Defining Phenotypic Causes of Obstructive Sleep Apnea: Identification of Novel Therapeutic Targets

Study Questions:

How frequent do nonanatomic pathophysiologic traits contribute to obstructive sleep apnea (OSA)?


Men and women with and without OSA, ages 20-65 years, were studied on three separate nights approximately 1 week apart. OSA patients withheld their positive airway pressure treatment for one night prior to initial study. 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. Genioglossus muscle activity was measured by electromyographic activity. Loop gain was quantified as the ventilatory response to a disturbance in ventilation.


Consents were obtained in 90 men and women (69 with OSA and 21 controls). Four controls and 11 OSA patients did not complete the protocol. Fifty-eight (15 women) patients with OSA and 17 (10 women) controls completed the study. Patients with OSA were older, more likely to be obese, and had significantly lower nadir nocturnal oxygen saturation, as expected. 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 [21.5-1.9] vs. 26.2 [212.4-23.6] cm H2O; p < 0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, 22-25 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit >22 cm H2O (25.9 [28.8-24.5] vs. 23.2 [24.8-22.4] dimensionless; p = 0.01). A 3-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.


This study highlights the multifactorial pathophysiology of OSA. The authors concluded that although anatomy is an important determinant (specifically the collapsibility of the upper airway), abnormalities in nonanatomic traits are also present in most OSA patients.


One or more of the nonanatomic traits are present in more than half of patients with OSA. The 3-point scale described here may stimulate future testing of therapies that target specific mechanisms of OSA. Hopefully, a simplified method in which traits can be targeted can be acquired in a single night study. Last, uncertainty remains over nonanatomic traits in the nonobese population with OSA and in rapid eye movement (REM) sleep, since these data were acquired in non-REM sleep and among predominantly obese individuals with OSA.

Clinical Topics: Heart Failure and Cardiomyopathies, Sleep Apnea

Keywords: Polysomnography, Cardiology, Body Weight, Obesity, Oxygen, Respiratory System, Sleep Apnea Syndromes

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