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1 The Woolcock Institute of Medical Research, Sleep and Circadian Group, 3 Centre for Respiratory Failure and Sleep Disorders, Royal Prince Alfred Hospital, Camperdown, 2 Centre for Sleep Health and Research, Royal North Shore Hospital, St Leonards, and 4 Dept of Medicine, University of Sydney, Sydney, NSW, Australia.
CORRESPONDENCE: R. R. Grunstein, Woolcock Institute of Medical Research, Camperdown, NSW, Australia. Fax: 61 295157070. E-mail: rrg{at}med.usyd.edu.au
Reactive 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.
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 apnoea-associated 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.
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 
-glutamyltransferase (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.
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 end-points 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.
REFERENCES
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