Endotypic Mechanisms of Successful Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea

Abstract Rationale Approximately one-third of patients with obstructive sleep apnea (OSA) treated with hypoglossal nerve stimulation (HGNS) therapy are incomplete responders, despite careful patient selection based on baseline characteristics and drug-induced sleep endoscopy. Objectives Here we use polysomnographic endotyping to assess the pathophysiological mechanisms underlying favorable versus incomplete responses to HGNS therapy. Methods Baseline polysomnography data of the STAR (Stimulation Therapy for Apnea Reduction) trial were included. Raw baseline polysomnographic data from 91/126 patients were available for analysis. Traits—loop gain, arousal threshold, collapsibility, and muscle compensation—were calculated from the baseline polysomnography data according to Sands and colleagues (AJRCCM 2018, SLEEP 2018). Logistic regression assessed apnea–hypopnea index (AHI)-adjusted associations between HGNS response (50% reduction in AHI to 10/h at 1 yr) and OSA traits. Measurements and Main Results Overall, HGNS treatment reduced AHI from 30.7 (24.9–39.9) to 8.5 (4.0–19.5) events/h (P 0.0001; median quartiles 1–3); N = 53/91 were responders. In adjusted analysis, a favorable response to therapy was independently associated with higher arousal threshold (odds ratio 95% confidence interval: 6.76 2.44–23.3, P = 0.001), greater compensation (odds ratio: 4.22 1.70–12.55 per SD, P = 0.004), and lower loop gain (in milder collapsibility, per significant interaction, P = 0.003). The higher arousal threshold was evident in responders before adjusted analysis. Predicted responders had an approximately fourfold lower treatment AHI versus predicted nonresponders (4.9 2.7–8.5 vs. 20.7 10.9–29.7, P 0.0001; median quartiles 1–3); differences remained significant after cross-validation. Conclusions Favorable responses to HGNS therapy are associated with the pathophysiological traits causing OSA, particularly a higher arousal threshold. Along with established criteria, individuals with favorable traits could potentially be prioritized for precision HGNS therapy. This analysis was a secondary analysis of the STAR trial registered with clinicaltrials.gov (NCT01161420).