SLEEP, OBSTRUCTIVE SLEEP APNEA AND
CIRCADIAN RHYTHMS
SUEÑO, APNEA OBSTRUCTIVA DEL SUEÑO Y RITMOS
CIRCADIANOS
Manuel Ángeles-Castellanos
Universidad Nacional Autónoma de México, México
Monserrat Martínez-Luna
Investigador Independiente
Adelina Rojas-Granados
Investigador Independiente
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DOI: https://doi.org/10.37811/cl_rcm.v9i2.17006
Sleep, Obstructive Sleep Apnea and Circadian Rhythms
Manuel Ángeles-Castellanos1
mangeles_castellanos@unam.mx
https://orcid.org/0000-0002-6496-9465
Universidad Nacional Autónoma de
México; Facultad de Medicina,
Departamento de Anatomía
México
Monserrat Martínez-Luna
mmluna_23@hotmail.com
https://orcid.org/0000-0002-3771-7617
Investigador Independiente
Adelina Rojas-Granados
rojas.adelina@comunidad.unam.mx
https://orcid.org/0000-0001-8313-1943
Investigador Independiente
ABSTRACT
A non-reversible obstructive inflammatory process of the small airways and destruction of the alveolar
walls characterizes Chronic Obstructive Pulmonary Disease (COPD). One of the direct consequences is
poorer quality sleep. It has also been proven that sleep-related symptoms correspond to significant
changes in the respiratory center, airway resistance, and muscle contractility. The main sleep disorder
that these patients may present is Obstructive Sleep Apnea Syndrome (OSAS), which is characterized
by repetitive airway obstruction during sleep with complete or partial cessation of airflow. This
alteration can have effects on the circadian rhythm of the sleep-wake cycle, such as a desynchronization
of the light-dark cycle or endogenously desynchronized, resulting in: insomnia, fatigue, and poor
performance in daily activities and symptoms such as insomnia or hypersomnia, common in patients
with circadian sleep disorders, although there are other causes to which they can be attributed and that
must be excluded before making the diagnosis of a circadian sleep disorder. In a patient without another
sleep pathology, a daily record of activities, meals, exercise, naps, and bedtime is an essential tool to
evaluate circadian sleep disorders.
Keywords: sleep, circadian rhythms, apnea, melatonin
1
Autor principal
Correspondencia: mangeles_castellanos@unam.mx
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Sueño, Apnea Obstructiva del Sueño y Ritmos Circadianos
RESUMEN
La Enfermedad Pulmonar Obstructiva Crónica es un proceso inflamatorio obstructivo no reversible de
las vías aéreas. Una de las consecuencias directas es la peor calidad del sueño. También se ha
comprobado que los síntomas relacionados con el sueño corresponden a cambios significativos en el
centro respiratorio, la resistencia de las vías aéreas y la contractilidad muscular. El principal trastorno
del sueño que pueden presentar estos pacientes es el Síndrome de Apnea Obstructiva del Sueño (SAOS),
que se caracteriza por la obstrucción repetitiva de las vías aéreas durante el sueño con cese completo o
parcial del flujo aéreo. Esta alteración puede tener efectos sobre el ritmo circadiano del ciclo sueño-
vigilia, como una desincronización del ciclo luz-oscuridad o desincronizarse endógenamente, dando
como resultado: insomnio, fatiga y bajo rendimiento en las actividades diarias y síntomas como
insomnio o hipersomnia, comunes en pacientes con trastornos circadianos del sueño, aunque existen
otras causas a las que se pueden atribuir y que deben excluirse antes de realizar el diagnóstico de un
trastorno circadiano del sueño. En un paciente sin otra patología del sueño, un registro diario de
actividades, comidas, ejercicio, siestas y hora de acostarse es una herramienta esencial para evaluar los
trastornos circadianos del sueño.
Keywords: sueño, AOS, ritmos circadianos, apnea, melatonina
Artículo recibido 20 febrero 2025
Aceptado para publicación: 25 marzo 2025
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INTRODUCTION
The prevalence of Obstructive Sleep Apnea (OSA) has increased due to the aging of the population and
the risk factors acquired by bad habits developed in daily life, which predispose to diseases such as
obesity. Sleep is essential for human beings. It is regulated by two processes, one circadian and one
homeostatic. Therefore, if sleep disturbances occur, essential functions of the body are affected. It has
demonstrated that circadian rhythms are involved in functions of the body and intervene in the form of
expression of chronic diseases, making it interesting to investigate the relationship that the deregulation
of these rhythms could have with OSA, one of the principal sleep disorders.
Neurobiology of sleep
Sleep is a natural, reversible state of reduced response to stimuli, relative neuronal inactivity, and loss
of consciousness. It hasn't been possible to have a specific definition that explains all the mechanisms
involved in sleep but now that it is a cyclical process essential for the optimal health and well-being of
human beings as well as for maintaining the homeostasis of the body. The time a person sleeps is
equivalent to a third of their life. We could think that it is only a period of rest but while we sleep, many
meaningful physiological processes happen, for example, memory, learning, moods, and behavior, as
well as immune responses, metabolic processes, hormone levels, digestion, among others (Acosta,
2019).
Sleep is regulated by the circadian system, imposing a sleep-wake cycle with 24 hours synchronized
mainly by the light-dark cycle. In this process, different interactions occur that include multiple neuronal
circuits, neurotransmitters, and hormones (Foster, 2020). Melatonin is one of the main hormones that,
due to its chronobiotic capacity, influences the suprachiasmatic nucleus and functions as a central
pacemaker that coordinates all circadian rhythms. Melatonin release is a phototransduction process that
is stimulated in the dark through the eye, sending nerve signals which, via the retinohypothalamic tract,
stop at the suprachiasmatic nucleus, which it inhibits, releasing the sympathetic system via a direct
projection to the paraventricular nucleus of the hypothalamus, which projects to the intermediate lateral
column of the spinal cord, terminating in the superior cervical ganglion which projects its sympathetic
fibers directly to the pineal gland. Melatonin usually peaks during the dark phase of the day (Poza et al.,
2022).
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Regarding neuronal circuits and neurotransmitters, it is important to know that while we sleep, the brain
is still active regulating sleep from various structures in the brain stem, hypothalamus, thalamus, and
forebrain. Sleep and awakening are regulated through the participation of the ascending reticular
activation system and nuclei in the hypocretinergic, GABAergic, histaminergic, adrenergic, and
cholinergic systems (Telias & Wilcox, 2019). When we are awake, neurons in the lateral hypothalamus
project and excite different populations of neurons that promote wakefulness within the mid-hindbrain,
among these neurons are monoaminergic neurons that release histamine, dopamine, and serotonin, as
well as cholinergic neurons that release acetylcholine in the hindbrain and neurons that release
glutamate. This set of neurotransmitters projects inhibits the ventrolateral preoptic nucleus, activating
wakefulness and consciousness in the cortex. In the case of sleep periods, the ventrolateral preoptic
nucleus is activated by the release of neurotransmitters gamma-aminobutyric acid and galanin that
inhibit orexin neurons in the lateral hypothalamus and monoaminergic, cholinergic, and glutamatergic
neuronal populations (Saper & Fuller, 2017).
Figure 1. Circadian sleep-wake rhythm. Release of melatonin in the dark phase of the day.
Sleep stages
Sleep is divided into two stages: rapid eye movement (REM) and non-REM sleep (NREM). In REM
sleep, high-frequency, low-amplitude electroencephalographic activity like wakefulness occurs, along
with a decrease in muscle tone. NREM sleep is divided into three stages: N1, N2 and N3;
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electroencephalographic activity is high amplitude, synchronized and low frequency (Kohtala et al.,
2021). Stage N1 occurs when the individual feels sleepy and marks the change from the awake state. In
the N2 stage, the dynamics of vital signals, such as eye movements, heart rate, body temperature, and
brain activity, begin to attenuate. Stage N3 is considered deep or slow wave sleep; no eye or muscle
movement occurs (Hussain et al., 2022).
Sleep stages alternate, presenting four to five sleep cycles per night. The first sleep cycle has a longer
duration of NREM sleep and a shorter duration of REM. In subsequent sleep cycles, the duration of
NREM sleep progressively shortens while the proportion of REM sleep increases (Kohtala et al., 2021).
Recapitulating, two basic processes are considered to regulate the time and duration of sleep: a circadian
one that defines the alternation of periods, independent of wakefulness and sleep but linked to
oscillations in core body temperature and melatonin secretion and a homeostatic process determined by
sleep-wake that allows an increase in sleep pressure when restricted or absent and a reduction in sleep
pressure in response to excess sleep. It's meaningful to remember that the circadian process determines
the quantity of sleep, while homeostasis determines the quality. When the two systems are in a state of
balance, the individual can stay awake for a long time in the day (approximately 16 hours) and maintain
long, stable sleep at night (approx. 8 hours) (Sun & Chen, 2021).
Sleep disorders
Due to the importance of the sleep process for human beings, the disorders that can occur during this
process and that will cause more than one of the main functions of the body to be affected have been to
be investigated. The American Academy of Sleep Medicine has made the third edition of the
classification of sleep disorders, establishing them as: insomnia, sleep-related breathing disorders,
central hypersomnolence disorders, sleep-wake circadian rhythm disorders, parasomnias, sleep-related
movement disorders and other sleep disorders (Sateia, 2014).
Although all the disorders mentioned above are important, in this case, we will focus on sleep-related
breathing disorders: obstructive sleep apnea (OSA), central sleep apnea, and non-obstructive
hypoventilation, because in recent years, it's prevalence has increased. Specifically, we will talk about
OSA since its prevalence records previously ranged between 2% in women and 4% in men. However,
they have increased abruptly, registering a prevalence of 23 to 26% in women and 40.6% to 49.7% in
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men in 2018 (Guerrero et al., 2018). This is derived from the increase in obesity, the aging of the
population and the accessibility of tests that detect the disease.
Obstructive sleep apnea (OSA)
OSA is a common, chronic, sleep-related respiratory disorder characterized by recurrent moments of
upper airway obstruction, precisely during sleep. It is an age-dependent disease, that is the older the age,
the greater the prevalence, reaching a plateau around the age of 65 (Chiu et al., 2022). The most
important clinical symptoms are loud snoring, night waking, increased respiratory effort, daytime
sleepiness and fatigue. Furthermore, it is associated with several comorbidities affecting different
systems, including cardiovascular, metabolic, psychiatric, and neurological complications (Gabryelska
et al., 2022).
Figure 2. Airflow obstruction. In the image on the left, you can see how the airflow is normal. When
the muscles relax, the uvula and soft palate collapse simultaneously with the tongue over the pharyngeal
portion of the airway, preventing the normal flow of air and becoming even more accentuated in the
REM sleep stage due to muscle atony (right image).
The obstruction is produced by pharyngeal collapse that can be complete (apnea) or partial (hypopnea).
During wakefulness, the upper airways are kept open by the constant activity of the muscles that dilate
but after the onset of sleep, when muscle activity is reduced, the airways collapse. Intermittent airway
obstruction generates hypoxia that can lead to autonomic activation and repeatedly cause transient
awakening. This leads to sleep fragmentation which in turn leads to somnolence, anxiety, poor work
performance, and increased risk of car and work accidents. A significant factor for the development of
OSA is morphological abnormalities such as reduced length of the mandible, low setting of the hyoid
bone, posterior displacement of the maxilla, narrowing of the pharyngeal space, enlargement of the soft
structures in and around the airways, for example lengthening of the soft palate, increased soft tissue in
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the neck and redundant pharyngeal mucosa (Lv et al., 2023). Deviation of the nasal septum, turbinate
hypertrophy, reduction of the oropharynx caused by palatine toncillary hypertrophy, macroglossia or
changes in dental occlusion can also contribute to the development of OSA (Laratta et al., 2017).
Risk factors
Risk factors can be divided into two categories - modifiable and non-modifiable. Non-modifiable risk
factors include male gender, age, race, genetic risk, family history of OSA, and craniofacial anatomy
that results in narrow airways. On the other hand, modifiable factors include obesity which is closely
correlated with body mass index. Obesity contributes to airway compression by increasing the volume
of fat in the throat, upper airways, and around the sinuses. Additionally, muscle relaxants such as
benzodiazepines, opiates, or alcohol can cause airway narrowing, which is also a risk factor (Chiu et al.,
2022; Lv et al., 2023).
Diagnosis
Polysomnography is the gold standard for diagnosing OSA. During the study, the patient spends the
night at a sleep clinic or lab, where several sensors are used to record electrophysiological data while
they sleep. The electroencephalogram provides neurophysiological data that helps detect different stages
of sleep, identify normal brain activity, and differentiate between wakefulness and sleep.
Electrooculography and electromyography can detect REM sleep by monitoring eye movements and
muscle tone changes. The test also includes electrocardiography, body position, and movement sensors,
as well as airway-related signals such as airflow, thoracic, abdominal movement. This comprehensive
approach enables accurate diagnosis and effective treatment, snoring, and oxygen saturation.
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Figure 3. Polysomnography is currently the gold standard for diagnosing obstructive sleep apnea. It is
performed in a sleep laboratory where the patient undergoes a real-time analysis, electrical and
mechanical signals are obtained from the different clinical variables that can be affected during sleep.
It is important to detect the frequency of obstructive respiratory events in patients with OSA (Obstructive
Sleep Apnea) as they can have various types of respiratory abnormalities. These events include apneas
(when breathing stops for more than 10 seconds) and hypopneas (when there is a decrease in oxygen
saturation by 3% or more or sleep arousal). The apnea-hypopnea index (AHI) is calculated by adding
all apneas and hypopneas and then dividing them by the total sleep time. The severity of OSA is
determined by the AHI, where an AHI of 5 to 15 indicates mild OSA, 16 to 30 indicates moderate OSA
and more than 30 events per hour indicate severe OSA (Benjafield et al., 2019;).
Polysomnography is a diagnostic tool for sleep disorders, but it is expensive, requires trained personnel,
and is not easily accessible for mass diagnoses. To overcome these limitations, respiratory polygraphy
has been introduced as a simplified version of polysomnography. Respiratory polygraphy records four
to seven signals, mainly cardiorespiratory, without measuring brain activity or sleep staging information.
It is a more comfortable option for patients as it does not require the presence of a technician (Kissow
Lildal et al., 2023).
Several studies have compared the results of polysomnography and respiratory polygraphy for
diagnosing obstructive sleep apnea (OSA). They have reported that respiratory polygraphy is a viable
alternative to polysomnography with a correlation of 0.98, sensitivity of 98%, and specificity of 88%.
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This means that respiratory polygraphy offers not only qualitative but also quantitative tests for more
accessible diagnoses and adequate statistics to improve treatments. It is important to note that OSA is
not only an adult disease, but it can also affect children (Kissow Lildal et al., 2023).
Circadian rhythms and OSA
Circadian rhythms are generated by the circadian system with periods of approximately 24 hours, where
central structures and peripheral organs participate and coordinate endogenous rhythms of behavior,
physiology, and hormonal environment. There are physiological and pathophysiological patterns
dependent on daily responses to behavioral changes in the environment, for example, night and day that
promote the daily sleep-wake cycle (Thosar et al., 2018).
OSA is not classified as a circadian rhythm disorder but has been linked to its alternation. Some authors
have proposed that the interaction between OSA and circadian dysregulation is bidirectional because the
circadian system influences the pattern of respiratory events in OSA, promoting circadian dysregulation
through hypoxia and hypoxia signaling sleep fragmentation. When deregulation of circadian rhythms
occurs, several homeostatic processes involved in the development of comorbidities related to OSA,
such as metabolic syndrome, cardiovascular disease, and cancer, are altered (Li et al., 2022).
There have been studies conducted on the circadian secretion of hormones in patients with Obstructive
Sleep Apnea (OSA), but the results have been conflicting. Unlike the control group, patients with OSA
do not have a maximum peak of melatonin at 02:00 am. Instead, the maximum peak occurs at 06:00 am,
and the concentration is much lower than the controls. One study found that the rhythm of melatonin
secretion was altered in 25.4% of OSA patients. However, other studies report that the circadian
waveforms of melatonin, heart rate, and cortisol are not affected by OSA, but blood pressure is, and the
circadian system contributes to the prolongation of apneas (Butler MP et al., 2020).
Patients with OSA are at a higher risk of developing circadian rhythm disruption. Recurrent apnea and
related nocturnal hypoxemia can affect pineal gland function as the expression of circadian rhythm genes
is disrupted. The main mechanism of interaction is probably mutual transcriptional regulation between
HIF-1 and BMAL1: CLOCK. The Per1, Cry1, and CLOCK genes have hypoxia response elements, so
they may be targets for HIF-1. An increased level of HIF-1 α subunits in OSA patients is associated with
overexpression of clock gene proteins (Gabryelska et al., 2022).
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CONCLUSIONS
Sleeping properly has great benefits for our body. However, we do not give it importance, or we are not
aware of these benefits. Now that we know the importance of sleeping well and some diseases that
negatively participate in the sleep-wake cycle and alterations in circadian rhythms, for example, Chronic
Obstructive Pulmonary Disease as one of the main causes of morbidity and mortality in the world, since
it generates significant changes in the respiratory center, resistance of the airways, which can result in
the development of Obstructive Sleep Apnea Syndrome, associated with a sleep disorder that is
characterized by repetitive obstruction of the airway during sleep with complete or partial cessation of
air. The symptoms of both pathologies can be confused with polygraphy or polysomnography in patients
where symptoms of sleep apnea are accentuated, such as persistent snoring, witnessed apneas, episodes
of suffocation and excessive daytime sleepiness, in order to provide the patient with correct clinical
management, which includes management of the sleep disorder as well as personalized attention in the
temporary reorganization of activities such as eating, locomotor activity and the use of chronobiotics
such as melatonin as chronotherapeutic support. Finally, it is recommended to visualize in an integrated
manner the patient with sleep disorders and sleep apnea syndrome.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgment
This study was partially supported by grants PAPIIT-IN216623-UNAM to Manuel Angeles-Castellanos.
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