Sleep is one of the pillars of good health along with a balanced diet and sufficient exercise. When sleep is fragmented, not deep enough, or short in duration, a chain of events is released that leads to failing health. Sleep apnea is arguably the most common offender of sleep and health among the close to 100 codified sleep disorders. Sleep apnea has emerged as a significant risk factor for vascular disease. It has been associated with atherosclerosis, and cardio- and cerebrovascular morbidity. Recent research has made important inroads in the pathophysiology that links sleep apnea and stroke.

Atherosclerosis, Vascular Inflammation, and Endothelial Disease.
Chronic intermittent hypoxia (CIH) is a key factor in initiating pro-atherogenic activity and a likely link for the close association between sleep apnea and vascular disease. Experiments in mice ¹ subjected to eight hours of cyclic hypoxia every 90 seconds, equivalent to a pO2 of 40mmHg and consistent with levels seen in patients with sleep apnea, led to elevations of arterial pressure after 35 days of CIH. Chronic intermittent hypoxia activates the transcription factor hypoxia inducible factor 1 (HIF-1), which induces the expression of endothelin-1(ET1), a HIF-1 inducible gene.² Endothelin-1 activates a signaling cascade that culminates in superoxide production. In turn, superoxide leads to vascular oxidative stress, which inactivates nitric oxide in cerebral blood vessels, a condition that alters cerebrovascular regulation, reducing cerebrovascular reserves and rendering the brain more susceptible to ischemic injury.³

It has been hypothesized ⁴ that CIH in patients with sleep apnea can initiate complex metabolic molecular and cellular changes that promote development of vascular inflammation leading to atherosclerosis and endothelial disease. Elevated markers of vascular inflammation, such as oxidized LDL, C-reactive protein, hypercoagulability and fibrinolytic system markers, adhesion molecules, pro-inflammatory cytokines and transcription factors have been shown to be altered in patients with sleep apnea. Increased oxidative stress, vascular inflammation and endothelial dysfunction triggered by CIH are potential links between sleep apnea and stroke. Paradoxically, CIH may also activate adaptive mechanisms, such as increased vascular collateralization and recruitment of bone marrow-derived endothelial progenitor cells, which can provide protection to post-ischemic injured tissues. The balance between pro-atherogenic and protective mechanisms may determine the predisposition of sleep apnea patients to stroke.⁵

Autonomic Alterations in Sleep Apnea
A significant increase in sympathetic activity, influencing heart rate and blood pressure, has been observed in patients with sleep apnea. Increased sympathetic activity in sleep apnea patients may be induced through a variety of different mechanisms that include the arousal response as well as chemoreflex stimulation by hypoxia and hypercapnia, impairment in venous return to the heart, and alterations in cardiac output.⁶ Sleep apnea influences heart rate variability not only during sleep, but also during wakefulness. Cortelli et al.⁷ have shown that normotensive sleep apnea patients have higher heart rate at rest during wakefulness and a higher blood pressure response to head-up tilt than controls, suggesting sympathetic overactivity. When performing cardiovascular reflex tests, sleep apnea patients show significantly lower values of respiratory arrhythmia and greater decrease in heart rate induced by cold face testing, indicating normal or increased cardiac vagal efferent activity. A significant improvement of autonomic modulation and cardiovascular variability is observed in patients with sleep apnea treated successfully with continuous positive airway pressure (CPAP).⁸

Atrial Fibrillation
Atrial fibrillation is a major risk factor for stroke that has been associated with sleep apnea. The prevalence of atrial fibrillation in the United States has been estimated at 3.03 million persons in 2005⁹ and has been increasing as more individuals survive into old age.¹⁰ Epidemiological studies and clinical data suggest that sleep apnea increases the risk of new-onset atrial fibrillation. A large study ¹¹ evaluating 3542 patients without atrial fibrillation followed subjects for an average of five years. All patients underwent polysomnogaphy. The study revealed that clinically significant nocturnal oxygen desaturation predicted new-onset atrial fibrillation in patients less than 65-years-old. Sleep apnea may also confer a poorer prognosis for recovery following atrial fibrillation interventions. In a study of 424 patients undergoing ablation, sleep apnea more than doubled the risk of acute intra-procedural failure ¹². Prospective randomized controlled trials will be necessary to determine the effect of sleep apnea therapy on atrial fibrillation outcomes.

Patent Foramen Ovale
In the general population,¹³ patent foramen ovale (PFO) occurs with a range of 10%-30% depending on the diagnostic method used. In one study, 27% of sleep apnea patients and only 15% of control subjects had PFO (p < 0.05).¹⁴. It has been hypothesized that sleep apnea in patients with PFO could augment the risk of paradoxical embolism and stroke, particularly in individuals who develop pulmonary hypertension as a result of nocturnal hypoxemia.¹⁵ In a prospective study of 335 patients with stroke and TIA,¹⁶, 202 (60%) had at least one long obstructive sleep apnea event and 116 (35%) a right to left shunting episode by contrast transcranial Doppler examination; 69 (21%) had both. There were significantly more wake-up strokes and TIAs in subjects with right to left shunting plus long obstructive sleep apnea events than in those without this association (27/69 vs. 70/266; OR 1.91, 95% CI 1.08 to 3.38; p=0.03). The authors concluded that the combination of long obstructive sleep apnea events and right to left shunting could be a major and potentially treatable risk for cerebrovascular ischemic events. Further studies are warranted.

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References

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Keywords: Atherosclerosis, Sleep Apnea Syndromes, Sleep Wake Disorders

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