OSA and atherosclerosis
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
Review Article
OSA and atherosclerosis
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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Abstract
Untreated obstructive sleep apnea (OSA) is increasingly recognized as a risk factor contributing to cardiovascular morbidity and mortality. Research in recent decades has uncovered many components of the complex pathological events leading to the atherosclerotic vascular diseases in OSA, which involve heightened oxidative stress as a result of intermittent hypoxia, vascular inflammation, activation of platelet and coagulation cascades, endothelial dysfunction and ultimately the formation of atherosclerotic plagues. The close association of OSA and conventional cardiovascular risk factors including hypertension, diabetes mellitus, dyslipidemia and obesity adds to the adverse cardiovascular sequelae. Further studies are required to clarify further on the pathophysiological processes, and the effect size of OSA therapy, and other potential preventive strategies.
Key words
Obstructive sleep apnea; atherosclerosis; intemittent hypoxia; inflammation; oxidative stress; endothelial dysfunction; coronary; artery disease; cerebrovascular accidentJ Thorac Dis 2012;4(2):164-172. DOI: 10.3978/j.issn.2072-1439.2012.01.06
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Introduction
Obstructive sleep apnea (OSA) is a common sleep related breathing disorder characterized by repetitive upper airway collapse during sleep resulting in intermittent hypoxia and sympathetic over-activity. The condition affects all age groups and is prevalent across different populations globally. According to a study undertaken in Fuzhou, China, the estimated prevalence of obstructive sleep apnea hypopnea syndrome (OSAS) in adults aged over 20 years, defined by apnea-hypopnea index (AHI)≥5/hour and Epworth sleepiness scale≥9, was 4.78% (1). Another study including more than 1000 primary snorers from Jiangsu found mild (AHI 5-20), moderate (AHI>20-40), and severe OSA (AHI>40) in 21.7%, 16.5% and 37.7% of subjects respectively (2). Such figures are similar to estimated prevalence rates of OSAS reported from epidemiologic studies involving diverse ethnic populations of Caucasians and Asians, which range from 1.2% to 7.5%, while asymptomatic OSA affected as many as one in five middle-aged adults (3). A previous community-based study of middle-aged Chinese subjects between 30-60 year old in Hong Kong reported the prevalence of OSAS (AHI≥5/hour plus presence of excessive sleepiness) to be 4.1% in men and 2.1% in women (4,5). A similar scale of problem is seen in children. A recent study recruiting community-dwelling students, aged 6-12 years, from 13 primary schools in Hong Kong found that OSAS, based on the International Criteria of Sleep Disorders version II, affected 5.8% and 3.8% of boys and girls respectively (6).
Obesity, in particular central obesity, is the most well-established risk factor of OSA (7). Obesity is increasingly prevalent in western countries since the last century, and the pandemic is sweeping across the oceans to Asia (8). With the rapid socioeconomic development occurring in many parts of China, many local customs including lifestyle and dietary habits have been gradually changing, which would result in a shift of disease pattern similar to developed countries in the west. According to several cross-sectional studies undertaken in the recent two decades, it is estimated that up to one-third of adults in China are overweight or obese, and 10%-20% of all adults are affected by metabolic syndrome (9). The prevalence of overweight and obesity among Chinese children and adolescents has also been increasing steadily from 1991 to 2006, and those from urban areas and high income families are particularly affected (10).
Undeniably, OSA is strongly linked to obesity and other obesity-related medical conditions such as hypertension, impaired glucose metabolism, cardiovascular diseases, or the metabolic syndrome (11,12). In western countries, atherosclerotic diseases and its associated morbidity and mortality lead to tremendous economic loss (13). Data from the China Health and Nutrition Survey revealed a dramatic increment in blood pressure levels and prevalence of
hypertension among Chinese children and adolescents from
1991 to 2004, after exclusion of confounding factors (14). The
prevalence of diabetes mellitus is also expected to escalate in
parallel with the sweeping epidemic of obesity (15). According
to the report of WHO Disease Control Priorities Project,
cerebrovascular disease and ischemic heart disease, diseases
predominantly due to atherosclerosis, were the first and third
leading causes of mortality in China and accounted for 18%
and 8% of total mortality in 2001. With the emerging evidence
illustrating potential independent contribution of OSA to
various cardiometabolic diseases, the clustering of these diseases
pose a significant healthcare burden.
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Pathogenesis of atherosclerosis
Atherosclerosis is a chronic inflammatory process involving
the vascular walls which takes years to evolve. The mechanisms
leading to the formation of atherosclerotic plagues involve
a complex interplay of dysfunctional endothelium and
systemic inflammatory and hemostatic mechanisms including
platelets and coagulation pathways. The vascular endothelium
is believed to be important in regulating vascular tone,
modulating platelet activation and cellular adhesion, in face
of a variety of circulatory signals and vascular stressors (16).
A healthy endothelium could also promote ongoing repair
mechanisms to maintain its integrity in response to various
insults. Endothelial dysfunction precedes the development of
atherosclerosis.
Shear stress triggers endothelial injury, which allows the
entry of serum lipoproteins and circulatory factors into the
vascular intima, leading to activation of macrophages and
T-lymphocytes locally. Such intrusion of vascular integrity
results in the release of many cytokines and chemokines from
damaged endothelial cells and macrophages, and increased
expression of endothelial cell-adhesion molecules, all of which
further encourage influx of circulatory inflammatory cells and
adhesion of platelets. Systemic oxidative stress and reactive
oxygen species released from activated leukocytes promote
oxidation of lipoproteins and various macromolecules,
perpetuating inflammation and further tissue injury. Along
with the systemic pro-inflammatory phenotypes of many
cardiovascular risk factors, a self-perpetuating cascade of
inflammation is formed inside the plague, leading to its
progression and even rupture. Rupture of atherosclerotic
plague would expose underlying tissue factors and switch
on the coagulation cascade, resulting in rapid progression
of vascular occlusion and clinical cardiovascular syndromes
including myocardial infarction and ischemic cerebrovascular
events.
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Detection of subclinical atherosclerosis
Several non-invasive tools are being used in clinical care and
research for the detection of subclinical atherosclerosis or
atherosclerotic burden, which could facilitate early initiation
or intensification of therapy. Carotid intima-media thickness
(CIMT) is a measurement of the thickness of the intima and
media layers of the carotid artery with the use of ultrasound.
Previously, concerns were raised about its reliability and
reproducibility, but with the availability of more sophisticated
technology wares and increasing experience with the technique,
the measurement has been shown to be highly reproducible
(17). Increased CIMT has been shown to be associated with
atherosclerosis, and predicts future cardiovascular events
including myocardial infarction and stroke. It has also been
shown to correlate well with traditional cardiovascular
risk factors, such as aging, hypertension, diabetes mellitus,
hyperlipidemia and smoking, and treatment of those modifiable
factors would improve CIMT (17).
Arterial stiffness reflects arterial properties including
compliance and distensibility, and can be assessed by analysis
of the arterial waveform or measurement of pulse-wave velocity
(PWV). Increased PWV correlates well with the presence and
extent of atherosclerosis, and traditional cardiovascular risk
factors (18). In later stages of development of atherosclerosis,
calcium deposits occur within the fibrous plaques and
assessment of coronary artery calcification by means of
computed tomography is shown to predict obstructive coronary
artery disease and future coronary events (19).
The intact endothelium maintains a homeostatic balance of
vasodilating and vasoconstricting substances which mediate
optimal response of arterial walls in the face of various
stimuli, and impairment of endothelial function antedates
the development of atherosclerosis and predicts related
cardiovascular diseases (20). Vascular responses on provocation
by pharmacolgoic or mechanical stimuli serve as an indicator of
vascular function mediated by either endothelium dependent
or independent mechanisms (20). Endothelium-dependent
vasodilatation can be assessed by measuring blood flow response
to pharmacologic or physical stimuli with the use of invasive
angiography or noninvasive imaging techniques such as doppler
echocardiography. Reactive hyperemic response of forearm
arteries after a brief period of occlusion, indicating endothelial
nitric oxide dependent vasodilation, is a commonly used
surrogate measure of the endothelial function, and has been
shown to correlate with coronary endothelial dysfunction (21).
Such hyperemic response can be assessed with the measurement
of flow-mediated dilatation (FMD) of brachial artery by doppler
ultrasound (22), or lately with another non-invasive device
assessing peripheral artery tonometry which await further
validating outcomes data (23,24). Numerous circulating substances, such as C-reactive protein (CRP), fibrinogen,
adipokines and cytokines, have been found to be biomarkers
of atherosclerosis (25). CRP level is increasingly important
as a prognostic biomarker of adverse cardiovascular events in
established cardiovascular diseases (26), though its exact role
and application in primary prevention of such events is not
conclusive (27,28).
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OSA and atherosclerosis – epidemiolgic and clinical studies
OSA has been shown to be closely linked to various
cardiovascular diseases (CVD), most of which are pathologically
related to atherosclerosis, including hypertension, coronary
heart diseases, cerebrovascular accidents, arrhythmias and
cardiac dysfunction (12). The Sleep Heart Health Study, which
included more than 6400 community-dwelling individuals, has
demonstrated a clear association between OSA and coronary
artery disease or stroke, with respective odds ratio being 1.27
(95% CI 0.99-1.62) and 1.58 (95% CI 1.02-2.46) comparing
those with OSA (AHI>11) and those without OSA (AHI<1.3)
(29). A longitudinal study of subjects free of cardiovascular
diseases and diabetes mellitus at baseline, followed up for 7
years, showed that OSA at baseline was a significant predictor
of future incident CVD (odds ratio 4.9; 95% CI 1.8-13.6) and
effective treatment with CPAP reduced such excess risk (30).
Subsequently, a large-scale prospective cohort study which
followed up more than 1500 subjects for a mean duration of 10
years, found that untreated severe OSAS significantly increased
the risk of fatal (odds ratio 2.87, 95% CI 1.17-7.51) and nonfatal
(3.17, 1.12-7.51) cardiovascular events compared with non-
OSA controls, and such risks were attenuated significantly with
CPAP treatment (31). Another observational study reported
a dose-dependent relationship between the severity of OSA
and the risk of stroke or death, after adjustment for known
confounders (32). With the emergence of these longitudinal
data, though observational, a causal relationship between OSA
and atherosclerotic vascular disease is highly suggested.
Apart from epidemiologic studies, numerous clinical studies
have focused on direct measurement of atherosclerosis or its
surrogate markers in subjects with different degrees of OSA.
The assessment of an independent association between OSA
and atherosclerosis is potentially affected by a number of
confounders, which would need vigilant exclusion or statistical
adjustments. Carotid intima-media thickness was found to
be elevated in OSA subjects, compared to non-OSA subjects
in several case-control studies (33,34) and cross-sectional
studies (35). Of note, the severity of OSA, as indicated by
apnea-hypopnea index or oxygen desaturation parameters, was
positively correlated with measures of early atherosclerosis including PWV and CIMT (35-37). In line with these findings,
the formation of atherosclerotic plagues and extracranial
stenosis were more pronounced in OSA individuals (36,38).
These associations were also found in Asian subjects. In a
Japanese study, brachial-ankle PWV was higher in the OSA
groups compared to the non-OSA counterparts independent of
other risk factors (39). Two subsequent Chinese studies have
demonstrated a higher brachial-ankle PWV (40) and CIMT
(41) in OSA group compared to non-OSA group, though
CIMT did not change after CPAP therapy for 3 months in the
latter non-randomized study (41). On the contrary, a Brazilian
randomized control trial has shown a reduction in CIMT and
PWV, as well as circulating CRP and catecholamine levels after
4 months of CPAP treatment (42). The presence of OSA in
addition to hypertension (43) and metabolic syndrome (44)
was found to have additive provoking effects on early markers
of atherosclerosis including CIMT, carotid distensibility and
carotid-femoral PWV. A recent randomised controlled crossover
study from India reported a significant improvement in lipid
profile, glycated hemoglobin, blood pressure as well as lowering
of frequency of metabolic syndrome in the CPAP treated
group compared with the sham-CPAP group, but significant
improvement of CIMT was only seen in the CPAP adherant
subgroup (45).
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Mechanistic links between OSA and atherosclerosis
Intermittent hypoxia and oxidative stress
The episodic complete or incomplete cessation of breathing in
OSA is coupled with intermittent hypoxia and reoxygenation to
body tissues and organs. Atherosclerosis is believed to represent
a state of heightened oxidative stress, which is the result of an
imbalance in production of reactive oxygen species (ROS) and
intrinsic antioxidant activity that prevent tissue damage from
oxidation (46). Repeated sequential hypoxia-reoxygenation in
OSA may lead to overproduction of ROS and resultant oxidative
stress (46). Many studies have provided supportive evidence
for the presence of oxidative stress in OSA, with the use of
different biomarkers, although the findings are not entirely
consistent (46). Lipid peroxidation is a marker of systemic
oxidative stress. OSA patients have been found to be more
susceptible to lipid peroxidation and this was mitigated by CPAP
treatment (47). Data from our group also demonstrated elevated
levels of plasma 8-isoprostane, an oxidative stress biomarker
produced in vivo by the free radical-catalyzed peroxidation of
arachidonic acid, in OSA subjects, and which was associated
with dysfunctional high density lipoprotein and increased
oxidation of low density lipoprotein (48). Other oxidative stress
biomarkers, thiobarbituric reactive substances (TBARS) and peroxides (PD), were found to be higher in OSA subjects with or
without CVD, compared to controls, and antioxidant protective
enzyme paraxonase-1 were lower in those with OSA and CVD
(49). Studies have also shown increased ROS production from
inflammatory leukocytes such as neutrophils and monocytes
in OSA patients, which were reversed with effective CPAP
treatment (50,51). Notwithstanding, such evidence for increased
oxidative stress in OSA was not reproducible in some other
studies (52-54). In order to demonstrate an association between
OSA and increased oxidative stress conclusively, multiple
confounders including obesity, comorbid conditions, smoking
and even dietary influence must be properly addressed. The
choice and adequacy of measured sleep parameters for reflecting
the severity of intermittent hypoxia may also contribute to
heterogeneity of findings.
Several studies have approached the question from another
angle by demonstrating a lower level of anti-oxidant activity
in OSA, which could be partially reversed by CPAP treatment
(55,56). Subsequently, another study has found impaired serum
albumin antioxidant properties in OSA patients (57). The
beneficial effect of intravenous vitamin C supplementation, a
dietary antioxidant, on endothelial function in OSA supported
the role of anti-oxidant imbalance in vascular pathogenesis in
OSA (58). Lately, a study focusing on in-situ red-ox kinetics
occurring in the microcirculation nicely demonstrated increased
oxidant production (microcirculatory peroxynitrite deposit) and
reduced anti-oxidant mechanisms (transcription of endothelial
nitric oxide synthase and superoxide dismutase 1) in the
microcirculation in OSA individuals (59).
Advanced glycation endproducts (AGE), products of nonenzymatic
glycation and oxidation of proteins and lipids, are
highly associated with angiopathy in the setting of diabetes
mellitus and aging (60). In our previous study, serum levels of
AGE of non-diabetic OSA patients were not as elevated as that in
diabetic subjects, but higher than control non-diabetic subjects
recruited from a general poupulation, and the AGE levels were
associated with severity of OSA and levels of 8-isoprostane
(61). Our latest study in healthy subjects with or without OSA
confirmed the association between elevated levels of AGEs
and OSA, though this association was independent of insulin
sensitivity (62).
Inflammatory cascade
It is now well-established that inflammation is involved in the
initiation, progression and acute rupture of atherosclerotic
plagues. Inflammatory markers, in particular C-reactive protein
(CRP), the assay for which is widely available in clinical
laboratories, have become important prognostic indicators for
cardiovascular morbidity and mortality.
Intermittent hypoxia/reoxygenation cycles and the resultant oxidative stress in OSA may activate pro-inflammatory signaling pathways involving nuclear factor kappa B (NF-ΚB), and this
was shown to be the case in OSA subjects (63,64). NF-ΚB is
a transcription factor mediating inflammatory and immune
responses by regulating inflammatory gene expression, including
the genes for cytokines, chemokines, growth factors and cell
adhesion molecules. Activated monocytes and neutrophils are
further sources of ROS resulting in self-perpetuating vicious
cycle of inflammation. Cell adhesion molecules (intercellular
adhesion molecule-1), enzymes (inducible nitric oxide synthase,
cycloxygenase-2), cytokines (interleukin-6, tumour necrosis
factor-alpha) and chemokines (monocyte chemoattractant
protein-1, interleukin-8), have been shown to be upregulated in
OSA subjects (65,66). Of note, these positive results were not
entirely consistent (67), particularly after taking into account the
effect of obesity and concomitant inflammatory diseases.
Leptin and adiponectin are hormones secreted from adipose
tissue, and they modulate a number of metabolic processes.
Both have been shown to play a role in suppressing insulin
resistance and its consequences including diabetes mellitus and
atherosclerosis (68). Many observational studies have found
an elevated level of leptin in OSA or sleep-deprived subject
independent of obesity though results were inconsistent (69-73). Leptin may also contribute to coexisting hypertension in
OSA (74). Adiponectin was found to be reduced in OSA in
several cross sectional studies (75-77), but not in others (78).
Furthermore, positive effects from CPAP treatment on reversing
these abnormal adipokine levels have not been demonstrated
convincingly by any randomized controlled study. Thus, the
relationship between these adipokines and OSA is still highly
controversial.
CRP, which is an acute phase reactant released from the
liver in response to stimulation from TNF-alpha, IL-6 and IL-
8, and a biomarker for CVD risks, has been extensively studied
in the setting of OSA. Despite a few negative studies, most
of the cross-sectional studies demonstrated that OSA was
independently associated with higher levels of CRP, supporting
heightened systemic inflammation in OSA (65). Our group has
also investigated such association in a group of healthy Chinese
adults free of cardio-metabolic diseases and found that CRP was
correlated with indices of severity of OSA after adjustment of
known confounders including visceral adiposity (79). However,
the effect of CPAP treatment on CRP level in OSA is much
less consistent, with some studies failing to show any beneficial
effect. A lack of response may be related to the relatively short
duration of treatment period in some studies, or the inflammatory
process in established atherosclerosis may not be fully reversible
(65). Another acute phase reactant, serum amyloid A, was also
found to be related to the severity of OSA (80), and the level
was reduced with CPAP treatment (81). Caroid intima media
thickness was demonstrated to be significantly correlated with CRP, IL-6, IL-18, duration of hypoxia and severity of OSA, and
the primary factor predicting CIMT was duration of hypoxia
during sleep (34). Taken in summary, these findings suggest
that systemic inflammation in OSA may be associated with the
development or progression of atherosclerosis.
Endothelial dysfunction
The endothelium is a crucial regulator of vascular homeostasis,
which exerts a number of vasoprotective effects, such as
vasodilation in response to ischemia or tissue injury, and
inhibition of inflammatory responses. Endothelial dysfunction
precedes the development of atherosclerosis (82).
The increased oxidative stress observed in OSA may
suppress nitric oxide synthase activity (83,84), which
results in dysregulation of vasomotor tone and endothelial
dysfunction. Our group has demonstrated that flow mediated
dilatation of brachial artery was significantly lower in men
with OSA free of comorbidities compared to non-OSA
counterparts, and such impairment was reversible with CPAP
treatment (85).
In addition to intermittent hypoxia, sleep deprivation and
fragmentation in OSA provide another potential pathway
linking to endothelial dysfunction. Sleep deprivation for 4
weeks was associated with reduced FMD in a group of healthy
young men (86). A number of studies have shown that
elevated inflammatory markers, sympathetic over-activity and
hypercoagulability occur in sleep-deprived subjects (87,88),
which could all contribute to vascular atherogenesis.
Recently, circulating cell-derived microparticles, a
relatively novel marker of endothelial dysfunction, was found
to be elevated in minimially symptomatic OSA, and the
correlation between elevated circulating microparticles and
OSA severity was also demonstrated in children (89,90).
Circulating endothelial progenitor cell levels, which reflect
the repair capacity of endothelium in response to stress and
injury, have also been found to be lower in those with OSA in
several small-scale studies, but the results were not repeatable
in others (84).
Platelet activation and coagulation abnormalities
Platelets exert a spectrum of pro-atherogenic properties by
adhering to diseased endothelium and secreting a series of
atherogenic mediators such as cytokines, chemokines, growth
factors, adhesion molecules and coagulation factors. Such
expressions would promote further leukocytes activation,
proliferation, adhesion, and migration into the atherosclerotic
plagues (91). Multiple studies have shown that platelets are
activated and more prone to aggregate in OSA subjects (92-94) and may be alleviated by CPAP treatment (92,95,96). In a recent study, greater degree of platelet activation was associated with more severe oxygen desaturation during sleep (97). OSA and sleep disruption have also been linked to an imbalance in
circulatory thrombotic and anti-thrombotic activity, resulting
in a switch of the coagulation profiles to a pro-thrombotic states
(98-100).
Mechanical and hemodynamic factors
Atherosclerosis is a common pathology in blood vessels in
hypertension. Abundant evidence support that untreated
OSA could predispose to systemic hypertension (12). The
exact pathophysiologic etiology of hypertension in OSA is not
definitely clear, but it is believed that sympathetic over-activity as
a result of intermittent hypoxia and repeated arousals and a series
of neuro-hormonal alterations account for the surges in blood
pressure (12). The heightening of sympathetic tone and elevated
nocturnal endothelin release lead to systemic vasoconstriction,
and thus higher systemic blood pressure (101), and the reninangiotensin-
aldosterone system is also activated resulting in
sodium and fluid retention (102). Systemic hypertension is
linked to increased shear stress to vascular endothelium, vascular
remodeling, endothelial dysfunction and atherogenesis (103).
Snoring is extremely common in subjects with OSA. The
process of snoring involves vibrations of soft tissues surrounding
the pharynx which can be transmitted to the carotid arteries
(104). A study using rat tail blood vessels found that vibration
at 60 Hz for 4 hours per day caused vasoconstriction, injury to
endothelial cells and endothelial denudation (105). Recently,
another study examined the effect of vibration simulating
snoring in a ventilated rabbit model. The vibrated carotid
artery showed decreased vasodilatation to acetylcholine
compared with control arteries, demonstrating a direct effect
of vibrations on endothelial function independent of hypoxia
or apnea (106). Indeed, independent of nocturnal hypoxia and
OSA severity, snoring was demonstrated to be associated with
carotid atherosclerosis but not femoral atherosclerosis (107).
These findings support the hypothesis of snoring vibrationinduced
endothelial injury contributing to subsequent carotid
atherosclerosis, providing a mechanical route in addition to
metabolic pathways by which subjects with OSA may be at
increased risk of carotid atherosclerosis.
Cardiovascular risk factors
Metabolic factors are established risk factors for atherosclerosis
and related cardiovascular diseases. The metabolic syndrome,
representing a cluster of metabolic phenotypic characteristics
comprising of central obesity, hypertension, insulin resistance
and dyslipidemia, is a classical risk factor for atherosclerotic
CVD and diabetes mellitus which itself is an important cause of atherosclerosis. Given the common risk factor of obesity, it is not
surprising that OSA is strongly associated with the metabolic
syndrome (108). But in addition, an association independent
of obesity has been repeatedly demonstrated between OSA and
various metabolic diseases which could aggravate atherosclerosis
(11,109). Animal and cellular experiments using intermittent
hypoxia as a model of OSA have also demonstrated many adverse
metabolic effects including promotion of dyslipidemia and
insulin resistance, and induction of relevant cellular or molecular
signaling pathways (110-112). Lipoproteins are directly involved
in the pathogenesis of atherosclerosis. Similarly, insulin resistance
and diabetes mellitus are also major pathogenetic factors for
atherosclerosis. Clinical evidence regarding the independent
association between OSA and dyslipidemia is conflicting with
some studies showing an increased LDL, increased triglycerides
or reduced HDL levels in OSA (113). The impact of OSA on
glucose metabolism is a hot topic under research, with many
observational studies supporting a deleterious effect (11,114).
However, the effects of CPAP treatment on metabolic profiles
have been conflicting. A recently published randomized
controlled study has nicely demonstrated beneficial effects of
CPAP treatment on metabolic parameters in OSA subjects (45).
Although it is an intuitively logical hypothesis that OSA may
lead to atherosclerosis through these metabolic pathways, much
remains to be understood regarding the complex interactions of
multiple risk factors in the pathogenesis of atherosclerosis and
clinical vascular disease in OSA.
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Conclusions
Clinically, OSA is connected to a network of cardiovascular risk
factors, while mechanistically, OSA may lead to oxidative stress,
heightened inflammation and endothelial dysfunction which
are pathological processes underlying atherosclerosis. However,
much remains to be delineated regarding vascular pathogenesis
in OSA. The demonstrated benefits of CPAP treatment of OSA
on some of these parameters are encouraging, since they imply
that potential adverse sequelae on the vasculature could be
halted with early detection and timely treatment of OSA. Further
evidence from large-scale randomized controlled trials with
comprehensive clinical outcomes as endpoints are necessary to
address many important clinical questions, including the optimal
threshold for treatment of OSA, effect size, interactions of OSA
with other cardiometabolic risk factors, and potential differences
in the vasculature at different sites.
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References
Cite this article as: Lui MM, Ip MS. OSA and atherosclerosis. J Thorac Dis
2012;4(2):164-172. doi: 10.3978/j.issn.2072-1439.2012.01.06
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