sleep apnoea in chronic heart failure

8/13/2019 Sleep apnoea in chronic heart failure

1/25

Chapter 23

Sleep apnoea in

chronic heart failureM.T. Naughton* and S. Andreas#

Summary

Sleep-related breathing disorders are present in ,50% ofpatients with chronic heart failure, with fairly equal prevalence

of obstructive sleep apnoea (OSA) and central sleep apnoea(CSA) with CheyneStokes respiration. While it is widelyaccepted that OSA exerts negative effects on the heart, con-troversy remains as to whether CSA contributes to morbidityand mortality in chronic heart failure patients or whether it issimply an epiphenomenon. The largest randomised trial to date,which involved patients with heart failure and CSA, did notdemonstrate a convincing effect of continuous positive airwaypressure on transplant-free survival. At least two large, long-term randomised trials examining the effect of ventilatory

strategies on patients survival with heart failure and sleep-related breathing disorders are in progress. To address thequestion of therapeutic benefit, suitable patients should beconsidered for enrolment in these studies.

Keywords: Chronic heart failure, sleep apnoea syndrome

*Alfred Hospital and MonashUniversity, Victoria, Australia.#Lungenfachklinik Immenhausen,Pneumologische Lehrklinik

Universitat Gottingen, Kassel,Germany.

Correspondence: M.T. Naughton,Alfred Hospital and MonashUniversity, Commercial Road,Prahran, 3181, Victoria, Australia,Email [email protected]

Eur Respir Mon 2010. 50, 396420.Printed in UK all rights reserved.Copyright ERS 2010.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.00026209

Heart failure is a complex syndrome with variable symptoms and signs, many of which arerelated to respiration and sleep. These can include: dyspnoea on exertion (an early symptom)or at rest (a late symptom), fatigue, tachypnoea, tachycardia, pulmonary crepitations,cardiomegaly and peripheral oedema [1, 2]. Duration, aetiology and symptoms of heart failurewill not only vary between individuals, but also provide an insight into the need and relevance ofsleep-disordered breathing therapies.

The prevalence of symptomatic heart failure in the general population of an industrialised countryis 0.42% and increases rapidly with age [3], such that between 10 and 20% of 7080-yr-olds areaffected [2]. The prognosis for heart failure patients is poor, with a 5-yr mortality rate of 4060%in the diagnosed population [2]. Heart failure is the most common reason for hospital admissionamong persons aged 65 yrs or older, accounting for ,2% of all admissions. In addition, thehospitalisation of patients in connection with heart failure has markedly increased in the pastdecades. As a direct result, 2% of the entire health expenditure is due to the socioeconomic burdenof heart failure [2].

Circulatory failure occurs when the heart is unable to pump sufficient blood to meet the metabolicneeds of the body [2]. The causes of circulatory failure can be cardiac, i.e. heart failure, ornoncardiac, i.e. thyroid disease, anaemia, or loss of circulating blood volume.

396

SLEEP

APNOEA

IN

CHF


2/25

Systolic heart failure is defined by impaired left ventricular contractility and is most commonlydue to coronary artery disease (,70%), with the remainder due to hypertension, inflammation orunknown (idiopathic). Objectively, systolic heart failure is defined by: 1) a left ventricular ejectionfraction (LVEF) of ,55%, which is measured by either nuclear angiography or anechocardiography, or 2) a left ventricular fractional shortening of ,28% that is measured byechocardiography.

Diastolic heart failure has recently been renamed as heart failure with normal systolic function

(HFNSF) [4]. It is defined by symptoms of heart failure, similar to systolic heart failure with anelevated left ventricular filling pressure, i.e. pulmonary capillary wedge pressure (Ppcw).12 mmHg, but with normal systolic contraction. HFNSF is commonly due to impaired leftventricular relaxation from hypoxia, tachycardia [5], increasing age and hypertension [3, 6]. Lesscommon causes include pericardial effusion, constrictive pericarditis and myocardial infiltrativedisorders, e.g. amyoid or haemochromatosis. Therefore, highlighting the need for an accuratediagnostic procedure, e.g. via echocardiography. Due to the close association of HFNSF withhypertension, hypoxaemia and tachycardia, obstructive sleep apnoea (OSA) is common in HFNSFpatients, albeit this has only been demonstrated in the rather small studies that have beenpublished [710].

Acute cardiogenic pulmonary oedema (APO) is a clinical condition in which acute dyspnoeaoccurs secondary to heart disease, over a period of less than 6 h. It is usually preceded by unstableischaemic heart disease or systemic hypertension. Additional common precipitants include:noncompliance with medical treatment; arrhythmias, e.g. paroxysmal atrial fibrillation; theaddition of negative inotropic agents, e.g. calcium channel, beta blockers and cytotoxins;pulmonary emboli; nonsteroidal anti-inflammatory drugs; excessive alcohol or illicit drugs;endocrine abnormalities, e.g. diabetes, hypothyroidism and hyperthyroidism; or concurrentinfections.

Classification of heart failure symptoms has traditionally been made using the New York HeartAssociation (NYHA) classification (table 1). However, there is a poor relationship betweenobjective cardiac dysfunction, symptoms and prognosis [11].

An alternative classification on heart failure status has been developed to incorporate patients withhigh risk of developing heart failure in addition to those with transient heart failure symptoms(table 2).

The diagnostic steps to confirm heart failure are based upon history, examination, chestradiographs and more recently biomarkers, e.g. the B-type natriuretic (brain) peptide (BNP) orprohormone N-terminal (proNT-BNP). In severe or unstable heart failure a reduced cardiac

output, in combination with the subsequent activation of both the sympathetic nervous systemand the renin angiotensin system, results in the accumulation of fluid. The diagnosis of APO canbe relatively straight forward with the use of BNP biomarkers, making only a small improvementupon the diagnoses of experienced clinicians [13]. Falsely low BNP readings may occur in patientstermed obese and can be falsely elevated in both patients suffering from renal failure and theelderly. Important to note here, is that BNP levels may be normal in flash pulmonary oedemaand in APO secondary to pericardial disease.

Table 1. New York Heart Association classification for heart failure symptoms

How fit are you?

1) No ordinary limitation of any physical activity

2) Ordinary physical activity results in fatigue, palpitations, dyspnoea or chest pain

3) Less than ordinary activity causes fatigue, palpitations, breathlessness or chest pain

4) Unable to carry out any physical activity without discomfort

397

M.T.NAUGHTON

AND

S.ANDREAS


3/25

However, in more mild or stable heart failure patients the clinical diagnosis of heart failure may bemore difficult [11], although it is usually defined by orthopnoea, paroxysmal nocturnal dyspnoea,exertional dyspnoea associated with cardiomegaly on chest radiographs and abnormal systolic ordiastolic functions on an echocardiograph. Orthopnoea is usually quite a sensitive symptom ofheart failure, although not specific. Other noncardiac causes of orthopnoea include diaphragmweakness and advanced obstructive/restrictive lung disease.

Epidemiology

Sleep-disordered breathing in chronic heart failure patients

Sleep-disordered breathing has been reported to occur in up to 70% of heart failure patients withan LVEF ,40% and 55% of patients with diastolic heart failure [14]. Within the heart failurepopulation OSA occurs in 2743% of the subjects, whilst central sleep apnoea (CSA) occurs in 2844% of the subjects.Table 3shows the variance, which may be explained by the study populations(especially age and sex), the threshold definitions used for both heart failure and sleep-disorderedbreathing, and the diagnostic tests employed, when ascertaining the prevelance of sleep-disorderedbreathing in patients with heart failure. Occasional and persistent sleep-disordered breathing, overa 12-month period, was observed in approximately 35 and 50% of the ambulatory heart failure

patients, respectively, using cardiopulmonary telemonitoring [26]. Despite obvious limitations ofthis study,e.g.the inability to differentiate OSA from CSA and technical failures (.20%), the moststriking observation was the high prevalence of persistent sleep-disordered breathing, similar tothat of previous studies.

Pathophysiology

OSA

As with non-heart failure populations, OSA in heart failure patients is likely to occur where there

is: 1) obesity, 2) craniofacial abnormalities, e.g. retrogathia, maxilliary restriction, adeno-tonsillarhypertrophy nasal obstruction, 3) the use of drugs associated with upper airway muscle hypotonia,i.e.alcohol, sedatives, glucocorticoid steroids or impaired arousal (e.g.anti-epileptic) drugs, and 4)upper airway oedema-related fluid retention [27].

OSA is characterised by recurring upper airway collapse with ongoing respiratory effort duringsleep, causing repetitive surges of negative intrathoracic pressure, arousals, hypoxaemia andhypercapnia. OSA gives rise to sympathetic activation, increased systemic blood pressure,oxidative stress coagulopathy, and is considered a risk factor towards the development of coronaryartery disease [28, 29] and heart failure.

Both animal [30] and human [31] studies suggest that negative, intrathoracic pressure swingscontribute to left ventricular hypertrophy and impaired cardiac function. These findings may explainthe rise in atrial natriuretic peptide in OSA (due to atrial stretch). These detrimental effects ofintrathoracic pressure on the heart are far more pronounced in those with chronic heart failurecompared with those of healthy subjects [32]. Human studies suggest that with heart failure, thepolysomnography patterns of OSA change: the hyperpnoea length and the lung-to-ear circulation time

Table 2. Heart failure classification [12]

A. High risk of heart failure without structural heart disease or symptoms of heart failure

B. Structural heart disease without signs or symptoms of heart failure

C. Structural heart disease with prior or current symptoms of heart failure

D. Refractory heart failure requiring specialised interventions

398

SLEEP

APNOEA

IN

CHF


4/25

Table3.

Preva

lenceofsleep-disorderedbreathing(SDB)inpatientswithheartfa

ilure

First

author

[Ref.]

Y

earPatients

EF#

SDB

OSA

CSA

Age

yrs

BMI

kg?m-

2

EF

OSA

CSA

SDB

-

blocker

ACE"

inhibitor

Setting

JAVAHERI

[15]

1

998

81(81)

,45%

o1

5

OAHI.15

OAHI,1

0

64

28

25

1

1

40

51

0

90

Outpatients

SIN

[16]

1

999

450(68)

o15

.50%

obstructive

.50%

cen

tral

60

29

27

3

2

29

61

0

73

SleepClinic

LANFRANCHI

[17]

2

003

47(42)

f40%

o15

Predominant

Predomina

nt

59

26

27

1

1

55

66

36

83

Rehabilitation

ROEBUCK

[18]

2

004

78(64)

,55%

.5

,85%

centralo85%

cen

tral

53

27

20

2

8

42

70

14

100

Heartfailure

clinic

MARED

[19]2

004191(130)

Na

na

Predominant

OSA

CSR.10

%

73

26

36

4

66

70

28

70

Heartfailure

unit

CARMONA-

BERNAL

[20]

2

005

90(75)

f45%

o10

.30%

obstructive

o70%

cent

ral+

CSR

57

29

29

6

28

34

29

100

outpatient

FERRIER

[21]

2

005

53(41)

,45%

.10

.50%

obstructive

.50%

cen

tral

60

28

34

5

3

15

68

32

96

Outpatient

JAVAHERI

[22]

2

006100(100),45%

o15

%

OAHIo15

.50%

central+

OAHI,10

64

24

1

2

37

49

10

91

Sleepcentre

SCHULTZ

[23]

2

007203(152)

f40

.15

CAHI,10

OAHI,10

+

CSR

65

27

28

4

3

28

71

90

91

In-+

outpatient

OLDENBURG

[24]

2

007700(561)

f40

o5%

Predominant

OSA

Predomina

nt

CSA

65

26

28

3

6

40

76

85

94

Inpatient

MACDONALD

[25]

2

008

108(92)

,40

o15

%

CSRtime

,33%

CSRtime

.33%

57

27

20

3

0

31

61

83

82

HFclinic

Dataarepresen

tedasn(malesn)or%,unlesso

therwisestated.

Forallresultsthe

meanhasbeengiven.

EF:ejectionfraction;OSA:obstructivesleepapnoea;CSA:central

sleepapnoea;B

MI:bodymassindex;ACE:angiotensin-convertingenzyme;OA

HI:obstructiveapnoea/hypopnoeaindex;CAHI:centralapnoea/hypopnoeaindex;CSR:

CheyneStokes

respiration

#:inclusions;

":patien

tstreatedwithACEinhibitorand

/orAT1-blocker.

399

M.T.NAUGHTON

AND

S.ANDREAS


5/25

(as measured by the time from beginning of ventilation to nadir of oximeter placed on ear lobe) areboth prolonged, whilst the overall cycle length is unchanged [33].

Pathophysiology

CSA

CSA is characterised by a crescendodecrescendo pattern of ventilation with central apnoeas (orhypopnoeas) usually during stages 1 and 2 of sleep, triggered by an arousal or state change inpatients with advanced subacute heart failure. An arousal often occurs at the peak of ventilation.This pattern of respiration is also referred to as CheyneStokes respiration. CSA is associated with:mild hypoxaemia; restrictive ventilatory defect, with reduced pulmonary diffusing capacity [34];elevated Ppcw[35]; and a low prevailing carbon dioxide arterial pressure Pa,CO2 [36], with highventilatory responses when measured awake [3739] or during exercise [40]. CSA does not appearto elicit such negative intrathoracic pressure swings, which occur with OSA [41, 42]. In heartfailure populations, although CSA is associated with greater sympathetic activity when comparedwith groups that have no sleep-disordered breathing [43, 44], the cause of elevated sympathetic

activity appears to relate to heart failure severity rather than CSA per se[45, 46]. Moreover, recentevidence suggests a close association between sympathoexitation and daytime sleepiness, due toclock gene dysfunction in OSA [47].

The pathophysiology underlying CSA relates to an oscillation of the negative feedback loopcontrolling respiration (fig. 1). Corresponding examples of 5-min epochs from the twopolysomnograms (PSGs) shown on figure 1 are shown in figures 2 and 3, OSA and CSA,respectively. The feedback loop consists of controller gain (ventilatory response to arterial bloodgases), the plant gain (blood gas response to changes in ventilation) and feedback gain (the timecourse of the feedback signal to the central controller). According to theoretic reasoning the

following synergistically acting mechanisms favour an oscillation of ventilation [39, 4852].First, hypocapnia is common in heart failure and partly explained by acute [53] and chronic [37, 54]changes in Ppcw(i.e. left atrial pressure), with parallel changes in minute ventilation (V9E). Thisresults in thePa,CO2moving closer to the apnoea threshold and thus may favour CSA [15, 36, 55].

Secondly, low oxygen and carbon dioxide stores, due to 1) greater oxygen uptake and carbondioxide production at rest both decrease with the severity of heart failure and with an increase inage and 2) restrictive lung volumes and impaired alveolar capillary membrane function, ascommonly found in chronic heart failure [34], increase the plant gain [51, 56].

Thirdly, a high ventilatory response, mainly to hypercapnia but also to hypoxia (i.e. a high

controller gain), favours ventilatory instability [51, 57, 58]. Diminished cerebrovascular responseto hypocapnia may contribute to ventilatory overshooting and undershooting in chronic heartfailure patients [59].

Fourthly, a low cardiac output, increased intracardiac dimensions and pulmonary congestionprolong the transit time between the lungs and chemoreceptors [60]. Alone the prolonged transittime is unlikely to cause CSA, but may contribute to ventilator instability. Circulation time isclosely related to the cycle time of a ventilatory period [6163].

Fifthly, sleep itself promotes CSA as lung volumes are reduced in the prone position comparedwith the upright posture. Furthermore, during sleep the stabilising influence of higher corticalstructures on respiration are reduced and the changes in sleep stages elicit the alterations inventilation, therefore, destabilising ventilatory control [64].

Finally, hypoxaemia, as it repetitively occurs in CSA, causes an increase of pulmonary arterypressure (Ppa) due to vasoconstriction and might, therefore, further reduce the right ventricularfunction with further possible negative effects [65]. However, right heart catheterisation has not

400

SLEEP

APNOEA

IN

CHF


6/25

been performed during CSA and in the one study where right ventricular ejection fraction wasevaluated, it was not specifically reduced in patients with CSA [15].

As opposed to sleep, periodic breathing or oscillatory ventilation during exercise is not unusual inpatients with heart failure, and is associated with worse clinical status, cardiac function andexercise capacity, lower end-tidal carbon dioxide tension (PET,CO2) and atrial fibrillation [6668]associated with nocturnal CSA and mortality [69], particularly sudden cardiac death [67].Oscillatory ventilation during exercise also occurs in diastolic heart failure and may provideprognostic clues in this patient group [70]. Given the intimate and intricate relationship betweenheart failure and control of ventilation, it still remains unclear whether oscillatory ventilationduring exercise independently contributes to morbidity and mortality in heart failure patients.

Diagnosis

The history in support of OSA, with or without heart failure, is that of long standing regularsnoring, audible in other rooms and loud enough to disturb the sleep of others. Witnessedapnoeas, unrefreshing sleep, and fatigue are all common place, while nocturnal dyspnoea isrelatively uncommon. Importantly, the usual symptoms of OSA do not occur in the presence ofheart failure [71]. Excessive daytime sleepiness in a heart-failure OSA population is less, both

Time h

a) b)

Epoch

SleepRSM

W1234

L

F

BR

100

70

80

30

stage

L

F

BR

REMMOV AWK

1234

Bodyposition

Sp,O2%

Ptc,CO2

mmHg

6 7543210

23:00

8417216014813612411211

05:0004:0003:0002:0001:0000:00

8

06:00

9610 10

22:00

9617214812411

06:0004:0002:0000:00 08:00

1201

Figure 1.Typical overnight polysomnogram (PSG) summary charts of two individual patients with a) obstructivesleep apnoea (OSA) and b) central sleep apnoea (CSA). W: wake; F: front; B: back; L: left: R: right; REM: rapid

eye movement; MOV: movement; AWAK: awake. The OSA patient is male, aged 74 yrs with long standing

snoring and witnessed apnoeas, type 2 diabetes mellitus and ischaemic heart disease, which requires coronarygraft surgery. The echocardiography indicates left ventricular diastolic dysfunction (left ventricular ejection

fraction (LVEF) 55%. The patient had an Epworth Sleepiness Scale (ESS) of 14, the New York Heart Association

(NYHA) classification was 3, body mass index (BMI) 34 kg?m-2. PSG results were: apnoea/hypopnoea index(AHI) 74 events?h-1, minimum arterial oxygen saturation measured by pulse oximetry (Sp,O2) 59%,

transcutaneous carbon dioxide tension (Ptc,CO2) 36 (range 3346) mmHg with pre-sleep arterial blood gases

(ABGs) of pH 7.32, arterial carbon dioxide tension (Pa,CO2) 40 mmHg and arterial oxygen tension (Pa,O2)73 mmHg. The CSA patient is male, 54-yrs of age, with a reduced left ventricular systolic function (LVEF 32%)

that is associated with hypertrophic cardiomyopathy, and has an arterial overdrive pacemaker in situ. The patient

had the following readings: ESS 14; NYHA 4; and BMI 25.8 kg?m-2. The PSG results were: AHI 51 events?h1;minimum Sp,O2 77%; Ptc,CO2 31 (range 2742) mmHg with corresponding pre-sleep ABGs of pH 7.52, Pa,CO231 mmHg and Pa,O2 75 mmHg.

401

M.T.NAUGHTON

AND

S.ANDREAS


7/25

symptomatically (Epworth Sleepiness Scale (ESS) score) and objectively (Multiple Sleep LatencyTesting; MSLT) compared with a large general community [71, 72]. In contrast, patients with CSAusually complain of more severe heart failure, such as orthpnoea, paroxysmal nocturnal dyspnoea,witnessed apnoeas, insomnia and fatigue. With CSA, there may have been a history of snoring thathas abated or disappeared entirely. Both OSA and CSA have a postural (i.e.supine) [73], and male

predominance [16].

On examination, the OSA patient is most likely to have standard OSA appearance, e.g. obesity,large neck circumference, retrognathia, nasal obstruction, enlarged tongue, high Mallampati index.In contrast, the typical CSA patient has signs of advanced heart failure, namely cardiomegaly,cardiac murmurs, third heart sound, pulmonary crepitations, peripheral oedema, elevated jugularvenous pressure and are often in atrial fibrillation or have a pacemaker, for cardiacresynchronisation therapy (CRT).

Cardiac tests that indirectly suggest CSA are markers of subacutely decompensated heart failure,namely elevated BNP and Ppcw, poorly dilated contracting left ventricle, and cardiomegaly with Kerley

B lines on chest radiographs. Both OSA and CSA patients may have distinctive heart rate variabilitypatterns on a holter monitor [74], reflective of the competing vagal and sympathetic patterns.

Pulmonary function tests may indicate a restrictive ventilatory defect, reduced diffusing capacity andreduced inspiratory muscle strength [75]. A lowPa,CO2(awake or asleep) with mild alkalosis and mildhypoxaemia suggest CSA [36]. During cardiopulmonary exercise testing, oscillatory ventilation,

C3-A2ARO RES ARO RES ARO RES ARO RES ARO RES ARO RES

128 uV

O1-A2128 uV

LOC128 uV

ROC128 uV

C4-A1128 uV

O2-A1128 uV

1G sub-men42.7 uV

Heart ratebpm

ECG

BP

EMG LLMG RLSnoreTherm

NasalCannular

Poes

mmHg

542.5 uV

125 mV

mmHg

mmHg20

4080

100

-30

10

Position

Rib cage

Abdominal2.05 mV

Sp,O2

Ptc,CO2%

528.5 uV

0

200

40

120

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Hyp

Ob.A

Ob.A

Ob.A

Ob.A

Ob.A

Ob.A

Ob.A

Ob.A

Ob.A

a)

b)

FB

LR

Figure 2. Two typical 5-min polysomnograms of patients with obstructive sleep apnoea and heart failure. Notethe obstructive apnoeas (Ob.A) with ongoing respiratory effort, as indicated by oesophageal pressure (Poes) and

relatively short cycle length (,

43 s). The cycle length is calculated from the beginning of one apnoea to thebeginning of the next apnoea. bpm: beats per minute; BP: blood pressure; Sp,O2: arterial oxygen saturation

measured by pulse oximetry. Ptc,CO2: transcutaneous carbon dioxide tension; F: front; B: back; L: left: R: right;

Hyp: hypopnoea.

402

SLEEP

APNOEA

IN

CHF


8/25

excessive ventilation without hypoxaemia and a reduced maximal work load are common in patientswith chronic heart failure and CSA, i.e.a steep ventilation to carbon dioxide slope [40].

A variety of diagnostic tests have been used to diagnose sleep-disorderd breathing, however all,apart from in laboratory PSG tests, have a low specificity for the detection of CSA versusOSA.Oximetry [76] and cardiopulmonary monitoring (ECG with respiratory inductance) [26] havebeen used with reasonable specificity for sleep-disorderd breathing, but without sensitivity todifferentiate CSA from OSA. Laboratory PSG is the standard diagnostic tool to identify sleep-disorderd breathing by allowing the accurate measurement of sleep stage, tidal volume, nasalversus oral ventilation, transcutaneous carbon dioxide (Ptc,CO2) lung-to-ear circulation time,apnoeahyperpnoea cycle length, sound, heart rate and associated variability, arrhythmiadetection, body position (supine versus lateral positioning, plus pillow number) and abnormalactivity (e.g. nocturia).

Although attempts have been made to differentiate OSA from CSA, for both epidemiological andtherapeutic reasons, they are known to commonly coexist within the same patient. Both are worse

in the supine position, possibly due to upper airway instability, as in the case of OSA, and reducedlung volume, as in the case of CSA. Single-night studies in chronic heart failure sleep-disorderedbreathing patients, suggest a shift from OSA to CSA associated with decreasing Pa,CO2 andincreasing circulatory time [77]. In the control arm of the Canadian Continuous Positive AirwayPressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial, thepredominant apnoea type changed in 18 of the 98 patients from a CSA to an OSA pattern,

C3-A2

O1-A2

LOC

ROC

C4-A1

Heart rate

O2-A1

ECG

EMG LGMG RLSnoreTherm

Poes

Rib cage

Abdominal

Position

Ptc,CO2

Sp,o2

Nasal542.5 uV

125 mV

mmHg

4.23 mV

8.19 mV

%

BP

1G sub-men

120

40

200

0

10

Mx.A Mx.A Cn.A Cn.A Cn.A

Cn.A

Cn.A

Cn.A

Cn.A

Cn.A

Cn.A

Mx.A Mx.A

Mx.A Mx.A

-30

100

8040

20FB

LR

128 uV

128 uV

128 uV

128 uV

128 uV

128 uV

42.7 uV

bpm

mmHg

cannular

mmHg

a)

b)

Figure 3.Two typical 5-min polysmonograms of a patient with chronic sleep apnoea and heart failure. Note thecentral apnoeas with the absence of respiratory effort, as indicated by oesophageal pressure ( Poes), and the long

cycle length (,

75 s). The cycle length is calculated from the beginning of one apnoea to the beginning of the nextapnoea. bpm: beats per minute; BP: blood pressure; Sp,O2: arterial oxygen saturation measured by pulseoxomitry.Ptc,CO2: transcutaneous carbon dioxide tension; F: front; B: back; L: left: R: right; CnA: central apnoea;

MxA: mixed apnoea.

403

M.T.NAUGHTON

AND

S.ANDREAS


9/25

which was associated with a rise in LVEF of 24 to 27%, and a fall in lung-to-ear circulation timefrom 21 to 13 s [78]. Common pathophysiological mechanisms connecting OSA with CSA arehighlighted by the pharyngeal narrowing during the expiratory phase of central hypopnoea [79],the fluid shift from the upright to the supine position with sleep that contributes to the upperairway obstruction [80], and decisive and reversible effects of OSA on ventilatory stability [81].Therefore, we will jointly address the effects of the different treatment modalities on both forms ofsleep-disordered breathing.

Treatment

The precise cause of heart failure and classification of symptoms are important factors todetermine prior to embarking upon therapy for sleep-disordered breathing, as some types of heartfailure may be more responsive to sleep-disordered breathing remedies. For example, disorders ofcardiac pump function, e.g. dilated cardiomyopathy, are more likely to be responsive to positiveairway pressure (PAP) than would heart failure secondary to valvular heart disease, e.g. aorticstenosis, or disorders of cardiac rhythm or rate, e.g. complete heart block. Moreover, CSAsecondary to heart failure with a conduction defect may be more responsive to a pacemaker or

cardiac resynchronisation therapy (CRT) (fig. 4).

Pharmacological heart failure therapy

Detailed guidelines for the treatment of heart failure exist [2]. Angiotensin-converting enzyme(ACE) inhibitors, angiotensin-receptor antagonists, beta-blockers, spironolactone, biventricular

No YesObserve

Sleep studyObstructive AHI >15 Central AHI >15

AHI 92% overnightPositional therapy#

Acetazolamide#

Lifestyle

Weight loss, if obeseCautious alcoholNasal steroidsCPAP trialPositional therapyNasal surgery

MAS trial Intolerant of treatment?

Figure 4. Flow diagram for the suggested management of patients with heart failure and suspected sleep-disordered breathing. CRT: cardiac resynchonisation therapy; AOP: atrial overdrive pacemaker; AHI: apnoea/hypopnoea index; CPAP: continuous positive airway pressure; MAS: mandibular advancement splints; Sp,O2:

arterial oxygen saturation measured by pulse oximetry. #: absence of randomised control trials.

404

SLEEP

APNOEA

IN

CHF


10/25

pacing, noninvasive ventilation (for acute pulmonary oedema), and the use of multidisciplinaryteams to treat heart failure have all been shown to substantially reduce the rate of hospitalisation,as well as to reduce mortality and improve functional status [2, 3, 12]. Therefore, the initialapproach to the CSA heart failure patients should be to ensure that they are on, or have trialledappropriate pharmacological therapy.

However, this recommendation is based on heart failure managementper se, rather than evidencethat these agents ameliorate CSA. Two small trials (n56 and n58) that investigated both before

and after (,1 month) use of heart failure medications found a fall in apnoea/hypopnoea index(AHI) from 34 to 11 events?h-1 [82] and from 35 to 20 events?h-1 [83] in their respective studies.The role of beta blockers on CSA has not been studied systematically; however, in a single centreheart failure clinic population (n5 108), 82% of whom were taking beta-blockers, 31% still hadCSA [25]. The use of beta blockers did not predict the presence or absence of CSA [25]. Similarly,YUMINO et al. [84] showed that beta-blocker use did not alter prevalence or type of sleep-disordered breathing in a heart failure population.

Anaemia occurs in about a third of patients with heart failure and is a risk factor for mortality,independent of heart failure severity (Ppcw), body mass index (BMI) and renal function. Reversal

of anaemia alleviates heart failure symptoms and improves objective markers of cardiacdysfunction in heart failure. Recently, ZILBERMANet al. [85] reported 38 heart failure patients withanaemia (haemoglobin (Hb) ,12 g?dL-1) had a 62% prevalence of pure CSA. Moreover,treatment of the heart failure-related anaemia with a combination of erythropoietin and iron overa 3-month period resulted in a rise in Hb (10.3 to 12.3 g?dL-1) and a slight fall in AHI from 27 to18 events?h-1 with a significant improvement in symptoms of heart failure (as assessed by theNYHA classification) and a significant reduction in sleepiness (as assessed by the ESS score).

Mitral valve surgery and heart transplantation

Surgical treatment of severe mitral regurgitation has been shown to result in a near or completeresolution of CSA [54, 86]. Heart transplantation with restoration of left ventricular function wasaccompanied by a significant reduction in the severity of CSA in 13 patients [87]. More than 6months after heart transplantation, six patients had no sleep apnoea, four patients converted toOSA and three patients had some residual CSA, although with a shorter apnoea-hyperpnoea cyclelength (65 versus31 s) [61], suggesting a marked improvement in cardiac output. While CSA israre after heart transplantation, OSA is highly prevalent in such patients (33%), and was found inassociation with pronounced weight gain since transplantation and prevalent arterial hypertension(16versus9 kg and 88% versus50% in the no OSA group, respectively) [88].

Cardioversion and pacemakers

The use of cardioversion from atrial fibrillation to sinus rhythm is associated with ,40%improvement in cardiac output. It is yet to be reported if reversal of atrial fibrillation to sinusrhythm, in heart failure patients, will alter the OSA or CSA severity. However, if successful andcardiac output subsequently improves then one would expect an improvement in CSA.

Atrial overdrive pacemakers (AOPs) were shown to reduce OSA and CSA in a tantalising Frenchpublication [89]. Subsequent trials in better defined patient cohorts in the acute [90] and chronicsetting [9193] were unable to confirm this positive result in OSA. Nevertheless, in a number of

studies AOP yielded a small but significant reduction, mainly in central hypopnoeas in patientswith bradycardia [90, 92, 94, 95]. These subtle effects, possibly related to an increase in cardiacoutput and a decrease in left atrial pressure, must be viewed in the context of the well knownnegative effects of increased heart rate [92]. Thus, continuous AOP is not a treatment opportunityfor CSA or OSA in patients with or without heart failure. However, in patients with bradycardiaand consequent low cardiac output, AOP might be beneficial [89, 96]. Whether manipulating

405

M.T.NAUGHTON

AND

S.ANDREAS


11/25

cardiac output and thereby ventilation by dynamically adjusting pacing rate will be of any clinicalbenefit in heart failure without bradycardia awaits further studies [97].

Cardiac resynchronisation therapy (CRT) uses electrodes in the right ventricle and the lateral leftventricle,viathe coronary sinus, to improve the mechanical sequence of left ventricular activationand contraction in patients with conduction delay, manifested by an increased cardioversion andpacemakers (QRS) in patients with heart failure. Numerous well controlled clinical trials havedemonstrated positive effects of CRT on mortality, quality of life and haemodynamics in this well

defined subset of heart failure patients [98]. Not surprisingly, therefore, the studies investigatingthe effects of CRT using polygraphy [24, 99] or PSG [94, 100, 101] found reductions in CSA. Intwo studies using PSG, sleep stages were not affected by CRT, indicating that the improvement inrespiratory events by CRT is not translated into an improvement of sleep stages [94, 100]. Theimprovement in subjective sleepiness might, therefore, be more related to an overall improvementof the general condition of the patient caused by CRT, rather than a specific effect of theimprovement of sleep [94, 99]. Likewise the positive effects of CRT on improvements of NYHAclass, LVEF, BNP, maximal oxygen uptake and quality of life were irrespective of the presence ofCSA [94, 99]. Given the underlying pathophysiology of sleep-disordered breathing in heart failure,most studies investigated patients with CSA but not OSA. Accordingly, in a retrospective study

CRT alleviated CSA but not OSA [24]. However, a single study described that CRT, even inpatients with OSA, resulted in a reduction of AHI [102].

Pharmacological sleep-disordered breathing therapy

Theophylline, best known for its actions in chronic obstructive pulmonary disease (COPD) withheart failure [103], is a nonselective phophodiesterase inhibitor: at supra-therapeutic concentra-tions, it inhibits inflammatory mediators and is an antagonist of adenosine receptors [104]. Heartfailure patients have been shown to have a three to four-fold increase in plasma adenosine levels[105]. Adenosine intensely inhibits respiration and mediates excitatory effects by peripheral

chemoreceptors [106]. In a placebo-controlled study in healthy controls and in heart failurepatients, theophylline increased muscle sympathetic nerve activity (MSNA), plasma renin andventilation. By contrast, in patients with heart failure, theophylline did not increase heart rate orMSNA traffic, although the excitatory effects on renin and breathing were still present [107]. In alarge retrospective epidemiological study, the use of theophylline for the treatment of lung diseasewas independently related to increased cardiovascular death in patients with heart disease [108].Therefore, despite some encouraging findings, theophylline has not gained acceptance in thetreatment of heart failure patients [109]. In a recent short-term controlled study, theophyllinereduced AHI in heart failure patients with CSA; however, it failed to reduce the frequency ofarousals or improve sleep structure or cardiac function [110].

Acetazolamide is a carbonic anhydrase inhibitor that stimulates central respiratory drive bycausing a metabolic acidosis [111]. In periodic breathing at high altitude, acetazolamide reducesthe frequency of central apnoeas and hypopnoeas [112]. In a study of non-heart failure subjects,with induced periodic breathing during sleep, acetazolamide induced a metabolic acidosis andincreased the difference between the prevailing carbon dioxide tension (PCO2) and thePCO2at theapnoeic threshold, thereby stabilising ventilation [113]. In a study of patients with heart failureand CSA, the AHI was reduced and subjective perception of daytime sleepiness was improved withacetazolamide [22]. However, metabolic acidosis and induced hyperventilation with aconcomitant increase in overall oxygen consumption may well be disadvantageous in heartfailure patients [109]. Thus, similar to theophylline, acetazolamide did not gain acceptance for the

chronic treatment of heart failure patients.

Mandibular advancement splints

There are numerous assessments of mandibular advancement splints (MAS) to treat OSA, butnone assess the cardiac function or the heart failure population with OSA. Two studies have

406

SLEEP

APNOEA

IN

CHF


12/25


13/25

is important for patients with OSA during sleep or in patients with APO that have been given CPAPand then relax and fall sleep.

Increasing lung volume

CPAP overcomes heart failure-associated restrictive ventilatory defect with a reduced diffusioncapacity [34]. The normal lungs contain 50% of the bodys oxygen stores; thereby a fall in total

lung capacity will increase the propensity to tissue hypoxaemia. It is estimated that patients withheart failure have a reduction in total lung capacity of 20%, an effect that is aggravated when in thehorizontal position, and more so during sleep. As the total lung capacity drops, the propensity tohypoxaemia increases. The application of 10 cmH2O CPAP increases lung volume by 0.5 to 1.0 L,which is often sufficient to correct mild hypoxaemia [128, 129]. Tidal volume also increases withCPAP [128].

Bronchodilatation

CPAP has a bronchodilating effect, particularly if the cause of bronchoconstriction is due to

mechanical factors (obesity) or oedema (heart failure). Bronchogram studies in asthmatics indicatedthat CPAP was associated with a 30% increase in airway diameter [130]. LENIQUE et al. [131]estimated lung resistance to fall by 40% with CPAP in adults who have subacute heart failure.

Assisting respiratory muscles

APO is associated with hypercapnia in approximately 2045% of cases, the mechanisms of whichare poorly understood, however, respiratory muscle weakness may be a contributory factor. AcuteCPAP studies in APO have indicated a reduction in respiratory rate and pleural pressure swings. Insubacute heart failure, this results in a reduction in the respiratory work. The effects are thought to

be mainlyviathe assistance of inspiratory muscles, without the recruitment of expiratory muscles(expiration is usually passive due to elastic recoil). It is estimated that CPAP reduces inspiratorypressure/maximal inspiratory pressure and time taken for inspiration/total time of respiratorycycle [132], and thereby has a significant effect in reducing the effort involved in breathing andavoiding fatigue. In the longer term (3 months), improvements in respiratory muscle strengthwere observed with CPAP in patients with severe heart failure and CSA [133].

Table 4. Mechanisms of action for positive airway pressure in heart failure

Effect Condition

APO OSA CSA

Stabilise UAW + +++ +

Increasing lung volume +++ + ++

Assist inspiratory muscles +++ + ++

Reduce LV transmural pressure

Attenuate large negative ITP

Provide positive ITP

Attenuate systolic BP

+

+++

+

+++

+

++

+

+++

+

Reduce venous return + + +

Bronchodilate +++ + +

Reduce cardiac radius ++ + ++

Time to improve chronic heart failure Minutes Days Weeks

APO: acute cardiac pulmonary oedema; OSA: obstructive sleep apnoea; CSA: central sleep apnoea; UAW:upper airway; LV: left ventricular; ITP: intrathoracic; BP: blood pressure.

408

SLEEP

APNOEA

IN

CHF


14/25


15/25

reductions in cardiac work have also been reported [135, 143]. CPAP, in stable heart failurepatients, has been associated with reductions in myocardial oxygen uptake [144] and cardiacsympathetic activity [46]. However, short-term CPAP may elicit sympathetic activation by anunloading of the aortic and/or cardiopulmonary baroreceptors [145].

The studies defining the effects of CPAP directly on stroke volume have been mixed. CPAP inpatients with APO have suggested an increase in most [146, 147], but not all, patients [148]. Someresearchers have shown increases in stroke volume in stable heart failure patients with elevated

filling pressures (Ppcw.18 mmHg) acutely [146, 147]. One research group suggested that CPAPdid not increase stroke volume (SV) in the setting of atrial fibrillation [149]. Other studies haveshown an increase in LVEF over a 1 to 3-month period in OSA [150, 151] and CSA patients [152,153]. Remodelling of the cardiac chamber has also been reported, with reductions in the mitralregurgitation and cardiac chamber dimensions over a period of weeks to months.

Reducing left ventricular preload

Elevation of intrathoracic pressure with PAP will impede venous return by up to 40% in caninemodels given 10 mmHg CPAP [154]. In normal subjects this may result in heart rate elevation to

maintain cardiac output. In patients with heart failure, a small amount of CPAP (510 cmH2O)may independently augment stroke volume, by virtue of ascending the Starling curve observed inheart failure. However, high levels of CPAP may cause a negative effect on stroke volume,especially if the patient is preload deficient (i.e. dehydration and or sepsis) and in suchcircumstances BPAP may be more beneficial.

Changing autonomic control

PAP may induce autonomic effects related to lung stretch and baroreceptors.

Based upon heart rate variability analysis, both temporal and power spectral analysis, the acuteeffects of CPAP in heart failure have been shown to increase vagal [52] and attenuate sympatheticactivity [46]. In the medium and long term, reductions in urinary and blood norepinephrine havebeen observed, and are associated with cardiac function improvement in patients with heart failureand OSA [150] or CSA [44] who use CPAP. Moreover, other neurohumoral markers of heartfailure and left ventricular wall stress (e.g.BNP) have also been shown to fall with the use of CPAP.In addition, abnormal baroreceptor functions have been shown to improve over a 4-week periodwhen CPAP was used in patients with heart failure and OSA [155]. In patients with chronic heartfailure the short-term use of CPAP may elicit sympathetic activation, caused by an unloading ofthe aortic and/or cardiopulmonary baroreceptors [145].

Supportive PAP clinical outcome studies

Clinically, CPAP has been effective in the treatment of APO, OSA and CSA heart failure patients(table 4).

The use of CPAP in APO has been supported by two meta-analyses [139, 140], which showed animproved survival rates, rapid improvement in physiology and reduced intubation rates. BPAP hasshown improvements in physiology and intubation, but not in survival. In one study of APOpatients, the rate of intubation and in-hospital mortality was three- to four-fold greater if CPAPwas delayed by 30 min [156], indicating an urgency to treat. In a randomised controlled trial of

patients recouperating from APO in hospital who had positive screening for OSA, it was foundthat those treated with PAP experienced a significantly greater improvement in LVEF than thenon-PAP treated controls [157]. A recent publication did not confirm the findings of the two metaanalyses [158]; perhaps due to the brief duration of CPAP (mean 2 h), a large population thatswapped from oxygen to PAP, the accuracy of the diagnostic algorithm for heart failure, theaetiology of heart failure, multicentred trials (efficacy of single expert centred trials versus

410

SLEEP

APNOEA

IN

CHF


16/25

efficiency of wide-spread real world centred trials) and local practice (intensive care facilityavailability and population age, etc.).

In OSA heart failure subjects, two randomised controlled parallel trials of CPAP over a 13-month period, in combination, suggested an improvement in LVEF and quality of life associatedwith cardiac remodelling and a fall in sympathetic activity [150, 151]. CPAP was delivered in eachstudy at 89 cmH2O for ,6 h per night. A third study [159], a randomised controlled crossovertrial of autotitrating CPAP of 6 weeks (7 cmH2O63.5 h) was unable to confirm the above

findings of improved cardiac function. Uncontrolled trials suggested the reversal of OSA withCPAP improved survival by up to 4 yrs [160], whereas controlled trials are lacking.

In heart failure CSA subjects, a series of single expert centre trials indicated CPAP to be effectivein the heart failure CSA population, in terms of improved quality of life and LVEF with reducedsympathetic activity and possibly reduced hospital admissions [152]. A large multicentre trialconducted over 2.2-yr follow-up period was able to confirm improvements in LVEF, the 6-minwalk distance and a reduction in sympathetic activity, while overall transplant-free survival wasnot improved [153]. Apost hocanalysis [161] indicated significantly greater survival in the groupwhose AHI at the 3-month follow-up sleep study was ,15 events?h-1, which occurred in

approximately 50% of patients). A gradual reduction in CSA severity with CPAP was shown byARZT et al. [162], where the group mean AHI fell from 42 to 22 and 13 events?h-1 on the firstCPAP night and at 3-month follow-up, respectively, in 10 CSA patients with chronic heart failureand who were treated with CPAP (8.6 cmH2O for 4.8 h per night). This important observationsuggests that CSA is not immediately abolished, but rather gradually alleviated over weeks tomonths.

The inability of CPAP to abolish the AHI to ,15 events?h-1 in all CSA patients, immediately or at3 months, has lead to the development of ASV. ASV provides a background CPAP sufficient toovercome upper airway instability (58 cmH2O), with a small amount of pressure support

(3 cmH2

O) and an adaptive pressure support (38 cmH2

O) that is only applied during centralapnoeas [163]. Commercially available devices are available from ResMed Inc and PhilipsRespironics use proprietary software. A single night study of ASV compared with room air, CPAPand BPAP was found favourable in terms of sleep quality, arousals, AHI and oxygenation. Ofimportance to note here is that PCO2levels rose on ASV; this is possibly related to fewer arousalsand the greater amounts of slow wave and rapid eye movement sleep encountered.

Three small randomised controlled trials of ASV in heart-failure subjects have been published.PEPPERELL et al. [164] reported, over a 4-week period, reduced sympathetic nerve system activity(SNA) and BNP, but not LVEF or exercise tolerance, with ASV compared with sham ASV. PHILLIPEet al. [165] reported improved quality of life and a trend to better LVEF with ASV compared with

CPAP over 6 months. Finally, FIETZE et al.[166] reported no change in LVEF with either ASV orBPAP over 6 weeks.

Two large multicentred trials to test the effect of ASV upon LVEF and survival are underway atpresent. These are the SERVE heart failure [167] and the ADVENT heart failure (D. Bradley,Toronto General Research Institute, Canada, ON; personal communication) trials, which areoccurring in CSA and sleep-disordered chronic heart failure breathing groups, respectively and weawait their results.

Positional therapy

Attention to body position in heart failure has important implications in terms of diagnosticsymptoms (e.g.orthopnea) as well as therapeutics (e.g. seated position for heart failure). Vertical(i.e. upright versus supine) and transverse rotational (i.e. right versus supine versus left lateralpositions) changes have been independently studied in heart failure and non-heart failurepopulations.

411

M.T.NAUGHTON

AND

S.ANDREAS


17/25


18/25

apnoea heart failure control subjects [34]. Therefore, it is likely that lateral rotational changesimpact upon upper airway stability as well as lung volumes.

Experimental dead space carbon dioxide

In patients with idiopathic CSA, inhaled carbon dioxide virtually eliminated apnoeas andhypopnoeas [182]. In heart failure patients, carbon dioxide inhalation increased , PCO2, abolished

central apnoeas and hypopnoeas, and increased arterial oxygen saturation [183]. Other authorsnoticed similar results by added dead space [184]. Nocturnal carbon dioxide plus oxygeninhalation eliminated CSA and increased arterial oxygen saturation as well as mean Ptc,CO2[116].Most importantly, this study showed a markedly increased sympathetic activation, indicating thatcarbon dioxide is clearly disadvantageous in chronic heart failure, despite the elimination of CSA[116]. Therefore, carbon dioxide or dead space gained no role in the treatment of sleep-disorderedbreathing in heart failure patients.

Exercise training

The beneficial effects of exercise training on neurovascular function, functional capacity andquality of life, in patients with systolic dysfunction and heart failure, is well documented in anumber of controlled studies. In one study, also investigating sleep-disordered breathing, thebeneficial effects were independent of the occurrence of sleep-disordered breathing [185].Interestingly, in this study, exercise training lessens the severity of OSA but does not affect CSA inpatients with heart failure and sleep-disordered breathing [185]. Weight loss has an advantage inimproving cardiac function directly [7], but little published work exists to support this concept.

Chronic heart failure sleep-disordered breathing mortality

Whether CSA contributes to morbidity and mortality in chronic heart failure patients or whetherit is simply an epiphenomenon remains controversial. It is evident, from very early publications,that untreated CSA during daytime is a sign of poor short-term prognosis [186, 187]. DaytimeCSA, which resembles nocturnal CSA, is less common when compared with nocturnal CSA [188,189]. In the studies that observed daytime CSA, this breathing pattern was related to an increasedmortality, while nocturnal CSA was not [188, 189]. Although some studies described anassociation between nocturnal CSA and mortality, independent of confounders, other studies werenot able to replicate this observation [17, 18, 26, 188, 190]. Treatment of CSA with CPAP wasassociated with an improvement in transplant free survival, if the AHI was ,15 events?h-1 at 3months [161]. Moreover, the mortality in the control arm of the CANPAP trial was better than

that seen in previous heart failure trials, an effect attributed to the use of beta-blockers [153]. Inpatients with OSA and heart failure, WANGet al.[160] identified a lower mortality in those treatedsuccessfully with CPAP compared with non-randomised controlled trials on chronic heart failurepatients with no sleep-disordered breathing and heart failure OSA populations. A recent studysuggested an association of sleep-disordered breathing (encompassing OSA as well as CSA) withmortality only in patients with ischaemic but not non ischaemic heart failure [191].

In general, one must keep in mind that the evaluated end-points, such as AHI and LVEF, are onlysurrogate end-points, and are not necessarily related to mortality [153]. Therefore, only largerandomised controlled trials with end-points clearly related to cardiovascular morbidity and

mortality will define the significance of CPAP, in the treatment of CSA, in a heart failurepopulation. When considering the impact of OSA on mortality in patients with heart failure, itshould be acknowledged that the negative impact of OSA on blood pressure, LVEF andneurohumoral activation has been clearly established [150, 151]. As covered elsewhere in thismonograph, there is convincing evidence that CPAP reduces blood pressure in patients withOSA [141]. Furthermore, large uncontrolled longitudinal studies suggest that CPAP reduces

413

M.T.NAUGHTON

AND

S.ANDREAS


19/25

cardiovascular mortality, including heart failure [192]. It is thereby reasonable to assume thatCPAP reduces mortality in heart failure patients with OSA.

The future

The role of sleep-disordered breathing in heart failure is burgeoning. In the next decade we hopeto better understand the mechanisms of dyspnoea and the pulmonary changes associated with

heart failure. Our understanding of CPAP, BPAP and ASV on acute and long-termcardiopulmonary, autonomic and ventilatory control will hopefully progress. Two largerandomised controlled trials are underway to show the impact of ASV on robust clinicalendpoints in patients with heart failure and sleep-disordered breathing.

Statement of Interest

M.T. Naughton has been invited to present at peer- and industry-organised international scientificmeetings. He has received peer-reviewed funding from CPAP manufactures to allow staff

employment and assist in the conduction of author initiated clinical research trials along withfunds from the National Health and Medical Research Council of Australia. He holds no stock inany organisation associated with sleep or cardiorespiratory diseases. At all times, his presentationsand research have been entirely independent of the funding agency. S. Andreas has received feesfor lectures and organising education of about u5,000 by Respironics, Resmed and Heinen &Lowenstein. He received consulting fees from Sanofi Synthelabo of about u1,000.

Acknowledgements

The authors would like to thank I. Szollosi and T. Roebuck (Alfred Hospital, Victoria, Australia)

for their polysomnograph recordings.

References1. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure.Eur Heart J2001;

22: 15271560.

2. Dickstein K, Cohen-Solal A,et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart

failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the

European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (heart

failureA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J2008; 29:

23882442.

3. Jessup M, Brozena S. Heart failure. N Engl J Med2003; 348: 20072018.

4. Maeder MT, Kaye DM. Heart failure with normal left ventricular ejection fraction.J Am Coll Cardiol2009; 53:905918.

5. Serizawa T, Vogal WM, Apstein CS,et al. Comparison of acute alterations in left ventricular relaxation and

diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand

imbalance. J Clin Invest1981; 68: 91102.

6. Diefenbach K, Kretschmer K, Bauer S,et al.Endothelin-1 gene variant Lys198Asn and plasma endothelin level in

obstructive sleep apnea.Cardiology2009; 112: 6268.

7. Alpert MA, Terry BE, Muleker M, et al. Cardiac morphology and left ventricular function in normotensive

morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol1997;

80: 736740.

8. Fung JW, Li TS, Choy DK, et al. Severe obstructive sleep apnea is associated with left ventricular diastolic

dysfunction. Chest2002; 121: 422429.

9. Luthje L, Andreas S. Obstructive sleep apnea and coronary artery disease. Sleep Med Rev2008; 12: 1931.10. Arias MA, Garca-Ro F, Alonso-Fernandez A, et al. Obstructive sleep apnea syndrome affects left ventricular

diastolic function: effects of nasal continuous positive airway pressure in men. Circulation2005; 112: 375383.

11. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart

failure.JAMA 1989; 261: 884888.

414

SLEEP

APNOEA

IN

CHF


20/25

12. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic

Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart

Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and

Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung

Transplantation; Endorsed by the Heart Failure Society of America. Circulation2001; 104: 29963007.

13. Schneider HG, Lam L, Lokuge A,et al.B-type natriuretic peptide testing, clinical outcomes, and health services

use in emergency department patients with dyspnea: a randomized trial. Ann Intern Med2009; 150: 365371.

14. Chan J, Sanderson J, Chan W,et al.Prevalence of sleep-disordered breathing in diastolic heart failure. Chest1997;

111: 14881493.

15. Javaheri S, Corbett WS. Association of low PaCO2with central sleep apnea and ventricular arrhythmias inambulatory patients with stable heart failure. Ann Intern Med1998; 128: 204207.

16. Sin DD, Fitzgerald F, Parker JD,et al.Risk factors for central and obstructive sleep apnea in 450 men and women

with congestive heart failure. Am J Respir Crit Care Med1999; 160: 11011106.

17. Lanfranchi PA, Braghiroli A, Bosimini E,et al. Prognostic value of nocturnal Cheyne-Stokes respiration in

chronic heart failure. Circulation1999; 99: 14351440.

18. Roebuck T, Solin P, Kaye DM,et al.Increased long-term mortality in heart failure due to sleep apnoea is not yet

proven.Eur Respir J2004; 23: 735740.

19. Mared L, Cline C, Erhardt L,et al.Cheyne-Stokes respiration in patients hospitalised for heart failure. Respir Res

2004; 5: 14.

20. Carmona-Bernal C, Quintana-Gallego E, Villa-Gil M,et al.Brain natriuretic peptide in patients with congestive

heart failure and central sleep apnea. Chest2005; 127: 16671673.

21. Ferrier K, Campbell A, Yee B,et al. Sleep-disordered breathing occurs frequently in stable outpatients withcongestive heart failure. Chest. 2005; 128: 21162122.

22. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study.Am J

Respir Crit Care Med2006; 173: 234237.

23. Schulz R, Blau A, Borgel J,et al.Sleep apnoea in heart failure: results of a German survey. Eur Respir J2007; 29:

12011205.

24. Oldenburg O, Faber L, Vogt J,et al. Influence of cardiac resynchronisation therapy on different types of sleep

disordered breathing. Eur J Heart Fail2007; 9: 820826.

25. MacDonald M, Fang J, Pittman AD,et al. The current prevalence of sleep-disordered breathing in congestive

heart failure patients treated with beta-blockers. J Clin Sleep Med2008; 4: 3842.

26. Pinna GD, Maestri R, Mortara A,et al. Pathophysiological and clinical relevance of simplified monitoring of

nocturnal breathing disorders in heart failure patients. Eur J Heart Fail2009; 11: 264272.

27. Chiu KL, Ryan CM, Shiota S,et al.Fluid shift by lower body positive pressure increases pharyngeal resistance inhealthy subjects. Am J Respir Crit Care Med2006; 174: 13781383.

28. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in

obstructive sleep apnea syndrome. Circulation2005; 112: 26602667.

29. Ryan CM, Usui K, Floras JS,et al. Effect of continuous positive airway pressure on ventricular ectopy in heart

failure patients with obstructive sleep apnoea. Thorax2005; 60: 781785.

30. Parker JD, Brooks D, Kozar LF,et al.Acute and chronic effects of airway obstruction on canine left ventricular

performance.Am J Respir Crit Care Med1999; 160: 18881896.

31. Hall MJ, Ando S, Floras JS,et al.Magnitude and time course of hemodynamic responses to Mueller maneuvers in

patients with congestive heart failure. J Appl Physiol1998; 85: 14761484.

32. Scharf SM, Bianco JA, Tow DE, et al. The effects of large negative intrathoracic pressure on left ventricular

function in patients with coronary artery disease. Circulation1981; 63: 871875.

33. Ryan CM, Bradley TD. Periodicity of obstructive sleep apnea in patients with and without heart failure.Chest2005; 127: 536542.

34. Szollosi I, Thompson BR, Krum H, et al. Impaired pulmonary diffusing capacity and hypoxia in heart failure

correlates with central sleep apnea severity. Chest2008; 134: 6772.

35. Solin P, Bergin P, Richardson M,et al.Influence of pulmonary capillary wedge pressure on central apnea in heart

failure.Circulation1999; 99: 15741579.

36. Naughton M, Benard D, Tam A,et al. Role of hyperventilation in the pathogenesis of central sleep apneas in

patients with congestive heart failure. Am Rev Respir Dis1993; 148: 330338.

37. Solin P, Roebuck T, Johns DP,et al.Peripheral and central ventilatory responses in central sleep apnea with and

without congestive heart failure. Am J Respir Crit Care Med2000; 162: 21942200.

38. Garcia-Touchard A, Somers VK, Olson LJ, et al. Central sleep apnea: implications for congestive heart failure.

Chest2008; 133: 14951504.

39. Andreas S. Nocturnal insights in chronic heart failure.Eur Heart J1999; 20: 11401141.

40. Arzt M, Harth M, Luchner A,et al. Enhanced ventilatory response to exercise in patients with chronic heart

failure and central sleep apnea. Circulation2003; 107: 19982003.

41. van de Borne P, Oren R, Abouassaly C,et al. Effect of Cheyne-Stokes respiration on muscle sympathetic nerve

activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J

Cardiol1998; 81: 432436.

415

M.T.NAUGHTON

AND

S.ANDREAS


21/25

42. Spicuzza L, Bernardi L, Calciati A, et al. Autonomic modulation of heart rate during obstructive versus

central apneas in patients with sleep-disordered breathing. Am J Respir Crit Care Med 2003; 167: 902910.

43. Solin P, Kaye DM, Little PJ,et al.Impact of sleep apnea on sympathetic nervous system activity in heart failure.

Chest2003; 123: 11191126.

44. Naughton MT, Benard DC, Liu PP,et al. Effects of nasal CPAP on sympathetic activity in patients with heart

failure and central sleep apnea. Am J Respir Crit Care Med1995; 152: 473479.

45. Mansfield D, Kaye DM, Brunner La Rocca H,et al.Raised sympathetic nerve activity in heart failure and central

sleep apnea is due to heart failure severity. Circulation2003; 107: 13961400.

46. Kaye DM, Mansfield D, Aggarwal A, et al. Acute effects of continuous positive airway pressure on cardiac

sympathetic tone in congestive heart failure. Circulation2001; 103: 23362338.47. Andreas S, Eichele G. Sleep apnoea: time to consider clock genes.Eur Respir J2008; 32: 12.

48. Longobardo GS, Cherniack NS, Fishman AP. Cheyne-Stokes breathing produced by a model of the human

respiratory system. J Appl Physiol1966; 21: 18391846.

49. Klein O. Untersuchumgen uber das Cheyne Stokesche Atmungsphanomen. Verh Dtsch Ges Inn Med1930; 42:

217222.

50. Khoo MC, Gottschalk A, Pack AI. Sleep-induced periodic breathing and apnea: a theoretical study.J Appl Physiol

1991; 70: 20142024.

51. Francis DP, Willson K, Davies LC, et al. Quantitative general theory for periodic breathing in chronic heart

failure and its clinical implications. Circulation2000; 102: 22142221.

52. Butler GC, Naughton MT, Rahman MA,et al.Continuous positive airway pressure increases heart rate variability

in congestive heart failure. J Am Coll cardiol1995; 25: 672679.

53. Olson TP, Frantz RP, Snyder EM, et al. Effects of acute changes in pulmonary wedge pressure on periodicbreathing at rest in heart failure patients. Am Heart J2007; 153: 104.e1104.e7.

54. Rubin AE, Gottlieb SH, Gold AR, et al. Elimination of central sleep apnoea by mitral valvuloplasty: the role of

feedback delay in periodic breathing. Thorax2004; 59: 174176.

55. Hanly P, Zuberi N, Gray G. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure.

Relationship to arterial PCO2. Chest1993; 104: 10791084.

56. Fanfulla F, Mortara A, Maestri R,et al.The development of hyperventilation in patients with chronic heart failure

and Cheyne-Strokes respiration: a possible role of chronic hypoxia. Chest1998; 114: 10831090.

57. Topor ZL, Johannson L, Kasprzyk J, et al. Dynamic ventilatory response to CO(2) in congestive heart failure

patients with and without central sleep apnea. J Appl Physiol2001; 91: 408416.

58. Javaheri S, Ahmed M, Parker TJ, et al. Effects of nasal O2 on sleep-related disordered breathing in ambulatory

patients with stable heart failure. Sleep1999; 22: 11011106.

59. Xie A, Skatrud JB, Khayat R,et al.Cerebrovascular response to carbon dioxide in patients with congestive heartfailure.Am J Respir Crit Care Med2005; 172: 371378.

60. Nylin G. The dilution curve of activity in arterial blood after intravenous injection of labeled corpuscles.Am

Heart J1945; 30: 111.

61. Solin P, Roebuck T, Swieca J,et al.Effects of cardiac dysfunction on non-hypercapnic central sleep apnea. Chest

1998; 113: 104110.

62. Lange RL, Hecht HH. The mechanism of Cheyne-Stokes respiration.J Clin Invest1962; 41: 4252.

63. Hall MJ, Xie A, Rutherford R,et al.Cycle length of periodic breathing in patients with and without heart failure.

Am J Respir Crit Care Med1996; 154: 376381.

64. Bulow K. Respiration and wakefulness in man. Acta Physiol Scand1963; 59: Suppl. 209, 3446.

65. de Groote P, Millaire A, Foucher-Hossein C,et al.Right ventricular ejection fraction is an independent predictor

of survival in patients with moderate heart failure. J Am Coll Cardiol1998; 32: 948954.

66. Olson LJ, Arruda-Olson AM, Somers VK,et al. Exercise oscillatory ventilation: instability of breathing controlassociated with advanced heart failure. Chest2008; 133: 474481.

67. Guazzi M, Raimondo R, Vicenzi M,et al. Exercise oscillatory ventilation may predict sudden cardiac death in

heart failure patients. J Am Coll Cardiol2007; 50: 299308.

68. Corra U, Giordano A, Bosimini E,et al. Oscillatory ventilation during exercise in patients with chronic heart

failure: clinical correlates and prognostic implications. Chest2002; 121: 15721580.

69. Corra U, Pistono M, Mezzani A,et al.Sleep and exertional periodic breathing in chronic heart failure: prognostic

importance and interdependence. Circulation2006; 113: 4450.

70. Guazzi M, Myers J, Peberdy MA, et al. Exercise oscillatory breathing in diastolic heart failure: prevalence and

prognostic insights. Eur Heart J2008; 29: 27512759.

71. Arzt M, Young T, Finn L,et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive

sleep apnea. Arch Intern Med2006; 166: 17161722.

72. Hastings PC, Vazir A, ODriscoll DM,et al.Symptom burden of sleep-disordered breathing in mild-to-moderate

congestive heart failure patients. Eur Respir J2006; 27: 748755.

73. Szollosi I, Roebuck T, Thompson B,et al. Lateral sleeping position reduces severity of central sleep apnea/

Cheyne-Stokes respiration. Sleep2006; 29: 10451051.

74. Szollosi I, Krum H, Kaye D,et al. Sleep apnea in heart failure increases heart rate variability and sympathetic

dominance. Sleep2007; 30: 15091514.

416

SLEEP

APNOEA

IN

CHF


22/25

75. Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure.Chest2004; 125: 669682.

76. Series F, Kimoff RJ, Morrison D,et al.Prospective evaluation of nocturnal oximetry for detection of sleep-related

breathing disturbances in patients with chronic heart failure. Chest2005; 127: 15071514.

77. Tkacova R, Niroumand M, Lorenzi-Filho G,et al.Overnight shift from obstructive to central apneas in patients

with heart failure: role of PCO2 and circulatory delay. Circulation2001; 103: 238243.

78. Ryan CM, Floras JS, Logan AG,et al.Shift in sleep apnoea type in heart failure patients in the CANPAP trial.Eur

Respir J2010; 35: 592-597.

79. Sankri-Tarbichi AG, Rowley JA, Badr MS. Expiratory pharyngeal narrowing during central hypocapnic

hypopnea.Am J Respir Crit Care Med2009; 179: 313319.

80. Redolfi S, Yumino D, Ruttanaumpawan P,et al. Relationship between overnight rostral fluid shift andobstructive sleep apnea in nonobese men. Am J Respir Crit Care Med2009; 179: 241246.

81. Salloum A, Rowley JA, Mateika JH,et al.Increased propensity for central apnea in patients with obstructive sleep

apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med2010; 181: 189193.

82. Dark DS, Pingleton SK, Kerby GR,et al.Breathing pattern abnormalities and arterial oxygen desaturation during

sleep in the congestive heart failure syndrome. Improvement following medical therapy. Chest1987; 91: 833836.

83. Walsh JT, Andrews R, Starling R,et al. Effects of captopril and oxygen on sleep apnoea in patients with mild to

moderate congestive cardiac failure. Br Heart J1995; 73: 237241.

84. Yumino D, Wang H, Flores JS,et al.Prevalence and physiological predictors of sleep apnea in patients with heart

failure and systolic dysfunction. J Card Fail2009; 15: 279285.

85. Zilberman M, Silverberg DS, Bits I, et al. Improvement of anemia with erythropoietin and intravenous iron

reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive

heart failure. Am Heart J2007; 154: 870876.86. Yasuma F, Hayashi H, Noda S,et al. A case of mitral regurgitation whose nocturnal periodic breathing was

improved after mitral valve replacement. Jpn Heart J1995; 36: 267272.

87. Mansfield DR, Solin P, Roebuck T, et al. The effect of successful heart transplant treatment of heart failure on

central sleep apnea. Chest2003; 124: 16751681.

88. Javaheri S, Abraham WT, Brown C,et al.Prevalence of obstructive sleep apnoea and periodic limb movement in

45 subjects with heart transplantation. Eur Heart J2004; 25: 260266.

89. Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med2002; 346:

404412.

90. Unterberg C, Luthje L, Szych J,et al.Atrial overdrive pacing compared to CPAP in patients with obstructive sleep

apnoea syndrome.Eur Heart J2005; 26: 25682575.

91. Simantirakis EN, Schiza SE, Chrysostomakis SI, et al. Atrial overdrive pacing for the obstructive sleep apnea-

hypopnea syndrome. N Engl J Med2005; 353: 25682577.92. Luthje L, Unterberg-Buchwald C, Dajani D,et al. Atrial overdrive pacing in patients with sleep apnea with

implanted pacemaker. Am J Respir Crit Care Med2005; 172: 118122.

93. Pepin JL, Defaye P, Garrigue S,et al. Overdrive atrial pacing does not improve obstructive sleep apnoea

syndrome. Eur Respir J2005; 25: 343247.

94. Luthje L, Renner B, Kessels R,et al. Cardiac resynchronization therapy and atrial overdrive pacing for the

treatment of central sleep apnoea. Eur J Heart Fail2009; 11: 273280.

95. Sharafkhaneh A, Sharafkhaneh H, Bredikus A,et al.Effect of atrial overdrive pacing on obstructive sleep apnea in

patients with systolic heart failure. Sleep Med2007; 8: 3136.

96. Kato I, Shiomi T, Sasanabe R, et al. Effects of physiological cardiac pacing on sleep-disordered breathing in

patients with chronic bradydysrhythmias. Psychiatry Clin Neurosci2001; 55: 257258.

97. Baruah R, Manisty CH, Giannoni A,et al. Novel use of cardiac pacemakers in heart failure to dynamically

manipulate the respiratory system through algorithmic changes in cardiac output. Circ Heart Fail2009; 2:166174.

98. Abraham WT, Fisher WG, Smith AL,et al.Cardiac resynchronization in chronic heart failure.N Engl J Med2002;

346: 18451853.

99. Sinha AM, Skobel EC, Breithardt OA,et al.Cardiac resynchronization therapy improves central sleep apnea and

Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol2004; 44: 6871.

100. Gabor JY, Newman DA, Barnard-Roberts V,et al. Improvement in Cheyne-Stokes respiration following cardiac

resynchronisation therapy.Eur Respir J2005; 26: 95100.

101. Kara T, Novak M, Nykodym J,et al.Short-term effects of cardiac resynchronization therapy on sleep-disordered

breathing in patients with systolic heart failure. Chest2008; 134: 8793.

102. Stanchina ML, Ellison K, Malhotra A,et al.The impact of cardiac resynchronization therapy on obstructive sleep

apnea in heart failure patients: a pilot study. Chest2007; 132: 433439.

103. Dowell AR, Heyman A, Sieker HO, et al. Effect of aminophylline on respiratory-center sensitivity in

Cheynestokes respiration and in pulmonary emphysema. N Engl J Med1965; 273: 14471453.

104. Morrow JD, Jackson Roberts L. Lipid-derived autocoids: eicosanoids and platelet-activating factor.In: Hardman

JG, Limbird LE, Gilman AG, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics. McGraw-

Hill, 1996; pp. 672682.

417

M.T.NAUGHTON

AND

S.ANDREAS


23/25

105. Funaya H, Kitakaze M, Node K, et al. Plasma adenosine levels increase in patients with chronic heart failure.

Circulation1997; 95: 13631365.

106. Engelstein ED, Lerman BB, Somers VK,et al. Role of arterial chemoreceptors in mediating the effects of

endogenous adenosine on sympathetic nerve activity. Circulation1994; 90: 29192926.

107. Andreas S, Reiter H, Luthje L,et al.Differential effects of theophylline on sympathetic excitation, hemodynamics

and breathing in congestive heart failure. Circulation2004; 110: 21572162.

108. Suissa S, Hemmelgarn B, Blais L,et al.Bronchodilators and acute cardiac death. Am J Respir Crit Care Med1996;

154: 15981602.

109. Pevernagie D, Janssens P, De Backeret W, et al. Ventilatory support and pharmacological treatment of patients

with central apnoea or hypoventilation during sleep. Eur Respir Rev2007; 16: 115124.110. Javaheri S, Parker TJ, Wexler L,et al.Effect of theophylline on sleep-disordered breathing in heart failure.N Engl

J Med1996; 335: 562567.

111. DeBacker WA, Verbraecken J, Willemen M,et al. Central apnea index decreases after prolonged treatment with

acetazolamide.Am J Respir Crit Care Med1995; 151: 8791.

112. Sutton JR, Houston CS, Mansell AL,et al. Effect of acetazolamide on hypoxemia during sleep at high altitude.

N Engl J Med1979; 301: 13291331.

113. Nakayama H, Smith CA, Rodman JR,et al.Effect of ventilatory drive on carbon dioxide sensitivity below eupnea

during sleep. Am J Respir Crit Care Med2002; 165: 12511260.

114. Gotsopoulos H, Chen C, Qian J,et al. Oral appliance therapy improves symptoms in obstructive sleep apnea: a

randomized, controlled trial. Am J Respir Crit Care Med2002; 166: 743748.

115. Barnes M, Houston D, Worsnop CJ,et al. A randomized controlled trial of continuous positive airway pressure

in mild obstructive sleep apnea. Am J Respir Crit Care Med2002; 165: 773780.116. Andreas S, Weidel K, Hagenah G, et al. Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon

dioxide.Eur Respir J1998; 12: 414419.

117. Hanly PJ, Millar TW, Steljes DG,et al.The effect of oxygen on respiration and sleep in patients with congestive

heart failure. Ann Intern Med1989; 111: 777782.

118. Staniforth AD, Kinnear WJ, Starling R,et al. Efffect of oxygen on sleep quality, cognitive function and

sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J1998; 19:

922928.

119. Krachman SL, DAlonzo GE, Berger TJ, et al. Comparison of oxygen therapy with nasal continuous positive

airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure. Chest1999; 116: 1550

1557.

120. Franklin KA, Eriksson P, Sahlin C,et al. Reversal of central sleep apnea with oxygen. Chest1997; 111: 163169.

121. Arzt M, Eriksson P, Sahlin C,et al.Nocturnal continuous positive airway pressure improves ventilatory efficiencyduring exercise in patients with chronic heart failure. Chest2005; 127: 794802.

122. Seino Y, Imai H, Nakamoto T,et al.Clinical efficacy and cost-benefit analysis of nocturnal home oxygen therapy

in patients with central sleep apnea caused by chronic heart failure. Circ J2007; 71: 17381743.

123. Sasayama S, Izumi T, Matsuzaki M,et al.Improvement of quality of life with nocturnal oxygen therapy in heart

failure patients with central sleep apnea. Circ J2009; 73: 12551262.

124. Mak S, Azevedo ER, Liu PP,et al.Effect of hyperoxia on left ventricular function and filling pressures in patients

with and without congestive heart failure. Chest2001; 125: 467473.

125. Haque WA, Boehmer J, Clemson BS,et al. Hemodynamic effects of supplemental oxygen administration in

congestive heart failure. J Am Coll Cardiol1996; 27: 353357.

126. Poulton EP. Left sided heart failure with pulmonary oedema.Lancet1936; 228: 981983.

127. Sullivan CE, Issa FG, Berthon-Jones M,et al.Reversal of obstructive sleep apnoea by continuous positive airway

pressure applied through the nares. Lancet1981; 317: 862865.128. Krachman SL, Crocetti J, Berger TJ, et al. Effects of nasal continuous positive airway pressure on oxygen body

stores in patients with Cheyne-Stokes respiration and congestive heart failure. Chest2003; 123: 5966.

129. Katz JA, Marks JD. Inspiratory work with and without continuous positive airway pressure in patients with acute

respiratory failure. Anesthesiology1985; 63: 598607.

130. Barach AL, Swenson P. Effect of breathing gases under positive pressure on lumens of smal and medium sized

bronchi.Arch Intern Med1939; 63: 946948.

131. Lenique E, Habis M, Lofaso F,et al.Ventilatory and hemodynamic effects of continuous positive airway pressure

(CPAP) in congestive heart failure. Am J Respir Crit Care Med1997; 155: 500505.

132. Bellemare F, Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue.J Appl Physiol

1982; 53: 11901195.

133. Granton JT, Naughton MT, Benard DC,et al.CPAP improves inspiratory muscle strength in patients with heart

failure and central sleep apnea. Am J Respir Crit Care Med1996; 153: 277282.

134. De Pasquale CG, Arnolda LF, Doyle IR,et al. Prolonged alveolocapillary barrier damage after acute cardiogenic

pulmonary edema. Crit Care Med2003; 31: 10601067.

135. Naughton MT, Rahman MA, Hara K,et al.Effect of continuous positive airway pressure on intrathoracic and left

ventricular transmural pressures in patients with congestive heart failure. Circulation1995; 91: 17251731.

418

SLEEP

APNOEA

IN

CHF


24/25


25/25

165. Philippe C, Stoica-Herman M, Drouot X, et al.Compliance with and effectiveness of adaptive servoventilation

versuscontinuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a

six month period. Heart2006; 92: 337342.

166. Fietze I, Blaua A, Glos M, et al. Bi-level positive pressure ventilation and adaptive servo ventilation in patients

with heart failure and Cheyne-Stokes respiration. Sleep Med2008; 9: 652659.

167. Simonds AK, Cowie MR. Taboo: crossing the specialty barrier.Eur Respir J2008; 31: 11531154.

168. Altschule MD, Iglauer A. The effect of position on periodic breathing in chronic cardiac decompensation.N Engl

J Med1958; 259: 10641066.

169. Shiota S, Ryan CM, Chiu KL,et al. Alterations in upper airway cross-sectional area in response to lower body

positive pressure in healthy subjects. Thorax2007; 62: 868872.170. Neill AM, Angus SM, Sajkov D, et al. Effects of sleep posture on upper airway stability in patients with

obstructive sleep apnea.Am J Respir Crit Care Med1997; 155: 199204.

171. Oksenberg A, Silverberg DS, Arons E, et al. Positional verusnonpositional obstructive sleep apnea patients:

anthropomorphic, nocturnal polysomnographic, and multiple sleep latency test data. Chest1997; 112: 629639.

172. Penzel T, Moller M, Becker HF, et al. Effect of sleep position and sleep stage on the collapsibility of the upper

airways in patients with sleep apnea. Sleep2001; 24: 9095.

173. Berger M, Oksenberg A, Silverberg DS, et al. Avoiding the supine position during sleep lowers 24 h blood

pressure in obstructive sleep apnea (OSA) patients. J Hum Hypertens1997; 11: 657664.

174. Dock W. The anatomical and hydrostatic basis of orthopnea and of right hydrothorax in cardiac failure. Am

Heart J1935; 10: 10471055.

175. Fujita M, Miyamoto S, Sekiguchi H,et al.Effects of posture on sympathetic nervous modulation in patients with

chronic heart failure. Lancet2000; 356: 18221823.176. Leung RS, Bowman ME, Parker JD,et al.Avoidance of the left lateral decubitus position during sleep in patients

with heart failure: relationship to cardiac size and function. J Am Coll Cardiol2003; 41: 2272230.

177. Sahlin C, Svanborg E, Stenlund H,et al.Cheyne-Stokes respiration and supine dependency.Eur Respir J2005; 25:

829833.

178. Pump B, Videbaek R, Gabrielsen A,et al.Arterial pressure in humans during weightlessness induced by parabolic

flights.J Appl Physiol1999; 87: 928932.

179. Hurewitz AN, Susskind H, Harold WH. Obesity alters regional ventilation in lateral decubitus position.J Appl

Physiol1985; 59: 774783.

180. Yap JC, Moore DM, Cleland JG, et al. Effect of supine posture on respiratory mechanics in chronic left

ventricular failure. Am J Respir Crit Care Med2000; 162: 12851291.

181. Brack T, Jubran A, Tobin MJ. Dyspnea and decreased variability of breathing in patients with restrictive lung

disease.Am J Respir Crit Care Med2002; 165: 12601264.182. Xie A, Rankin F, Rutherford R, et al. Effects of inhaled CO2 and added dead space on idiopathic central sleep

apnea.J Appl Physiol1997; 82: 918926.

183. Lorenzi-Filho G, Rankin F, Bies I, et al. Effects of inhaled carbon dioxide and oxygen on cheyne-stokes

respiration in patients with heart failure. Am J Respir Crit Care Med1999; 159: 14901498.

184. Khayat RN, Xie A, Patel AK,et al.Cardiorespiratory effects of added dead space in patients with heart failure and

central sleep apnea. Chest2003; 123: 15511560.

185. Ueno LM, Drager LF, Rodrigues AC, et al.Effects of exercise training in patients with chronic heart failure and

sleep apnea. Sleep2009; 32: 637647.

186. Cheyne J. A case of apoplexy, in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep1818;

2: 216223.

187. Stokes W. The Disease of the Heart and the Aorta. Dublin, Hodges and Smith, 1854; pp. 323326.

188. Andreas S, Hagenah G, Moller C,et al.Cheyne-Stokes respiration and prognosis in congestive heart failure. Am JCardiol1996; 78: 12601264.

189. Brack T, Thuer I, Clarenbach CF, et al. Daytime Cheyne-Stokes respiration in ambulatory patients with severe

congestive heart failure is associated with increased mortality. Chest2007; 132: 14631471.

190. McNicholas WT, Bonsigore MR. Sleep apnoea as an independent risk factor for cardiovascular disease: current

evidence, basic mechanisms and research priorities. Eur Respir J2007; 29: 156178.

191. Yumino D, Wang H, Floras JS,et al.Relationship between sleep apnoea and mortality in patients with ischaemic

heart failure. Heart2009; 95: 819824.

192. Punjabi NM, Caffo BS, Goodwin JL,et al.Sleep-disordered breathing and mortality: a prospective cohort study.

PLoS Med2009; 6: e1000132.

SLEEP

APNOEA

IN

CHF

sleep apnoea in chronic heart failure

Documents