Association of Endotypic Traits and Their Interaction With Severity of Obstructive Sleep Apnea

Endotypic traits of obstructive sleep apnea (OSA) are being increasingly identified as potential treatment targets. Nevertheless, their clinical relevance remains debated, as they are not consistently associated with OSA severity. This study aimed to examine endotypic traits' associations and their interaction effects with OSA severity.

A total of 1167 adults with moderate-to-severe OSA were prospectively recruited from a sleep center and underwent in-laboratory full-night polysomnographic studies. Endotypic traits-collapsibility (V_passive, ventilation at eupenic drive), loop gain, arousal threshold, and compensation-were estimated using polysomnographic signals, and OSA severity was examined by apnea-hypopnea index (AHI) and hypoxic burden. The associations between individual endotypic traits and OSA severity were visualised using generalised additive models. The interaction between arousal threshold and compensation on OSA severity was examined.

A more collapsible upper airway and higher loop gain were linearly associated with greater OSA severity. Arousal threshold was positively associated with hypoxic burden, whereas the relationship between arousal threshold and AHI followed an inverse U-shaped pattern. Among patients with a relatively low arousal threshold (< 173.5 %eupnea), favourable upper airway patency was observed, and AHI increased with rising arousal threshold. The combination of a high arousal threshold and high compensation was associated with elevated AHI during NREM sleep, where the high compensation resulted from a very low V_passive.

A higher arousal threshold predicted a more severe hypoxic burden but showed a nonlinear association with AHI. Arousal threshold and compensation should be considered together when evaluating OSA severity.