European Journal of Heart Failure (2009) 11, 602–608

doi:10.1093/eurjhf/hfp057

Sleep-disordered breathing in heart failure with

normal left ventricular ejection fraction
Thomas Bitter*, Lothar Faber, Detlef Hering, Christoph Langer, Dieter Horstkotte,
and Olaf Oldenburg
Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Georgstasse 11, D – 32545 Bad Oeynhausen, Germany

Received 1 September 2008; revised 25 February 2009; accepted 6 March 2009

Aims In patients with systolic heart failure (SHF) a high prevalence of sleep-disordered breathing (SDB) has been documen-
ted. The purpose of this study was to investigate the prevalence and type of SDB in patients with heart failure with
normal left ventricular ejection fraction (HFNEF).
.....................................................................................................................................................................................
Methods Two hundred and forty-four consecutive patients (87 women, aged 65.3 + 1.4 years) with HFNEF underwent capil-
and results lary blood gas analysis, measurement of NT-proBNP concentrations, echocardiography, cardiopulmonary exercise
testing (CPX), cardiorespiratory polygraphy, and simultaneous right and left heart catheterization. Sleep-disordered
breathing was defined as an apnoea–hypopnoea-index (AHI) 5/h. Sleep-disordered breathing was documented in
69.3% of all patients, 97 patients (39.8%) presented with OSA and 72 patients (29.5%) with CSA. With an increasing
impairment of diastolic function the proportion of SDB, and CSA in particular, increased. Patients with SDB per-
formed worse on CPX and six-minute walk test. Partial pressure of CO2 was lower in CSA, whereas AHI, left
atrial diameter, NT-proBNP, LVEDP, PAP, and PCWP were higher.
.....................................................................................................................................................................................
Conclusion There is a high prevalence of SDB in HFNEF. In parallel to SHF, CSA patients in particular are characterized by a more
impaired cardiopulmonary function. Whether SDB is of prognostic relevance in HFNEF needs to be determined.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Heart failure with normal left ventricular ejection fraction † HFNEF † Diastolic heart failure † Sleep disordered
breathing † Prevalence

The association between sleep-disordered breathing (SDB) and

Introduction SHF is well known. In large-scale studies including up to 700
Congestive heart failure (CHF) is a major public health patients, a high prevalence of SDB among patients with SHF had
problem in many countries.1 Patients who meet the criteria been documented.8 – 11 Obstructive sleep apnoea (OSA) is con-
for clinical diagnosis of heart failure are heterogeneous, with sidered an independent risk factor for hypertension, CHF, and pul-
an increasing proportion of heart failure with normal left ven- monary hypertension.12 – 14 Hypertensive patients with heart
tricular ejection fraction (HFNEF).2 By the seventh decade of failure often present with preserved left ventricular systolic func-
life the prevalence of HFNEF approaches, and by the eighth tion but compromised diastolic function and comprise a substantial
decade of life it exceeds that of systolic heart failure (SHF).3 proportion of the patients with HFNEF. On the other hand,
Several authors and guidelines have presented a definition for Cheyne –Stokes-Respiration (CSR) and central sleep apnoea
HFNEF, all propose a classification scheme including the fol- (CSA) are highly prevalent in patients with pulmonary hyperten-
lowing criteria: clinical evidence of CHF, normal or mildly sion,15 one possible consequence of diastolic dysfunction.
abnormal LV systolic function expressed as ejection fraction The purpose of this study was to investigate the prevalence and
(EF), and evidence of abnormal LV relaxation, filling, or dias- type of SDB in 244 patients with HFNEF and to evaluate subjective
tolic stiffness.4 – 6 Survival of patients with HFNEF is similar to and objective clinical, echocardiographic, and haemodynamic par-
that of patients with SHF.7 ameters in these patients.

* Corresponding author. Tel: þ49 5731 97 1258, Fax: þ49 5731 97 2194, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
SDB in patients with HFNEF 603

Methods Cardiorespiratory polygraphy

Sleep studies were performed by in-hospital unattended cardiorespira-
Patients tory polygraphy (Embletta, Embla, The Netherlands). Nasal air flow,
Between January 2006 and March 2008, a total of 878 patients with chest and abdominal effort, pulse oximetry, and body position were
symptoms of heart failure, admitted to our cardiology facility were recorded continuously. The temporary loss of not more than one
screened for presence and type of SDB. Of these, 244 patients with channel, except for nasal air flow, was allowed. Analyses were per-
HFNEF, defined according to the guidelines mentioned previously,4 – 6 formed using Somnologica for EmblettaTM software (Medcare,
were eligible according to the inclusion and exclusion criteria, and Embla, The Netherlands) and reviewed by two independent SDB
were enrolled into the study. In summary, patients had to be in a specialists not involved in the patients’ treatment. Hypopnoea was
stable clinical condition, in NYHA class II – IV, with normal systolic func- defined as a 30% reduction in airflow in combination with an
tion according to echocardiographic and invasive criteria (LVEF .55%) oxygen desaturation of at least 3%. Apnoea was defined as a cessation
with an end-diastolic volume index (LVEDVI) ,97 mL/m2.2 Diagnostic of airflow for 10 s, and in case of CSA without any thoracic or
evidence of diastolic dysfunction was obtained invasively [LV end- abdominal breathing effort.
diastolic pressure (LVEDP) .16 mmHg or mean pulmonary wedge If the apnoea– hypopnoea-index (AHI) was ,5/h patients were con-
pressure (PCWP) .12 mmHg]. In addition patients had to be on sidered to have no SDB (noSDB, AHI ,5), patients with an AHI 5/h,
stable medication for at least 4 weeks. The majority of the remaining were classified as central (CSA) or OSA according to the majority of
634 patients were excluded from the trial due to compromised LV sys- events. An AHI 5 – 14/h was considered to indicate mild, an AHI 15 –
tolic function (n ¼ 511). Other reasons for exclusion were significant 29/h moderate, and an AHI 30/h severe, SDB.
valvular heart disease (any valve insufficiency or stenosis .first
degree), a history of SDB or ongoing treatment of SDB, evidence of pul-
monary disease, hypercapnia (pCO2 .45 mmHg) in capillary blood gas
Echocardiography
samples, pregnancy, acute coronary syndrome, or acute cardiac decom- Diameters and dimensions of the left atrium (LA) and left ventricle
pensation. This was a prospective observational study that used cardior- were measured by M-Mode and corrected by 2D echocardiography
espiratory polygraphy as an approved diagnostic procedure. The study following American Society of Echocardiography guidelines.16 Left ven-
flow-chart is summarized in Figure 1. Sleep studies as well as all other tricular ejection fraction was measured according to the modified
investigations were performed during the patients’ primary admission Simpsońs method using apical four and two chamber views. Blood
to the cardiology department of our hospital. flow Doppler as well as tissue Doppler were used to assess diastolic
All patients gave written informed consent to the clinical pro- function. Peak early (E) and peak atrial (A) Doppler mitral valve flow
cedures. The study was retrospectively approved by the Ethical velocity, ratio of peak early and peak atrial Doppler mitral valve flow
Review Board of the University of Ruhr, Bochum. velocity (E/A), and deceleration time (DT) of early Doppler mitral
valve flow velocity were documented. Left ventricular filling patterns
were classified as normal, impaired relaxation, pseudonormal, or
restrictive, taking into account early diastolic (E0 ) lengthening velocities
and the ratio of early mitral valve flow velocity and early diastolic
lengthening velocities (E/E0 ). Normal pattern was defined by an E/A
ratio .1, a DT between 150, and 220 ms and E/E0 ,10. Impaired
relaxation was determined by E/A ,1, DT .220 ms, and E/E0 .10.
Pseudonormal pattern was identified by E/A between 1 and 2, DT
between 150 and 220 ms, and E/E0 .10. Finally, restrictive pattern
was defined by E/A .2, DT ,150 ms, and E/E0 .10.

Left and right heart catheterization

Left heart angiography was performed with a 5 –7F pigtail catheter
(Cordis, Langenfeld, Germany), which was introduced retrogradely
into the LV and connected to a cardiac functional laboratory for acqui-
sition of left ventricular end-diastolic pressure (LVEDP). Pulmonary
artery pressure (PAP) and pulmonary capillary wedge pressure
(PCWP) were recorded using a balloon-tipped flotation thermodilu-
tion catheter (7F Arrow, Arrow International) via the right femoral
vein.

Six-minute walk test

A six-minute walk test was performed according to guidelines issued
by the American Thoracic Society.17

Capillary blood gas analysis

Partial pressure of carbon dioxide (pCO2), partial pressure of oxygen
Figure 1 Flow chart of patients’ inclusion. (pO2), and capillary oxygen saturation were measured using ABL 330
(Radiometer, Copenhagen, Denmark).
604 T. Bitter et al.

N-terminal pro-brain natriuretic peptide Results

N-terminal pro-brain natriuretic peptide (NT-proBNP) was used as
an additional marker of the severity of HFNEF. Analyses were Patients
performed using the Elecsys 2010 analyzer (Roche, Basel,
A total of 244 patients with HFNEF were enrolled into the study, of
Switzerland).
these 96 patients presented with an impaired left ventricular relax-
ation filling pattern, 104 with a pseudonormal left ventricular filling
pattern, and 44 patients with a restrictive left ventricular filling
Cardiopulmonary exercise testing pattern. The cause of heart failure was hypertensive heart
In order to evaluate exercise tolerance, peak oxygen consumption disease in 108 patients (44%), coronary artery disease in 80
(VO2-peak), oxygen consumption at the individual patients (33%), and cardiomyopathies (hypertrophic, restrictive)
aerobic-anaerobic threshold (VO2-AT), and relationship of minute
in 56 patients (23%). Baseline demographic and clinical data are
ventilation and carbon dioxide production (VE/VCO2), a symptom-
summarized in Table 1. The proportion of male patients was
limited bicycle exercise test was performed. Starting at 10 W,
workload was increased by 10 W every minute. Maximum work-
highest in patients with CSA, and lowest in patients with noSDB.
load and total exercise time were recorded; predicted VO2-peak Patients with SDB were significantly older, presented with a
was calculated automatically taking patients gender and age into higher NYHA-class and were more obese than patients with
account. noSDB. A history of hypertension was also more frequent in
these two subgroups. The percentage of patients with diabetes
was significantly higher in patients with OSA than in those with
Statistics CSA or noSDB. Compared with patients without SDB, more
Statistical analyses were performed using SPSS (version 10.2.6) soft- patients with central sleep apnoea had atrial fibrillation.
ware (SPSS Inc. Chicago, IL, USA). Differences between groups were
compared by ANOVA test. Correlation analysis was performed Sleep-disordered breathing
using Spearman rank correlation. A value of P , 0.05 was considered Among the 244 patients with HFNEF, SDB was documented in 169
significant for all comparisons. patients (69.3%), of these 97 patients (39.8%) presented with OSA

Table 1 Baseline demographic and clinical data for the study population

Variable CSA OSA noSDB

...............................................................................................................................................................................
n (%) 72 (29.5) 97 (39.8) 75 (30.7)
Ð
Male, n (%) 60 (83.3)‡ 61 (63.0)† 36 (48.0)
Age, years 66.9 + 2.4‡ 66.8+1.9† 61.6 + 3.3
Ð
Height, cm 174.9 + 1.9‡ 170.1 + 2 171.3 + 2.4
Ð
Weight, kg 89.8 + 3.4‡ 84.9 + 3.2† 77.9 + 3.7
‡
BMI 29.3 + 0.9 29.3+1.1† 26.42 + 1
NYHA class 2.5 + 0.2‡ 2.4 + 0.24† 2.2 + 0.33
Hypertension, n (%) 67 (87.0)‡ 88 (88.0)† 60 (80.0)
Ð
Diabetes, n (%) 22 (28.6) 45 (45.0) † 11 (14.7)
Atrial fibrillation, n (%) 17 (23.6)‡ 19 (19.6) 13 (17.3)
Cerebrovascular disease, n (%) 9 (12.5) 14 (14.4) 10 (13.3)
Medication, n (%)
Beta-blockers 64 (83.1) 78 (78.0) 64 (85.3)†
ACE/AT1-inhibitors 66 (85.7) 76 (76.0) 56 (74.6)
Calcium-channel blockers 30 (39.0) 46 (46.0) 29 (38.7)
Nitrates 16 (20.8) 24 (24.0) 12 (16.0)
Digitalis glycosides 9 (11.7) 9 (9.0) 3 (4.0)
Diuretics 53 (68.8) 57(57.0) 41 (54.7)
Other 76 (98.7)‡ 97(97.0)† 67 (89.3)
Capillary blood gas analysis
Ð
pCO2 (mmHg) 34.9 + 0.8‡ 39.4 + 0.7† 37.2 + 0.8
pO2 (mmHg) 76.0 + 2.1 80.6 + 15.4 79.9 + 2.5

†
P , 0.05 OSA vs. noSDB.
‡
ÐP , 0.05 CSA vs. noSDB.
P , 0.05 OSA vs. CSA.
SDB in patients with HFNEF 605

and 72 patients (29.5%) with CSA. Only 75 patients (30.7%) had no and 39 patients (40.6%) with noSDB. Of the patients with a pseu-
relevant SDB. Severity of SDB was mild in 21 patients with CSA donormal left ventricular filling pattern, 30 had a CSA (29.1%), 48
(8.3%) and in 40 patients with OSA (40%), moderate in 15 patients an OSA (46.6%), and 25 patients (24.3%) had noSDB. Of the
with CSA (6.0%) and 36 patients with OSA (36%), and severe in 41 patients with a restrictive left ventricular filling pattern, 18 had
patients with CSA (16.3%) and 24 patients with OSA (24%). In the CSA (40.9%), 16 had OSA (36.4%), and 10 had noSDB in 10
group with an impaired left ventricular relaxation filling pattern, 24 (22.7%) (Figure 2). Additional findings are presented in Table 2.
patients (25%) presented with CSA, 33 patients (34.4%) with OSA, The AHI in the restrictive and pseudonormal left ventricular
filling pattern group was higher than in the impaired relaxation
left ventricular filling pattern group. In addition, patients with a
pseudonormal left ventricular filling pattern had longer apnoea
and hypopnoea periods compared with the other subgroups.

Echocardiographic parameters
Echocardiographic findings are presented in Table 3. Left atrial
enlargement was more pronounced in the CSA group than in
the OSA and noSDB groups (P , 0.05). Patients with OSA had a
larger left atrial diameter compared with patients with noSDB
(P , 0.05). E wave was higher in the CSA group than in the
noSDB group (P , 0.05), E/A ratio was higher in the CSA group
compared with OSA (P , 0.05) and DT was higher in the
noSDB group than in the OSA group (P , 0.05).

N-terminal pro-brain natriuretic peptide

A significantly higher level of NT-proBNP was observed in patients
with CSA (1237 + 544 pg/mL) compared with those with OSA
(643 + 378 pg/mL) and those with noSDB (376 + 192 pg/mL).

Blood gas analysis

pCO2 was lower in patients with CSA than in those with noSDB
and those with OSA (P , 0.05). The noSDB group presented
with a lower pCO2 compared with the OSA group (P , 0.05,
Table 1). There was no significant difference in pO2 among the
three groups.

Six-minute walk test

Figure 2 Relative proportions of different types of sleep- The mean walk distance was 296 + 68 m in CSA patients, 334 +
disordered breathing in patients in different stages of heart 59 m in OSA patients, and 423 + 63 m in noSDB patients (P ,
failure with normal left ventricular ejection fraction. 0.05 noSDB vs. CSA; P , 0.05 noSDB vs. OSA, P , 0.05 OSA
vs. CSA).

Table 2 Cardiorespiratory polygraphy results

Variable Impaired relaxation Pseudonormal Restrictive

...............................................................................................................................................................................
n (%) 96 (39.3) 104 (42.6) 44 (18.0)
AHI, h21 15.0 + 3.6 20.0 + 3.3† 23.4 + 6.2‡
Mean oxygen saturation, % 92.6 + 0.6 92.9 + 0.6 92.6 + 0.9
Maximum oxygen desaturation, % 84.6 + 1.0 83.6 + 1.2 83.5 + 1.8
Average oxygen desaturation, % 4.5 + 0.4 5.2 + 0.6 5.0 + 0.7
Longest apnoea duration, s 22.3 + 4.0 30.1 + 4.0† 25.4 + 7.5
Longest hypopnoea duration, s 32.1 + 3.0 39.1 + 3.7† 37.8 + 6.3

†
P , 0.05 pseudonormal vs. impaired relaxation.
‡
P , 0.05 restrictive vs. impaired relaxation.
606 T. Bitter et al.

Table 3 Results from echocardiography, cardiopulmonary exercise testing, and invasive haemodynamic measurements

Variable CSA OSA noSDB

...............................................................................................................................................................................
Echocardiographic results
E wave (m/s) 0.91 + 0.11‡ 0.86 + 0.06 0.78 + 0.06
A wave (m/s) 0.71 + 0.08 0.77 + 0.05 0.75 + 0.06
Ð
E/A ratio 1.57 + 0.28 1.26 + 0.15 1.27 + 0.22
DT (ms) 216 + 23 199 + 15† 236 + 23
Ð
LA (mm) 49.6 + 1.6 ‡ 46.1 + 1.5† 43 + 1.7
Cardiopulmonary exercise testing
VO2 AT (mL/min/kg) 13.7 + 1.2‡ 14.1 + 1.2 19.5 + 6.5
VO2 peak (mL/min/kg) 15.9 + 1.4‡ 16.3 + 1.3† 19.8 + 1.5
Pred. VO2 peak (%) 73.5 + 7.3‡ 74.8 + 5.3† 85.9 + 5.8
Workload (W) 89.9 + 12.6 91.1 + 10.7† 108.2 + 13.6
VE/VCO2 slope 31.6 + 2.1‡ 29.6 + 1.6 28.2 + 1.5
Invasive haemodynamics
Ð
PAP (mmHg) 31 + 2.4‡ 27.8 + 1.8 26.4 + 2.3
Ð
PCWP (mmHg) 21 + 1.3‡ 19 + 1.2 18.7 + 1.9
Ð
LVEDP (mmHg) 23.4 + 1.8‡ 21.1 + 1.2 21.0 + 1.3

†
P , 0.05 OSA vs. no SDB.
‡
ÐP , 0.05 CSA vs. noSDB.
P , 0.05 OSA vs. CSA.

Cardiopulmonary exercise test about 50% of heart failure patients with reduced ejection frac-
Results from cardiopulmonary exercise testing are presented in tion.8 – 11
Table 3. VO2 at the aerobic/anaerobic threshold in the CSA group In contrast, data on patients with HFNEF are rare. In a small
was lower than in the noSDB group, whereas patients with CSA cohort of 20 patients, Chan et al.18 reported that 55% had signifi-
and patients with OSA showed a more severely reduced VO2 cant SDB, mainly OSA, which is mostly consistent with our results.
peak in comparison to patients with noSDB. While the OSA Furthermore, they demonstrated that E-wave deceleration time of
group presented with a lower maximum workload compared with mitral inflow, an index of diastolic relaxation, was more prolonged
patients with noSDB, the CSA group had a higher VE/VCO2-slope in the group with SDB. We could not show analogous results,
in comparison to patients with OSA or noSDB (P , 0.05). mainly because our study population included a higher proportion
of patients with pseudonormal or restrictive left ventricular filling
pattern which produces a faster E-wave deceleration time.
Invasive haemodynamic measurements However, our finding that with greater impairment of diastolic
Haemodynamic parameters are summarized in Table 3. Patients function the proportion of patients with SDB, and CSA in particu-
with CSA had higher LVDEP, a higher PAP, and a higher PCWP lar, increases is supported by similar findings for SHF, where a
compared with patients with OSA and noSDB (P , 0.05). greater impairment of systolic function is linked to a larger inci-
dence of SDB and CSA as well.8
Whether SDB occurs as a consequence of HFNEF or SDB
induces diastolic dysfunction has not yet been clarified.
Discussion On the one hand, Fung et al.19 investigated 68 OSA patients for
This is the first large-scale-study to show a high prevalence of SDB parameters of diastolic dysfunction and stated that more severe
in patients with HFNEF, with the proportion rising in parallel to an SDB was associated with a higher degree of diastolic dysfunction.
increased impairment of diastolic function measured by echocar- These results were supported by Otto et al.,20 who compared
diography. Patients with SDB and especially central sleep apnoea 23 otherwise healthy patients with OSA to 18 patients without
presented with more advanced symptoms and more impaired car- OSA and found an increased left atrial volume index as well as
diovascular function. abnormal diastolic filling parameters in the OSA group. Besides
In patients with CHF and reduced LV-function, a high prevalence an increased left atrial volume index, Romero-Corral et al. 21
of SDB is well documented. In a study of 700 patients with SHF, reported an association between SDB and an impaired myocardial
SDB was documented in 76% of patients, of whom 40% had performance index. Correspondingly Sidana et al.22 found a higher
central sleep apnoea and 36% OSA, using an apnoea– prevalence of diastolic dysfunction in moderate-to-severe OSA
hypopnoea-index cut-off of 5/h.8 Using an AHI cut-off of 15/h, than in those with mild or no OSA. The main reason for this
several studies have documented moderate-to-severe SDB in could be repeated nocturnal hypoxaemias leading to sympathetic
SDB in patients with HFNEF 607

nerve activation with a consequent increase in hormonal activation In conclusion, we found a high prevalence of SDB in patients
and arterial blood pressure,14 thus predisposing to wall thickening with HFNEF, with a correlation between impairment of diastolic
and compromised diastolic function. function assessed by echocardiography and frequency of SDB.
On the other hand, a mechanism of central sleep apnoea is said Patients with SDB presented with more advanced symptoms
to be based upon pulmonary congestion induced stimulation of and greater impairment of cardiovascular function. Controlled
pulmonary vagal irritant receptors and enhanced central and per- studies are now required to investigate the prognostic impact of
ipheral chemosensitivity leading to hyperventilation and respiratory SDB in HFNEF and to evaluate whether treatment of obstructive
instability.23 – 27 In HFNEF, pulmonary congestion may arise from a and central sleep apnoea in patients with heart failure with
compromised left ventricular filling pattern which supports the preserved left ventricular ejection fraction can ameliorate symp-
theory that SDB, and CSA in particular, could be a consequence toms of heart failure and improve cardiopulmonary exercise
of HFNEF. Our findings of a correlation between PCWP and tolerance.
AHI in the entire cohort and in the CSA-group specifically,
support this idea as do the findings of Bucca et al.28 that diuretic Conflict of interest: none declared.
treatment of HFNEF produces a significant decrease in AHI, poss-
ibly due to a reduction in pulmonary congestion.
Finally, the impaired clinical, haemodynamic, and echocardio-
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