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Recent Advances in Understanding the Pathogenesis of Obstructive Sleep Apnea

 

Amy S. Jordan, David P. White, Robert B. Fogel

Curr Opin Pulm Med 9(6):459-464, 2003. © 2003 Lippincott Williams & Wilkins

Posted 11/04/2003

Abstract

Purpose of review: The pathogenesis of obstructive sleep apnea (OSA) is incompletely understood. Historically it was believed that patients with OSA have a small upper airway (often due to obesity) that is kept patent during wakefulness by the activity of upper airway dilating muscles. With the reduction in muscle tone at sleep onset, the airway collapses and causes apnea. While this appears to be the case for many patients with OSA, other patients show no major airway anatomic defects or minimal obesity.
Recent findings: This has led to the concept that other factors such as unstable ventilatory control and changes in lung volume during sleep may be involved in the pathogenesis of OSA. Recently there have been several advances in our understanding of how these mechanisms are involved in OSA pathogenesis.
Summary: A more complete understanding of apnea pathogenesis may improve therapeutic techniques and reduce the consequences of OSA.

Introduction

Obstructive sleep apnea (OSA) is a disorder characterized by repetitive upper airway collapse during sleep that affects approximately 4% of adult men and 2% of adult women.[1] The pathophysiology of obstructive sleep apnea is likely multifactorial with contributions from airway anatomy, the state-dependent control of upper airway dilator muscles, and ventilatory stability (Fig. 1). A small or collapsible pharyngeal airway is central to the pathogenesis of OSA. During wakefulness, the collapsible airway remains patent due to the high activity of upper airway muscles. However, at sleep onset, this compensatory activation is reduced or lost resulting in partial or complete upper airway collapse. Other changes at sleep onset may also contribute to airway collapse such as the reduction in central respiratory drive and falling lung volume. During airway obstruction, hypoxemia and hypercapnia develop, which cause a progressive increase in drive to the respiratory pump and upper airway muscles. However this rarely results in re-opening of the upper airway unless accompanied by arousal from sleep. Following arousal, hyperventilation reverses the blood gas disturbance and correspondingly central drive is reduced. The patient then falls back asleep and the cycle repeats itself. How the well-identified epidemiological risk factors such as obesity, older age, and male gender influence these processes is largely unknown.

Figure 1. Cyclical nature of obstructive sleep apnea and possible pathophysiologic factors.
UA, upper airway. See introductory section for further explanation.

The sleep fragmentation and repetitive hypoxemia associated with OSA contribute to the primary symptoms of the disorder: excessive daytime sleepiness,[2] neurocognitive impairment,[3, 4] and increased risk for motor vehicle accidents.[5, 6] OSA has also been associated with adverse cardiovascular consequences such as hypertension.[7-9] Understanding the pathogenesis of OSA is therefore important such that alternative treatments and preventions for these adverse outcomes can be identified.

Upper Airway Anatomy

A number of previous studies have clearly demonstrated that the pharyngeal airway of the apnea patient is smaller than that seen in controls.[10-12] In addition, a number of anatomic structures in the upper airway have been described as being larger in the apnea patient, including the tongue, parapharyngeal fat pads, and the lateral walls surrounding the pharyngeal airway.[13] However, it is unclear whether these changes are of sufficient magnitude to explain disease pathogenesis, especially as there is substantial overlap in anatomic structure between OSA patients and controls.

Two recent studies have used anatomic measurements in an attempt to define the mechanism explaining the increased prevalence of OSA in men. Previous studies have shown men to have a larger or similar-sized pharyngeal airway as women,[14, 15] a feature that would not be expected to lead to increased airway collapsibility during sleep. Malhotra et al. [16**] used MRI to examine anatomic characteristics of the pharyngeal airway in healthy men and women. This data was then combined with finite element modeling techniques to estimate the pathophysiologic importance of their findings. They observed men to have a significantly longer pharyngeal airway (choanae to epiglottis) than women, even when corrected for body height. Furthermore, the modeling analysis demonstrated that increasing airway length is associated with an increase in pharyngeal collapsibility.

In a second study, Rowley et al.[17*] used endoscopic techniques to measure the cross-sectional area of the pharyngeal airway during tidal breathing in healthy subjects. They combined this technique with simultaneous pharyngeal pressure measurements to assess the compliance of the upper airway. They confirmed that men have a larger cross-sectional area of the retropalatal airway than women although this area was not different after correcting for body surface area. They also reported that the retropalatal airway was more compliant in men than women (greater change in area during inspiration) both during wakefulness and sleep. This difference disappeared after correcting for neck circumference and the authors suggest that the larger neck circumference in men renders the male airway more compliant. However, Malhotra et al.'s[16**] observation of a longer airway in men might explain the greater compliance as well. While both of these studies represent important advances, further work is clearly required before the gender difference in apnea susceptibility is completely understood.

Upper Airway Muscles

The pharyngeal dilator muscles are important in maintaining pharyngeal patency as they oppose the negative collapsing force developed during inspiration. Furthermore, physiologic data have shown that airway collapse during sleep in patients with OSA occurs as upper airway muscle activity falls.[18] Although there are over 20 muscles in the human pharyngeal airway, the most-studied dilator muscle is the genioglossus.

Previous studies have shown that the genioglossus is more active in apnea patients during wakefulness (increased EMG) and that at sleep onset this activity falls to a greater extent than in controls.[19] However during stable sleep in healthy individuals, genioglossal activity (GGEMG) is maintained at or above waking levels.[20, 21] The mechanisms behind this activation remain unclear as previous studies have demonstrated GGEMG to be much less responsive to stimuli such as negative intrapharyngeal pressure and changes in arterial blood gases during sleep.[22, 23] Stanchina et al.[24*] have attempted to shed light on this by examining the responsiveness of GGEMG to chemical and mechanical stimuli during NREM sleep in humans. GGEMG was measured under basal conditions and during hypoxia, hypercapnia, and inspiratory resistive loading. They found that although there was a trend toward higher GGEMG during hypercapnia, the only statistically higher muscle activity was seen during the combination of inspiratory resistive loading and hypercapnia. They conclude that during stable NREM sleep, the combination of mechanical and chemical stimuli are much more effective at increasing upper airway muscle activity than either stimulus alone. However, the muscles are clearly less responsive when the subject is asleep rather than awake.

Two studies have used the rat to better understand mechanisms controlling genioglossal muscle activity. First, Ryan et al.[25*] performed neuromuscular blockade in anesthetized, mechanically ventilated rats and recorded directly from the hypoglossal nerve (which controls genioglossal activation). They found that neuromuscular blockade led to decreased basal activity in the hypoglossal nerve, as well as decreased responsiveness to stimuli such as asphyxia and pulses of negative pressure. These data suggest that basal upper airway muscle activation is important in determining the output of the motor neuron systems that control such muscle activity, although the mechanism for this finding is unclear. If true, raising basal muscle activity might also increase muscle responsiveness and thus protect against pharyngeal collapse.

Second, Morrison et al.[26] attempted to define the neurochemical mechanisms controlling genioglossal activity across natural sleep-wake states using a freely behaving rat model. Most recently, they assessed the importance of the inhibitory transmitter GABA in controlling GGEMG. Using a microdialysis probe they infused bicuculline (a selective GABA antagonist) at the hypoglossal motor nucleus while recording GGEMG. They found that bicuculline led to an increase in GGEMG during wake and NREM sleep, but did not prevent the marked inhibition of GGEMG seen during REM sleep. These findings suggest that GABA exerts a tonic inhibitory influence in the hypoglossal nucleus during wakefulness and NREM sleep, but is not responsible for the inhibition of genioglossal muscle activity during REM sleep. This may suggest a pharmacologic target for apnea therapy although considerably more work is needed in this area.

Ventilatory Control

The notion that ventilatory control may be important in the pathogenesis of OSA is not new, but has not been investigated as actively as either upper airway anatomy or pharyngeal muscle function. In the early 1980s Weitzman et al.[27] and Onal and Lopata[28] reported that some tracheostomized patients with OSA still had cyclical breathing during sleep suggesting that central respiratory control may be central to the pathogenesis of OSA. More recently Hudgel et al.[29] and Younes et al.[30] have examined respiratory control stability and reported that patients with OSA have less stable breathing patterns than either less severe patients[30] or similarly aged healthy subjects.[29] Although the pathophysiologic importance of these findings is uncertain, a study by Warner et al.[31] reported that 7 of 9 otherwise healthy snoring subjects developed obstructive apneas when periodic breathing was induced with hypoxia, suggesting that respiratory stability may have a causal role in OSA.

Asyali et al.[32] have recently assessed respiratory stability in patients with OSA and controls in a different manner than previous investigators.[29, 30] These authors measured the oscillations in ventilation following tone-induced arousals from sleep in six patients with OSA and five controls. In contrast to the previous studies,[29, 30] Asyali et al. found only a trend suggesting a difference in the overall gain of the respiratory system between the two groups. They did find, however, that their measures of the chemoreflex component of the response "exhibited more rapid and underdamped dynamics" in patients with OSA, providing more evidence that respiratory control is altered in OSA.[32]

There have also been recent comparisons of respiratory control between the genders aimed at shedding light on the male predominance in OSA. Zhou et al.[33] previously reported that women required a greater reduction in CO2 to induce apnea during sleep than men and that this appeared to be unrelated to female sex hormones as no menstrual phase effects were observed. This suggests that men may be more prone than women to periodic oscillations in breathing as less hypocapnia was required to inhibit ventilation in men than in women. In 2002, the same group investigated possible mechanisms for this gender difference by studying the effect of 10 to 12 days of exogenous testosterone on ventilation in the hypocapnic range in young women [34**]. The authors reported that the PETCO2 at which apnea occurred was higher (closer to the resting PETCO2) following testosterone and that the hypocapnic ventilatory response was also increased. It therefore appears that males, in part due to higher testosterone levels, require smaller reductions in CO2 to induce apnea/hypopnea.

Other Factors

Lung Volume

The influence of lung volume on the upper airway has been recognized for some time with changes in airway size[14, 35, 36] and resistance[37, 38] reported with changing lung volume. In 1990, Begle et al.[37] conducted a study to investigate the mechanisms of these effects. The authors demonstrated that raising lung volume reduced pulmonary resistance independent of GGEMG or chemical stimuli and concluded that caudal traction on the upper airway structures may have caused this effect. Recently, two additional reports of the effect of caudal traction on the isolated airway of Vietnamese pot-bellied pigs were published.[39, 40] Caudal tracheal displacement decreased the compliance and closing pressure of the pig airway and increased the maximal airflow during progressive decreases in pressure at the larynx. As these studies were performed on an isolated airway during general anesthesia with neuromuscular blockade, these effects are likely due to the mechanical effects of displacement as opposed to muscle recruitment.

The influence of lung volume on upper airway collapse in humans during sleep has been minimally studied.[37, 41] However, a recent study indicates that lung volume may be a determinant of the closing pressure of the airway (PCRIT) in anesthetized humans.[42] In this study, PCRIT was determined at three levels of anesthesia while subjects breathed spontaneously. PCRIT became more positive (ie, the airway was more collapsible) with increasing depth of anesthesia, despite the fact that GGEMG was low at all times. The authors concluded that the increase in airway collapsibility was likely due to the decreased lung volume associated with deeper anesthesia as the end expiratory esophageal pressure was reduced with lighter anesthesia. Further studies of the influence of lung volume on airway collapsibility in humans during sleep are required to determine the role in the pathogenesis of OSA.

Surface Tension

For some time it has been recognized that the pressure required to open an occluded airway is greater than that required to collapse it.[43-45] This effect has been ascribed to surface tension forces in the occluded airway and has propagated ideas that there may be a role of such forces in the pathogenesis of OSA. In support of this theory, Jokic et al.[46] originally reported that topical lubricant applied to the upper airway reduced the severity of OSA in 10 patients. The role of surface tension in determining upper airway patency has been further examined in two recent papers.[47, 48] Kirkness et al.[47] assessed the effect of saline and exogenous surfactant on the airway opening and closing pressures of anesthetized rabbits. Samples of the liquid lining the airway showed that surface tension was reduced with surfactant and increased with saline. Correspondingly the opening pressure increased with saline and decreased with surfactant. Furthermore the closing pressure was increased with saline but the reduction with surfactant did not reach statistical significance.

Finally, Morrell et al.[48] reported the effect of exogenous surfactant and saline on the inspiratory pharyngeal resistance during sleep of snoring subjects and the severity of sleep apnea in patients with mild-moderate OSA. In the snoring subjects, surfactant reduced the resistance at peak pressure while saline did not significantly influence resistance. The respiratory disturbance index was slightly reduced in patients with OSA after administration of surfactant. However, sleep quality did not improve. Saline did not significantly alter the sleep characteristics or disordered breathing events. Taken together, these two studies suggest that surface tension forces acting on the upper airway play some role in the pathogenesis of sleep-disordered breathing although the effect is likely small.

Evoked Potentials/Sensory Inputs

Airway obstruction during sleep is generally terminated with arousal from sleep. It is therefore possible that a reduced ability to arouse would influence the duration of apnea and the likelihood of further obstructive events. OSA patients have been demonstrated to have a higher arousal threshold to airway occlusion than normal subjects[49]; however whether this is a cause or effect of the disorder is unknown. Even if the higher arousal threshold is due to repeated obstruction and sleep fragmentation, it may still contribute to the progression of OSA. Two recent studies have examined the mechanisms for the reduced arousal response seen in OSA patients.[50, 51]

Gora et al.[50] reported that the respiratory related evoked potential (RREP) to mid-inspiratory occlusions in six patients with untreated mild OSA was similar to six healthy controls matched for age and body mass index while awake. During sleep the response was reduced in patients with OSA. This suggests that the increase in arousal threshold in OSA patients is due to a state-related blunting of the cortical response to occlusion, rather than abnormal mechanoreceptor function.

More recently Akay et al.[51] have studied the RREP following brief negative pressure pulses during wakefulness in a group of OSA patients (n = 14) and control subjects (n = 18). These authors analyzed the EEG responses differently than Gora et al.[50] and reported that the global field power was reduced in OSA patients. These authors suggest this indicates reduced mechanoreceptor sensitivity or stimulation, a conclusion that differs from that of Gora et al..[50] The differences between these two studies may be related to the different methods, analysis techniques, or the number of subjects studied. The role of the reduced arousal threshold in the pathogenesis of OSA remains unclear.

Conclusion

The pathogenesis of OSA is complex and still incompletely understood. However, it seemingly involves aspects of upper airway anatomy, pharyngeal muscle control, and the central control of respiration. Factors such as lung volume, pharyngeal surface tension, and the ability to arouse from sleep may independently influence the likelihood of developing OSA. Alternatively they may alter pharyngeal collapsibility by altering respiratory or pharyngeal muscle control. The contribution of each of these factors to the pathogenesis of OSA probably varies between individuals, partially explaining why some patients are not obese or have minimal anatomic abnormalities. Similarly it is possible, if not likely, that the male predominance of OSA is explained by differences in several pathogenic factors. While our knowledge continues to increase, we still do not have a complete understanding of the pathogenesis of this highly prevalent condition.

References

Papers of particular interest, published within the annual period of review, have been highlighted as:

* Of special interest

** Of outstanding interest

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Funding Information

This work was supported by the National Institutes of Health Grants HL60292 and HL48531-10. Dr. Jordan is a recipient of the Allen and Hanbury's/TSANZ respiratory fellowship. Dr. Fogel is a recipient of the National Sleep Foundation's Pickwick Fellowship.

Reprint Address

Correspondence to Amy S. Jordan, PhD, Sleep Disorders Research Program at BIDMC, Brigham and Women's Hospital, 75 Franc's St., RFB-486 Boston, MA 02115, USA. E-mail: ajordan@rics.bwh.harvard.edu

Amy S. Jordan, David P. White, Robert B. Fogel, Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA