Pulmonary hypertension in obstructive sleep apnoea ...

European Heart Journal (2006) 27, 1106–1113 Clinical research
doi:10.1093/eurheartj/ehi807
Hypertension

Pulmonary hypertension in obstructive sleep apnoea: Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
effects of continuous positive airway pressure

A randomized, controlled cross-over study

Miguel A. Arias1, Francisco Garc´ıa-R´ıo2*, Alberto Alonso-Fern´andez2, Isabel Mart´ınez3,
and Jose´ Villamor2

1 Servicios de Cardiolog´ıa, Hospital Universitario La Paz, Universidad Auto´noma de Madrid, Madrid, Spain; 2 Neumolog´ıa,
Hospital Universitario La Paz, Universidad Auto´noma de Madrid, c/Alfredo Marquer´ıe 11, izqda-18A, 28034 Madrid, Spain;
and 3 Laboratorio de Bioqu´ımica, Hospital Universitario La Paz, Universidad Auto´noma de Madrid, Madrid, Spain

Received 23 June 2005; revised 10 January 2006; accepted 3 February 2006; online publish-ahead-of-print 23 February 2006

See page 1016 for the editorial comment on this article (doi:10.1093/eurheartj/ehi850)

KEYWORDS Aims We tested the hypothesis that: (i) obstructive sleep apnoea (OSA) by itself originates pulmonary
hypertension (PH); and (ii) the application of continuous positive airway pressure (CPAP) can reduce
Obstructive sleep apnoea; pulmonary pressure.
Pulmonary hypertension; Methods and results In this randomized and cross-over trial, 23 middle-aged OSA (apnoea–hypopnoea
Continuous positive airway index, 44.1 + 29.3 h21) and otherwise healthy patients and 10 control subjects were included. OSA
patients randomly received either sham or effective CPAP for 12 weeks. Echocardiographic parameters,
pressure blood pressure recordings, and urinary catecholamine levels were obtained at baseline and after both
treatment modalities. At baseline, OSA patients had higher pulmonary artery systolic pressure than
control subjects (29.8 + 8.8 vs. 23.4 + 4.1 mmHg, respectively, P ¼ 0.036). Ten out of 23 patients
[43%, (95% CI: 23–64%)] and none of the control subjects had PH at baseline (P ¼ 0.012). Two patients
were removed from the study because of inadequate CPAP compliance. Effective CPAP induced a signifi-
cant reduction in the values for pulmonary systolic pressure (from 28.9 + 8.6 to 24.0 + 5.8 mmHg,
P , 0.0001). The reduction was greatest in patients with either PH or left ventricular diastolic dysfunc-
tion at baseline.
Conclusion Severe OSA is independently associated with PH in direct relationship with disease severity
and presence of diastolic dysfunction. Application of CPAP reduces pulmonary systolic pressure levels.

Introduction The goals of this study were: (i) to compare the levels of
pulmonary artery systolic pressure (PASP) between
Obstructive sleep apnoea syndrome (OSA) is the most middle-aged adults with OSA and no other concomitant
common form of sleep-disordered breathing.1 Cardio- heart and lung diseases that may affect pulmonary haemo-
vascular disturbances are the most important complications dynamics, and healthy subjects with a similar age, gender
producing severe morbidity and mortality.2 Many risk factors distribution, and body mass index; and (ii) to evaluate
for OSA, such as male gender, increasing age, and obesity are the effects of CPAP therapy on pulmonary artery pressure
the same as for cardiovascular disease. This fact makes it in OSA patients in a double-blind placebo-controlled
difficult to establish a causal relationship between OSA and manner.
cardiovascular disorders.
Methods
Acute pulmonary artery pressure changes during sleep
have been extensively reported in association with obstruc- Subjects
tive apnoeas.3 However, the role of OSA as an independent
risk factor for the development of day-time pulmonary Figure 1 shows both the study protocol and the fate of participating
hypertension (PH) is not well known. Indeed, the effects patients. Twenty-eight newly diagnosed OSA patients and 15 healthy
of nasal continuous positive airway pressure (CPAP) subjects were recruited into the study. OSA patients fulfilled the fol-
therapy, the treatment of choice for OSA, on pulmonary lowing inclusion criteria: (i) apnoea–hypopnoea index (AHI) 10 h21
artery pressure has not been addressed in prospective and excessive day-time sleepiness (Epworth sleepiness scale 10
placebo-controlled trials. points);4 and (ii) no previous treatment for OSA. Inclusion criteria
for control subjects were AHI ,5 h21 and Epworth sleepiness scale
*Corresponding author. Tel: þ34 91 7300170; fax: þ34 91 7277096. ,10. Exclusion criteria for both study groups were: (i) obstructive
or restrictive lung disease demonstrated on pulmonary function
E-mail address: [email protected] testing; (ii) connective-tissue or chronic thrombo-embolic diseases;

& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]

Pulmonary hypertension in OSA 1107

Figure 1 Study protocol. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016

(iii) current cardioactive drugs; (iv) cardiac rhythm disturbances, preliminary study of our group, which showed a mean PASP of
including sinus bradycardia and sinus tachycardia; (v) known hyper- 27 + 5 mmHg in OSA patients. By two-sided contrast of paired
tension, or 24-h mean blood pressure of 135 and/or 85 mmHg or samples, the required sample size to show a significant reduction
more; (vi) left ventricular (LV) ejection fraction (EF) ,50%, ischae- after treatment of at least 5 mmHg with an estimated correlation
mic or valvular heart disease, cardiomyopathy, pericardial disease coefficient of 0.22 and assuming a loss of 20% was 23 patients
or stroke, by history, physical examination, electrocardiogram, (a-risk of 0.05 and b-risk of 0.1). The sham CPAP device consists
chest radiography, conventional stress testing, and echocardio- of a conventional CPAP device in which the area of the exhalation
graphy; (vii) diabetes mellitus, on history or two random blood port is amplified thereby nearly cancelling nasal pressure, and an
glucose levels 126 mg/dL; (viii) morbid obesity (body mass index orifice resistor is connected between the tubing and the CPAP unit
.40 kg/m2); (ix) day-time hypoxaemia or hypercapnia; (x) history that load the blower with the same airflow resistance as in effective
of cocaine or appetite-suppressant drug use. Withdrawal criteria CPAP. All patients underwent a full-night CPAP titration study using
were: (i) clinical exacerbation leading to a change in medication; an automated pressure setting device (Auto Set; ResMed, Sydney,
(ii) hospital admission for 10 or more days; and (iii) average night Australia).7 Patients were not informed of the type of therapy
nCPAP usage less than 3.5 h. they were receiving. Compliance to CPAP or sham CPAP was
measured using the run-time counter built into each CPAP device.
Finally, only subjects (23 OSA patients and 10 healthy subjects) in
whom PASP could be estimated by echocardiography, because of All subjects underwent baseline sleep study, 24-h ambulatory
the presence of less than moderate tricuspid regurgitation,5 were blood pressure monitoring, and transthoracic echocardiogram.
evaluated. Urine specimens and demographic data were also collected.
Patients were randomized to receive either effective or sham
Control subjects were recruited from a list of healthy subjects CPAP therapy for 12 weeks. They were then readmitted to the hos-
from our sanitary area that had had a health routine test in the pre- pital, and the CPAP device was switched to the alternate mode of
vious 3 months. We randomly selected a control subject similar in therapy for another 12 weeks. Echocardiogram and ambulatory
gender, age (+2 years), weight (+2 kg), and height (+5 cm) with blood pressure monitoring (ABPM) were repeated just after each
regard to the two preceding patients included in the study. period with either effective or sham CPAP treatment. Urine speci-
mens were obtained at the same time at each visit.
The study was approved by the Institutional Ethics Committee at
the hospital and all subjects gave their written informed consent. Lung function study
We performed a single-centre, prospective, randomized, double-
blind, placebo-controlled, and cross-over clinical trial. Patients Baseline spirometry was performed in accordance with American
were randomized by one of the investigators, by means of a Thoracic Society recommendations8 using a pneumotachograph spi-
computer-generated randomization list using random numbers, to rometer (MasterLab 6.0, Jaeger, Wurzburg, Germany). The values
receive either effective CPAP or sham CPAP for two 12-week were expressed as a percentage of predicted normal.9 Day-time
periods.6 Immediately after, the other treatment was applied with
no washout period. The sample size was estimated from a

1108 M.A. Arias et al.

blood gases were non-invasively analysed by a finger pulsioximeter deceleration time and isovolumic relaxation time, and S/D and Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
(Oscar II, Datex, Helsinki, Finland). Expiratory pressure of carbon A/AR duration ratios ,1. Finally, restrictive pattern was defined
dioxide (PECO2) and estimated arterial pressure of carbon dioxide by E/A ratio .1, short deceleration time (,160), isovolumic
(PaCO2) were obtained by the simultaneous monitoring of capno- relaxation time (,70), and S/D and A/AR duration ratios ,1.
graph and ventilation at rest (Oxycon Alpha, Jaeger).
Statistical analysis
Sleep study
Values are expressed as mean + SD or percentage. All statistical
The same night when the urine specimens were collected, a sleep tests were two-sided. The comparisons between patient groups
study was performed in OSA patients and control subjects. We were performed using linear mixed models that included a random
used a previously validated portable respiratory recording device intercept for each subject trio (two OSA patients and one
(Sibel Home-300; Sibel S.A., Barcelona, Spain).10 control). In the model, the study group was selected as factor,
whereas gender, age, and BMI were selected as covariates. The
Respiratory events were classified as either obstructive or group was included as the fixed effect, and the random effects
central on the basis of the presence or absence of respiratory were the factor, covariates, and the intercept. The subject trio
effort. Respiratory events were scored as apnoea when there was was selected as a subject identification variable in the subjects’
a cessation of oronasal airflow lasting 10 s. Hypopnoea was group. The chi-square was used to compare proportions.
defined as a decrease of 50% in oronasal airflow lasting .10 s,
associated with a fall in arterial oxygen saturation (SaO2) .4% of A multiple logistic regression analysis was performed to identify
the preceding baseline level. Mean and minimum night-time SaO2, the factors determining PH. The independent variables included
desaturation index, and sleep time with SaO2 , 90% on nocturnal in the model were gender, age, AHI, mean nocturnal SaO2, and
oximetry were computed as indexes of nocturnal oxygen saturation. the variables that reached statistical significance in univariate
analysis. In this analysis, a forward Wald stepwise method was
Twenty-four-hour ABPM used with a F , 0.05 and a F . 0.10 as criteria to enter or
remove, respectively.
Twenty-four-h ABPM was performed on each patient with a
Spacelabs device (model 90207, Redmond, WA, USA), using an Comparisons of effects of the treatments over time were made by
oscillometric method as previously described.11 linear mixed models with correlated residuals within the random
effects (MIXED procedure). For each dependent variable, treatment
Catecholamines in urine was selected as factor and the period, the sequence and the
baseline value of the variable were selected as covariates. For
Urinary excretion of norepinephrine and epinephrine were deter- the specification of the model, the treatment and the covariates
mined as previously described.12 were selected as fixed factors. Because of the reduced number of
patients, the mixed model used only main effects (i.e. no inter-
Echocardiography actions). The slope and the intercept were modelled as random
effects. These comparisons were only performed on 22 patients
Examinations were performed using high-quality echocardiograph who completed the trial. The comparison of the number of patients
with 2.0–4.0 MHz probes (Hewlett Packard Sonos 5500, Andover, with PH at baseline and after treatment was done by means of the
MA). The parameters were measured from at least three cardiac McNemar test.
cycles. All echocardiograms were performed by the same experi-
enced echocardiographer, who was unaware of both the subject’s These analyses were performed using the Statistical Package for
group and the patient’s treatment assignment at each visit. the Social Sciences for Windows Release 11.0 software (SPSS Inc.,
Chicago, IL). A value of P , 0.05 was considered statistically
Non-invasive estimation of PASP by the Doppler transthoracic significant.
echocardiography method was chosen because of the close corre-
lation with invasive measurements.13 Peak tricuspid regurgitant Results
jet velocity (V) was determined by continuous-wave Doppler to
calculate the right ventricular systolic pressure using the simplified General characteristics and baseline LV size
Bernoulli equation (right ventricular systolic pressure ¼ 4V2 þ right and function
atrial pressure). Right atrial pressure was assumed to be 10 mmHg.
For this study, PH was defined as an estimated PASP of greater than There were no significant differences between OSA patients
30 mmHg.14 randomized (n ¼ 23) and those finally not included owing to
lack of tricuspid regurgitation (n ¼ 5), with respect to sever-
Data on both LV systolic function and structure and left atrial end- ity of OSA (AHI and minimum SaO2), lung function, blood
systolic dimension were also obtained. LV diastolic function was pressure, urinary catecholamines, and demographic data.
assessed with both two-dimensional and Doppler echocardiography. Control subjects included (n ¼ 10) and those not evaluated
The following variables were measured: peak flow velocity in early because of the absence of measurable tricuspid regurgita-
diastole or E-wave, peak velocity at atrial contraction or A-wave, tion (n ¼ 5) were also comparable for the aforementioned
isovolumic relaxation time, mitral deceleration time, and mitral A data characteristics.
wave duration. To obtain pulmonary venous flow, an apical four-
chamber view was used and pulsed wave Doppler sample volume Baseline characteristics as well as LV size and function in
was placed 1–2 cm into the right upper pulmonary vein. Peak systo- both study groups are shown in Tables 1 and 2, respectively.
lic velocity or S-wave, peak diastolic velocity or D-wave, and the
duration of reverse flow at atrial contraction or AR wave were At baseline, an abnormal LV filling pattern was present in
measured. LV filling patterns were classified as either normal, 13 of the 23 OSA patients (56%) and only in two of the 10
impaired relaxation, pseudonormal, or restrictive by a modification healthy control subjects (20%) (P ¼ 0.045). We observed
of the Appleton et al.15 approach. Normal pattern was defined by impaired relaxation pattern in nine OSA patients (39%),
E/A ratio .1, normal deceleration time (160–240 ms), isovolumic and pseudonormal pattern was present in the remaining
relaxation time (70–110 ms), and S/D and A/AR duration ratios four patients (17%). In the two control subjects with dias-
.1. Impaired relaxation was determined by E/A ratio ,1, pro- tolic dysfunction, impaired relaxation was the LV filling
longed deceleration time (.240 ms), isovolumic relaxation time pattern.
(.110), and S/D and A/AR duration ratios .1. Pseudonormal
pattern was identified by E/A ratio in the range of 1–1.5, normal

Pulmonary hypertension in OSA 1109

Table 1 Baseline characteristics

OSA patients Control subjects P
(n ¼ 23) (n ¼ 10)

Male (%) 96 100 0.523 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
51 + 13 50 + 10 0.546
Age (years) 30.9 + 4 27.7 + 3 0.091
Body mass index (kg/m2) 1.99 + 0.18 1.95 + 0.15 0.212
Body surface area (m2) 39 20 0.291
44.1 + 29.3 4.2 + 3.5 ,0.001
Smoker (%) 97 + 6 58 + 37 0.001
AHI (h21) 19.21 + 20.6 0.07 + 0.05 0.004
44 + 28.4 5.6 + 4.8 ,0.001
Obstructive events (%) 92 + 3 94 + 1 0.217
72 + 12 85 + 5 0.009
Time with SaO2 , 90% (min) 107 + 18 99 + 19 0.377
Desaturation index (h21) 111 + 17 109 + 19 0.689
85 + 7 89 + 3 0.094
Mean nocturnal SaO2 (%) 96 + 1 96 + 1 0.273
Minimum SaO2 (%) 32.6 + 3.2 32.6 + 1.7 0.359
Forced vital capacity (% predicted) 40.3 + 3.1 39.8 + 2.3 0.269
127 + 9 120 + 10 0.111
FEV1 (% predicted) 79 + 5 78 + 6 0.598
FEV1/forced vital capacity (%) 118 + 11 110 + 9 0.090
Day-time SaO2 (%) 71 + 7 68 + 6 0.230
PECO2 (mmHg) 35.1 + 13.6 32.1 + 13.8 0.422
Estimated PaCO2 (mmHg) 7.2 + 5.4 8.8 + 5.5 0.316
Day-time SBP (mmHg) 22.4 + 13.2 13.2 + 7.2 0.041
6.8 + 5.6 4.1 + 2.8 0.073
Day-time DBP (mmHg)

Night-time SBP (mmHg)

Night-time DBP (mmHg)

Diurnal norepinephrine (mg/g)

Diurnal epinephrine (mg/g)

Nocturnal norepinephrine (mg/g)

Nocturnal epinephrine (mg/g)

AHI, apnoea–hypopnoea index; DBP, diastolic blood pressure; FEV1, forced expiratory volume in 1 s; PaCO2, arterial carbon dioxide
pressure; PECO2, expiratory carbon dioxide pressure; SaO2, oxyhaemoglobin saturation; SaO2 , 90%, time with oxygen saturation
,90%; SBP, systolic blood pressure.

Table 2 Echocardiographic parameters in OSA patients and control subjects

OSA patients Control subjects P
(n ¼ 23) (n ¼ 10)
0.723
E-wave (m/s) 0.70 + 0.13 0.72 + 0.12 0.687
A-wave (m/s) 0.71 + 0.34 0.61 + 0.20 0.779
E/A ratio 1.15 + 0.43 1.24 + 0.27 0.066
Deceleration time (ms) 244 + 61 212 + 88 0.123
Isovolumic relaxation time (ms) 103 + 18 0.894
Left atrial diameter (mm) 37.3 + 3.7 91 + 17 0.657
LV diastolic diameter (mm) 52.0 + 2.8 37.0 + 5.7 0.123
LV systolic diameter (mm) 32.5 + 2.5 51.5 + 4.5 0.081
LV shortening fraction (%) 37.6 + 3.3 30.7 + 4.6 0.069
LVEF (%) 66.8 + 3.6 40.4 + 5.1 0.012
Interventricular septum (mm) 10.7 + 1.3 70.4 + 6.5 0.0004
Posterior wall (mm) 10.8 + 1.2 0.001
LV mass (g) 217 + 39 9.2 + 1.5 0.013
LV mass index (g/m2) 108.9 + 19.9 8.9 + 1.0
172 + 29
88.8 + 17.1

Pulmonary artery systolic pressure and impaired relaxation pattern, respectively. Conversely,
only one OSA patient with PH (10%) had a normal pattern,
The mean values for PASP at baseline were 29.8 + 8.8 mmHg whereas five (55%) and four (40%) presented an impaired
for the OSA group and 23.4 + 4.1 mmHg for the control relaxation and pseudonormal patterns, respectively. Multiple
group (P ¼ 0.036) (Figure 2). Doppler-defined PH was logistic regression analysis selected both AHI and forced vital
present in 10 of the 23 OSA patients [43% (95% CI: capacity (% of predicted) as independent factors related to
23–64%)] and in none of the 10 control subjects (0%) the development of PH (r2 ¼ 0.75, P ¼ 0.000).
(P ¼ 0.012). A detailed comparison of OSA patients with
and without PH is shown in Table 3. Effects of CPAP

There was a direct association between the presence of Two patients failed to complete the trial because of an
diastolic dysfunction and PH (P ¼ 0.006). Nine (69%) and average night usage of CPAP of less than 3.5 h. Both patients
four (31%) OSA patients without PH presented normal filling

1110 M.A. Arias et al.

Figure 2 Individual values for the PASP in OSA patients and control subjects. had PH at baseline. Twenty-one OSA patients completed
both treatment arms. Eleven patients received sham CPAP
and 10 patients effective CPAP throughout the first
12-week period of the study. Mean CPAP pressure was
10 + 2 cm H2O, and average night usage was similar on
effective CPAP (6.2 + 1.1 h) and sham CPAP (5.8 + 1.4 h).

Main demographic, blood pressure, urinary catechol-
amines, and echocardiographic data after the two treat-
ment modalities in OSA patients are shown in Table 4.
Twelve weeks on effective CPAP therapy induced a reduction
of 4.9 + 3.9 mmHg (95% CI: 3.04–6.67 mmHg) [15.1 + 11.2%
(95% CI: 10.1–20.3%)] in the level of PASP, changing from
28.9 + 8.6 to 24.0 + 5.8 mmHg (P , 0.0001). Indeed, the
number of OSA patients with PH was also reduced from
eight (38%) to three (14%) out of 21 patients (P ¼ 0.001).
Individual values for the PASP at baseline and after both

Table 3 Comparison of OSA patients with and without PH OSA patients P Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
without PH
OSA patients (n ¼ 13) 0.380
with PH 0.976
(n ¼ 10) 92 0.006
52 + 12 0.166
Male (%) 100 28.9 + 2.9 0.417
Age (years) 51 + 15 1.96 + 0.10 0.0001
Body mass index (kg/m2) 31 0.203
Body surface area (m2) 33.6 + 4.4 25.1 + 14.5 0.080
Smoker (%) 2.05 + 0.24 98.9 + 1.8 0.043
AHI (h21) 9.8 + 10.6 0.012
Obstructive events (%) 50 31.1 + 16.5 0.148
SaO2 , 90% (min) 68.7 + 24.9 93 + 2 0.002
Desaturation index (h21) 94.0 + 8.1 75 + 12 0.067
Mean nocturnal SaO2 (%) 30.6 + 24.6 117 + 15 0.115
Minimum SaO2 (%) 58.2 + 32.5 117 + 14 0.863
Forced vital capacity (% predicted) 82.5 + 7.4 0.832
FEV1 (% predicted) 90 + 4 96 + 1 0.166
FEV1/forced vital capacity (%) 68 + 12 32.4 + 2.9 0.471
Day-time SaO2 (%) 94 + 12 39.5 + 2.6 0.647
PECO2 (mmHg) 103 + 17 126 + 11 0.082
Estimated PaCO2 (mmHg) 88.4 + 6.5 79 + 6 0.144
Daytime SBP (mmHg) 96 + 2 115 + 10 0.522
Day-time DBP (mmHg) 32.7 + 3.5 69 + 8 0.879
Night-time SBP (mmHg) 40.8 + 3.4 33.2 + 11.9 0.410
Night-time DBP (mmHg) 128 + 7 7.1 + 5.0 0.927
Diurnal norepinephrine (mg/g) 79 + 5 21.9 + 15.3 0.376
Diurnal epinephrine (mg/g) 123 + 10 6.6 + 5.3 0.284
Nocturnal norepinephrine (mg/g) 74 + 7 0.69 + 0.13 0.522
Nocturnal epinephrine (mg/g) 37.6 + 15.8 0.71 + 0.43 0.563
E-wave (m/s) 7.4 + 6.2 1.21 + 0.49 0.186
A-wave (m/s) 23.2 + 10.8 243 + 71 0.115
E/A ratio 7.0 + 6.3 99 + 20 0.605
Deceleration time (ms) 0.72 + 0.14 36.3 + 3.4 0.483
Isovolumic relaxation time (ms) 0.72 + 0.20 51.7 + 2.1 0.648
Left atrial diameter (mm) 1.08 + 0.35 32.1 + 2.2 0.522
LV diastolic diameter (mm) 247 + 48 37.8 + 3.2 0.042
LV systolic diameter (mm) 108 + 16 67.1 + 3.7 0.004
LV shortening fraction (%) 38.7 + 3.8 10.2 + 1.2 0.012
LVEF (%) 52.5 + 3.6 10.2 + 1.1 0.148
Interventricular septum (mm) 32.9 + 2.9 199 + 32
Posterior wall (mm) 37.2 + 3.6 102.0 + 15.4
LV mass (g) 66.4 + 3.6
LV mass index (g/m2) 11.3 + 1.2
11.6 + 0.8
239 + 37
117.8 + 22.2

Abbreviations as in Table 1.

Pulmonary hypertension in OSA 1111

Table 4 Heart rate, weight, blood pressure data, urinary catecholamines and levels of pulmonary artery
pressure in OSA patients after sham and effective CPAP

Sham CPAP (n ¼ 11) CPAP (n ¼ 10) P

Weight (kg) 90 + 16 90 + 17 0.891 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
Heart rate (bpm) 72 + 10 82 + 21 0.243
Body mass index (kg/m2) 30.9 + 4.3 30.8 + 4.7 0.285
Day-time SBP (mmHg) 128 + 10 127 + 8 1.0
Day-time DBP (mmHg) 78 + 6 78 + 5 0.753
Night-time SBP (mmHg) 118 + 10 117 + 13 0.844
Night-time DBP (mmHg) 71 + 5 70 + 9 0.361
Diurnal norepinephrine (mg/g) 32.8 + 11.5 30.7 + 12.0 0.742
Diurnal epinephrine (mg/g) 7.9 + 3.5 7.8 + 4.4 0.921
Nocturnal norepinephrine (mg/g) 22.6 + 12.9 20.7 + 9.7 0.883
Nocturnal epinephrine (mg/g) 6.6 + 5.4 6.5 + 4.2 0.765
PASP (mmHg) 28.8 + 7.9 24.0 + 5.8 ,0.0001
E-wave (m/s) 0.74 + 0.10 0.74 + 0.10 0.461
A-wave (m/s) 0.78 + 0.37 0.65 + 0.21 0.127
E/A ratio 0.12 + 0.41 1.26 + 0.39 0.002
Deceleration time (ms) 246 + 62 224 + 43 0.001
Isovolumic relaxation time (ms) 104 + 17 97 + 14 0.062
Left atrial diameter (mm) 37.5 + 3.4 37.1 + 3.6 0.551
LV diastolic diameter (mm) 51.4 + 2.5 51.6 + 2.7 0.844
LV systolic diameter (mm) 32.0 + 2.9 31.9 + 2.6 0.832
LV shortening fraction (%) 37.9 + 3.7 38.1 + 3.0 0.767
LVEF (%) 67.1 + 4.1 67.6 + 3.1 0.721
Interventricular septum (mm) 10.7 + 1.1 10.9 + 1.3 0.612
Posterior wall (mm) 10.5 + 1.2 10.6 + 1.0 0.979
LV mass (g) 207 + 33 212 + 35 0.103
LV mass index (g/m2) 103.1 + 15.6 105.6 + 15.6 0.121

Figure 3 Individual values for the PASP after both sham and effective CPAP significant heart and lung diseases, and CPAP therapy
treatment in OSA patients. significantly reduced the levels of day-time pulmonary

sham and effective CPAP in OSA patients are shown in artery pressure.
Figure 3. The used definition of PH as a PASP .30 mmHg may over-

Higher reduction in PASP after effective CPAP therapy estimate the prevalence of PH in the OSA patients of our
was observed in OSA patients with either LV diastolic study. For healthy subjects with demographic data similar to
dysfunction (7.3 + 3.3 vs. 1.6 + 1.8 mmHg, P , 0.001) or
presence of PH at baseline (8.5 + 2.8 vs. 2.6 + 2.8 mmHg, our OSA patients, specifically male subjects from 50 to 59
P , 0.001). years of age, and those with body mass index higher than 30
and lower than 35 kg/m2, McQuillan et al.16 reported
Discussion
normal ranges of 21.0–40.6 and 20.5–40.9 mmHg, respect-
The main findings in this study were that severe OSA ively. Indeed, in 6% of subjects older than 50 years of age
frequently caused day-time PH in the absence of either and 5% of those with body mass index higher than 30 kg/m2,

PASP .40 mmHg was reported. However, the presence of
sleep-disordered breathing in their patients was not ruled
out and this could have contributed to the results because
of the high prevalence of OSA in middle-aged male subjects.1

Previous studies dealing with the presence of PH in OSA
subjects have estimated its prevalence to be from 17 to
53%.17 Only three studies,18–20 however, controlled the

influence of concomitant heart and lung diseases, especially
the presence of chronic obstructive pulmonary disease. In
the study by Bady et al.20 only pre-capillary PH was
reported in 12 out of 44 (27%) patients. Sajkov et al.19
found a PH prevalence of 41% in a group of 27 patients,
and Sanner et al.18 found post-capillary and pre-capillary

PH in 8 and 12 out of 92 patients, respectively. Similar to
our research, day-time PH was mild in these studies.
These differences between the studies may be mainly
because of inter-individual differences in the magnitude of

cardiovascular response to factors such as intermittent
hypoxia or increased ventricular afterload, length of

1112 M.A. Arias et al.

illness, different definitions of PH, and the limited number and they could not differentiate the possible different grades Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
of patients studied. of severity of diastolic dysfunction in their patients.

Contrary to most studies, we found AHI to be the Limitations include, first, the limited number of patients
parameter that had the closest correlation with PASP included does not let us to know the real prevalence of PH
level. Also, we have found a relationship between LV dias- in OSA patients. Indeed, our OSA and otherwise healthy
tolic dysfunction and PH. They probably establish a vicious patients do not represent the general OSA population
pathophysiologic cycle in which the contribution of diastolic because of the high morbidity usually present in this
dysfunction to the development of PH seems to be more patient population. However, the thorough selection
likely than the opposite. In a group of 120 patients with process was extremely arduous in order to achieve the
PH of different aetiologies, Moustapha et al.21 observed objectives of the study. Possible gender differences cannot
that only when PASP was higher than 60 mmHg impaired be established because of the fact that patients were pre-
relaxation was developed. Although data on LV end-diastolic dominantly males. Another limitation is that right ventricu-
and pulmonary artery wedge pressures were not assessed in lar function and structure were not assessed, and pulmonary
our study, we believe that the presence of diastolic dysfunc- artery pressure depends on both. In this regard, Guidry
tion supports the hypothesis that high filling pressure may be et al.28 found only minimal right ventricular hypertrophy
an important determinant of PH in our OSA patients. in patients with sleep-disordered breathing but a high
percentage of patients with systemic hypertension, obstruc-
We speculate that day-time PH could have a pre-capillary tive pulmonary disease, and diabetes had been included.
component related to repetitive hypoxia-reoxygenation22 However, asymptomatic mild PH observed in our patients
leading to both pulmonary vasoconstriction and vascular without these disorders, along with the fact that both LV sys-
endothelial remodelling, but also a post-capillary component tolic function and structure were normal in all patients,
in relation with permanent or episodic elevations in LV filling render unlikely the presence of significant right ventricular
pressure.14 In patients with PH secondary to chronic heart hypertrophy or failure that could significantly affect the
failure because of elevated LV filling pressure, the main com- level of PASP.
ponent of PH is reversed in minutes to days by vasodilator
agents and is related to deregulation of pulmonary vascular Our results show that, even in the absence of other lung
endothelial function. This could be the component of PH and heart diseases, day-time PH can develop in severe OSA
reversed after CPAP therapy in our study. However, the poss- patients. The level of pulmonary artery pressure maintained
ible presence of structural pulmonary vascular abnormalities a direct relationship with both the severity of OSA and the
could play an important role in some patients preventing the presence of LV diastolic dysfunction. Given that the appli-
reversion of PH after only 12 weeks on CPAP. cation of CPAP reduced the level of PASP, we speculate
that long-term CPAP therapy might avoid the development
It has been reported that OSA patients have higher levels of irreversible structural pulmonary vascular and right ven-
of circulating endothelin-1 and lower levels of nitric oxide tricular changes that could impair the prognosis of these
than healthy subjects. Also, CPAP therapy readily restores patients.
the normal levels of these vasoactive mediators,23,24 that
share an opposite regulatory pathway on both pulmonary Acknowledgements
vascular tone and vascular smooth-muscle cell proliferation.
Indeed, the increased production of prostanoids might try to This research was partly supported by a grant from the Fondo de
compensate the trend towards endothelial cell proliferation Investigacio´n Sanitaria (F.I.S.; exp. 01/0278) and Neumomadrid
and vasoconstrictor tone.25 The effects of inter-related (2000).
factors such as elimination of both nocturnal hypoxemia
and nocturnal sympathetic surges, improvement in LV dias- Conflict of interest: none declared.
tolic relaxation properties, and decreased LV afterload
may restore the balance between these endothelial vaso- References
active mediators with the application of CPAP. The degree
of reduction in PASP may depend on both the balance 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence
between the components of PH because of structural of sleep-disordered breathing among middle-aged adults. N Engl J Med
remodelling and the functional deregulation in vascular 1993;328:1230–1235.
endothelial tone and the duration of therapy. In a short
treatment time, only functional effects on endothelial 2. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular out-
tone might be apparent. comes in men with obstructive sleep apnoea–hypopnoea with or without
treatment with continuous positive airway pressure: an observational
In two prospective non-placebo controlled studies, study. Lancet 2005;365:1046–1053.
application of CPAP for 4 and 6 months, respectively, was
associated with significant reduction in the level of pul- 3. Marrone O, Bonsignore MR. Pulmonary haemodynamics in obstructive
monary artery pressure (mean pulmonary artery pressure sleep apnoea. Sleep Med Rev 2002;6:175–193.
was reduced from 16.8 + 1.2 to 13.9 + 0.6 in the total
study population in one work26 and from 25.6 + 4.0 to 4. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The
19.5 + 1.6 mmHg in patients with PH at baseline in the Epworth Sleepiness Scale. Chest 1993;103:30–36.
other,27 respectively). As occurred in our study, the greatest
reduction was observed in patients with day-time PH at base- 5. Choong CY, Abascal VM, Weyman J, Levine RA, Gentile F, Thomas JD,
line. Indeed, Sajkov et al.26 concluded that the effects of Weyman AE. Prevalence of valvular regurgitation by Doppler echocardio-
CPAP on pulmonary haemodynamics were not because of graphy in patients with structurally normal hearts by two-dimensional
changes in LV diastolic function. However, they only used echocardiography. Am Heart J 1989;117:636–642.
the E/A ratio as a parameter to assess the diastolic function,
6. Farre R, Hernandez L, Montserrat JM, Rotger M, Ballester E, Navajas D.
Sham continuous positive airway pressure for placebo-controlled studies
in sleep apnoea. Lancet 1999;353:1154.

7. Massie CA, McArdle N, Hart RW, Schmidt-Nowara WW, Lankford A,
Hudgel DW, Gordon N, Douglas NJ. Comparison between automatic
and fixed positive airway pressure therapy in the home. Am J Respir
Crit Care Med 2003;167:20–23.

Pulmonary hypertension in OSA 1113

8. American Thoracic Society. Standardization of spirometry, 1994 update. 19. Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, Mcevoy RD. Pulmonary Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
Am J Respir Crit Care Med 1995;152:1107–1136. hypertension and hypoxemia in obstructive sleep apnea syndrome.
Am J Respir Crit Care Med 1994;149:416–422.
9. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC.
Lung volumes and forced ventilatory flows. Report Working Party 20. Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial
Standardization of Lung Function Tests, European Community for Steel hypertension in patients with sleep apnoea syndrome. Thorax
and Coal. Official Statement of the European Respiratory Society. Eur 2000;55:934–939.
Respir J 1993;16(suppl.):5–40.
21. Moustapha A, Kaushik V, Diaz S, Kang SH, Barasch E. Echocardiographic
10. Ballester E, Solans M, Vila X, Hernandez L, Quinto L, Bolivar I, Bardagi S, evaluation of left-ventricular diastolic function in patients with chronic
Montserrat JM. Evaluation of a portable respiratory recording device for pulmonary hypertension. Cardiology 2001;95:96–100.
detecting apnoeas and hypopnoeas in subjects from a general population.
Eur Respir J 2000;16:123–127. 22. Fagan KA. Selected Contribution: Pulmonary hypertension in mice follow-
ing intermittent hypoxia. J Appl Physiol 2001;90:2502–2507.
11. Garcia-Rio F, Pino JM, Alonso A, Arias MA, Martinez I, Alvaro D, Villamor J.
White coat hypertension in patients with obstructive sleep apnea–hypopnea 23. Ip MS, Lam B, Chan LY, Zheng L, Tsang KW, Fung PC, Lam WK. Circulating
syndrome. Chest 2004;125:817–822. nitric oxide is suppressed in obstructive sleep apnea and is reversed by
nasal continuous positive airway pressure. Am J Respir Crit Care Med
12. Garcia-Rio F, Racionero MA, Pino JM, Martinez I, Ortuno F, Villasante C, 2000;162:2166–2171.
Villamor J. Sleep apnea and hypertension. Chest 2000;117:1417–1425.
24. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK.
13. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic Effects of obstructive sleep apnea on endothelin-1 and blood pressure.
pressure by Doppler ultrasound in patients with tricuspid regurgitation. J Hypertens 1999;17:61–66.
Circulation 1984;70:657–662.
25. Kimura H, Niijima M, Abe Y, Edo H, Sakabe H, Kojima A, Hasako K,
14. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension Masuyama S, Tatsumi K, Kuriyama T. Compensatory excretion of prostacy-
in chronic heart failure: the role of the endothelium in pathophysiology clin and thromboxane metabolites in obstructive sleep apnea syndrome.
and management. Circulation 2000;102:1718–1723. Intern Med 1998;37:127–133.

15. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity pat- 26. Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive
terns to left ventricular diastolic function: new insights from a combined airway pressure treatment improves pulmonary hemodynamics in
hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002;
1988;12:426–440. 165:152–158.

16. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and 27. Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S,
reference intervals for pulmonary artery systolic pressure among echo- Jordanoglou JB. Daytime pulmonary hypertension in patients with
cardiographically normal subjects. Circulation 2001;104:2797–2802. obstructive sleep apnea: the effect of continuous positive airway
pressure on pulmonary hemodynamics. Respiration 2001;68:566–572.
17. Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS. Pulmonary
artery hypertension and sleep-disordered breathing: ACCP evidence- 28. Guidry UC, Mendes LA, Evans JC, Levy D, O’Connor GT, Larson MG,
based clinical practice guidelines. Chest 2004;126:72S–77S. Gottlieb DJ, Benjamin EJ. Echocardiographic features of the right
heart in sleep-disordered breathing: the Framingham Heart Study. Am J
18. Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary Respir Crit Care Med 2001;164:933–938.
hypertension in patients with obstructive sleep apnea syndrome. Arch
Intern Med 1997;157:2483–2487.