Chest
Volume 147, Issue 1, January 2015, Pages 266-274
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Contemporary Reviews in Sleep Medicine
Intermittent Hypoxemia and OSA: Implications for Comorbidities

https://doi.org/10.1378/chest.14-0500Get rights and content

OSA is a common chronic disorder that is associated with significant morbidity and mortality including cardiovascular, metabolic, and neurocognitive disease and increased cancer-related deaths. OSA is characterized by recurrent episodes of apneas and hypopneas associated with repetitive episodes of intermittent hypoxemia, intrathoracic pressure changes, and arousals. Intermittent hypoxemia (IH) is now being recognized as a potential major factor contributing to the pathogenesis of OSA-related comorbidities. OSA-related high-frequency IH is characterized by cycles of hypoxemia with reoxygenation that is distinctly different than sustained low-frequency hypoxia and contributes to ischemia-reperfusion injury. Data from both animal and human studies support mechanistic links between IH and its adverse impact at the tissue level. IH promotes oxidative stress by increased production of reactive oxygen species and angiogenesis, increased sympathetic activation with BP elevation, and systemic and vascular inflammation with endothelial dysfunction that contributes to diverse multiorgan chronic morbidity and mortality affecting cardiovascular disease, metabolic dysfunction, cognitive decline, and progression of cancer. Data from observational studies in large population groups also support the role for hypoxia in the pathogenesis of OSA comorbidity. Treatment with CPAP to reverse OSA-related symptoms and comorbidities has been shown to provide variable benefit in some but not all patient groups. Early treatment with CPAP makes intuitive sense to promote maximal functional recovery and minimize residual injury. More studies are needed to determine the interacting effects of IH and obesity, differential effects of both short-term and long-term hypoxemia, and the effect of CPAP treatment.

Section snippets

Pathogenesis of IH and Its Impact at the Tissue Level

Two broad patterns of hypoxemia have been recognized.4 Patients with OSA typically manifest short intermittent high-frequency hypoxemia (cyclical pattern of oxygen desaturation lasting 15-60 s followed by reoxygenation) that occurs for 8 to 9 h during sleep and lasts for weeks to months or longer. In contrast, sustained or low-frequency hypoxemia with oxygen saturation ranging between 80% and 85% that lasts from a few minutes to hours can be seen during rapid ascent and descent from altitude

Cardiovascular Dysfunction and Disease

While it is likely that apnea-related stressors such as negative intrathoracic pressure swings, sleep fragmentation, and arousal-related sympathetic activation during sleep contribute to OSA-related cardiovascular pathophysiology, the available evidence strongly implicates repetitive hypoxemia as a major mediator of cardiac and vascular disease and dysfunction.18, 19, 20, 21, 22

IH and Metabolic Dysfunction: Mechanisms

Animal experiments in mice exposed to IH for 14 days showed marked changes in insulin resistance, impaired β-cell function, and increases in oxidative stress that improved only partially after cessation of hypoxic exposure.46 Intermittent hypoxia as compared with room air also caused dyslipidemia in mice with elevation in serum total cholesterol and triglyceride levels that correlated with the degree of hypoxemia and was more marked in lean than obese mice.7 Data also suggest differential

OSA, Glucose Intolerance, and Diabetes Risk

Cross-sectional studies in subjects with OSA have shown an association between severity of sleep apnea and glucose intolerance and the likely risk for developing diabetes.50 The Sleep Heart Health Study that followed 2,665 subjects for 5 years showed an independent association between severity of sleep apnea as determined by AHI and nocturnal hypoxemia and an increased risk of developing glucose intolerance and potentially type 2 diabetes mellitus.51 This effect was independent of BMI and waist

IH and Cognitive Impairment: Mechanisms

Adults rats exposed to IH (12 h/d up to 14 days) showed impaired cognition that persisted at 14 days of recovery. A sevenfold to eightfold greater increase in apoptosis was also noted in the CA-1 hippocampus and cortical region after 1 to 2 days of IH.61 Experiments in a rat model showed differential effects of intermittent hypoxia and OSA on the brain.62 Brain tissue oxygen levels were higher in rats subjected to obstructive apneas compared with those subjected to intermittent hypoxia, and

IH, OSA, and Cognitive Impairment

Cognitive impairment in OSA includes daytime sleepiness and other cognitive and behavioral deficits that extend well beyond daytime sleepiness. Mild cognitive impairment similar to aging is also noted in patients with severe OSA. Cognitive impairment and dementia were seen more commonly in elderly women who had OSA as compared with no OSA and correlated with the severity of sleep apnea and hypoxia.67 Mild cognitive impairment as noted in the Apnea Positive Pressure Long-term Efficacy Study

OSA, Oncogenesis, and Cancer Risk

In vitro studies have demonstrated the pro-oncogenic properties of hypoxia.74 This is mediated mainly by the enhanced posttranslational effect of HIF, which in turn results in increased expression of vascular endothelial growth factor (VEGF), formation of new capillaries, tumor growth, and metastasis.15, 16, 74 Laboratory studies have also demonstrated that low-frequency intermittent hypoxia has similar proangiogenic and tumor growth promoting effects.14, 75, 76

Based on this evidence, a

Conclusions

In summary, data from both animal and human studies suggests a dominant role for OSA-associated IH as a major contributor to multiorgan comorbidity and mortality. More studies are needed to address the interacting effects of IH and obesity, the differential effects of both short-term and long-term hypoxia, and the effect of CPAP treatment.

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Somers has served as a consultant for ResMed; Respicardia, Inc; Sorin Group; and PricewaterhouseCoopers LLP, and as a principal investigator or co-investigator on grants from Respironics Charitable Foundation. He is also involved in intellectual property development in sleep and cardiovascular disease with Mayo Clinic Health Solutions (Mayo Foundation for Medical Education and

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    Parts of this article were presented as a Sleep Network Highlight session at CHEST 2013, October 26-31, 2013, Chicago, IL.

    FUNDING/SUPPORT: Dr Nieto's contributions were supported in part by the National Institutes of Health (NIH) [Grant R01HL062252-11] and by the University of Wisconsin Helfaer Endowed Chair of Public Health. Dr Somers' contribution to this work was supported by the NIH [Grant HL-65176].

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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