Methods Twenty-four patients with a depressed left ventricularejection fraction (45 percent or less) and obstructive sleepapnea who were receiving optimal medical treatment for heartfailure underwent polysomnography. On the following morning,their blood pressure and heart rate were measured by digitalphotoplethysmography, and left ventricular dimensions and leftventricular ejection fraction were assessed by echocardiography.The subjects were then randomly assigned to receive medicaltherapy either alone (12 patients) or with the addition of continuouspositive airway pressure (12 patients) for one month. The assessmentprotocol was then repeated.
Conclusions In medically treated patients with heart failure,treatment of coexisting obstructive sleep apnea by continuouspositive airway pressure reduces systolic blood pressure andimproves left ventricular systolic function. Obstructive sleepapnea may thus have an adverse effect in heart failure thatcan be addressed by targeted therapy.
Heart failure affects approximately 4,700,000 people in theUnited States, with annual costs of approximately $20 billion.1Despite advances in pharmacologic therapy, morbidity, mortality,and rates of hospitalization for heart failure remain high.2,3,4These data emphasize the importance of identifying all treatableconditions that could aggravate heart failure. One such conditionmay be obstructive sleep apnea.
Sleep-related breathing disorders, including obstructive andcentral sleep apnea, often coexist with heart failure. The largestepidemiologic studies, which involved 450 and 81 patients withchronic heart failure, found rates of prevalence of obstructivesleep apnea of 37 percent and 11 percent, respectively.5,6 Inaddition, obstructive sleep apnea is associated with significantlyincreased odds of having heart failure.7
Normally, sleep is accompanied by reductions in central sympatheticoutflow, heart rate, blood pressure, and cardiac output.8 However,recurrent obstructive apnea disrupts sleep and subjects theheart to bouts of hypoxia, exaggerated negative intrathoracicpressure, and bursts of sympathetic activity provoking surgesin blood pressure and heart rate.8,9,10 Such nocturnal stresscan be relieved by therapy with continuous positive airway pressure.10Randomized trials involving patients without heart failure alsosuggest that treating obstructive sleep apnea with continuouspositive airway pressure can lower daytime blood pressure,11,12but the results of randomized trials of continuous positiveairway pressure in patients with heart failure and obstructivesleep apnea have yet to be published.
We previously reported a significant improvement in the leftventricular ejection fraction in eight patients with heart failureand obstructive sleep apnea who were treated with continuouspositive airway pressure for one month.13 However, that studywas not randomized, lacked a control group, included only patientswith nonischemic dilated cardiomyopathy, and did not assessother cardiovascular variables. We therefore undertook a randomized,controlled trial involving patients with heart failure to testthe primary hypothesis that treatment of obstructive sleep apneawith continuous positive airway pressure would improve the leftventricular ejection fraction when patients were awake and thesecondary hypothesis that continuous positive airway pressurewould lower daytime blood pressure.
Methods
Study Subjects
The study subjects were recruited from the heart failure clinicsof Mount Sinai Hospital and Toronto General Hospital in Toronto.Patients referred to these clinics routinely undergo overnightpolysomnography. The entry criteria were a history of heartfailure due to ischemic or nonischemic dilated cardiomyopathy(defined as a left ventricular end-diastolic dimension above27 mm per square meter of body-surface area14) for at leastsix months; a left ventricular ejection fraction of 45 percentor less at rest, as quantified by gated radionuclide angiography;assignment to New York Heart Association functional class II,III, or IV; the absence, within the previous three months, ofexacerbations of heart failure while the patient was receivingstable, optimal pharmacologic therapy at the highest tolerateddoses15; and evidence, during a clinical sleep study, of obstructivesleep apnea, defined as at least 20 episodes of apnea and hypopneaper hour of sleep, of which more than 50 percent were obstructive.
The exclusion criteria were primary valvular heart disease;the presence of an implanted cardiac pacemaker; and unstableangina, myocardial infarction, or cardiac surgery within theprevious three months. The protocol was approved by the researchethics board of the University of Toronto. Written informedconsent was obtained from all patients at enrollment.
Sleep Studies
The patients were evaluated with the use of the Epworth SleepinessScale16 and then underwent base-line overnight sleep studiesin a hospital sleep laboratory. Sleep stages and arousals werescored according to standard criteria.17,18 Thoracoabdominalmovements were monitored by respiratory inductance plethysmography,17and oxyhemoglobin saturation was monitored by oximetry. Signalswere recorded on a polysomnographic system. The desaturationindex was the number of times per hour of sleep that the oxyhemoglobinsaturation fell below 90 percent. The lowest saturation valuewas also recorded. Obstructive and central apneas and hypopneaswere scored as previously described.5,10 The number of apneasand hypopneas per hour of sleep was calculated.
Cardiovascular Assessments
Two hours after the patient awakened, blood pressure and heartrate were measured continuously by digital photoplethysmography,with the patient supine, and averaged over a period of 15 minutes.Next, two-dimensional echocardiographic images were acquiredfrom the parasternal long and short axes, apical long axis,apical four-chamber, and subcostal views by an echocardiographerwho was unaware of the patient's treatment assignment. The leftventricular end-diastolic and end-systolic dimensions were determined,and the left ventricular ejection fraction was calculated accordingto a modification of Simpson's method.19
Intervention
The patients were then randomly assigned to either a controlgroup that continued to receive optimal drug therapy or a treatmentgroup that received continuous positive airway pressure in additionto optimal drug therapy. The night after the base-line sleepstudy, those assigned to continuous positive airway pressureunderwent overnight titration of continuous positive airwaypressure, during which the pressure was adjusted to abolishapnea and hypopnea, or to the highest level tolerated. Patientsin the treatment group were sent home with a continuous-positive-airway-pressuredevice and were instructed to use it every night for at leastsix hours. The number of hours during which the device was switchedon was documented by a built-in meter. All procedures were repeatedone month after the base-line study.
Statistical Analysis
The data are given as means ±SE. The base-line characteristicsof the control group and the group that received continuouspositive airway pressure were compared by two-tailed unpairedt-tests for continuous variables and Fisher's exact test fornominal variables. Two-way repeated-measures analysis of varianceand Tukey's test were used to compare differences within andbetween groups in variables measured at base line and one monthlater. P values of less than 0.05 were considered to indicatea statistically significant difference.
Results
Characteristics of the Patients
Twenty-four patients participated, 12 with ischemic and 12 withnonischemic dilated cardiomyopathy. All had a history of habitualsnoring. Twelve patients were randomly assigned to the controlgroup, and 12 to the group given continuous positive airwaypressure; all 24 completed the study. Most of the patients weremiddle-aged, overweight men with mild-to-moderate symptoms ofheart failure and a markedly depressed left ventricular ejectionfraction. At base line there were no significant differencesbetween the two groups in age, sex distribution, body-mass index,cardiac diagnosis, New York Heart Association class, left ventricularejection fraction, or medications (Table 1). Twenty-two patientshad normal sinus rhythm, and two in the control group had atrialfibrillation. The scores on the Epworth Sleepiness Scale weresimilar in the two groups. There were no significant differencesbetween the two groups in the base-line frequency of apneasand hypopneas, desaturation index, lowest oxyhemoglobin saturationvalue, frequency of arousals from sleep, or distribution ofsleep stages (Table 2).
Table 2. Anthropomorphic and Polysomnographic Data.
Effects of Continuous Positive Airway Pressure
There were no significant changes in body-mass index from baseline to one month in either group (Table 2). In the controlgroup, there were no significant changes in the frequency ofapneas and hypopneas or any of the other polysomnographic variablesduring the study. In the treatment group, continuous positiveairway pressure was administered at a mean of 8.9±0.7cm of water (range, 6 to 14) for 6.2±0.5 hours per nightduring the study. As compared with base line, the treatmentgroup had significant reductions in the frequency of obstructiveapneas and hypopneas and arousals from sleep and significantimprovements in the desaturation index and the lowest oxyhemoglobinsaturation value (P<0.01 for all differences), which weremore pronounced than in the control group.
There were no changes in medications during the study in eithergroup. Control patients had no significant changes in bloodpressure or heart rate (Table 3), but the group treated withcontinuous positive airway pressure had a reduction in daytimesystolic blood pressure of 10±4 mm Hg (P=0.02 for thecomparison with base line) and a reduction in heart rate of4±2 beats per minute (P=0.007). The fall in systolicblood pressure was proportional to the base-line value (r=0.596,P=0.04). The changes in systolic blood pressure were significantlygreater in the patients treated with continuous positive airwaypressure than in the control group (P=0.008). The changes inheart rate also tended to be more pronounced in the patientstreated with continuous positive airway pressure than in thecontrols, but the difference was not significant (P=0.09).
After one month, there was no significant change in left ventricularejection fraction in the control group (an increase of 1.5±2.3percent, based on left ventricular end-diastolic and end-systolicvolumes of 221±14 and 160±13 ml, respectively,at base line and 215±14 and 149±9 ml, respectively,at one month). In contrast, the group treated with continuouspositive airway pressure had a significant absolute increaseof 8.8±1.6 percent in the left ventricular ejection fraction(P<0.001) and a relative increase of 35 percent (Figure 1),based on left ventricular end-diastolic and end-systolic volumesof 184±14 and 140±13 ml, respectively, at baseline and 192±14 and 129±12 ml, respectively, atone month. The improvement was significantly greater than thatin the control group (P=0.009).
Figure 1. Individual Values for the Left Ventricular Ejection Fraction in All Patients.
In the control group, there was no significant change in the left ventricular ejection fraction from base line to one month (from a mean [±SE] of 28.5±1.8 to 30.0±2.1 percent). In contrast, the left ventricular ejection fraction increased in all 12 subjects treated with continuous positive airway pressure, and the mean increase was significant (from 25.0±2.8 to 33.8±2.4 percent, P<0.001). The change in the left ventricular ejection fraction from base line to one month was significantly greater in the group treated with continuous positive airway pressure than in the control group (8.8±1.6 percent vs. 1.5±2.3 percent, P=0.009). The one patient in the group that received continuous positive airway pressure who had a base-line left ventricular ejection fraction of 48 percent met the pretrial screening eligibility criterion (the left ventricular ejection fraction was 39 percent). NS denotes not significant. Short horizontal lines and I bars are means ±SE.
This effect of continuous positive airway pressure on the leftventricular ejection fraction was similar in patients receivingbeta-blockers and those not receiving beta-blockers (increasesof 9.1±2.4 percent [P=0.008] and 8.5±2.1 percent[P=0.02], respectively). In addition, subjects with ischemicdilated cardiomyopathy and those with nonischemic dilated cardiomyopathyhad similar improvements in the left ventricular ejection fractionduring treatment with continuous positive airway pressure (increasesof 8.1±1.3 percent [P=0.02] and 9.7±3.0 percent[P=0.02], respectively). There were no significant changes inleft ventricular end-diastolic or end-systolic dimensions inthe control group, but there was a significant reduction inend-systolic dimension in the group treated with continuouspositive airway pressure (P=0.009). This reduction was significantlygreater than that in the control group (P=0.02) (Figure 2).
Figure 2. Mean (±SE) Changes in Left Ventricular Dimensions.
There were no significant changes in left ventricular end-diastolic dimension (LVEDD) or left ventricular end-systolic dimension (LVESD) during the study period in the control group (LVEDD changed from 65.6±2.8 to 67.2±2.4 mm, and LVESD from 56.6±3.0 to 57.3±2.5 mm). In the group treated with continuous positive airway pressure, there was no significant change in LVEDD during the study period (LVEDD changed from 64.3±1.8 to 63.4±1.8 mm). However, there was a significant reduction in LVESD (from 54.5±1.8 to 51.7±1.2 mm, P=0.009). The change in LVESD from base line to one month was significantly greater in the group that received continuous positive airway pressure than in the control group (–2.8±1.1 vs. 0.7±0.8 mm, P=0.02). NS denotes not significant.
Discussion
Our results demonstrate that nocturnal continuous positive airwaypressure significantly improves the daytime left ventricularsystolic function of patients with heart failure and coexistingobstructive sleep apnea whose condition is stable. One monthof therapy with continuous positive airway pressure resultedin a 9 percent absolute increase and a 35 percent relative increasein left ventricular ejection fraction, in conjunction with significantreductions in left ventricular end-systolic dimension, daytimesystolic blood pressure, and heart rate. Because continuouspositive airway pressure reduced the frequency of obstructiveevents and arousals and improved arterial oxygenation duringsleep, we attribute these cardiovascular effects primarily tothe alleviation of obstructive sleep apnea.
In our previous uncontrolled study, involving eight patientswith nonischemic dilated cardiomyopathy and obstructive sleepapnea, therapy with continuous positive airway pressure alsoresulted in a significant augmentation of the left ventricularejection fraction.13 The present study confirms, in the morerigorous setting of a randomized trial, that one month of nocturnalcontinuous positive airway pressure causes substantial improvementin the daytime left ventricular ejection fraction. Our studyalso broadens the application of these findings to both ischemicand nonischemic causes of heart failure. By demonstrating thatcontinuous positive airway pressure also lowers daytime systolicblood pressure and heart rate, our study provides evidence thatthis improvement in the left ventricular ejection fraction isachieved at a lower myocardial workload and points to sustainedreduction in afterload as one likely mechanism for this improvement.
Obstructive sleep apnea has several adverse effects with thepotential both to impair ventricular systolic function and toraise systemic vascular resistance. Acutely, inspiratory effortsduring obstructive apnea generate exaggerated negative intrathoracicpressure, which leads to both an increase in left ventricularafterload and a decrease in left ventricular preload, whichin turn cause a reduction in stroke volume.8,9,22,23,24 Intermittenthypoxia during obstructive apnea may impair cardiac contractilitydirectly or reduce cardiac output indirectly by increasing pulmonary-arterypressure.25,26 It may also induce a mismatch between the supplyof oxygen and the demand, provoking myocardial ischemia in thosewith coronary disease.27 Apnea-induced hypoxia, hypercapnia,and arousal from sleep trigger sympathetic vasoconstrictor outflowthat raises systemic blood pressure and further increases afterload.28,29,30These adverse hemodynamic and sympathetic effects are more pronouncedin subjects with heart failure.31,32 Long-term exposure to elevatedsympathetic neural activity can induce hypertrophy and apoptosisof myocytes and predispose patients to cardiac arrhythmias.33,34None of these adverse nocturnal effects of obstructive apneaare remedied by pharmacologic therapy.35
In contrast, continuous positive airway pressure reverses manyof these pathophysiological effects during sleep. In patientswith obstructive sleep apnea but without heart failure, continuouspositive airway pressure attenuates apnea-related surges insympathetic vasoconstrictor tone.29 In patients with heart failure,short-term abolition of obstructive apnea by continuous positiveairway pressure dampens negative intrathoracic-pressure swingsand lowers systemic blood pressure, causing a reduction in leftventricular afterload.10 By abolishing hypoxic dips, continuouspositive airway pressure also augments the myocardial oxygensupply while reducing oxygen demand.
In the present study, we found that the effects of nocturnalcontinuous positive airway pressure carry over into wakefulness.After one month, subjects treated with continuous positive airwaypressure had a 9 percent absolute and a 35 percent relativerise in left ventricular ejection fraction and a 3-mm decreasein left ventricular end-systolic dimension during wakefulness.These improvements in systolic function were accompanied bya decrease in systolic blood pressure of 10 mm Hg and a decreasein heart rate of 4 beats per minute, suggesting a concomitantlowering of myocardial oxygen requirements.
The mechanisms contributing to this sustained increase in leftventricular ejection fraction were probably abolition of cyclicalsurges in left ventricular wall tension during sleep and chronicdownward resetting of sympathetic outflow and peripheral resistancesecondary to the abolition of obstructive apnea.29,36 Similarimprovements in the left ventricular ejection fraction thatwere associated with reductions in the plasma norepinephrineconcentration have been described in patients with heart failureand Cheyne–Stokes respiration who were treated with continuouspositive airway pressure.17,37 Our observation, that continuouspositive airway pressure used only at night leads to improvementin the left ventricular ejection fraction that persists intothe daytime, is similar to the sustained improvement in leftventricular systolic function that occurs after removal of aleft ventricular assist device. With both mechanical interventions,myocardial workload is reduced and heart failure is alleviated.Over time, this change may lead to sustained aftereffects, includingreduction in sympathetic outflow, up-regulation of myocardial-adrenergic–receptor responsiveness,37,38 restorationof the expression of cardiac metabolic genes, and improvementin contractility.39
Improvements in cardiovascular function in response to continuouspositive airway pressure occurred relatively rapidly in ourstudy in patients in stable condition who were receiving optimalmedical therapy, including combinations of drugs that reducevascular resistance (Table 1). Furthermore, the magnitude ofchange in the left ventricular ejection fraction did not differbetween the majority of patients treated with continuous positiveairway pressure who were receiving beta-blockers and the minoritywho were not. Those with ischemic and those with nonischemicdilated cardiomyopathy had similar improvements in left ventricularejection fraction, a result indicating that continuous positiveairway pressure has beneficial effects beyond those of contemporarypharmacologic therapy that are independent of the cause of heartfailure. Although it is possible that the response to continuouspositive airway pressure might differ between patients withischemic cardiomyopathy and those with nonischemic cardiomyopathy,a larger study would be required to detect this difference.
The presence of obstructive sleep apnea was not associated withreports of daytime sleepiness, as indicated by normal scoreson the Epworth Sleepiness Scale (under 10).16 Nevertheless,compliance was excellent among those randomly assigned to continuouspositive airway pressure, indicating that patients with heartfailure and obstructive apnea need not have daytime sleepinessto derive cardiovascular benefits from continuous positive airwaypressure. Our data also suggest that continuous positive airwaypressure can be readily tolerated across a wide spectrum ofage and severity of heart failure, since our patients rangedin age from 28 to 72 years and had class II, III, or IV symptomsof heart failure.
Although the patients were aware of their treatment assignments,the key measurements of cardiovascular outcome were obtainedby persons blinded to treatment assignment. The control grouphad no significant changes in sleep or cardiovascular outcomes,a result confirming the stability of their condition duringthe study. Therefore, the changes detected in the treatmentgroup can be attributed specifically to continuous positiveairway pressure, even in the absence of a placebo intervention.
In general, therapies that lower blood pressure (i.e., afterload)and heart rate and improve the left ventricular ejection fractionreduce cardiovascular morbidity and mortality among patientswith heart failure.2,3 Ideally, therefore, larger randomizedtrials should be undertaken to determine whether the beneficialeffects of continuous positive airway pressure on cardiovascularfunction translate into similar long-term outcomes. However,such studies may be difficult if not impossible to conduct becauseof the ethical concerns that would arise if continuous positiveairway pressure, which is now standard therapy for obstructiveapnea in patients without heart failure, were withheld froma control group over prolonged periods.
In conclusion, treatment of obstructive sleep apnea by nocturnalcontinuous positive airway pressure in medically treated patientswith heart failure improves daytime left ventricular systolicfunction while lowering systolic blood pressure. Since nocturnalcontinuous positive airway pressure does not induce such responsesin patients with heart failure but without sleep apnea,41 ourfindings imply that obstructive apnea has specific detrimentaleffects on ventricular function and blood pressure that areat least partially reversible.8,9,10,20
Because obstructive sleep apnea has been reported to occur inup to one third of patients with stable heart failure,5 continuouspositive airway pressure could become an important nonpharmacologicadjunct to conventional drug therapy in this population. Ourresults therefore raise the question of whether routine screeningfor sleep apnea should be performed in patients with heart failure.Currently, the standard method for the diagnosis of sleep apneais polysomnography conducted in a sleep laboratory, an expensiveand not universally available procedure. However, the developmentand validation of less expensive and more readily availabletechniques, such as ambulatory monitoring, may make widespreadscreening for sleep apnea feasible in patients with heart failure.Nevertheless, there needs to be greater awareness among physiciansthat obstructive sleep apnea may have an adverse pathophysiologicalrole in heart failure that can be addressed by targeted therapy.
Supported by a grant (MOP-11607) from the Canadian Institutesof Health Research, a research fellowship from the Japan InformationCenter for Respiratory Failure Patients (to Dr. Kaneko), a CareerScientist Award from the Heart and Stroke Foundation of Ontario(to Dr. Floras), a Senior Scientist Award from the CanadianInstitutes of Health Research (to Dr. Bradley), unrestrictedResearch Fellowships from Respironics (to Drs. Usui, Plante,and Tkacova), unrestricted postdoctoral support from Merck Frosst,SmithKlineBeecham, and Roche Pharmaceuticals (to Dr. Kubo),and a Canadian Hypertension Society–Merck Frosst CanadaResearch Fellowship and a grant from the Gardiner Foundationof Toronto (to Dr. Ando).
Drs. Floras and Bradley report having received research fundingunrelated to the current study from Respironics, ResMed, andTyco. Dr. Usui reports having received grant support from Respironics.
We are indebted to Fiona Rankin, B.Sc., and Candice Silversides,M.D., for their technical assistance.
Source Information
From the Sleep Research Laboratories, Toronto Rehabilitation Institute (Y.K., K.U., J.P., R.T., T.D.B.); Toronto General Hospital–University Health Network and Mount Sinai Hospital (J.S.F., T.K., S.A., T.D.B.); and the Department of Medicine and the Centre for Sleep Medicine and Circadian Biology, University of Toronto (Y.K., J.S.F., K.U., J.P., R.T., T.D.B.) — all in Toronto.
Address reprint requests to Dr. Bradley at the Toronto General Hospital/UHN, NU 9-112, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada, or at douglas.bradley{at}utoronto.ca.
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-adrenergic–receptor responsiveness,37,38 restoration of the expression of cardiac metabolic genes, and improvement in contractility.39 
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