Endotyping in Patients with Obstructive Sleep Apnea and Hypoglossal Nerve Stimulation. The Golden Goal to a Successful Treatment?

In this issue of the Journal, Op de Beeck and colleagues (pp. 746–755) report about the different endotypes in patients with obstructive sleep apnea (OSA) and which of these factors have influence on outcomes for hypoglossal nerve stimulation (HGNS) (1). The authors’ tremendous work will help future patient selection to be more precise regarding various treatment options. HGNS for patients who are noncompliant with the standard treatment of continuous positive airway pressure (CPAP) therapy has rapidly emerged in the foundational clinical routine in Western industrialized countries (2, 3). Nonetheless, approximately one-third of the patients are incomplete responders, fueling the need for more discerning selection criteria. Op de Beeck and colleagues used polysomnographic data from the STAR trial to assess the pathophysiological mechanisms, namely, arousal threshold, loop gain, collapsibility, and muscle compensation (4). The authors demonstrated that all four key traits were associated with clinical outcomes in HGNS therapy. Somewhat paradoxically, collapsibility was more severe in responders versus nonresponders and arousal threshold higher in patients who responded to HGNS therapy. These results are striking and provide novel insights into the mechanism of HGNS in patients with OSA. Most notably, a high arousal threshold showed a significantly favorable effect on outcomes, which is really surprising, because one would normally expect that a higher arousal threshold is associated with poorer sleep quality and that patients who receive HGNS would complain more about disturbing stimulations during sleep at night. The authors found that a higher arousal threshold at baseline corresponded with a larger therapeutic window for HGNS. However, a plausible, mechanistic explanation of this phenomenon remains elusive. Regarding the critical closing pressure (Pcrit), another interesting point arose. Measuring Pcrit is the gold standard to measure the pharyngeal airway collapsibility (5). As Pcrit increases, the more collapsible the upper airway seems to be. In clinical trials, the Pcrit was associated with therapeutic CPAP pressures (6). Patients with modest collapsibility of the upper airway (lower Pcrit) had a lower therapeutic CPAP level (7). One would also expect that patients with a lower Pcrit would be easier to treat with HGNS. The reverse was, in fact, true. Op de Beeck and colleagues explain this phenomenon by elucidating that lower pharyngeal collapsibility is associated with more nonanatomical deficits underlying the OSA etiology (high loop gain, low arousal threshold). Although compelling, the relatively modest number of patients with severe collapsibility available for this analysis was too low to draw conclusions, and further clinical trials are merited.

Next, a higher loop gain was associated with lower HGNS response, which makes sense, in that a more severe loop gain indicates a more central-OSA phenotype (8). Anatomical factors, which are contributing to OSA in patients with HGNS therapy, are easier to treat versus attempts to solve a hypersensitive ventilatory control.

Regarding the muscular compensation of the upper airway, which is mainly mediated by the genioglossus muscle group, a greater response was found in patients with high muscle compensation (9). From extant studies we know that upper airway muscle activity vis-à-vis OSA is a highly complex process with phenotypic variability. Not only the anatomy and function of the muscles play crucial roles; furthermore, neurological processes can undergird much of the pathophysiology (7). All the more striking were these findings on muscle compensation, and the authors are correspondingly positing the hypothesis that patients with a low muscle compensation cannot transfer the electrical impulse from the HGNS successfully toward dilating upper airway muscles.

Making this groundbreaking analysis even more remarkable, and quite possibly representing a major milestone for further treatment decisions, is the fact that with oral appliances similar characteristics in responders’ rates have been detected (10). For both treatment options, the combination of low loop gain, moderate collapsibility, and higher arousal thresholds seems to portend greater likelihood of therapeutic efficacy. Using a cross-validated model and adding these endotypic mechanisms holds promise to improve the outcome parameters.

One major limitation of this study is its retrospective design. The next step to incorporate these findings into clinical routine will be a randomized trial that includes endotyped versus nonendotyped patients with the prevailing (i.e., U.S. Food and Drug Administration–indicated/CE mark) inclusion criteria.

This study raises many important questions. How can we implement measuring these endotypic traits for patient selection in the future? Much careful work will be needed to measure these parameters during polysomnography. Determining which patient-related outcome parameters are relevant should play an increasingly important role in the treatment of patients with OSA.

There is no doubt that we still have much to learn especially about the pathophysiology of OSA and which patients are suitable for which treatment option. Until then, studies such as this one from Op de Beeck and colleagues will continue to add pieces to this puzzle.