Morbidities Associated With Obstructive Sleep Apnea

Pathophysiology

OSA-induced biological changes include intermittent hypoxia, intermittent hypercapnia, intrathoracic pressure changes, sympathetic activation and sleep fragmentation.^[4] During intermittent hypoxia, there will be repeated episodes of hypoxia and normoxia resembling ischemia/perfusion events.^[5] During the hypoxic/ischemic phase, the cells adapt to a low oxygen environment; and during the reoxygenation/reperfusion phase, there will be a sudden increase of oxygen in the cells resulting in the production of reactive oxygen species.^[5–7]

OSA can cause sympathetic activation, metabolic dysregulation, endothelial dysfunction, systemic inflammation, oxidative stress, and hypercoagulation and neurohumoral changes. These changes may lead to hypertension (both systemic and pulmonary), heart failure, arrhythmias, myocardial infarction, stroke and sudden cardiac death. Repetitive episodes of upper airway narrowing and/or occlusion cause hypoxemia, reoxygenation, swings in intrathoracic pressure and CNS arousals. These factors can cause acute stress on the cardiovascular system, and the cumulative effects from these can lead to disruption of cardiovascular homeostatic mechanisms. These may lead to daytime abnormalities in sympathetic nervous system function and to heart rate variability.^[8]

Oxidative Stress

The majority of data suggest a role of oxidative stress in patients with OSA. Studies have demonstrated that there was an increase in thiobarbituric acid-reactive substance levels in patients with severe OSA compared with healthy control subjects and that treatment with continuous positive airway pressure (CPAP) reduced the lipid peroxidation events.^[9–12] It was also reported that there was an increased level of oxidized low-density lipoprotein levels in OSA.^[13] Inhibition of xanthine oxidase by allopurinol^[14] and supplemental intake of vitamin C have been shown to improve endothelial function in patients with OSA.^[15] Glycation products, the end result of oxidative stress, were also reported to be increased in OSA patients with normal glucose homeostasis.^[16] The demonstration that urinary 8-hydroxy-29-deoxyguanosine excretion was significantly higher in patients with severe OSA versus control subjects suggests oxidative DNA damage in OSA.^[17] The antioxidant capacity in the blood that acts as a defense line against free radicals has also been found to be reduced in OSA patients compared with control subjects.^[18] In an experimental human model of chronic intermittent hypoxia, it has been shown that there is an increase in oxidative stress by increasing the production of reactive oxygen species without a compensatory increase in antioxidant activity. The changes in oxidative stress have been shown to be associated with increased ventilatory sensitivity to hypoxia.^[19] In observational studies, a derangement in the oxidant–antioxidant balance with a shift towards oxidative stress was documented and treatment with the antioxidants (vitamin E, vitamin C and N-acetylcysteine) has demonstrated a reduction in oxidative stress in OSA patients.^[12,20] The results from these studies indicate the occurrence of oxidative stress in patients with OSA. However, there are studies that have not demonstrated increased oxidative stress in OSA.^[21,22] In a study of 41 moderate-to-severe OSA male patients without comorbidities and 35 matched control subjects, the authors could not demonstrate evidence for higher oxidative stress and lipid peroxidation.^[22]

Systemic Inflammation

It has been noticed that CD4 and CD8 T cells of patients with OSA undergo phenotypic and functional changes with a shift towards dominance of type 2 cytokines and increased IL-4 production.^[23] There was a negative correlation of IL-10 expression in T cells with the severity of OSA, and AHI had a positive correlation with TNF-α. A marked increase in TNF-α and CD40 ligand in CD8 T cells in patients with OSA was also reported. CPAP treatment improved or reversed all these abnormalities in OSA patients.^[23–25] Increased circulating levels of C-reactive protein (CRP) have been consistently reported in both adults,^[26,27] as well as in children with OSA,^[28] and are reduced on effective treatment.^[26,29] It has been reported that there is an independent association between severity of OSA and elevated CRP level in men without comorbidities.^[30] However, a randomized controlled trial did not show any change in CRP levels after CPAP treatment.^[31] NF-κB, an important factor for activation of inflammatory pathways, has been found to be increased in OSA.^[32] Increased expression of adhesion molecules, CD15 and CD11c, and increased adherence of monocytes in culture to human endothelial cells have also been reported in OSA.^[25] Expression of adhesion molecules on circulating monocytes may indicate activation of systemic inflammation in OSA.^[33] It has been reported that the TNF-α-308 polymorphism is associated with OSA.^[34]

Sympathetic Nerve Activation

It has been observed that there is increased sympathetic nerve activity in OSA.^[35] This increase in sympathetic activity during sleep may be due to the activation of peripheral chemoreceptors by hypoxia, hypercapnea and apneas leading to peripheral vasoconstriction and increase in BP.^[36] It has also been demonstrated that there is exaggerated sympathetic activity during daytime wakefulness despite normoxia.^[37] Increased concentrations of catecholamines in urine and elevated levels of norepinephrine in plasma were also seen in patients with OSA.^[38,39] Muscle sympathetic nerve activity has been found to be elevated in OSA during wakefulness^[35,40] and CPAP therapy reduces the high sympathetic activity.^[41] An increase in resting heart rate during wakefulness has been observed in OSA patients, suggesting that there is an increase in cardiac sympathetic drive in OSA.^[42] Thus chronic sympathetic activation may be an important factor for the development of cardiovascular disease in OSA.^[43]

Endothelial Dysfunction

Endothelial dysfunction in OSA is a risk factor for cardiac abnormalities that may be caused by chronic intermittent hypoxia, sleep loss and fragmentation.^[44] The dysfunction results in increased vasoconstriction and reduced vasodilation. Decreased levels of nitric oxide, which is a powerful vasodilator, in OSA may contribute to reduced vasodilation, platelet adhesion and aggregation, and recurrent hypoxemia has been found to increase endothelin levels. Endothelin is a potent vasoconstrictor causing elevated BP. Treatment in both cases give favorable results, increasing nitric oxide levels and reducing endothelin levels.^[45–47]

Procoagulant Activity

Analysis of several studies in OSA patients has shown that there are elevated levels of plasma fibrinogen, exaggerated platelet activity and reduced fibrinolytic activity, suggesting that there is a hypercoagulable state in OSA.^[48] The exaggerated platelet activity has been found to be reduced following treatment with CPAP.^[49] There is also an increase in mean platelet volume that has been reduced by CPAP therapy in OSA patients.^[50]

Intrathoracic Pressure Changes

During OSA, the repetitive inspiratory efforts against a closed upper airway lead to increased negative intrathoracic pressure. As a result, there will be an increase in transmural gradients across the atria, ventricles and aorta. This is similar to the Muller maneuver in which an individual inspires against a closed glottis leading to a pleural pressure of -30 cm H₂O. These changes in transmural gradients can result in autonomic and hemodynamic instability.^[51,52] An increase in aortic transmural pressure can cause aortic dissection in OSA patients.

Metabolic Syndrome

There are evidences suggesting that OSA is independently associated with metabolic syndrome.^[53,54] Chronic intermittent hypoxia and sleep deprivation with sleep loss may play a role in triggering inflammation leading to metabolic syndrome. OSA may be a risk factor for metabolic syndrome. Obesity, particularly central adiposity, is a potent risk factor for sleep apnea.^[55] An interaction of obesity–OSA-metabolic syndrome involving many mechanisms has been postulated.^[56] The National Cholesterol Education Program Adult Treatment Panel III report recommends the use of five variables (hypertension, insulin resistance or glucose intolerance, low serum high-density lipoprotein cholesterol, elevated serum triglyceride and abdominal obesity) with set threshold values for each variable for clinical characterization of metabolic syndrome. Subjects meeting three of these five criteria are classified as having metabolic syndrome. The cutoff value for defining abdominal obesity may vary based on ethnicity.^[57] Features associated with metabolic syndrome are proinflammatory state, prothrombotic state, hyperleptinemia, hypoadiponectinemia, hyperuricemia, endothelial dysfunction and microalbuminuria.^[58] In a double-blind, placebo-controlled trial of 86 patients with moderate-to-severe OSAS, it has been shown that 3 months of CPAP therapy lowers BP and partially reverses metabolic abnormalities.^[59]