Risk Factors for Central and Obstructive Sleep Apnea ... - ATS Journals

Risk Factors for Central and Obstructive Sleep Apnea in 450 Men And Women with Congestive Heart Failure DON D. SIN, FABIA FITZGERALD, JOHN D. PARKER, GARY NEWTON, JOHN S. FLORAS, and T. DOUGLAS BRADLEY Sleep Research Laboratory of the Toronto Rehabilitation Institute and the Departments of Medicine, The Toronto Hospital and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

In previous analyses of the occurrence of central (CSA) and obstructive sleep apnea (OSA) in patients with congestive heart failure (CHF), only men were studied and risk factors for these disorders were not well characterized. We therefore analyzed risk factors for CSA and OSA in 450 consecutive patients with CHF (382 male, 68 female) referred to our sleep laboratory. Risk factors for CSA were male gender (odds ratio [OR] 3.50; 95% confidence interval [CI], 1.39 to 8.84), atrial fibrillation (OR 4.13; 95% CI 1.53 to 11.14), age . 60 yr (OR 2.37; 95% CI 1.35 to 4.15), and hypocapnia (PCO2 , 38 mm Hg during wakefulness) (OR 4.33; 95% CI 2.50 to 7.52). Risk factors for OSA differed by gender: in men, only body mass index (BMI) was significantly associated with OSA (OR for a BMI . 35 kg/m2, 6.10; 95% CI 2.86 to 13.00); whereas, in women, age was the only important risk factor (OR for age . 60 yr, 6.04; 95% CI 1.75 to 20.0). We conclude that historical information, supplemented by a few simple laboratory tests may enable physicians to risk stratify CHF patients for the presence of CSA or OSA, and the need for diagnostic polysomnography for such patients. 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;160:1101–1106.

Obstructive sleep apnea (OSA) is an important risk factor for the development of hypertension, angina pectoris, myocardial infarction, and cor pulmonale (1–4). More recent data suggest that sleep apnea can also lead to the progression of cardiac dysfunction in patients with chronic congestive heart failure (CHF) (5, 6). This adverse effect on cardiac function probably arises from repetitive apneas causing arterial oxyhemoglobin desaturation, excessive stimulation of the sympathetic nervous system, and increases in systemic blood pressure (5–7). The presence of central sleep apnea (CSA) in patients with CHF is associated with a significantly increased risk for death and cardiac transplantation (8, 9). In addition, fragmentation of sleep architecture by frequent arousals can also lead to the development of excessive daytime sleepiness and fatigue in CHF patients with either OSA or CSA (5, 6, 10). Treatments specifically aimed at OSA and CSA in patients with CHF have been shown to improve cardiovascular function and clinical status. For example, continuous positive airway pressure (CPAP) has been shown to alleviate both OSA and CSA, and to improve left ventricular ejection fraction (LVEF), decrease urinary and plasma norepinephrine concentrations, and improve

(Received in original form March 1, 1999 and in revised form May 19, 1999 ) Supported by an operating grant from the Ontario Thoracic Society. D. Sin is supported by a research fellowship from the Alberta Heritage Foundation for Medical Research. G. Newton is supported by a Research Scholarship from the Heart and Stroke Foundation of Ontario, and J. Floras is supported by a Career Investigator award from the Heart and Stroke Foundation of Ontario. Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., ES 12-421 The Toronto Hospital (General Division), 200 Elizabeth St., Toronto, ON, M5G 2C4 Canada. E-mail: [email protected] Am J Respir Crit Care Med Vol 160. pp 1101–1106, 1999 Internet address: www.atsjournals.org

symptoms of heart failure (5, 11, 12). Oxygen also alleviates CSA and reduces nocturnal urinary norepinephrine concentrations (13). A recent report suggests that both CSA and OSA are common in the CHF population (14). The clinical characteristics of patients with CSA appear to differ from those with OSA, probably reflecting important differences in the underlying pathophysiologies of these two breathing disorders. In a study of men with CHF, Javaheri and coworkers found that those with OSA were heavier and had a higher prevalence of snoring than those with CSA or no sleep apnea (14). Patients with CSA, on the other hand, had a lower LVEF. However, because only 81 patients (of whom only nine had OSA) were evaluated in their study, other factors that distinguish risk for OSA from those for CSA or no sleep-related breathing disorder (SBD) may have escaped detection. More importantly, because only men were studied, risk factors for sleep apnea in women with CHF remain unknown. Indeed, risk factors for CSA in women either with or without CHF have not been reported. The purpose of our study, therefore, was twofold: first, to determine the overall risk factors for CSA and OSA in a large group of 450 patients with CHF referred to our sleep laboratory; and second, to determine whether there are differences in risk factors for CSA and OSA between men and women with chronic, stable CHF.

METHODS Subjects We conducted a retrospective analysis of 450 consecutive patients with CHF, referred to the Toronto Rehabilitation Institute Sleep Research Laboratory between July 1987 and November 1998. All patients were referred to the sleep laboratory by cardiologists. The crite-

1102

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

ria for entry were: (1) a diagnosis of CHF established by a cardiologist on the basis of a history of CHF of at least 6 mo duration as defined by at least one prior episode of symptomatic heart failure, characterized by dyspnea at rest or on exertion and radiographic evidence of cardiomegaly and pulmonary congestion; (2) continued dyspnea (New York Heart Association [NYHA] Class 2–4) despite optimal medical therapy; (3) stable clinical status with no medication adjustment for at least 2 wk prior to the sleep study; and (4) sleep duration of greater than 30 min in the sleep laboratory. We excluded patients with unstable angina or myocardial infarction within 4 wk of the study. There were two principal reasons for referral to our sleep laboratory: (1) symptoms suggestive of a sleep apnea syndrome including excessive daytime sleepiness, snoring, nocturnal dyspnea, or restless sleep; or (2) persistent dyspnea and exercise limitation despite optimal medical management of their CHF, or both. A total of 450 consecutive patients with CHF who underwent sleep studies was identified. Data from review of the patients’ medical history and physical examination, echocardiographic or radionuclide studies of left ventricular function, and nocturnal polysomnography were tabulated.

Sleep Studies Overnight polysomnography was performed using standard polysomnographic techniques described for our laboratory (12) and sleep was staged according to standard criteria (15). Movement arousals were defined as a shift to increased electroencephalographic frequencies for > 3 s accompanied by an increase in submental electromyographic activity (16). Thoracoabdominal movements and tidal volume (VT) were measured by a respiratory inductance plethysmograph (Respitrace; Ambulatory Monitoring Inc., White Plains, NY) calibrated against a spirometer (17). Oxyhemoglobin saturation (SaO2) was measured continuously in all patients using a pulse oximeter (Oxyshuttle; Sensormedics Corp., Anaheim, CA). Mean SaO2 during sleep was calculated by averaging the highest and lowest SaO2 for each 30-s epoch of sleep for the entire night. Mean low SaO2 was calculated by averaging the lowest SaO2 for each 30-s epoch of sleep. Transcutaneous PCO2 (PtcCO2) was recorded with a transcutaneous capnograph (Kontron Medical; Hoffman LaRoche, Basel, Switzerland), calibrated as previously described (18) with the electrode placed on the anterior chest. Mean PtcCO2 was determined as for mean SaO2 over the entire sleep period and mean awake PtcCO2 was also determined using the same method just prior to the onset of sleep. Cardiac rhythm was recorded using a single precordial lead. Central apneas were defined by the absence of VT excursion for at least 10 s accompanied by an absence of rib cage and abdominal movements. Central hypopneas were defined as a 50% or greater reduction in VT from the baseline value, without paradoxical chest wall motion, persisting for at least 10 s. Obstructive apneas and hypopneas were defined similarly, except that paradoxical motion of rib cage and abdomen had to be present during the event. The apnea–hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep. Because there is no universally accepted polysomnographic definition of SBD, we used three different AHI cutoff values (10, 15, and 20 per hour of sleep) to evaluate its presence among CHF patients referred to our sleep laboratory. A SBD in which greater than 50% of events were central was defined as CSA; whereas, if > 50% of events were obstructive, it was defined as OSA.

Data Analysis To enhance comparability of our study results to those reported in the literature (5, 19), we decided a priori to use an AHI cutoff of 10 for risk factor analyses. In addition, this cutoff has been shown in previ-

1999

ous studies to be associated with important physiologic and patient outcome differences between those with and without sleep apnea (8, 9, 19). Direct comparisons of data among the three groups were made by analysis of variance with post hoc correction for multiple comparisons by Tukey’s test. Values of p , 0.05 were considered statistically significant. Logistic regression was used to model the association between various baseline variables and the risk of CSA and OSA, using patients with no SBD as the reference group. The candidate-independent variables used to analyze risk factors for CSA and OSA were body mass index (BMI), NYHA functional class, LVEF, presence of atrial fibrillation, presence of a paced cardiac rhythm, age, gender, mean PtcCO2 during wakefulness, medications, and cause of CHF. In the final model, we included only those variables which conferred a significant change in the log likelihood statistic of the reference model. PtcCO2 and age were also converted into dichotomous variables because previous studies have suggested that hypocapnia (PtcCO2 < 38 mm Hg) and older age (age > 60 yr) are associated with sleep apnea (18–20). In addition, BMI was divided into quartiles to control for the influential effects of extreme outliers. The bottom two quartiles (BMI , 30 kg/m2) were subsequently combined because their risk for sleep apnea was similar. All data were analyzed with SAS software modules for descriptive statistics, contingency tables, multiple logistic and regression analyses. Standard formulas were used to calculate odds ratios (OR) and 95% confidence intervals (CI) (21).

RESULTS Of the 450 patients, 382 (85%) were men and 68 (15%) were women. The mean LVEF was (mean 6 SD) 27.3 6 15.6%. The largest proportion of patients were in NYHA Class 2 (62% of total). Thirty-four percent of patients were in NYHA Class 3, whereas only 4% were in NYHA Class 4. The causes of CHF were ischemic heart disease (66% of total), nonischemic cardiomyopathy (25%), and others (9%), which included valvular heart disease, congenital heart disease, and alcohol-induced cardiomyopathy. Atrial fibrillation was present in 15% of the patients; paced cardiac rhythm was present in 7% during the sleep study. The rest were in sinus rhythm. Angiotensin-converting enzyme (ACE) inhibitors, digoxin, and diuretics were used by 75%, 67%, and 76% of the patients, respectively at the time of clinic assessment. Using an AHI cutoff of 10, 15, and 20 per hour of sleep, the overall occurrences of SBD in CHF patients referred to our sleep clinic were 72%, 61%, and 53%, respectively; of CSA were 33%, 29%, and 25%, respectively; and of OSA were 38%, 32%, and 27%, respectively. Using an AHI cutoff of 10 per hour of sleep, there were 148 patients with CSA, 168 patients with OSA, and 134 patients without any SBD.

TABLE 1 CLINICAL FEATURES OF 450 CHF PATIENTS WITH AND WITHOUT SLEEP APNEA*

Cardiac Assessment LVEF recorded within 6 mo of the diagnostic sleep study was used as an objective measure of cardiac function. LVEF was determined at rest during the daytime while patients were awake using either 99mTc equilibrium radionuclide angiography or 2-D echocardiography. The quantitation and reporting of LVEF were performed by personnel who were not aware of the patients’ sleep study findings. For echocardiography, where LVEF is routinely reported as a range of values for a given individual, the median value was used for analysis.

VOL 160

No. of patients Age, yr Male, n (%) BMI, kg/m2 LVEF, % Atrial fibrillation, n (%) Paced cardiac rhythm, n (%) ACE inhibitor, (%) Digoxin, n (%) Diuretic, n (%)

No SBD

CSA

OSA

134 56.8 6 14.4 97 (72.4)† 28.3 6 6.1 26.1 6 14.9 10 (7.5) 9 (6.7) 103 (78.6) 98 (74.8) 106 (80.3)

148 64.8 6 11.1† 138 (93.2) 26.3 6 4.5 23.2 6 15.1 34 (23.0)† 15 (10.1) 100 (67.6) 105 (71.0) 115 (79.9)

168 58.2 6 12.6 147 (87.5) 32.3 6 7.0† 31.5 6 15.6† 20 (11.9) 7 (4.2) 128 (77.1) 107 (64.5) 120 (72.3)

Definition of abbreviation: ACE 5 angiotensin-converting enzyme. * Data are expressed as mean 6 SD, unless otherwise indicated. † p , 0.05 compared with other two groups, after adjustment for multiple comparison.

1103

Sin, Fitzgerald, Parker, et al.: Risk Factors for Sleep Apnea in Heart Failure TABLE 2 BASELINE POLYSOMNOGRAPHIC CHARACTERISTICS OF THE PATIENTS*

AHI, no. per hour of sleep Total sleep time, min Sleep efficiency, % Stage 1 sleep, % of total sleep period time Stage 2 sleep, % of total sleep period time Slow-wave sleep, % of total sleep period time Rapid eye movement sleep, % of total sleep period time Arousal, no. per hour of sleep Mean SaO2, % Mean low SaO2, % Mean awake PtcCO2, mm Hg

No SBD (n 5 134)

CSA (n 5 148)

OSA (n 5 168)

4.0 6 2.8† 343.4 6 76.0 67.5 6 19.5 4.1 6 3.4† 47.6 6 14.1 11.7 6 9.9† 11.0 6 6.1 20.7 6 20.7† 93.4 6 2.4 92.2 6 3.0 40.9 6 5.3

40.5 6 20.5 369.9 6 76.2 61.1 6 21.1 7.9 6 6.7 44.0 6 17.0 5.8 6 5.8 8.3 6 6.2‡ 37.3 6 31.6 92.9 6 2.5 90.6 6 3.7 36.6 6 6.8†

35.0 6 20.2 343 6 86.3 65.8 6 21.1 6.6 6 5.6 48.9 6 16.4 7.0 6 7.0 11.3 6 6.9 38.3 6 28.0 92.2 6 3.1† 89.9 6 4.6† 42.5 6 6.1

* Data are expressed as mean 6 SD, unless otherwise indicated. † p , 0.05, and ‡ p , 0.001 compared with the other two groups, after adjustment for multiple comparison.

The clinical characteristics of the study population, stratified by sleep apnea status, are presented in Table 1. Patients with CSA were older and had a higher prevalence of atrial fibrillation compared with those with OSA or without any SBD (p , 0.05). On the other hand, those with OSA had higher BMI and LVEF than those in the other two groups (p , 0.05). Male gender was a risk factor for both CSA and OSA in the univariate analysis (p , 0.05). Baseline polysomnographic characteristics of the patients are shown in Table 2. Patients with CSA and OSA had moderately severe sleep apnea as evidenced by similar AHI of 40 and 35 events per hour of sleep, respectively. Patients with OSA had significantly lower mean and mean low SaO2 than did the other two groups (p , 0.05). However, the degree of hypoxia was very mild indicating that, overall, CHF patients with either CSA or OSA do not suffer from marked hypoxia during sleep. Mean PtcCO2 during wakefulness was significantly lower in patients with CSA than in the other two groups (p , 0.05). Therefore, patients with CSA were hypocapnic, thus confirming our previous findings (18), whereas those with OSA or without any SBD were eucapnic while awake. Patients with CSA and OSA had significantly more stage 1 sleep and arousals, as well as less slow-wave sleep than patients without any SBD (p , 0.05), indicating worse sleep quality. Those with CSA also had less rapid eye movement (REM) sleep than either of the other two groups. However, total sleep

time and sleep efficiency did not differ significantly among the three groups. Gender-specific demographic and historical data are displayed in Table 3. There were no significant differences in any of these characteristics between the two groups and in particular, men and women were receiving similar pharmacologic therapy for CHF. Overall, among patients referred to our laboratory for evaluation, women had a 26% lower occurrence of SBD than men. The relative occurrence of both CSA and OSA was significantly greater in men than in women. Important risk factors for CSA are shown in Figure 1. Men had an almost fourfold greater adjusted risk for CSA than women. The presence of atrial fibrillation, increasing age, and lower mean PtcCO2 during sleep were also significant risk factors for CSA. Hypocapnia (PtcCO2 < 38 mm Hg) was associated with a 4.3-fold (95% CI 2.5 to 7.5) increase in risk for CSA compared with normo- or hypercapnic patients. On the other hand, those 60 yr of age or older had 2.4 (95% CI 1.4 to 4.2) times the risk of CSA compared with those younger than 60 yr of age. Variations in BMI and LVEF were not significant independent risk factors for CSA. Separate analyses were done in men and women to determine whether gender modifies these risk factors for CSA. However, CSA risk factors were similar for both men and

TABLE 3 GENDER-SPECIFIC CLINICAL CHARACTERISTICS OF PATIENTS WITH CHF* Variable No. of patients Age, yr Prevalence of SBD, % Prevalence of CSA, % Prevalence of OSA, % Mean awake PtcCO2, mm Hg BMI, kg/m2 LVEF, % Atrial fibrillation, % Paced cardiac rhythm, % ACE inhibitor, % Digoxin, % Diuretics, %

Women

Men

68 60.0 6 14.2 47 15 31 41.3 6 6.7 29.3 6 7.0 29.6 6 18.0 10 4 72 72 82

382 60.0 6 13.0 75† 36† 38‡ 39.8 6 8.2 28.8 6 6.5 26.8 6 15.2 15 7 75 69 76

* Values are expressed as mean 6 SD, unless otherwise indicated. † p , 0.001. ‡ p , 0.005.

Figure 1. Adjusted relative OR for CSA in men and women. All categories are compared with women less than 60 yr of age with PtcCO2 . 38 and without atrial fibrillation. Adjustments were made for BMI, LVEF, and all the variables listed in the figure. A.Fib 5 atrial fibrillation.

1104


women. In women, those 60 yr of age or older had 6 (95% CI 1.22 to 35.47) times the risk of CSA compared with those below this age cutoff; whereas, in men, the risk was increased by 2.2-fold (95% CI 1.24 to 4.11). Similarly, those who were hypocapnic had over a 6-fold (95% CI 1.42 to 29.08) increase in risk for CSA in women and a 4-fold (95% CI 2.27 to 7.22) increase in men. The presence of atrial fibrillation was also an independent risk factor for CSA in both men and women. Risk factors for OSA were different than those for CSA. For the entire group, the only factors associated with a significant increase in relative risk for OSA were male sex (OR 5 2.78; 95% CI 1.47 to 5.24) and increasing BMI (OR 5 1.68; 95% CI 1.37 to 2.06). However, risk factors for OSA differed fundamentally between men and women. In men, obesity, as defined by a BMI > 30 kg/m2, was the dominant risk factor for OSA (Figure 2). Men in the highest quartile of BMI (. 35 kg/ m2) had the highest risk, with an adjusted OR for OSA of 6.1 (95% CI 2.9 to 13.0). However, obesity was not a significant risk factor for OSA in women (Figure 2). In contrast to men, age was the most important risk factor for OSA in women. As shown in Figure 3, we divided patients into two age categories: < 60 and . 60 yr based on previous data in the literature suggesting that the risk of OSA increases several years postmenopausally (23). In a model that controlled for the effects of BMI, women older than 60 yr of age were shown to have six times the risk for OSA (OR 5 6.0, 95% CI 1.8 to 20.0) than women below this age. In contrast, age was not a risk factor for OSA in men (Figure 3).

DISCUSSION In this report, we describe several risk factors for SBD in 450 patients with CHF. To date, this is the largest report of its kind, and the first to include risk factor analyses for women as well as for men with CHF. The most important findings were that risk factors for CSA differed from those for OSA, and that risk factors for OSA in women differed from those in men. In several important respects, our findings are consistent with those of Javaheri and coworkers (14). Although theirs was a prospective prevalence study and ours is not, it is interesting that the prevalence of SBD in our population is similar to theirs. This suggests that CSA and OSA are very common

Figure 2. Age-adjusted relative OR for OSA in men and women at different levels of BMI. For each gender, all categories are compared with those with BMI of less than 30 kg/m 2. Adjustments were made for BMI, and cause of CHF.

VOL 160

1999

in the CHF population, but are probably being underdiagnosed. With respect to CSA, our findings support theirs in showing that decreasing awake PCO2 was a significant risk factor for CSA. However, because we studied a much larger group of patients with CHF, we were able to show that male gender and increasing age were additional independent risk factors for CSA. Whereas they demonstrated that atrial fibrillation was a risk factor for sleep-disordered breathing in general, they were unable to distinguish whether atrial fibrillation was a risk factor for CSA or OSA or both because of their small sample size. We extended their findings by showing that atrial fibrillation is a risk factor for CSA but not for OSA. In addition, because we included women as well as men, we made the novel observation that hypocapnia was the chief risk factor for CSA in both sexes. Low PaCO2, close to the apnea threshold, is a key predisposing factor for CSA in patients with CHF (18). Our present findings are consistent with this concept. In this setting, PaCO2 can readily fall below the apnea threshold and trigger central apneas when ventilation increases following arousals. Hypocapnia in CHF appears to be related to the presence of high left ventricular filling pressures and pulmonary congestion which provoke hyperventilation through stimulation of pulmonary vagal irritant receptors (22). Atrial fibrillation is a marker for loss of atrial contraction and poorer cardiac pumping function, that can lead to a higher left ventricular filling pressure (23). Increasing age may play a role in increasing the risk for CSA through similar mechanisms. Compared with younger CHF patients, those who are older tend to have less compliant left ventricles with higher left ventricular filling pressures, as well as an increased prevalence of pulmonary venous hypertension (23, 24). This may place them at a higher risk for nocturnal hyperventilation and CSA. Previous studies have shown that central events occur most frequently during the lighter stages of non-REM, particularly after arousals and sleep stage changes (18). Male gender may be a risk factor for CSA because, in general, men have a less stable sleep architecture than women, with a greater number of sleep–wake transitions and shorter slow-wave sleep, which may predispose to respiratory control system instability and central apneas (25).

Figure 3. BMI-adjusted relative OR for OSA in men and women younger and older than 60 yr of age. For men and women, all age categories are compared with those younger than 60 yr of age. Adjustments were made for BMI, and cause of CHF.

Sin, Fitzgerald, Parker, et al.: Risk Factors for Sleep Apnea in Heart Failure

We found OSA to be more common in our population than Javaheri and coworkers (14) in theirs (i.e., 32% versus 11%, respectively). One possible explanation for this is that suspicion of sleep apnea was one criterion for referral to our laboratory, whereas they studied all patients with CHF without regard to symptoms of sleep apnea. This may have biased our study sample toward a higher prevalence of OSA. Our data also indicate that the single most important risk factor for OSA in men was increasing BMI, in keeping with the findings of Javaheri and coworkers (14). However, those investigators did not study women with CHF. In contrast, because we studied women with CHF, we were able to make the novel observation that the most important risk factor for OSA in them was increasing age. Conversely, increasing age was not a risk factor for OSA in men, nor was increasing BMI a risk factor for OSA in women. Many of the complications of obesity, including sleep apnea, appear to be related to an android pattern of adiposity, characterized by increased accumulation of visceral and upper body fat (26). Increased fat deposition around the neck may contribute to pharyngeal narrowing and collapsibility (27). In contrast to men, younger women tend to have a gynoid distribution of fat which is predominantly subcutaneous and is distributed particularly over the thighs, with only a minor deposition of fat in the visceral and upper body regions (26, 28). Postmenopausally, however, fat distribution in women changes and becomes more android, thereby increasing the risk for complications of obesity, including cardiovascular diseases and possibly OSA (29). The risk for these diseases, however, does not rise sharply until reaching 60 yr of age (30). In the present study, the average age for OSA in women with CHF was 64 yr, which is very similar to that reported by Redline and coworkers in a group of female OSA patients without heart disease (20). We found that female CHF patients 60 yr of age or older have a fivefold increase in the risk for OSA, compared with those below this age. Redline and coworkers also found that BMI was not a significant independent predictor for OSA in women. This is probably so because BMI is insensitive to changes in fat distribution. On the other hand, age is probably a better predictive factor for OSA in women, because for the same degree of obesity, postmenopausal women would have a greater fat deposition in the abdomen and neck compared with premenopausal women. Evidence is accumulating that CSA places additional stresses on the already failing heart and circulation. Recurrent central apneas are associated with nocturnal oxyhemoglobin desaturation, increased sympathetic nervous system activity, and an increased prevalence of ventricular arrhythmias (11, 19). In addition, recurrent apneas and arousals markedly fragment sleep, thereby exacerbating fatigue and causing daytime hypersomnolence (10). Moreover, two recent studies suggest that CSA is an independent predictor of a higher mortality rate (9) or higher combined mortality and heart transplantation rate (8) in patients with CHF. Treatments aimed specifically at alleviating CSA can improve LVEF and reduce mitral regurgitation, atrial natriuretic peptide, and sympathetic nervous system activity (11–13, 31). Identification of OSA in patients with CHF is also important because OSA has similar adverse effects on the failing heart and circulation as CSA. OSA has additional adverse effects related to the generation of exaggerated negative intrathoracic pressure swings against the occluded upper airway. These negative pressure swings can lead to adverse ventricular interactions, increased ventricular wall stress, reductions in cardiac output, and increases in pulmonary capillary wedge pressure (32, 33). OSA can also lead to both nocturnal and daytime hypertension (2, 7, 34). Abolition of OSA in CHF pa-

1105

tients by nasal CPAP eliminates these exaggerated negative intrathoracic pressure swings, lowers blood pressure (7, 35), and improves LVEF and symptoms of heart failure (5). In summary, the present study demonstrates that in patients with CHF, there are different risk factors for CSA than for OSA. These observations are in keeping with the concept that these two conditions have different underlying pathogeneses. We also found that risk factors for OSA in men were different than in women. Increased awareness of these breathing disorders as possible complicating factors in patients with CHF may alter the approach to their therapy. Accordingly, our findings indicate that historic and demographic information, including BMI and age, supplemented by a few simple laboratory tests may enable physicians to risk stratify CHF patients for evaluation of possible CSA or OSA by polysomnography. Once diagnosed, specific therapy aimed at alleviating CSA and OSA, such as supplemental oxygen or CPAP, may provide therapeutic benefits that complement standard pharmacologic therapy for CHF (5, 11–13). Although ours was not a prevalence study, the fact that we were able to detect so many cases of CSA and OSA in patents with CHF in our laboratory alone adds to the evidence that these breathing disorders are common in patients with CHF (14).

References 1. Hung, J., E. G. Whitford, R. W. Parsons, and D. R. Hillman. 1990. The association of sleep apnea with myocardial infarction in men. Lancet 336:261–264. 2. Young, T., P. Peppard, M. Palta, K. M. Hla, L. Finn, B. Morgan, and J. Skatrud. 1997. Population based study of sleep-disordered breathing as a risk factor for hypertension. Arch. Interm. Med. 157:1746–1752. 3. Andreas, S., R. Schulz, G. S. Werner, and H. Kreuzer. 1996. Prevalence of obstructive sleep apnea in patients with coronary artery disease. Coron. Artery Dis. 7:541–545. 4. Bradley, T. D., R. Rutherford, R. F. Grossman, F. Lue, N. Zamel, H. Moldofsky, and E. A. Phillipson. 1985. The role of daytime hypoxemia in the pathogenesis of right heart failure in patients with obstructive sleep apnea. Am. Rev. Respir. Dis. 131:835–839. 5. Malone, S., P. P. Liu, R. Holloway, R. Rutherford, A. Xie, and T. D. Bradley. 1991. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 338:1480–1484. 6. Bradley, T. D., and J. S. Floras. 1996. Pathophysiologic and therapeutic implications of sleep apnea in congestive heart failure. J. Card. Fail. 2:223–240. 7. Tkacova, R., F. Rankin, F. S. Fitzgerald, J. S. Floras, and T. D. Bradley. 1998. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 96:2269–2275. 8. Hanly, P., and N. Zuberi-Khokhar. 1996. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am. J. Respir. Crit. Care Med. 153:272–276. 9. Lanfranchi, P. A., A. Braghiroli, E. Bosimini, G. Mazzuero, R. Colombo, C. F. Donner, and P. Giannuzzi. 1999. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 99:1435–1440. 10. Hanly, P., and N. Zuberi-Khokhar. 1995. Daytime sleepiness in patients with congestive heart failure and Cheyne-Stokes respiration. Chest 107: 952–958. 11. Naughton, M. T., D. C. Benard, P. P. Liu, R. Rutherford, F. Rankin, and T. D. Bradley. 1995. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am. J. Respir. Crit. Care Med. 152:473–479. 12. Naughton, M. T., P. P. Liu, D. C. Bernard, R. S. Goldstein, and T. D. Bradley. 1995. Treatment of congestive heart failure and CheyneStokes respiration during sleep by continuous positive airway pressure. Am. J. Respir. Crit. Care Med. 151:92–97. 13. Staniforth, A. D., W. J. M. Kinnear, R. Starling, D. J. Hetmanski, and A. J. Cowley. 1998. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur. Heart J. 19:922–928.

1106


14. Javaheri, S., T. J. Parker, J. D. Liming, W. S. Corbett, H. Nishiyama, L. Wexler, and G. A. Roselle. 1998. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 97:2154–2159. 15. Rechtschaffen, A., and A. Kales, editors. 1968. A Manual of Standardized Terminology, Techniques and Scoring Systems for Sleep Stages of Human Subjects. U.S. Government Printing Office, Washington, DC. NIH Publication No. 204. 16. The Atlas Task Force. 1992. EEG arousals: scoring rules and examples. Sleep 15:173–184. 17. Chada, T. S., H. Watson, S. Birch, A. Jenouri, A. W. Schneider, M. A. Cohn, and M. A. Sackner. 1982. Validation of respiratory inductive plethysmography using different calibration procedures. Am. Rev. Respir. Dis. 125:644–649. 18. Naughton, M. T., D. Benard, A. Tam, R. Rutherford, and T. D. Bradley. 1993. The role of hyperventilation in the pathogenesis of central sleep apnea in patients with congestive heart failure. Am. Rev. Respir. Dis. 148:330–338. 19. Javaheri, S., and W. S. Corbett. 1998. Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann. Intern. Med. 128:204–207. 20. Redline, S., K. Kump, P. V. Tishler, I. Browner, and V. Ferrette. 1994. Gender differences in sleep disordered breathing in community based sample. Am. J. Respir. Crit. Care Med. 149:722–726. 21. Cochran, W. G. 1997. Sampling Techniques. John Wiley, New York. 107. 22. Solin, P., P. Bergin, M. Richardson, D. M. Kaye, E. H. Walters, and M. T. Naughton. 1999. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation 99:1574–1579. 23. Schlant, R. C. 1986. Normal physiology of the cardiovascular system. In J. W. Hurst, editor. The Heart. McGraw-Hill, New York. 37–72. 24. Badgett, R. G., C. R. Lucey, and C. D. Mulrow. 1998. Can the clinical examination diagnose left-sided heart failure in adults? J.A.M.A. 277: 1712–1719.

VOL 160

1999

25. Hume, K. I., F. Van, and A. Watson. 1998. A field study of age and gender differences in habitual adult sleep. J. Sleep Res. 7:85–94. 26. Ladipus, L., C. Bengtsson, B. Larsson, K. Penner, E. Rybo, and L. Sjostrom. 1984. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gotheburg, Sweden. Br. Med. J. 289:1257–1261. 27. Horner, R. L., R. H. Mohiaddin, D. G. Lowell, S. A. Shea, E. D. Burman, D. B. Longmore, and A. Guz. 1989. Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls. Eur. Respir. J. 2:613–622. 28. Slyper, A. H. 1998. Childhood obesity, adipose tissue distribution, and the pediatric practitioner. Pediatrics 102:E4. 29. Ley, C. J., B. Lees, and J. C. Stevenson. 1992. Sex- and menopause-associated changes in body fat distribution. Am. J. Clin. Nutr. 55:950–954. 30. Barrett-Connor, E. 1997. Sex differences in coronary heart disease: why are women so superior? Circulation 95:252–264. 31. Tkacova, R., P. P. Liu, M. T. Naughton, and T. D. Bradley. 1997. Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J. Am. Coll. Cardiol. 30:739–745. 32. Hall, M. J., S. I. Ando, J. S. Floras, and T. D. Bradley. 1998. Magnitude and time course of hemodynamic responses to Mueller maneuvers in patients with congestive heart failure. J. Appl. Physiol. 85:1476–1484. 33. Buda, A. J., M. R. Pinsky, N. B. Ingles, Jr., G. T. Daughters, E. B. Stinson, and E. L. Alderman. 1979. The effect of intrathoracic pressure on left ventricular performance. N. Engl. J. Med. 301:453–459. 34. Brooks, D., R. L. Horner, L. F. Kozar, C. L. Render-Teixeira, and E. A. Phillipson. 1997. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J. Clin. Invest. 99:106–109. 35. Akashiba, T., K. Kurashina, H. Minemura, H. Yamamoto, and T. Horie. 1995. Daytime hypertension and the effects of short term nasal continuous positive airway pressure treatment in obstructive sleep apnea syndrome. Intern. Med. 34:528–532.