Intermittent hypoxemia and OSA: implications for comorbidities

Abstract

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.

Figure 1 –

Pathway for intermittent hypoxemia (IH) and OSA comorbidities. OSA-associated IH promotes increased activity of NADPH oxidase via stimulation of HIF-1 with impaired mitochondrial function and reduction in antioxidant levels via HIF-2 to increase ROS and RNS contributing to oxidative stress. Increased activity of HIF-1 may also contribute to tumor growth by increased expression of VEGF and angiogenesis. IH also promotes increased carotid body-mediated sympathetic nerve activity with BP elevation, systemic and vascular inflammation by increased activity of NF-κB, with enhanced levels of cytokines such as TNF-α, IL-6, and CRP with increased expression of adhesion molecules on the endothelial surface. IH also causes activation of type 1 angiotensin II receptors with increased aldosterone levels, increased endothelin 1 levels, and decreased activity of eNOS to promote vasoconstriction and BP elevation. OSA thus leads to increased oxidative stress, systemic and vascular inflammation, vasoconstriction, and elevated BP to promote multiorgan comorbidity. Angio II = angiotensin II receptor; CRP = C-reactive protein; eNOS = endothelial nitric oxide synthetase; HIF = hypoxia-inducible factor; NADPH = reduced nicotinamide adenine dinucleotide phosphate; NF-KB = nuclear factor-κΒ; RNS = reactive nitrogen species; ROS = reactive oxygen species; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor. (Partly adapted with permission from Kohler and Stradling.¹²)

Figure 2 –

Survival free of cancer mortality according to categories of sleep-disordered breathing, Wisconsin Sleep Cohort, 1989-2011; Kaplan-Meier estimates. AHI = apnea-hypopnea index. (Reproduced with permission from Nieto et al.³)