or surgery. This regime may involve positive airway pressure. In acute cardiogenic pulmonary oedema, continuous positive airway pressure (CPAP) is quite effective in many patients. In stable HF patients, CPAP may be required to overcome co-existent OSA or to increase lung volumes in CSA-CSR to offset hypoxemia. 9. Recognition Should sleep apnoea be considered in patients with HF? In this author's opinion, the answer is yes. The two large HF population studies [5,27] suggested 2 in 5 patients having either OSA or CSA-CSR, a frequency double that seen in the general population (1 in 5 patients) [26]. The Sleep Heart Health Study highlighted statistically significant correlations between OSA and the presence of hypertension, atrial fibrillation, ischaemic heart disease, left ventricular hypertrophy, heart failure and increased mortality using both cross sectional [42] and prospective studies [17] controlled for standard risk factors. This link was strongest in males under the age of 70 years with considerable nocturnal hypoxemia. Treatment of OSA in the setting of HF is associated with improved LVEF, blood pressure control, LVEF, quality of life and exercise tolerance [43], yet mortality, is to be conclusively shown. The SAVE trial (NCT00738179) will attempt to answer this. This would suggest identification and treatment of OSA to be a potentially reversible factor in the development and/or progression of HF. The identification of CSA-CSR would highlight the need to further optimize therapy directed towards the HF. However, in the real world, this rarely occurs. A retrospective cohort in US Medicare standard analysis in 2004 [44] identified ~31,000 new cases on HF (with no prior diagnosis of sleep apnoea) of whom only 4% were clinically suspected of having sleep apnea and 2% were investigated. Of the group who were investigated and treatment for SA, they had a better 2 year survival rate after adjustment of age, gender and comorbidities. 10. Conclusion
8. Compensatory theory Could CSA-CSR have some compensatory role to play in patients with advanced HF? It is this author's opinion that this may be true [40, 41], through the mechanisms of increasing lung volume and oxygen stores during the hyperventilation period, augmentation of stroke
Table 1 Four large studies in patients with heart failure investigating impact of CSA-CSR upon mortality. (PG = polygraphy; PSG = polysomnography). Author (ref)
Corra et al. [30]
Luo et al. [37]
Khayat et al. [38]
Grimm et al. [39]
Patient numbers LVEF mean (%) AHI threshold CSA-CSR (%) OSA (%) Follow-up (months) Monitoring type Mortality
133 23 30 35 17 39 PG Yes
124 36 5 39 43 35 PSG Yes
1117 26 15 31 47 36 PG Yes
267 34 15 + 30 39 61 43 PSG No
In conclusion, breathing disorders during sleep occur in ~70% of patients with symptomatic HF with CSA-CSR occurring in about half. Risk factors for CSA-CSR include age N60 years, male gender, atrial fibrillation and low PaCO2 (b38 mm Hg). Identification of CSA-CSR should alert the clinician to unstable or progressive HF warranting greater attention and treatment. Whether CSA-CSR in isolation is associated with greater mortality is likely. Conflict of interest MTN has received positive airway devices for clinician directed research trials. He holds no stock in any industry that makes devices to diagnose or treat sleep disorders or heart failure. References [1] M.T. Naughton, S. Andreas, Sleep apnoea in chronic heart failure, Eur. Respir. Mon. 50 (2010) 396–420. [2] S. Redline, R. Budhiraja, V. Kapur, et al., Reliability and validity of respiratory event measurement and scoring, J. Clin. Sleep Med. 3 (2) (2007) 169–200.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
4
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
[3] I. Szollosi, T. Roebuck, B. Thompson, M.T. Naughton, Lateral sleeping position promotes ventilatory stability in central sleep apnea/Cheyne–Stokes respiration, Sleep 29 (2006) 1045–1051. [4] M.D. Altschule, A. Iglauer, The effect of position on periodic breathing in chronic cardiac decompensation, N. Engl. J. Med. 259 (22) (Nov 27, 1958) 1064–1066. [5] D.D. Sin, F. Fitzgerald, J.D. Parker, G. Newton, J.S. Floras, T.D. Bradley, Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure, Am. J. Respir. Crit. Care Med. 160 (1999) 1101–1106. [6] M. Naughton, D. Benard, A. Tam, et al., Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure, Am. Rev. Respir. Dis. 148 (2) (1993) 330–338. [7] P. Solin, T. Roebuck, D.P. Johns, E.H. Walters, M.T. Naughton, Peripheral and central ventilatory responses in central sleep apnea with and without heart failure, Am. J. Respir. Crit. Care Med. 162 (2000) 2194–2200. [8] I. Szollosi, B.R. Thompson, H. Krum, D.M. Kaye, M.T. Naughton, Impaired pulmonary diffusing capacity and hypoxia in heart failure correlates with central sleep apnea severity, Chest 134 (2008) 67–72. [9] K. Kee, M.T. Naughton, Heart failure and the lung, Circ. J. 74 (2010) 2507–2516. [10] M.T. Naughton, D.C. Benard, P.P. Liu, R. Rutherford, F. Rankin, T.D. Bradley, Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea, Am. J. Respir. Crit. Care Med. 152 (1995) 473–479. [11] D.R. Mansfield, D.M. Kaye, P. Hans Brunner, M. Esler, M.T. Naughton, Raised sympathetic nerve activity in heart failure and central sleep apnea is due to heart failure severity, Circulation 107 (2003) 1396–1400. [12] D. Yumino, H. Wang, J.S. Floras, G.E. Newton, S. Mak, P. Ruttanaumpawan, et al., Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction, J. Card. Fail. 15 (2009) 279–285. [13] M. MacDonald, et al., The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers, J. Clin. Sleep Med. 4 (2008) 38–42. [14] P. Solin, P. Bergin, M. Richardson, D.M. Kaye, E.H. Walters, M.T. Naughton, Influence of pulmonary capillary wedge pressure on central apnea in heart failure, Circulation 99 (1999) 1574–1579. [15] P. Solin, G.I. Snell, T.J. Williams, M.T. Naughton, Central sleep apnoea in congestive heart failure despite vagal denervation after bilateral lung transplantation, Eur. Respir. J. 12 (1998) 495–498. [16] I.H. Iftikhar, C.W. Valentine, L.R.A. Bittencourt, D.L. Cohen, A.C. Fedson, T. Gıslason, et al., Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis, J. Hypertens. 32 (2014) 2341–2350. [17] D.J. Gottleib, G. Yenokyan, A.B. Newman, G.T. O'Connor, et al., Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study, Circulation 122 (2010) 352–360. [18] S.A. Sands, B.A. Edwards, K. Kee, A. Turton, E.M. Skuza, T. Roebuck, et al., Loop gain as a means to predict a positive airway pressure suppression of Cheyne–Stokes respiration in heart failure patients, Am. J. Respir. Crit. Care Med. 184 (2011) 1067–1075. [19] R.S.T. Leung, M.A. Huber, T. Rogge, et al., Association between atrial fibrillation and central sleep apnea, Sleep 28 (2005) 1543–1546. [20] C. Bassetti, M.S. Aldrich, Sleep apnea in acute cerebrovascular diseases: final report on 128 patients, Sleep 22 (1999) 217–223. [21] H. Teichtahl, A. Prodromidis, B. Miller, G. Cherry, I. Kronborg, Sleep-disordered breathing in stable methadone programme patients: a pilot study, Addiction 96 (2001) 395–403. [22] P.J. Berger, E.M. Skuza, V. Brodecky, S.M. Cranage, T.M. Adamson, M.H. Wilkinson, Unusual respiratory response to oxygen in an infant with repetitive cyanotic episodes, Am. J. Respir. Crit. Care Med. 161 (2000) 2107–2111. [23] Y. Nussbaumer-Ochsner, N. Schuepfer, S. Ulrich, K.E. Bloch, Exacerbation of sleep apnoea by frequent central events in patients with the obstructive sleep apnoea syndrome at altitude: a randomised trial, Thorax 65 (2010) 429–435.
[24] A. Rechtschaffen, A. Kales, A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects, Public Health Service, U.S. Government Printing Office, 1968. [25] R. Tkacova, M. Niroumand, G. Lorenzi-Filho, et al., Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO2 and circulatory delay, Circulation 103 (2001) 238–243. [26] F.J. Nieto, T.B. Young, B.K. Lind, E. Shahar, J.M. Samet, S. Redline, et al., Association of sleep-disordered breathing, sleep apnea, and hypertension in a large communitybased study, JAMA 283 (2000) 1829–1836. [27] O. Oldenburg, B. Lamp, L. Faber, H. Teschler, Topfer V. Horstkotte, Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients, Eur. J. Heart Fail. 9 (2007) 251–257. [28] M. Macdonald, J. Fang, S.D. Pittman, D.P. White, A. Malhotra, The current prevalence of sleep disordered breathing in congestive heart failure patients treated with betablockers, J. Clin. Sleep Med. 4 (2008) 38–42. [29] G.D. Pinna, R. Maestri, A. Mortara, P. Johnson, D. Andrews, P. Ponikowski, et al., Longterm time-course of nocturnal breathing disorders in heart failure patients, Eur. Respir. J. 35 (2010) 361–367. [30] U. Corrà, M. Pistono, A. Mezzani, A. Braghiroli, A. Giordano, P. Lanfranchi, et al., Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence, Circulation 113 (2006) 44–50. [31] P.J. Hanly, N.S. Zuberi-Khokhar, Increased mortality associated with Cheyne Stokes respiration in patients with congestive heart failure, Am. J. Respir. Crit. Care Med. 53 (1996) 272–276. [32] P.A. Lanfranchi, A. Braghiroli, E. Bosimini, et al., Prognostic value of nocturnal Cheyne– Stokes respiration in chronic heart failure, Circulation 99 (1999) 1435–1440. [33] D.D. Sin, A.G. Logan, F.S. Fitzgerald, P.P. Liu, T.D. Bradley, Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne–Stokes respiration, Circulation 102 (2000) 61–66. [34] S. Andreas, G. Hagenah, G.S. Moller Werner, H. Kreuzer, Cheyne–Stokes respiration and prognosis in congestive heart failure, Am. J. Cardiol. 78 (1996) 1260–1264. [35] E. Traversi, G. Callegari, M. Pozzoli, C. Opasich, L. Tavazzi, Sleep disorders and breathing alterations in patients with chronic heart failure, G. Ital. Cardiol. 27 (1997) 423–429. [36] T. Roebuck, P. Solin, D.M. Kaye, P. Bergin, M.T. Naughton, Increased long term mortality due to sleep apnea in heart failure is yet to be proven, Eur. Respir. J. 23 (2004) 735–740. [37] Q. Luo, H.-L. Zhang, X.-C. Tao, Y.-J. Yang, Z.-H. Liu, Impact of untreated sleep apnea on prognosis of patients with congestive heart failure, Int. J. Cardiol. 3 (2009) 420–422. [38] R. Khayat, D. Jarjoura, K. Porter, A. Sow, J. Wannemacher, R. Dohar, et al., Sleep disordered breathing and post-discharge mortality in patients with acute heart failure, Eur. Heart J. 36 (2015) 1463–1469. [39] W. Grimm, A. Sosnovskaya, N. Timmesfeld, O. Hildebrandt, U. Koehler, Prognostic impact of central sleep apnea in patients with heart failure, J. Card. Fail. 21 (2015) 126–133. [40] M.T. Naughton, Controversies in sleep medicine. Is Cheyne–Stokes detrimental in patients with congestive heart failure? Sleep Breath. 4 (2000) 127–128. [41] M.T. Naughton, Cheyne Stokes respiration: friend or foe? Thorax 67 (2012) 357–360. [42] E. Shahar, C.W. Whitney, S. Redline, E.T. Lee, A.B. Newman, F.J. Nieto, et al., Sleepdisordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study, Am. J. Respir. Crit. Care Med. 163 (2001) 19–25. [43] D.R. Mansfield, N.C. Gollogly, M. Richardson, P. Bergin, D.M. Kaye, M.T. Naughton, Randomised trial of continuous positive airway treatment of obstructive sleep apnea in heart failure, Am. J. Respir. Crit. Care Med. 169 (2004) 1–6. [44] S. Javaheri, E.B. Caref, E. Chen, K.B. Tong, W.T. Abraham, Sleep apnea testing and outcomes in a large cohort of Medicare beneficiaries with newly diagnosed heart failure, Am. J. Respir. Crit. Care Med. 183 (2011) 539–546.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Epidemiology of central sleep apnoea in heart failure Matthew T. Naughton General Respiratory & Sleep Medicine, The Alfred Hospital & Monash University, Melbourne, Victoria, Australia
a r t i c l e
i n f o
Article history: Received 15 November 2015 Received in revised form 27 January 2016 Accepted 21 February 2016 Available online xxxx Keywords: Central and obstructive sleep apnoea
a b s t r a c t Central sleep apnoea occurs in about a third of patients with reduced systolic heart failure and is a marker of increased mortality. Such patients usually are older males with advanced heart failure (i.e., high pulmonary wedge pressure), often in atrial fibrillation, with evidence of hyperventilation (i.e., low PaCO2) in the absence of hypoxemia. Characteristically, ventilation waxes and wanes in a sinusoidal pattern, with mild hypoxemia, occurring in the lighter levels of sleep usually when supine. Snoring may also occur in central sleep apnoea, often at the peak of hyperventilation, sometimes contributing to the confusion or overlap with obstructive sleep apnoea. Central sleep apnoea is associated with orthopnoea, paroxysmal nocturnal dyspnoea and an oscillatory respiratory pattern with an incremental cardiopulmonary exercise study. Importantly, heart failure therapies (e.g., afterload reduction, diuresis, pacemakers, transplantation) attenuate central sleep apnoea. Night to night variability in severity of central sleep apnoea may occur with changes in patients' posture during sleep (less severe when sleeping on-side or upright). Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Whilst dyspnoea has long been known to be a cardinal feature in the heart failure (HF) syndrome, it has only been in recent times that the patterns of breathing have been studied in depth. One particular type of dyspnoea results in an oscillatory or periodic breathing pattern during sleep, and is referred to as central sleep apnoea with Cheyne Stokes respiration (CSA-CSR). Occasionally in patients with CSA-CSR, a similar periodic breathing pattern (without apnoeas) occurs during an incremental exercise study and is referred to as exertional oscillatory ventilation (EOV).
2. Clinical features Central sleep apnoea with Cheyne Stokes respiration is often associated with advanced heart failure as indicated by a reduced LVEF and exercise capacity (VO2 max and 6 min walk distance) and an elevated PCWP, BNP and sympathetic nerve activity (SNA) [1]. In such patients with CSA-CSR, an elevated VE/VCO2 slope during exercise and central and peripheral ventilatory chemoreceptor activity with hyperventilation are also observed. During sleep, CSA-CSR is associated with a prevailing hyperventilation and hypocapnia, triggered by an arousal or state change. The oscillatory pattern continues for at least 3 cycles and periods of greater than 10 min [2]. Characteristically it is observed during the transition from wake to nonREM sleep stages 1 and 2, worse when supine and E-mail address: [email protected].
alleviated when non-supine [3] or when the head of the bed is raised [4]. The ventilation pattern in patients with CSA-CSR usually normalizes during slow wave sleep and REM sleep. Patients with CSA-CSR complain of fatigue, insomnia and occasionally orthopnoea with paroxysmal nocturnal dyspnoea. The bed partner often observes apnoeas during their partner's sleep, sometimes with snoring during the peak of hyperventilation. The risk factors which should alert clinicians to the possibility of CSA-CSR are age ≥60 years, male gender, atrial fibrillation and low PaCO2 [5] in patients with unstable HF. CSA-CSR is relieved by improving the underlying cardiac function (pump, rhythm and valves) through medications, devices (pacemakers, left ventricular assist device), surgery (valve repair & transplantation) or correction of co-existent medical problems such as anaemia or OSA. 3. Pathogenesis Studies into the pathogenesis of CSA-CSR have suggested the following mechanisms: an elevated respiratory drive (due to increased SNA or increase pulmonary vagal afferent activity) [6,7], reduced lung function (i.e., reduced volume and impaired diffusing capacity [8,9]) and a delay in the chemical signal (PaCO2) required to stimulate ventilation reaching the brain from the heart (i.e., due to low cardiac output). The periodic breathing pattern relates to the prevailing PaCO2 level oscillating above and below the apnoea threshold [6]. The mean SNA (plasma and urine norepinephrine) is higher in the CSA-CSR patient group than in groups with HF and no sleep apnoea [10]. Initially, it was thought that recurring arousals and hypoxemia due to CSA-CSR were responsible for the elevated SNA. However,
http://dx.doi.org/10.1016/j.ijcard.2016.02.125 0167-5273/Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
2
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
detailed multivariate analyses indicate that the severity of HF is a more important factor responsible for the elevated SNA than is the severity of CSA (i.e., the AHI) [11]. In addition, CSA-CSR is not always associated with hypoxemia, a potent stimulus for elevated SNA. Moreover, patients without CSA-CSR frequently have arousals (due to periodic limb movements) without necessarily having high SNA. Of note beta blockers do not appear to have altered the prevalence of CSA-CSR [12,13]. Although increased vagal activity is an additional proposed mechanism supported by the elevated PCWP [14], vagally denervated patients (due to lung transplantation) still have CSA-CSR [15]. 4. Differentiation from other breathing disorders during sleep The CSA-CSR breathing disturbance should be distinguished from two other common breathing disorders during sleep. The first breathing disorder is snoring with obstructive sleep apnoea which is thought to contribute to difficult to control hypertension [16] and heart failure [17] via large negative intrathoracic pressures, swings in oxygenation and associated surges in systemic and pulmonary pressures during the supposedly “restful” and recuperative period of sleep. Upper airway collapse at the base of the tongue occurs often in the setting of obesity or craniofacial abnormalities. The second breathing disorder is central apnoea with hypoventilation and elevated PaCO2 due to conditions such as kyphoscoliosis, motor neurone disease or morbid obesity.
change, as markers of ventilation are non-linear measurements of flow. Accordingly, a 25% reduction in either nasal pressure or oronasal thermistor does not translate to a 25% reduction in ventilation. By convention, an apnoea is when ventilation is b10% and hypopnoeas b50% of preceding normal airflow flow lasting N10 s and associated with either an arousal or a drop in SpO2 of ≥3%. Nasal ventilation may cease or be overwhelmed by oral flow in cases of nasal obstruction or hyperventilation. The effect of using only nasal pressure as the single monitoring signal of ventilation may over estimate obstructive sleep apnoea. The oximeter averaging time and storage capacity can also influence the sensitivity of SpO2 readings. Fifth, the exact categorization into “obstructive” (where there is complete or partial reduction in ventilation with incremental respiratory effort) or “central” apnoea groups can be difficult to measure without accurate measures of respiratory effort (e.g., intrathoracic pressure) and total flow (i.e., with an oronasal pneumotachograph). Moreover, the type of apnoea may vary across the night from obstructive to central [25] and alter with changes in body position (rotation, head elevation and neck flexion). Finally, the severity (AHI) and type of apnoea (Obstructive vs CSACSR) may vary from night to night depending upon HF control, nasal resistance and various factors that can alter respiratory control (blood glucose level, thyroid status, medications [progesterone, aminophylline, narcotics] and social drugs [alcohol, cigarettes]).
5. Definition 6. Epidemiology CSA-CSR is defined by a frequency of apnoeas or hypopnoeas (complete or partial reductions in tidal volume) per hour sleep occurring in a cyclic nature for N3 cycles and N10 min duration, from which the apnoea hypopnoea index (AHI) is derived [1]. A less commonly used metric of CSA-CSR is the % of sleep time in which CSA-CSR occurs [1]. A third metric, recently found to be indicative of treatment response is loop gain, defined as a ratio of the response (apnoea) to the trigger (hyperpnoea) [18]. Typically the apnoea and hyperpnoea cycle length is 45–75 s in patients with advanced HF. If a shorter (b45 s) cycle length is observed, non-HF causes for CSA should be considered such as atrial fibrillation with otherwise normal cardiac function [19], stroke [20], narcotic ingestion [21], premature infancy [22] and high altitude [23]. Although the “AHI” definition of CSA-CSR that is commonly used in research papers and epidemiological studies appears straight forward, it is open to some parochial interpretation and variation for several reasons. First is that the threshold of significant CSA-CSR used by various investigators varies from ≥5 to ≥30 events per hour. Second, the AHI is a ratio of the numbers of apnoeas and hyopnoeas per hour sleep, where the denominator of the AHI should be the number of hours sleep. Sleep duration is measured by using polysomnography (monitoring of sleep [EEG, EOG and EMG], ventilation and ECG) in either an attended or unattended environment. However several research groups use polygraphy (monitoring of ventilation and ECG, i.e., not sleep) and use “recording time” as the denominator. Given that the average sleep efficiency (sleep time/recording time) of patients with HF is ~ 70% [6], the AHI based upon recoding time may underestimate the AHI based upon sleep time by ~25%. Third, although in the research studies that recorded sleep duration, it is well recognised that patients with HF have poor quality sleep characterised by fragmentation with brief (b15 s) periods of sleep, making precise sleep scoring for quality and duration with standard measures [24] difficult resulting in potential variation from one centre to another. The R + K criteria were based upon normal subjects in 1960s. Fourth, the definition of apnoea or hypopnoea is also dependent upon the method of assessing ventilation (pressure, temperature or pneumotachograph) and whether this measurement is of the nasal, oral or oronasal flow. Measurements of pressure and temperature
The Sleep Heart Health Study was a longitudinal study of 6441 community dwellers, aged N40 years in USA who had an unattended home polysomnogram in 1994 along with general and cardiovascular assessment [26]. The polysomnogram was repeated in a subgroup 4 to 8 years later with data censored in 2006 and again in 2011. The SHHS indicated that OSA occurred in about 1 in 5 subjects (46% had AHI ≥ 5; 18% had AHI ≥ 15 and 6% had AHI ≥ 30 events per hour) whereas CSA-CSR was exceptionally rare (b1%). Two large epidemiological studies of HF populations assessing apnoea prevalence have been published in 1999 [5] and 2007 [27]. In the 1999 report [5], 450 clinically defined HF patients in Toronto (85% male, mean age ~ 60 years and BMI ~ 29 kg/m2) underwent polysomnograms between 1987 and 1998 [5]. The group mean LVEF was 27% and 75% took ACEI, 67% digoxin and 76% diuretics. The % of patients with OSA and CSA-CSR with AHI ≥ 10 were 38 and 33, AHI ≥ 15 were 32 and 29% and AHI ≥ 20 events/h were 27 and 25% respectively. Risk factors for CSA-CSR were male gender, age N60, atrial fibrillation and awake PaCO2 ≤38 mm Hg. Risk factor for OSA in males was a BMI ≥ 35 kg/m2 and in women age ≥ 60 years. The same group repeated the prevalence studies after the introduction of beta blocker and spironolactone therapy (between 1996 and 2004) and found no significant difference in the prevalence of either OSA or CSA-CSR within the HF population [12]. This has been confirmed by McDonald et al. [28]. The 2007 report [27] indicated similar prevalence of OSA and CSACSR. Seven hundred prospective HF patients (LVEF b40%) attending a single health service in Germany between 2003 and 2005 underwent polygraphy in addition to cardiopulmonary exercise testing [27]. As a group, 80% were male with mean age of 65 years, BMI ~ 27 kg/m2 and were optimally managed with 94% taking ACE and/or AT-1-receptor inhibitors, 85% taking beta blockers, 84% taking diuretics, and 60% taking spironolactone. Using an AHI threshold of N5 events per hour, 40% had CSA-CSR and 36% had OSA, whereas a threshold of N 15 events per hour, 32% had CSA-CSR and 19% had OSA. Both CSA-CSR and OSA had a significantly male predominance (~ 85%). Compared with the OSA group, the CSA-CSR group had lower BMI, higher NYHA class, greater frequency of nocturia and atrial fibrillation, lower work load and reduced distance walked in 6 min despite relatively similar severities of cardiac function and medications.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
Thus based upon the large Canadian [5] and German [27] prevalence studies, (and the 4 large mortality studies below) about 1 in 3 HF patients have CSA-CSR and 1 in 4 have OSA, unaltered by the introduction of beta blockers or spironolactone [12,28]. Moreover, both these prevalences were greater than that seen in the general population [26]. The incidence of CSA-CSR (i.e., new cases) is not known. Pinna et al. [29] undertook monthly polygraphy studies over 12 months in 79 moderate to severe HF patients (mean age 59 years, 90% male, BMI = 26 kg/m2, LVEF = 29%) and observed 30% to have occasional and 50% persistent sleep apnoea (undefined as to whether OSA or CSA-CSR) and 20% with no sleep apnoea. This would suggest that in some patients, CSA-CSR may unknowingly emerge and acquiesce when HF is better controlled. The relationship between CSA-CSR and EOV has been rarely studied. Corra et al. [30] reported in the 133 patients, that CSA occurred in 46% and EOV in 21%. In 16%, both CSA-CSR and EVO were observed, 29% had CSA without EOV and 4% EOV without CSA-CSR. Of note CSA-CSR was defined as AHI ≥30 and EOV as ≥15% variation in tidal volume for ≥60% of the exercise time. The main difference between those patients with both CSA-CSR and EOV with those without either was a greater VE/VCO2 slope and reduced VO2 max in the CSA-CSR and EOV group. The cumulative survival Kaplan–Meier curve indicated a worse prognosis in those patients with CSA-CSR and worse still with combined CSA-CSR and EOV compared with EOV and no periodic breathing groups. 7. Mortality Is CSA-CSR associated with greater mortality? Initial studies suggested this to be possible [31–33] whereas other studies did not [34–36]. However these early studies were generally based upon small patient numbers and did not control for markers of HF severity or other well known risk factors of mortality (e.g., age). In the past 10 years, there have been 4 prospective studies with N100 patients per study [30,37–39] with three (30,37,38) indicating CSA-CSR to be an independent marker of increased mortality (Table 1). Corra et al. [30] identified a greater mortality, but in the subsequent studies [39] the AHI did not predict mortality when controlled for age and severity of HF. A more recent study reported a significant greater mortality (controlled for various cardiovascular markers) in 1117 patients with acute heart failure with either CSA-CSR and OSA (confirmed by polygraphy pre-hospital discharge) at the 36 month follow-up [38] Therefore, it is now generally considered that CSA-CSR is a marker of greater HF severity and probably an independent risk factor for mortality.
3
volume with the swings in intrathoracic pressure due to unobstructed hyperventilation, development of respiratory alkalosis to buffer against respiratory acidosis due to fulminant pulmonary oedema, periodic rest to the respiratory muscles and the provision of intrinsic PEEP during expiration, sympathetic nerve attenuation induced by lung stretch and bronchodilatation. Does this mean that CSA-CSR should be ignored? In this author's opinion, no. As previously stated, CSA-CSR is a signal that the HF is increasing in severity associated with hypoxemia and elevated sympathetic activity. It may also explain the symptoms of subacute pulmonary oedema. It therefore should trigger attention in increasing HF management via medication, devices or surgery. This regime may involve positive airway pressure. In acute cardiogenic pulmonary oedema, continuous positive airway pressure (CPAP) is quite effective in many patients. In stable HF patients, CPAP may be required to overcome co-existent OSA or to increase lung volumes in CSA-CSR to offset hypoxemia. 9. Recognition Should sleep apnoea be considered in patients with HF? In this author's opinion, the answer is yes. The two large HF population studies [5,27] suggested 2 in 5 patients having either OSA or CSA-CSR, a frequency double that seen in the general population (1 in 5 patients) [26]. The Sleep Heart Health Study highlighted statistically significant correlations between OSA and the presence of hypertension, atrial fibrillation, ischaemic heart disease, left ventricular hypertrophy, heart failure and increased mortality using both cross sectional [42] and prospective studies [17] controlled for standard risk factors. This link was strongest in males under the age of 70 years with considerable nocturnal hypoxemia. Treatment of OSA in the setting of HF is associated with improved LVEF, blood pressure control, LVEF, quality of life and exercise tolerance [43], yet mortality, is to be conclusively shown. The SAVE trial (NCT00738179) will attempt to answer this. This would suggest identification and treatment of OSA to be a potentially reversible factor in the development and/or progression of HF. The identification of CSA-CSR would highlight the need to further optimize therapy directed towards the HF. However, in the real world, this rarely occurs. A retrospective cohort in US Medicare standard analysis in 2004 [44] identified ~31,000 new cases on HF (with no prior diagnosis of sleep apnoea) of whom only 4% were clinically suspected of having sleep apnea and 2% were investigated. Of the group who were investigated and treatment for SA, they had a better 2 year survival rate after adjustment of age, gender and comorbidities. 10. Conclusion
8. Compensatory theory Could CSA-CSR have some compensatory role to play in patients with advanced HF? It is this author's opinion that this may be true [40, 41], through the mechanisms of increasing lung volume and oxygen stores during the hyperventilation period, augmentation of stroke
Table 1 Four large studies in patients with heart failure investigating impact of CSA-CSR upon mortality. (PG = polygraphy; PSG = polysomnography). Author (ref)
Corra et al. [30]
Luo et al. [37]
Khayat et al. [38]
Grimm et al. [39]
Patient numbers LVEF mean (%) AHI threshold CSA-CSR (%) OSA (%) Follow-up (months) Monitoring type Mortality
133 23 30 35 17 39 PG Yes
124 36 5 39 43 35 PSG Yes
1117 26 15 31 47 36 PG Yes
267 34 15 + 30 39 61 43 PSG No
In conclusion, breathing disorders during sleep occur in ~70% of patients with symptomatic HF with CSA-CSR occurring in about half. Risk factors for CSA-CSR include age N60 years, male gender, atrial fibrillation and low PaCO2 (b38 mm Hg). Identification of CSA-CSR should alert the clinician to unstable or progressive HF warranting greater attention and treatment. Whether CSA-CSR in isolation is associated with greater mortality is likely. Conflict of interest MTN has received positive airway devices for clinician directed research trials. He holds no stock in any industry that makes devices to diagnose or treat sleep disorders or heart failure. References [1] M.T. Naughton, S. Andreas, Sleep apnoea in chronic heart failure, Eur. Respir. Mon. 50 (2010) 396–420. [2] S. Redline, R. Budhiraja, V. Kapur, et al., Reliability and validity of respiratory event measurement and scoring, J. Clin. Sleep Med. 3 (2) (2007) 169–200.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125
4
M.T. Naughton / International Journal of Cardiology xxx (2016) xxx–xxx
[3] I. Szollosi, T. Roebuck, B. Thompson, M.T. Naughton, Lateral sleeping position promotes ventilatory stability in central sleep apnea/Cheyne–Stokes respiration, Sleep 29 (2006) 1045–1051. [4] M.D. Altschule, A. Iglauer, The effect of position on periodic breathing in chronic cardiac decompensation, N. Engl. J. Med. 259 (22) (Nov 27, 1958) 1064–1066. [5] D.D. Sin, F. Fitzgerald, J.D. Parker, G. Newton, J.S. Floras, T.D. Bradley, Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure, Am. J. Respir. Crit. Care Med. 160 (1999) 1101–1106. [6] M. Naughton, D. Benard, A. Tam, et al., Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure, Am. Rev. Respir. Dis. 148 (2) (1993) 330–338. [7] P. Solin, T. Roebuck, D.P. Johns, E.H. Walters, M.T. Naughton, Peripheral and central ventilatory responses in central sleep apnea with and without heart failure, Am. J. Respir. Crit. Care Med. 162 (2000) 2194–2200. [8] I. Szollosi, B.R. Thompson, H. Krum, D.M. Kaye, M.T. Naughton, Impaired pulmonary diffusing capacity and hypoxia in heart failure correlates with central sleep apnea severity, Chest 134 (2008) 67–72. [9] K. Kee, M.T. Naughton, Heart failure and the lung, Circ. J. 74 (2010) 2507–2516. [10] M.T. Naughton, D.C. Benard, P.P. Liu, R. Rutherford, F. Rankin, T.D. Bradley, Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea, Am. J. Respir. Crit. Care Med. 152 (1995) 473–479. [11] D.R. Mansfield, D.M. Kaye, P. Hans Brunner, M. Esler, M.T. Naughton, Raised sympathetic nerve activity in heart failure and central sleep apnea is due to heart failure severity, Circulation 107 (2003) 1396–1400. [12] D. Yumino, H. Wang, J.S. Floras, G.E. Newton, S. Mak, P. Ruttanaumpawan, et al., Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction, J. Card. Fail. 15 (2009) 279–285. [13] M. MacDonald, et al., The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers, J. Clin. Sleep Med. 4 (2008) 38–42. [14] P. Solin, P. Bergin, M. Richardson, D.M. Kaye, E.H. Walters, M.T. Naughton, Influence of pulmonary capillary wedge pressure on central apnea in heart failure, Circulation 99 (1999) 1574–1579. [15] P. Solin, G.I. Snell, T.J. Williams, M.T. Naughton, Central sleep apnoea in congestive heart failure despite vagal denervation after bilateral lung transplantation, Eur. Respir. J. 12 (1998) 495–498. [16] I.H. Iftikhar, C.W. Valentine, L.R.A. Bittencourt, D.L. Cohen, A.C. Fedson, T. Gıslason, et al., Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis, J. Hypertens. 32 (2014) 2341–2350. [17] D.J. Gottleib, G. Yenokyan, A.B. Newman, G.T. O'Connor, et al., Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study, Circulation 122 (2010) 352–360. [18] S.A. Sands, B.A. Edwards, K. Kee, A. Turton, E.M. Skuza, T. Roebuck, et al., Loop gain as a means to predict a positive airway pressure suppression of Cheyne–Stokes respiration in heart failure patients, Am. J. Respir. Crit. Care Med. 184 (2011) 1067–1075. [19] R.S.T. Leung, M.A. Huber, T. Rogge, et al., Association between atrial fibrillation and central sleep apnea, Sleep 28 (2005) 1543–1546. [20] C. Bassetti, M.S. Aldrich, Sleep apnea in acute cerebrovascular diseases: final report on 128 patients, Sleep 22 (1999) 217–223. [21] H. Teichtahl, A. Prodromidis, B. Miller, G. Cherry, I. Kronborg, Sleep-disordered breathing in stable methadone programme patients: a pilot study, Addiction 96 (2001) 395–403. [22] P.J. Berger, E.M. Skuza, V. Brodecky, S.M. Cranage, T.M. Adamson, M.H. Wilkinson, Unusual respiratory response to oxygen in an infant with repetitive cyanotic episodes, Am. J. Respir. Crit. Care Med. 161 (2000) 2107–2111. [23] Y. Nussbaumer-Ochsner, N. Schuepfer, S. Ulrich, K.E. Bloch, Exacerbation of sleep apnoea by frequent central events in patients with the obstructive sleep apnoea syndrome at altitude: a randomised trial, Thorax 65 (2010) 429–435.
[24] A. Rechtschaffen, A. Kales, A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects, Public Health Service, U.S. Government Printing Office, 1968. [25] R. Tkacova, M. Niroumand, G. Lorenzi-Filho, et al., Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO2 and circulatory delay, Circulation 103 (2001) 238–243. [26] F.J. Nieto, T.B. Young, B.K. Lind, E. Shahar, J.M. Samet, S. Redline, et al., Association of sleep-disordered breathing, sleep apnea, and hypertension in a large communitybased study, JAMA 283 (2000) 1829–1836. [27] O. Oldenburg, B. Lamp, L. Faber, H. Teschler, Topfer V. Horstkotte, Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients, Eur. J. Heart Fail. 9 (2007) 251–257. [28] M. Macdonald, J. Fang, S.D. Pittman, D.P. White, A. Malhotra, The current prevalence of sleep disordered breathing in congestive heart failure patients treated with betablockers, J. Clin. Sleep Med. 4 (2008) 38–42. [29] G.D. Pinna, R. Maestri, A. Mortara, P. Johnson, D. Andrews, P. Ponikowski, et al., Longterm time-course of nocturnal breathing disorders in heart failure patients, Eur. Respir. J. 35 (2010) 361–367. [30] U. Corrà, M. Pistono, A. Mezzani, A. Braghiroli, A. Giordano, P. Lanfranchi, et al., Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence, Circulation 113 (2006) 44–50. [31] P.J. Hanly, N.S. Zuberi-Khokhar, Increased mortality associated with Cheyne Stokes respiration in patients with congestive heart failure, Am. J. Respir. Crit. Care Med. 53 (1996) 272–276. [32] P.A. Lanfranchi, A. Braghiroli, E. Bosimini, et al., Prognostic value of nocturnal Cheyne– Stokes respiration in chronic heart failure, Circulation 99 (1999) 1435–1440. [33] D.D. Sin, A.G. Logan, F.S. Fitzgerald, P.P. Liu, T.D. Bradley, Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne–Stokes respiration, Circulation 102 (2000) 61–66. [34] S. Andreas, G. Hagenah, G.S. Moller Werner, H. Kreuzer, Cheyne–Stokes respiration and prognosis in congestive heart failure, Am. J. Cardiol. 78 (1996) 1260–1264. [35] E. Traversi, G. Callegari, M. Pozzoli, C. Opasich, L. Tavazzi, Sleep disorders and breathing alterations in patients with chronic heart failure, G. Ital. Cardiol. 27 (1997) 423–429. [36] T. Roebuck, P. Solin, D.M. Kaye, P. Bergin, M.T. Naughton, Increased long term mortality due to sleep apnea in heart failure is yet to be proven, Eur. Respir. J. 23 (2004) 735–740. [37] Q. Luo, H.-L. Zhang, X.-C. Tao, Y.-J. Yang, Z.-H. Liu, Impact of untreated sleep apnea on prognosis of patients with congestive heart failure, Int. J. Cardiol. 3 (2009) 420–422. [38] R. Khayat, D. Jarjoura, K. Porter, A. Sow, J. Wannemacher, R. Dohar, et al., Sleep disordered breathing and post-discharge mortality in patients with acute heart failure, Eur. Heart J. 36 (2015) 1463–1469. [39] W. Grimm, A. Sosnovskaya, N. Timmesfeld, O. Hildebrandt, U. Koehler, Prognostic impact of central sleep apnea in patients with heart failure, J. Card. Fail. 21 (2015) 126–133. [40] M.T. Naughton, Controversies in sleep medicine. Is Cheyne–Stokes detrimental in patients with congestive heart failure? Sleep Breath. 4 (2000) 127–128. [41] M.T. Naughton, Cheyne Stokes respiration: friend or foe? Thorax 67 (2012) 357–360. [42] E. Shahar, C.W. Whitney, S. Redline, E.T. Lee, A.B. Newman, F.J. Nieto, et al., Sleepdisordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study, Am. J. Respir. Crit. Care Med. 163 (2001) 19–25. [43] D.R. Mansfield, N.C. Gollogly, M. Richardson, P. Bergin, D.M. Kaye, M.T. Naughton, Randomised trial of continuous positive airway treatment of obstructive sleep apnea in heart failure, Am. J. Respir. Crit. Care Med. 169 (2004) 1–6. [44] S. Javaheri, E.B. Caref, E. Chen, K.B. Tong, W.T. Abraham, Sleep apnea testing and outcomes in a large cohort of Medicare beneficiaries with newly diagnosed heart failure, Am. J. Respir. Crit. Care Med. 183 (2011) 539–546.
Please cite this article as: M.T. Naughton, Epidemiology of central sleep apnoea in heart failure, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.02.125