Clinical and Experimental Pharmacology and Physiology (2012) 39, 9951003
12024
INVITED REVIEW
Obstructive sleep apnoea and cardiovascular complications:
perception versus knowledge
Joi J Thomas and Jun Ren
Division of Kinesiology and Health & Biomedical Science, University of Wyoming College of Health Sciences,
Laramie, WY, USA
SUMMARY
1. Epidemiological evidence has conrmed that obstructive
sleep apnoea (OSA) signicantly promotes cardiovascular risk,
independent of age, sex, race and other common risk factors
for cardiovascular diseases, such as smoking, drinking, obes-
ity, diabetes mellitus, dyslipidaemia and hypertension.
2. Patients with severe OSA exhibit a higher prevalence of
coronary artery disease, heart failure and stroke. Despite the
tight correlation between sleep apnoea and these comorbidi-
ties, the mechanisms behind increased cardiovascular risk in
OSA remain elusive. Several theories have been postulated,
including sympathetic activation, endothelial dysfunction,
oxidative stress and inammation.
3. The association between OSA and cardiovascular diseases
may be rather complicated and compounded by the presence of
components of metabolic syndrome, such as obesity, hyperten-
sion, diabetes mellitus and dyslipidaemia. The present minire-
view updates current knowledge with regard to the
cardiovascular sequelae of OSA and the mechanisms involved.
Key words: cardiovascular disease, obstructive sleep apnoea,
risk factor.
INTRODUCTION
Although the overall morbidity and mortality of cardiovascular
disease have declined signicantly in recent years, cardiovascular
disease remains the number one cause of death and a major health
threat. From 1997 to 2007 there was a 27.8% decline in the
cardiovascular mortality rate in the US, although cardiovascular
disease continues to impose a signicant nancial burden on
health care.1 Identifying risk factors and instituting early treatment
for the risk factors is of paramount importance. One of the emerg-
ing risk factors for cardiovascular disease is obstructive sleep
apnoea (OSA), a rather serious, potentially life-threatening
Correspondence: Dr J Ren, University of Wyoming College of Health
Sciences, Laramie, WY 82071, USA. Email: jren@uwyo.edu
Received 9 March 2012; revision 13 October 2012; accepted 15
October 2012.
2012 The Authors
Clinical and Experimental Pharmacology and Physiology
2012 Wiley Publishing Asia Pty Ltd
doi: 10.1111/1440-1681.
condition. Activation of the sympathetic nervous system during
respiratory events in sleep may potentiate vasoconstriction and
trigger increases in blood pressure and heart rate.2,3 Obstructive
sleep apnoea is also associated with several cardiorespiratory
problems (e.g. loud snoring, loud gasps and daytime breathless-
ness). Both clinical and epidemiological evidence demonstrates a
tight association between OSA and increased risk of cardiovascu-
lar disease, including endothelial dysfunction, hypertension, ar-
rhythmias and heart failure.46 Nonetheless, the presence of
confounding factors in patients with OSA, such as obesity, makes
proper delineation of sleep apnoea-induced cardiovascular risk
somewhat difcult.
Obstructive sleep apnoea involves episodes of partial and/or
total collapse of the upper airway alternating with normal breath-
ing. It is characterized by repeated cessation of breathing in
sleep, likely due to complete or partial pharyngeal obstruction.
This may lead to cycles of desaturation and rapid re-oxygenation,
referred to as intermittent hypoxia. Clinically, OSA is recognized
and diagnosed by a combination of symptoms and laboratory
results, including repetitive apnoeas and hypopnoeas accompa-
nied by hypoxia, sleep arousals and haemodynamic changes.7,8
These hypopnoeic/apnoeic events usually lead to chronic inter-
mittent hypoxia (CIH), increased sympathetic response, sleep
fragmentation and increased afterload. Obstructive sleep apnoea
can be classied as mild, moderate or severe. It has been reported
that approximately one in ve adults suffer from mild OSA,
whereas one in 15 adults suffer from moderate OSA.9 Mild OSA
refers to an apnoeahypopnoea index (AHI) of 515 (events/h),
moderate OSA denotes an AHI of 1530, whereas severe OSA
suggests a AHI > 30.10 Across the spectrum of sleep-disordered
breathing, many researchers also consider snoring as a part of the
upper airway resistance syndrome.11 Usually, snoring may
constitute the main preliminary symptom of OSA. The current
most effective non-invasive management technique for OSA is
application of continuous positive airway pressure (CPAP) to
assist in the maintenance of proper airway patency.12
CARDIOVASCULAR COMPLICATIONS IN OSA
Endothelial function
Endothelial dysfunction usually precedes visible clinical mani-
festations of cardiovascular disease, particularly hypertension.
996 JJ Thomas and J Ren

Abbreviations:

AHI Apnoea hypopnoea index H/R Hypoxiare-oxygenation

CIH Chronic intermittent hypoxia hs-CRP High-sensitivity C-reactive protein
CPAP Continuous positive airway pressure NAFLD Non-alcoholic fatty liver disease
FFA Free fatty acids NEFA Non-esteried fatty acids

Endothelial dysfunction triggers the onset and progression of Metabolic syndrome OSA
atherosclerotic injury in the vasculature. Hypoxia and hypercap-
nia, hallmarks of OSA, may serve as potent stimulators of vasoac- Intermittent hypoxia

tive substances to initiate a cascade of events resulting in

endothelial defect. Elevated adhesion molecules are implicated in
the pathogenesis of atherosclerosis and other cardiovascular dis- Altered hepatic ROS Sympathetic LV dysfunction
metabolism production activity
orders. Adherence of monocytes to the vascular endothelium is
mediated by either resident or circulating leucocytes. Monocyte NAFLD
Endothelial
Hypertension
dysfunction
adherence often results in the release of several inammatory
mediators, including tumour necrosis factor (TNF)-a and interleu- Liver cirrhosis Platelet
Arrhythmias

kin (IL)-1.4,5,9 Dyugovskaya et al.13 reported signicantly activation

increased adhesion molecules, including CD15 and CD11c, in Liver failure Adhesion
monocytes and increased adherence of monocytes to human endo- molecules

thelial cells in patients with OSA. In addition, they reported reac- Atherosclerosis
tive oxygen species (ROS) accumulation in monocyte and
granulocyte subpopulations in patients with OSA.13 Furthermore, Fig. 1 Schematic diagram showing the proposed mechanisms involved
nasal CPAP treatment was associated with downregulation of in obstructive sleep apnoea (OSA)-induced organ complications. NAFLD,
non-alcoholic fatty liver disease; LV, left ventricular; ROS, reactive
CD15 and CD11c monocyte expression and decreased ROS
oxygen species.
production in CD11c+ monocytes in patients with OSA.13 Sleep
apnoea was also found to be associated with the release of chemo-
kines, such as IL-8 or monocyte chemoattractant protein-1, and
Hypoxaemia/reoxygenation
adhesion molecules, including intercellular adhesion molecule 1
(ICAM-1) and selectins.14 Heat shock protein (HSP) 70 and
TNF-a levels were investigated in patients with OSA.15 Basal lev- Intermittent hypoxaemia
els of HSP70 in monocytes were signicantly higher in patients
with OSA and were positively correlated with both AHI and time
below 90% arterial oxygen saturation. In contrast, heat stress-
induced HSP70 was signicantly decreased in patients with OSA hs-CRP IL-6 IL-18 ADMA TNF-
and was inversely correlated with AHI and time below 90%.
Furthermore, TNF-a levels were inversely correlated with the abil-
ity to synthesize de novo heat stress-induced HSP70.15 Decreased
levels of nitrite and nitrate have also been reported in hypertensive
and normotensive subjects with OSA16 and lower ow-mediated ROS production/ ROS inactivation
dilation was noted in patients with OSA who were otherwise free
of any cardiovascular diseases.17,18 Continuous positive airway
Bioactive NO
pressure treatment signicantly improved ow-mediated dilation,
even after only 4 weeks, in a small cohort of men (n = 28) with
Endothelial dysfunction
OSA.17 Discontinuation of CPAP for 1 week compromised ow-
mediated dilation,17 suggesting a pivotal role of endothelial func-
tion in pathophysiological changes in patients with OSA. Proliferation of vascular
Vascular
Endothelial dysfunction is greater as the severity of OSA inflammation Thrombosis Vasospasm SMC
increases. This may be due, in part, to the fact that levels of essen-
tial adhesion molecules, such as vascular cell adhesion molecule-1 Fig. 2 Schematic diagram showing proposed mechanism involved in
(VCAM-1) and ICAM-1, are correlated with the severity of obstructive sleep apnoea (OSA)-induced endothelial dysfunction. ADMA,
OSA.14,19 Similarly, an association has been demonstrated between asymmetric dimethylarginine; hs-CRP, high-sensitivity C-reactive protein;
IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; SMC,
OSA and levels of soluble IL-6 receptors, IL-6 concentrations and
smooth muscle cells; TNF-a, tumour necrosis factor-a.
TNF-a.20,21 In rodent models, CIH triggers an increase in TNF-a
levels.22 The mechanisms for endothelial dysfunction in patients
with OSA may be associated with inammation and oxidative dysfunction in patients with OSA may easily facilitate cardiovascu-
stress. Figure 1 shows the proposed mechanisms involved in lar anomalies, including atherosclerosis, myocardial ischaemia,
OSA-induced organ complications. It is of note that endothelial stroke, arrhythmias and hypertension. A summary of the proposed

2012 The Authors

Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
 Sleep apnoea and cardiovascular diseases
mechanisms and the resulting complications from OSA-induced
endothelial dysfunction is given in Fig. 2.
Hypertension
Obstructive sleep apnoea is associated with hypertension.10,2325
Even moderate OSA may increase the propensity for hyperten-
sion.26 Although OSA and hypertension often occur jointly in the
presence of common cardiovascular comorbidities, such as
obesity and metabolic syndrome, an independent association
between the two has been consolidated. In the Wisconsin Sleep
Cohort Study, a tight positive correlation has been found between
the sleep-disordered breathing AHI and increases in blood pres-
sure independent of other known comorbidities.26 The authors
reported that subjects with an AHI > 15 events/h exhibit a
3.2-fold increase in the odds of developing hypertension com-
pared with individuals without OSA. Other large cohort studies
have also documented a trend for a correlation between OSA and
hypertension. For example, the Sleep Heart Health Study exam-
ined 2470 normotensive individuals and found that the odds ratio
for hypertension according to AHI values was not signicant
after adjusting for body mass index (BMI).27 In contrast, OCon-
nor et al.27 reported a possible modest association between
severe OSA and hypertension independent of BMI. Their ndings
indicate that subjects with an AHI  30 events/h exhibit a
1.5-fold increased risk of developing hypertension. The apparent
discrepancies in the study outcomes for the association between
OSA and hypertension may be related to differences in study
design, sample population and baseline AHI.28 Nevertheless, a
trend for a positive association has been noted in these studies.
The prevalence of OSA is higher in hypertensive individuals
compared with the estimated prevalence of the general population,
who often go undiagnosed.23 In a unique study by Drager et al.29,
subjects with established hypertension were screened for OSA.
Overall, 56% of patients were diagnosed OSA based on sleep ques-
tionnaires and polysomnographic tests, representing a much greater
incidence compared with the general population (29%). More-
over, levels of pro-inammatory circulating markers, including
high-sensitivity C-reactive protein (hs-CRP), IL-6, IL-18, TNF-a
and asymmetric dimethylarginine, were higher in hypertensive
individuals with than without OSA.30,31 Tumour necrosis factor-a
is an inammatory cytokine independently associated with OSA or
hypertension.3234 Li et al. reported increased levels of TNF-a and
neuropeptide Y in hypertensive subjects with OSA compared with
hypertensive subjects without OSA, normotensive subjects with
OSA, and controls.35 These markers of inammation in patients
with OSA and hypertension give us a better understanding of the
mechanisms underlying the health risks associated with OSA.
In addition to proinammatory markers, an overt increase in
sympathetic activity has been noted in hypertensive subjects.2
This rise in sympathetic activity may be observed in the presence
and absence of OSA.36,37 ODriscoll et al.38 investigated sympa-
thetic activity in adolescents diagnosed with OSA and found a
tight association between noradrenaline levels and AHI, as well
as a signicant association between adrenaline and AHI, support-
ing a likely role for sympathetic activation in the onset and
development of hypertension in patients with OSA. The increase
in sympathetic activity, which carries over into the waking hours,
suggests a causative relationship between OSA and hypertension.
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
997
Treatment with CPAP has been reported to lower blood pres-
sure in hypertensive OSA subjects. In a large multihospital cohort
in Spain, newly diagnosed hypertensive patients with OSA exhib-
ited decreases of 2.1 and 1.3 mmHg in systolic and diastolic
blood pressure, respectively, following 3 months CPAP treat-
ment.39 In a similar study, 96 patients with resistant hypertension
experienced a signicant reduction in blood pressure following
3 months CPAP treatment.40 Other studies also report similar
results in terms of blood pressure reductions following CPAP
treatment, despite unchanged TNF-a and IL-6 levels.31 Further
studies are warranted to identify the possible mechanisms and
particular inammatory markers involved in the blood pressure-
lowering effect of CPAP treatment.
Cardiac dysfunction and arrhythmias
It is well known that sympathetic overactivation may promote
ventricular dysfunction and arrhythmia. Subjects with severe
OSA often have a much higher prevalence of atrial brillation,
non-sustained ventricular tachycardia and complex ectopic excita-
tion compared with individuals without OSA.41 After correction
for age, sex, BMI and prevalent coronary disease, subjects with
severe OSA have an odds ratio of 4.02 for atrial brillation
compared with controls. Obstructive sleep apnoea may serve as a
useful predictor for atrial brillation independent of obesity, as
found in a large cohort (3542 patients).42 Not surprisingly, the
degree of nocturnal oxygen desaturation as a result of OSA also
independently predicts the incidence of atrial brillation.43 In one
study, the myocardial performance index was evaluated in
patients with OSA.43 In patients with severe OSA, the myocardial
performance index was signicantly higher compared with that in
patients with mild OSA. Patients with both moderate and severe
OSA exhibit left ventricular (LV) diastolic dysfunction, whereas
patients with mild OSA often display normal LV function.44 In
addition, patients with severe OSA often develop moderate LV
hypertrophy (LVH), as well as increases in the thickness of the
interventricular septum (IVS) and LV posterior wall, LV mass
(LVM) and LVM index compared with patients with moderate
OSA.44 Severe OSA is also associated with LVH, left atrial
enlargement, right atrial enlargement and right ventricular hyper-
trophy.44 A signicant reduction in LVH was reported in patients
with OSA following 6 months CPAP therapy in the absence of
changes in the enlarged atria.45 In obese patients with severe
OSA, signicantly lower LV ejection fraction and stroke volume
were reported compared with values in overweight, age-matched
controls.45 After 6 months CPAP treatment, there was a signi-
cant reduction in the thickness of the IVS and a signicant
increase in stroke volume.
The cardiac arrhythmias associated with OSA may be the
consequence of a reex response to apnoea and hypoxia, and are
much more common during sleep. Increased sympathetic activity
can initiate myocardial irritability, leading to the onset of
arrhythmia. These arrhythmias may occur in the absence of any
anatomical defects in the cardiac conduction system.9 It has been
postulated that the severity of arrhythmias may be directly
related to low nocturnal oxygen saturation and the duration of
sleep with oxygen saturations < 90%.46 These indices may be
used to predict arrhythmias in patients with OSA. In addition,
OSA has been used as a predictive marker for the incidence of
998 JJ Thomas and J Ren
postoperative arrhythmias in subjects undergoing coronary bypass
surgery.47 Although the precise mechanisms underlying the develop-
ment of cardiac arrhythmias in the presence of OSA are unknown,
increased sympathetic tone has been commonly considered as a
likely culprit. Figure 1 summarizes several commonly accepted
mechanisms underlying OSA-triggered cardiac arrhythmias. Further
studies are needed to clearly delineate the risk of arrhythmia in
patients with OSA and to develop optimal treatment regimens.
Myocardial ischaemia
Recent evidence indicates an increased risk of coronary artery
disease in patients with OSA, independent of other cardiovas-
cular comorbidities.6,48,49 In the Sleep Heart Health Study,
sleep-disordered breathing was associated with an all-cause
mortality and, specically, mortality associated with coronary
artery diseases.50 In particular, coronary artery calcication
was present in 67% of patients diagnosed with OSA,
compared with only 31% of patients without OSA.48 More-
over, the degree of coronary artery calcication was signi-
cantly greater in patients with than without OSA. This
association remained unchanged after adjusting for age and
sex, and was reported in the absence of pre-existing coronary
diseases. In rat models of chronic intermittent hypoxia, 1 week
of hypoxic treatment is capable of compromising the function
of the hypothalamicpituitaryadrenal (HPA) axis.51 This alter-
ation may result in an increased sensitization to the HPA axis
under acute stress and an increased release of adrenocorticotro-
pic hormone. Increased sensitization of the HPA axis may be
a central mechanism explaining the overall increase in cardio-
vascular disease risk.
Obstructive sleep apnoea has been shown to retard the recov-
ery of ventricular function after acute myocardial infarction.52
This phenomenon coincides with a much more frequent inci-
dence of myocardial ischaemia, as well as haemodynamic and
neurohormonal abnormalities at night, possibly due to the higher
incidence of cardiac arrhythmias at night in patients with OSA.5
Inammation has been shown to be a potent mediator of
myocardial ischaemia. Of the cellular mechanisms reported for
myocardial ischaemic injury, hypoxia inducible factor (HIF)-1a
and the endothelin system play signicant roles in inammation-
associated myocardial injury in patients with OSA.53 Similar to
its benecial roles in hypertension and arrhythmia, CPAP treat-
ment for > 4 months reduced signs of early atherosclerosis,
including carotid intimamedia thickness, arterial thickness (eval-
uated by pulse wave velocity), hs-CRP and catecholamines,
compared with controls.54 Continuous positive airway pressure
treatment for  4 h/night markedly reduced blood pressure,
total cholesterol, TNF-a and insulin resistance in patients with
severe OSA and metabolic syndrome.55 In contrast, an indepen-
dent trial failed to note any signicant change in hs-CRP, IL-6,
adiponectin and interferon-c after 4 weeks CPAP treatment in
patients with OSA.56 More large-scale randomized trials are
needed.
Oxidative stress also serves as a potential mechanism underly-
ing coronary artery disease and myocardial ischaemia. The
hypoxiareperfusion cycles associated with OSA lead to an
increase in the production of ROS. Changes in vascular reactiv-
ity also contribute to enhanced ROS production during OSA.
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
Mice exposed to 14 days of CIH experienced enhanced vaso-
constriction.57 In mice with an intact sympathetic nervous sys-
tem, noradrenaline produced changes in vascular resistance,
whereas mice with a defective sympathetic nervous system (e.g.
under sustained hypoxia) only responded to high doses of nor-
adrenaline. Interestingly, responsiveness to acetylcholine
remained unchanged.57 This change in the vasoconstriction
vasodilatation balance may play a role in OSA-induced myocar-
dial ischaemic injury.
Heart failure
Heart failure is usually the ultimate cardiac sequel of OSA.
Given that independent associations have been established for
OSA and cardiovascular diseases, it is not surprising that an inde-
pendent association exists between OSA and heart failure.5861 In
the Sleep Heart Health Study cohort, men with severe OSA were
58% more likely to develop heart failure than those without
OSA.59 In a cohort of post-myocardial infarction patients,
patients with severe OSA had a signicantly higher incidence of
major adverse events (15.9%) compared with patients with mild
and moderate OSA (3.3%).62 Major adverse events included
re-infarctions, unplanned target vessel revascularizations, hospital-
ization for heart failure and death. At the 18-month follow up,
severe OSA was associated with a lower event-free survival rate
compared with patients with mild and moderate OSA.62
The prevalence of OSA in patients with heart failure ranges
from 15% to 50%.61 In OSA, upper airway stability is altered and
may be further compromised in patients with heart failure.
Increased lling pressure in the supine position during sleep may
contribute to increased airway collapsibility.60 Obstructive sleep
apnoea occurs more frequently in men with heart failure than in
women.61 In addition, patients with concurrent systolic and
diastolic heart failure had a high prevalence of OSA, although a
large majority of patients may go unrecognized and underreport-
ed.60 The mortality rate has been evaluated in heart failure
patients with either severe or moderate OSA.63 In that study,
patients with severe OSA were found to have a signicantly
higher mortality rate. Several mechanisms have been postulated to
explain the association between heart failure and OSA, including
increased sympathetic tone, oxidative stress and inammation.9,61
Treatment with CPAP may improve LV ejection fraction,64
although CPAP failed to improve LV ejection fraction following a
pilot 3 month treatment in newly diagnosed OSA patients with
stable systolic dysfunction.65 The benets of CPAP are inconclu-
sive in patients with heart failure and further research is needed to
better elucidate the interplay between OSA and heart failure.
CELLULAR AND MOLECULAR MECHANISMS IN
OSA
Increased sympathetic activity
Patients with OSA are prone to episodes of intermittent hypoxia
throughout sleep, triggering surges in blood pressure and sympa-
thetic activation via carotid chemoreceptors. These surges and
sympathetic activation (peripheral, adrenal and renal) may result
in diurnal increases in blood pressure.66 Long-term facilitation of
sympathetic tone via carotid chemoreceptors has been reported in
 Sleep apnoea and cardiovascular diseases
animals models of CIH.67 In addition, the baroreceptor reex
may reset to allow for increased blood pressure. Patients with
OSA do not exhibit a nocturnal dip in blood pressure. Rather,
sympathetic activity will vary solely as a function of the cyclic
apnoeic episodes.68
Increased noradrenaline levels are common manifestation of
sympathetic overactivation and are found in hypertensive subjects
with OSA. It has been reported that normotensive subjects with
OSA may also exhibit increased noradrenaline levels.69 An
increase in noradrenaline levels was found in subjects with OSA
during waking hours.70 This increased sympathetic trafc has
been reported in the presence of increased muscle nerve sympa-
thetic activity compared with normotensive controls.3 This
increased sympathetic activity has been postulated to play a role
in the link between OSA and cardiac arrhythmias and hyperten-
sion. In addition to this increased sympathetic activity, oxidative
stress has also been proposed to play a pivotal role in OSA
patients with hypertension.36
Oxidative Stress
Oxidative stress occurs as a result of an imbalance between the
production of ROS and anti-oxidant capacity. This oxidative
stress increases as a consequence of ischaemiareperfusion cycles
like those seen in ischemic disease.5,13 Obstructive sleep apnoea
is characterized by intermittent hypoxaemiare-oxygenation
(H/R) cycles that closely resemble these ischaemiareperfusion
cycles.13 Several cells sources have been proposed as the origin
of the increased ROS, including mitochondria, leucocytes and/or
endothelial cells, or the ROS may be the result of H/R cycling.71
There are several redox-activated transcription factors pertinent to
OSA, including HIF-1a, nuclear factor (NF-jB, activator protein-
1, early growth response-1 and IL-6. Using an in vitro model of
intermittent H/R, Ryan et al.72 used HeLa cells transfected with
reporter constructs and DNA binding assays to evaluate the
master transcriptional regulators of the inammatory and adaptive
pathways (NF-jB and HIF-1, respectively). HeLa cells exposed
to intermittent H/R exhibited selective activation of the proin-
ammatory transcription factor NF-jB, whereas the adaptive
regulator HIF-1 was not activated. These investigators went on to
examine 19 OSA patients and 17 matched normal subjects.
Circulating levels of the proinammatory cytokine TNF-a were
found to be much higher in patients with OSA, but were normal-
ized with CPAP therapy. Furthermore, circulating neutrophil lev-
els were much higher in patients with OSA.72 These ndings
received support from another independent study in which acti-
vated NF-jB was observed in mice exposed to CIH and in
patients with OSA.73 Not surprisingly, the NF-jB activity was
signicantly decreased when obstructive apnoeas and their resul-
tant CIH were eliminated by CPAP therapy. Further scrutiny
revealed the involvement of increased inducible nitric oxide
synthase levels in CIH-induced increases in NF-jB activity.73
Therefore, NF-jB may serve as an essential molecular messenger
linking OSA and cardiovascular pathologies in patients with
OSA. Nuclear factor-jB is known to upregulate a cascade of
adhesion molecules involved in leucocyte recruitment and migra-
tion to the inammatory site, including ICAM-1, E-selectin and
VCAM-1.74 This is in line with the pronounced endothelial
dysfunction, platelet activation and adhesion molecule accumula-
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
999
tion, as well as atherosclerotic lesions, in OSA.74 Consequently,
oxidative stress may be exacerbated during OSA, leading to
inammation and endothelial dysfunction.
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of con-
ditions characterized histologically by hepatic steatosis in individ-
uals without signicant alcohol consumption who are negative
for markers of viral, congenital and autoimmune disease. The
spectrum ranges from fat accumulation in hepatocytes without a
concomitant inammation or brosis (classied as simple hepatic
steatosis) to hepatic steatosis with a necroinammatory compo-
nent (steatohepatitis) with or without brosis or cirrhosis.75 Such
hepatic lipid accumulation can result from an imbalance between
lipid availability and lipid disposal, leading ultimately to lipoper-
oxidative stress and hepatic injury.76 Non-alcoholic fatty liver
disease was rst described 30 years ago and represents the lead-
ing cause of liver disease in developed countries, with a preva-
lence of 2035% in general populations.77 It was originally
postulated that NAFLD develops as a result of insulin resistance,
although recent evidence favours a bidirectional mechanism
between NAFLD and insulin resistance.78
Mounting evidence has been accumulated to indicate the role
of OSA as a risk factor for hepatic injury.7981 Obstructive sleep
apnoea has been associated with NAFLD. Animal research using
CIH reported increased hepatic lipid biosynthesis in genetically
obese ob/ob mice.82 Savransky et al.83found overt lipid peroxida-
tion, inammation and brosis in livers from mice on a high-fat/
high-cholesterol diet along with 6 months CIH. Oxidative stress
is believed to play a role in OSA-induced NAFLD because hepa-
tic protein expression and phosphorylation of the superoxide
generating enzyme p47phox were found to be signicantly ele-
vated after 4 weeks exposure to CIH.84
Because it is difcult to examine the pure correlation between
OSA and NAFLD independent of obesity and other confounding
factors in human subjects, Norman et al.85 evaluated the associa-
tions among OSA, serum aminotransferase levels, metabolic syn-
drome and markers of hypoxia and identied a tight association
between hypoxia and serum aminotransferase levels. Oxyhaemo-
globin desaturation may be associated with markers of NAFLD
instead of metabolic syndrome. Mishra et al.86 further evaluated
patients undergoing bariatric surgery, with their data suggesting
that patients with OSA and steatohepatitis have a signicantly
higher alanine aminotransferase : aspartate aminotransferase ratio
and lower desaturation and nocturnal oxygen saturation. The
lowest desaturation was independently associated with histologi-
cal steatohepatitis in these individuals with OSA. In another
study of bariatric surgery patients, NAFLD lesions, NAFLD
activity score and brosis were signicantly more severe in
patients with the highest oxygen desaturation index.87 This asso-
ciation remained after adjustment for age, obesity and insulin
resistance. In patients already diagnosed with NAFLD, 46% were
diagnosed with OSA, including lean subjects (BMI < 25 kg/m2).88
Treatment with CPAP has been shown to have equivocal effects
on hepatic enzymes and to provide benecial effects against
oxidative stress.89 Shpirer et al.90 investigated the effects of
23 years CPAP treatment in patients with deteriorating liver
function. Patients with moderatesevere OSA exhibited a lower
1000 JJ Thomas and J Ren

Table 1 Proposed mechanisms underlying the development of non-alcoholic fatty liver disease in patients with obstructive sleep apnoea

Risk factor Mechanism References

Hepatic insulin resistance
Altered hepatic metabolism
Oxidative stress
81
Increased FFA from adipocytes in circulating blood is taken
up by the liver, inhibiting hepatic glucose production and
leading to increased glucose production
84,97100
Increased NEFA from peripheral fat in adipose tissue
Upregulation of SREBP-1c and SCD-1 increases monounsaturated
fats and the biosynthesis of cholesterol esters and triglycerides
72,100
Altered cell membrane properties modify membrane receptor and
enzyme activity, antigen expression, membrane permeability
and intercellular interactions

FFA, free fatty acids; NEFA, non-esteried fatty acid; SREBP, sterol regulatory element-binding proteins; SCD-1, stearoyl coenxyme A desaturase 1.

liver attenuation index compared with patients with mild OSA.
Patients who were more compliant with CPAP treatment had sig-
nicantly improved mean liver attenuation indices. It is therefore
apparent that a link between OSA and NAFLD does exist, but
the mechanisms are not entirely clear. Of all the mechanisms pro-
posed for NAFLD, insulin resistance, altered hepatic metabolism
and oxidative stress seem to play a role in the interaction
between OSA and NAFLD. Table 1 provides a brief overview of
the proposed mechanisms underlying the development of NAFLD
in patients with OSA.
Hepatic insulin resistance
Insulin resistance is instrumental in the onset and development of
NAFLD.80 The term insulin resistance refers to a reduced insu-
lin-mediated glucose disposal response in tissues such as the
liver, muscle and adipose tissues. Insulin resistance may lead to
an increased release of free fatty acids (FFA) from adipocytes,
prompting elevated FFA levels in the circulation that can be
taken up by the liver. With increased hepatic fat accumulation,
the ability of insulin to inhibit hepatic glucose production
becomes impaired.91 Hepatic insulin resistance will lead to a rise
in plasma glucose levels and a concomitant stimulation of insulin
secretion, ultimately serving as an initiating factor for NAFLD.
Barcelo et al.92 identied a correlation between increased FFA
levels and AHI, suggesting a role of sleep fragmentation in the
release of FFA into the circulation.
In OSA, elevated circulating levels of adrenaline, noradrenaline
and angiotensin II may suppress the inhibitory effect of insulin
on glucose.93 This exacerbates glucose intolerance and insulin
resistance. Lin et al.94 examined components of metabolic
syndrome in non-obese patients diagnosed with OSA. Their data
suggest a role for the AHI as an independent risk factor and
predictor of insulin resistance. Nonetheless, one major argument
against a role of OSA in triggering insulin resistance is that
CPAP treatment seems to be somewhat ineffective against insulin
resistance.95
Altered hepatic metabolism
Studies using stable (non-radioactive) isotopes have revealed
metabolic pathways pivotal for fatty accumulation in the liver.96
There are four major pathways identied that contribute to the
fatty acid pool in the liver. First and foremost, peripheral fat
stored in adipose tissues may be delivered to the liver via the
plasma non-esteried fatty acid (NEFA) pool. The second path-
way belongs to fatty acids newly made within the liver through
de novo lipogenesis. Both the third and fourth pathways involve
dietary fatty acids entering the liver through spillover into the
plasma NEFA pool (third pathway) or the intestinally derived
chylomicron remnants (fourth pathway). It has been reported that
the majority of NEFA in the liver originate from the rst meta-
bolic pathway.96 Accumulation of NEFA from adipose tissue
indicates a failure of suppression of adipose fatty acid ux in the
fed and fasting state, a hallmark of NAFLD.96 This altered hepa-
tic metabolism may be further exacerbated by OSA. For example,
using animal models has revealed an upregulation of sterol regu-
latory element binding protein 1c (SREBP-1c) and stearoyl
coenxyme A desaturase 1 (SCD-1) associated with OSA83,97;
SREBP-1c is a hepatic transcription factor for lipid biosynthesis,
whereas SCD-1 is an SREBP-1c-regulated enzyme that converts
saturated fatty acids into monounsaturated fatty acids. The abun-
dance of monounsaturated fatty acids promotes the biosynthesis
of cholesterol esters and triglycerides. In humans, increased levels
of cholesterol, low-density lipoprotein and triglycerides have all
been reported in patients with OSA.98
Oxidative stress
Oxidative stress is a commonly accepted mechanism in OSA for
the development of NAFLD and cardiovascular diseases.66,71,99
In NAFLD, oxidative stress may directly modify the properties
of cell membranes to impact membrane receptor integrity and
enzyme activity, antigen expression, membrane permeability and
intercellular interactions.80 This will cause liver cell degeneration
and necrosis. Liver stellate cells may be activated, leading to
altered morphology, synthesis of extracellular matrix components,
collagen deposition and liver brosis. Another important tran-
scriptional factor turned on during OSA is NF-jB, which is
known to promote inammatory responses in the liver. As a
result of NF-jB activation, TNF-a, FFA and oxidative stress may
work in concert to facilitate overt apoptosis of hepatocytes, lead-
ing to inammation, brosis, degeneration and necrosis of
hepatocytes, all of which are characteristics of steatohepatitis and
the progression from hepatic steatosis to steatohepatitis.79,87 The
oxidative stress pathway, initiated by ROS-induced lipid peroxi-
dation, is expected to represent a particularly important mecha-
nism for the interaction between OSA and NAFLD.

2012 The Authors

Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
 Sleep apnoea and cardiovascular diseases
CONCLUSIONS AND FUTURE DIRECTIONS
Obstructive sleep apnoea represents a serious condition with
grave ramications. It has been associated with a myriad of car-
diovascular complications, including endothelial dysfunction,
hypertension, cardiac dysfunction, arrhythmias and heart failure.
In addition, OSA may contribute to the metabolic dysfunction
seen in metabolic syndrome and NAFLD. Although many compli-
cations have been identied regarding OSA, there are still many
unanswered questions, including the exact mechanisms by which
OSA can give rise to these cardiovascular and metabolic issues.
Although associations between OSA and cardiovascular disease
are better established, studies investigating OSA and NAFLD are
less prolic.100 Despite the confounding factors, obesity in particu-
lar, making independent associations difcult, more human studies
are needed to elucidate these associations. In addition, further
investigations into the effects of CPAP are needed. Equivocal
results regarding the effectiveness of CPAP as a therapeutic option
for metabolic dysregulation call for more well-controlled studies.
Although CPAP treatment has been shown to ameliorate the
cardiovascular impairments of OSA, the exact mechanisms under-
lying this improvement need to be determined. As investigations
continue, it is widely acknowledged that early identication of
OSA is important to reduce its cardiovascular and metabolic
ramications.
REFERENCES
1. Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and
stroke statistics: 2011 update. Circulation 2011; 123: e18209.
2. Narkiewicz K, van de Borne PJH, Cooley RL, Dyken ME, Somers
VK. Sympathetic activity in obese subjects with and without
obstructive sleep apnea. Circulation 1998; 98: 7726.
3. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic
neural mechanisms in obstructive sleep apnea. J. Clin. Invest.
1995; 96: 1897904.
4. Butt M, Dwivedi G, Khair O, Lip GYH. Obstructive sleep apnea
and cardiovascular disease. Int. J. Cardiol. 2010; 139: 716.
5. Fava C, Montagnana M, Favaloro EJ, Guidi GC, Lippi
G. Obstructive sleep apnea syndrome and cardiovascular diseases.
Semin. Thromb. Hemost. 2011; 37: 28097.
6. Shahar E, Whitney CW, Redline S et al. Sleep-disordered breath-
ing and cardiovascular disease: Cross-sectional results of the sleep
heart health study. Am. J. Respir. Crit. Care Med. 2001; 163:
1925.
7. Hudgel DW. Mechanisms of obstructive sleep apnea. Chest 1992;
101: 5419.
8. Pinto JM, Garpestad E, Weiss JW, Bergau DM, Kirby DA. Hemo-
dynamic changes associated with obstructive sleep apnea followed
by arousal in a porcine model. J. Appl. Physiol. 1993; 75: 143943.
9. Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep
apnea: Implications for cardiac and vascular disease. JAMA 2003;
290: 190614.
10. Young T. Epidemiology of obstructive sleep apnea: A population
health perspective. Am. J. Respir. Crit. Care Med. 2002; 165:
121739.
11. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause
of excessive daytime sleepiness. The upper airway resistance
syndrome. Chest 1993; 104: 7817.
12. Jean-Louis G, Brown CD, Zizi F et al. Cardiovascular disease risk
reduction with sleep apnea treatment. Expert Rev. Cardiovasc.
Ther. 2010; 8: 9951005.
13. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules
expression and production of reactive oxygen species in leuko-
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
1001
cytes of sleep apnea patients. Am. J. Respir. Crit. Care Med.
2002; 165: 9349.
14. Kent BD, Ryan S, McNicholas WT. Obstructive sleep apnea and
inammation: Relationship to cardiovascular co-morbidity. Respir.
Physiol. Neurobiol. 2011; 178: 47581.
15. Lavie L, Dyugovskaya L, Golan-Shany O, Lavie P. Heat-shock
protein 70: Expression in monocytes of patients with sleep apnoea
and association with oxidative stress and tumour necrosis factor-
alpha. J. Sleep Res. 2010; 19: 13947.
16. Mohsenin V, Urbano F. Circulating antiangiogenic proteins in
obstructive sleep apnea and hypertension. Respir. Med. 2011; 105:
8017.
17. Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial func-
tion in obstructive sleep apnea and response to treatment. Am. J.
Respir. Crit. Care Med. 2004; 169: 34853.
18. Chung S, Yoon IY, Lee CH, Kim JW. The association of noctur-
nal hypoxemia with arterial stiffness and endothelial dysfunction
in male patients with obstructive sleep apnea syndrome. Respira-
tion 2010; 79: 3639.
19. El-Solh AA, Mador MJ, Sikka P, Dhillon RS, Amsterdam D, Grant
BJB. Adhesion molecules in patients with coronary artery disease
and moderate-to-severe obstructive sleep apnea. Chest 2002; 121:
15417.
20. Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K,
Chrousos GP. Elevation of plasma cytokines in disorders of exces-
sive daytime sleepiness: role of sleep disturbance and obesity. J.
Clin. Endocrinol. Metab. 1997; 82: 13136.
21. Mehra R, Storfer-Isser A, Kirchner HL et al. Soluble interleukin 6
receptor: A novel marker of moderate to severe sleep-related
breathing disorder. Arch. Intern. Med. 2006; 166: 172531.
22. Del Rio R, Moya EA, Iturriaga R. Differential expression of
pro-inammatory cytokines, endothelin-1 and nitric oxide synthas-
es in the rat carotid body exposed to intermittent hypoxia. Brain
Res. 2011; 1395: 7485.
23. Das AM, Khayat R. Hypertension in obstructive sleep apnea: Risk
and therapy. Expert Rev. Cardiovasc. Ther. 2009; 7: 61926.
24. Devulapally K, Pongonis R Jr, Khayat R. OSA: The new cardio-
vascular disease: Part II: Overview of cardiovascular diseases
associated with obstructive sleep apnea. Heart Fail. Rev. 2009;
14: 15564.
25. Budhiraja R, Budhiraja P, Quan SF. Sleep-disordered breathing
and cardiovascular disorders. Respir. Care 2010; 55: 132232.
26. Palta M, Skatrud J, Young T, Peppard PE. Prospective study of
the association between sleep-disordered breathing and hyperten-
sion. N. Engl. J. Med. 2000; 342: 137884.
27. OConnor GT, Caffo B, Newman AB et al. Prospective study of
sleep-disordered breathing and hypertension: The Sleep Heart
Health Study. Am. J. Respir. Crit. Care Med. 2009; 179: 115964.
28. Peppard PE. Is obstructive sleep apnea a risk factor for hyperten-
sion? Differences between the Wisconsin Sleep Cohort and the
Sleep Heart Health Study J. Clin. Sleep Med. 2009; 5: 4045.
29. Drager LF, Genta PR, Pedrosa RP et al. Characteristics and
predictors of obstructive sleep apnea in patients with systemic
hypertension. Am. J. Cardiol. 2010; 105: 11359.
30. Thomopoulos C, Tsious C, Dimitriadis K et al. Obstructive sleep
apnoea syndrome is associated with enhanced sub-clinical inam-
mation and asymmetric dimethyl-arginine levels in hypertensives.
J. Hum. Hypertens. 2009; 23: 657.
31. Vgontzas AN, Zoumakis E, Bixler EO et al. Selective effects of
CPAP on sleep apnoea-associated manifestations. Eur. J. Clin.
Invest. 2008; 38: 58595.
32. Yue HJ, Mills PJ, Ancoli-Israel S, Loredo JS, Ziegler MG, Dims-
dale JE. The roles of TNF-alpha and the soluble TNF receptor I
on sleep architecture in OSA. Sleep Breath. 2009; 13: 2639.
33. Tamaki S, Yamauchi M, Fukuoka A et al. Production of inam-
matory mediators by monocytes in patients with obstructive sleep
apnea syndrome. Intern. Med. 2009; 48: 125562.
1002 JJ Thomas and J Ren
34. Navarro-Gonzalez JF, Mora C, Muros M, Jarque A, Herrera H,
Garcia J. Association of tumor necrosis factor-alpha with early tar-
get organ damage in newly diagnosed patients with essential
hypertension. J. Hypertens. 2008; 26: 216875.
35. Li N-F, Yao X-G, Zhu J et al. Higher levels of plasma TNF-alpha
and neuropeptide Y in hypertensive patients with obstructive sleep
apnea syndrome. Clin. Exp. Hypertens. 2010; 32: 5460.
36. Tsious C, Kordalis A, Flessas D et al. Pathophysiology of resis-
tant hypertension: The role of sympathetic nervous system. Int. J.
Hypertens. 2011; 2011: 642416.
37. Drager LF, Ueno LM, Lessa PS, Negrao CE, Lorenzi-Filho G,
Krieger EM. Sleep-related changes in hemodynamic and
autonomic regulation in human hypertension. J. Hypertens. 2009;
27: 165563.
38. ODriscoll DM, Horne RSC, Davey MJ et al. Increased sympa-
thetic activity in children with obstructive sleep apnea: Cardiovas-
cular implications. Sleep Med. 2011; 12: 4838.
39. Duran-Cantolla J, Aizpuru F, Montserrat JM et al. Continuous
positive airway pressure as treatment for systemic hypertension in
people with obstructive sleep apnoea: Randomised controlled trial.
BMJ 2010; 341: c5991.
40. Lozano L, Tovar JL, Sampol G et al. Continuous positive airway
pressure treatment in sleep apnea patients with resistant hypertension:
A randomized, controlled trial. J. Hypertens. 2010; 28: 21618.
41. Mehra R, Benjamin EJ, Shahar E et al. Association of nocturnal
arrhythmias with sleep-disordered breathing: The Sleep Heart
Health Study. Am. J. Respir. Crit. Care Med. 2006; 173: 91016.
42. Gami AS, Hodge DO, Herges RM et al. Obstructive sleep apnea,
obesity, and the risk of incident atrial brillation. J. Am. Coll.
Cardiol. 2007; 49: 56571.
43. Gami AS, Somers VK. Implications of obstructive sleep apnea for
atrial brillation and sudden cardiac death. J. Cardiovasc. Electro-
physiol. 2008; 19: 9971003.
44. Dursunoglu D, Dursunoglu N, Evrengul H et al. Impact of
obstructive sleep apnoea on left ventricular mass and global func-
tion. Eur. Respir. J. 2005; 26: 2838.
45. Cloward TV, Walker JM, Farney RJ, Anderson JL. Left ventricu-
lar hypertrophy is a common echocardiographic abnormality in
severe obstructive sleep apnea and reverses with nasal continuous
positive airway pressure. Chest 2003; 124: 594601.
46. Shivalkar B, Van De Heyning C, Kerremans M et al. Obstruc-
tive sleep apnea syndrome: More insights on structural and
functional cardiac alterations, and the effects of treatment with
continuous positive airway pressure. J. Am. Coll. Cardiol. 2006;
47: 14339.
47. Mooe T, Gullsby S, Rabben T, Eriksson P. Sleep-disordered
breathing: A novel predictor of atrial brillation after coronary
artery bypass surgery. Coron. Artery Dis. 1996; 7: 4758.
48. Sorajja D, Gami AS, Somers VK, Behrenbeck TR, Garcia-Tou-
chard A, Lopez-Jimenez F. Independent association between
obstructive sleep apnea and subclinical coronary artery disease.
Chest 2008; 133: 92733.
49. Chami HA, Resnick HE, Quan SF, Gottlieb DJ. Association of
incident cardiovascular disease with progression of sleep-disor-
dered breathing. Circulation 2011; 123: 12806.
50. Punjabi NM, Caffo BS, Goodwin JL et al. Sleep-disordered
breathing and mortality: A prospective cohort study. PLoS Med.
2009; 6: 19.
51. Ma S, Mifin SW, Cunningham JT, Morilak DA. Chronic inter-
mittent hypoxia sensitizes acute hypothalamicpituitaryadrenal
stress reactivity and Fos induction in the rat locus coeruleus in
response to subsequent immobilization stress. Neuroscience 2008;
154: 163947.
52. Nakashima H, Katayama T, Takagi C et al. Obstructive sleep
apnoea inhibits the recovery of left ventricular function in patients
with acute myocardial infarction. Eur. Heart J. 2006; 27: 2317
22.
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
53. Karkoulias K, Lykouras D, Sampsonas F et al. The role of endo-
thelin-1 in obstructive sleep apnea syndrome and pulmonary arte-
rial hypertension: Pathogenesis and endothelin-1 antagonists. Curr.
Med. Chem. 2010; 17: 105966.
54. Drager LF, Bortolotto LA, Figueiredo AC, Kreiger EM, Lorenzi
GF. Effects of continuous positive airway pressure on early signs
of atherosclerosis in obstructive sleep apnea. Am. J. Respir. Crit.
Care Med. 2007; 176: 70612.
55. Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M,
Tkacova R. Effects of continuous positive airway pressure on car-
diovascular risk prole in patients with severe obstructive sleep
apnea and metabolic syndrome. Chest 2008; 134: 68692.
56. Kohler M, Ayers L, Pepperell JC et al. Effects of continuous posi-
tive airway pressure on systemic inammation in patients with
moderate to severe obstructive sleep apnoea: A randomised
controlled trial. Thorax 2009; 64: 6773.
57. Julien C, Sam B, Patrick L. Vascular reactivity to norepinephrine
and acetylcholine after chronic intermittent hypoxia in mice.
Respir. Physiol. Neurobiol. 2003; 139: 2132.
58. Kasai T, Bradley TD. Obstructive sleep apnea and heart failure:
Pathophysiologic and therapeutic implications. J. Am. Coll.
Cardiol. 2011; 57: 11927.
59. Gottlieb DJ, Yenokyan G, Newman AB et al. Prospective study
of obstructive sleep apnea and incident coronary heart disease and
heart failure: The Sleep Heart Health Study. Circulation 2010;
122: 35260.
60. Kahwash R, Kikta D, Khayat R. Recognition and management of
sleep-disordered breathing in chronic heart failure. Curr. Heart
Fail. Rep. 2011; 8: 729.
61. Brisco MA, Goldberg LR. Sleep apnea in congestive heart failure.
Curr. Heart Fail. Rep. 2010; 7: 17584.
62. Lee C-H, Khoo S-M, Chan MY et al. Severe obstructive sleep
apnea and outcomes following myocardial infarction. J. Clin.
Sleep Med. 2011; 7: 61621.
63. Wang H, Parker JD, Newton GE et al. Inuence of obstructive
sleep apnea on mortality in patients with heart failure. J. Am. Coll.
Cardiol. 2007; 49: 162531.
64. Egea CJ, Aizpuru F, Pinto JA et al. Cardiac function after CPAP
therapy in patients with chronic heart failure and sleep apnea: A
multicenter study. Sleep Med. 2008; 9: 6606.
65. Khayat RN, Abraham WT, Patt B, Roy M, Hua K, Jarjoura D.
Cardiac effects of continuous and bilevel positive airway pressure
for patients with heart failure and obstructive sleep apnea: A pilot
study. Chest 2008; 134: 11628.
66. Khayat R, Patt B, Hayes D Jr. Obstructive sleep apnea: The new
cardiovascular disease. Part I. Obstructive sleep apnea and the
pathogenesis of vascular disease. Heart Fail. Rev. 2009; 14: 143
53.
67. Dematteis M, Godin-Ribuot D, Arnaud C et al. Cardiovascular
consequences of sleep-disordered breathing: Contribution of
animal models to understanding of the human disease. ILAR J.
2009; 50: 26281.
68. Fletcher E. Sympathetic over activity in the etiology of hyperten-
sion of obstructive sleep apnea. Sleep 2003; 23: 1519.
69. McArdle N, Hillman D, Beilin L, Watts G. Metabolic risk factors
for vascular disease in obstructive sleep apnea: A matched
controlled study. Am. J. Respir. Crit. Care Med. 2007; 175: 1905.
70. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin B.
Augmented resting sympathetic activity in awake patients with
obstructive sleep apnea. Chest 1993; 103: 17638.
71. Lavie L. Obstructive sleep apnoea syndrome: An oxidative stress
disorder. Sleep Med. Rev. 2003; 7: 3551.
72. Ryan S, Taylor CT, McNicholas WT. Selective activation of
inammatory pathways by intermittent hypoxia in obstructive
sleep apnea syndrome. Circulation 2005; 112: 26607.
73. Greenberg HYeX, Wilson D, Htoo AK, Henderson T, Liu SF.
Chronic intermittent hypoxia activates nuclear factor-kappaB in
 Sleep apnoea and cardiovascular diseases
cardiovascular tissues in vivo. Biochem. Biophys. Res. Commun.
2006; 343: 5916.
74. Quercioli A, Mach F, Montecucco F. Inammation accelerates
atherosclerotic processes in obstructive sleep apnea syndrome
(OSAS). Sleep Breath. 2010; 14: 2619.
75. Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver
disease. Best Pract. Res. Clin. Gastroenterol. 2010; 24: 695708.
76. Musso G, Gambino R, Cassader M. Recent insights into hepatic
lipid metabolism in non-alcoholic fatty liver disease (NAFLD).
Prog. Lipid Res. 2009; 48: 126.
77. Moore JB. Non-alcoholic fatty liver disease: The hepatic conse-
quence of obesity and the metabolic syndrome. Proc. Nutr. Soc.
2010; 69: 21120.
78. Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jarvinen
H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD
or vice versa? Dig. Liver Dis. 2010; 42: 32030.
79. Ahmed MH. Obstructive sleep apnea syndrome and fatty liver:
Association or causal link? World J. Gastroenterol. 2010; 16:
4243.
80. Tian JL, Zhang Y, Chen BY. Sleep apnea hypopnea syndrome
and liver injury. Chin. Med. J. 2010; 123: 8994.
81. Daltro C, Cotrim HP, Alves E et al. Nonalcoholic fatty liver
disease associated with obstructive sleep apnea: Just a coinci-
dence? Obes. Surg. 2010; 20: 153643.
82. Li J, Grigoryev DN, YeSQ et al. Chronic intermittent hypoxia
upregulates genes of lipid biosynthesis in obese mice. J. Appl.
Physiol. 2005; 99: 16438.
83. Savransky V, Bevans S, Nanayakkara A et al. Chronic intermit-
tent hypoxia causes hepatitis in a mouse model of diet-induced
fatty liver. Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 293:
G8717.
84. Jun J, Savransky V, Nanayakkara A et al. Intermittent hypoxia
has organ-specic effects on oxidative stress. Am. J. Physiol.
Regul. Intergr. Comp. Physiol. 2008; 295: R127481.
85. Norman D, Bardwell WA, Arosemena F et al. Serum aminotrans-
ferase levels are associated with markes of hypoxia in patients
with obstructive sleep apnea. Sleep 2008; 31: 1216.
86. Mishra P, Nugent C, Afendy A et al. Apnoeic-hypopnoeic
episodes during obstructive sleep apnoea are associated with
histological nonalcoholic steatohepatitis. Liver Int. 2008; 28:
10806.
87. Aron-Wisnewsky J, Minville C, Tordjman J et al. Chronic inter-
mittent hypoxia is a major trigger for non-alcoholic fatty liver dis-
ease in morbid obese. J. Hepatol. 2012; 56: 22533.
2012 The Authors
Clinical and Experimental Pharmacology and Physiology 2012 Wiley Publishing Asia Pty Ltd
1003
88. Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY.
Symptoms of obstructive sleep apnea in patients with nonalcoholic
fatty liver disease. Dig. Dis. Sci. 2005; 50: 233843.
89. Kohler M, Pepperell JC, Davies RJ, Stradling JR. Continuous
positive airway pressure and liver enzymes in obstructive sleep
apnoea: Data from a randomized controlled trial. Respiration
2009; 78: 1416.
90. Shpirer I, Copel L, Broide E, Elizur A. Continuous positive
airway pressure improves sleep apnea associated fatty liver. Lung
2010; 188: 3017.
91. Bugianesi E, Gastaldelli A, Vanni E et al. Insulin resistance in
non-diabetic patients with non-alcoholic fatty liver disease: Sites
and mechanisms. Diabetologia 2005; 48: 63442.
92. Barcelo A, Pierola J, de la Pena M et al. Free fatty acids and the
metabolic syndrome in patients with obstructive sleep apnoea.
Eur. Respir. J. 2011; 37: 141823.
93. Volgin DV, Kubin L. Chronic intermittent hypoxia alters hypotha-
lamic transcription of genes involved in metabolic regulation.
Auton. Neurosci. 2006; 127: 939.
94. Lin Q-C, Zhang X-B, Chen G-P, Huang D-Y, Din H-B, Tang
A-Z. Obstructive sleep apnea syndrome is associated with some
components of metabolic syndrome in nonobese adults. Sleep
Breath. 2012; 16: 5718.
95. Sharma SK, Agrawal S, Damodaran D et al. CPAP for the meta-
bolic syndrome in patients with obstructive sleep apnea. N. Engl.
J. Med. 2011; 365: 227786.
96. Donnelly KL. Sources of fatty acids stored in liver and secreted
via lipoproteins in patients with nonalcoholic fatty liver disease. J.
Clin. Invest. 2005; 115: 134351.
97. Savransky V, Nanayakkara A, Li J et al. Chronic intermittent
hypoxia induces atherosclerosis. Am. J. Respir. Crit. Care Med.
2007; 175: 12907.
98. Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep
apnea: An emerging risk factor for atherosclerosis. Chest 2011;
140: 53442.
99. Kohler M, Stradling JR. Mechanisms of vascular damage in
obstructive sleep apnea. Nat. Rev. Cardiol. 2010; 7: 67785.
100. Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep
apneahypopnea syndrome and nonalcoholic fatty liver disease:
Emerging evidence and mechanisms. Semin. Liver Dis. 2012; 32:
4964.