Phenotypic approaches to obstructive sleep apnoea – New pathways for targeted therapy  Danny J. Eckert  Sleep Medicine Reviews  Volume 37, Pages 45-59 (February 2018) DOI: 10.1016/j.smrv.2016.12.003 Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 1 Schematic of the four key phenotypes that cause obstructive sleep apnoea. All obstructive sleep apnoea patients have some degree of impairment in upper airway anatomy (black box). However, this phenotype varies widely between patients. Approximately 19% have similar impairment in upper airway collapsibility to many people who do not have obstructive sleep apnoea. There are also at least three other non-anatomical phenotypes that contribute to obstructive sleep apnoea pathogenesis which collectively are present in almost 70% of obstructive sleep apnoea patients (% estimates are derived from Eckert and colleagues, 2013 [19]). Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 2 Sagittal magnetic resonance images from a 33 year old, non-obese (body mass index = 24 kg/m2), male without obstructive sleep apnoea (Healthy Individual) and a 33 year old male (body mass index = 28 kg/m2) with obstructive sleep apnoea of moderate severity (apnoea/hypopnoea index = 17 events/h sleep). Note the decreased pharyngeal size in the person with obstructive sleep apnoea and the potential contributing factors (e.g., retrognathia, large tongue volume, differences in genioglossus muscle fibre angulation and increased pharyngeal length). Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 3 – Raw tracings of the technique used to quantify the passive critical closing pressure of the upper airway (Pcrit) during sleep. In the top panel, the continuous positive airway pressure (CPAP) delivered to the mask (Pmask) is transiently reduced during stable non-rapid eye movement sleep as shown on the electroencephalogram (EEG) for 5 breaths. This causes inspiratory flow-limitation, defined as no increase in airflow (Flow) despite increasing respiratory effort as shown by the epiglottic pressure swings (Pepi). The lower panel shows three examples of Pcrit quantification where multiple reductions in CPAP have been delivered throughout the night and the relationship between Pmask and peak inspiratory flow has been plotted for breaths 3–5 for all flow-limited breaths (including the 3 flow-limited breaths from the example in the top panel). The point at which the linear regression crosses the x-axis is the Pcrit. The coloured shading shows the range of Pcrit values in which the majority of people with obstructive sleep apnoea span (−5 to +5 cmH2O). The green range (Pcrit −5 to −2 cmH2O) represents only minor impairment in upper airway collapsibility. Many people without obstructive sleep apnoea also fall within this range. The blue shading represents the intermediate or moderate anatomical impairment range (−2 to +2 cmH2O). The red range (>+2 cmH2O) indicates severe impairment in upper airway anatomy. Consistent with the importance of upper airway anatomy in the pathogenesis of obstructive sleep apnoea, the individual with a Pcrit of 4.8 cmH2O has very severe sleep apnoea (apnoea/hypopnoea index [AHI] = 64 events/h sleep). Conversely, the individual with a Pcrit of −3.9 cmH2O is largely protected from obstructive sleep apnoea in non-rapid eye movement (NREM) sleep, NREM AHI = 4 events/h sleep, due to robust upper-airway dilator muscle activation but has an elevated AHI during rapid eye movement (REM) sleep when pharyngeal muscle activity is markedly reduced (REM AHI = 18 events/h sleep). Refer to the text for further detail. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 4 Raw examples of (A) an individual with excellent upper airway muscle responsiveness (robust pharyngeal muscle activation [orange dashed lines] in response to increasing negative pharyngeal pressure [respiratory stimuli: purple dashed line]). This individual also has excellent muscle effectiveness (ability to translate increased neural drive into airway opening and increased airflow when the upper airway is challenged/narrowed [blue dashed line]). Conversely, in example (B), this individual has poor muscle responsiveness (orange dashed line) and therefore poor muscle effectiveness in response to airway narrowing due to a transient reduction in continuous positive airway pressure (Pmask). It is only when cortical arousal occurs that this individual is able to recruit pharyngeal muscle activity and restore airflow. A.u. = arbitrary units, EEG = electroencephalogram, EMG = electromyography, EMG % max = rectified, moving time average (100 ms) of the raw EMG signal as a % of maximal activation measured awake (in response to a swallow or tongue protrusion), GG = genioglossus muscle, Pepi = epiglottic pressure, TP = tensor palatini muscle. Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 5 Calculation of genioglossus muscle responsiveness. Peak genioglossus electromyographic (EMG) activity is plotted against the corresponding nadir epiglottic pressure for all arousal and artifact-free breaths (each dot represents a breath) during a night of upper airway and respiratory phenotyping [19]. Specifically, multiple transient reductions in continuous positive airway pressure are applied throughout the night during stable non rapid eye movement sleep to induce airflow limitation (e.g., Fig. 4) for up to 3 min each. Muscle responsiveness is the slope of the regression fit. The blue line and corresponding data points show an individual with excellent muscle responsiveness (0.86% maximum increase in EMG activity per 1 unit increase in negative epiglottic pressure). Conversely, the red line and corresponding data points show virtually no muscle responsiveness during sleep in this individual (0.004% maximum increase in EMG activity per 1 unit increase in negative epiglottic pressure). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 6 Example negative effort dependence to a transient reduction in continuous positive airway pressure (Pmask). Note the decrease in airflow with increasing negative epiglottic pressure (Pepi) between and within (insert) breaths. EEG = electroencephalogram. Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 7 Schematic representations of low (A) versus high loop gain (B). In these examples breathing is stable for the first 7 breaths (e.g., a patient with obstructive sleep apnoea on continuous positive airway pressure [CPAP] therapy at their required therapeutic level). A disruption in breathing then occurs (e.g., a transient reduction in CPAP for approximately 3 min). This causes a rapid reduction in breathing because the upper airway narrows (similar to a mild hypopnoea). Overtime, CO2 and negative pharyngeal pressure (respiratory drive) builds up and in these examples there is some restoration of breathing due to partial compensation by the upper-airway dilator muscles until a new steady-state is reached (slightly below the level obtained on therapeutic CPAP as shown in blue shading). In example A, (low loop gain), when the upper airway is rapidly reopened (e.g., with reintroduction of therapeutic CPAP), the breathing response (orange shading) to the breathing disturbance (blue shading), peaks at approximately 3-fold. Following a small oscillation, breathing then returns to the baseline therapeutic CPAP level. However, in response to the same breathing disturbance, in the high loop gain example (B), breathing peaks at approximately 9-fold before steadily decreasing until an apnoea occurs due to the subsequent reduction in respiratory drive from the initial excessive response. For more information see Wellman and colleagues [35,72] and refer to the text. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 8 Respiratory arousal threshold. Note the increasing negative epiglottic pressure (Pepi) swings (purple dashed line) prior to cortical arousal (green shaded box on the electroencephalogram [EEG]). The respiratory arousal threshold is calculated as the nadir epiglottic pressure (difference between end expiration and nadir during inspiration) on the breath prior to arousal (in this instance approximately −11 cmH2O [purple circle]). Also note the genioglossus muscle responsiveness (orange dashed line) prior to arousal. Accordingly, if arousal had not occurred (or had been delayed with a hypnotic) in this individual with a low arousal threshold, they may have continued to compensate and restore airflow to avoid the subsequent potentially destabilising effects associated with the arousal (i.e., ventilatory response to arousal [blue circle]). A.u. = arbitrary units, EMG = electromyography, EMG % max = rectified, moving time average (100 ms) of the raw EMG signal as a % of maximal activation measured awake (in response to a swallow or tongue protrusion), GG = genioglossus muscle. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 9 Venn diagram showing the overlap between different levels of anatomical impairment and various non-anatomical contributions to obstructive sleep apnoea. Values are the numbers of patients that fall into each category from N = 54 patients with obstructive sleep apnoea in whom Pcrit (critical closing pressure of the upper airway) data were available from Eckert et al., 2013 [19]. PALM scale = Pcrit, arousal threshold, loop gain and muscle responsiveness scale. Refer to the text for further detail. Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 10 A flow diagram of the Pcrit, Arousal Threshold, Loop gain and Muscle responsiveness (PALM) scale categorisation concepts and potential treatment decision tree. Percent estimates are derived from Eckert et al., 2013 [19]. Refer to the text and Tables 1 and 2 for further detail. CPAP = continuous positive airway pressure therapy, HNS = hypoglossal nerve stimulation, MAS = mandibular advancement splint, UA = upper airway. Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions

Fig. 11 Schematic of the four key phenotypes that cause obstructive sleep apnoea and potential non-continuous positive airway pressure targeted therapies. Refer to the text and Tables 1 and 2 for further detail. HNS = hypoglossal nerve stimulation, MAS = mandibular advancement splint, UA = upper airway. Sleep Medicine Reviews 2018 37, 45-59DOI: (10.1016/j.smrv.2016.12.003) Copyright © 2016 Elsevier Ltd Terms and Conditions