High Respiratory Arousal Threshold as a Potential Pathophysiological Biomarker of Excessive Daytime Sleepiness in Obstructive Sleep Apnoea

Obstructive sleep apnoea (OSA) is caused by impaired pharyngeal anatomy of varying severity, and in most cases, accompanying contributions from one or more non-anatomical mechanisms or “endotypes” [1, 2]. Non-anatomical endotypes include poor pharyngeal dilator muscle function, oversensitivity of the respiratory control system (high loop gain) and waking up too easily to minor airway narrowing episodes (low respiratory arousal threshold) [1]. In a recent publication in Respirology, Wang and colleagues applied the “phenotyping using polysomnography (PUP)” algorithm [3] to estimate the four key OSA endotypes from overnight diagnostic study data in > 500 people with an apnoea/hypopnea index (AHI) > 5 events per hour/sleep. Consistent with gold standard quantification of OSA endotypes combined with machine learning analytical approaches in a smaller sample that indicate different combinations OSA endotypes contribute to OSA severity as defined by the AHI [4], and recent related findings [5], Wang and colleagues also found that OSA endotypes contribute to OSA severity [6]. These data provide further support for the importance of OSA endotypes in driving OSA pathophysiology. In addition to providing important mechanistic insight, identification of OSA endotypes has increasingly been used in the research setting to deliver therapy that targets specific OSA mechanisms and predict responders to different treatment approaches including combinations of therapies [7]. For example, interventions that lower loop gain such as oxygen therapy and carbonic anhydrase inhibitors reduce loop gain and OSA severity [8, 9]. Different combinations of OSA endotypes predict treatment response to oral appliance therapy [10]. Specific endotypes such as a low respiratory arousal threshold are associated with treatment failure to continuous positive airway pressure (CPAP) therapy [11] and hypoglossal nerve stimulation [12]. High loop gain is also associated with more pronounced improvements in 24-h blood pressure with CPAP [13]. Accordingly, a recent American Thoracic Society statement has outlined a research road map to translate these concepts from the research setting into clinical practice at scale to transform the current trial-and-error care model to a targeted precision sleep medicine approach [2]. To date, less work has been done to link specific OSA endotypes or combinations of endotypes with common OSA consequences. In this issue, Wang and colleagues investigated the potential role of OSA endotypes on a common symptom of OSA, excessive daytime sleepiness. PUP-derived OSA endotypes were associated with daytime sleepiness as defined by an Epworth Sleepiness Scale (ESS) score of ≥ 10 [6]. In general, consistent with worse OSA severity, daytime sleepiness was more common in those with more impairment in key OSA endotypes such as a more collapsible upper airway, higher loop gain and poorer upper airway muscle function. This is similar to a recent study that used PUP to estimate OSA endotypes in > 500 people diagnosed with moderate to severe OSA and used latent class analyses to identify three different endotype clusters linked to different symptom profiles where the excessively sleepy group had increased upper airway collapsibility and high loop gain [14]. Similar methodology was also recently used on Multi-Ethnic Study of Atherosclerosis (MESA) community cohort data where excessive daytime sleepiness was also associated with higher loop gain [15]. Interestingly, excessive daytime sleepiness was associated with shorter respiratory event duration and higher rather than lower pharyngeal muscle compensation in females highlighting the potential for important sex differences. In the Wang and colleagues study, arousal threshold was higher (harder to wake up) in those with elevated ESS scores [6]. Waking up too easily can drive a pattern of light sleep and accompanying unstable breathing and contribute to OSA pathogenesis in susceptible individuals [1]. However, as OSA severity increases along with accompanying chronic sleep deprivation, homeostatic sleep drive increases and so too does the threshold for arousal to respiratory events [16]. Indeed, CPAP therapy for OSA rapidly reduces the arousal threshold, presumably by restoring stable sleep to reduce chronic sleep deprivation effects [17]. Accordingly, the current novel findings of a high arousal threshold in those with daytime sleepiness by Wang and colleagues are in line with a “sleep deprived” or “sleepy” brain that persists into the daytime. Whether a high arousal threshold endotype is a consistent pathophysiological biomarker of excessive daytime sleepiness in OSA, or simply a modifiable consequence of severe OSA/sleep deprivation, remains to be determined in future well-designed mechanistic studies. Earlier data that mapped changes in ESS and gold standard quantification of the arousal threshold over 90 days of CPAP therapy indicate rapid reductions in arousal threshold with slower improvements in daytime sleepiness [17]. Thus, there may be a disconnect between changes in physiology and symptom responses to treatment. Other important questions as to whether sleepy people with higher arousal thresholds respond more favourably to OSA treatments such as CPAP and beyond also require further careful investigation. Nonetheless, the novel findings by Wang and colleagues represent an important contribution to the field. They provide fertile ground for further research into the potential links between specific OSA endotypes or combinations of endotypes and different disease consequences and responses to therapy which may prove useful in the much-needed development of precision medicine approaches for OSA. Danny J. Eckert: conceptualization (lead), writing – original draft (lead), writing – review and editing (lead). D.J.E. is funded by a National Health and Medical Research Council of Australia Leadership Fellowship (1116942). This work was supported by the National Health and Medical Research Council (1116942). D.J.E. reports grants from Restera, Eli Lilly, Restora, HuMannity Medtec, Oura, Withings and Takeda and serves on Scientific Advisory Boards for Restera, Mosanna, SleepRes, Restora, HuMannity Medtec, Takeda and Apnimed.