Effects of Continuous Positive Airway Pressure on Early
Signs of Atherosclerosis in Obstructive Sleep Apnea
Luciano F. Drager1, Luiz A. Bortolotto1, Adelaide C. Figueiredo2, Eduardo M. Krieger1, and Geraldo Lorenzi-Filho2
1Hypertension Unit and2Sleep Laboratory, Pulmonary Division, Heart Institute (InCor), University of Sa ˜o Paulo Medical School,
Sa ˜o Paulo, Brazil
Rationale: Obstructive sleep apnea (OSA) is associated with adverse
cardiovascular outcomes, including myocardial infarction and
stroke. Atherosclerosis is a key mechanism for these cardiovascular
events. Recent cross-sectional studies showed the presence of early
signs of atherosclerosis in patients with OSA who were free of
Objectives: To determine the impact of treatment with continuous
positive airway pressure (CPAP) on atherosclerosis.
Methods: We randomly assigned 24 patients with severe OSA (age,
46 6 6 yr) who were free of comorbidities to receive no treatment
catecholamines were determined at baseline and after 4 months.
Measurements and Main Results: At baseline, all measurements were
media thickness (707 6 105 vs. 645 6 95 mm, P 5 0.04), pulse-wave
velocity (10.4 6 1.0 vs. 9.3 6 0.9 m/s, P , 0.001), C-reactive protein
(3.7 6 1.8 vs. 2.0 6 1.2 mg/L, P 5 0.001), and catecholamines (365 6
125 vs. 205 6 51 ng/ml, P , 0.001) after 4 months of CPAP. Carotid
diameter did not change significantly. Regarding the whole group,
changes in carotid intima-media thickness were correlated with
changes in catecholamines (r 5 0.41, P , 0.05). Changes in pulse-
0.58, P , 0.01) and catecholamines (r 5 0.54, P , 0.01).
atherosclerosis, supporting the concept that OSA is an independent
risk factor for atherosclerosis.
Clinical trial registered with www.clinicaltrials.gov (NCT 00400543).
Keywords: obstructive sleep apnea; intima-media thickness; arterial
stiffness; atherosclerosis; continuous positive airway pressure
Obstructive sleep apnea (OSA) is characterized by recurrent
episodes of partial or complete obstruction of the upper airway
during sleep, resulting in oxygen desaturation and arousals from
sleep (1). OSA is recognized as an important public health prob-
lem, affecting 9 and 24% of middle-aged females and males,
respectively (2). Compelling evidence now indicates that severe
OSA is associated with increased cardiovascular morbidity and
mortality, mainly due to acute myocardial infarction and stroke
(3, 4). One uncontrolled observational study showed that contin-
uous positive airway pressure (CPAP), the standard treatment for
OSA, was associated with decreased nonfatal and fatal cardio-
vascular events (4). However, the mechanisms linking OSA and
poor cardiovascular outcome are not completely understood.
ful to the cardiovascular system, including systemic inflammation,
sympathetic activation, production of reactive oxygen species, and
endothelial dysfunction (5). Together, all these factors could con-
tribute to atherosclerosis progression, a key mechanism impli-
cated in myocardial infarction and stroke (6). OSA could also
contribute to atherosclerosis indirectly, by causing systemic hy-
pertension, insulin resistance, and impaired lipid metabolism (5, 7,
8). Recently, Savransky and colleagues demonstrated that chronic
intermittent hypoxia, a hallmark of OSA, induces atherosclerosis
in mice (9). The studies in humans are difficult because the pa-
tients with OSA frequently have numerous risk factors for
atherosclerosis. However, the demonstration of early signs of
atherosclerosis in patients with OSA who were free of hyperten-
sion or other significant comorbidities (10) suggests an indepen-
dent association between OSA and atherosclerosis.
We performed a randomized study to evaluate the hypoth-
esis that the treatment of OSA with CPAP therapy significantly
improves validated markers of early signs of atherosclerosis
(11–13), namely carotid intima-media thickness (primary out-
come), arterial stiffness, and carotid diameter (secondary out-
comes). We also measured 24-hour blood pressure monitoring,
plasma C-reactive protein, and catecholamines. To test the
hypothesis that OSA contributes to atherosclerosis directly,
we only included patients with severe OSA who were free of
comorbidities. Some of the results of these studies have been
previously reported in the form of an abstract (14).
The patients were recruited from the Sleep Laboratory, Heart Institute
(InCor), University of Sa ˜o Paulo Medical School (Brazil). Over a 2-year
period (January 2004 to January 2006), all male adults with a sleep
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Obstructive sleep apnea (OSA) is associated with in-
creased risk of myocardial infarction and stroke. OSA
has been associated with atherosclerosis, a key mechanism
for these cardiovascular events.
What This Study Adds to the Field
This randomized study showed that effective treatment of
OSA with continuous positive airway pressure for 4
months significantly improves early signs of atherosclerosis
in patients with severe OSA. These results suggest that
OSA is an independent risk factor for atherosclerosis.
(Received in original form March 28, 2007; accepted in final form June 7, 2007)
Supported by the Fundac xa ˜o de Amparo a ` Pesquisa do Estado de Sa ˜o Paulo
(FAPESP), Conselho Nacional de Desenvolvimento Cientı ´fico e Tecnolo ´gico
(CNPq), and the E.J. Zerbini Foundation. All the CPAP machines were provided
by Respironics, Inc.
Correspondence and requests for reprints should be addressed to Luciano F.
Drager, M.D., Hypertension Unit–Heart Institute (InCor), University of Sa ˜o Paulo
Medical School, Av Dr Ene ´as Carvalho de Aguiar, 44, CEP 05403-904 Sa ˜o Paulo,
Brazil. E-mail: email@example.com
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200703-500OC on June 7, 2007
Internet address: www.atsjournals.org
Vol 176. pp 706–712, 2007
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