Defining phenotypic causes of obstructive sleep apnea: Identification of novel therapeutic targets

Danny J. Eckert, David P. White, Amy S. Jordan, Atul Malhotra, Andrew Wellman

Research output: Contribution to journalArticlepeer-review

737 Citations (Scopus)


Rationale: The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary amongpatients but havenot 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, 22 to 25 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than 22 cmH2O (-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 studyconfirms thatOSAisaheterogeneous disorder. AlthoughPcrit-anatomy is animportantdeterminant, abnormalities in nonanatomic traits are also present in most patients with OSA.

Original languageEnglish
Pages (from-to)996-1004
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number8
Publication statusPublished - 15 Oct 2013
Externally publishedYes


  • Arousal
  • Muscle
  • Respiratory physiology
  • Sleep-disordered breathing
  • Upper airway pathophysiology


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