Occult Sleep-Disordered Breathing in Stable Congestive Heart Failure

October 29, 2002

<A HREF= " http://www.acponline.org/journals/annals/01apr95/occult.htm " >Occult

Sleep-Disordered Breathing in..., ls 22 Apr 98</A> ls of Internal

Medicine

Occult Sleep-Disordered Breathing in Stable Congestive Heart Failure

ls of Internal Medicine, 1 April 1995; 122: 487-492.

Shahrokh Javaheri, MD; J. , MD; Wexler, MD; E.

s, PhDâ€ ; Stanberry, PhD; Hiroshi Nishyama, MD; and A.

Roselle, MD

Objective: To determine the prevalence and effect of sleep-disordered

breathing in ambulatory patients with stable, optimally treated congestive

heart failure.

Design: A prospective, longitudinal study.

Setting: Referral sleep laboratory of a Department of Veterans Affairs

medical center.

Patients: 42 of the 48 eligible patients with stable congestive heart failure

and left ventricular systolic dysfunction (left ventricular ejection fraction

less than or equal to 45%).

Measurements: After an adaptation night, polysomnography and Holter

monitoring were done in the sleep laboratory. Arterial blood gases and pH

were measured, and cardiac radionuclide ventriculography and pulmonary,

renal, and thyroid function tests were done.

Results: Patients were divided into two groups. Group I (n = 23) had an

hourly rate of apnea and hypopnea (apnea-hypopnea index) of 20 episodes per

hour or less; group II (n = 19 [45%; CI, 30% to 60%]) had an index of more

than 20 episodes per hour. In group II, the index varied from 26.5 to 82.2

episodes per hour (mean Â± SD, 44 Â± 13 episodes per hour; CI, 38 to 51

episodes per hour). Group II had significantly more arousals (24 Â± 12

compared with 3 Â± 3 in group I) that were directly attributable to episodes

of apnea and hypopnea, longer periods of time with an arterial oxyhemoglobin

saturation of less than 90% (23% Â± 24% of total sleep time compared with 2% Â±

4%), lower arterial oxyhemoglobin saturation during sleep (74% Â± 13% compared

with 87% Â± 4%), lower left ventricular ejection fraction (22% Â± 9% compared

with 30% Â± 10%), and a significantly increased number of episodes of

nocturnal ventricular arrhythmias. Multiple regression analyses showed that

left ventricular systolic dysfunction was an independent risk factor for

sleep apnea in patients with congestive heart failure.

Conclusions: The prevalence of severe occult sleep-disordered breathing is

high in ambulatory patients with stable, optimally treated chronic congestive

heart failure. The breathing episodes are associated with severe nocturnal

arterial blood oxyhemoglobin desaturation and excessive arousals. Severe

untreated sleep-disordered breathing may adversely affect left ventricular

function, resulting in a vicious cycle that could contribute to death in

patients with congestive heart failure. Prospective, longitudinal studies on

survival are needed.

Ann Intern Med. 1995;122:487-492. ls of Internal Medicine is published

From the Department of Veterans Affairs Medical Center and the University of

Cincinnati College of Medicine, Cincinnati, Ohio. For current author addresse

s, see <A HREF= " http://www.acponline.org/journals/annals/01apr95/#end " >end of

text</A>.

â€ Dr. s is deceased.

Despite recent advances in its treatment, congestive heart failure associated

with depressed left ventricular function is highly prevalent and continues to

be associated with excess morbidity and mortality. Multiple factors may

contribute to the progressively declining course of congestive heart failure.

Severe nocturnal arterial oxyhemoglobin desaturation caused by

sleep-disordered breathing could be a contributing factor, particularly

because it has been associated with excess mortality in patients with chronic

obstructive pulmonary disease <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note1 " >(1)</A>.

Cheyne and Stokes were the first to observe periodic breathing in patients

with heart failure (Cheyne-Stokes respiration). In a subsequent systematic

study, on and colleagues <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note2 " >(2)</A> reported

that periodic breathing

characterized by repeated episodes of apnea and hypopnea during sleep

occurred in patients with congestive heart failure. Since this early

observation, several investigators have used standard polysomnography to

study periodic breathing during sleep in patients with congestive heart

failure <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note3 " >(3-7)</A>. The

differences in prevalence rates in these studies (36% to

100%) might have been caused by several factors, including the few patients

studied (4 to 11), the varying inclusion of patients with risk factors

predisposing them to sleep apnea (such as loud snoring, witnessed apnea, and

obesity), the varying severity of heart failure and systolic dysfunction, the

inclusion of patients with unstable (as opposed to stable, maximally treated)

congestive heart failure, and the presence of other factors that may

influence periodic breathing. These important factors, which were not

considered in most of previous studies, could considerably affect the

prevalence and the severity of sleep apnea.

We determined the prevalence and effect of sleep-disordered breathing in a

relatively large group of clinically well-defined patients with stable,

optimally treated congestive heart failure. We also determined the predictors

of sleep-disordered breathing in these patients.

Methods

Entry CriteriaForty-two ambulatory patients with stable congestive heart

failure (no change in signs or symptoms of congestive heart failure and no

change in medications for at least 4 weeks before polysomnography) and

systolic dysfunction (left ventricular ejection fraction less than or equal

to 45%) participated in the study. Patients were recruited from the

cardiology and medical clinics of the Department of Veterans Affairs Medical

Center, Cincinnati, Ohio. The cardiologist coinvestigator evaluated all

patients to confirm that their condition was stable and that they were

receiving optimal therapy, which included digoxin (26 patients), diuretics

(38 patients), angiotensin-converting enzyme inhibitors (37 patients), or

hydralazine (2 patients).

At the time of recruitment, no information was sought about symptoms or risk

factors for sleep apnea. The following were the exclusion criteria: unstable

angina; unstable congestive heart failure; acute pulmonary edema; congenital

heart disease; primary valvular heart disease; use of benzodiazepines or

theophylline; intrinsic pulmonary diseases, including interstitial lung

disease, moderate to severe chronic obstructive lung defect (percentage of

the ratio of the predicted forced expiratory volume in 1 second and forced

vital capacity < 68%); intrinsic renal and liver disorders; untreated

hypothyroidism; and kyphoscoliosis. For uniformity, we studied only male

patients (female patients are rarely referred to this center). Only 6 of the

48 patients who met the entry criteria and were asked to participate in the

study refused. The main reasons for refusal were an unwillingness to stay in

the hospital or an unwillingness to travel to the hospital because of

distance. The study was approved by the Research and Development Committee of

the Veterans Affairs Medical Center, Cincinnati, Ohio, and the Institutional

Review Board at the University of Cincinnati College of Medicine.

Baseline StudiesAfter giving written informed consent, the patients were

hospitalized for 2 consecutive nights. On the first day, a detailed history

was obtained and physical examination and screening tests were done,

including complete blood count; tests for serum electrolytes, digoxin,

thyroid, and renal function; radionuclide ventriculography; determinations of

arterial blood gases and pH; and pulmonary function tests. Strict criteria

described elsewhere <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note8 " >(8, 9)</A> were

used for doing pulmonary function tests and

for obtaining arterial blood samples and their measurements. Because some

studies <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note10 " >(10)</A> have

suggested that a low baseline Paco2 is a risk factor for

periodic breathing, skin over the radial artery was anesthetized with 2%

lidocaine to minimize pain (which could potentially induce hyperventilation

during arterial blood sampling). While the patient was sitting, arterial

blood was collected anaerobically in heparinized syringes during several

breath cycles. Duplicate determinations of arterial blood gases and pH were

immediately made with appropriate electrodes <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note9 " >(9)</A>.

PolysomnographyOn the first night, patients were taken to the sleep

laboratory. Surface electrodes were attached, but no recording was obtained.

This adaptation night was used to minimize the first-night effect of sleeping

in the laboratory. On the next night, polysomnography was done using standard

techniques described previously <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note11 " >(11-13)</A>. For

staging sleep, we recorded

electroencephalograms (two channels), chin electromyograms (one channel), and

electro-oculograms (two channels). Thoracoabdominal excursions were measured

qualitatively by respiratory inductance plethysmography (Respitrace;

Ambulatory Monitoring, Inc., Ardsley, New York) or by pneumatic respiration

transducers (Grass Instrument Company, Quincy, Massachusetts) placed over the

rib cage and abdomen. Airflow was qualitatively monitored using an oral-nasal

thermocouple (Model TCT1R; Grass Instrument Company). Arterial oxyhemoglobin

saturation was recorded using an ear oximeter (Biox IIA; BT, Inc., Boulder,

Colorado). These variables were recorded on a multichannel polygraph (Model

78D; Grass Instrument Company). An apnea was defined as cessation of

inspiratory airflow lasting 10 seconds or longer. An obstructive apnea was

defined as the absence of airflow in the presence of rib cage and abdominal

excursions. A central apnea was defined as the absence of airflow and of rib

cage and abdominal excursions <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note11 " >(11-13)</A>.

However, a central apnea may not be

easily distinguished from an obstructive apnea if esophageal pressure is not

measured. Hypopnea was defined as a reduction of airflow lasting 10 seconds

or more that was associated with at least a 4% decrease in arterial

oxyhemoglobin saturation or an arousal. An arousal was defined as the

appearance of alpha waves on an electroencephalogram that were at least 3

seconds in duration <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note14 " >(14)</A>. The

number of episodes of apnea and hypopnea per

hour is referred to as the apnea-hypopnea index. Scoring of polysomnograms

was blinded.

The prevalence of sleep-disordered breathing in patients with congestive

heart failure was determined using an apnea-hypopnea index of more than 20

episodes per hour. In a retrospective study of patients with the sleep apnea

syndrome <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note15 " >(15)</A>, an

index of more than 20 apneas per hour was associated with

excess mortality. Because this study was done before hypopnea was recognized,

the investigators did not include it in their calculation of the index. Lower

thresholds (for example, an apnea-hypopnea index of 10 episodes per hour)

have been used in other studies; however, the clinical importance,

particularly of low cutoff points, has not been adequately determined.

Other StudiesHolter monitoring was done during polysomnography. Three

electrocardiographic channels (leads V1, V3, and V5) were recorded using a

Laser SxP Holter monitor system (Marquett Electronics Inc., Milwaukee,

Wisconsin). The tapes were analyzed by computer and were manually overread by

the cardiologist coinvestigator.

Using standard techniques <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note16 " >(16)</A>, we

calculated right and left ventricular

ejection fractions from gated first-pass and multigated radionuclide

ventriculograms, respectively <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note16 " >(16)</A>.

Statistical AnalysisWe used the Wilcoxon rank-sum test to assess the

significance of differences between the two groups because the common

variance assumption required by the t-test was not appropriate for many of

the measurements. A P value of less than 0.05 was considered significant. We

calculated 95% CIs using the approximate degrees of freedom for the t

-statistic <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note17 " >(17)</A>.

The relations between certain pathophysiologically important variables and

the apnea-hypopnea index were examined by regression analysis and stepwise

multiple regression analysis. Calculations were done using SAS software <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note17 " >(17)</A>.

Results

The apnea-hypopnea index varied from 0.3 to 82.2 episodes per hour. The

frequency histogram of the index is shown in Figure 1. In 23 patients (group

I), the apnea-hypopnea indexes varied from 0.3 to 13.4 episodes per hour

(mean Â± SD, 4.4 Â± 4 episodes per hour [CI, 2.7 to 6.0 episodes per hour;

median, 3.2 episodes per hour]). In the 19 patients in group II (45%), the

apnea-hypopnea index varied from 26.5 to 82.2 episodes per hour (mean, 44 Â±

13 episodes per hour [CI, 37.6 to 50.6 episodes per hour; median, 40.4

episodes per hour).

The two groups did not differ significantly in demographic and historical

data (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb1.htm " >Table

1</A>). Congestive heart failure was caused by ischemic

cardiomyopathy (16 patients in group I and 13 patients in group II),

idiopathic cardiomyopathy (5 patients in group I and 6 patients in group II),

and alcohol-related cardiomyopathy (2 patients in group I).

The mean values for selected laboratory test results for both groups are

shown in <A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb2.htm " >Table

2</A>. The respective sleep architecture values did not differ

significantly. The mean value of the arousal index (the number of arousals

per hour) was significantly greater in group II than in group I (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb3.htm " >Table

3</A>).

In group II, the mean apnea-hypopnea index was high (44 Â± 13 episodes per

hour [CI, 38 to 51 episodes per hour; Figure 2]). The obstructive

apnea-hypopnea index (10 Â± 13 episodes per hour [CI, 4 to 16 episodes per

hour]) accounted for only a few of these episodes; in contrast, more than 50%

of the episodes were classified as central apneas. Approximately half of the

disordered breathing episodes were associated with arousals (Figure 2).

Blood gas values did not differ significantly while the patients were awake:

Pao2, 79 Â± 13 mm Hg in group I compared with 81 Â± 12 mm Hg in group II;

Paco2, 39 Â± 5 mm Hg compared with 37 Â± 7 mm Hg; and [H+], 37 Â± 2 mmol/L

compared with 36 Â± 3 nmol/L. However, because of sleep-disordered breathing

episodes, duration and severity of arterial oxyhemoglobin desaturation were

significantly greater in group II than in group I: duration, 7 Â± 13 minutes

(CI, 1 to 13 minutes; median, 0.4 minutes) in group I compared with 61 Â± 63

minutes (CI, 30 to 92 minutes; median, 42 minutes) in group II; severity, 87%

Â± 4% (CI, 85% to 89%; median, 87%) in group I compared with 74% Â± 13% (CI,

68% to 80%; median, 77%) in group II (Figure 2).

Ventricular ectopy was more prevalent and left ventricular ejection fraction

was lower in group II (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb4.htm " >Table

4</A>).

CorrelationsWe determined regression coefficients for some potentially

related variables and used disordered breathing episodes as the dependent

variables. Age was not significantly correlated with any episodes of

disordered breathing, including the apnea-hypopnea index (b = -0.01; CI,

-0.081 to 0.79; n = 42) (b is the regression coefficient). Body mass index

was significantly and positively correlated with the obstructive

apnea-hypopnea index (b = 0.77 episodes per hour per unit of body mass index;

CI, 0.38 to 1.16 episodes per hour) but not with the central apnea-hypopnea

index (b = -0.52; CI, -1.29 to 0.25). These correlations suggested that our

recognition and classification of central and obstructive disordered

breathing episodes (see Methods section) were probably correct. Left

ventricular ejection fraction was significantly and negatively correlated

with the apnea-hypopnea index (b = -0.79 episodes per hour per unit of left

ventricular ejection fraction; CI, -1.47 to -0.11). Right ventricular

ejection fraction was not significantly correlated with any of the disordered

breathing episodes.

In a stepwise multiple regression analysis in which the apnea-hypopnea index

was used as the dependent variable and age, body mass index, left ventricular

ejection fraction, Paco2, and Pao2 were used as independent variables, only

left ventricular ejection fraction was a significant factor.

In another stepwise multiple regression analysis, left ventricular ejection

fraction, Pao2 Paco2, the lowest arterial oxyhemoglobin saturation, the

apnea-hypopnea index, the central apnea index, and the serum potassium level

were used as independent candidates for predicting ventricular arrhythmias.

The central apnea index was the only significant independent variable for the

number of premature ventricular contractions (b =0.52 contractions per hour;

CI, 0.48 to 0.56 contractions per hour), couplets (b = 0.76 couplets per

hour; CI, 0.32 to 1.20 couplets per hour), and ventricular tachycardia (b =

4.8 episodes per hour; CI, 1.97 to 7.65 episodes per hour).

Discussion

We show that 45% of the patients with stable and optimally treated congestive

heart failure had an apnea-hypopnea index of more than 26 episodes per hour

(mean, 44 episodes per hour). The disordered breathing episodes were

associated with excessive arousals and severe arterial oxyhemoglobin

desaturation (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb3.htm " >Table

3</A> and Figure 2). This degree of occult sleep-disordered

breathing is probably associated with excess morbidity and possibly mortality

in patients whose heart function is already compromised.

Our study differs from previous studies in several important ways. We

approached 48 patients with well-defined criteria (stability of congestive

heart failure, optimally treated congestive heart failure, absence of other

medical disorders, use of drugs that could affect breathing, and so forth)

and were able to recruit 42. We believe that this degree of recruitment

minimized bias and therefore makes our results applicable to many male

patients with stable congestive heart failure.

Furthermore, although we studied patients with stable congestive heart

failure and systolic dysfunction (the latter mild to severe in degree), we

found a surprisingly high prevalence of clinically unsuspected

sleep-disordered breathing. According to our results, the latter may be

caused, in part, by the high prevalence of central apneas. Finally, because

we studied a relatively large number of patients and used several tests,

including measuring left ventricular ejection fraction and monitoring for

ventricular arrhythmias, we could determine some predictors and consequences

of sleep apneas and hypopneas.

Predictors of periodic breathing in congestive heart failure have not been

systematically studied and are unknown. Limited data suggest that periodic

breathing is more prevalent during decompensation of congestive heart failure

and improves with treatment <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note2 " >(2, 18)</A>. One

of our objectives was to determine

potential predictors of periodic breathing, if any, in patients with stable,

optimally treated congestive heart failure.

One possible predictor of sleep-disordered breathing is loud snoring.

However, the prevalence of habitual snoring was similar between the two

groups (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb1.htm " >Table

1</A>). This was not surprising because most episodes of periodic

breathing noted in our patients with congestive heart failure were classified

as central rather than obstructive apneas.

We had hypothesized that older patients with congestive heart failure may

have a higher prevalence of sleep-disordered breathing than the younger

patients, but mean values for various ages were similar between the two

groups; more than 50% of the patients in group II were younger than 65 years.

Furthermore, in both regression analysis and multiple regression analysis,

age was not significantly correlated with any of the sleep-disordered

breathing episodes.

Although Young and associates <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note19 " >(19)</A> showed

that the prevalence of

sleep-disordered breathing did not change significantly in patients aged 30

to 60 years, studies by Ancoli-Israel <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note20 " >(20)</A> showed

that in three randomly

selected groups of patients older than 65 years, 4% of the 427 independently

living patients, 11% of the 235 patients living in nursing homes, and 14% of

the 300 patients in medical wards had an apnea index of 20 or more episodes

per hour. It was suggested that increased prevalence in patients in medical

wards (14% of the patients) might be caused by the high prevalence of

congestive heart failure. In our study, however, 45% of ambulatory patients

with chronic stable congestive heart failure had an apnea-hypopnea index of

26.5 or more episodes per hour (mean, 44 episodes per hour), which was

associated with severe arterial oxyhemoglobin desaturation. We emphasize,

however, that a prospective study larger than ours is necessary to accurately

estimate the prevalence of periodic breathing in patients with stable

congestive heart failure.

Our results indicate that the severity of left ventricular systolic

dysfunction was an important risk factor in predicting periodic breathing

during sleep in patients with stable congestive heart failure. The left

ventricular ejection fraction was significantly lower in group II than in

group I and was significantly correlated with the apnea-hypopnea index.

Obesity is recognized as an important risk factor for the obstructive sleep

apnea-hypopnea syndrome <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note19 " >(19)</A>.

Interestingly, our study shows that body mass

index correlated only with the obstructive apnea-hypopnea index, indicating

that obesity remains a risk factor for sleep-disordered breathing in patients

with congestive heart failure and systolic dysfunction.

Sleep-disordered breathing and associated hypoxemia (and hypercapnia) may

adversely affect sleep architecture and cardiac function. In our study,

patients in group II had excessive episodes of arousal that occurred

approximately 24 times per hour and were directly attributable to disordered

breathing (Figure 2). Excessive arousals may cause daytime fatigue,

irritability, exhaustion, inability to concentrate, and sleepiness <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note21 " >(21)</A>. In

our study, the prevalence of subjective excessive daytime sleepiness was

higher in patients with sleep disordered breathing, but the difference was

not significant (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb1.htm " >Table

1</A>). However, our study was not designed to

quantitatively measure daytime sleepiness <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note21 " >(21)</A>.

Disordered breathing and nocturnal arterial oxyhemoglobin desaturation could

adversely affect cardiac function by various mechanisms <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note22 " >(22-28)</A>. We

found

that left ventricular systolic function was significantly more impaired in

patients with congestive heart failure and sleep-disordered breathing (group

II) than in those without disordered breathing (group I) (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb4.htm " >Table

4</A>). As also

noted earlier, regression analysis showed that the left ventricular ejection

fraction was the most important risk factor for periodic breathing. We cannot

determine from these data whether sleep-disordered breathing exacerbated left

ventricular dysfunction or whether patients with more severe left ventricular

dysfunction had excessive sleep-disordered breathing. However, we speculate

that interaction between sleep-disordered breathing and left ventricular

dysfunction could result in a vicious cycle.

Another important finding in our study was the increased prevalence of

ventricular arrhythmias in patients with sleep-disordered breathing and

congestive heart failure (<A

HREF= " http://www.acponline.org/journals/annals/01apr95/occulttb4.htm " >Table

4</A>). In the multiple regression analysis, the

left ventricular ejection fraction, serum potassium level, and arterial

oxyhemoglobin desaturation were not significantly correlated with ventricular

arrhythmias during sleep. Interestingly, we found central sleep apnea to be

the main predictor of ventricular arrhythmias during sleep, a provocative

finding that needs confirmation.

The mechanisms underlying ventricular arrhythmias in patients with congestive

heart failure remain poorly understood <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note29 " >(29, 30)</A>. It

has been suggested that

activation of the sympathetic nervous system mediates the increase in the

frequency of ventricular extrasystoles noted in sleep in some patients <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note31 " >(31)</A>.

In sleep apnea, this activation may be linked to episodes of hypoxemia and

hypercapnia <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note25 " >(25)</A> or

arousals (the latter is ill-defined by

electroencephalography and therefore cannot be accurately quantified).

Alternatively, Massumi and Nutter <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note32 " >(32)</A>

suggested that variation in arterial

and cerebrospinal fluid Pco2 affecting cardioregulatory centers may be a

potential mechanism.

The long-term effects of sleep-disordered breathing on congestive heart

failure are unknown. Because of disordered breathing, patients in our study

with congestive heart failure had considerable nocturnal hypoxemia (Figure

2), despite normal Pao2 during wakefulness. Nocturnal hypoxemia of this

degree may result in excess mortality, as has been shown in patients with

chronic obstructive lung disease <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note1 " >(1)</A>.

Furthermore, retrospective studies <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note15 " >(15)</A>

of patients with the classic sleep apnea syndrome have suggested that an

apnea index of more than 20 episodes per hour is associated with excess

mortality. Longitudinal studies with appropriate control groups are needed to

determine the potential contribution of disordered breathing to death in

patients with congestive heart failure.

Mechanisms of periodic breathing have been reviewed elsewhere <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note32 " >(32-35)</A> and

are

beyond the scope of this article. However, we emphasize that in an

overwhelming majority of patients with the sleep apnea-hypopnea syndrome,

sleep-disordered breathing episodes were predominantly caused by upper airway

occlusion (obstructive apneas). This contrasts with the prevalence of central

sleep apnea found in most of our patients with congestive heart failure <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note6 " >(6,

10, 12, 36)</A>. Among many other factors <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note32 " >(32-35)</A>, a

prolonged circulation time

(caused by pulmonary congestion and decreased cardiac output) could be an

important factor contributing to periodic breathing (repetitive episodes of

central apnea and hypopnea) in patients with congestive heart failure.

In summary, we showed that 45% of patients with stable, optimally treated

congestive heart failure associated with systolic dysfunction experience a

moderate to severe degree of sleep-disordered breathing. These episodes were

associated with prolonged and severe nocturnal hypoxemia. The only risk

factor that was associated with the apnea-hypopnea index was the severity of

left ventricular dysfunction (obesity was only associated with the

obstructive apnea-hypopnea index). Future studies emphasizing mortality rates

are needed to evaluate the effects of sleep-disordered breathing on daytime

sleepiness, neuropsychiatric function, and the natural history of congestive

heart failure. Meanwhile, physicians caring for patients with congestive

heart failure need to be aware of the magnitude and severity of

sleep-disordered breathing, particularly in patients with more severe left

ventricular systolic dysfunction. Furthermore, because we also found that

central apneas were strongly correlated with ventricular arrhythmias,

patients with stable congestive heart failure who are found to have excess

arrhythmias on Holter monitoring probably should be evaluated for

sleep-disordered breathing and appropriately treated <A

HREF= " http://www.acponline.org/journals/annals/01apr95/#Note5 " >(5, 12, 36)</A>

if

necessary.

Grant Support: By Merit Review Grants from the Department of Veterans

Affairs.

Requests for Reprints: Shahrokh Javaheri, MD, Sleep Disorders Laboratory,

Pulmonary Section (111F), Veterans Affairs Medical Center, 3200 Vine Street,

Cincinnati, OH 45220.

Current Author Addresses: Dr. Javaheri: Sleep Disorders Laboratory, Pulmonary

Section (111F), Veterans Affairs Medical Center, 3200 Vine Street,

Cincinnati, OH 45220.

Dr. : Group Health Associates, 2001 Ferry Road, Cincinnati, OH

45238.

Dr. Wexler: Veterans Affairs Medical Center (111C), 3200 Vine Street,

Cincinnati, OH 45220.

Dr. Stanberry: Pharmacy Service, Veterans Affairs Medical Center (119), 3200

Vine Street, Cincinnati, OH 45220.

Dr. Nishyama: Veterans Affairs Medical Center (115), 3200 Vine Street,

Cincinnati, OH 45220.

Dr. Roselle: Veterans Affairs Medical Center (111), 3200 Vine Street,

Cincinnati, OH 45220.

References

1. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen

therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann

Intern Med. 1980;93:391-8.

2. on TR, King CE, Calhoun JA, on WG. Congestive heart failure.

Cheyne-Stokes respiration as the cause of paroxysmal dyspnoea at the onset of

sleep. Arch Intern Med. 1934;53:891-910.

3. Rees PJ, TJ. Paroxysmal nocturnal dyspnoea and periodic respiration.

Lancet. 1979;2:1315-7.

4. Findley LJ, Zwillich CW, Ancoli-Israel S, Kripke D, Tisi G, Moser KM.

Cheyne-Stokes breathing during sleep in patients with left ventricular heart

failure. South Med J. 1985;78:11-5.

5. Takasaki Y, Orr D, Popkin J, Rutherford R, Liu P, Bradley TD. Effect of

nasal continuous positive airway pressure on sleep apnea in congestive heart

failure. Am Rev Respir Dis. 1989;140:1578-84.

6. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. Respiration

and abnormal sleep in patients with congestive heart failure. Chest.

1989;96:480-8.

7. Yasuma F, Nomura H, Hayashi H, Okada T, Tsuzuki M. Breathing abnormalities

during sleep in patients with chronic heart failure. Jpn Circ J.

1989;53:1506-10.

8. Javaheri S, Bosken CH, Lim SP, Dohn MN, Greene NB, Baughman RP. Effects of

hypohydration on lung functions in humans. Am Rev Respir Dis. 1987;135:597-9.

9. Javaheri S, Guerra LF. Effects of domperidone and medroxyprogesterone

acetate on ventilation in man. Respir Physiol. 1990;81:359-70.

10. Hanly P, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in

patients with congestive heart failure. Relationship to arterial PCO2. Chest.

1993;104:1079-84.

11. Javaheri S, Colangelo G, Lacey W, Gartside PS. Chronic hypercapnia in

obstructive sleep apnea-hypopnea syndrome. Sleep. 1994;17:416-23.

12. Dowdell WT, Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting

as sleep apnea syndrome. Clinical and polysomnographic features. Am Rev

Respir Dis. 1990;141:871-9.

13. Dowdell WT, Javaheri S. Lack of effect of external warming on sleep

architecture in sleep apnea/hypopnea syndrome. Am Rev Respir Dis.

1992;145:137-40.

14. ASDA Report. EEG arousals: scoring rules and examples. Sleep.

1992;15:174-84.

15. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index

in obstructive sleep apnea. Chest. 1988;94:9-14.

16. Zaret BL, Wackers FJ, Soufer R. Nuclear cardiology. In: Braunwald E, ed.

Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: W.B.

Saunders; 1992:276-311.

17. SAS Institute, Inc. SAS/STAT Users Guide. Cary, North Carolina; 1988:

Release 6.03.

18. Dark DS, Pingleton SK, Kerby GR, Crabb JE, Gollub SB, Glatter TR, et al.

Breathing pattern abnormalities and arterial oxygen desaturation during sleep

in the congestive heart failure syndrome. Improvement following medical

therapy. Chest. 1987;91:833-6.

19. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence

of sleep-disordered breathing among middle-aged adults. N Engl J Med.

1993;328:1230-5.

20. Ancoli-Israel S. Epidemiology of sleep disorders. Clin Geriatr Med.

1989;5:347-62.

21. Roth T, Roehrs T, Carskadon M, Dement W. Daytime sleepiness and

alertness. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of

Sleep Medicine. 2d ed. Philadelphia: W.B. Saunders; 1994: 40-9.

22. Fletcher EC, Lesske J, Qian W, CC 3d, Unger T. Repetitive,

episodic hypoxia causes diurnal elevation of blood pressure in rats.

Hypertension. 1992;19:555-61.

23. Fletcher EC, Lesske J, Behm R, CC 3d, Stauss H, Unger T. Carotid

chemoreceptors, systemic blood pressure, and chronic episodic hypoxia

mimicking sleep apnea. J Appl Physiol. 1992;72:1978-84.

24. Blumberg H, Janig W, Rieckmann C, Szulczyk P. Baroreceptor and

chemoreceptor reflexes in postganglionic neurones supplying skeletal muscle

and hairy skin. J Auton Nerv Syst. 1980;2:223-40.

25. Rose CE Jr, Althaus JA, Kaiser DL, ED, Carey RM. Acute hypoxemia

and hypercapnia: increase in plasma catecholamines in conscious dogs. Am J

Physiol. 1983;245:H924-9.

26. Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of

pulmonary hypertension. Chest. 1971;59:82-94.

27. Flemons WW, Horne SG, Guilleminault CG, Gillis AM. Cardiac function

during sleep. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice

of Sleep Medicine. 2

October 29, 2002