Rationale: The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.

Objectives: To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.

Methods: Seventy-five men and women with and without OSA aged 20–65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.

Measurements and Main Results: Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [−1.5 to 1.9] vs. −6.2 [−12.4 to −3.6] cm H₂O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, −2 to −5 cm H₂O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than −2 cm H₂O (−5.9 [−8.8 to −4.5] vs. −3.2 [−4.8 to −2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA.

Conclusions: This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.