Review

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Intermittent hypoxia: the

culprit of oxidative stress,
vascular inflammation and
dyslipidemia in obstructive
sleep apnea
Expert Rev. Resp. Med. 2(1), 75–84 (2008)

Lena Lavie
Unit of Anatomy and Cell
Biology, The Ruth and Bruce
Rappaport Faculty of
Medicine, Technion,
PO Box 9649, 31096,
Haifa, Israel
Tel.:+972 4829 5234
Fax: +972 4834 3934/
4829 5403
lenal@tx.technion.ac.il
Obstructive sleep apnea, a breathing disorder in sleep characterized by intermittent and
recurrent pauses in respiration, is also a major risk factor for cardiovascular morbidity and
mortality. Accumulated evidence implicates the apnea-related multiple cycles of
hypoxia/reoxygenation in promoting the formation of reactive oxygen species that oxidize and
damage macromolecules and activate critical redox-sensitive signaling pathways and
transcription factors. This activation facilitates the expression of sets of genes encoding
proteins in various pathways, including inflammatory and lipogenic, as well as proteins
essential to adaptation to hypoxia. Consequently, inflammatory and immune responses are
activated, thus resulting in the activation of endothelial cells/leukocytes/platelets. These
activated cells express adhesion molecules and proinflammatory cytokines that in turn may
further exacerbate inflammatory responses and cause endothelial cell injury and dysfunction,
promoting the development of cardiovascular morbidities in sleep apnea. No less important in
activating such inflammatory cascades is the hyperlipidemia that is another characteristic of
obstructive sleep apnea. Evidence supporting the existence of endothelial dysfunction and
early clinical signs of atherosclerosis in these patients provides a firm support to the above
chain of events. If left untreated, this cascade of events may eventually lead to overt
cardiovascular morbidity.

KEYWORDS: atherosclerosis • endothelial cells • hyperlipidemia • inflammation • leukocytes • obstructive sleep apnea
• oxidative stress • platelets

In 1993, based mainly on theoretical consid- to the underlying pathophysiology of cardio-

erations and the knowledge available at the
time, the foundation of the ‘free radi-
cal/inflammatory theory in sleep apnea’ was
laid [1]. In this seminal paper, Dean and Wil-
cox suggested that the repeated breathing
arrests accompanied by drastic changes in
PO 2, which are the hallmark of obstructive
sleep apnea (OSA) syndrome, are analogous to
hypoxia and reoxygenation and may lead to
free radical bursts, as was demonstrated in
conditions of ischemia and reperfusion [2].
Based on this assumption of free radical produc-
tion in sleep apnea, combined with Ross’s
hypothesis of ‘the response to injury’ describing
the development of atherosclerosis [3], this prop-
osition provided a very attractive explanation
vascular morbidity in sleep apnea [4,5]. Only in
the early 2000s was the first direct evidence
demonstrating increased oxidative stress in OSA
published [6,7] and indirect evidence substanti-
ated it [8,9]. By 2003, in a comprehensive review
by Lavie [10] based on the same theoretical con-
siderations and on newly acquired data perti-
nent to hypoxia/reoxygenation biology of leuko-
cytes/endothelial cell interactions [11] and on
sporadic data on sleep apnea, the links
between atherosclerosis and OSA were further
elaborated [10].
Since then, more than 80 publications on oxi-
dative stress and more than 100 on inflamma-
tion and sleep apnea have been published and
provided unequivocal support to this hypothesis.

www.future-drugs.com 10.1586/17476348.2.1.75 © 2008 Future Drugs Ltd ISSN 1747-6348 75

 Review Lavie
Several mechanisms were proposed to delineate the associa-
tion between OSA and cardiovascular morbidity. These
included increases in sympathetic nerve activity, swings in
intrathoracic pressure, altered blood coagulability and, as out-
lined previously, the participation of atherogenic sequelae and
their underlying mechanisms that are uniquely triggered by
apnea-related intermittent hypoxia (IH) [4] and resultant oxi-
dative stress [10,12,13]. These include inflammation and possi-
bly hyperlipidemia, which is a well-established risk factor for
cardiovascular morbidity.
The present paper summarizes the current knowledge on
atherosclerosis in OSA. It describes the underlying fundamental
mechanisms of oxidative stress leading to cellular inflammatory
and immune activation as well as the associated dyslipidemia.
OSA & cardiovascular morbidity
Sleep apnea syndrome is characterized by intermittent and
recurrent pauses in respiration that result in decreases in
blood oxygen saturation and sleep fragmentation. OSA is a
prevalent syndrome [5], one in four men and one in ten
women have at least five disordered breathing events in each
hour of sleep in the form of apneas or hypopneas [14]. Apneas
are complete cessations of breathing for at least a 10-s dura-
tion, while hypopneas are partial cessations for the same dura-
tion (defined as apnea–hypopnea index [AHI], denoting the
number of breathing arrests per hour of sleep). In 4% of adult
men and 2% of adult women, sleep apnea syndrome is accom-
panied by characteristic symptoms, such as excessive daytime
sleepiness, chronic fatigue or neurocognitive decline, which
comprise the sleep apnea syndrome [14]. Specifically, the syn-
drome is associated with the male gender, middle age, central
obesity, smoking, sedentary lifestyle and a postmenopausal
status in women [15].
At the time of diagnosis, at least 50% of sleep apnea
patients are hypertensive and 10–15% have cardiovascular
disease, including myocardial infarction and stroke [16,17]. On
the other hand, breathing disorders in sleep are prevalent
among patients with cardiovascular diseases [18,19]. These
cross-sectional data on the association between cardiovascular
morbidity and breathing disorders in sleep are supported by
large population-based studies demonstrating that this associ-
ation is independent of all possible confounding cardiovascu-
lar risk factors [20–22] and by prospective studies [23]. There is
particularly strong evidence supporting a causal relationship
between sleep apnea and hypertension, which is based on
large epidemiological studies [16,20–22], prospective studies [23],
the effect of treatment that ameliorated the apnea on blood
pressure [24] and on an animal model of sleep apnea [25]. Sev-
eral studies also demonstrated that sleep apnea syndrome is
an independent risk factor for cardiovascular mortality [26–28]
and that effective treatment of the syndrome significantly
decreased mortality [29,30]. McNicholas et al. provided a
recent up-to-date review on sleep apnea as an independent
76
risk factor for cardiovascular morbidity [31], while Lavie sum-
marized the evidence on the risk of mortality in sleep apnea
patients [32].
OSA & dyslipidemia
Hyperlipidemia is also a prevalent finding among sleep apnea
patients. In a multiethnic cohort of 6440 men and women of the
Sleep Health Heart Study, Newman et al. demonstrated an
increase in total serum cholesterol and triglycerides levels and a
decrease in high-density lipoproteins (HDLs) independent of age
and BMI [33]. Similar data were reported on a matched control
study of sleep apnea patients [34]. Moreover, effective ameliora-
tion of the apneas with nasal continous positive airway pressure
(nCPAP) treatment lowered serum total cholesterol levels [35–37].
In accord with this line, HDL of patients with OSA was shown
to be dysfunctional by lacking the ability to inactivate oxidized
lipids [38]. This HDL dysfunction can be at least partially attrib-
uted to the lower activity of paraoxonase-1 detected in patients
with OSA, particularly in those who also have cardiovascular
comorbidities [39]. Paraoxonase-1 is an antioxidant enzyme that
is located exclusively on HDL and protects both low-density
lipoprotein (LDL) and HDL from oxidative modifications.
Thus, lower activities of paraoxonase-1 render patients with OSA
susceptible to HDL dysfunction.
Oxidative stress: its sources & consequences in OSA
Oxidative stress
Oxidative stress is characterized by an imbalance between oxi-
dant-producing systems and antioxidant defense mechanisms
(redox balance), which results in excessive formation of reactive
oxygen species (ROS). It represents a common threat and a haz-
ard to all aerobic organisms, as it may severely influence the
progress of various pathological conditions. The predominant
-
ROS molecule is the superoxide anion (O2• ) radical. It is gener-
ated by univalent reduction of molecular oxygen mainly during
respiration, but also by several other enzymic systems:
- -
O2 + e →O2•
-
Once formed, the O2• can be dismutated spontaneously or
by the superoxide dismutase (SOD) enzyme. This reaction
yields molecular oxygen and hydrogen peroxide (H2O2):
- -
O2• + O2• + 2H+ →O2 + H2O2
•-
When O2 reacts with its product of dismutation (H2O2), a
hydroxyl radical (OH• ), which is a highly oxidant molecule, can
be formed. The formation of OH• is facilitated by the presence
of reduced transition metals such as Fe3+ and Cu+2 [40]:
- -
O2• + H2O2 →O2 + OH• + OH
-
Collectively, these molecules (O2• , H2O2 and OH• ) are
termed ROS.
Additional toxic radicals, termed reactive nitrogen species
(RNS), also contribute to oxidative/nitrosative stress, such as the
-
peroxynitrite (OONO ). This molecule is formed by the reaction
•-
of O2 with the primary vasodilator nitric oxide (NO):
Expert Rev. Resp. Med. 2(1), (2008)
 Intermittent hypoxia in obstructive sleep apnea
- -
O2• + NO →OONO
-
The presence of OONO drastically affects endothelial
function as it diminishes NO availability [41].
Pathways of increased ROS formation in OSA
Generally, one of the main sources of ROS formation is from
mitochondria through electron leakage during respiration, which
serves for signaling purposes. It is estimated that, under normal
physiological conditions, approximately 5% of the inspired oxy-
gen is converted to ROS. During hypoxia/reoxygenation condi-
tions, mitochondria become dysfunctional [42]. However, forma-
tion of ROS can result from activation of various ROS-
producing enzymes, such as xanthine oxidase and NADPH oxi-
dase, from activated leukocytes and endothelial cells [11,43].
Additional possible sources include enzymes such as cyclooxyge-
nase, lipooxyganase, NO synthase and heme oxygenases [12]. In
OSA, mitochondrial dysfunction was demonstrated through
measurement of changes in the cytochrome oxidase redox state
during obstructive apnea [44]. Activation of xanthine oxidase was
implicated indirectly through increases in the levels of metabolic
by-products that characterize this pathway [2]. Thus, increases in
by-products such as uric acid and adenosine were reported in
OSA [10]. However, the data implicating increased activity of
NADPH oxidase are the most convincing. The NADPH oxidase
is the primary enzyme that is utilized by inflammatory phagocytic
cells to generate ROS in order to kill invading microorganisms.
However, ROS are also produced by phagocytes at low levels
under basal conditions [45]. In patients with OSA, both mono-
cytes and granulocytes were shown to be activated and to release
two- to threefold higher amounts of ROS compared with control
subjects [6,7]. In mice exposed to IH conditions, NADPH oxidase
was implicated in brain injury [46]. The result of such increases in
ROS formation in OSA, as well as in animal models treated by
IH, is evident by the presence of oxidized macromolecules, such as
lipids, proteins DNA and carbohydrates [8,9,39,46–50]. In parallel,
sleep apnea patients also demonstrate decreased antioxidant
capacities [51,52,39], which further disrupt the tightly regulated
cellular oxidation–reduction (redox) state.
Collectively, the wealth of data accumulated thus far clearly
attest to the presence of oxidative stress in OSA by increased
production of ROS as well as by decreased antioxidant capacity.
Consequences of oxidative stress
A large body of evidence demonstrates that ROS molecules
play a dual role. On the one hand, due to their high chemical
reactivity, as mentioned previously, ROS can damage various
biomolecules and cellular components, such as lipids, proteins,
carbohydrates and DNA, by oxidation and, by that, can alter
their functions and induce various pathologies. On the other
hand, under normal physiological conditions, ROS function as
signaling molecules [53]. Thus, the altered ROS balance may
activate some signaling pathways and inhibit others, leading to
altered gene expression. Consequently, the plethora of signaling
pathways that are activated can initiate inflammatory
www.future-drugs.com
Review
responses that ultimately lead to atherosclerosis [54]. In partic-
ular, ROS were implicated in initiation of inflammatory path-
ways via activation of nuclear transcription factors, such as
nuclear factor (NF)κB and activator protein (AP)-1, which
orchestrate the production of adhesion molecules and inflam-
matory cytokines. Another group of transcription factors that
could possibly be affected by redox imbalance and oxidative
stress are the sterol regulator element-binding proteins
(SREBPs) [55]. These SREBPs that activate genes regulating
lipid metabolism [56,57] were shown to be upregulated in
experimental models of IH [58,59].
Induction of the master regulator hypoxia-inducible factor
(HIF)-1α, which is essential for oxygen homeostasis and
adaptive response to hypoxia, was documented primarily in
several experimental models of IH in tissue culture and
rodents exposed to chronic IH [60]. Moreover, delineating the
transduction signals that activate HIF-1α under IH condi-
tions were found to differ from sustained hypoxia [61].
Although HIF-1α activation was not directly demonstrated in
patients with OSA, upregulation of some of its gene products,
including erythropoietin, VEGF and heat-shock proteins,
supports this notion [10,62,63].
Additional redox-sensitive transcription factors with far-
reaching implications to cardiovascular morbidity that merit
intensive investigation in OSA include members of the GATA
family. Emerging evidence implicates GATA-4 and -6 in regula-
tion of cardiac development and growth as well as in heart fail-
ure. Altered balance of these transcription factors may cause car-
diac hypertrophy or promote cardioprotection [64]. In recent
studies headed by Suzuki and colleagues utilizing a mouse
model of IH, GATA-4 was shown to exert preconditioning-like
cardioprotective effects by protecting cardiomyocytes from
apoptosis. However, while acute IH was cardioprotective, expo-
sure of mice to prolonged IH resulted in increased susceptibility
of the heart via increased oxidative stress. Further exposure to
prolonged IH facilitated reversal of the enhancement of myo-
cardial damage [65,66]. Thus, elucidating the complex effects of
IH on these transcription factors in the human heart could be
helpful in identifying patients with OSA at risk of developing
cardiovascular morbidity or, alternatively, cardioprotection.
NFκB & inflammatory pathway activation in
sleep apnea
Activation of the inflammatory pathways via NFκB upregu-
lation was recently demonstrated in neutrophils and mono-
cytes of patients with OSA [67–69], as well as in a tissue cul-
ture model utilizing HeLa cells that were exposed to IH
in vitro [70]. Also, increased AP-1 activity and tyrosine
hydroxylase mRNA, an AP-1-regulated downstream gene,
were shown in PC12 cells exposed to IH [71]. Accordingly,
upregulation of adhesion molecules and inflammatory
cytokines, the gene products of NFκB and AP-1, in patients
with OSA further support NFκB and AP-1 activation [10,12].
77
 Review Lavie
Moreover, IH in vitro was shown to activate NFκB in an IκB
kinase (IKK)-dependent manner at least in part via activation
of p38 MAPK [72].
Thus, the ROS molecules produced in response to IH by the
ROS-producing enzymes and dysfunctional mitochondria, pre-
sumably from endothelial cells and leukocytes, initiate a cascade
of inflammatory pathways resulting in overexpression of adhesion
molecules and proinflammatory cytokines. These adhesion mole-
cules facilitate the recruitment and accumulation of leukocytes
and platelets on the endothelial cells lining the vasculature and
promote neutrophils/monocyte/lymphocyte/platelets/endothelial
cell interactions. Such cellular interactions between blood cells
and endothelial cells may result in injury to the endothelium.
Adhesion molecules on leukocytes & interactions with
endothelial cells
Adhesion molecules are upregulated in endothelial cells and
blood leukocytes in response to various pathological conditions
and insults, such as hypoxia/reoxygenation. Their expression is
a highly regulated, sequential process and is exhibited in both
endothelial cells and leukocytes and promotes the interactions
between these cell types. These sequential interactions involve
three independent steps: rolling, firm adhesion and trans-
migration [54]. In each step, a defined set of adhesion molecules
participate, having specific receptors and counter-receptors on
leukocytes and endothelial cells [54]. The interactions between
endothelial cells and various leukocyte subpopulations of
patients with OSA, including monocytes, granulocytes and
numerous cytotoxic T cells expressing CD8, CD4 and γ δ, were
rigorously investigated in our laboratory [7,73–77].
Neutrophils
The expression of the CD15 carbohydrate complex on selectins (of
the family of adhesion molecules that mediate rolling) of OSA
neutrophils was increased in a severity-dependent manner. Treat-
ment with nCPAP downregulated its expression. On the other
hand, the expression of CD11c, a β-subunit of the integrins (and a
counter receptor for intercellular adhesion molecule (ICAM)-1 on
endothelial cells responsible for firm adhesion), was unaffected.
Furthermore, neutrophil apoptosis – a fundamental injury-limit-
ing mechanism that prevents its destructive potential – was
delayed in OSA; thus, together with increased expression of adhe-
sion molecules, delayed neutrophil apoptosis may promote
endothelial injury [77].
Monocytes
The expression of two adhesion molecules was increased in mono-
cytes of patients with OSA compared with controls. Notably,
CD15 and CD11c were elevated, while treatment with nCPAP
attenuated their expression [7]. Moreover, increased CD15 expres-
sion on monocytes was dependent on the severity of the syn-
drome [76] and treatment of monocytes from healthy individuals
with hypoxia in vitro upregulated their expression. Thus, increased
adhesion of monocytes from patients with OSA to endothelial cells
78
of venous (HUVEC) and arterial origin (HCAEC) was noted.
Moreover, by utilizing antibodies to selectins (anti-CD62) and
integrins (anti-CD54), the adhesion to endothelial cells was
attenuated to values comparable with controls [7].
Cytotoxic T lymphocytes
The cytotoxic T-lymphocyte subpopulation of patients with OSA
that were investigated also expressed an activated and cytotoxic
phenotype. Increased adhesion to endothelial cells and increased
cytotoxicity towards endothelial cells were shown by the CD8+,
CD4+ and γ δ-cytotoxic T lymphocytes compared with controls
+
[73–75]. Moreover, the killing abilities of CD8 T lymphocytes
were found to also be AHI-severity dependent. Yet, each sub-
population employed different killing mechanisms to damage
endothelial cells [73–75]. While CD8+ T lymphocytes primarily
expressed higher amounts of the CD56 natural killer receptors and
perforin, CD4+ killing relied on the presence of CD4+/CD28null T
cells and the killing by γ δ+ T lymphocytes was primarily mediated
by the presence of the proinflammatory cytokine TNF-α, which
was found to be elevated in patients with OSA.
Platelets
Similarly to circulating leukocytes, platelets have also been
shown to acquire an activated and a prothrombotic phenotype
in response to hypoxia/reoxygenation. Platelets from patients
with OSA expressed increased activation and aggregability
in vitro. The percentage of platelets expressing P-selectin
(CD62P) was higher [78,79], mainly in the severe group of
patients [80] and was effectively lowered by treatment with
nCPAP [81]. In addition, increases in hematocrit, blood viscosity
and fibrinogen in patients with OSA could further affect hyper-
coagulability [82,83]. Furthermore, in an ongoing study in our
lab, we found that platelets of patients with OSA form higher
amounts of platelets/monocytes aggregates compared with their
age-, sex- and BMI-matched controls (VISHNEVSKY A, LAVIE P, LAVIE L,
UNPUBLISHED OBSERVATIONS ). Owing to the fact that platelets were
shown to play a key role in ischemic cardiovascular diseases,
their altered activation state and hyperaggregability may also
contribute to increased cardiovascular morbidity in OSA.
Collectively, the higher expression of adhesion molecules on
leukocytes, their higher avidity and the ability to strongly attach
to endothelial cells in culture conditions, the stronger cyto-
toxicity of T cells against endothelial cells, the delayed apoptosis
expressed by neutrophils, the higher ROS generated by mono-
cytes and neutrophils, and the higher aggregability of platelets
are all markers of activation of the various blood cells investi-
gated in patients with OSA and can serve as markers of the pos-
sible ongoing processes that may damage the endothelium and
initiate atherogenesis.
Activated endothelial cells in OSA
The occurrence of soluble variants of adhesion molecules origi-
nating in endothelial cells were found in plasma or sera of
patients with OSA. These variant adhesion molecules are shed
Expert Rev. Resp. Med. 2(1), (2008)
 Intermittent hypoxia in obstructive sleep apnea
when endothelial cells become activated. Several well-estab-
lished markers were identified, including P- and E-selectin,
ICAM-1 and vascular cell adhesion molecule (VCAM)-1. All
are considered as markers of active atherosclerotic diseases and
as predictors of future cardiovascular disease [12].
Proinflammatory cytokines
Proinflammatory cytokines, similar to adhesion molecules,
are affected by the redox state of the cells in which they are
synthesized and actively participate and modulate inflam-
matory responses. Cytokines are multipurpose molecules and
regulate both the innate and adaptive immune system. They
regulate macrophage activation via expression of scavenger
receptors and secretion of metalloproteinases, modulate the
proliferation of smooth muscle cells, the production of nitric
oxide and apoptosis, and stimulate the activation of endothe-
lial cells: all of which are steps in the progression of athero-
sclerosis. The main cytokines investigated in OSA include
TNF-α, IL-6 and IL-8, and the anti-inflammatory cytokine
IL-10, which were all shown to be affected by OSA. Evi-
dently, once the inflammatory response is initiated, these
cytokines can in turn activate NFκB and, by that, further
exaggerate inflammation. In patients with OSA, increases in
proinflammatory cytokine levels were primarily found in the
circulation [84]. However, elevated levels in monocytes (GOLAN-
SHANY O, LAVIE P, LAVIE L, UNPUBLISHED OBSERVATIONS) and in various cyto-
toxic T lymphocytes were also observed [74,75]. Critically,
patients with sleep apnea, besides having increased expression
of proinflammatory cytokines, also display an altered proin-
flammatory/anti-inflammatory cytokine balance. For
instance, CD8+ T lymphocytes expressed higher levels of
TNF-α than controls. However, the levels of the anti-inflam-
matory cytokine IL-10 were also increased, presumably as a
protective mechanism to counteract TNF-α actions; yet, this
increase in IL-10 levels was not proportional to the increases
obtained in the production of TNF-α [75].
Sterol regulator element-binding proteins
Another possible set of transcription factors that could be a
plausible candidate for the growing list of redox-regulated tran-
scription factors in OSA is the family of SREBPs. The SREBPs
are endoplasmic reticulum membrane-bound transcription fac-
tors that activate more then 30 genes encoding the enzymes
that regulate the synthesis and uptake of cholesterol, fatty acids,
triglycerides and phospholipids [57]. The activity of SREBPs is
regulated by sterol feedback inhibition. Normally, SREBP is
activated in sterol-depleted cells and is inactivated with high
cholesterol levels. However, under IH conditions, there could
be an over-ride of this mechanism due to lack of oxygen, which
leads to upregulation of SREBPs [85–87].
Recently, in a series of elegant studies, Polotsky’s group
established the development of atherosclerosis in a rodent
model exposed to chronic IH [88]. This group also found that
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Review
lipid peroxidation and atherosclerosis were both dependent on
the severity of the chronic IH and that the SREBP-1 pathway
mediated the hyperlipdemia observed in this model [86,89].
Given that OSA is associated with hyperlipidemia independ-
ent of obesity, as manifested by various studies [33–37] and
based on the above cited animal studies, it is reasonable to
assume that the hyperlipidemia observed in OSA is mediated
via upregulation of the SREBP-1 pathway. No less important
is the fact that oxidative stress was implicated in the upregula-
tion of SREBP, while this upregulation was sensitive to anti-
oxidants [55]. Thus, IH and oxidative stress in humans, as in
experimental models, may upregulate SREBP-1, leading to the
hyperlipidemia associated with OSA.
Endothelial dysfunction & early signs
of atherosclerosis
In the normal state, the endothelium is responsible for regula-
tion of the vascular tone and interactions between the vessel wall
and circulating substances and blood cells. Thus, it maintains an
anticoagulant and anti-inflammatory phenotype. Upon disrup-
tion of this balance, the endothelium is activated and can
acquire a prothrombotic and proinflammatory phenotype that
leads to endothelial dysfunction – the earliest sign of atheroscle-
rosis [54,90]. Basically, endothelial dysfunction represents a state
in which vasodilatation of the blood vessels is compromised due
to decreased NO bioavailability. NO is the most potent vasodi-
lator but it also mediates many of the protective functions of the
endothelium. It limits leukocyte recruitment and leukocyte
expression of adhesion molecules. It prevents proliferation of
vascular smooth muscle cells and platelet aggregation and adhe-
sion. Thus, it protects from atherosclerosis. Exposure to oxida-
tive stress, inflammatory mediators or hypercholesterolemia, all
of which promote endothelial cell activation and endothelial
dysfunction, impair NO bioavailability [54,90,91]. In patients with
OSA, several studies have demonstrated diminished NO bioa-
vailability, which was restored after nCPAP treatment [92–94].
These data further implicate atherosclerotic sequlae in the devel-
opment of cardiovascular morbidity in OSA. In addition, several
measures that represent early signs of atherosclerosis were also
shown to be elevated in OSA, including increased intima–media
thickness that was also severity dependent [95–97], arterial plaque
formation [98], calcified artery atheromas [99] and higher pulse
wave velocity [97,100]. Thus, cardiovascular morbidity in sleep
apnea is foreseeable. Moreover, this is further demonstrated by a
recent study showing that such early signs of atherosclerosis were
significantly improved by 4-month treatment with nCPAP [95].
However, these recent findings should also be reproduced and
investigated in patients of moderate severity.
This course of events, starting with sleep apnea IH and oxidative
stress through activation of cellular inflammatory pathways and
pathways that cause hyperlipidemia, may injure the endothe-
lium and consequently impose cardiovascular morbidity or,
alternatively, may confer cardioprotection, as illustrated in FIGURE 1.
79
 Review Lavie

OSA/IH

ROS

Redox-sensitive transcription factor activation

??*
NFκB, AP-1 SREBP HIF-1a

??
Inflammation Hyperlipidemia Adaptation
GATA-4
• Adhesion molecules • Cholesterol and fatty acid synthesis • VEGF
• Cytokines • Cellular uptake of lipoproteins • EPO
• Leukocytes Protection • HSPs
• Platelets
• Endothelial cells
Endothelial dysfunction

Atherosclerosis

Cardiovascular morbidity Cardioprotection?

Cardiac hypertrophy?

Figure 1. Accelerated atherosclerosis and development of cardiovascular morbidity in OSA. IH initiates activation of ROS-
producing systems, resulting in an altered redox balance and activating various redox-sensitive transcription factors. Activation of
the inflammatory pathway via NFκB leads to activation of various leukocyte subpopulations (neutrophils, monocytes and
lymphocytes), platelets and endothelial cells, facilitating increased injury to endothelial cells via adhesion molecules,
proinflammatory cytokines, further increases in ROS molecules and diminished NO bioavailability, culminating in endothelial
dysfunction, the primary step in the development of atherosclerosis. Activation of SREBPs increases lipogenesis and elevates
cholesterol levels in the circulation, which also leads to endothelial dysfunction. The question arises as to whether this mechanism
then acts through inflammatory pathways, further exacerbating them. Adaptive mechanisms are also activated via HIF-1 and
upregulation of its protein products and may protect some individuals more than others. Altered expression of GATA-4, a cardiac
muscle cell survival transcription factor, may directly promote either cardioprotection or development of cardiac hypertrophy.
AP: Activator protein; EPO: Erythropoietin; HIF: Hypoxia-inducible factor; HSP: Heat-shock protein; OSA: Obstructive sleep apnea;
ROS: Reactive oxygen species; SREBP: Sterol regulator element-binding protein; VEGF: Vascular endothelial growth factor.
*
So far supported by induction via oxidative stress induced by Hepatitis C virus [55].

diseases by the time of diagnosis. It is evident that mecha-

Expert commentary
In recent years, a large body of evidence implicates oxidative
stress, inflammation and, more recently, hyperlipidemia as
fundamental mechanisms in the pathophysiology of cardio-
vascular morbidity in OSA. These confirmed the identifica-
tion of OSA as an independent risk factor for cardiovascular
morbidity. As outlined in this review, the sequence of events
starting with the nightly occurrence of IH and ending with
endothelial dysfunction provides an explanation of why OSA
patients, free of any overt cardiovascular diseases, have dis-
played early signs of atherosclerosis as increased carotid
intima–media thickness, arterial plaque formation, calcified
artery atheromas, atherosclerotic lesions and higher pulse
wave velocity, and why many of them display cardiovascular
nisms such as increased oxidative stress, activation of redox-
sensitive transcription factors and the inflammatory/immune
cells, accompanied by expression of various adhesion mole-
cules and inflammatory cytokines that culminate on endothe-
lial dysfunction, share many similarities with atherogenic
pathways of ischemia/reperfusion injury and most likely with
hypercholesterolemia as well.
Some of these early clinical signs are dependent on apnea
severity and could be reversed by treatment with nCPAP.
These early clinical signs of atherosclerosis most probably
start to accrue during the early stages of the disease, regard-
less of patient’s symptoms. Patients, however, are generally
referred for diagnosis only when the characteristic symptoms
of snoring or excessive daytime sleepiness start to affect them

80 Expert Rev. Resp. Med. 2(1), (2008)

 Intermittent hypoxia in obstructive sleep apnea Review

or are noticed by people around them, generally around the
age of 50 years. Diagnosis and treatment of OSA at this age,
which is delayed by 10–20 years from the time damage to the
cardiovascular system was incited, may be too late. Further-
more, as mortality risk in sleep apnea is maximal at younger
ages [101], it is also too late for many of the patients who are at
maximal risk of dying. Thus, one of the most important clin-
ical lessons learnt from understanding the underlying patho-
physiology of OSA is that, in order to prevent cardiovascular
morbidity, treatment of breathing disorders in sleep should
start at the earliest possible age.
Five-year view
Sleep medicine has seen unprecedented growth in the last
two decades, mostly owing to the growing awareness of OSA
and its profound impact on patients’ quality of life and
cardiovascular health. In the next few years, based on the
mechanistic insights accumulated in OSA and from the
ongoing studies on in vivo and in vitro models of IH,
research will further elaborate and refine the understanding
of the cellular and molecular mechanisms mediating the
effects of IH on the cardiovascular system. Specifically, I
believe that the importance of nitrosative mechanisms that
induce nitrosative stress under IH conditions and additional
redox-sensitive transcription factors activated in OSA
patients, by IH, will be identified. Specific transduction
pathways of the redox-activated transcription factors will
most likely be elucidated with their similarities/dis-
similarities to mechanisms of sustained hypoxia and to
ischemia/reperfusion already established. Likewise, the
sequence of interactions of various leukocytes with the
endothelium exposed to IH in animal models in vivo will be
clarified using various knockout and transgenic animal mod-
els exposed to IH and utilizing methods such as intravital
microscopy.
The pathophysiology of IH on the major metabolic organ –
the liver – is only just being unveiled. Currently, the unknown
exceeds by far the knowledge accumulated; this is also true for
the heart. It is very likely that, in the next few years, the effects
of IH will be expanded to additional internal organs, such as
the brain, kidneys, spleen, endocrine organs and muscles.
Moreover, the interactions of OSA and the resultant oxidative
stress with hypertension, diabetes, hyperlipidemia and obesity
will be delineated at the cellular and molecular levels.
Importantly, as not all patients with sleep apnea develop
cardiovascular morbidity, it is obvious that OSA not only
elicits inflammatory and hyperlipidemic pathways but also
adaptive pathways that result in ischemic preconditioning of
the heart and possibly the brain and liver. The question as to
who is at risk of developing cardiovascular morbidity, and if
there is a genetic basis for this adaptation, will be addressed in
the next few years.
Finally, in the last 25 years, treatment of OSA almost
exclusively relies on the nCPAP, which was shown to be effec-
tive in reversing endothelial dysfunction and preventing car-
diovascular sequela. In the next few years, research will focus
on examining the efficacy of other treatment modalities, such
as more effective and more friendly user alternatives to
nCPAP, dental devices or massive weight reduction. In view
of the pivotal role played by oxidative stress and hyper-
lipidemia in this process, the possible effects of antioxidants
and statins will also be explored.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Obstructive sleep apnea is an independent risk factor for cardiovascular morbidity and mortality.
• The intermittent recurrent pauses in respiration in sleep apnea, in a similar manner to hypoxia/reoxygenation, induce oxidative stress
and diminish nitric oxide availability.
• Increased production of reactive oxygen species (ROS) and/or decreased antioxidant capacity that result in oxidative stress and altered
redox balance activate redox-sensitive transcription factors.
• These transcription factors activate inflammatory, hyperlipidemic and adaptive pathways but may also directly damage the heart or
induce cardioprotection.
• Activation of the inflammatory pathways, characterized by increased expression of adhesion molecules and proinflammatory
cytokines, leads to an increase in adhesion and cytotoxicity by various leukocyte subpopulations towards endothelial cells.
• Activation of lipogenic pathways by intermittent hypoxia results in hypercholesterolemia. This may exaggerate ongoing inflammatory
pathways already activated by the intermittent hypoxia.
• The above chain of events results in atherosclerotic sequelae, such as endothelial dysfunction and early signs of atherosclerosis,
which, if untreated, will eventually manifest in overt cardiovascular diseases.
• Treatment of sleep apnea should be initiated as early as possible in order to abort the atherosclerotic chain of events.

www.future-drugs.com 81
 Review Lavie
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Affiliation
Lena Lavie, PhD
Unit of Anatomy and Cell Biology, The Ruth and
Bruce Rappaport Faculty of Medicine, Technion,
PO Box 9649, 31096, Haifa, Israel
Tel.: +972 4829 5234
Fax: +972 4834 3934/4829 5403
lenal@tx.technion.ac.il
Expert Rev. Resp. Med. 2(1), (2008)