Canadian Journal of Cardiology 31 (2015) 898e908
Review
Heart Failure and Sleep Apnea Owen D. Lyons, MBBCh,a,b and T. Douglas Bradley, MDa,b,c a
Sleep Research Laboratory of the University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada b c
Centre for Sleep Medicine and Circadian Biology of the University of Toronto, Toronto, Ontario, Canada
Department of Medicine of the University Health Network Toronto General Hospital, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Obstructive and central sleep apnea are far more common in heart failure patients than in the general population and their presence might contribute to the progression of heart failure by exposing the heart to intermittent hypoxia, increased preload and afterload, sympathetic nervous system activation, and vascular endothelial dysfunction. There is now substantial evidence that supports a role for fluid overload and nocturnal rostral fluid shift from the legs as unifying mechanisms in the pathogenesis of obstructive and central sleep apnea in heart failure patients, such that the predominant type of sleep apnea is related to the relative distribution of fluid from the leg to the neck and chest. Despite advances in therapies for heart failure, mortality rates remain high. Accordingly, the identification and treatment of sleep apnea in patients with heart failure might offer a novel therapeutic target to modulate this increased risk. In heart failure patients
e obstructive et l’apne e centrale du sommeil sont beaucoup L’apne quentes chez les patients souffrant d’insuffisance cardiaque plus fre ne rale. Par conse quent, leur pre sence conque dans la population ge tribuerait à la progression de l’insuffisance cardiaque en exposant le charge cœur à une hypoxie intermittente, à une augmentation de la pre et de la postcharge, à l’activation du système nerveux sympathique et liale vasculaire. Il existe de sormais des preá la dysfonction endothe uves solides qui appuient le rôle de la surcharge liquidienne et du placement rostral des fluides des jambes pendant la nuit puisqu’il de canismes de la pathogenèse de l’apne e obstructive et de unifie les me e centrale du sommeil chez les patients souffrant d’insuffisance l’apne dominant d’apne e du sommeil soit cardiaque de façon que le type pre à la distribution relative des fluides des jambes vers le cou et la lie pit des avance es dans les traitements de l’insuffisance poitrine. En de
It is estimated that heart failure (HF) affects > 260,000 Canadians.1 These patients have a poor prognosis with average 1-year mortality of 33%.2 Furthermore, HF accounts for approximately 30,000 hospital admissions in Canada each year, with readmission rates within 1 year as high as 24%.2 Until the last decade of the 20th century, 5-year mortality rates for HF were as high as 70%.3 However, over the past 20 years, improvements in the treatment of HF with angiotensinconverting enzyme inhibitors, mineralocorticoid receptor antagonists, b-blockers, implantable cardioverter defibrillators, and cardiac resynschronization therapy have led to improved survival and reduced hospitalizations.3-6 Despite these advances in HF therapy, mortality remains high.3-6 Obstructive and central sleep apnea (OSA and CSA, respectively) are common in HF patients with either reduced7-9 or preserved left ventricular (LV) ejection fraction
(LVEF).10-12 OSA and CSA might participate in the progression of HF by exposing the heart to intermittent hypoxia, increased preload, afterload,13,14 and sympathetic nervous system activity (SNA),15 and vascular endothelial dysfunction.16 However, although there is substantial evidence that the presence of sleep apnea in HF patients contributes to disease progression and that treatment of OSA and CSA improves cardiovascular function in patients with HF, large longterm randomized trials of different interventions are required to determine whether treatment of OSA and CSA can improve morbidity and mortality. The high prevalence of OSA and CSA in HF is similar to that in end-stage renal disease,17 another condition characterized by fluid overload. This observation suggests that fluid overload might contribute to the pathogenesis of OSA and CSA in these conditions. Overnight rostral fluid shift from the legs to the neck and lungs has been shown to contribute to the pathogenesis of OSA and CSA, respectively, in various patient populations, including HF, and treatment that reduces total body fluid or overnight fluid shift can attenuate sleep apnea. The aims of this article are to: review the clinical features and epidemiology of OSA and CSA in HF patients; discuss the pathophysiology of OSA and CSA including the role of fluid retention and displacement; consider the effect of OSA
Received for publication February 2, 2015. Accepted April 12, 2015. Corresponding author: Dr T. Douglas Bradley, University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. Tel.: þ1-416-340-4719; fax: þ1-416-340-4197. E-mail: [email protected] See page 905 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.04.017 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Lyons and Bradley Heart Failure and Sleep Apnea
899
with obstructive or central sleep apnea, continuous positive airway pressure has been shown to improve cardiovascular function in shortterm trials but this has not translated to improved mortality or reduced hospital admissions in long-term randomized trials. Other forms of positive airway pressure such as adaptive servoventilation have shown promising results in terms of attenuation of sleep apnea and improvement in cardiovascular function in short-term trials. Large scale, randomized trials are required to determine whether treating sleep apnea with various interventions can reduce morbidity and mortality.
restent e leve s. Par conse quent, cardiaque, les taux de mortalite e du sommeil chez les patients l’identification et le traitement de l’apne souffrant d’insuffisance cardiaque offriraient une nouvelle cible rapeutique pour moduler cette augmentation du risque. Chez les the e obstructive ou d’apne e centrale du sompatients souffrant d’apne te de montre au cours d’essais de courte dure e que meil, il a e liore la fonction la pression positive expiratoire continue ame lioration de la cardiovasculaire, mais cela ne s’est pas traduit par l’ame ou la re duction des admissions à l’hôpital au cours d’essais à mortalite partition ale atoire de longue dure e. D’autres types de pression pore e a montre des sitive expiratoire comme la servoventilation adapte sultats prometteurs en matière d’atte nuation de l’apne e du sommeil re lioration de la fonction cardiovasculaire au cours d’essais et d’ame e. Des essais à re partition ale atoire de grande e chelle de courte dure cessaires pour de terminer si le traitement de l’apne e du sont ne duire la morbidite et la sommeil selon diverses interventions peut re . mortalite
and CSA on cardiac function and clinical outcomes in HF; discuss treatment; and finally, consider gaps in knowledge in need of resolution. Because of the relative paucity of literature concerning sleep apnea in HF with preserved LVEF, the main focus of this article is on sleep apnea in HF with reduced LVEF.
subsequent prospective analysis of the same study involving 1927 men and 2495 women 40 years of age, free of heart disease at the time of PSG, and who were followed for 8 years, found that after adjusting for confounders, OSA increased the risk of new-onset HF in men (hazard ratio [HR], 1.13 [95% confidence interval (CI), 1.02-1.26] per 10-unit increase in AHI) but not in women. Men with an AHI > 30 events per hour are 58% more likely to develop HF than those with an AHI < 5.22 Among HF patients, reported prevalence of OSA varies widely; using an AHI cutoff of 15, prevalence was 12%, 15%, 26%, and 32%.7,8,23,24 Some of these differences could be because of differing populations in which men and women,8,23 or only men were included,7,24 or to differing medical therapy that has changed over time. Nevertheless, in general, these rates are higher than in the general population. Risk factors for OSA in the general population, such as older age, male sex, and higher body mass index (BMI) are also risk factors for OSA in HF.23 However, HF patients have a lower BMI for any given AHI than the general population and the correlation between BMI and AHI is weak.25
Definitions and Diagnosis Obstructive apneas and hypopneas are caused by complete or partial upper airway (UA) collapse during sleep, respectively. Central apneas and hypopneas arise from complete or partial reductions in central neural outflow to the respiratory muscles during sleep. OSA and CSA are usually diagnosed using overnight polysomnography (PSG). Apneas are defined as the absence of tidal volume for at least 10 seconds and hypopnea is defined as a decrease in the tidal volume of 30% for at least 10 seconds that is accompanied by at least a 3% decrease in oxygen saturation or terminated by an arousal from sleep.18 Apneas are classified as obstructive if they are accompanied by inspiratory effort against the occluded pharynx and central if they are not. Hypopneas are classified as obstructive if there are signs of UA flow limitation, or central if there are not.18 The apnea-hypopnea index (AHI) is the number of apneas and hypopneas per hour of sleep. Sleep apnea severity can be classified according to the AHI; no sleep apnea is defined as an AHI of < 5, mild sleep apnea as an AHI of 5-15, moderate as an AHI of 15-30, and severe as an AHI > 30.19
CSA The prevalence of CSA in the general population is very low at < 1%.26 In contrast, among HF patients, prevalence of CSA, using an AHI cutoff of 15 were 21%, 29%, and 37%.7,8,23 Risk factors for CSA in HF patients include male sex, hypocapnia, atrial fibrillation, and increasing age.8 Pathogenesis of Sleep Apnea in HF
Epidemiology OSA In a recent study, the prevalence of OSA in the general population aged 30-70 years, using an AHI cutoff 5 were 34% among men and 17% among women, and using an AHI cutoff 15, 13% among men and 6% among women.20 In a cross-sectional analysis of the Sleep Heart Health Study, comprised of > 6000 men and women, the presence of OSA, with an AHI 11, conferred a 2.38 relative increase in the likelihood of having HF independent of other risk factors.21 A
OSA Obstructive apneas and hypopneas are caused by complete or partial UA collapse, which occurs when sleep-related loss in UA dilator muscle tone is superimposed on a narrow and/or collapsible UA.27,28 Compared with subjects without OSA, patients with OSA have a smaller UA cross-sectional area, and higher UA resistance and compliance.29,30 The UA of patients with OSA is more collapsible when exposed to negative pressure during wakefulness or under passive conditions during sleep than in healthy subjects.31,32 UA narrowing is
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often due to an increase in surrounding soft tissue because of muscular hypertrophy, and fat or fluid accumulation in the tongue, soft palate, uvula, and lateral pharyngeal walls. In OSA patients, UA narrowing is predominantly in the lateralmedial direction rather than in the anterior-posterior direction and UA cross-sectional area is inversely related to thickness of the lateral pharyngeal walls.33,34 The internal jugular veins lie lateral to the pharynx and their volume and pressure increase with movement from upright to supine.35,36 Their distension in hypervolemic states, such as renal failure and HF, displaces their lateral walls outwardly, increasing neck circumference. Because neck circumference correlates with the AHI, outward expansion of the neck might be accompanied by inward displacement of the lateral pharyngeal walls that could impinge on the UA lumen.37 Pharyngeal mucosal edema could result from increased pressure of the neck veins. In patients with renal failure, internal jugular vein volume and pharyngeal mucosal water content, assessed using magnetic resonance imaging, are related to the AHI, suggesting that fluid overload facilitates UA collapse and OSA by contributing to extravascular and intravascular fluid accumulation surrounding the UA.38 There is now substantial evidence in HF patients to support a role for fluid overload in the pathogenesis of OSA, by contributing to increased neck fluid accumulation with a consequent increase in peripharyngeal tissue pressure and a reduction in UA size as discussed later herein. CSA Ventilation is almost exclusively dependent on the metabolic respiratory control system during nonrapid eye movement (NREM) sleep, and during wakefulness and rapid eye movement (REM) sleep, it is also influenced by the behavioural control system. The primary stimulation for ventilation during sleep is the partial pressure of carbon dioxide in arterial blood (PaCO2). Central apneas during sleep occur when PaCO2 decreases to below the threshold level of PaCO2 required to stimulate breathing.39 HF patients with CSA chronically hyperventilate, causing hypocapnia with PaCO2 closer to the apnea threshold than normal.40,41 Subsequently, during sleep, an increase in ventilation from any cause, such as an arousal, can drive the PaCO2 toward or below the apnea threshold, causing a partial or complete cessation of central drive to the respiratory muscles, triggering central hypopneas and apneas, respectively. Chronic hyperventilation occurs in HF because of pulmonary vagal irritant receptor stimulation, due to pulmonary congestion,9,42 and increases in central and peripheral chemosensitivity of unknown origin.43,44 Because central apneas are due to instability of the metabolic control system, they occur predominantly in NREM sleep, and seldom in REM sleep when ventilation is mainly under nonmetabolic/behavioural control and is relatively insensitive to changes in PaCO2. In HF patients, it has been shown that there is an overnight rostral fluid shift out of the intravascular and interstitial compartments of the legs due to gravity.45 The resulting increase in venous return to the heart and thorax could increase pulmonary capillary wedge pressure and lung water.46,47 The role of fluid overload and overnight fluid shift in the pathogenesis of CSA is discussed in the following section.
Canadian Journal of Cardiology Volume 31 2015
Figure 1. Relationship between overnight change in leg fluid volume (LFV) and apnea-hypopnea index (AHI) in heart failure patients with either predominantly obstructive or central sleep apnea. Reproduced from Yumino et al.51 with permission from the American Heart Association.
Fluid overload and overnight fluid shiftda unifying mechanism in the pathogenesis of OSA and CSA in HF Using bioelectrical impedance to measure leg fluid volume before and after sleep, it was shown that there are strong relationships between the overnight reduction in leg fluid volume and OSA severity determined according to the AHI or apnea-hypopnea time in nonobese men, patients with drugresistant hypertension, renal failure, and HF.48-50 In HF patients, Yumino et al. investigated the role of overnight rostral fluid shift in the pathogenesis of OSA and CSA.51 Among patients with predominantly OSA, there were strong relationships between the overnight reduction in leg fluid volume and the overnight increase in neck circumference (r ¼ 0.780; P < 0.001) and the AHI (r ¼ 0.881; P < 0.001; Fig. 1).51 In central-dominant patients, the overnight reduction in leg fluid volume correlated inversely with the AHI (r ¼ 0.919; P < 0.001) and the overnight change in neck circumference (r ¼ 0.568; P ¼ 0.013) and directly with transcutaneous partial pressure of carbon dioxide (PCO2) (r ¼ 0.569; P ¼ 0.009; Fig. 1). This latter observation suggested that some of the fluid from the legs was accumulating in the lungs where it would stimulate irritant receptors, increase ventilation, and reduce PCO2. In a subsequent study, Kasai et al.52 mimicked overnight rostral fluid shift by applying 40 mm Hg pressure to the legs via inflation of antishock trousers. Inflating the trousers reduced leg fluid volume and increased neck circumference in obstructive- and central-dominant groups. In the OSA-dominant group, fluid displacement from the legs also led to an increase in UA resistance that was accompanied by a reduction in minute volume of ventilation and an increase in PCO2. These data indicated that fluid shift from the legs induced a significant degree of UA obstruction while awake, and imply that spontaneous rostral fluid shift from the legs overnight could cause similar effects and provoke or worsen OSA in HF patients. In contrast, among HF patients with CSA, inflating the trousers reduced UA resistance, increased minute volume of ventilation, and reduced PCO2. These findings indicated that in HF patients with CSA, rostral fluid shift augmented respiratory drive, presumably via fluid accumulation in the lungs
Lyons and Bradley Heart Failure and Sleep Apnea
that stimulated pulmonary vagal irritant receptors. Such stimulation probably increased UA dilator muscle and respiratory pump muscle activity, resulting in reduced UA resistance and PCO2. Compared with the OSA patients, those with CSA had higher baseline right ventricular systolic pressure, more mitral regurgitation, and higher brain natriuretic peptide (BNP) levels. These findings suggested that CSA patients were more fluid-overloaded with a higher left atrial pressure than those with OSA and were therefore more susceptible to fluid accumulation in the lungs. Taken together, these findings suggest that nocturnal rostral fluid shift is a unifying mechanism in the pathogenesis of OSA and CSA in HF patients with the type of sleep apnea being determined by whether fluid shift from the leg is redistributed predominantly to the neck or chest. In patients with HF and other fluid overload conditions, interventions that reduce total body fluid volume attenuate sleep apnea. In patients with renal failure, conversion from conventional to nocturnal hemodialysis alleviated OSA and CSA.53 Although fluid volumes were not measured, it is likely that greater fluid volume removal by nocturnal hemodialysis contributed to the reduction in AHI. Also, conversion from nocturnal to continuous ambulatory peritoneal dialysis, in which less fluid was removed at night, led to a decrease in UA size, an increase in tongue volume, and a 55% increase in the AHI, in association with an increase in total body water.54 In patients with nephrotic syndrome, leg edema, and OSA, treatment with steroids resolved edema, reduced total body water, and reduced the AHI by 50%.55 In patients with exacerbations of diastolic heart failure who had coexisting OSA, aggressive diuresis was accompanied by an increase in UA size and a 24% decrease in the AHI. These findings suggested that UA edema contributed to severity of OSA.56 In patients with drug-resistant hypertension, treatment with spironolactone for 8 weeks was accompanied by a 50% decrease in the AHI, in association with diuresis and reduced blood pressure.57 More recently, Kasai et al. showed that intensified diuretic therapy over a 14-day period in patients with drug-resistant hypertension reduced the AHI by 16% and the overnight change in leg fluid volume by 26% (P < 0.001).58 These data strongly support a role of fluid retention and/or nocturnal rostral fluid shift in the pathogenesis of OSA and CSA in a variety of conditions including HF. Pathophysiological Consequences of OSA and CSA in HF During NREM sleep, the cardiovascular system is normally in a state of relaxation.59 Vagal output increases and SNA, heart rate, cardiac output, and systemic vascular resistance all decrease.60-62 Although there might be intermittent surges in SNA, heart rate, and blood pressure in REM sleep and after spontaneous arousals, typically the mean heart rate and blood pressure during sleep are below waking levels.60 The presence of OSA or CSA, however, disrupts this quiescent state with adverse cardiovascular consequences that might contribute to the progression of HF.63,64 OSA In OSA, repetitive cycles of apneas and hypopneas lead to exaggerated swings in negative intrathoracic pressure in an
901
effort to overcome UA occlusion.14,65 This increases LV transmural pressure (the difference between intracardiac and intrathoracic pressure) and hence afterload.65 Venous return also increases, which augments right ventricular preload, resulting in right ventricular distension and a leftward shift of the interventricular septum during diastole that impedes LV filling.66,67 The combination of reduced LV preload and increased LV afterload reduce stroke volume and cardiac output.63,68 OSA-induced intermittent hypoxia and hypercapnia stimulate peripheral and central chemoreceptors, leading to increases in SNA.69,70 Arousal from sleep at apnea termination further augments SNA and reduces cardiac vagal activity. Together these lead to postapneic surges in blood pressure and heart rate.71 The long-term consequences of OSA-induced increases in SNA coupled with intermittent hypoxia might include cardiac myocyte necrosis and apoptosis, and worsening ventricular function.59,72 OSA-induced intermittent hypoxia and subsequent postapneic reoxygenation might also lead to oxidative stress with subsequent increase of inflammatory mediators, such as tumour necrosis factor-a,73 reductions of plasma nitrate, and nitrite levels,74 and activation of transcription factors, such as nuclear factor-kb,75 which might cause vascular endothelial dysfunction.16 CSA The literature on the pathophysiological effects of CSA in HF is not as extensive as for OSA. Nevertheless, CSA has effects similar to OSA, but without the generation of exaggerated negative intrathoracic pressure, because of a lack of inspiratory effort during apneas. Central apneas, hypoxia, and arousals can cause increases in SNA, with surges in blood pressure and heart rate.76,77 SNA is further augmented during apneas by the elimination of reflex inhibition of SNA by pulmonary stretch receptors.78 This increase in SNA in HF patients with CSA also predisposes to an increased risk of ventricular ectopy.79 Clinical Features OSA Among patients with HF, OSA is often accompanied by a history of snoring.80 However, compared with the general population, HF patients complain of hypersomnolence less often and have lower Epworth Sleepiness Scale scores at any given AHI,25 even though they sleep on average 1.3 hours less than patients without HF.25 One factor that appears to contribute to the lack of hypersomnolence is markedly increased SNA during sleep and wakefulness that probably acts as an alerting stimulus via the reticular activating system in the brainstem.81,82 Two observational studies have reported that HF patients with untreated, moderate to severe OSA have an approximate 2-fold increase in all-cause mortality compared with HF patients with mild or no sleep apnea (Fig. 2).83,84 In contrast, another observational study did not find a difference in mortality rates in HF patients with and without OSA.85 However, in that study, OSA patients were not divided into those who were treated or untreated, making interpretation of
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Canadian Journal of Cardiology Volume 31 2015
Figure 3. Cumulative survival without cardiac mortality according to apnea-hypopnea index (AHI). Reproduced from Lanfranchi et al.64 with permission from Wolters Kluwer Health, Inc.
Figure 2. Multivariate Cox proportional hazards survival plots show worse survival of heart failure patients with untreated obstructive sleep apnoea (OSA) (apnea-hypopnea index 15) than in those with mild or no sleep apnea (M-NSA with apnea-hypopnea index 15 did not.116 Although not conclusive, these results suggested that CPAP might improve LVEF and heart transplant-free survival if CSA is suppressed soon after its initiation. This has led to interest in other forms of positive airway pressure, such as bilevel pressure support and adaptive servoventilation (ASV), which might be more effective in reducing the AHI than CPAP in patients with CSA. Bilevel pressure support, in the spontaneous-timed mode with a back-up rate, provides a greater pressure during inspiration and a lower pressure during expiration. ASV
904
Canadian Journal of Cardiology Volume 31 2015
Table 2. Results of short-term trials investigating effects of ASV in HF patients with CSA
Reference
Study design
AHI, events per hour N*
Duration
Pepperell et al.119
RCT Parallel
30
1 Month
Philippe et al.120
RCT Parallel RCT Parallel
25
6 Months
30
6 Weeks
RCT Parallel RCT Parallel RCT Parallel
31
3 Months
70
12 Months
72
3 Months
Fietze et al.121 Kasai et al.122,z Randerath et al.123 Arzt et al.124
LVEF, %
Intervention
Before
After
P
Before
After
P
ASV Sub-therapeutic ASV ASV CPAP ASV Bilevel pressure support ASV CPAP ASV CPAP ASV Medical therapy
21.9 11.3 17.7 13.3
5.0 1.4 20.6 2.3
< 0.001
36.5 11.5 35.7 11.3
38.3 3.3 36.3 3.8
0.7y
47.0 40.5 31.7 9.8 33.3 34.0
20.5 2.0 11.2 9.4 12.4 15.0
< 0.05y
29.0* 30.0* 24.6 7.9 25.5 9.2
36.0* 28.0* 26.5 8.8 31.1 10.5
< 0.05y
35.7 36.0 47.4 15.9 43.2 16.4 29.9 7.2 29.4 6.9
26.6 34.1 45.5 16.0 48.1 11.9 33.1 8.6 31.7 8.9
< 0.05y
36.3 38.6 46.8 40.8 48.0 47.0
19.4 13.9 23.6 17.1 18.0 19.0
1.9 15.4 11.1 17.0 11.0 47.0
2.1 12.8 11.6 17.9 10.0 22.0
< 0.001 < 0.01 < < < <
Review
Heart Failure and Sleep Apnea Owen D. Lyons, MBBCh,a,b and T. Douglas Bradley, MDa,b,c a
Sleep Research Laboratory of the University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada b c
Centre for Sleep Medicine and Circadian Biology of the University of Toronto, Toronto, Ontario, Canada
Department of Medicine of the University Health Network Toronto General Hospital, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Obstructive and central sleep apnea are far more common in heart failure patients than in the general population and their presence might contribute to the progression of heart failure by exposing the heart to intermittent hypoxia, increased preload and afterload, sympathetic nervous system activation, and vascular endothelial dysfunction. There is now substantial evidence that supports a role for fluid overload and nocturnal rostral fluid shift from the legs as unifying mechanisms in the pathogenesis of obstructive and central sleep apnea in heart failure patients, such that the predominant type of sleep apnea is related to the relative distribution of fluid from the leg to the neck and chest. Despite advances in therapies for heart failure, mortality rates remain high. Accordingly, the identification and treatment of sleep apnea in patients with heart failure might offer a novel therapeutic target to modulate this increased risk. In heart failure patients
e obstructive et l’apne e centrale du sommeil sont beaucoup L’apne quentes chez les patients souffrant d’insuffisance cardiaque plus fre ne rale. Par conse quent, leur pre sence conque dans la population ge tribuerait à la progression de l’insuffisance cardiaque en exposant le charge cœur à une hypoxie intermittente, à une augmentation de la pre et de la postcharge, à l’activation du système nerveux sympathique et liale vasculaire. Il existe de sormais des preá la dysfonction endothe uves solides qui appuient le rôle de la surcharge liquidienne et du placement rostral des fluides des jambes pendant la nuit puisqu’il de canismes de la pathogenèse de l’apne e obstructive et de unifie les me e centrale du sommeil chez les patients souffrant d’insuffisance l’apne dominant d’apne e du sommeil soit cardiaque de façon que le type pre à la distribution relative des fluides des jambes vers le cou et la lie pit des avance es dans les traitements de l’insuffisance poitrine. En de
It is estimated that heart failure (HF) affects > 260,000 Canadians.1 These patients have a poor prognosis with average 1-year mortality of 33%.2 Furthermore, HF accounts for approximately 30,000 hospital admissions in Canada each year, with readmission rates within 1 year as high as 24%.2 Until the last decade of the 20th century, 5-year mortality rates for HF were as high as 70%.3 However, over the past 20 years, improvements in the treatment of HF with angiotensinconverting enzyme inhibitors, mineralocorticoid receptor antagonists, b-blockers, implantable cardioverter defibrillators, and cardiac resynschronization therapy have led to improved survival and reduced hospitalizations.3-6 Despite these advances in HF therapy, mortality remains high.3-6 Obstructive and central sleep apnea (OSA and CSA, respectively) are common in HF patients with either reduced7-9 or preserved left ventricular (LV) ejection fraction
(LVEF).10-12 OSA and CSA might participate in the progression of HF by exposing the heart to intermittent hypoxia, increased preload, afterload,13,14 and sympathetic nervous system activity (SNA),15 and vascular endothelial dysfunction.16 However, although there is substantial evidence that the presence of sleep apnea in HF patients contributes to disease progression and that treatment of OSA and CSA improves cardiovascular function in patients with HF, large longterm randomized trials of different interventions are required to determine whether treatment of OSA and CSA can improve morbidity and mortality. The high prevalence of OSA and CSA in HF is similar to that in end-stage renal disease,17 another condition characterized by fluid overload. This observation suggests that fluid overload might contribute to the pathogenesis of OSA and CSA in these conditions. Overnight rostral fluid shift from the legs to the neck and lungs has been shown to contribute to the pathogenesis of OSA and CSA, respectively, in various patient populations, including HF, and treatment that reduces total body fluid or overnight fluid shift can attenuate sleep apnea. The aims of this article are to: review the clinical features and epidemiology of OSA and CSA in HF patients; discuss the pathophysiology of OSA and CSA including the role of fluid retention and displacement; consider the effect of OSA
Received for publication February 2, 2015. Accepted April 12, 2015. Corresponding author: Dr T. Douglas Bradley, University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. Tel.: þ1-416-340-4719; fax: þ1-416-340-4197. E-mail: [email protected] See page 905 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.04.017 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Lyons and Bradley Heart Failure and Sleep Apnea
899
with obstructive or central sleep apnea, continuous positive airway pressure has been shown to improve cardiovascular function in shortterm trials but this has not translated to improved mortality or reduced hospital admissions in long-term randomized trials. Other forms of positive airway pressure such as adaptive servoventilation have shown promising results in terms of attenuation of sleep apnea and improvement in cardiovascular function in short-term trials. Large scale, randomized trials are required to determine whether treating sleep apnea with various interventions can reduce morbidity and mortality.
restent e leve s. Par conse quent, cardiaque, les taux de mortalite e du sommeil chez les patients l’identification et le traitement de l’apne souffrant d’insuffisance cardiaque offriraient une nouvelle cible rapeutique pour moduler cette augmentation du risque. Chez les the e obstructive ou d’apne e centrale du sompatients souffrant d’apne te de montre au cours d’essais de courte dure e que meil, il a e liore la fonction la pression positive expiratoire continue ame lioration de la cardiovasculaire, mais cela ne s’est pas traduit par l’ame ou la re duction des admissions à l’hôpital au cours d’essais à mortalite partition ale atoire de longue dure e. D’autres types de pression pore e a montre des sitive expiratoire comme la servoventilation adapte sultats prometteurs en matière d’atte nuation de l’apne e du sommeil re lioration de la fonction cardiovasculaire au cours d’essais et d’ame e. Des essais à re partition ale atoire de grande e chelle de courte dure cessaires pour de terminer si le traitement de l’apne e du sont ne duire la morbidite et la sommeil selon diverses interventions peut re . mortalite
and CSA on cardiac function and clinical outcomes in HF; discuss treatment; and finally, consider gaps in knowledge in need of resolution. Because of the relative paucity of literature concerning sleep apnea in HF with preserved LVEF, the main focus of this article is on sleep apnea in HF with reduced LVEF.
subsequent prospective analysis of the same study involving 1927 men and 2495 women 40 years of age, free of heart disease at the time of PSG, and who were followed for 8 years, found that after adjusting for confounders, OSA increased the risk of new-onset HF in men (hazard ratio [HR], 1.13 [95% confidence interval (CI), 1.02-1.26] per 10-unit increase in AHI) but not in women. Men with an AHI > 30 events per hour are 58% more likely to develop HF than those with an AHI < 5.22 Among HF patients, reported prevalence of OSA varies widely; using an AHI cutoff of 15, prevalence was 12%, 15%, 26%, and 32%.7,8,23,24 Some of these differences could be because of differing populations in which men and women,8,23 or only men were included,7,24 or to differing medical therapy that has changed over time. Nevertheless, in general, these rates are higher than in the general population. Risk factors for OSA in the general population, such as older age, male sex, and higher body mass index (BMI) are also risk factors for OSA in HF.23 However, HF patients have a lower BMI for any given AHI than the general population and the correlation between BMI and AHI is weak.25
Definitions and Diagnosis Obstructive apneas and hypopneas are caused by complete or partial upper airway (UA) collapse during sleep, respectively. Central apneas and hypopneas arise from complete or partial reductions in central neural outflow to the respiratory muscles during sleep. OSA and CSA are usually diagnosed using overnight polysomnography (PSG). Apneas are defined as the absence of tidal volume for at least 10 seconds and hypopnea is defined as a decrease in the tidal volume of 30% for at least 10 seconds that is accompanied by at least a 3% decrease in oxygen saturation or terminated by an arousal from sleep.18 Apneas are classified as obstructive if they are accompanied by inspiratory effort against the occluded pharynx and central if they are not. Hypopneas are classified as obstructive if there are signs of UA flow limitation, or central if there are not.18 The apnea-hypopnea index (AHI) is the number of apneas and hypopneas per hour of sleep. Sleep apnea severity can be classified according to the AHI; no sleep apnea is defined as an AHI of < 5, mild sleep apnea as an AHI of 5-15, moderate as an AHI of 15-30, and severe as an AHI > 30.19
CSA The prevalence of CSA in the general population is very low at < 1%.26 In contrast, among HF patients, prevalence of CSA, using an AHI cutoff of 15 were 21%, 29%, and 37%.7,8,23 Risk factors for CSA in HF patients include male sex, hypocapnia, atrial fibrillation, and increasing age.8 Pathogenesis of Sleep Apnea in HF
Epidemiology OSA In a recent study, the prevalence of OSA in the general population aged 30-70 years, using an AHI cutoff 5 were 34% among men and 17% among women, and using an AHI cutoff 15, 13% among men and 6% among women.20 In a cross-sectional analysis of the Sleep Heart Health Study, comprised of > 6000 men and women, the presence of OSA, with an AHI 11, conferred a 2.38 relative increase in the likelihood of having HF independent of other risk factors.21 A
OSA Obstructive apneas and hypopneas are caused by complete or partial UA collapse, which occurs when sleep-related loss in UA dilator muscle tone is superimposed on a narrow and/or collapsible UA.27,28 Compared with subjects without OSA, patients with OSA have a smaller UA cross-sectional area, and higher UA resistance and compliance.29,30 The UA of patients with OSA is more collapsible when exposed to negative pressure during wakefulness or under passive conditions during sleep than in healthy subjects.31,32 UA narrowing is
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often due to an increase in surrounding soft tissue because of muscular hypertrophy, and fat or fluid accumulation in the tongue, soft palate, uvula, and lateral pharyngeal walls. In OSA patients, UA narrowing is predominantly in the lateralmedial direction rather than in the anterior-posterior direction and UA cross-sectional area is inversely related to thickness of the lateral pharyngeal walls.33,34 The internal jugular veins lie lateral to the pharynx and their volume and pressure increase with movement from upright to supine.35,36 Their distension in hypervolemic states, such as renal failure and HF, displaces their lateral walls outwardly, increasing neck circumference. Because neck circumference correlates with the AHI, outward expansion of the neck might be accompanied by inward displacement of the lateral pharyngeal walls that could impinge on the UA lumen.37 Pharyngeal mucosal edema could result from increased pressure of the neck veins. In patients with renal failure, internal jugular vein volume and pharyngeal mucosal water content, assessed using magnetic resonance imaging, are related to the AHI, suggesting that fluid overload facilitates UA collapse and OSA by contributing to extravascular and intravascular fluid accumulation surrounding the UA.38 There is now substantial evidence in HF patients to support a role for fluid overload in the pathogenesis of OSA, by contributing to increased neck fluid accumulation with a consequent increase in peripharyngeal tissue pressure and a reduction in UA size as discussed later herein. CSA Ventilation is almost exclusively dependent on the metabolic respiratory control system during nonrapid eye movement (NREM) sleep, and during wakefulness and rapid eye movement (REM) sleep, it is also influenced by the behavioural control system. The primary stimulation for ventilation during sleep is the partial pressure of carbon dioxide in arterial blood (PaCO2). Central apneas during sleep occur when PaCO2 decreases to below the threshold level of PaCO2 required to stimulate breathing.39 HF patients with CSA chronically hyperventilate, causing hypocapnia with PaCO2 closer to the apnea threshold than normal.40,41 Subsequently, during sleep, an increase in ventilation from any cause, such as an arousal, can drive the PaCO2 toward or below the apnea threshold, causing a partial or complete cessation of central drive to the respiratory muscles, triggering central hypopneas and apneas, respectively. Chronic hyperventilation occurs in HF because of pulmonary vagal irritant receptor stimulation, due to pulmonary congestion,9,42 and increases in central and peripheral chemosensitivity of unknown origin.43,44 Because central apneas are due to instability of the metabolic control system, they occur predominantly in NREM sleep, and seldom in REM sleep when ventilation is mainly under nonmetabolic/behavioural control and is relatively insensitive to changes in PaCO2. In HF patients, it has been shown that there is an overnight rostral fluid shift out of the intravascular and interstitial compartments of the legs due to gravity.45 The resulting increase in venous return to the heart and thorax could increase pulmonary capillary wedge pressure and lung water.46,47 The role of fluid overload and overnight fluid shift in the pathogenesis of CSA is discussed in the following section.
Canadian Journal of Cardiology Volume 31 2015
Figure 1. Relationship between overnight change in leg fluid volume (LFV) and apnea-hypopnea index (AHI) in heart failure patients with either predominantly obstructive or central sleep apnea. Reproduced from Yumino et al.51 with permission from the American Heart Association.
Fluid overload and overnight fluid shiftda unifying mechanism in the pathogenesis of OSA and CSA in HF Using bioelectrical impedance to measure leg fluid volume before and after sleep, it was shown that there are strong relationships between the overnight reduction in leg fluid volume and OSA severity determined according to the AHI or apnea-hypopnea time in nonobese men, patients with drugresistant hypertension, renal failure, and HF.48-50 In HF patients, Yumino et al. investigated the role of overnight rostral fluid shift in the pathogenesis of OSA and CSA.51 Among patients with predominantly OSA, there were strong relationships between the overnight reduction in leg fluid volume and the overnight increase in neck circumference (r ¼ 0.780; P < 0.001) and the AHI (r ¼ 0.881; P < 0.001; Fig. 1).51 In central-dominant patients, the overnight reduction in leg fluid volume correlated inversely with the AHI (r ¼ 0.919; P < 0.001) and the overnight change in neck circumference (r ¼ 0.568; P ¼ 0.013) and directly with transcutaneous partial pressure of carbon dioxide (PCO2) (r ¼ 0.569; P ¼ 0.009; Fig. 1). This latter observation suggested that some of the fluid from the legs was accumulating in the lungs where it would stimulate irritant receptors, increase ventilation, and reduce PCO2. In a subsequent study, Kasai et al.52 mimicked overnight rostral fluid shift by applying 40 mm Hg pressure to the legs via inflation of antishock trousers. Inflating the trousers reduced leg fluid volume and increased neck circumference in obstructive- and central-dominant groups. In the OSA-dominant group, fluid displacement from the legs also led to an increase in UA resistance that was accompanied by a reduction in minute volume of ventilation and an increase in PCO2. These data indicated that fluid shift from the legs induced a significant degree of UA obstruction while awake, and imply that spontaneous rostral fluid shift from the legs overnight could cause similar effects and provoke or worsen OSA in HF patients. In contrast, among HF patients with CSA, inflating the trousers reduced UA resistance, increased minute volume of ventilation, and reduced PCO2. These findings indicated that in HF patients with CSA, rostral fluid shift augmented respiratory drive, presumably via fluid accumulation in the lungs
Lyons and Bradley Heart Failure and Sleep Apnea
that stimulated pulmonary vagal irritant receptors. Such stimulation probably increased UA dilator muscle and respiratory pump muscle activity, resulting in reduced UA resistance and PCO2. Compared with the OSA patients, those with CSA had higher baseline right ventricular systolic pressure, more mitral regurgitation, and higher brain natriuretic peptide (BNP) levels. These findings suggested that CSA patients were more fluid-overloaded with a higher left atrial pressure than those with OSA and were therefore more susceptible to fluid accumulation in the lungs. Taken together, these findings suggest that nocturnal rostral fluid shift is a unifying mechanism in the pathogenesis of OSA and CSA in HF patients with the type of sleep apnea being determined by whether fluid shift from the leg is redistributed predominantly to the neck or chest. In patients with HF and other fluid overload conditions, interventions that reduce total body fluid volume attenuate sleep apnea. In patients with renal failure, conversion from conventional to nocturnal hemodialysis alleviated OSA and CSA.53 Although fluid volumes were not measured, it is likely that greater fluid volume removal by nocturnal hemodialysis contributed to the reduction in AHI. Also, conversion from nocturnal to continuous ambulatory peritoneal dialysis, in which less fluid was removed at night, led to a decrease in UA size, an increase in tongue volume, and a 55% increase in the AHI, in association with an increase in total body water.54 In patients with nephrotic syndrome, leg edema, and OSA, treatment with steroids resolved edema, reduced total body water, and reduced the AHI by 50%.55 In patients with exacerbations of diastolic heart failure who had coexisting OSA, aggressive diuresis was accompanied by an increase in UA size and a 24% decrease in the AHI. These findings suggested that UA edema contributed to severity of OSA.56 In patients with drug-resistant hypertension, treatment with spironolactone for 8 weeks was accompanied by a 50% decrease in the AHI, in association with diuresis and reduced blood pressure.57 More recently, Kasai et al. showed that intensified diuretic therapy over a 14-day period in patients with drug-resistant hypertension reduced the AHI by 16% and the overnight change in leg fluid volume by 26% (P < 0.001).58 These data strongly support a role of fluid retention and/or nocturnal rostral fluid shift in the pathogenesis of OSA and CSA in a variety of conditions including HF. Pathophysiological Consequences of OSA and CSA in HF During NREM sleep, the cardiovascular system is normally in a state of relaxation.59 Vagal output increases and SNA, heart rate, cardiac output, and systemic vascular resistance all decrease.60-62 Although there might be intermittent surges in SNA, heart rate, and blood pressure in REM sleep and after spontaneous arousals, typically the mean heart rate and blood pressure during sleep are below waking levels.60 The presence of OSA or CSA, however, disrupts this quiescent state with adverse cardiovascular consequences that might contribute to the progression of HF.63,64 OSA In OSA, repetitive cycles of apneas and hypopneas lead to exaggerated swings in negative intrathoracic pressure in an
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effort to overcome UA occlusion.14,65 This increases LV transmural pressure (the difference between intracardiac and intrathoracic pressure) and hence afterload.65 Venous return also increases, which augments right ventricular preload, resulting in right ventricular distension and a leftward shift of the interventricular septum during diastole that impedes LV filling.66,67 The combination of reduced LV preload and increased LV afterload reduce stroke volume and cardiac output.63,68 OSA-induced intermittent hypoxia and hypercapnia stimulate peripheral and central chemoreceptors, leading to increases in SNA.69,70 Arousal from sleep at apnea termination further augments SNA and reduces cardiac vagal activity. Together these lead to postapneic surges in blood pressure and heart rate.71 The long-term consequences of OSA-induced increases in SNA coupled with intermittent hypoxia might include cardiac myocyte necrosis and apoptosis, and worsening ventricular function.59,72 OSA-induced intermittent hypoxia and subsequent postapneic reoxygenation might also lead to oxidative stress with subsequent increase of inflammatory mediators, such as tumour necrosis factor-a,73 reductions of plasma nitrate, and nitrite levels,74 and activation of transcription factors, such as nuclear factor-kb,75 which might cause vascular endothelial dysfunction.16 CSA The literature on the pathophysiological effects of CSA in HF is not as extensive as for OSA. Nevertheless, CSA has effects similar to OSA, but without the generation of exaggerated negative intrathoracic pressure, because of a lack of inspiratory effort during apneas. Central apneas, hypoxia, and arousals can cause increases in SNA, with surges in blood pressure and heart rate.76,77 SNA is further augmented during apneas by the elimination of reflex inhibition of SNA by pulmonary stretch receptors.78 This increase in SNA in HF patients with CSA also predisposes to an increased risk of ventricular ectopy.79 Clinical Features OSA Among patients with HF, OSA is often accompanied by a history of snoring.80 However, compared with the general population, HF patients complain of hypersomnolence less often and have lower Epworth Sleepiness Scale scores at any given AHI,25 even though they sleep on average 1.3 hours less than patients without HF.25 One factor that appears to contribute to the lack of hypersomnolence is markedly increased SNA during sleep and wakefulness that probably acts as an alerting stimulus via the reticular activating system in the brainstem.81,82 Two observational studies have reported that HF patients with untreated, moderate to severe OSA have an approximate 2-fold increase in all-cause mortality compared with HF patients with mild or no sleep apnea (Fig. 2).83,84 In contrast, another observational study did not find a difference in mortality rates in HF patients with and without OSA.85 However, in that study, OSA patients were not divided into those who were treated or untreated, making interpretation of
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Canadian Journal of Cardiology Volume 31 2015
Figure 3. Cumulative survival without cardiac mortality according to apnea-hypopnea index (AHI). Reproduced from Lanfranchi et al.64 with permission from Wolters Kluwer Health, Inc.
Figure 2. Multivariate Cox proportional hazards survival plots show worse survival of heart failure patients with untreated obstructive sleep apnoea (OSA) (apnea-hypopnea index 15) than in those with mild or no sleep apnea (M-NSA with apnea-hypopnea index 15 did not.116 Although not conclusive, these results suggested that CPAP might improve LVEF and heart transplant-free survival if CSA is suppressed soon after its initiation. This has led to interest in other forms of positive airway pressure, such as bilevel pressure support and adaptive servoventilation (ASV), which might be more effective in reducing the AHI than CPAP in patients with CSA. Bilevel pressure support, in the spontaneous-timed mode with a back-up rate, provides a greater pressure during inspiration and a lower pressure during expiration. ASV
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Canadian Journal of Cardiology Volume 31 2015
Table 2. Results of short-term trials investigating effects of ASV in HF patients with CSA
Reference
Study design
AHI, events per hour N*
Duration
Pepperell et al.119
RCT Parallel
30
1 Month
Philippe et al.120
RCT Parallel RCT Parallel
25
6 Months
30
6 Weeks
RCT Parallel RCT Parallel RCT Parallel
31
3 Months
70
12 Months
72
3 Months
Fietze et al.121 Kasai et al.122,z Randerath et al.123 Arzt et al.124
LVEF, %
Intervention
Before
After
P
Before
After
P
ASV Sub-therapeutic ASV ASV CPAP ASV Bilevel pressure support ASV CPAP ASV CPAP ASV Medical therapy
21.9 11.3 17.7 13.3
5.0 1.4 20.6 2.3
< 0.001
36.5 11.5 35.7 11.3
38.3 3.3 36.3 3.8
0.7y
47.0 40.5 31.7 9.8 33.3 34.0
20.5 2.0 11.2 9.4 12.4 15.0
< 0.05y
29.0* 30.0* 24.6 7.9 25.5 9.2
36.0* 28.0* 26.5 8.8 31.1 10.5
< 0.05y
35.7 36.0 47.4 15.9 43.2 16.4 29.9 7.2 29.4 6.9
26.6 34.1 45.5 16.0 48.1 11.9 33.1 8.6 31.7 8.9
< 0.05y
36.3 38.6 46.8 40.8 48.0 47.0
19.4 13.9 23.6 17.1 18.0 19.0
1.9 15.4 11.1 17.0 11.0 47.0
2.1 12.8 11.6 17.9 10.0 22.0
< 0.001 < 0.01 < < < <
