Obstructive sleep apnea

LUU V PHAM; JONATHAN JUN; VSEVOLOD Y POLOTSKY

doi:10.1016/B978-0-323-91532-8.00017-3

. Author manuscript; available in PMC: 2025 Apr 10.

Published in final edited form as: Handb Clin Neurol. 2022;189:105–136. doi: 10.1016/B978-0-323-91532-8.00017-3

Obstructive sleep apnea

LUU V PHAM ^1,^*, JONATHAN JUN ¹, VSEVOLOD Y POLOTSKY ¹

PMCID: PMC11984752 NIHMSID: NIHMS2071304 PMID: 36031300

Abstract

Obstructive sleep apnea (OSA) is a disease that results from loss of upper airway muscle tone leading to upper airway collapse during sleep in anatomically susceptible persons, leading to recurrent periods of hypoventilation, hypoxia, and arousals from sleep. Significant clinical consequences of the disorder cover a wide spectrum and include daytime hypersomnolence, neurocognitive dysfunction, cardiovascular disease, metabolic dysfunction, respiratory failure, and pulmonary hypertension. With escalating rates of obesity a major risk factor for OSA, the public health burden from OSA and its sequalae are expected to increase, as well. In this chapter, we review the mechanisms responsible for the development of OSA and associated neurocognitive and cardiometabolic comorbidities. Emphasis is placed on the neural control of the striated muscles that control the pharyngeal passages, especially regulation of hypoglossal motoneuron activity throughout the sleep/wake cycle, the neurocognitive complications of OSA, and the therapeutic options available to treat OSA including recent pharmacotherapeutic developments.

DISCOVERY OF OSA

Obstructive sleep apnea is recurrent collapse of the upper airway during sleep caused by the loss of muscular tone of pharyngeal muscles (Fig. 6.1) (Gastaut et al., 1965). An association of obesity with profound daytime sleepiness has been well known for long time and described in classical literature, including Charles Dickens “Pickwick Papers,” (Kryger, 1985) in which the vivid description of an obese young man who fell asleep during a hand of poker was later recalled by Sir William Osler in 1918 (Osler and McCrae, 1920). This association was conspicuously present in several historical figures, such as a composer Johannes Brahms (Margolis, 2000) and the US President William Howard Taft (Sotos, 2003). Finally, in 1956, Burwell described Pickwickian or Obesity Hypoventilation syndrome as a constellation of severe obesity resulting in hypoventilation with chronic hypoxia, cyanosis, polycythemia, and hypersomnolence (Burwell et al., 1956). In fact, Burwell et al. described periodic breathing in patients with Pickwickian syndrome, but did not identify upper airway closure and resulting intermittent hypoxia and sleep fragmentation as the main cause of sleepiness and cardiovascular pathology associated with the disease. In 1966, Gastaut et al. published the first comprehensive recording of breathing during sleep in Pickwickian patients and discovered OSA (Gastaut et al., 1966). Gastaut et al. described “hypotonia of the muscles of the floor of the mouth, so rapid and pronounced that the tongue moves back and causes the obstructive apnoea responsible for a hypoxia which arouses the subject, who returns to sleep after a short while” (Gastaut et al., 1966). In 1978, John Remmers discovered the role of a major tongue protrudor, the genioglossus muscle of the tongue, in the pathogenesis of the disease, “The genioglossus EMG consistently revealed periodicity, low level of activity at the onset of occlusion and prominent discharge at the instant of pharyngeal opening” (Remmers et al., 1978). A major breakthrough in the treatment of OSA occurred in 1981, when Colin Sullivan described the application of continuous positive airway pressure (CPAP) to splint open the upper airway, reversing oxyhemoglobin desaturations and arousal from sleep (Sullivan et al., 1981). Since then, CPAP therapy has proven highly efficacious in relieving airway obstruction and OSA, and remains the first-line treatment of OSA to this day.

DEFINITION

During sleep, patients with OSA experience recurrent periods of hypoventilation, hypoxia, and arousals (Fig. 6.2). To differentiate between normal respiratory patterns and OSA, scoring rules have been developed to codify the analysis of polysomnographic recordings. The apnea–hypopnea index (AHI) is a measure of OSA periodicity, which has been used to investigate the prevalence and health impact of OSA. This method of sleep apnea assessment has multiple advantages including objectivity, reproducibility, and scalability. Apneas are usually defined as complete cessation of flow for 10 s. Hypopneas, events characterized by reduction, but not complete cessation of airflow, are more difficult to define and multiple definitions exist with the degree of flow reduction and desaturation varying between definitions. The American Academy of Sleep Medicine accepts two definitions for hypopneas as events with >30% reduction in flow associated with >3% oxyhemoglobin desaturation or arousal (Berry et al., 2021). Although disease severity exists along a continuum, AHI thresholds of greater 5, 15, and 30 per hour are often used to define mild, moderate, and severe OSA, respectively.

Several limitations of AHI should be considered when interpreting studies of OSA. First, arousal scoring can vary between scorers, decreasing reproducibility for hypopneas that are not associated with large desaturations (Loredo et al., 1999; Wong et al., 2004). Second, obesity (Benedik et al., 2009), age (Don et al., 1971; Craig et al., 1971; Ruff, 1974), and cardiopulmonary disease can increase the degree oxyhemoglobin desaturations with reductions in flow and confound observational studies. Fourth, the use of discrete cutoffs to define hypopneas and differences between oximeters (Louie et al., 2018) are susceptible to misclassifications of individual events and disease severity overall, especially when desaturations are near the threshold for defining hypopneas. Finally, the AHI does not fully capture disease heterogeneity and patients with similar AHI may experience vastly differing severity of hypoxemia, obstruction, and sleep fragmentation.

EPIDEMIOLOGY

OSAwas perceived as a rare and unusual disease in morbidly obese patients until a landmark study by Terry Young et al. in the Wisconsin Sleep Cohort, who reported the prevalence of OSA based on the apnea–hypopnea index ≥5/h of 24% in men and 9% in women, whereas a combination of the AHI ≥5 and excessive daytime somnolence was reported in 4% of men and 2% of women (Young et al., 1993). Improvements in diagnostic techniques and increasing prevalence of obesity, a major OSA risk factor, led to several revisions and current understanding, that OSA is one of the most prevalent diseases. Using the diagnostic criteria of AHI ≥5/h, OSA is present in 34% of men and 17.4% of women in the United States. The prevalence of obesity (BMI ≥30) in the United States is nearly 40%, and greater than 50% of obese individuals have OSA (Young et al., 1993, 2002; Vgontzas et al., 2000; Punjabi et al., 2002; Tufik et al., 2010; Peppard et al., 2013). A least 13% of men and 6% of women have moderate-to-severe disease with the AHI ≥15/h (Peppard et al., 2013; Benjafield et al., 2019). The latest estimate suggests that 54 million Americans have OSA, including 24 million with moderate-severe disease (Benjafield et al., 2019).

PATHOGENESIS

Anatomy and physiology

The human pharynx consists of greater than 20 muscles and can be subdivided in four parts: (1) the nasopharynx, from the nasal turbinates to the soft palate, (2) velopharynx, from the start of the soft palate to the tip of the uvula, (3) oropharynx, from the tip of the uvula to the tip of the epiglottis, and (4) the hypopharynx, from the tip of the epiglottis to the vocal cords (Patil et al., 2007a). As a result of speech development, the human pharynx is uniquely different from other mammals. The hyoid bone is floating unattached to any other bony structure. Hence, the pharynx lacks the bony foundation and susceptible to the collapse. Soft tissues and bony structure surrounding the pharynx may create excessive extraluminal pressure resulting in collapse.

The site of airway collapse during sleep has always been a subject of interest (Dempsey et al., 2010). The site of collapse does not influence the efficacy of CPAP therapy, but it may be important for other therapeutic options, such as hypoglossal nerve stimulation and surgery. Computer tomography, magnetic resonance imaging, pharyngeal pressure monitoring in sleeping patients, and drug induced sleep endoscopy (Dempsey et al., 2010; Genta et al., 2017; Sebastian et al., 2021; Volner et al., 2021) have shown that upper airway collapse may occur at one or more sites including soft palate, tongue, lateral pharyngeal wall, and/or epiglottis (Genta et al., 2017).

Upper airway biomechanics—The Starling resistor model

Collapse of the pharynx during sleep is essential to OSA pathogenesis. In healthy volunteers, inducing upper airway collapse with negative nasal pressure results in recurrent apneas, oxyhemoglobin desaturations, and arousals from sleep (Schwartz et al., 1988). Continuous application of negative pressure in healthy subjects reproduces daytime sleep apnea symptoms including daytime somnolence (King et al., 2000). Reversing upper airway obstruction with CPAP normalizes respiratory patterns and daytime sleepiness (Sullivan et al., 1981; Kushida et al., 2012). Thus, upper airway obstruction is both necessary and sufficient for the development of OSA.

In OSA, the dynamic collapse of the upper airway during sleep is a key biomechanical feature. Several investigators have applied models of collapsible tubes in several biological systems. One such model is the Starling Resister, a collapsible structure, which begins to occlude when the pressure differential between the lumen and surrounding structures (transmural pressure, P_TM) falls below a critical closing pressure (P_CRIT). An important consideration of the biomechanics of upper airway obstruction is a collapsible portion of the upper airway located between two rigid structures with fixed diameters and resistances: nasal passages and trachea, which are upstream and downstream, respectively, of the site of collapse during inspiration (Fig. 6.3). As air flows through the airway, intraluminal pressure falls along the length of the airway. During inspiration, the pressure downstream (P_DS) of the collapsible segment falls and becomes progressively more negative, whereas pressure in the upstream segment (P_US) remains essentially constant. Intraluminal pressure also varies throughout the respiratory cycle, reaching a nadir during inspiration. As a result, obstruction during sleep occurs most often during inspiration.

Fig. 6.3. — Starling resistor model of the upper airway. The upper airway is modeled by a collapsible segment that is flanked by the rigid nasal passages and trachea. During inspiration, pressure in the upstream segment (Pus), lumen of the collapsible segment (P_lumen) and downstream segment (P_DS) progressively fall. Depending on the relative values of PUS and PDS compared with the critical closing pressure (P_CRIT), the upper airway can assume one of three levels of patency, which are associated with three distinct respiratory and flow patterns.

The collapsible segment has three potential states which depend on the evolution of pressure at the collapsible segment relative to P_CRIT during the respiratory cycle. The first state occurs when P_US and P_DS remain greater than P_CRIT throughout inspiration. As a result, the airway is fully patent and inspiratory flow is largely dependent on respiratory effort. The second state occurs when both P_US and P_DS are less than P_CRIT throughout the respiratory cycle. As a result, the airway is fully occluded and complete apneas are observed. A third state occurs when P_US is greater than P_CRIT, but P_DS falls below P_CRIT during inspiration. Under these circumstances, pressure at the collapsible segment is greater than P_CRIT at the onset of a breath but falls below P_CRIT as air flows across the rigid nasal passages. As pressure starts to fall below P_CRIT, the airway starts to collapse and inspiratory flow starts to decrease. As a result of the reduction in flow, pressure at the site of collapse starts to increase toward nasal pressure, leading to opening of the airway and increased inspiratory flow. As the airway cycles rapidly between an open and closed state, the pressure at the collapsible segment remains nearly constant at P_CRIT. Because pressure in the collapsible segment is constant, airflow also remains constant. This cyclic relationship between P_TM and inspiratory flow leads to plateauing of flow during inspiration. Rapid cyclic pressure oscillations could also lead to audible snoring. An important feature predicted by this model dissociation of flow and diaphragmatic effort once the airway obstructs. Therefore, during apneas and hypopneas, increasing respiratory efforts do not result in restoration of ventilation, which can only occur with improvements in upper airway patency through upper airway muscle recruitment. In fact, cyclic respiratory events occur when ventilation decreases by more than 12%–20% of baseline or peak inspiratory flow falls below 250 mL/s (Gastaut et al., 1965; Kryger, 1985).

Evidence suggests that elevations in upper airway collapsibility play a primary role in OSA pathogenesis. Investigators have found that OSA patients have elevated P_CRIT compared to age, sex, and BMI-matched controls under general anesthesia and neuromuscular blockade (Isono et al., 1997a) as well as during sleep (Gleadhill et al., 1991). Numerous studies have demonstrated differences in P_CRIT between healthy individuals and OSA patients (Issa and Sullivan, 1984a,b; Schwartz et al., 1988; Smith et al., 1988; Meurice et al., 1996; Philip-Joet et al., 1996; Sforza et al., 1999; Gold et al., 2002; Choi et al., 2010). In the aggregate, these studies demonstrated that nearly all persons with OSA have a P_CRIT greater than −5cmH₂O, indicating that increased upper airway collapsibility necessary for the development of OSA (Pham and Schwartz, 2015).

Determinants of upper airway collapsibility

Increased upper airway collapsibility can be attributed to both defects in the structure (anatomy) of the upper airway and active control of upper airway musculature. To separate the structure from neuromuscular causes of upper airway occlusion, researchers have employ specialized physiologic techniques to measure P_CRIT during sleep under conditions of reduced (passive) and elevated (active) neuromuscular activity (Isono et al., 1997b; Patil et al., 2007b). Under passive conditions, they found that airway collapsibility was elevated in OSA patients compared to normal age, sex, and BMI-matched normal controls, suggesting that underlying anatomic defects predisposed to OSA. Under active conditions, the OSA patients also exhibited blunted responses to airway obstruction compared to controls, indicating impaired pharyngeal neuromuscular control (Patil et al., 2007b). Furthermore, healthy subjects may have passive structural defects comparable to those OSA patients, but markedly greater neuromuscular responses. These findings suggest that elevations in P_CRIT in OSA patients are due to defects in both upper airway structure and neuromuscular control, and that neuromuscular responses play a pivotal role in defending against the development of OSA. In fact, even patients with severe OSA and impaired pharyngeal anatomy do not have apneas while awake. Thus, although anatomic predisposition is necessary for OSA to develop, it is not sufficient. OSA can only develop when neuromuscular responses do not adequately mitigate the obstruction caused by structural defects.

Anatomic predisposition.

Anatomic predisposition is a key feature of OSA.

Obesity.

The main anatomical feature predisposing to sleep apnea in adults is obesity. Obese patients with OSA have significantly narrower the upper airway lumen, especially in the lateral dimension, and enlargement of the soft palate and the tongue due to adiposity (Fig. 6.4) (Schwab et al., 1995). Adipose tissue surrounding the pharynx results in increased extraluminal pressure (P_CRIT), predisposing to upper airway closure during sleep. Weight loss is an effective treatment for OSA (Smith et al., 1985; Patil et al., 2007a; Schwartz et al., 2008, 2009; Tuomilehto et al., 2009; Dixon et al., 2012), although effects of weight loss on upper airway patency are multifactorial and related both to widening of the pharynx and to improvement of neuromuscular control and increased lung volumes (Patil et al., 2007a; Schwartz et al., 2009; Squier et al., 2010). Reduction in tongue fat with the weight loss correlates strongly with the reduction in the apnea–hypopnea index (Wang et al., 2020). Besides obesity, craniofacial skeletal anatomy characterized by small maxillo-mandibular dimensions, i.e., retrognathia, may also predispose to OSA in the adult population (Lee et al., 2010). High prevalence of OSA at lower BMI in East Asians has been attributed, at least in part, to facial anatomy (Sutherland et al., 2012).

Fig. 6.4. — Comparison of a midsagittal image of a representative normal subject (*left*) and apneic patient (*right*). Soft palate area and the tongue are larger in the apneic subject, which results in narrowing of the pharynx. Reproduced with permission from Schwab RJ et al. (1995). Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 152: 1673–1689 and the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved.

Pediatric OSA.

The most common risk factor for OSA in children is adenotonsillar hypertrophy, and the primary treatment of pediatric OSA is adenotonsillectomy (Marcus et al., 2013). However, in older children and adolescents, obesity plays a major role in the pathogenesis of the disease, and adenotonsillectomy is no longer curative (Van de Perck et al., 2021). OSA is widely described in rare genetic disorders, such as achondroplasia, Down syndrome, Prader–Willi syndrome, Treacher Collins syndrome, Pierre Robin sequence, and mucopolysaccharidosis (Kaditis et al., 2016; Zaffanello et al., 2018). Predisposing to OSA factors are usually anatomical, i.e., macroglossia and narrow pharynx in Down syndrome, mandibular hypoplasia in Treacher Collins and Pierre Robin sequence, but physiological factors also play a role (e.g., decreased upper airway muscle tone in Down syndrome).

Muscles and nerves.

The pharynx is a unique structure composed entirely of muscles. Pharyngeal collapse, a hallmark manifestation of OSA, occurs exclusively in sleep suggesting a critical role for neuromuscular responses to maintain pharyngeal opening. The muscles of the pharynx essentially function as a muscle hydrostat, i.e., an organ composed entirely of muscles (Kairaitis, 2010; Oliven et al., 2020). Muscles and nerves controlling pharyngeal function are listed in Table 6.1.

Table 6.1.

Muscle and Nerves controlling pharyngeal patency

Muscle group	Muscle	Origin	Insertion	Efferent nerve innervation	Primary action
Extrinsic muscles of the tongue	Genioglossus	Mental spine of the mandible	Base of the tongue	Hypoglossal (medial branch)	Protrudes (and depresses) the tongue
	Styloglossus	Styloid process	Base of the tongue	Hypoglossal (lateral branch)	Raises and retracts the tongue
	Hyoglossus	The hyoid bone	Base of the tongue	Hypoglossal (lateral branch)	Depresses and retracts the tongue
	Palatoglossus	Palatal aponeurosis	Base of the tongue	Vagus (pharyngeal branch)	Elevates tongue and pulls palate down
Muscles controlling soft palate	Tensor palatini	The cranial base, auditory tube cartilage	Palatal aponeurosis	Trigeminal (mandibular branch)	Stiffens the soft palate
	Levator palatini	Temporal bone of the skull	Palatal aponeurosis	Vagus (pharyngeal branch)	Raises the soft palate
	Palato pharyngeus	Palatal aponeurosis	Lateral pharyngeal wall	Vagus (pharyngeal branch)	Lifts the pharyngeal wall and moves the soft palate anteriorly
	Muscular Uvula	Soft palate	Uvula	Vagus (pharyngeal branch)	Raises uvula
Muscles influencing hyoid bone position	Geniohyoid	Genial tubercle of mandible	The hyoid bone	Hypoglossal (anterior ramus of C1)	Elevates and draws the hyoid forward
Muscles influencing hyoid bone position	Mylohyoid	Mylohyoid line of mandible	The hyoid bone	Trigeminal (mandibular branch)	Elevates hyoid bone and supports the floor of the mouth
	Thyrohyoid	Lamina of thyroid cartilage	Greater cornu of hyoid bone	Cervical (first branch)	Raises and changes the form of the larynx
	Sternohyoid	Manubrium and clavicle	Body ofhyoid bone	Ansa cervicalis	Depresses hyoid bone and larynx
	Stylohyoid	Styloid process	Body ofhyoid bone	Facial nerve	Draws the hyoid and tongue superiorly and posteriorly
	Omohyoid	Upper border of the scapula	Body ofhyoid bone	Ansa cervicalis	Depresses/stabilizes hyoid bone
Pharyngeal constrictor	Superior, middle, and inferior	Aponeurosis in the posterior midline	Anterior pharynx including the tongue	Pharyngeal plexus (the vagus and glossopharyngeal nerves)	Close the airway as part of swallowing. At high lung volumes act as constrictors, at low lung volumes they act as dilators

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From Edwards BA, White DP (2011). Control of the pharyngeal musculature during wakefulness and sleep: implications in normal controls and sleep apnea. Head Neck 33: S37–S45.

Tongue.

The main determinant of upper airway patency during sleep is the tongue. If the anterior tongue plays a critical role in speaking and chewing, the posterior tongue is a key role in upper airway maintenance (Zaidi et al., 2012). The tongue is composed of eight muscles. The four intrinsic muscles of the tongue, the transversalis, verticalis, inferior longitudinalis, and superior longitudinalis, are contained within the body of the tongue and unattached to any bony structure. These muscles innervated by the hypoglossal nerve determine the tongue shape, but do not appear to contribute greatly to the pharyngeal opening (Zaidi et al., 2012; Doyle et al., 2021). In contrast, the four extrinsic tongue muscles are major muscles controlling upper airway patency during sleep. These muscles are genioglossus, the main tongue protrudor, innervated by the medial branch of the hypoglossal nerve, styloglossus and hyoglossus muscles, tongue retractors, innervated by the lateral branch of the hypoglossal nerve, and palatoglossus, which elevates tongue, innervated by the pharyngeal branch of the vagus (Edwards and White, 2011; Zaidi et al., 2012; Fleury Curado et al., 2018a; Doyle et al., 2021) (Table 6.1 and Fig. 6.5).

Fig. 6.5. — Musculature and innervation of the tongue. HN (XII), hypoglossal nerve.

The genioglossus is the main pharyngeal dilator and tongue protrudor muscle, which keeps the pharynx open. Significant insight in the role of genioglossus muscle was provided from electrophysiological studies in animals and humans (Fleury Curado et al., 2018a). Studies by Oliven et al. in anesthetized dogs showed that genioglossus muscle stimulation improves pharyngeal patency by dilating stiffening the pharynx (Oliven et al., 1996). Nerve stimulation studies in the isolated feline airway showed that pharyngeal opening was achieved by stimulating the main trunk of the hypoglossal nerve and its medial branch innervating the genioglossus (Schwartz et al., 1993). Human studies also showed the efficacy of stimulation of the hypoglossal nerve distally, which ensures exclusive innervation of genioglossus, after the lateral branch innervating tongue retractors take off (Fleury Curado et al., 2018a). The isolated stimulation of genioglossus by stimulation of the distal hypoglossal nerve laid the ground for the STAR trial followed by the FDA approval of the Inspire device (Strollo Jr. et al., 2014, 2015; Woodson et al., 2015, 2018). In contrast, stimulation of the lateral branch of the hypoglossal nerve innervating tongue retractors shuts the upper airway close (Fleury Curado et al., 2018a). Interestingly, studies in rodents showed that combined stimulation of tongue protrudors and retractors may be advantageous to the stimulations of protrudors alone. Stimulation of protrudors (genioglossus) dilates the pharynx, but does not decrease its collapsibility, whereas the combined stimulation both dilates and stiffens the airway (Fuller et al., 1998, 1999). Human studies showed similar results (See hypoglossal nerve stimulation therapy) (Eisele et al., 1997; Oliven et al., 2003, 2007).

Muscles Controlling Soft Palate and Hyoid Bone Position.

There are five muscles controlling the soft palate: palatoglossus (also a tongue muscle), levator palatini, tensor palatini, palatopharyngeus, and musculus uvula (Table 6.1) (Edwards and White, 2011). Contribution of this muscle to the upper airway patency during sleep is variable and depends if respiration is oral or nasal. For instance, the levator palatini closes the nasal airway promoting oral breathing, which may decrease the pharyngeal lumen. The palatoglossus opens nasal airway, but it also elevates the tongue and pulls the palate down constricting the airway. The tensor palatini improves the pharyngeal patency by stiffening soft palate (Edwards and White, 2011). There are six muscles controlling the hyoid position (Table 6.1) (Edwards and White, 2011). The most studied is the geniohyoid muscle (Fig. 6.5), which can pull hyoid forward dilating the upper airway (Wiegand et al., 1990a,b; Fleury Curado et al., 2018a; Schwab et al., 2018). Recent studies showed that electrical stimulation of ansa cervicalis branch innervating the sternoclaidoclavicular muscle dilates the pharynx greatly enhancing the effect of hypoglossal nerve stimulation. This effect can be attributed to caudal tracheal traction, which also pulls the distal edge of the soft palate caudally (Kent et al., 2020, 2021).

Pharyngeal Muscle Activity during sleep: Normal sleep.

Tonic and phasic EMG activity of pharyngeal dilators (genioglossus, geniohyoid, and tensor palatini) are significantly reduced from wakefulness to NREM to REM sleep and further resulting in pharyngeal narrowing. The decrease in tongue muscle activity is especially profound during REM sleep, both in animals (Kubin et al., 1998; Sood et al., 2005; Grace et al., 2013) and humans (Eckert et al., 2009; Dempsey et al., 2010). The upper airway is protected against the collapse by two reflexes, negative pressure reflex sensed by mechanoreceptors, and the chemoreflex in response to hypercapnea (Stanchina et al., 2002; Berry et al., 2003; Lo et al., 2006; Dempsey et al., 2010; Kubin, 2016). During inspiration, negative intraluminal pressure promotes passive narrowing of the pharynx triggering mechanoreceptors of the larynx and pharyngeal wall innervated by the superior laryngeal wall (the branch of vagus), glossopharyngeal, and trigeminal nerves (Mathew et al., 1982; Mathew, 1984; Horner et al., 1991a,b, 1994). Negative intraluminal pressure also inhibits the diaphragm activity via the vagal reflex, which would result in negative feedback attenuating negative pressure swings and decreasing airway collapse (Harms et al., 1996). The genioglossus and tensor palatini muscles are also highly responsive to CO₂, which decreases P_crit counteracting the pharyngeal collapse. CO₂ increases genioglossal activity and dilates the pharynx (Stanchina et al., 2002; Lo et al., 2006) by stimulating central chemoreceptors in the retrotrapezoid nucleus (Guyenet et al., 2017; Souza et al., 2019). The CO₂ effect on the upper airway patency to large extent is due to arousals from sleep (Kaur and Saper, 2019).

OSA.

The genioglossus muscle is a major tongue protrudor and pharyngeal dilator. Remmer et al. were the first to report decreases in genioglossus EMG immediately prior obstructive events and significant increases in genioglossus activity at termination of apneas (Remmers et al., 1978). Mezzanotte et al. later reported that genioglossus activity is increased in OSA patients during wakefulness (Mezzanotte et al., 1992) concluding that OSA patients depend on airway muscle activity to maintain pharyngeal patency during wakefulness (Mezzanotte et al., 1992). Patil et al. found that, compared to healthy subjects, patients with OSA have diminished neuromuscular responses to the upper airway obstruction during sleep (Patil et al., 2007b). These diminished responses were a result of loss of both tonic and phasic (coincided with inspiration) activity of the genioglossus (McGinley et al., 2008; Fleury Curado et al., 2018a). Thus, diminished negative pressure upper airway reflex is an important contributor to the pathogenesis of OSA (Patil et al., 2002, 2007a,b; McGinley et al., 2008; Eckert et al., 2013). Blunting of the chemoreflex may also play a role, but the evidence for this in OSA patients is more controversial (Yuan et al., 2012; Borel et al., 2016).

Hypoglossal motoneurons (HMN) and their activity throughout seep/wake states: Anatomy of the HMNs in the mouse brain (Fig. 6.6).

The hypoglossal nerve, the XII cranial nerve, innervates most of the tongue muscles branching into the medial branch innervating tongue protrudors and lateral branch innervating retractors (Dobbins and Feldman, 1995; Zaidi et al., 2012). The hypoglossal nerve originates in the hypoglossal nucleus of the medulla (Figs. 6.5 and 6.6A). A retrograde tracer cholera toxin B (CTB) injections into protrudor (genioglossus) and retractors (styloglossus and hyoglossus) of the mouse tongue localize protrudor HMNs to the ventro-rostral portion and retractor HMNs to the dorso-caudal portion of the XII nucleus (Fleury Curado, n.d.) (Fig. 6.6B). HMNs receive monosynaptic input from multiple regions of the medulla, pons, midbrain, and hypothalamus (Guo et al., 2020), which regulate their activity across sleep/wake states.

Synaptic input to HMN (Fig. 6.6 and Table 6.2).

Table 6.2.

Key neuromediators modulating hypoglossal motoneuron (HMN) activity (Kubin et al., 1992; Gatti et al., 1999; Fenik et al., 2005, 2008; Chan et al., 2006; Sood et al., 2006; McKay and Feldman, 2008; Grace et al., 2013, 2014; Zhang et al., 2014; Yokota et al., 2015; Kubin, 2016; Rukhadze et al., 2017; Dergacheva et al., 2019; Dutschmann et al., 2021)

		Change throughout sleep/wake cycle
Neuromediator	Origin	Awake	NREM sleep	REM sleep	Effect on HMN
Acetylcholine	Intermediate reticular nucleus (IRN) Medullary reticular nucleus (MDRN) Nucleus of the solitary tract (NTS) Dorsal pontine tegmentum	↑	↓	↑↑	↓
Serotonin (5-HT)	Raphe obscurus Raphe pallidum Dorsal raphe	↑↑	↓	↓↓	↑
Norepinephrine	Locus coeruleus, Areas A1/C1, A 5, A7, and SubC	↑↑	↓	↓↓	↑
Orexin	Lateral hypothalamus	↑↑	↓	↓↓	↑
Glutamate	Parabrachial nucleus The Kölliker-Fuse nucleus Ventral respiratory group (pre-Bőtzinger complex) Dorsal pontine tegmentum	↑↑	↓	↓↓	↑
GABA/glycine	Lateral paragigantocellular nucleus Dorsal pontine tegmentum	↓↓	↑	↑↑	↓
Thyrotropin-releasing hormone	Co-localized with 5-HT	↑↑	↓	↓↓	↑

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HMNs receive monosynaptic input from multiple areas in the medulla, including cholinergic neurons of reticular nuclei and the nucleus of the solitary tract (NTS). In general, cholinergic input decreases HMNs activity predisposing to pharyngeal narrowing (Zhu et al., 2019). In contrast, serotoninergic neurons of medullary raphe (raphe obscurus and raphe pallidum) provide excitatory input (Kubin et al., 1992; Ptak et al., 2009; Kubin, 2016). There is also a significant input from the ventral medulla, especially glutamatergic excitatory input from the ventral respiratory group including the respiratory rhythm generating neurons of the pre-Bőtzinger complex (Fregosi, 2011; Yang and Feldman, 2018). Other important areas of medulla directly projecting to the HMNs are noradrenergic A1/C1 neurons, which activate HMNs (Rukhadze et al., 2017), and GABA/glycine inhibitory neurons of the lateral paragigantocellular nucleus (LPGi) (Dergacheva et al., 2019).

HMNs also receive monosynaptic input from several area in the pons, including excitatory neurotransmission from noradrenergic locus coeruleus and A7 neurons (Fenik et al., 2005, 2008; Kubin, 2016) and glutamatergic parabrachial and Kölliker-Fuse neurons (Bautista and Dutschmann, 2014; Yokota et al., 2015; Silva et al., 2016; Dutschmann et al., 2021). Neurons of the dorsal pontine tegmentum provide both excitatory glutamatergic and inhibitory GABA/glycine and cholinergic inputs (Kubin, 2016).

Excitatory transmissions from serotoninergic neurons of the midbrain in the dorsal raphe (Kubin, 2016) and orexinergic neurons in the lateral hypothalamus (Fung et al., 2001) may also play a role in the upper airway patency during sleep.

Neuromediator input is changing dramatically throughout sleep/wake states (Table 6.2). Specifically, acetylcholine transmission to HMNs decreases in NREM but significantly increases in REM sleep acting predominantly on muscarinic receptors M2 and relaxing airway muscles (Grace et al., 2013; Torontali et al., 2014; Horner et al., 2017; Rukhadze and Fenik, 2018). GABA/glycine transmission progressively increases from wakefulness to REM sleep also having an inhibitory effect (Peever and Duffin, 2001; Kubin, 2016; Rukhadze and Fenik, 2018). In contrast, serotonin, norepinephrine, orexin, glutamate (Kubin, 2016), and thyrotropin releasing hormone excitatory transmission (Liu et al., 2020a) progressively decreases from wakefulness to REM sleep.

The extent at which different mediators modulate HMNs activity in different sleep stages varies greatly. For instance, in anesthetized and vagotomized rats, serotonin blockade by microdialysis perfusion of the inhibitory serotonin receptor 5-HT_1A agonist 8-OH-DPAT into the nucleus raphe obscurus decreased genioglossus activity and diaphragm activity. However, despite the robust effects observed in anesthetized and vagotomized rats, there was no effect of 8-OH-DPAT on genioglossus or diaphragm activities in conscious rats awake or asleep (Sood et al., 2006). Microdialysis perfusion of the α₁ receptor antagonist terazosin into the HMN significantly decreased genioglossus activity in wakefulness during NREM sleep but not during REM sleep. The α₁ receptor agonist phenylephrine increased genioglossus activity in wakefulness and NREM sleep, but periods of motor inactivity persisted in REM sleep (Fig. 6.7A) (Chan et al., 2006). In contrast, the muscarinic blockade with the muscarinic receptor blocker scopolamine increased genioglossus activity in REM sleep without any effect on wakefulness and NREM sleep (Fig. 6.7B) (Sood et al., 2003).

Fig. 6.7. — The effect of noradrenergic and cholinergic stimuli on tongue muscle activity. (A) Microdialysis perfusion of the α₁ receptor antagonist terazosin into the hypoglossal nucleus significantly decreased genioglossus activity during wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. All rights reserved. (B) Muscarinic blockade with the muscarinic receptor blocker scopolamine increased genioglossus activity in REM sleep without any effect on wakefulness and NREM sleep. Panel (A) Reprinted with permission from Chan E, Steenland HW, Liu H et al. (2006). Endogenous excitatory drive modulating respiratory muscle activity across sleep–wake states. Am J Respir Crit Care Med 174: 1264–1273 and the American Thoracic Society. Copyright © 2021 American Thoracic Society. (B) Reprinted with permission from Grace KP, Hughes SW, Horner RL (2013). Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med 187: 311–319 and the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved.

Several hormones also affect HMN activity. Adipose tissue hormone leptin stimulate hypoglossal motoneurons (Freire et al., 2020) decreasing pharyngeal collapsibility (P_crit) (Polotsky et al., 2012) and relieving upper airway obstruction both in NREM and REM sleep (Pho et al., 2016, 2021; Yao et al., 2016; Berger et al., 2018). Hypoglossal motoneurons do not express leptin receptors (Berger et al., 2018). Although initial work suggested that leptin may work either in the nucleus of the solitary tract (Inyushkina et al., 2010; Do et al., 2020) or ventrolateral medulla (Bassi et al., 2014, 2016), in vivo experiments in sleeping mice showed that the primary site of the respiratory effects of leptin is the dorsomedial hypothalamus (Pho et al., 2021).

Oxytocin neurons in the paraventricular nucleus of the hypothalamus project to the HMNs and have an excitatory effect (Wrobel et al., 2010), which may have a therapeutic role in patients with OSA (Jain et al., 2017, 2020).

Probing the effect of different mediators on HMN paved the road to novel pharmacotherapies of OSA with several agents are being tested in clinical trials as we will discuss further.

CNS circuits terminating apnea

Two major mechanisms of termination of apnea and respiratory cyclicity are chemoreflex and arousal. CO₂ is a much more potent respiratory stimulus than hypoxia.

Chemoreflex.

CO₂ is being sensed by peripheral chemoreceptors in the carotid body and by central chemoreceptors, which are predominantly located in the retrotrapezoid nucleus (RTN). The RTN neuronal response to protons is mediated by TASK-2 (Kcnk5) and GPR4 (Guyenet et al., 2010, 2017; Guyenet and Bayliss, 2015). Mechanisms by which RTN activation by CO₂ contributes to increased genioglossus activity is not well studied, but it appears that RTN neurons provide synaptic input to the pontine Kölliker-Fuse region, and KF neurons provide glutamatergic excitatory projections to the hypoglossal nucleus (Silva et al., 2016).

Hypoxia is the main stimulus for carotid body chemosensory activity. However, CB chemosensitive glomus cells can sense acidic pH via Twik-related acid-sensitive K(+) channel 1 and 3 (TASK1/TASK3) heterodimeric channels (Buckler, 2015); however, other redundant pathways are possible (Ortega-Sáenz et al., 2010). Afferent chemosensory inputs from glomus cells reach the brainstem respiratory network via the carotid sinus nerve (CSN), a branch of the glossopharyngeal nerve, which projects into the nucleus of the solitary tract (NTS) respiratory motoneurons via the petrosal ganglion, inducing hyperventilation (Prabhakar, 2013, 2016; Nurse, 2014). It is conceivable that “second carotid body neuron” located in the NTS mediates increases in genioglossal muscle activity in response to CO₂ (Lui et al., 2018).

Arousals.

Experiments in rodents showed that RTN lesions impaired CO₂-induced arousals but had no effect on hypoxia-induced arousals. CB ablation impaired arousal to hypoxia and, to a lesser extent, hypercapnia (Souza et al., 2019). These arousals are likely mediated via synaptic connections to serotoninergic neurons of the dorsal raphe which, in turn, provide input to critically important for arousal calcitonin gene-related peptide neurons in the lateral parabrachial nucleus (Kaur et al., 2013, 2017, 2020; Kaur and Saper, 2019).

In brief, molecular mechanisms determining termination of apneas are mostly related to responses to CO₂, which could (Gastaut et al., 1965) directly increase genioglossal muscle activity via the RTN-KF-XII nucleus circuit or, probably to the less extent, via the carotid body-NTS-XII nucleus circuit (Kryger, 1985); induce arousals predominantly via the RTN-dorsal rapheparabrachial circuit. However, further studies have to be done to elucidate these potentially therapeutically important pathways.

Models of cyclic OSA patterns

Thus far, we have discussed factors leading to upper airway obstruction and individual events sleep-disordered breathing events. Once the upper air has collapsed, however, several factors determine the frequency and duration of apneic episodes, degree of hypoxia, frequency of arousals from sleep, and ultimately the severity of sleep apnea. Modeling respiratory dynamics during sleep evolved out of the study of negative feedback control systems (Cherniack and Longobardo, 1973). In simplified models, ventilatory perturbations are reversed by proportional changes in demand (Cherniack et al., 1966; Longobardo et al., 1966, 1982). The ventilatory response to perturbations is often called “loop gain” (Khoo et al., 1991; Khoo, 2001; Jo et al., 2003). In cross-sectional studies by Wellman, Malhotra and colleagues, loop gain was identified as one of several possible determinants of OSA severity (Wellman et al., 2004, 2013). In these studies, the investigators found a linear association between the AHI and loop gain in patients with atmospheric P_CRIT, suggesting that loop gain influenced the severity of sleep apnea in a subset of patients once the airway occludes (Wellman et al., 2004).

Elevations in loop gain may have divergent effects on OSA severity and clinical outcomes. In general, high loop gain predisposes to under- and over-shoots. During upper airway obstruction, ventilatory demand and neuromuscular reflexes progressively increase. If neuromuscular reflexes do not compensate for mechanical airway loads, patients will arouse. As a result, the airway opens, releasing pent-up demand. Under these circumstances, high loop gain leads to vigorous ventilatory responses and hypocapnia. Since upper air neuromuscular activity is modulated by CO₂, an exuberant response can lead to further reductions in airway patency and predispose to additional obstructive apneic events. Reductions in loop gain, on the other hand, blunt ventilatory response and could preserve neuromuscular reflexes that mitigate obstruction, potentially stabilizing ventilation during sleep (Jordan et al., 2007; Patil et al., 2007b). It is also possible that cyclic responses might offer some protection against some adverse consequence of OSA. Shorter events decrease hypoxia severity. In addition, greater degrees of oxyhemoglobin improvement after apneic events is associated with greater improvements in nocturnal glucose. Thus, loop gain can modify responses to upper airway obstruction and could potentially augment respiratory cycling in OSA.

Several key features of OSA that were not originally incorporated by control theorists limit the ability to apply feedback principles to predict disease severity and responses to therapy. First, upper airway obstruction is a unique feature of OSA that results in dissociation between effort and ventilation. Under these circumstances, ventilatory flow does not mirror respiratory demand. Second, the relationship between ventilation and CO₂ is hyperbolic rather than linear. Since CO₂ is a major determinant of ventilatory demand, respiratory responses are not proportional to ventilatory perturbations across a broad range. Third, respiratory demand and upper airway patency are affected by variations in arousals from sleep and sleep stages throughout the night. Thus, OSA does not adhere to key principles, linearity and time-invariance, on which mathematical models relay to predict negative feedback control system behavior accurately (Khoo, 2001). Indeed, OSA appears to be characterized by abrupt transitions in upper airway patency and ventilation rather than smooth oscillations in airflow as observed in patients with Cheyne–Stokes respirations (CSR) that are accurately predicted by models of ventilation (Guyton et al., 1956; Cherniack et al., 1966; Cherniack and Longobardo, 1973), suggesting a striking departure from the principles of negative feedback theories. As such, additional work is required to develop robust, generalizable models of OSA severity and responses to therapy remain.

COMPLICATIONS OF SLEEP APNEA

In this section, we will review clinical complications of sleep apnea with a focus on neurocognitive outcomes such as sleepiness, vigilance, headache, and dementia. Cardiovascular effects of OSA are expertly reviewed elsewhere (Cowie et al., 2021) and we will focus on hypertension, pulmonary hypertension, cardiovascular disease, stroke, arrhythmia, and metabolic dysfunction. It is important to recognize that some outcomes associated with OSA are direct consequences of the disorder, while other outcomes may be a manifestation of visceral obesity, which in turn is a major driver of cardiovascular and metabolic dysfunction (Younas et al., 2019). Fig. 6.8 illustrates distinctive patterns of fat distribution in a person with subcutaneous fat, as opposed to an obese person with visceral fat. Individuals with visceral fat tend to have insulin resistance which leads to hypertension and diabetes. These individuals may have large tongues, thicker necks, pharyngeal fat depots, and lower lung volumes predisposing them to sleep apnea. The co-occurrence of visceral obesity and OSA makes it difficult to determine the causal role of OSA in cardiometabolic dysfunction solely from observational studies. Investigators have used animal models of OSA (Chopra et al., 2016) to study its potential consequences in humans. For example, animals have been exposed to stimuli such as intermittent hypoxia (Drager et al., 2010) to selectively induce certain features of OSA. In the discussion below, we will address neurocognitive and cardiovascular complications associated with OSA.

Fig. 6.8. — The role of obesity in OSA pathogenesis, illustrating anatomical differences between man of (A) normal weight, (B) subcutaneous obesity, and (C) visceral obesity. Visceral obesity is a shared risk factor for both OSA and metabolic syndrome.

Neurocognitive complications

OSA—the most common primary sleep disturbance in adults—has many overt clinical consequences. Airway collapse leads to repeated microarousals from sleep, changes in overall sleep architecture, and intermittent hypoxemia. Hallmark features of OSA include loud snoring, awakenings from sleep, headaches, and daytime sleepiness. Beyond these symptoms, OSA is also associated with adverse neurocognitive and cardiovascular outcomes. Here, we will focus on neurocognitive outcomes and briefly review the relevant cardiovascular effects of OSA.

Sleepiness and Vigilance

Early reports of the “sleep apnea syndromes” included descriptions of loud snoring, abnormal sleep movements, enuresis, morning headache, and “fog” (Guilleminault et al., 1978). In modern practice, physicians screen for OSA using the STOP-BANG (Silva et al., 2011) or Berlin (Silva et al., 2011) questionnaires, which assign points to symptoms such as snoring and daytime sleepiness. OSA increases risks of accidents in private and commercial transportation, and significant debate exists regarding how to screen and treat drivers for OSA in commercial settings (Netzer et al., 1999). Perhaps more dangerous is the fact that many patients with OSA (or other disorders that cause chronic insufficient sleep) are not aware of their impairment and may report only “fatigue” and or “lack of energy” (Chervin, 2000). Methods such as psychomotor vigilance task testing (Sforza et al., 2004) may be required to detect and quantify sleep loss-associated deficits. Paradoxically, some with OSA report insomnia (Ong et al., 2021) rather than sleepiness due recurrent awakenings, a finding more common in females (Subramanian et al., 2011).

Morning headache

Many patients with OSA report morning headache. In a Swedish cross-sectional study, 5% of the general population reported frequent morning headaches, while 18% of persons with heavy snoring or OSA reported frequent morning headaches (Russell et al., 2014). Several other studies have showed a similar (2–3-fold) risk of morning headache in OSA. The International Classification of Headache Disorders III (ICHD-3) (Headache Classification Committee of the International Headache Society (IHS), 2013) classifies “sleep apnea headache” as a type of secondary headache characterized by presence upon awakening, usually bilateral, and self-resolving within 4 hours. However, morning headaches are not a specific symptom for OSA. In a general adult European population (n = 18,890), chronic morning headaches were reported in 7.6%. Associated factors included anxiety, depression, insomnia, circadian rhythm disorder, and sleep-related breathing disorder (Ulfberg et al., 1996). Similarly, morning headaches were not a reliable diagnostic marker of OSA for patients presenting to a sleep disorders center (Aldrich and Chauncey, 1990), as these patients often have several comorbid sleep pathologies. There are also no polysomnographic features of OSA that predict morning headache. Hypoxemia and hypercapnia have been proposed as causal factors, but supporting evidence is weak. In a study conducted in Turkey, 156 OSA patients reported morning headache and 306 denied morning headache. Those with morning headache exhibited modestly greater oxygen desaturation (average O₂ 82.7% versus 84.9%) and higher AHI (38.7 versus 34.1) than those without (Goksan et al., 2009). In a Norwegian study that included polysomnography in a cohort of patients with OSA and headache questionnaires, the severity of OSA and extent of hypoxemia did not differ between those with or without morning headache (Kristiansen et al., 2012). Despite ambiguous predictors or mechanisms of morning headache in OSA, most patients who report morning headache respond well to CPAP therapy (Poceta and Dalessio, 1995; Goksan et al., 2009).

Cognitive impairment

OSA has been associated with cognitive defects ranging from mild cognitive impairment (MCI) to Alzheimer’s disease (Bubu et al., 2020). MCI usually involves impaired memory (amnestic MCI) but other cognitive domains such as executive functioning or visual spatial skills may be involved. As shown in six-study meta-analysis of prospective studies, sleep-disordered breathing was associated with a 1.26 risk ratio of developing cognitive impairment and a modest reduction in executive function (Yaffe et al., 2011). A subset of the Study of Osteoporotic Fractures examined 298 women without dementia and examined risks of incident MCI or dementia as a function of sleep-disordered breathing over a mean of 4.7 years of follow-up (Yaffe et al., 2011). The adjusted OR for MCI or dementia was 1.85 compared to those without sleep-disordered breathing. The same group examined cross-sectional associations between sleep and cognition in older men in the Osteoporotic Fractures in Men Sleep Study. Home sleep studies and several cognitive tests were performed. In adjusted models, patients with less REM sleep, lighter (higher percentage of stage N1) sleep, or greater hypoxemia performed worse on certain tests.

Sleep apnea-related cognitive deficits may have varied manifestations. In some studies, deficits of memory and attention were ascribed to sleep fragmentation and daytime sleepiness, while frontal-lobe–related abnormalities of executive functioning were related to nocturnal hypoxemia (Naegele et al., 1995). Among severe OSA patients, short-term CPAP was shown to reverse attentive, visuospatial learning, and motor performance deficits but not executive functions or constructional abilities (Ferini-Strambi et al., 2003). In a small study by Bedard et al., vigilance (measured using a multiple sleep latency test) was related to hypoxemia, while reaction time tests were more related to sleep disruption (Bédard et al., 1991). Among healthy older (>50 years old) adults, effects of OSA on cognitive outcomes have been inconsistent (Cross et al., 2017). Potentially, subtle cognitive deficits require more specialized testing. For example, Mullins et al. tested cognitively normal adults (age 67, n = 52), 22 of which had untreated OSA in a 3D maze environment and studied 3 timed trials before and after a sleep study. Participants with OSA performed similarly to those without, but they failed to improve with serial trials (Mullins et al., 2021). Authors interpreted the results to reflect deleterious effects of OSA on hippocampal memory cells. Other factors may interact with OSA conferring vulnerability to cognitive impacts. Age may be one such factor; 30- to 60-year-old adults with OSA had impairments in memory and executive function, whereas older adults did not (Bubu et al., 2020). It is not clear whether this finding is related to a ceiling effect, survivor bias, or altered physiological responses to OSA (Jun and Polotsky, 2020).

Dementia

Alzheimer’s disease (AD) is the most common form of dementia worldwide, but the underlying pathophysiology of AD remains unclear. A 2016 meta-analysis of five small cross-sectional studies found that OSA was five times more common in AD than in cognitively nonimpaired subjects (Emamian et al., 2016). The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal multicenter study launched in 2004 to study AD progression. In the ADNI cohort, investigators examined subsets of patients who reported sleep-disordered breathing or CPAP use (Osorio et al., 2015). They found that self-reported sleep apnea was associated with earlier onset MCI (77.4 versus 89.9) and Alzheimer dementia (83.5 versus 88.1). It is also possible that a common pathway toward dementia is loss of REM sleep, of which OSA is one of many causes. In a sample from the Framingham Heart Study, 321 subjects underwent polysomnography and were followed for incident dementia over a mean period of 12 years (Pase et al., 2017). They showed that lower REM percentage and longer REM latency were associated with a higher risk of incident dementia after adjustments for age and sex. Varga et al. performed experiments where CPAP was selectively turned off during REM sleep in subjects with severe underlying OSA, to cause REM sleep fragmentation. They compared improvements in 3D spatial maze testing after timed trials across 2 days. Improvements in maze performance after a night of normal sleep were attenuated after REM disruption (Varga et al., 2014). These cognitive impairments are similar to animal experiments where rodents were exposed to chronic intermittent hypoxia (Gozal et al., 2003). Hence OSA-induced REM impairment may have acute and potentially cumulative impacts on certain functions. However, studies have shown inconsistent benefits of CPAP to the course of AD (Legault et al., 2021).

One of the pathological features of Alzheimer’s disease (AD) is increased cerebral amyloid deposition. In a small Korean study of cognitively normal middle-aged subjects, 19 OSA subjects and 19 education and sex-matched controls underwent PET imaging. The OSA patients showed higher amyloid deposition in the right posterior cingulate gyrus and right temporal cortex (Yun et al., 2017). Liguori et al. performed neuropsychological testing, sleep studies, and CSF measurement of AD biomarkers (amyloid β42, tau proteins, lactate) in 25 OSA subjects, 10 OSA subjects treated with CPAP, and 15 controls (Liguori et al., 2017). The CSF of patients with untreated OSA contained lower amyloid β42 concentrations, higher CSF lactate levels, and higher t-tau/amyloid β42 ratio than that of the other groups. Sharma et al. followed a sample of cognitively normal subjects aged 55–90 over 2 years and obtained serial CSF samples of amyloid β42. The annual rate of change of CSF amyloid β42 was associated with OSA severity (Sharma et al., 2018). These studies raise concern that sleep apnea could promote MCI or AD and associated protein markers, but further interventional studies are required.

Cardiovascular complications

Hypertension

Hypertension is arguably the most studied and established cardiovascular complication of OSA. The Sleep Heart Health Study showed an adjusted 37% increase in the prevalence of hypertension comparing the highest AHI category to this lowest (Nieto et al., 2000). The Wisconsin Sleep Cohort Study showed 2–3-fold increased risk of incident hypertension with OSA over a 4-year follow-up period (Peppard et al., 2000). More definitively, CPAP has been shown to modestly lower blood pressure in several randomized controlled trials (Fava et al., 2014). The response to CPAP is heterogeneous: benefit may be limited to symptomatic OSA patients (Barbe et al., 2012) or those with underlying hypertension. For example, in children with OSA, adenotonsillectomy only lowered blood pressure among those with pre-existing hypertension (Kang et al., 2021). The mechanisms of OSA-induced hypertension are not fully understood but likely involve increase sympathetic activation, oxidative stress, renin-angiotensin axis activation (Younas et al., 2019).

Cardiovascular disease

OSA is associated with a variety of adverse cardiovascular outcomes including atherosclerotic heart disease, arrhythmia, and mortality (Yeboah et al., 2011). In the aforementioned Sleep Heart Health Study (Punjabi et al., 2009) and Wisconsin Sleep Cohort (Young et al., 2008) studies (which showed risk of incident hypertension), all-cause mortality was also found to be increased in severe OSA, even after adjustment for hypertension. Other longitudinal studies reported risk reduction of cardiovascular outcomes with CPAP (Anandam et al., 2013) or mandibular advancement therapies (Anandam et al., 2013). However, unlike hypertension, randomized controlled trials have not demonstrated reductions in rates of cardiovascular disease with CPAP. CPAP did not improve cardiovascular outcomes or blood pressure in a randomized trial that enrolled nonsleepy OSA patients without prior CVD (Barbe et al., 2012). In terms of secondary prevention, three major RCTs of CPAP including the SAVE (McEvoy et al., 2016), RICCADSA (Peker et al., 2016), and ISAAC (Sánchez-de-la-Torre et al., 2019) did not show an impact of OSA therapy on cardiovascular mortality. In some of these studies, post-hoc analyses showed that more CPAP-adherent patients derived CV risk benefit. It is also important to recognize that these trials were ethically constrained to study relatively asymptomatic OSA patients, in order to justify randomization to a no-CPAP (or sham CPAP) arm. If there exists an effect of CPAP on cardiovascular disease, it is likely limited to symptomatic patients.

Stroke

Theoretically, OSA could increase the risk of ischemic stroke by several mechanisms including (Gastaut et al., 1965): hypoxia-induced endothelial dysfunction and sympathetic activation (Kryger, 1985), increased cerebral blood flow from hypercapnia or negative intrathoracic pressure during inspiration (Osler and McCrae, 1920), hypertension, or (Margolis, 2000) right-to-left shunting through patent foramen ovale (Beelke et al., 2002). OSA may also aggravate underling risk factors for stroke such as diabetes, atrial fibrillation, or pro-inflammatory states (Somers et al., 2008).

Several observational studies have shown increased risk of ischemic stroke in OSA, independent of established vascular risk factors (Valham et al., 2008). For example, in patients with established coronary artery disease (n = 392) followed for 10 years, 12% developed stroke and the adjusted hazard ratio for OSA was 2.89 (Barbe et al., 2012). Similarly, in a cohort of patients referred to Yale Sleep Medicine followed for a median duration of 3.3 years, OSA was associated with stroke or death (hazard ratio, 1.97). In the Sleep Heart Health Study, a large community-based multicenter study, OSA severity was positively associated with ischemic stroke risk after adjustment for age, BMI, smoking, blood pressure, diabetes, and race. The causal role of OSA in stroke risk is still controversial. CPAP did not reduce hypertension or cardiovascular events (including stroke) in aforementioned multicenter SAVE clinical trial (McEvoy et al., 2016). From an ethical perspective, these trials appropriately excluded symptomatic (sleepy) OSA patients, but this limits clinical application and causal inference.

In the poststroke period, sleep apnea is highly prevalent (Slonkova et al., 2017) and is marker of poorer outcome (Xie et al., 2014). Small studies suggest improved neurologic outcome after 1 month, if CPAP was initiated early in the poststroke period (Slonkova et al., 2017). However, other studies showed initial improvements which no longer were statistically significant after 3 months (Parra et al., 2011) Stroke rehabilitation patients randomized to CPAP or sham CPAP did not exhibit improved Functional Independence Measure scores at 18 months (Ryan et al., 2011). Therefore, it remains to be determined whether sleep disordered breathing is a mediator or merely a marker of more significant neurologic injury after stroke.

Arrhythmias

Classically, apneas and hypopneas are accompanied by dynamic changes in heart rate, with relative bradycardia (during apnea) followed by tachycardia (postapneic arousal) (Somers et al., 1995). OSA can increase risks of atrial as well as ventricular arrhythmias (Hoffstein and Mateika, 1994) by up to 4-fold (Mehra et al., 2006) and these may occur during the daytime or night-time (Alonso-Fernandez et al., 2005). OSA has been closely associated with new-onset atrial fibrillation (AF) (Gami et al., 2007) as well as drivers such as elevated sympathetic activity (Somers et al., 1995), prolonged coronary sinus conduction times, longer P-wave duration, and atrial enlargement (Dimitri et al., 2012). Observational studies of AF recurrence after cardioversion showed elevated risks in untreated OSA versus treated/non-OSA patients (Gami et al., 2004). Greater risks were observed in those <65 years of age, and dose-dependently related to BMI and extent of nocturnal hypoxemia (Gami et al., 2007). However, randomized trials of CPAP versus usual care examining rates of AF recurrence after cardioversion (Caples et al., 2019), or mean time in AF (Traaen et al., 2021) did not find statistical reductions in AF burden with therapy.

In terms of ventricular abnormalities, Gami et al. examined sudden cardiac death (SCD) among patients with OSA and compared time of death against the general population. Interestingly, those with OSA exhibited a peak in cardiac-related SCD between midnight and 06:00, corresponding with the nadir of SCD in the general population (Gami et al., 2013).

Hypercapnia

Although OSA causes intermittent upper airway obstruction, overt hypercapnia is uncommon in OSA. An exception to this rule is in cases of obesity hypoventilation syndrome (OHS), a disorder of morbidly obese patients who hypoventilate while awake (Masa et al., 2019). The majority of OHS patients have OSA, and treatment of OSA (regardless of whether CPAP or bi-level ventilation is used (Piper et al., 2008; Sánchez-de-la-Torre et al., 2019) can decrease or even normalize carbon dioxide levels in many patents. Thus, airway obstruction contributes to hypercapnia in a subset of patients—potentially those with low ventilatory drive (Rapoport et al., 1986)—who have combined OHS and OSA.

Pulmonary hypertension

OSA is associated with increased risks of pulmonary hypertension (PH), usually defined as a mean pulmonary artery pressure >25mmHg at rest. PH resulting from “pure” OSA (in the absence of other pulmonary disorders) is usually modest. For example, in a small study of patients with severe OSA, CPAP for 12 weeks decreased estimated pulmonary artery systolic pressure from 29 to 24mmHg (Arias et al., 2006). The improvement may be related to alleviation of nocturnal hypoxemia (right ventricular afterload) as well as left ventricular diastolic dysfunction (left ventricular afterload) (Arias et al., 2005). In the case of OSAwith comorbid cardiopulmonary disease, particularly OHS, PH can be significant and a cause of right heart failure.

Metabolism

OSA increases the risks of type 2 diabetes (T2DM) in prospective studies (Botros et al., 2009; Kendzerska et al., 2014) after adjusting for potential confounders. In another study, OSAwas associated with higher T2DM prevalence but not 4-year incidence (Reichmuth et al., 2005). In human and animal studies, OSA or intermittent hypoxia have been shown to lead to acute sympathetic activation and changes in fat and glucose metabolism (Polotsky et al., 2011; Jun et al., 2014). CPAP did not alter metabolic outcomes in several randomized trials (Jullian-Desayes et al., 2015). However, small studies with directly observed CPAP adherence suggest improvements in insulin resistance with consistent CPAP use (Pamidi et al., 2015). Conversely, discontinuing CPAP for three nights in patients with severe OSA increased plasma glucose, fatty acid, and cortisol levels during sleep (Chopra et al., 2017). Therefore, there may be an effect of OSA on metabolic function which is often overshadowed by underlying obesity.

TREATMENT

Continuous positive airway pressure (CPAP)

The application of nasal CPAP to treat OSA was first described by Sullivan and colleagues in 1981 (Sullivan et al., 1981) and remains the first-line therapy for patients with moderate-to-severe OSA. Modern CPAP devices use a variable speed fan instead of specialized valves to maintain constant pressure at the nose but the underlying principles remain unchanged. CPAP works by elevating the luminal pressure in the collapsible segment of the upper above P_CRIT throughout the respiratory cycle (Schwartz et al., 1989). Compared to other modes of treatment, CPAP’s advantages include high efficacy and the ability to track adherence. Its effects rely on continuous application; however, infrequent or short duration of usage leaves large segments of patient populations untreated or only partially treated. Estimates of nonadherence from clinical trials and large usage data sets range from approximately a quarter of patients prescribed CPAP in the short term and approaches 50% of patients after 3 years (Gottlieb et al., 2014; Pépin et al., 2018, 2021a; Cistulli et al., 2019).

Studies on effects of CPAP on clinical outcomes have yielded mixed outcomes. Investigators have demonstrated that CPAP treatment improves neurocognitive outcomes, including sleepiness measured subjectively by Epworth Sleepiness Scale (ESS) and objectively by tests examining the ability to maintain wakefulness (Kushida et al., 2012; Craig et al., 2012), short-term memory (Kushida et al., 2012), and global sleepiness-related daytime functional impairments (Weaver et al., 2012). Effects were most pronounced in the patients with severe OSA. Moreover, daytime alertness was improved even in patients who did not have excessive levels of sleepiness (ESS>9) at baseline. In contrast to neurocognitive outcomes, studies of CPAP on cardiovascular outcomes have been largely negative. In large multicenter randomized controlled trials of CPAP compared to no CPAP in patients with moderate-to-severe OSA, CPAP treatment did not prevent incidence of initial or recurrent cardiovascular events and mortality (McEvoy et al., 2016; Peker et al., 2016). Low adherence with usage average 3–4h per night may have reduced the ability to detect the effects of treating OSA on cardiovascular outcome and it remains unknown whether CPAP prevents cardiovascular complications in adherent patients. Nevertheless, it appears that infrequent CPAP usage is sufficient to provide neurocognitive benefits.

Weight loss

Obesity is a major risk factor for OSA, and weight loss has significantly improved OSA (Schwartz et al., 1991; Foster et al., 2009; Ashrafian et al., 2015; Kuna et al., 2020). Weight loss improved upper airway patency in nearly all patients, resulting in resolution of OSA in those patients whose P_CRIT fell below −4cmH₂O (Schwartz et al., 1991). In trial in patients with OSA and type 2 diabetes, intensive lifestyle intervention resulted in a mean reduction of 10kg over 1 year and an average AHI decrease of 9.7 events/h. Patients with greater weight loss also had greater AHI reductions (Foster et al., 2009). Because of its safety and beneficial effects on cardiometabolic risk, weight loss is recommended as initial therapy in patients with mild asymptomatic disease and as an adjunctive therapy in OSA of all severity (Hudgel et al., 2018). Bariatric surgery is more effective for weight loss than lifestyle interventions alone. However, more pronounced weight loss in obese patients with severe OSA, who underwent bariatric surgery led to a similar improvement in the AHI to the lifestyle group with a significant residual disease (Dixon et al., 2012).

Oral appliances

Oral appliances represent an alternative treatment for OSA. Although efficacy of oral appliances for OSA treatment is inferior to CPAP, the adherence rate is higher resulting in similar effectiveness in mild-moderate disease with similar reductions in daytime sleepiness and 24h blood pressure, compared to CPAP (Phillips et al., 2013).

Positional therapy

The upper airway is generally more collapsible in the supine position compared to the nonsupine position (Boudewyns et al., 2000). As a result, OSA severity may vary significantly depending on a body position during sleep. In some patients, lateral sleep position can improve or even resolve OSA (Permut et al., 2010; de Vries et al., 2015; Barnes et al., 2017). However, the efficacy of positional treatment is inferior to CPAP therapy. Multiple positional devices are currently available. In the past, most of the devices impeded the supine position by preventing rotation in bed, which sometimes resulted in patients’ intolerance. Tolerability is improved with newer devices that train sleeping nonsupine position by vibrating when the supine position is detected (Eijsvogel et al., 2015; Beyers et al., 2019). Patient-candidates for positional therapy should be selected based on the results of sleep studies showing a marked reduction in the AHI in the nonsupine position.

Training of pharyngeal muscles

Emerging body of literature suggest that pharyngeal muscle training by speech therapists as well as myofunctional therapy, which is a combination of isotonic and isometric exercises engaging lips, tongue, and oropharyngeal muscles, can be effective predominantly in mild disease (Camacho et al., 2015).

Hypoglossal nerve stimulation

Stimulation of the hypoglossal nerve is an option for patients who are intolerant of CPAP. The Inspire device is the first FDA-approved implantable hypoglossal nerve stimulator and employs an electrical stimulation cuff around the distal branch of the hypoglossal nerve. The initial trial recruited patients with BMI ≤ 32kg/m², AHI ≤ 50/h, and a noncircumferential pattern of upper airway collapse on drug-induced sleep endoscopy (Strollo Jr. et al., 2014). In aggregate, hypoglossal nerve stimulation reduced mean AHI from 29.3 to 9.0 events/h. Efficacy remained stable during follow-up over 3 years (Woodson et al., 2015). Despite rigorous inclusion criteria, 33% of participants did not meet the endpoint of a reduction in AHI of 50% from baseline and an AHI < 20/h. Thus, additional studies are needed to improve selection of patients for this therapy. Newer hypoglossal nerve stimulators and the genioglossus muscle are currently undergoing clinical trials (Mwenge et al., 2013; Eastwood et al., 2020).

Surgery

Surgery can address anatomical predisposition for OSA and represents a therapeutic option in some OSA patients. Several approaches have been described in the literature, but few controlled investigations have been undertaken to study the efficacy of surgeries to treat OSA. Uvulopalatopharyngoplasty (UPPP) involves resecting the uvula and portions of the soft palate and is the most frequently studied procedure to treat OSA. In the largest of RCTs of UPPP, 32 individuals who underwent surgery experienced a mean reduction in AHI from 53.3 to 21.1events/h, whereas the control group experienced significant change in AHI (Browaldh et al., 2013). A longitudinal study found that elevations in BMI at baseline and weight gain during follow-up were associated with higher AHI 8 years after surgery (Sundman et al., 2021). Maxillomandibular advancement (MMA) is an approach to address skeletal contributions to upper airway collapse. In a meta-analysis, data analyzed from 518 patients who underwent MMA indicated that AHI fell by 47.8 event/hr on average after surgery and resulted in a postoperative 50% AHI reduction in 85.5% of patients and AHI < 5 events/h in 38.5% of patients. Weight loss after upper airway surgery frequently occurred and represents a significant confounder in studies of surgery on OSA. In addition, selection criteria have not been well defined.

Pharmacotherapy

Currently, there is no FDA-approved pharmacotherapy for OSA in adults. In 2019, Gaisl et al. performed a systematic review of the literature and network meta-analysis and identified 58 randomized clinical trials in OSA investigating 44 different drugs (Gaisl et al., 2019). Several RCTs have been published since (Taranto-Montemurro et al., 2018; Hoff et al., 2020), but to date, no phase III RCTs have been completed. Recent data suggest that the patient population in OSA is heterogeneous. Although upper airway collapse is a predominant feature of the disease, contributions of anatomy, neuromuscular responses, chemoreflex, and the arousal threshold vary greatly between patients (Eckert et al., 2013). There is a growing consensus that “one size fits all” approach is not going to be successful. Although patient phenotyping is still in the experimental phase, routine sleep studies may allow to do it and guide therapeutic approaches targeting neuromuscular reflexes, ventilatory drive, or the arousal threshold (Sands et al., 2018).

Medications targeting upper airway muscles

Tricyclic antidepressants (TCA).

Historically, protriptyline was one of the first drugs tested in OSA patients. This medication blocks norepinephrine and serotonin reuptake and also has a moderate anticholinergic effect. A small study in 12 patients showed a reduction in apnea time and oxygen desaturations in NREM, but not in REM sleep, reduction of REM time with significant adverse effects, such as mouth dryness (Smith et al., 1983). However, subsequent studies did not confirm benefits (Brownell et al., 1982). Subsequent trials of another TCA, a norepinephrine reuptake inhibitor desipramine showed an increase in genioglossus activity and improved upper airway collapsibility during sleep, but no or minimal effect on OSA severity (Taranto-Montemurro et al., 2016a,b).

Serotoninergic agents.

Animal studies in the English bulldog showed efficacy of serotoninergic drugs such as a serotonin antagonist and reuptake inhibitor trazodone, a serotonin precursor L-tryptophan, and a 5-HT₃ blocker ondansetron in treating OSA by increasing genioglossus activity (Veasey et al., 1999, 2001). However, human studies of the selective serotonin reuptake inhibitor (SSRI) paroxetine (Berry et al., 1999) and ondansetron Stradling et al., 2003) were negative, whereas a combination of paroxetine and ondansetron and trazadone (Prasad et al., 2010) had minimal effects (Smales et al., 2015).

Cholinergic agents.

Animal studies demonstrated that muscarinic blockade increases genioglossus muscle tone in REM sleep (Grace et al., 2013). An acetylcholinesterase inhibitor donepezil had no effect on OSA in a small clinical trial (Li et al., 2016).

Adrenergic Agents.

Rodent studies showed that noradrenergic agonists increase genioglossus muscle tone in NREM sleep (Chan et al., 2006) or under anesthesia (Song and Poon, 2017). However, neither desipramine (Taranto-Montemurro et al., 2016a,b) nor α2 antagonists mirtazapine (Marshall et al., 2008) treated OSA in small clinical trials.

Adrenergic/Anticholinergic combination.

Based on animal studies in Horner’s laboratory (Sood et al., 2005; Chan et al., 2006; Grace et al., 2013), Taranto-Montemurro et al. performed a one-night randomized placebo control double-blind cross-over clinical trial of a norepinephrine reuptake inhibitor atomoxetine and a muscarinic blocker oxybutynin (ato-oxy) (Taranto-Montemurro et al., 2018). Both drugs are approved by FDA for different indications (ADHD and overactive bladder, respectively). The investigators studied 20 patients with mild-moderate OSA and found that ato-oxy increases genioglossus muscle activity and dramatically improves OSA both during NREM and REM sleep compared with the placebo night. However, the treatment did not reduce arousals from sleep and suppressed REM sleep. Another concern is that the treatment may be contraindicated in patients with cardiovascular disease due to an increase in sympathetic activity, and in patients with urinary retention (e.g., benign prostatic hyperplasia), glaucoma, and gastric motility disorders (Fleury Curado et al., 2018b). Nevertheless, ato-oxy potentially represents the most significant advancement in OSA pharmacotherapy to this day.

Cannabinoids may increase the genioglossus muscle tone acting either via serotoninergic pathways (Calik and Carley, 2014) or binding to cannabinoid receptors on the hypoglossal motoneurons (Horner et al., 2017). Non-selective cannabinoid agonist dronabinol decreased central apneas in rats and this effect was abolished by cannabinoid receptors 1 and 2 blockers (Calik and Carley, 2014). In a small clinical trial in patients with mild-moderate OSA, dronabinol induced a small decrease in AHI and reduced daytime sleepiness (Carley et al., 2018); however, clinical significance of this small improvement was questionable.

Thyrotropin releasing hormone (TRH).

TRH receptors are abundantly expressed in the hypoglossal nucleus (Horner et al., 2017), and TRH positive neurons have multiple projections to the HMNs (Bayliss et al., 1994). Experiments in sleeping rats showed that thyrotropin-releasing hormone (TRH) and its analog taltirelin act at the HMN to tongue motor activity throughout NREM and REM sleep (Liu et al., 2020b). However, clinical trials have yet to be performed.

Ampakines.

Glutamatergic input plays a fundamental role in respiratory motoneuron activity and it is mediated in part by α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors. Ampakines, pharmaceutics augmenting glutamatergic transmission by modulating AMPA receptors, have been extensively studied and found to be effective for central apnea in animal models (Wollman et al., 2020a,b). In a rodent model, ampakines increase hypoglossal motoneuron output (ElMallah et al., 2015; Turner et al., 2016), but the efficacy of ampakines for OSA is to be determined.

Chemoreflex

Overly robust ventilatory response to hypercapnia during the apneic results in hyperventilation upon airway opening and hypocapnia, which may predispose to recurrent airway closure. In contrast, inadequate ventilatory response to hypercapnia predisposes to prolonged airway obstruction with hypoventilation and severe hypoxemia.

Methylxanthine derivatives such as aminophylline (Espinoza et al., 1987) and theophylline (Mulloy and McNicholas, 1992; Orth et al., 2005) had a minimal effect on OSA, but disrupted sleep and had a potential for adverse cardiovascular effects.

Acetazolamide and other carbon anhydrase inhibitors induce metabolic acidosis, which results in respiratory alkalosis. Paradoxically, it stabilizes breathing by increasing the difference between eupneic P_ETCO₂ and the apneic threshold P_ETCO₂ (Nakayama et al., 2002). Based on this effect, acetazolamide has been widely used to treat central sleep of high altitude (Richalet et al., 2005; Teppema et al., 2007) and Cheyne–Stokes respiration (Javaheri, 2006). Animal experiments showed that acetazolamide reduces hypercapnic and hypoxic ventilatory responses (Yamauchi et al., 2007), which stabilize breathing decreasing breathing instability (high loop gain). Human studies showed that, in fact, acetazolamide was successful in treating OSA (Edwards et al., 2012, 2013; Schmickl et al., 2020), but only in patients with exaggerated ventilatory responses to obstructive events, i.e., high loop gain (Edwards et al., 2012).

Carotid Bodies as a target.

Ventilatory instability in patients with OSA may induce increased activity of the carotid bodies. Carotid bodies have been implicated in the pathogenesis of Cheyne–Stokes respiration in heart failure (Schultz et al., 2013, 2015a,b). Prabhakar’s laboratory showed that gaseous mediators, carbon monoxide (CO) and hydrogen sulfide (H₂S), play an important role in carotid body activity with CO decreasing and H₂S increasing carotid body activity (Prabhakar, 2012). CO deficiency induces apnea in mice. An inhibitor of H₂S-synthetic enzyme cystathionine-ϫ-lyase abolished central and obstructive apneas in CO deficient mice and in spontaneously hypertensive rats (Peng et al., 2017). However, human studies were not performed. A potassium channel TASK1 inhibitor doxapram acting in the carotid bodies did not improve OSA in a small clinical study (Suratt et al., 1986). Overall, convincing evidence on the role of the carotid body in the pathogenesis of OSA and, consequently, as a drug target in OSA is still lacking.

Leptin.

Leptin-deficient ob/ob mice have suppressed hypercapnic ventilatory response and recurrent obstructive hypopneas in REM sleep, which can be treated with leptin (O’Donnell et al., 1999; Pho et al., 2016; Yao et al., 2016). Obese humans and diet-induced mice are resistant to respiratory effects of leptin due to limited permeability of the blood–brain barrier (BBB) (Banks, 2012; Berger et al., 2018). Intranasal leptin circumvents the BBB and can treat upper airway obstruction in sleep in mice (Berger et al., 2018; Freire et al., 2020). However, clinical studies of leptin in OSA have not been performed.

Arousal threshold

A number of clinical studies are targeting the arousal threshold. A majority of the clinical trials investigated GABAergic medication (reviewed in Gaisl et al., 2019). These studies invariably showed that GABAergic medications, such as eszopiclone (Eckert et al., 2011), zopiclone (Carter et al., 2016), and temazepam (Wang et al., 2011), treat OSA, significantly decreasing AHI in patients with low arousal threshold. However, these medications are not helpful and may be even detrimental leading to severe nocturnal hypoxemia in patients with high arousal threshold.

Anti-inflammatory

Nasal corticosteroids.

In adults, the efficacy of nasal steroids can be attributed to improvement of rhino-sinusitis and, consequently nasal breathing. Predominantly oral breathing decreases the pharyngeal space predisposing to OSA (Cai et al., 2020). In addition, nasal breathing may stimulate upper airway muscles (McNicholas et al., 1993), probably via the genioglossus and trigeminal afferent input to respiratory motoneurons. In patients with mild-moderate OSA and concurrent rhinitis, AHI significantly decreased following 4 weeks of nasal fluticasone treatment (Kiely et al., 2004). In children, adenotonsillar hypertrophy is an important predisposing factor to OSA, and corticosteroids may be important for anti-inflammatory effects (Kuhle et al., 2020), but a largest placebo-controlled clinical trial (60 patients) in mild OSA showed no improvement in AHI.

Leukotriene antagonists have been used in pediatric settings due to high levels of expression of leukotriene receptor in adenoids and tonsils in children with OSA (Goldbart et al., 2004). Goldbart et al. showed a significant improvement in adenoid size and respiratory-related sleep disturbances in children with mild OSA (Goldbart et al., 2005), which was confirmed by anther investigator (Kheirandish et al., 2006).

Other approaches

Small clinical trials showed limited benefits of surfactant topical therapy due to a decrease in collapsibility of the airway (Morrell et al., 2002). Thyroid replacement in patients with hypothyroidism (Lin et al., 1992) and hormone replacement in menopausal women (Young et al., 2003) were beneficial only in patients with concurrent alveolar hypoventilation due to upregulation of hypercapnic responses.

Treatment of the complications of OSA:

CPAP therapy remains the mainstream therapy of OSA due to the lack of effective pharmacotherapy. However, adjunct drug therapy for residual hypersomnolence in CPAP-treated patients is FDA-approved and widely used. Historically, modafinil, a drug which inhibits the reuptake of dopamine by binding to the dopamine reuptake pump, and activates glutamatergic circuits while inhibiting GABA (Fry, 1998), was the first to be used in OSA patients (Kingshott et al., 2001). Another widely used in OSA stimulant with a similar mechanism is armodafinil (Chapman et al., 2018), while a norepinephrine–dopamine reuptake inhibitor solriamfetol (Subedi et al., 2020) and an histamine H3 receptor blocker pitolisant (Pépin et al., 2021b), which increases brain histamine levels, have just started being used.

Summary:

There is a significant bench-to-beside gap between basic research knowledge and drug development. The efficacy of OSA pharmacotherapy depends on patient’s phenotype. Universally available simple phenotyping tools based on regular sleep studies should be developed. The novel phenotyping tools should be complemented by a wide range of drugs developed based on molecular mechanisms of the disease.

ACKNOWLEDGMENTS

We are grateful to Prof. Corinne Sandone for her artwork, and to Dr. Thomaz Fleury Curado for his helpful suggestions.

The authors are supported by the NIH grants R01HL 133100, R01HL128970, R01HL138932, R61HL156 240, and by U18DA052301 to Dr. Polotsky, and R01 HL135483 to Dr. Jun and American Academy of Sleep Medicine Foundation Grant 238-BS-20 to Dr. Pham.

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PERMALINK

Obstructive sleep apnea

LUU V PHAM

JONATHAN JUN

VSEVOLOD Y POLOTSKY

Abstract

DISCOVERY OF OSA

Fig. 6.1.

DEFINITION

Fig. 6.2.

EPIDEMIOLOGY

PATHOGENESIS

Anatomy and physiology

Upper airway biomechanics—The Starling resistor model

Fig. 6.3.

Determinants of upper airway collapsibility

Anatomic predisposition.

Obesity.

Fig. 6.4.

Pediatric OSA.

Muscles and nerves.

Table 6.1.

Tongue.

Fig. 6.5.

Muscles Controlling Soft Palate and Hyoid Bone Position.

Pharyngeal Muscle Activity during sleep: Normal sleep.

OSA.

Hypoglossal motoneurons (HMN) and their activity throughout seep/wake states: Anatomy of the HMNs in the mouse brain (Fig. 6.6).

Fig. 6.6.

Synaptic input to HMN (Fig. 6.6 and Table 6.2).

Table 6.2.

Fig. 6.7.

CNS circuits terminating apnea

Chemoreflex.

Arousals.

Models of cyclic OSA patterns

COMPLICATIONS OF SLEEP APNEA

Fig. 6.8.

Neurocognitive complications

Sleepiness and Vigilance

Morning headache

Cognitive impairment

Dementia

Cardiovascular complications

Hypertension

Cardiovascular disease

Stroke

Arrhythmias

Hypercapnia

Pulmonary hypertension

Metabolism

TREATMENT

Continuous positive airway pressure (CPAP)

Weight loss

Oral appliances

Positional therapy

Training of pharyngeal muscles

Hypoglossal nerve stimulation

Surgery

Pharmacotherapy

Medications targeting upper airway muscles

Tricyclic antidepressants (TCA).

Serotoninergic agents.

Cholinergic agents.

Adrenergic Agents.

Adrenergic/Anticholinergic combination.

Thyrotropin releasing hormone (TRH).

Ampakines.

Chemoreflex

Carotid Bodies as a target.

Leptin.

Arousal threshold

Anti-inflammatory

Nasal corticosteroids.

Other approaches

Treatment of the complications of OSA:

Summary:

ACKNOWLEDGMENTS

References

ACTIONS