Obstructive sleep apnoea: time for a radical change? EDITORIAL

Eur Respir J 2006; 27: 671–673
DOI: 10.1183/09031936.06.00017206
CopyrightßERS Journals Ltd 2006
EDITORIAL
Obstructive sleep apnoea: time for a radical change?
C.L. Phillips*,# and R.R. Grunstein*,",+
eactive oxygen species (ROS) are highly reactive
molecules that originate from both (intra- and extracellular) endogenous sources and from exogenous
sources. They can be broadly divided into free radicals and
nonradical reactive species; STOCKER and KEANEY [1] have
examined this in a more extensive review. In the basal state,
ROS play an essential physiological role in cellular signalling
pathways and transcriptional regulation, which act to maintain
cellular homeostasis [2]. In contrast, oxidative stress is
characterised by an excess of ROS, which can ultimately result
in cellular injury via reactions with proteins, nucleic acids and
lipids. As such, oxidative stress is hypothesised to play a
primary role in the development of many disease processes,
including atherosclerosis.
R
The oxidative modification hypothesis of atherosclerosis
centres on the well-known association between low-density
lipoprotein (LDL) cholesterol and atherosclerosis and, in
particular, on the uptake of oxidised LDL by macrophages
within the arterial wall to form foam cells, the earliest stage in
atherogenesis. In addition to inflammatory cells, there are a
number of vascular cell types, including vascular smooth
muscle cells, endothelial cells and adventitial fibroblasts,
which all provide a source of oxidants within the vessel wall
and could play a role in the conversion of LDL into its oxidised
(high-uptake) form. The metabolic and enzymatic sources of
ROS include (but are not limited to) nicotinamide adenine
dinucleotide phosphate oxidases, xanthine oxidase, nitric
oxide synthase, myeloperoxidase, lipoxygenase and mitochondrial respiration [1, 3].
The intra- and extracellular accumulation of the various forms
of ROS are limited by several endogenous and dietary-derived
antioxidants. These antioxidant defences act by directly
suppressing the generation of free radicals, by scavenging
radicals and repairing damaged cells [4]. They can be broadly
divided into three types. Enzymatic antioxidants include the
superoxide dismutases and peroxidases (e.g. glutathione
peroxidase), which act to remove most superoxides and
peroxides from within cells. Metal-chelating proteins are
antioxidants involved in the sequestration of transition metals
(iron and copper) that can induce oxidative damage. Finally,
the nonproteinaceous antioxidants include water-soluble (e.g.
ascorbate and uric acid) and lipid-soluble (e.g. vitamin E, the
tocopherols) forms, of which the latter plays a crucial
antioxidant role in radical-induced lipid peroxidation.
The potential role of oxidative stress in the aetiopathogenesis
of atherosclerosis has been extensively investigated in conditions that predispose to cardiovascular disease. Obstructive
sleep apnoea (OSA) is one such condition. In the past decade,
numerous studies have increasingly provided evidence linking
OSA to the development of both cardiovascular and cerebrovascular disease [5–7]. The associated risk attributable to OSA
has been found to be independent of traditional risk factors
such as age, sex and obesity. A number of mechanistic studies
that have included treatment with continuous positive airway
pressure (CPAP) have provided several potential pathways by
which OSA may increase cardiovascular disease. Many of
these studies bear all the hallmarks of redox imbalance and
include both an increase in ROS levels [8, 9] and a decrease
in antioxidant levels [9, 10]. Several studies also demonstrate alterations to endothelial integrity marked by
reduced production and/or enhanced destruction of nitric
oxide [11, 12] and increased vascular inflammation [13, 14],
both of which underpin the demonstrated endothelial dysfunction associated with this disorder [15]. Endothelial
dysfunction is considered to be an early marker of atherosclerotic disease [16].
These studies have typically involved patients with apnoeaassociated intermittent hypoxia, and this has led to the
proposal that the development of atherosclerosis in OSA
subjects is due to oxidative stress arising from hypoxia
reoxygenation, which is similar to the hypoxia-reperfusion
injury seen when ischaemic or hypoxic tissue is resupplied
with oxygen-rich blood. LAVIE [17] provides a comprehensive
discussion on this subject.
CORRESPONDENCE: R.R. Grunstein, Woolcock Institute of Medical Research, Camperdown, NSW,
Australia. Fax: 61 295157070. E-mail: [email protected]
Adding to the studies cited previously, in this issue of the
European Respiratory Journal, BARCELÓ et al. [18] find further
evidence in support of an altered redox state in subjects with
OSA. The study compared the antioxidant status of subjects
with OSA at baseline and again following 12 months of CPAP
treatment with that of a control group without OSA. BARCELÓ
et al. [18] found that in OSA, compared with controls, there was
a decrease in total antioxidant status (TAS) together with
decreased levels of vitamins A and E and increased levels of cglutamyltransferase (GGT), a suggested marker of oxidative
stress [19]. CPAP was found to normalise the TAS and GGT
activity without altering vitamin levels. Glutathione peroxidase, vitamin B12 and folate (antioxidants), as well as
homocysteine (a marker of increased cardiovascular risk),
were not elevated at baseline.
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*The Woolcock Institute of Medical Research, Sleep and Circadian Group, "Centre for Respiratory
Failure and Sleep Disorders, Royal Prince Alfred Hospital, Camperdown, #Centre for Sleep Health
and Research, Royal North Shore Hospital, St Leonards, and +Dept of Medicine, University of
Sydney, Sydney, NSW, Australia.
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OBSTRUCTIVE SLEEP APNOEA
C.L. PHILLIPS AND R.R. GRUNSTEIN
Whilst this study does lend support for a partially reversible
altered redox status in OSA, it does little to explain the
mechanism behind these alterations. In another recent study
[20], acute intravenous administration of vitamin C was found
to improve endothelial dysfunction in OSA subjects. However,
the studies by GREBE et al. [20] and BARCELÓ et al. [18] were
unable to establish any relationship between vascular antioxidant status and/or function with apnoea/hypopnoea index
or measures of hypoxaemia. However, this association is
hypothesised to underpin the process of atherosclerosis in OSA
[17]. Furthermore, in contrast to the study by BARCELÓ et al.
[18], other studies have failed to even establish links with
increased oxidative stress, both within OSA cohorts [21, 22]
and in cohorts that are strongly associated with OSA, such as
type 2 diabetes and metabolic syndrome [23, 24].
These inconsistent findings probably reflect the complexity of
the vascular pathophysiology of atherosclerosis in all conditions that are associated with an increased risk for cardiovascular disease. STOCKER and KEANEY [1] highlighted that the
process of lipoprotein lipid peroxidation can be dissociated
from atherosclerosis, and studies that do demonstrate an
association have, to date, been unable to demonstrate causation. Furthermore, human antioxidant clinical trials have, to a
large extent, failed to demonstrate any improvement in
cardiovascular outcomes [25, 26]. These failures may be
attributable to the potential for more than one oxidant (or
combinations of oxidants) to promote disease that cannot be
ameliorated by one single antioxidant agent. Furthermore, in
concert with environmental influences, there may be genetically determined heritable polymorphisms for pro- and
antioxidant enzymes, which dictate the ‘‘oxidative enzymopathies’’ that ultimately determine individual susceptibility to
cardiovascular disease development [3].
The reality is that it is probably simplistic to link intermittent
hypoxaemia in obstructive sleep apnoea to cardiovascular endpoints as a direct cause–effect relationship. Certain obstructive
sleep apnoea patients may well be more susceptible to
cardiovascular disease, and methods for the detection of these
patients need to be developed. Ultimately, large intervention
studies will be required that are beyond the resources of one
centre and will require multinational initiatives. Such studies
may include factorial designs with continuous positive airway
pressure, sham continuous positive airway pressure and,
indeed, dietary antioxidant supplementation, and collect data
on genetic factors. Given the increasing evidence that
obstructive sleep apnoea is a cardiovascular hazard, it is
probably time for the sleep apnoea field to move away from
small mechanistic studies and make the radical change to
implement such a research programme.
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