ERS International Congress 2023: Highlights from the Sleep Disordered Breathing Assembly

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ERS International Congress 2023: Highlights from
the Sleep Disordered Breathing Assembly
Matteo Siciliano, Matteo Bradicich, Pasquale Tondo, Canan Gunduz Gurkan, Wojciech Kuczyński,
Alessia Martini, Özge Aydin Güçlü, Dries Testelmans, Manuel Sánchez-de-la-Torre, Winfried
Randerath, Esther Irene Schwarz, Sophia Schiza
Please cite this article as: Siciliano M, Bradicich M, Tondo P, et al. ERS International Congress
2023: Highlights from the Sleep Disordered Breathing Assembly. ERJ Open Res 2023; in press
(https://doi.org/10.1183/23120541.00823-2023).
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ERS Internaonal Congress 2023: Highlights from the Sleep
Disordered Breathing Assembly
Maeo Siciliano1*, Maeo Bradicich2*, Pasquale Tondo3,4*, Canan Gunduz Gurkan5*, Wojciech
Kuczyński6*, Alessia Marni1*, Özge Aydin Güçlü7*, Dries Testelmans8*, Manuel Sánchez-de-la-
Torre9*, Winfried Randerath10*, Esther Irene Schwarz2*, Sophia Schiza11*
*Contributed equally
1 Fondazione Policlinico Universitario A.Gemelli IRCCS- Università Caolica del Sacro Cuore, Rome, Italy
2 Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
3 Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy;
4 HP2 Laboratory, Université Grenoble Alpes, Grenoble, France
5 Department of Chest Diseases, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital,
Istanbul, Turkey
6 Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, Lodz, Poland
7 Uludag University Faculty of Medicine, Department of Pulmonary Medicine, Bursa, Turkey
8 Department of Pulmonology, University Hospitals Leuven, Leuven, Belgium
9 Centro de Invesgación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; Precision Medicine
in Chronic Diseases, Hospital Universitari Arnau de Vilanova-Santa Maria, IRB Lleida, Department of Nursing and
Physiotherapy, Faculty of Nursing and Physiotherapy, University of Lleida, Lleida, Spain.
10 Bethanien Hospital, Clinic of Pneumology and Allergology, Center for Sleep Medicine and Respiratory Care, Instute
of Pneumology at the University of Cologne, Solingen, Germany
11 Sleep Disorders Centre, Dept of Respiratory Medicine, School of Medicine, University of Crete, Greece
Corresponding Author: Maeo Siciliano, Fondazione Policlinico Universitario A.Gemelli IRCCS-
Università Caolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome (Italy). mat.sic89@gmail.com

Abstract
The topic of sleep-related breathing disorders is always evolving, and during the European Respiratory Society (ERS)
Internaonal Congress 2023 in Milano (Italy), the latest research and clinical topics in respiratory medicine have been
presented. The most interesng issues ranged from new diagnosc tools, including cardiovascular parameters and
arcial intelligence, pathophysiological traits of SDB from roune polysomnography or polygraphy signals, up to new
biomarkers and the diagnosc approach in paents with excessive dayme sleepiness. This arcle summarises the most
relevant studies and topics to this extent presented at the ERS Internaonal Congress 2023. Each secon has been
wrien by Early Career Members of the ERS Assembly 4.
Plain language summary
The annual European Respiratory Society Internaonal Congress 2023 brings together respiratory medicine specialists
from across the globe. At this event, they share and deliberate on the latest scienc ndings with their peers and fellow
experts in the eld. This arcle summarises the most novel research aspects that emerged in this year’s European
Respiratory Society Internaonal Congress. The presented research trends focused mainly on the latest data about sleep-
disordered breathing in associaon with cardiovascular disease; new insights from recent clinical trials and meta-
analyses about the diagnosis of sleep-disordered breathing (SDB); the endotypes or pathophysiological traits allowing
to indicate personalised therapy. Each paragraph has been wrien by Early Career Members of the ERS Assembly 4.
Abbreviaons
AASM: American Academy Sleep Medicine
AHI: apnoea hypopnoea index
ASV: adapve servo-venlaon
CPAP: connuous posive airway pressure
CSA: central sleep apnoea
CV: cardiovascular
DLco: diusing capacity of the lungs for carbon monoxide
EDS: excessive dayme sleepiness
ERS: European Respiratory Society
ERV: expiratory reserve volume
ESS: Epworth Sleepiness Scale
ESADA: European Sleep Apnoea Database
FEV1/FVC: forced expiratory volume rst second/forced vital capacity
FRC: funconal residual capacity
HR: heart rate
ICU: intensive care unit
IL: interleukine
LVEF: le ventricular eject fracon

MACEs: major adverse cardiovascular events
MAS: mandibular advancement splint
NIV: non-invasive venlaon
OHS: Obesity Hypovenlaon Syndrome
OSA: obstrucve sleep apnoea
PALM: Pcrit, arousal threshold, loop gain, and muscle responsiveness
PAP: posive airway pressure
PWAD: pulse wave amplitude drops
PSG: polysomnography
RCTs: Randomized clinical trials
RV: residual volume
SDB: sleep disordered breathing
SESI-MS: secondary electrospray ionizaon mass spectrometry
TECSA: treatment emergent central sleep apnoea
TLC: total lung capacity
Introducon
At the 2023 European Respiratory Society (ERS) Internaonal Congress held in Milano, Italy, experts addressed the most
recent research and clinical topics within the eld of respiratory medicine. The presentaons and symposia on sleep -
disordered breathing brought together pulmonologists, cardiologists, physiologists, and researchers and introduced
novel perspecves on understanding the underlying causes of sleep-related breathing disorders, their diagnosis, and
emerging direcons in both translaonal research and clinical applicaons. Focus topics included phenotype-based
therapy for obstrucve sleep apnoea, technical innovaons and novel prognosc markers, the eects of obesity on
respiraon, and recent ndings on the treatment of Cheyne Stoke's breathing in heart failure. This arcle serves as a
concise overview of the key studies and themes that were showcased during the ERS Internaonal Congress in 2023,
with each secon authored by early-career members of ERS Assembly 4.
Symposium: New insights into diagnosc aspects of sleep-disordered breathing
The symposium focused on novel sleep disordered breathing (SDB) diagnosc techniques and their clinical implicaons.
Moreover, the pathophysiological traits of SDB that can be derived from sleep studies as well as new diagnosc
approaches to excessive dayme sleepiness (EDS) have been discussed.
Dr. Renata Riha (Edinburgh, Scotland), rst author of the most recent ERS technical standards for level III sleep studies,
assessed the role of big data in sleep medicine. She discussed dierent types of sleep monitoring systems and outlined
their applicaon, potenal, and limitaons. She underlined the need of data integraon derived from various sensors,
as they assess the same phenomenon from dierent perspecves, including treatment adherence. Moreover, the
analysis of commonly underulised data, either derived from novel analysis of already acquired raw data (e.g. hypoxic
burden) or transcending the raw measurements adopng a holisc approach, plays a growing role in big data
management. Aerwards, she summarised the main limitaons concerning data acquiring device validaon against gold

standard; night-to-night variability; intrinsic limitaons of the used technologies; changing denions or scoring rules
which might redene the applicaon potenal of a technology. The aim of structured big data management is, in
conclusion, a beer paent stracaon. She also pointed out that despite the advantages of the technical innovaons,
it remains important to have access to the raw data and to know the analysis algorithms.
Prof. Malcolm Kohler (Zurich, Switzerland) held a presentaon on the role of biomarkers in SDB, focusing on paent
proling using exhalomics. Exhalomics is a branch of metabolomics, assessing the molecular spectrum measured by
sampling exhaled breath. This includes not only the molecules coming directly from the lungs and airways, but all the
molecules able to pass the blood-alveolar barrier and therefore being exhaled. He showed the results of a connuous
posive airway pressure (CPAP) withdrawal trial in obstrucve sleep apnoea (OSA), where exhaled pentenal measured
with secondary electrospray ionizaon mass spectrometry (SESI-MS), a quancaon technique used in exhalomics,
signicantly increased in response to CPAP withdrawal and thus OSA recurrence and compared to the control group
connuing CPAP[1]. This technology has been further validated by a cross-seconal analysis focusing on OSA diagnosis
[2]. A further applicaon of exhalomics is the detecon of up- and down-regulated metabolism pathways during wake
and sleep stages [3]. On a subcellular metabolic level, exhalomics was able to quanfy stress-induced oxidave
mitochondrial damage [4]. These ndings suggest an applicaon potenal for exhalomics, which might allow the
idencaon of paents with clinically signicant OSA from a metabolic point of view.
Prof. Winfried Randerath (Solingen, Germany) discussed how polysomnographic traits can be translated into clinical
decisions. This topic is of utmost relevance and, at the same me, enormously complex, as it is based on a network of
intertwining pathophysiological sleep apnoea determinants, such as loop gain and upper airway collapsibility. An analysis
of pathophysiological traits derived from and applicable in clinical roune depends on the integraon of informaon on
various pathophysiologic components derived from dierent diagnosc methods – such as venlatory drive, muscle
acvity, and chemosensivity [5]. All these techniques have limitaons, which do not allow a direct implementaon of
a unique method into clinical roune, applicable to all clinical scenarios. One of the most relevant shortcomings is the
need of arcial intelligence to analyse this kind of data from a quantave perspecve. A visual qualitave analysis of
polysomnographic data, a feasible clinical roune acvity, might give some hints on potenally treatable
pathophysiological aspects of the specic paent.
Prof. Maria Rosaria Bonsignore (Palermo, Italy) presented an overview on the diagnosc approach to EDS. Various EDS
predictors have been idened, such as hypoxic load, OSA severity, sleep-inducing medicaon and caeine
consumpon, self-reported sleep duraon, and depressive symptoms [6]. A clinical challenge involving EDS is the
objecve assessment of a subjecve sensaon: the mulple sleep latency test and the Oxford sleep resistance test,
which are currently used in clinical roune, are complex procedures and are praccally carried out only when central
hypersomnia is suspected. Acgraphy and sleep diaries are less resource-consuming procedures enabling sleep paerns’
assessment. The Epworth Sleepiness Scale (ESS) is widely used quesonnaire and scoring system to quanfy subjecve
EDS. Although broadly used and easy-to-perform, the ESS has some limitaons – e.g., it does not provide any informaon
on sleepiness determinants or the related sleep disorder; it also cannot be performed in cognive impaired paents.
Alternavely, psychomotor vigilance tests are a promising opon, reducing the uncertainty associated with a subjecve
assessment like ESS. This kind of test is correlated to some SDB-specic characteriscs such as desaturaon and
obstrucon severity, as well as higher slow wave acvity during sleep.
Year in review: Advances in sleep breathing disorders
Prof. Sophia Schiza (Crete, Greece) analysed the latest evidence on prognosc markers from sleep studies in OSA and
paent clusters with a favourable response to CPAP therapy in terms of incident major cardiovascular (CV) events.
The group of Prof. Mary Ip conducted a clinic-based retrospecve cohort study to assess the associaon between
polysomnographic parameters and incident major adverse cardiovascular events (MACEs), and to invesgate if the CPAP
eect could be beer delineated among specic phenotypes [6]. In a retrospecve analysis of more than 1500 paents
with OSA, the apnoea hypopnoea index (AHI) did not predict incident MACEs during a median follow-up of more than 8
years. In contrast, sleep me with oxygen saturaon <90% and mean nocturnal heart rate (HR) were independen t

predictors of adverse cardiovascular outcome. Regular CPAP treatment (>4 hours/night) was not associated with a lower
rate of MACEs, but cluster analysis idened idened a subgroup that was younger, more obese, and had more severe
OSA (higher AHI and TST90) in whom CPAP therapy reduced the risk of MACE.
The group of Prof. Frederic Gagnadoux analysed the associaon between CV outcomes and quarles of average daily
CPAP use using data from the Pays de la Loire Sleep Cohort and the French administrave healthcare database. They
concluded that there was a dose-response relaonship between CPAP adherence and the incidence of MACEs in OSA.
In parcular, they observed a reducon in morbidity and mortality of CV diseases in paents who used CPAP for more
than 6 hours per day [7]. This associaon was stronger in sleepy OSA paents without established cardiovascular disease
Another paper that was discussed in this “Year in review” session evaluated the associaon between pulse wave
amplitude drops (PWAD) index and incident or recurrent cardiovascular events in three prospecve cohorts: HypnoLaus
(general populaon), ISAACC (acute coronary syndrome with OSA), and the Pays de la Loire Sleep Cohort (PLSC, OSA
cohort) [8]. The study aimed to invesgate the value of PWAD as a biomarker of CV risk in OSA, related to sympathec
acvaon and vasoreacvity. They considered PWAD with an amplitude > 30% from baseline and a duraon >4
heartbeats. Data from these three prospecve cohorts showed that a low PWAD index in paents with OSA was
independently associated with a higher risk of incident CV events compared with parcipants who had OSA and a high
PWAD index or those without OSA. Regarding PWAD as a biomarker of CV health, there are some physiological
hypotheses related to a low PWAD index and a poorly reacve autonomic nervous system.
State of the art session: Sleep-disordered breathing and the heart. What is next?
OSA is recognized as a possible causave factor of arterial hypertension, especially therapy -resistant arterial
hypertension. Prof. Silke Ryan (Dublin, Ireland) discussed recent relevant studies in this eld of research, including a
meta-analysis that idened predictors of a blood pressure-lowering eect of CPAP in OSA. Uncontrolled or hypertensive
blood pressure before CPAP therapy, younger age, and lower oxygen desaturaons were associated with a greater blood
pressure-lowering eect of CPAP. [9]. A network meta-analysis showed the greatest blood pressure-lowering eect in
OSA with hypertension from anhypertensive medicaons, but also a signicant eect from CPAP therapy [10]. It was
also pointed out that the eect of CPAP on blood pressure in OSA may be variable and that treatment of arterial
hypertension in OSA requires a comprehensive assessment including consideraon of nocturnal blood pressure. I t
should also not be forgotten that weight loss and a change in lifestyle have beneficial effects on both sleep apnoea
severity and comorbidities [11].
Prof. Douglas Bradley (Toronto, Canada) presented addional results from the not-yet-published ADVENT-HF trial,
parcularly on the eects of adapve servo-venlaon (ASV) therapy in paents with sleep apnoea and systolic heart
failure on quality of life and paent-centred outcomes. The conclusions were that although ASV therapy for systolic heart
failure with OSA and/or Cheyne Stoke's breathing in ADVENT-HF had no signicant eect on the combined cardiovascular
end point and did not signicantly reduce mortality, but in contrast to SERVE-HF-trial [12] (dierent algorithms of ASV),
no worsening of these outcomes was observed either, and the therapy can be safely used to control sleep apnoea in
systolic heart failure, and an improvement in sleep quality and symptoms is possible, especially in Cheyne Stoke’s
breathing.
Prof. Manuel Sanchez-de-la-Torre (Lledia, Spain) has shown that nocturnal hypertension is associated with parcularly
high risk of poor cardiovascular outcome and that OSA may be an important cardiovascular predictor in paents with
nocturnal non-dipping blood pressure proles and especially in paents without manifest cardiovascular end-organ
damage. On the basis of new data, addional features characterizing the OSA phenotype "vulnerable" for cardiovascular
events were revealed, including a high hypoxic burden and a high heart rate variability. He also pointed out that RCTs on
the eect of OSA therapy on cardiovascular outcomes would be important in these vulnerable phenotypes [13]. .
Another useful tool from the perspecve of phenotyping is the PWAD index, which would allow the recognion of

individuals most at risk for cardiovascular disease [14]. He also pointed out that RCTs on the eect of OSA therapy on
cardiovascular outcomes would be important in these vulnerable phenotypes.
Dr. Elisa Perger (Milano, Italy) referred to the concept of precision medicine in OSA and showed recent studies on drug
therapy approaches in OSA. Some studies have focused on carbonic anhydrase inhibitors, such as acetazolamide that
reduces events in both OSA and central sleep apnea (CSA) paents [15] and Sulthiame that reduces obstrucve events
in OSA without increasing BP or heart rate [16]. In addion, the number of studies on drugs addressing poor muscle
responsiveness during night has increased in recent years [17]. In parcular, combinaons of dierent noradrenergic
and anmuscarinic drugs have been shown to be eecve in reducing OSA severity (AHI) in some short-term trials (whilst
other RCTs were negave) but with a slight increase in HR [18-20]. It would be useful to research individual drug
responses across studies and to perform longer and larger RCTs with paents aected by cardiovascular disease.
Phenotypes of Central Sleep Apnea: therapeuc opons and future management perspecves
Prof. Winfried Randerath (Solingen, Germany) gave an expert interview on “Phenotypes of central sleep apnoea (CSA):
therapeutic options and future management perspectives”. Prof. Randerath performed his presentation in three parts,
with respect to clinical entities, pathophysiological differences and indicators of outcomes in CSA. According to the
American Academy of Sleep Medcine (AASM) international classification of sleep disorders, the heterogeneous goup of
CSA is classified according to underlying conditions [21]. In addition, CSA is categorised into two groups, hypercapnic
and hypocapnic CSA. However, these classifications lack details in regards to presentation differences in sleep studies.
The relevance of loop gain in CSA has been emphasizedIn a study conducted by Pavsic K et al [22], they have measured
loop gain in PSGs and have detected significant differences in the loop gain characteristics between patients. While
some patients have demonstrated narrow spectrum of loop gain, some of the patients have demonstrated a very wide
spectrum of loop gain with increased variances in regards to body position, sleep stage and across different nights. Thus,
defining loop gain as a characteristic of a CSA patient may not be accurate. Nevertheless, assessment of loop gain is
essential for understanding the pathophysiology of CSA as well as for determining appropriate therapeutic approaches
addressing different mechanisms including arousablity, chemosensitivity and alveolar ventilation.
The third part of the presentation focused on the unique outcomes of CSA in the light of recent data affecting outcomes
of CSA. In the study of Gianonni A et al [23], patients with high loop gain have shown worse outcomes compared to
patients with milder chemoreceptor response. Lung mechanics also have an impact on treatment outcomes in CSA. Low
end expiratory lung volume has been associated with worse cardiac function and outcome [24]. Using data from the
FACE study, a prosepctive cohort study on ASV in patients with diastolic or systolic heart failure, it was emphasized that
phenotype determines survival.
According to the currently siggested therapeutic algorithm in CSA with Cheyne Stoke’s breathing in systolic heart failure,
CPAP is the mainstay treatment option for symptomatic patients after providing optimal treatment of heart failure. For
patients with persistent CSA on CPAP (AHI>=15/h), ASV may be a more effective therapy. However, ASV is curently still
contraindicated in patients with LVEF<=%45 [25].
Prof. Randerath also mentioned the importance of differentiating treatment emergent central sleep apnoea (TECSA)
from CPAP-resistant and presented an algorhitm for precise diagnosis and treatment approach.
Symposium: Obesity and the lung: from wakefulness to sleep

The aim of this session was to provide new insights into the pathophysiological mechanism linking obesity and lung
dysfuncon from childhood to adults. Obesity is a growing problem regardless of age. Nearly one billion people
worldwide suer from obesity [26]. The consequences of obesity besides adverse eects on respiratory mechanics are
systemic inammaon, metabolic changes, immune dysfuncon, and alteraon in gut microbiota.
The rst speaker was Prof. Stefania Redol (Cagliari, Italy) who provided an overview of pathophysiologic mechanisms
linking obesity and lung dysfuncon from childhood to adults. The most eect of obesity on respiratory mechanics is the
reducon in funconal residual capacity (FRC), usually not associated with changes in residual volume (RV) or total lung
capacity (TLC) compared to healthy. The reduced FRC and expiratory reserve volume (ERV) and changes in compliance
of the respiratory system lead predisoses to early collapse of the small airways [27]. The FRC reducon leads to lower
venlaon of the lung bases, resulng in venlaon-perfusion-mismatch, recognized as mild hypoxemia. Among
children, a reducon of ERV, FRC and RV was observed with an increase in weight. The dierences in RV reducon among
children compared to adults is due to lack of early airway closure which is present among adults [28] . Obesity does not
aect the FEV1/FVC rao among adults compared to children. The impact of obesity on diusing capacity of
the lungs for carbon monoxide (DLco) is uncertain.
Prof. Anne Dixon (Burlington, USA) talked about the mechanics of the lungs and chest wall in obesity and respiratory
compliance. Paents with obesity and shortness of breath might present with an overlap of mulple independent factors
like ow limitaon during dal breathing, increased airway collapsibility on exhalaon or venlaon-perfusion -
mismatch.
Prof. Niki Ubags (Lausanne, Switzerland) provided an overview of the relaonships between the gut microbiota and lung
diseases. Asthma may lead to microbiota changes by decrease in Proteobacteria, M. catarrhalis, Haemophilus spp., and
decrease in Provotella. Thus, due to microbiota changes, immune system respond in Il-4, Il-5 and Il-17 increase, with Il-
10 decrease [29].
Prof. Juan-Fernando Masa Jimenez (Caceres, Spain) presented the findings from the Pickwick project. Compared to
CPAP, non-invasive ventilation (NIV) had an earlier on pCO2 in obesity hypoventilation syndrome (OHS) with relevant
OSAHowever, in the long-term, in the phenotype of OHS with severe OSA, there was no significant difference in with
days of hospitalization or mortality [30]. The cost-effectiveness plan converting the effectiveness to monetary terms
was in favour to CPAP compared to NIV. Finally, Prof. Masa showed meta-analyses that compared studies on NIV and
CPAP. There were no differences in mortality, cardiovascular events, and health care resources use between patients
with OHS and relevant OSA treated with NIV or CPAP, as well as no significant difference in adherence to NIV or CPAP
therapy [31].
Hot topics: Precision medicine in obstrucve sleep apnoea
The session on precision medicine hot topics in obstructive sleep apnoea showcased physiological
phenotypes/endotypes, and treatable traits, OSA risk stratification beyond the apnoea-hypopnoea index and its
relevance to patient-reported outcome measures, and detection of CPAP treatment failure by telemonitoring platforms
and early interventions.
An introduction to the clinical and sleep phenotypes of OSA was given by Prof. Stefania Redolfı (Cagliari, Italy). OSA has
been recognized as a heterogeneous disorder. Despite this heterogeneity, the diagnosis, severity evaluation, and
management of OSA are often based on a single indicator, the AHI. The one-size-fits-all approach considers
diagnosis/severity based on AHI and treatment with CPAP, followed by trials of alternatives if CPAP is not accepted or
tolerated. There is growing agreement that AHI alone is insufficient for diagnosing and managing people with OSA.
Precision medicine aims to improve clinical outcomes by identifying individuals at risk of long-term health
complications and matching patients to more precise therapies. Symptom clusters, physiological endotypes, advanced
polysomnographic metrics, and biomarkers could all help to identify OSA phenotypes [32]. The first study that used
cluster analysis to classify patients with OSA who had different combinations of symptoms and comorbidities found
three distinct clusters: "disturbed sleep group" (cluster 1), "minimally symptomatic group" (cluster 2), and "excessive

daytime sleepiness group" (cluster 3). In terms of age, sex, BMI, or AHI, the clusters did not differ significantly, and the
probability of having comorbid hypertension and CV disease was highest in cluster 2 but lowest in cluster 3 [33]. The
relationship of demographic characteristics, comorbid diseases, and sleep-related health issues with OSA phenotypes
and their effects on positive airway pressure (PAP) adherence were evaluated in the study, which followed these three
phenotypes receiving PAP therapy for two years, and it was determined that OSA treatment response and adherence
were related to the initial phenotype. The major improvement in daytime and nocturnal OSA symptoms was in the
excessive sleepy patient group [34]. The European Sleep Apnea Database (ESADA) was used to assess responses to PAP
treatment change in apnoea severity and ESS in relation to baseline patient clusters and at short- and long-term follow-
up. In this large, multinational study where seven distinct clusters were identified, daytime sleepiness response to PAP
treatment varied between clusters, although there was a homogeneous AHI reduction. Young healthy symptomatic
males and young men with psychiatric disorders had the highest decline in ESS [35]. In a study evaluating OSA symptom
subgroups and their relationship with prevalent and incident CV diseases, the excessively sleepy subtype demonstrated
worse survival and was associated with an increased risk of prevalent heart failure than other subtypes [36]. In the study
evaluating the effect of OSA phenotypes on mortality at 5-year follow-up, the absence of CPAP treatment and the cluster
subtype were associated with a higher risk of mortality for all causes [37].
Prof. Danny J. Eckert (Adelaide, Australia) talked about physiological phenotypes/endotypes and treatable traits. Four
"phenotypes" have been identified as contributing to OSA pathogenesis: "anatomical compromise" such as a narrow,
crowded, or collapsible upper airway and "non-anatomical" contributors such as ineffective pharyngeal dilator muscle
function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable breathing control (high
loop gain) [38][39]. With CPAP treatment the goal is to lower the Pcrit rate below -5 cmH2O. Physiologic studies have
demonstrated interventions that lower Pcrit, increase the electrical activity to genioglossus, increase the arousal
threshold, or lower loop gain can reduce OSA severity. According to the PALM (Pcrit, arousal threshold, loop gai n, and
muscle responsiveness) scale, which aids in categorizing patients with OSA based on anatomic and nonanatomic
phenotypic traits, 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a
low arousal threshold, and 36% had a high loop gain [40].
OSA endotype knowledge has been used to inform the selection of available therapies, showing that patients with low
arousal thresholds typically do not respond well to CPAP. A low arousal threshold phenotype is associated with worse
long-term CPAP adherence in people with CV disease and OSA [41]. There are novel treatment strategies to activate
upper airway muscle activity to treat OSA. Hypoglossal nerve stimulation activates upper airway dilator muscles, and
drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency
during sleep. A randomized, placebo-controlled, double-blind crossover trial showed that a combination of
noradrenergic and antimuscarinic agents (atomoxetine+oxybutynin) administered orally before bedtime on 1 night
greatly reduced OSA severity [42]. A translational, placebo-controlled trial found that topical potassium channel
antagonist improves pharyngeal collapsibility [43]. A stepwise approach to add-on and endotype-informed targeted
combination therapy may control OSA in incomplete mandibular advancement splint (MAS) responders [38]. Apnoea-
hypopnoea ratio and higher therapeutic CPAP levels, which are known to be associated with increased Pcrit, can be
used in clinical practice to guide treatment selection.
Prof. Raphael Heinzer (Lausanne, Switzerland) spoke about OSA risk stratification beyond the AHI and its relevance to
patient-reported outcome measures. New markers of OSA severity have been recently developed and related to
hypoxemia severity, sleep fragmentation, autonomic response to respiratory events. The hypoxic burden of OSA was
measured not only by the number of saturations but also by the duration and depth of the saturations, resulting in the
magnitude of the area above the curve. It was confirmed in various cohorts and discovered that hypoxic burden was a
predictor of CV death [44]. Another cohort study found that a hypoxic burden of more than 30% was related with a
higher probability of a major adverse health event or all-cause mortality [45]. Furthermore, hypoxic burden and time
spent with saturation < 90% were linked to an increased risk of stroke [46]. At five -year follow-ups, hypoxic measures
were the greatest predictors of cognitive decline in OSA patients [47]. Arousal burden, that has been defined as total
duration of all arousals divided by the total sleep time (%), associated with long-term all-cause and CV mortality [48].
Sleep apnea-specific pulse rate response (Δ heart rate- Δ HR) is the difference between the maximum pulse rate after

the airway reopening and the minimum pulse rate during respiratory events, associated with CV morbidity and mortality
[49][50]. PWAD as another marker, is related to variations of the tissue blood volume and reflect peripheral
vasoconstriction resulting from sympathetic activation after arousal. The amount of PWADs per hour during sleep was
characterized as the PWAD index, which declines with age, a history of CV disease, and varies between sleep stages
(REM>N1>N2>N3) [51]. A cohort study showed that a low PWAD index was associated with a higher CV risk in patients
with OSA [50]. A low PWAD index is related with a higher prevalenc e of CV events due to endothelial dysfunction caused
by oxidative stress over many years, as well as impaired autonomic response due to baroreceptor overstimulation.
Prof. Jean Louis Pepin (Grenoble, France) talked about detection of CPAP treatment failures by telemonitoring platforms
and proposal of early interventions. CPAP device telemonitoring platforms used for follow-up of hundreds of millions of
patients worldwide. CPAP treatment failures could be detected using telemonitoring platforms and early intervention
proposals. A telemonitoring system could identify high or variable residual AHI related to CPAP equipment or triggered
by exacerbating CV comorbidities. Hidden Markov model segmentation could be used to personalize follow-up and
prevent treatment failure in CPAP-treated sleep apnea patients by demarcating trajectories of residual AHI. The
potential effect of oronasal CPAP on upper-airway patency was investigated, and it was discovered that nasal CPAP
splints the upper airway and pushes the soft palate against the tongue, whereas oronasal CPAP may neutralize the
splinting effect of nasal CPAP due to positive pressure transmission to the mouth [52], CPAP telemonitor ing can track
Cheyne-stokes respiration and detect serious cardiac events [53].
In conclusion, OSA is a heterogeneous disease, and a one-size-fits-all strategy is unlikely to be effective. Precision
medicine aims to deliver the correct therapies to the suitable patients at the right time.
Take Home Messages
In the field of SDB, the current focus is on recognizing the heterogeneity of OSA population, different outcomes in
different phenotypes of both OSA and CSA, and finding markers for phenotyping, shifting from one-size-fits-all to
phenotype based approach.
References
1. Schwarz EI, Marnez-Lozano Sinues P, Bregy L, et al. Eects of CPAP therapy withdrawal on exhaled breath
paern in obstrucve sleep apnoea. Thorax. Feb 2016;71(2):110-7. doi:10.1136/thoraxjnl-2015-207597
2. Nowak N, Engler A, Thiel S, et al. Validaon of breath biomarkers for obstrucve sleep apnea. Sleep Med. Sep
2021;85:75-86. doi:10.1016/j.sleep.2021.06.040
3. Nowak N, Gaisl T, Miladinovic D, et al. Rapid and reversible control of human metabolism by individual sleep
states. Cell Rep. Oct 26 2021;37(4):109903. doi:10.1016/j.celrep.2021.109903
4. Schmidt F, Nowak N, Baumgartner P, et al. Severe Obstrucve Sleep Apnea Disrupts Vigilance-State-Dependen t
Metabolism. Int J Mol Sci. Nov 14 2022;23(22)doi:10.3390/ijms232214052
5. Sands SA, Edwards BA, Terrill PI, et al. Phenotyping Pharyngeal Pathophysiology using Polysomnography in
Paents with Obstrucve Sleep Apnea. Am J Respir Crit Care Med. May 01 2018;197(9):1187-1197.
doi:10.1164/rccm.201707-1435OC.
6. Xu, P.-H. et al. Cardiovascular outcomes in obstrucve sleep apnoea and implicaons of clinical phenotyping on
eect of CPAP treatment Sleep. doi:10.1136/thoraxjnl-2021-217714.
7. Gervès-Pinquié, C. et al. Posive Airway Pressure Adherence, Mortality, and Cardiovascular Events in Paents
with Sleep Apnea. Am J Respir Crit Care Med 206, 1393–1404 (2022).

8. Solelhac, G. et al. Pulse Wave Amplitude Drops Index: A Biomarker of Cardiovascular Risk in Obstrucve Sleep
Apnea. Am J Respir Crit Care Med 207, 1620–1632 (2023).
9. Pengo MF, Soranna D, Giontella A, et al. Obstrucve sleep apnoea treatment and blood pressure: which
phenotypes predict a response? A systemac review and meta-analysis. Eur Respir J. 2020;55(5):1901945.
Published 2020 May 7. doi:10.1183/13993003.01945 -2019
10. Kou C, Zhao X, Lin X, Fan X, Wang Q, Yu J. Eect of dierent treatments for obstrucve sleep apnoea on blood
pressure. J Hypertens. 2022;40(6):1071-1084. doi:10.1097/HJH.0000000000003131
11. Carneiro-Barrera A, Amaro-Gahete FJ, Guillén-Riquelme A, et al. Eect of an Interdisciplinary Weight Loss and
Lifestyle Intervenon on Obstrucve Sleep Apnea Severity: The INTERAPNEA Randomized Clinical Trial. JAMA
Netw Open. 2022;5(4):e228212.
12. Cowie MR, Woehrle H, Wegscheider K, et al. Adapve Servo-Venlaon for Central Sleep Apnea in Systolic Heart
Failure. N Engl J Med. 2015;373(12):1095-1105.
13. Azarbarzin A, Zinchuk A, Wellman A, et al. Cardiovascular Benet of Connuous Posive Airway Pressure in
Adults with Coronary Artery Disease and Obstrucve Sleep Apnea without Excessive Sleepiness. Am J Respir
Crit Care Med. 2022;206(6):767-774.
14. Solelhac G, Sánchez-de-la-Torre M, Blanchard M, et al. Pulse Wave Amplitude Drops Index: A Biomarker of
Cardiovascular Risk in Obstrucve Sleep Apnea. Am J Respir Crit Care Med. 2023;207(12):1620-1632.
15. Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and Central Sleep Apnea: A Comprehensive
Systemac Review and Meta-Analysis. Chest. 2020;158(6):2632-2645.
16. Hedner J, Stenlöf K, Zou D, et al. A Randomized Controlled Clinical Trial Exploring Safety and Tolerability of
Sulthiame in Sleep Apnea. Am J Respir Crit Care Med. 2022;205(12):1461-1469.
17. Perger E, Bertoli S, Lombardi C. Pharmacotherapy for obstrucve sleep apnea: targeng specic
pathophysiological traits. Expert Rev Respir Med. 2023;17(8):663-673.
18. Taranto-Montemurro L, Messineo L, Sands SA, et al. The Combinaon of Atomoxene and Oxybutynin Greatly
Reduces Obstrucve Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover
Trial. Am J Respir Crit Care Med. 2019;199(10):1267-1276.
19. Perger E, Taranto Montemurro L, Rosa D, et al. Reboxene Plus Oxybutynin for OSA Treatment: A 1 -Week,
Randomized, Placebo-Controlled, Double-Blind Crossover Trial. Chest. 2022;161(1):237-247.
20. Rosenberg R, Abaluck B, Thein S. Combinaon of atomoxene with the novel anmuscarinic aroxybutynin
improves mild to moderate OSA. J Clin Sleep Med. 2022;18(12):2837-2844.
21. Iber C, Ancoli-Israel S, Chesson A, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules,
Terminology and Technical Specicaons. Westchester, American Academy of Sleep Medicine, 2007.
22. Pavsic K, Herkenrath S, Treml M, Hagmeyer L, Khayat RN, Hellmich M, Randerath WJ. Mixed Apnea Metrics in
Obstrucve Sleep Apnea Predict Treatment-Emergent Central Sleep Apnea. Am J Respir Crit Care Med. 2021
Mar 15;203(6):772-775.

23. Giannoni A, Emdin M, Braman F, Iudice G, Francis DP, Barso A, Piepoli M, Passino C. Combined increased
chemosensivity to hypoxia and hypercapnia as a prognoscator in heart failure. J Am Coll Cardiol. 2009 May
26;53(21):1975-80.
24. Brack T, Jubran A, Laghi F, Tobin MJ. Fluctuaons in end-expiratory lung volume during Cheyne-Stokes
respiraon. Am J Respir Crit Care Med. 2005 Jun 15;171(12):1408-13.
25. Randerath W, Verbraecken J, Andreas S, Arzt M, Bloch KE, Brack T, Buyse B, De Backer W, Eckert DJ, Grote L,
Hagmeyer L, Hedner J, Jennum P, La Rovere MT, Miltz C, McNicholas WT, Montserrat J, Naughton M, Pepin JL,
Pevernagie D, Sanner B, Testelmans D, Tonia T, Vrijsen B, Wijkstra P, Levy P. Denion, discriminaon, diagnosis
and treatment of central breathing disturbances during sleep. Eur Respir J. 2017 Jan 18;49(1):1600959.
26. Balakrishnan VS. Europe's obesity burden on the rise: WHO report. Lancet Diabetes Endocrinol. 2022;10(7):488.
doi:10.1016/S2213-8587(22)00165-6
27. Holtz M, Perossi L, Perossi J, Oliveira Dos Santos D, de Souza HCD, Gastaldi AC. Respiratory system impedance
in dierent decubitus evaluated by impulse oscillometry in individuals with obesity. PLoS One.
2023;18(2):e0281780. Published 2023 Feb 14. doi:10 .1371/journal.pone.0281780
28. Davidson WJ, Mackenzie-Rife KA, Witmans MB, et al. Obesity negavely impacts lung funcon in children and
adolescents. Pediatr Pulmonol. 2014;49(10):1003-1010. doi:10.1002/ppul.22915
29. Kim YJ, Womble JT, Gunsch CK, Ingram JL. The Gut/Lung Microbiome Axis in Obesity, Asthma, and Bariatric
Surgery: A Literature Review. Obesity (Silver Spring). 2021;29(4):636 -644. doi:10.1002/oby.23107
30. Masa JF, Mokhlesi B, Benítez I, et al. Long-term clinical eecveness of connuous posive airway pressure
therapy versus non-invasive venlaon therapy in paents with obesity hypovenlaon syndrome: a
mulcentre, open-label, randomised controlled trial. Lancet. 2019;393(10182):1721-1732. doi:10.1016/S0140-
6736(18)32978-7
31. Soghier I, Brożek JL, Afshar M, et al. Noninvasive Venlaon versus CPAP as Inial Treatment of Obesity
Hypovenlaon Syndrome. Ann Am Thorac Soc. 2019;16(10):1295-1303. doi:10.1513/AnnalsATS.201905-
380OC
32. Liu Y, Ghafoor AA, Hajipour M, Ayas N. Role of precision medicine in obstrucve sleep apnoea. BMJ medicine.
2023;2(1).
33. Ye L, Pien GW, Ratclie SJ, et al. The dierent clinical faces of obstrucve sleep apnoea: a cluster analysis.
European Respiratory Journal. 2014;44(6):1600-1607.
34. Pien GW, Ye L, Keenan BT, et al. Changing faces of obstructive sleep apnea: treatment effects by cluster
designation in the Icelandic Sleep Apnea Cohort. Sleep. 2018;41(3):zsx201.
35. Yassen A, Coboeken K, Bailly S, et al. Baseline clusters and the response to posive airway pressure treatment
in obstrucve sleep apnoea paents: longitudinal data from the European Sleep Apnea Database cohort. ERJ
Open Research. 2022;8(4).
36. Mazzo DR, Keenan BT, Lim DC, Golieb DJ, Kim J, Pack AI. Symptom subtypes of obstrucve sleep apnea
predict incidence of cardiovascular outcomes. American journal of respiratory and crical care medicine.
2019;200(4):493-506.
37. Silveira MG, Sampol G, Mota-Foix M, Ferrer J, Lloberes P. Cluster-derived obstructive sleep apnea phenotypes
and outcomes at 5-year follow-up. Journal of Clinical Sleep Medicine. 2022;18(2):597-607.

38. Aishah A, Eckert DJ. Phenotypic approach to pharmacotherapy in the management of obstrucve sleep
apnoea. Curr Opin Pulm Med. 2019;25(6):594-601. doi:10.1097/MCP.0000000000000628
39. Carberry JC, Amatoury J, Eckert DJ. Personalized management approach for OSA. Chest. 2018;153(3):744-755.
40. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Dening phenotypic causes of obstrucve sleep apnea.
Idencaon of novel therapeuc targets. American journal of respiratory and crical care medicine.
2013;188(8):996-1004.
41. Zinchuk AV, Chu J-h, Liang J, et al. Physiological traits and adherence to sleep apnea therapy in individuals with
coronary artery disease. American Journal of Respiratory and Critical Care Medicine. 2021;204(6):703-712.
42. Taranto-Montemurro L, Messineo L, Sands SA, et al. The Combination of Atomoxetine and Oxybutynin Greatly
Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover
Trial. Am J Respir Crit Care Med. 2019;199(10):1267-1276. doi:10.1164/rccm.201808-1493OC
43. Osman AM, Mukherjee S, Altree TJ, et al. Topical potassium channel blockage improves pharyngeal
collapsibility: a translational, placebo-controlled trial. Chest. 2023;163(4):953-965.
44. Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-
related mortality: the Osteoporoc Fractures in Men Study and the Sleep Heart Health Study. European heart
journal. 2019;40(14):1149-1157.
45. Trzepizur W, Blanchard M, Ganem T, et al. Sleep apnea–specic hypoxic burden, symptom subtypes, and risk of
cardiovascular events and all-cause mortality. American journal of respiratory and crical care medicine.
2022;205(1):108-117.
46. Blanchard M, Gervès-Pinquié C, Feuilloy M, et al. Hypoxic burden and heart rate variability predict stroke
incidence in sleep apnoea. European Respiratory Journal. 2021;57(3).
47. Marchi NA, Solelhac G, Berger M, et al. Obstrucve sleep apnoea and 5-year cognive decline in the elderly.
European Respiratory Journal. 2023;61(4).
48. Shahrbabaki SS, Linz D, Hartmann S, Redline S, Baumert M. Sleep arousal burden is associated with long-term
all-cause and cardiovascular mortality in 8001 community-dwelling older men and women. European heart
journal. 2021;42(21):2088-2099.
49. Azarbarzin A, Sands SA, Younes M, et al. The sleep apnea–specic pulse-rate response predicts cardiovascular
morbidity and mortality. American journal of respiratory and crical care medicine. 2021;203(12):1546-1555.
50. Solelhac G, Sánchez-de-la-Torre M, Blanchard M, et al. Pulse wave amplitude drops index: a biomarker of
cardiovascular risk in obstrucve sleep apnea. American Journal of Respiratory and Crical Care Medicine.
2023(ja).
51. Hirotsu C, Bea M, Bernardi G, et al. Pulse wave amplitude drops during sleep: clinical signicance and
characteriscs in a general populaon sample. Sleep. 2020;43(7):zsz322.
52. Genta PR, Kaminska M, Edwards BA, et al. The Importance of Mask Selecon on Connuous Posive Airway
Pressure Outcomes for Obstrucve Sleep Apnea. An Ocial American Thoracic Society Workshop Report. Ann
Am Thorac Soc. 2020;17(10):1177-1185.

53. Prigent A, Pellen C, Texereau J, et al. CPAP telemonitoring can track Cheyne–Stokes respiraon and detect
serious cardiac events: The AlertApnée Study. Respirology. 2022;27(2):161-169.