The present findings indicate that OSA rather than obesity is a major determinant of endothelial dysfunction, inflammation and elevated oxidative stress in obese patients. Increased body weight and central obesity were not associated with vascular endothelial dysfunction, inflammation and elevated oxidative stress in the absence of OSA. Furthermore, increasing adiposity does not appear to exacerbate the effects of OSA on the vascular endothelium.
A quarter of the American adult population suffers from OSA that remains overwhelmingly unrecognized.1,3,4
Moreover, only half of the patients diagnosed with OSA receive treatment.4
The prevalence of unrecognized OSA increases markedly with increasing adiposity. When adiposity increases by 1 SD, the risk of unrecognized sleep-disordered breathing increases by a 3-fold.1
Pervasive under-diagnosis of OSA may be due to the lack of daytime symptoms such as excessive sleepiness in the vast majority of OSA patients.1
A thorough history and physical examination cannot reliably exclude the presence of OSA even in severely obese patients.26
Regardless of the presence of daytime symptoms, OSA is an independent risk factor for cardiovascular diseases and increased mortality.5,27
Patients with OSA experience repetitive episodes of hypoxia/reoxygenation during transient cessation of breathing that reduce NO availability and promote inflammation and oxidative stress.11-13,28,29
Endothelial alterations similar to that of OSA have been reported in apparently healthy obese subjects.9
Cross-sectional studies suggest that endothelium-dependent arterial dilation, as assessed by FMD or direct intra-arterial administration of acetylcholine, is reduced in obesity.7,30
Moreover, BMI and visceral obesity correlate inversely with endothelium-dependent vasodilation in apparently healthy subjects.30-32
Elevated levels of soluble intra-cellular and vascular adhesion molecule-1 and E-selectin in obesity are consistent with endothelial inflammation and activation.33-35
Increased systemic oxidative stress is thought to contribute to endothelial dysfunction in obesity.36-39
Central distribution of adiposity, a major determinant of endothelial dysfunction, inflammation, and increased oxidative stress, is strongly associated with OSA.2,33,36,39
Since the majority of obese subjects suffer from unrecognized OSA, it is likely that OSA was present in a substantial subset of apparently healthy obese subjects who participated in the studies that linked obesity to endothelial dysfunction and cardiovascular disease.
Direct evidence that obesity is associated with endothelial inflammation and increased vascular oxidative stress was recently reported.9,40
Venous endothelial expression of NFκB and nitrotyrosine was found to be greater in apparently healthy overweight and obese subjects than in normal-weight counterparts.9
However, as in above studies, the presence of unsuspected OSA was not systematically excluded. In contrast to previous studies that directly and indirectly supported an association between obesity and endothelial dysfunction and inflammation, we could not link central obesity to vascular endothelial dysfunction, inflammation and increased oxidative stress in the absence of OSA. Although various factors may have contributed to these discrepant findings, the systematic exclusion of coexistent OSA clearly differentiates the present study from others.
Our findings of OSA-related vascular endothelial dysfunction in otherwise healthy obese patients concur with previous reports11,12
When compared to healthy subjects matched for adiposity, endothelium-dependent vasodilation is impaired in patients with OSA and improves after treatment. Our findings are also concordant with the observation that muscle sympathetic nerve activity is increased in obese patients with OSA but not in obesity alone.14
Increased endothelial expression of eNOS and P-eNOS and decreased expression of nitrotyrosine and NFκB after effective CPAP therapy provide further evidence that OSA, rather than obesity, was predominantly responsible for endothelial alterations in our study sample. Patients with OSA exhibited endothelial alterations that were reversible with CPAP regardless of the severity of adiposity. Although CPAP was not allocated randomly to our patients, reversal of endothelial dysfunction and inflammation in the absence of change in body weight strongly suggests that OSA is largely responsible for these endothelial alterations in obesity. The observed correlation between severity of OSA and the extent of endothelial alterations supports further OSA as a major contributor to endothelial dysfunction, inflammation and oxidative stress in obese patients.
While adipose tissue is a well known source of inflammation, the mechanisms that trigger and maintain the inflammatory response in obesity are incompletely understood. Adipose tissue hypoxia has been recently proposed as one of the major triggers of macrophage infiltration in adipose tissue.15-17
However, the cascade of events that leads to adipose tissue hypoxia remains unclear.15
The cyclic hypoxia associated with cessation of breathing in OSA may promote adipose tissue hypoxia and inflammation in obesity.
The precise mechanisms underlying cardiovascular risk in OSA and obesity cannot be ascertained from the study of the venous endothelium. Local biomechanical forces that affect arterial endothelial cells at specific sites play an essential role in determining regional susceptibility to atherosclerosis.41-44
Thus, endothelial biopsy at specific sites of the arterial vasculature will likely be required to determine the precise mechanisms underlying atherosclerosis in OSA and obesity. Endothelial cells undergo significant phenotypic drift when removed from their native environment and cultured in vitro
Direct characterization of harvested venous endothelial cells without the artifact of culture conditions provides novel insight into the mechanisms that mediate the vascular response to systemic inflammation in OSA and obesity.
In conclusion, OSA rather than obesity appears to be predominantly responsible for vascular endothelial dysfunction, inflammation and increased oxidative stress in obese patients. Accurate assessment of obesity-related vascular risk requires systematic exclusion of unsuspected OSA. Reversal of vascular inflammation with effective therapy for OSA emphasizes the importance of vigilant search and prompt treatment of OSA in overweight and obese subjects.
Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obese subjects. Both obesity and OSA have been associated with vascular endothelial alterations that underlie the development and progression of atherosclerosis and increased risk for cardiovascular diseases. Whereas obesity is commonly regarded as a confounding factor when evaluating vascular endothelial function in patients with OSA, the likely presence of OSA is not routinely considered when evaluating endothelial function in obesity. We investigated directly whether endothelial alterations that are frequently attributed to obesity are in fact related to OSA. Proteins that regulate basal nitric oxide (NO) production and inflammation, and markers of oxidative stress were quantified in venous endothelial cells harvested from normal-weight, overweight, and obese subjects who were systematically evaluated for OSA. The present data provide direct evidence that OSA rather than obesity is a major determinant of endothelial dysfunction, inflammation and elevated oxidative stress in obese patients. Increased body weight and central obesity were not associated with vascular endothelial dysfunction, inflammation and elevated oxidative stress in the absence of OSA. Furthermore, increasing adiposity did not exacerbate effects of OSA on the vascular endothelium. Systematic exclusion of unsuspected OSA is mandatory for accurate assessment of vascular risk in obesity. Reversal of vascular inflammation with effective therapy for OSA emphasizes the importance of a vigilant search and prompt treatment of OSA in overweight and obese subjects.