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Curr Opin Pulm Med. Author manuscript; available in PMC 2021 May 01.
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Published in final edited form as:

Curr Opin Pulm Med. 2020 November ; 26(6): 609–614. doi:10.1097/MCP.0000000000000724.

Endotypes and phenotypes in obstructive sleep apnea

Atul Malhotra, Omar Mesarwi, Jean-Louis Pepin, Robert L. Owens
INSERM Grenoble Alpes University

Abstract
Purpose of review—The purpose of this review is to describe the variability of obstructive
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sleep apnea (OSA), both from a standpoint of underlying mechanisms and in terms of clinical
manifestations.

Recent findings—Recent data suggest that not all patients with sleep apnea get their disease for
the same reason. As such, no one variable is effective at defining which patients do or do not have
sleep apnea. Identifying the mechanism(s) underlying OSA for an individual is helpful as it can
help to determine whether personalized therapy could be developed based on an individual’s
characteristics. In addition, these underlying mechanisms may be helpful in predicting response to
therapy and prognosticating regarding future complications.

Summary—OSA is a heterogeneous disease with highly varying underlying mechanisms. OSA

has variable clinical manifestations with definable subsets having risk of particular complications.
Future studies will be helpful to identify mechanisms underlying OSA using clinically accessible
tools and then using these data to focus individualized treatment approaches.
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Keywords
airway; apnea; lung; sleep; ventilation

INTRODUCTION
Obstructive sleep apnea (OSA) affects nearly one billion people worldwide, with substantial
associated morbidity, mortality, and financial and social costs [1▀ ▀]. OSA is a disease
characterized by repetitive pharyngeal collapse during sleep [2]. This intermittent collapse
results in reduced airflow which has two sets of consequences: arousal from sleep to resume
airflow, and gas exchange disturbances from hypopneas (reductions in breathing) or apneas
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(cessations of breathing) [3]. The recurrent arousals in OSA lead to neurocognitive

consequences including diminished memory consolidation, daytime sleepiness, and reduced
quality of life [4]. Hypoxemia and hypercapnia with resulting catecholamine surges,
oxidative stress, and low-grade inflammation are thought to underlie the cardio-metabolic
consequences of OSA [5]. However, the mechanisms contributing to these adverse health
outcomes of OSA are complex and incompletely understood.

Correspondence to: Atul Malhotra, Pulmonary, Critical Care, Sleep and Physiology Division, UC San Diego, 9500 Gilman Drive, La
Jolla, CA 92037, USA. Tel: +1 858 657 7130; [email protected].
Conflicts of interest A.M. reports income from Merck and Livanova related to medical education. ResMed provided a philanthropic
donation for UC San Diego.
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Recent studies have suggested that OSA is a heterogeneous disease both from the standpoint
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of underlying mechanisms (endotypes) and in its clinical expression (phenotypes) [6–8].

Disease heterogeneity has been long recognized in the cancer field, but more recently has
been discussed in other respiratory disorders such as asthma (e.g. allergic, occupational,
exercise-induced, cough-variant), chronic obstructive pulmonary disease (e.g. pink puffers
and blue bloaters, but also small airways fibrosis and other manifestations), acute respiratory
distress syndrome (hypo-inflammatory, hyper inflammatory, variable lung compliance, and
response to positive pressure ventilation) [9]. The recognition of this heterogeneity in
disease states is potentially helpful because therapy can sometimes be personalized based on
individual characteristics [6]. Other biological insights such as predictive models and genetic
susceptibility are more likely to be fruitful if homogeneous patient groups can be identified
rather than searching in broad groups of disease e.g. analogous to searching for a single
‘cancer’ gene for all types of cancers.
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Although individuals with OSA are generally categorized under the same universal
diagnosis, the diagnosis of OSA carries with it variable and complex underlying
mechanisms and various clinical and polysomnographic features. The OSA diagnosis is
usually defined by a single data point captured by polysomnography or polygraphy, the
apnea-hypopnea index, but recent studies have demonstrated that this simplistic approach
has the potential to underestimate the complex heterogeneity of OSA. Determining
individual risks and anticipating treatment responses (both in routine practice and for
designing clinical trials) requires a better characterization of the disease complexity. There is
growing evidence that a new delineation of specific OSA subgroups is the prerequisite for
the development of precision and personalized medicine in this field. [10▀ ▀,11,12,13]

Obstructive sleep apnea endotypes

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The pathogenesis of OSA is generally accepted to be highly variable. The underlying

endotypes include anatomical compromise, impaired pharyngeal dilator muscle function,
unstable ventilatory control (elevated loop gain), and low arousal threshold (being
predisposed to wake up with respiratory disturbances) [14,15]. Other factors such as end
expiratory lung volume, arousal intensity, and redistribution of body fluid, are also likely
important [16–18]. The studies on anatomical compromise have consisted of imaging and
sophisticated measures of mechanics under passive conditions [19,20▀]. In general, patients
with OSA have anatomical compromise as compared to matched controls, but considerable
overlap exists since pharyngeal anatomy explains only a portion of the variance in the
occurrence and severity of OSA [21,22]. Thus, anatomy is not the whole story, perhaps
explaining the variable benefits seen with surgical interventions directed primarily at
anatomical compromise.
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Pharyngeal dilator muscle function is also important, because patients with OSA have been
shown to have increased activity in the major dilator muscles during wakefulness as
compared to matched controls [23]. Compensatory reflexes exist during wakefulness which
increase the activity of these muscles; however, with the onset of sleep there is a loss of
protective reflexes which yields a fall in pharyngeal dilator muscle activity, resulting in
collapse in those who are anatomically susceptible [24]. The negative pressure reflex (NPR)

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refers to the robust activation of the pharyngeal dilator muscles in response to a collapsing
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(subatmospheric) perturbation. The NPR has been shown to be highly variable both during
wakefulness and during sleep, implying that a therapy to augment this reflex would also be
predicted to have variable efficacy [25]. Of note, muscle activation, as assessed by EMG, is
an important component of muscle activity but abnormalities of electrical–mechanical
coupling have also been reported in some OSA studies [26–28]. The importance of these
upper airway muscles and reflexes is emphasized by the observation that these muscles are
both necessary and sufficient to stabilize breathing if adequate respiratory stimuli (negative
pressure, carbon dioxide) can accumulate with sufficient magnitude and for adequate
duration [29]. For example, some very obese patients do not have OSA, because of robust
upper airway muscle responses [30].

Regarding unstable ventilatory control, engineers use the concept of ‘loop gain’, which is a
term that has been adapted into the medical literature. An elevated loop gain refers to a
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system which is unstable with perturbation, whereas a low loop gain system describes one
that is intrinsically stable [17,31]. An analogy to room temperature is often helpful when
considering the factors that can lead to instability in negative feedback control. Although the
human body generally tries to maintain a PaCO2of roughly 40 mmHg, the temperature in a
room is generally set to roughly 208C. The temperature in a room might be prone to
oscillation if the thermostat were too sensitive. That is, if a change to 19.998C were enough
to turn on a furnace, the temperature in the room would likely overshoot and the result
would be fluctuations in room temperature [32]. By analogy, if an individual had robust
chemosensitivity (high loop gain), such that for a minor change in PaCO2there resulted a
major change in ventilation, there would similarly be fluctuations in PaCO2[33]. Another
analogy would be a furnace that was too powerful, such that a temperature fall to 198C led
to a major output of the furnace to 708C, there would clearly be risk of major fluctuations in
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room temperature. By analogy, if an individual were to wake up from sleep with a PaCO2of
45 mmHg, and the ventilatory response led to a fall in a PaCO2down to 10 mmHg (below
the chemical apnea threshold), there would clearly be an unstable control system and marked
fluctuations in PaCO2would be predictable [34].

The classic breathing pattern defined by high loop gain is Cheyne–Stokes breathing, or
periodic breathing, as seen at high altitude [35]. Elevated loop gain, however, is also thought
to be important in OSA, and several classic studies have showed an important role of high
loop gain in OSA [17,31]. Fluctuations in output from the central pattern generator in the
brainstem affect the activity of both the diaphragm and the upper airway dilator muscles. As
a result, the upper airway may be vulnerable to collapse when output to the upper airway
dilator muscles is at its nadir, particularly in those who are anatomically susceptible. High
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loop gain is important particularly in a subset of individuals in whom anatomical factors are
not the predominant mechanism underlying the presence or absence of OSA [36]. High loop
gain has also been shown to predict failure of upper airway surgery, presumably because the
surgery does not address the underlying abnormalities in control of breathing [37]. Efforts to
lower loop gain using either oxygen or acetazolamide have been helpful, although these
studies have also emphasized the complexity of the situation given the multiple interacting
variables [38].

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Some patients with OSA have a propensity to wake up readily in response to respiratory
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disturbance; this inclination to easy arousal from sleep is termed low arousal threshold.
Several points deserve emphasis:

A low arousal threshold has been demonstrated in roughly one-third of patients with OSA
[15].

Premature awakening from sleep, as occurs with low arousal threshold, might lead to
insufficient accumulation of respiratory stimuli to activate the pharyngeal dilator muscles.
As such, repetitive apnea may result [39].

Agents which raise the arousal threshold, such as hypnotic agents like trazodone or
eszopiclone, may have a role to allow more accumulation of respiratory stimuli and thus
activate dilator muscles which could stabilize breathing. Some physiological studies have
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shown potential benefits although hard outcome data are lacking [40].

The arousal threshold interacts in complex ways with other pathophysiological traits,
because the stimulus to arouse from sleep is thought to be negative intrathoracic pressure.
Thus, factors that affect control of breathing can impact the time to arousal, depending on
ventilatory drive and prevailing mechanics [16].

OSA endotypes are worth consideration for several reasons (see Fig. 1). First, as stated, the
endo types may guide individualized therapies to allow interventions to be guided based on
underlying mechanism. In some cases, with multiple underlying mechanisms, combination
therapies may be needed to yield an acceptable result [38]. Second, underlying endotypes of
OSA may be related to risk factors for disease. For example, posttraumatic stress disorder is
a known risk factor for OSA, which may reflect a low arousal threshold seen in some of
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these patients [41]. Moreover, patients with neuro muscular disease commonly have OSA,
perhaps as a result of underlying upper airway dilator muscle dysfunction. Third, the
endotypes of OSA may be important predictors of therapeutic response to clinical
interventions. For instance, a high loop gain is predictive of treatment-emergent central sleep
apnea (complex sleep apnea). High loop gain and low arousal threshold can also predict
failure of uvulopalatopharyngoplasty surgery. Moreover, patients with low arousal threshold
are reported to have decreased adherence to positive airway pressure (PAP) therapy
compared to those with normal arousal threshold [42]. Fourth, the recognition for the
variability in clinical expression of OSA (phenotypes) has led to the assertion that OSA
endotypes may predict disease complications. These findings amplify the potential
importance of OSA pathogenesis in guiding clinical management. Nonetheless, these
concepts have not been widely adopted into clinical practice because of rigorous outcome
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data remain sparse, and simplified methods to identify the various pathophysiological traits
clinically are still evolving. [43].

Obstructive sleep apnea phenotypes

Ye et al. was one of the first teams to perform cluster analyses on a cohort of patients with
OSA [7], defining three distinct groups: sleepiness with cardiovascular risk [8], disrupted
sleep with insomnia, and asymptomatic patients. Further work by these authors has shown

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little symptomatic improvement in those ‘asymptomatic’ patients, whereas sleepy patients

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who adhere to PAP therapy become less somnolent. In addition, sleepy patients are
apparently those patients with OSA at greatest cardiovascular risk [44,45].

OSA phenotypes have been principally identified through different methodologies of cluster
analysis such as latent class analysis, hierarchical ascending clustering, or K-means
clustering. The goal of these efforts has been to identify clearly distinct subgroups of OSA
with minimal differences between two individuals within a same phenotype and clear
differences between two individuals having distinct phenotypes. Across previous studies,
anywhere from three to seven clusters have been identified in such analyses, the number
depending on the clustering method employed, and the different selections and combinations
of variables included in the clustering analyses. Some studies have been based on the
anatomic and/or craniofacial characteristics of OSA patients, others on symptoms,
polysomnographic indices, or comorbidities. A combination of comorbidities and symptoms
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has been mostly used. Few studies have included extensive combinations of lifestyle,
clinical, polysomnographic, and comorbidity variables. The majority of studies have been
based on local or national databases whereas geographical factors, lifestyle, behaviors and
genetic background might also impact OSA phenotypes [46].

The importance of these phenotypic clusters has drawn increasing attention in part because
of the failure of some large multicenter trials to improve cardiovascular risk of OSA [47].
Given that only a subset of patients appear to be at OSA-related cardiovascular risk [8], the
finding that a large group of patients with OSA does not derive cardiovascular benefit from
OSA treatment is perhaps not surprising [48]. Major efforts are underway to identify those
patients who are likely to be at high cardiovascular risk so that such patients can be
identified prospectively in designing interventional trials.
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Several approaches may be viable to identify patients with OSA who may be at high
cardiovascular risk:

Certain endotypes may be important in predicting cardiovascular risk. For example, short
respiratory events, perhaps associated with high loop gain and low arousal threshold, have
been associated with cardiovascular risk [49]. Short respiratory events compared to longer
events are typically those with minimal desaturation. In contrast, hypoxic burden, based on
the area under the hypoxia curve, is predictive of cardiovascular risk. Marked hypoxemia
can be a marker of high arousal threshold [15,50▀]. Thus, the data are not consistent
regarding the epidemiological findings, emphasizing the need for further mechanistic
research.
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Cardiovascular biomarkers, or panels of biomarkers, may be useful in predicting

cardiovascular risk [51]. hsCRP is a robust marker of cardiovascular risk but has been
inconsistent in its association with OSA versus obesity. A panel of biomarkers could assess
sympathoexcitation (e.g. muscle sympathetic nerve activity, heart rate variability), oxidative
stress (e.g. lipid peroxidation), and inflammatory path ways (interleukin-6, hsCRP), and may
be useful to optimize the prediction of OSA-associated cardiovascular risk [51–53].

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Novel biomarkers such as microRNAs, the air way or gut microbiome, metabolomics,
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exosomes, and other techniques are now being assessed in the context of OSA-associated
cardiovascular risk. Trimethylamine N-oxide (TMAO) is a cardiovascular biomarker which
has been shown to be released by gut bacteria; antibiotics have been shown to suppress
TMAO in humans. Recurrent hypoxia from OSA may lead to changes in gut bacteria which
could release metabolites affecting cardiovascular risk. In theory, drug targets could block
the impact of the metabolites thereby diminishing cardiovascular risk. Studies in rodents
have shown proof of concept although human interventional data with hard outcomes are
lacking [54–56].

The use of exosomes is being increasingly examined whereby extracellular vesicles acquired
from humans can be examined in vitro to assess their impact on endothelial cell function and
barrier permeability. Bhattacharjee et al. [57] have shown endothelial dysfunction induced
by exosomes from humans with obesity hypoventilation syndrome; these abnormalities
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largely resolved after the patients were treated with PAP. Such approaches could be used in
clinical trials since patients who had high cardiovascular risk could ostensibly be defined
based on in vitro analyses of the participant’s exosomes.

A subset of patients with OSA do not respond well to PAP. Some individuals have treatment
emergent central sleep apnea, which in some cases can persist in the long term (treatment
persistent central sleep apnea) [58]. The natural history of these patients is unclear, but long-
term adherence and cardiovascular protection may well be compromised. Individuals with
high loop gain are those thought to be at risk of reduced PAP efficacy, and thus their disease
may be particularly amenable to interventions targeting this endotype (e.g. acetazolamide or
oxygen).
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Adaptive trial designs are being used such that the outcomes and interventions in studies can
be changed on an ongoing basis depending on response to therapies. Such studies have been
used in the oncology world but are increasingly being applied to trials in sepsis, asthma, and
other respiratory diseases. One example would be to enroll patients and, prior to
randomization, determine for which outcomes a particular patient is at risk. In theory some
patients could be enrolled to assess Alzheimer’s risk (perhaps based on impaired memory or
ApoE status), whereas others could be enrolled examining cardiovascular outcomes (perhaps
based on endothelial dysfunction or other biomarkers), and yet others may be likely to
remain asymptomatic and thus treatment benefits would be difficult to demonstrate
[52,53,59▀ ▀,60,61].

CONCLUSION
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Major progress has been made in the OSA field via recognition of the heterogeneity of this
disease, both in terms of its pathogenesis (endotypes) and its expression (phenotypes). Only
through further mechanistic and multidisciplinary clinical translational and basic research
are new therapeutic targets and approaches likely to emerge. Further research is also needed
for recognizing sex-based phenotypes and the impact of these subtypes on treatment
prescription. The majority of the relevant studies have been cross-sectional and the impact

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on treatment adherence or prognosis of these clusters remains to be studied ideally by

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combining existing databases in large international consortia.

Financial support and sponsorship

A.M. is funded by NHLBI and NIA. O.M. is funded by K08. R.L.O. is funded by NHLBI RO1.

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29867728]
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KEY POINTS
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• OSA is a heterogeneous disease with multiple underlying mechanisms.

• The mechanism underlying OSA might affect clinical manifestations.

• The clinical presentation of OSA is highly variable with some patients

asymptomatic and others at major cardiovascular risk.

• Further research regarding OSA endotypes and phenotypes is imperative.

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FIGURE 1.
Three factitious patients to illustrate the potential variability in underlying mechanisms and
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clinical manifestations of obstructive sleep apnea (BMI, body mass index; CBTI, cognitive
behavioral therapy for insomnia; CPAP, continuous positive airway pressure; NIPPV,
noninvasive positive pressure ventilation; OSA, obstructive sleep apnea; RLS, restless legs
syndrome).
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Curr Opin Pulm Med. Author manuscript; available in PMC 2021 May 01.