Obstructive Sleep Apnea and Heart Failure

Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 57, No. 2, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.08.627

STATE-OF-THE-ART PAPER

Obstructive Sleep Apnea and Heart Failure Pathophysiologic and Therapeutic Implications Takatoshi Kasai, MD, PHD,*† T. Douglas Bradley, MD*†‡ Toronto, Ontario, Canada Obstructive sleep apnea (OSA) exposes the cardiovascular system to intermittent hypoxia, oxidative stress, systemic inflammation, exaggerated negative intrathoracic pressure, sympathetic overactivation, and elevated blood pressure (BP). These can impair myocardial contractility and cause development and progression of heart failure (HF). Epidemiological studies have shown significant independent associations between OSA and HF. On the other hand, recent prospective observational studies reported a significant association between the presence of moderate to severe OSA and increased risk of mortality in patients with HF. In randomized trials, treating OSA with continuous positive airway pressure suppressed sympathetic activity, lowered BP, and improved myocardial systolic function in patients with HF. These data suggest the potential for treatment of OSA to improve clinical outcomes for patients with HF. However, large-scale randomized trials with sufficient statistical power will be needed to ascertain whether treatment of OSA will prevent development of, or reduce morbidity and mortality from HF. (J Am Coll Cardiol 2011;57:119–27) © 2011 by the American College of Cardiology Foundation

Despite therapeutic advances, morbidity and mortality from heart failure (HF) remain high (1). Accordingly, it is important to identify treatable conditions that might contribute to the progression of HF. One such condition may be obstructive sleep apnea (OSA) (2). OSA is caused by repetitive collapse of the pharynx that triggers apneas during sleep. Repetitive apneas expose the cardiovascular system to a cascade of intermittent hypoxia, exaggerated negative intrathoracic pressure, surges in sympathetic nervous system activity (SNA) and blood pressure (BP), and frequent awakenings, all of which may have adverse cardiovascular consequences (3– 6). The purpose of this review is to highlight pathophysiological and therapeutic implications of OSA in patients with HF, and to identify areas of investigation with potential to advance the field. We confine our discussion to HF due to left ventricular (LV) systolic dysfunction. Diagnosis of OSA Apnea is defined as a ⬎90% reduction in tidal volume lasting ⱖ10 s, and hypopnea is a reduction in tidal volume

of 50% to 90%, lasting ⱖ10 s accompanied by ⱖ3% decrease in oxyhemoglobin saturation (SaO2) or terminated by arousal from sleep (7). An OSA disorder is generally defined as the presence of ⱖ5 episodes of apnea or hypopnea per hour of sleep (i.e., apnea-hypopnea index [AHI]) and when accompanied by either hypersomnolence or at least 2 episodes of choking or gasping during sleep, recurrent awakenings, unrefreshing sleep, daytime fatigue, or impaired concentration or memory, constitutes an OSA syndrome (7). OSA is usually confirmed by overnight polysomnography in a sleep laboratory during which sleep architecture, cardiac rhythm, SaO2, airflow, and thoracoabdominal movements are recorded (7,8). Because of limited availability of polysomnography, portable cardiorespiratory monitoring devices have been developed for in-home screening and diagnosis of OSA. However, many different devices are on the market, several of which have not undergone rigorous validation, particularly in the HF population. Therefore, more research is required to demonstrate their validity in HF patients. Pathogenesis of OSA

From the *Toronto Rehabilitation Institute Sleep Research Laboratory, Toronto, Ontario, Canada; †University of Toronto Centre for Sleep Medicine and Circadian Biology, Toronto, Ontario, Canada; and the ‡Department of Medicine, University Health Network Toronto General Hospital, Toronto, Ontario, Canada. This study was supported by operating grants MOP-82731 and IS2-95225 from the Canadian Institutes of Health Research (CIHR), the latter in conjunction with an unrestricted research grant from Philips-Respironics Inc. in accordance with the policies of the CIHR’s UniversityIndustry program. Dr. Kasai was supported by an unrestricted research fellowship from Fuji-Respironics Inc. Dr. Bradley received grant support from Philips-Respironics Inc. in partnership with the CIHR. Manuscript received January 12, 2010; revised manuscript received June 18, 2010, accepted August 1, 2010.

Patients with OSA generally have a narrow pharynx related to fat accumulation in the neck that compromises the pharyngeal lumen, to micrognathia, or to tonsillar hypertrophy. At sleep onset, loss of pharyngeal dilator muscle tone causes complete or partial pharyngeal collapse causing obstructive apneas and hypopneas, respectively (9). Although OSA probably contributes to the development or progression of HF, HF might also contribute to causation of OSA. According to this view, fluid accumulation in the legs

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while upright during the day could shift into the neck when recumbent during sleep. Such fluid disAF ⴝ atrial fibrillation placement might cause distension AHI ⴝ apnea-hypopnea of the neck veins and/or edema of index the peripharyngeal soft tissue that BMI ⴝ body mass index increases peripharyngeal tissue BP ⴝ blood pressure pressure, predisposing to pharynCPAP ⴝ continuous geal obstruction. positive airway pressure To explore this possibility, CSA ⴝ central sleep apnea several studies employed lower HF ⴝ heart failure body positive pressure via antiHR ⴝ heart rate shock trousers inflated to 40 mm Hg to mimic overnight rostral LV ⴝ left ventricular fluid movement in healthy nonoLVEF ⴝ left ventricular ejection fraction bese men. Lower body positive pressure displaced approximately OSA ⴝ obstructive sleep apnea 300 to 350 ml of fluid from both QOL ⴝ quality of life legs, increased neck circumference, pharyngeal airflow resisRV ⴝ right ventricle/ ventricular tance, and collapsibility, and reduced pharyngeal caliber (10 –12). SNA ⴝ sympathetic nervous system activity In 23 otherwise healthy nonobese men, Redolfi et al. (13) demonstrated that the greater the amount of fluid displaced spontaneously from the legs overnight, the greater the overnight increase in neck circumference and the AHI (R ⫽ ⫺0.773, p ⬍ 0.001). Yumino et al. (14) made similar observations in men with HF and predominantly OSA. Overnight reduction in leg fluid was, in turn, directly proportional to sitting time during the day and degree of leg edema, and inversely proportional to physical fitness. These observations strongly suggest that in HF, overnight rostral fluid displacement from the legs contributes to the severity of OSA by causing fluid accumulation in the neck that narrows the pharynx and increases its collapsibility during sleep. The volume of fluid displacement is related to sedentary living and leg edema. Nevertheless, whether OSA precedes or arises secondary to HF, once present, it is likely to provoke adverse cardiovascular effects. Night-to-night variations in rostral fluid displacement may help to explain some of the internight variability in the AHI that has been described in OSA patients without HF (15). Therefore, alterations in volume status in HF patients might also be accompanied by alterations in the AHI. However, there are few data on night-to-night variability of AHI in patients with HF. Both OSA and central sleep apnea (CSA) are common in patients with HF and can coexist in the same patient (16,17). Yumino et al. (14) showed in HF patients that with progressively greater amounts of nocturnal rostral fluid displacement, there was a gradation from an AHI ⬍15, to OSA with an AHI ⱖ15, to CSA with AHI ⱖ15. These findings help to explain why OSA and CSA can coexist in HF patients, and why the predominant type can change over time (16,18): apnea type and severity may vary accordAbbreviations and Acronyms

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ing to alterations in fluid volume status and cardiac function. For example, data from the CANPAP (CANadian continuous Positive Airway Pressure for patients with heart failure and central sleep apnea) trial demonstrated a spontaneous conversion from predominantly CSA to predominantly OSA in 18% of subjects in the control arm in association with an improvement in left ventricular ejection fraction (LVEF) (19). If the improvement in LVEF was accompanied by decreased fluid retention and overnight rostral fluid shift, this might be 1 mechanism through which this conversion occurred. Cardiovascular Effects of OSA Effects of sleep. Normally, metabolic rate, SNA, BP, and heart rate (HR) decrease (20), and cardiac vagal activity increases during non-rapid eye movement (REM) sleep (21). Although intermittent surges in SNA, BP, and HR occur in REM sleep, in general, the average BP and HR remain below waking levels (20). Thus, sleep is characterized by cardiovascular quiescence. However, this is disrupted by OSA with potentially adverse consequences. In addition, patients with HF sleep approximately 1.3 h less than subjects without HF, and may not enjoy fully the restorative effects of sleep (22,23). Mechanical effects. During obstructive apneas, negative inspiratory intrathoracic pressure generated against the occluded pharynx increases LV transmural pressure, and hence afterload (Fig. 1) (24). It also increases venous return, augmenting right ventricular (RV) pre-load, whereas OSAinduced hypoxic pulmonary vasoconstriction increases RV afterload (25). Consequent RV distension and leftward septal displacement during diastole impairs LV filling (26). This combination of increased LV afterload and diminished preload reduces stroke volume and cardiac output more in HF patients than in healthy subjects (27,28). Whereas stroke volume recovers abruptly to baseline in healthy subjects at apnea termination, recovery is delayed in patients with HF (24). Increased LV transmural pressure also increases myocardial oxygen demand while simultaneously reducing coronary blood flow during which apnea-related hypoxia reduces oxygen delivery (2,24,29). This can precipitate myocardial ischemia and impair cardiac contractility and diastolic relaxation (30,31). Over time, such stresses may contribute to development or progression of cardiac remodeling, hypertrophy, and failure. Autonomic effects. Intermittent hypoxia and CO2 retention stimulate central and peripheral chemoreceptors that augment SNA (32) (Fig. 2). Apnea also enhances SNA by eliminating reflex inhibition of SNA arising from pulmonary stretch receptors (33). Reductions in stroke volume and BP during obstructive apneas unload carotid sinus baroreceptors and reflexively augment SNA. This is exaggerated in patients with HF (29). Arousal from sleep at apnea termination also augments SNA and reduces cardiac vagal activity

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Figure 1

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Effects of OSA on the RV and LV

During obstructive sleep apnea (OSA), negative intrathoracic pressure generated against the occluded upper airway (UA) increases left ventricular (LV) transmural pressure (intracardiac minus intrathoracic pressure) and LV afterload. It also increases venous return, augmenting right ventricular (RV) pre-load, whereas OSA-induced hypoxia causes PA vasoconstriction and pulmonary hypertension. These cause RV distension and leftward displacement of the interventricular septum during diastole, which impairs LV filling and diminishes LV pre-load and stroke volume. PA ⫽ pulmonary artery; ⫹ ⫽ positive intracardiac pressure; ⫺ ⫽ negative intrathoracic pressure.

that precipitate post-apneic surges in BP and HR (34). These adverse autonomic effects of OSA may persist into wakefulness (35–37). Spaak and colleagues (38) demonstrated that among patients with HF, the presence of OSA was associated with higher muscle SNA than in those without OSA. These observations in conjunction with those of Usui et al. (39), that treating OSA with continuous positive airway pressure (CPAP) in HF patients reduced muscle SNA in association with BP lowering, indicated that OSA contributes to BP elevations partly via sympathetic excitation. Elevated SNA is associated with increased mortality risk in patients with HF (40), probably by causing cardiac beta-adrenoreceptor desensitization, myocyte injury and necrosis, and hypertension (41). Reduced cardiac vagal activity that increases HR but reduces high frequency HR variability may also contribute to an increased risk for cardiac arrhythmias and mortality (42). Therefore, OSA may contribute to worse prognosis in HF at least partly through autonomic dysregulation. Oxidative, inflammatory, and vascular endothelial effects. Intermittent hypoxia and post-apneic reoxygenation induce oxidative stress, generate reactive oxygen species, and provoke inflammation. Reactive oxygen species diminishes nitric oxide levels and hence, impairs endothelially mediated vasodilation that could contribute to development of hypertension (43). Patients with OSA have low plasma nitrite

concentrations and attenuated endothelium-dependent vasodilatation that can improve with CPAP (44). Reactive oxygen species can also activate nuclear transcriptional factors, including nuclear factor-kappa B (NF␬B), which stimulates production of inflammatory mediators such as tumor necrosis factor-␣, interleukin [IL]-6, IL-8, and C-reactive protein, as well as adhesion molecules such as intracellular and vascular cell adhesion molecules, E selectin, and CD15 (45). Such effects could facilitate endothelial damage and atherogenesis. In mice, exposure to intermittent hypoxia and a high cholesterol diet provokes lipid peroxidation and induces aortic atherosclerosis, although neither stimulus alone has this effect (46). Therefore, the combination of OSA with hypercholesterolemia may be atherogenic. Compared with control subjects, patients with OSA display greater signs of early atherosclerosis, including increased carotid intima-media thickness, and a higher prevalence of silent brain infarcts (47– 49). Nonrandomized studies reported that treatment of OSA by CPAP lowered levels of several inflammatory mediators (50,51), and a randomized trial demonstrated that treatment of OSA by CPAP reduced carotid intima-media thickness, supporting a cause– effect relationship between OSA and atherosclerosis (52). Therefore, promotion of coronary atherosclerosis, the commonest cause of HF, is another means by which OSA could contribute to the development of HF.

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Figure 2

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Cardiovascular Autonomic Effects of OSA

This diagram illustrates a number of mechanisms by which obstructive sleep apnea (OSA) augments sympathetic and diminishes parasympathetic activity. BP ⫽ blood pressure; CV ⫽ cardiovascular; HF ⫽ heart failure; HR ⫽ heart rate; HRV ⫽ heart rate variability; PNA ⫽ parasympathetic nervous system activity; SNA ⫽ sympathetic nervous system activity; SV ⫽ stroke volume.

Arrhythmogenic effects. Intermittent hypoxia can cause HR to decrease, increase, or remain constant depending on whether parasympathetic or sympathetic activity dominates, or whether their influences are relatively equal, respectively (53). In dogs, pacing of the right atrium increases the autonomic activity of the right pulmonary arterial ganglionated plexi during apnea, and induces atrial fibrillation (AF) (54). Stimulation of such ganglionated plexi during obstructive apneas may therefore be one means by which OSA can induce AF. Myocardial stretch caused by the mechanical effects of OSA may also precipitate atrial and ventricular arrhythmias (55). Myocardial ischemia and activation of cardiac inflammatory pathways can also predispose to atrial and ventricular arrhythmias (56,57). Although epidemiological studies have not demonstrated an increased prevalence of bradyarrhythmias in OSA (58), apneainduced hypoxia can provoke atrioventricular block and asystole that is reversible by atropine or treatment of OSA (59 – 61). These observations demonstrate a role for OSA in their causation. Compared with subjects without OSA, those with severe OSA are more likely to have AF, nonsustained ventricular tachycardia, ventricular bigeminy, and trigeminy (58). Several studies showed that OSA predicts new-onset AF (62,63) or its recurrence following cardioversion to sinus

rhythm (64). On the other hand, 2 studies in patients with and without HF demonstrated strong relationships between AF and CSA, but not OSA (65,66). Such discrepancies may be explained by differences in patient populations and classification of respiratory events. Two observational studies reported that treatment of OSA by tracheostomy was accompanied by a reduction in the frequency of tachyarrhythmias (67), and that the recurrence rate of AF 1 year after cardioversion was significantly lower in patients with CPAP-treated OSA than those with untreated OSA (64). In a randomized trial, treatment of OSA by CPAP in patients with HF reduced the frequency of nocturnal ventricular ectopy (68). In HF patients with cardioverterdefibrillators, device discharges occurred more frequently in patients with than those without sleep apnea, particularly during sleep time, suggesting a link between OSA and nocturnal malignant arrhythmias (4,69,70). Epidemiology and Clinical Features of OSA Data from the Sleep Heart Health Study showed that OSA with an AHI ⱖ11 was independently associated with 2.38 relative odds of having HF (4). Hypertension is likely an intermediate step between OSA and HF (3). Indeed, hypertensive subjects whose BP does not fall normally at

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Figure 3

The Prevalences of OSA Reported in 4 Studies

The prevalences of OSA reported in 4 studies involving unselected patients with HF who underwent overnight polysomnography. Ferrier et al. (73) used an apnea-hypopnea index cutoff of ⱖ10 whereas the others used ⱖ15. Abbreviations as in Figure 2.

night (i.e., nondippers) have greater risk for LV hypertrophy and failure than those whose BP falls normally at night (i.e., dippers) (71). Since OSA causes nondipping of BP at night, it may contribute to this increased risk (72). Other factors, described above, may also contribute to the development of HF. Several polysomnographic studies in HF patients reported prevalences of OSA (12% to 53%) higher than in the general population (Fig. 3) (17,73–75). Risk factors for OSA in patients with HF include older age, male sex, and

Figure 4

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greater body mass index (BMI) (17). Arzt et al. (22) reported that compared with the general population, in whom AHI increases as a function of BMI, HF patients have lower BMI for any given AHI, with a much weaker correlation between AHI and BMI. Consequently, factors other than obesity, such as nocturnal rostral fluid displacement, must play a greater role in the pathogenesis of OSA in the HF than in the general population. In patients with HF, OSA is more common in men than in women (17), and most are habitual snorers (76). However, compared with the general population, HF patients with OSA complain of hypersomnolence less often, and have lower Epworth Sleepiness Scale scores at any given AHI (22). In contrast to the general population, there is no significant relationship between the Epworth score and increasing AHI. Furthermore, for any given AHI, patients with HF have a longer sleep-onset latency, and less sleep than the general population despite being less sleepy (22). Marin et al. (5) reported, in subjects without HF, that those with untreated, severe OSA (AHI ⬎30) had a 2.9 times higher fatal cardiovascular event rate than controls (AHI ⬍5). Punjabi et al. (77) reported similar results. Wang et al. (78) reported that among 37 patients with untreated moderate to severe OSA, the mortality rate was higher than in 113 patients with mild or no OSA (p ⫽ 0.029) after controlling for confounding factors (Fig. 4). In another study, patients with HF were divided into those

Multivariate Cox Proportional Hazards Survival Plots of M-NSA Versus Untreated OSA

Multivariate Cox proportional hazards survival plots show worse survival of HF patients with untreated OSA (AHI ⱖ15) than in those with M-NSA (AHI ⬍15) (hazard ratio: 2.81, p ⫽ 0.029), after adjusting for significant confounders (left ventricular ejection fraction, New York Heart Association functional class, and age). Reproduced, with permission, from Wang et al. (78). M-NSA ⫽ mild to no sleep apnea; other abbreviations as in Figures 2 and 3.

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with ischemic (n ⫽ 79) and nonischemic (n ⫽ 114) cardiomyopathy, and were subdivided into those with and without SA of whom approximately 50% had mainly OSA. In the ischemic group, mortality was significantly higher in those with, than in those without SA (p ⫽ 0.043), due mainly to a higher sudden death rate (70). Mortality rate appeared to increase with an AHI ⬎15. In contrast, in the nonischemic group, SA was not associated with increased mortality. These data imply that patients with ischemic HF are more susceptible to the adverse effects of apnea-related hypoxia, elevated SNA, and/or cardiac arrhythmias, possibly related to worsening of myocardial ischemia, than those with nonischemic HF. In contrast, Roebuck et al. (79) did not find increased mortality associated with OSA in patients with HF. However, since they did not analyze separately those with treated and untreated OSA, conclusions are difficult to draw. Treatment of OSA in Patients With HF Effects of HF therapy on OSA. There are no studies in which the effects of therapy of HF on OSA have been tested. However, Kraiczi et al. (80) compared the efficacy of atenolol, enalapril, losartan, and hydrochlorothiazide, frequently used HF medications, on BP among hypertensive OSA patients without HF. AHI was not influenced by any of those drugs. Since fluid retention from HF may contribute to the pathogenesis of OSA, Bucca et al. (81) tested the effects of furosemide and spironolactone among 15 patients with diastolic HF and OSA in an uncontrolled trial. Following therapy, pharyngeal caliber increased in association with a slight but significant reduction in weight and AHI (from 75 to 57, p ⬍ 0.001). In 1 prospective observational study involving patients with optimally treated HF, prevalences of OSA, and CSA were unchanged over a 7-year period despite increasing use of beta-blockers and spironolactone during that time (17). These findings sug-

gest that these drugs have little effect on prevalence of OSA in stable HF patients. In a single-night cross-over study involving 15 HF patients with OSA, atrial overdrive pacing had no significant effect on the AHI (p ⫽ 0.08) (82). However, after 7 months of cardiac resynchronization therapy in 13 HF patients with OSA, the AHI decreased significantly (p ⫽ 0.04) in association with a reduction in circulation time (83). In contrast, Oldenburg et al. (84) reported that in HF patients after 5 months of cardiac resynchronization therapy, whereas the AHI fell in patients with CSA, it did not change in patients with OSA. In another uncontrolled trial, the AHI decreased by 30% in 8 HF patients with OSA following a 4-month exercise program (85). However, none of these studies examined the effect of interventions on nocturnal fluid displacement. In addition, because of their uncontrolled nature, results of these studies are inconclusive. Accordingly, randomized trials are needed to determine whether, and by what mechanisms, treatment of HF can alleviate OSA. Effects of OSA treatment on HF. CPAP acutely alleviates OSA, abolishes negative intrathoracic pressure swings, and reduces nocturnal BP and HR, resulting in reduced LV afterload (86). This cardiac unloading is accompanied by improved myocardial oxidative metabolism (87). In a 1-month randomized trial involving HF patients with severe OSA, but normal Epworth Sleepiness scores (⬍10), fixed-pressure CPAP increased LVEF by 9% in association with reduced systolic BP and HR (88). CPAP also reduced sympathetic vasoconstrictor activity (39), indicating that this was a mechanism by which BP was lowered. CPAP also increased high-frequency HR variability and baroreflex sensitivity, indicating an increase in parasympathetic modulation of HR (89,90). Egea et al. (91) also reported that in 50 HF patients with normal Epworth

Clinical Assessing of CPAP on Cardiac in HF Patients With OSA With OSA Table 1TrialsClinical TrialsEffects Assessing Effects of CPAPFunction on Cardiac Function in HF Patients Baseline

n

Duration (Months)

Control

12

1.0

CPAP

12

First Author (Ref. #) Year Kaneko et al. (88) 2003

Mansfield et al. (92) 2004

Smith et al. (93) 2007

Study Design

Changes

AHI

LVEF (%)

ESS

45.2

28.5

5.7

⫺0.5

1.5

37.1

25.0

6.8

⫺28.8*

8.8*

26.6

33.6

8.8

⫺8.4

1.5

25.0

37.6

9.5

⫺21.1*

5.0†

1

⫺3.1*

36.0

29.0

10.0

NA

1.0

NA

⫺2.0

NA

1.0

NA

SBP/DBP (mm Hg)

⫺3.0†

⫺1.6/1.2

⫺1.7

0.0/0.4

⫺3.6

ESS

RCT

RCT

6/⫺2

NA

⫺10*/⫺3

NA

Mean BP

Control

21

CPAP

19

3.0

⫺6

1.1

RCT-double crossover Sham ACPAP

23

1.5

ACPAP Egea et al.‡ (91) 2008

AHI

LVEF (%)

RCT Sham CPAP

25

CPAP

20

3.0

35.0

27.2

6.9

⫺7.3

44.0

28.8

8.6

⫺32.9

⫺0.5 2.2†

*p ⬍ 0.01 for comparison between groups. †p ⬍ 0.05 for comparison between groups. ‡This study included patients with both obstructive and central sleep apnea. Therefore, all data shown here were for patients with OSA only, except for AHI. ACPAP ⫽ auto-titrating continuous positive airway pressure; AHI ⫽ apnea-hypopnea index; CPAP ⫽ continuous positive airway pressure; DBP ⫽ diastolic blood pressure; ESS ⫽ Epworth sleepiness scale; HF ⫽ heart failure; LVEF ⫽ left ventricular ejection fraction; NA ⫽ data not available; RCT ⫽ randomized-controlled trial; SBP ⫽ systolic blood pressure.

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Observational Studies Assessing of CPAP on Morbidity and Mortalityand in HF Patients With OSA With OSA Table 2 Observational StudiesEfficacy Assessing Efficacy of CPAP on Morbidity Mortality in HF Patients Baseline Characteristics

First Author (Ref. #) Year Wang et al. (78) 2007

n

Mean/Maximum Follow-Up (yrs)

Age (yrs)

BMI (kg/m2)

Male (%)

AHI

LVEF (%)

ICM (%)

Untreated: 37

2.9/7.3

58.5

30.1

87

32.8

25.9

41

53.2

32.3

100

38.8

23.9

36

59.8

24.9

83

38.1

35.0

30

59.6

27.5*

95

45.1

36.2

22

Treated: 14 Kasai et al. (94) 2008

Untreated: 65 Treated: 23

2.1/4.8

Outcome Trend for reduced mortality in treated group (p ⫽ 0.07) Lower death and hospitalization risk in treated group (p ⫽ 0.03)

*p ⬍ 0.05 for comparison between groups. BMI ⫽ body mass index; ICM ⫽ ischemic cardiomyopathy; OSA ⫽ obstructive sleep apnea; other abbreviations as in Table 1.

scores, CPAP improved LVEF after 3 months. However, CPAP did not improve Epworth scores, quality of life (QOL), New York Heart Association functional class, or 6-min walking distance. In a 3-month randomized trial involving 40 patients with less severe HF and OSA but an elevated Epworth score (⬎10), Mansfield et al. (92) reported that CPAP reduced urinary norepinephrine concentration, and improved LVEF and QOL, but not BP. In another randomized trial, Smith et al. (93) found no improvement in LVEF in HF patients with OSA while on CPAP. In contrast to the previously mentioned trials, they used autotitrating CPAP, and did not confirm that it eliminated OSA on a sleep study at the end of the trial. These observations lead to several conclusions (Table 1). First, fixed-pressure CPAP consistently increased LVEF and decreased SNA (39,68,88,92). Second, larger CPAPrelated increases in LVEF and reductions in BP occurred in trials involving patients with lower LVEF and higher AHIs (88,91–93). Third, CPAP improved Epworth scores and QOL in patients with Epworth scores ⬎10 (92), but failed to do so in patients with Epworth scores ⬍10 (91). Finally, autotitrating-CPAP failed to improve LVEF (93). Thus, differences in trial design, methodologies, patient characteristics, and the type of CPAP employed may explain some of the discrepancies in their results. Two nonrandomized observational studies addressed the effects of treating OSA on morbidity and mortality in HF patients (Table 2). In the first, there was a trend to lower mortality in the 14 who accepted CPAP than in the 37 who did not (p ⫽ 0.07) over 2.9 years (78). In the second, involving 88 HF patients with OSA, hospitalization-free survival was significantly greater in the 65 CPAP-treated patients than in the 23 untreated patients over 2.1 years (94). Although promising, these results are not conclusive due to the nonrandomized nature of the studies and their small sample sizes. The evidence in the preceding text suggests that, just as in the non-HF population, the main indication for treating OSA in HF patients is hypersomnolence, where treating OSA reduces sleepiness and improves QOL (92). However, most HF patients with OSA are not hypersomnolent (22). In such patients, indications for treating OSA have not been clearly defined. Adequately powered randomized trials will

be required to assess whether treating OSA in nonsleepy HF patients improves cardiovascular outcomes. Conclusions OSA has adverse cardiovascular effects and is associated with reduced survival in patients with HF. Although smallscale randomized trials demonstrate that treating OSA in HF patients improves cardiovascular and autonomic function, and in patients with hypersomnolence, reduces sleepiness, such trials have not established whether treating OSA reduces morbidity and mortality. Consequently, further research is required to establish basic mechanisms by which OSA contributes to cardiac dysfunction, and large-scale randomized trials are needed to determine whether treating OSA in nonsleepy HF patients reduces morbidity and mortality. In the broader context, it would also be valuable to examine alternatives to CPAP for treating OSA in patients with HF. For example, intensified diuresis or applying the principles of chronopharmacology to block adverse nocturnal cardiovascular effects of OSA might be explored. Accordingly, opportunities abound to advance knowledge in this field and to improve the outlook for the many patients with HF who also suffer from OSA. Reprint requests and correspondence: Dr. T. Douglas Bradley, University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. E-mail: [email protected]. REFERENCES

1. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;53:e1–90. 2. Bradley TD, Floras JS. Sleep apnea and heart failure: part I: obstructive sleep apnea. Circulation 2003;107:1671– 8. 3. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378 – 84. 4. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19 –25. 5. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046 –53.

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6. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82–93. 7. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667– 89. 8. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686 –717. 9. Ryan CM, Bradley TD. Pathogenesis of obstructive sleep apnea. J Appl Physiol 2005;99:2440 –50. 10. Shiota S, Ryan CM, Chiu KL, et al. Alterations in upper airway cross-sectional area in response to lower body positive pressure in healthy subjects. Thorax 2007;62:868 –72. 11. Su MC, Chiu KL, Ruttanaumpawan P, et al. Lower body positive pressure increases upper airway collapsibility in healthy subjects. Respir Physiol Neurobiol 2008;161:306 –12. 12. Chiu KL, Ryan CM, Shiota S, et al. Fluid shift by lower body positive pressure increases pharyngeal resistance in healthy subjects. Am J Respir Crit Care Med 2006;174:1378 – 83. 13. Redolfi S, Yumino D, Ruttanaumpawan P, et al. Relationship between overnight rostral fluid shift and Obstructive Sleep Apnea in nonobese men. Am J Respir Crit Care Med 2009;179:241– 6. 14. Yumino D, Redolfi S, Ruttanaumpawan P, et al. Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in heart failure. Circulation 2010;121:1598 – 605. 15. Meyer TJ, Eveloff SE, Kline LR, Millman RP. One negative polysomnogram does not exclude obstructive sleep apnea. Chest 1993;103: 756 – 60. 16. Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD. Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO2 and circulatory delay. Circulation 2001;103:238 – 43. 17. Yumino D, Wang H, Floras JS, et al. Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction. J Card Fail 2009;15:279 – 85. 18. Tkacova R, Wang H, Bradley TD. Night-to-night alterations in sleep apnea type in patients with heart failure. J Sleep Res 2006;15:321– 8. 19. Ryan CM, Floras JS, Logan AG, et al. Shift in sleep apnoea type in heart failure patients in the CANPAP trial. Eur Respir J 2010;35: 592–7. 20. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328: 303–7. 21. Trinder J, Kleiman J, Carrington M, et al. Autonomic activity during human sleep as a function of time and sleep stage. J Sleep Res 2001;10:253– 64. 22. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Intern Med 2006;166:1716 –22. 23. Ayas NT, White DP, Manson JE, et al. A prospective study of sleep duration and coronary heart disease in women. Arch Intern Med 2003;163:205–9. 24. Bradley TD, Hall MJ, Ando S, Floras JS. Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure. Chest 2001;119:1827–35. 25. Stoohs R, Guilleminault C. Cardiovascular changes associated with obstructive sleep apnea syndrome. J Appl Physiol 1992;72:583–9. 26. Brinker JA, Weiss JL, Lappe DL, et al. Leftward septal displacement during right ventricular loading in man. Circulation 1980;61:626 –33. 27. Tolle FA, Judy WV, Yu PL, Markand ON. Reduced stroke volume related to pleural pressure in obstructive sleep apnea. J Appl Physiol 1983;55:1718 –24. 28. Parker JD, Brooks D, Kozar LF, et al. Acute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med 1999;160:1888 –96. 29. Bradley TD, Tkacova R, Hall MJ, Ando S, Floras JS. Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure. Clin Sci (Lond) 2003;104:231– 8. 30. Kusuoka H, Weisfeldt ML, Zweier JL, Jacobus WE, Marban E. Mechanism of early contractile failure during hypoxia in intact ferret

JACC Vol. 57, No. 2, 2011 January 11, 2011:119–27

31. 32. 33. 34. 35. 36. 37. 38. 39.

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.

51. 52.

53. 54. 55.

heart: evidence for modulation of maximal Ca2⫹-activated force by inorganic phosphate. Circ Res 1986;59:270 – 82. Cargill RI, Kiely DG, Lipworth BJ. Adverse effects of hypoxaemia on diastolic filling in humans. Clin Sci (Lond) 1995;89:165–9. Somers VK, Mark AL, Zavala DC, Abboud FM. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1989;67:2101– 6. Somers VK, Mark AL, Zavala DC, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 1989;67:2095–100. Horner RL, Brooks D, Kozar LF, Tse S, Phillipson EA. Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol 1995;79:151– 62. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997;99:106 –9. Xie A, Skatrud JB, Puleo DS, Morgan BJ. Exposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol 2001;91:1555– 62. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897–904. Spaak J, Egri ZJ, Kubo T, et al. Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea. Hypertension 2005;46:1327–32. Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol 2005;45:2008 –11. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819 –23. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993;22:72A– 84A. Bigger JT Jr., Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol 1993;21:729 –36. Carlson JT, Rangemark C, Hedner JA. Attenuated endotheliumdependent vascular relaxation in patients with sleep apnoea. J Hypertens 1996;14:577– 84. McNicholas WT, Bonsigore MR. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156 –78. Garvey JF, Taylor CT, McNicholas WT. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. Eur Respir J 2009;33:1195–205. Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007;175:1290 –7. Minoguchi K, Yokoe T, Tazaki T, et al. Increased carotid intimamedia thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:625–30. Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:613– 8. Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med 2007;175:612–7. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129 –34. Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824 –30. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:706 –12. Leung RS. Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 2009;51:324 –38. Ghias M, Scherlag BJ, Lu Z, et al. The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol 2009;54:2075– 83. Franz MR, Cima R, Wang D, Profitt D, Kurz R. Electrophysiological effects of myocardial stretch and mechanical determinants of stretchactivated arrhythmias. Circulation 1992;86:968 –78.

JACC Vol. 57, No. 2, 2011 January 11, 2011:119–27 56. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –10. 57. Sinno H, Derakhchan K, Libersan D, Merhi Y, Leung TK, Nattel S. Atrial ischemia promotes atrial fibrillation in dogs. Circulation 2003; 107:1930 – 6. 58. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910 – 6. 59. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement WC. Sleep-induced apnea syndrome. Prevalence of cardiac arrhythmias and their reversal after tracheostomy. Am J Med 1977;63:348 –58. 60. Grimm W, Hoffmann J, Menz V, et al. Electrophysiologic evaluation of sinus node function and atrioventricular conduction in patients with prolonged ventricular asystole during obstructive sleep apnea. Am J Cardiol 1996;77:1310 – 4. 61. Becker H, Brandenburg U, Peter JH, Von Wichert P. Reversal of sinus arrest and atrioventricular conduction block in patients with sleep apnea during nasal continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:215– 8. 62. Mooe T, Gullsby S, Rabben T, Eriksson P. Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis 1996;7:475– 8. 63. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565–71. 64. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589 –94. 65. Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD. Association between atrial fibrillation and central sleep apnea. Sleep 2005;28:1543– 6. 66. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:1101– 6. 67. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490 – 4. 68. Ryan CM, Usui K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on ventricular ectopy in heart failure patients with obstructive sleep apnoea. Thorax 2005;60:781–5. 69. Serizawa N, Yumino D, Kajimoto K, et al. Impact of sleep-disordered breathing on life-threatening ventricular arrhythmia in heart failure patients with implantable cardioverter-defibrillator. Am J Cardiol 2008;102:1064 – 8. 70. Yumino D, Wang H, Floras JS, et al. Relationship between sleep apnoea and mortality in patients with ischaemic heart failure. Heart 2009;95:819 –24. 71. Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;81:528 –36. 72. Portaluppi F, Provini F, Cortelli P, et al. Undiagnosed sleepdisordered breathing among male nondippers with essential hypertension. J Hypertens 1997;15:1227–33. 73. Ferrier K, Campbell A, Yee B, et al. Sleep-disordered breathing occurs frequently in stable outpatients with congestive heart failure. Chest 2005;128:2116 –22. 74. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol 2006;106:21– 8. 75. Vazir A, Hastings PC, Dayer M, et al. A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction. Eur J Heart Fail 2007;9:243–50.

Kasai and Bradley Obstructive Sleep Apnea and Heart Failure

127

76. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97:2154 –9. 77. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009;6: e1000132. 78. Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007;49:1625–31. 79. Roebuck T, Solin P, Kaye DM, Bergin P, Bailey M, Naughton MT. Increased long-term mortality in heart failure due to sleep apnoea is not yet proven. Eur Respir J 2004;23:735– 40. 80. Kraiczi H, Hedner J, Peker Y, Grote L. Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:1423– 8. 81. Bucca CB, Brussino L, Battisti A, et al. Diuretics in obstructive sleep apnea with diastolic heart failure. Chest 2007;132:440 – 6. 82. Sharafkhaneh A, Sharafkhaneh H, Bredikus A, Guilleminault C, Bozkurt B, Hirshkowitz M. Effect of atrial overdrive pacing on obstructive sleep apnea in patients with systolic heart failure. Sleep Med 2007;8:31– 6. 83. Stanchina ML, Ellison K, Malhotra A, et al. The impact of cardiac resynchronization therapy on obstructive sleep apnea in heart failure patients: a pilot study. Chest 2007;132:433–9. 84. Oldenburg O, Faber L, Vogt J, et al. Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing. Eur J Heart Fail 2007;9:820 – 6. 85. Ueno LM, Drager LF, Rodrigues AC, et al. Effects of exercise training in patients with chronic heart failure and sleep apnea. Sleep 2009;32: 637– 47. 86. Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998; 98:2269 –75. 87. Yoshinaga K, Burwash IG, Leech JA, et al. The effects of continuous positive airway pressure on myocardial energetics in patients with heart failure and obstructive sleep apnea. J Am Coll Cardiol 2007;49:450 – 8. 88. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233– 41. 89. Gilman MP, Floras JS, Usui K, Kaneko Y, Leung RS, Bradley TD. Continuous positive airway pressure increases heart rate variability in heart failure patients with obstructive sleep apnoea. Clin Sci (Lond) 2008;114:243–9. 90. Ruttanaumpawan P, Gilman MP, Usui K, Floras JS, Bradley TD. Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea. J Hypertens 2008;26:1163– 8. 91. Egea CJ, Aizpuru F, Pinto JA, et al. Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study. Sleep Med 2008;9:660 – 6. 92. Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361– 6. 93. Smith LA, Vennelle M, Gardner RS, et al. Auto-titrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnoea: a randomized placebo-controlled trial. Eur Heart J 2007;28:1221–7. 94. Kasai T, Narui K, Dohi T, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest 2008;133:690 – 6. Key Words: heart failure y pathophysiology y prognosis y sleep apnea.