Obstructive sleep apnea (OSA) is a multifactorial disorder with probably four main causes or physiologic traits: 1) an anatomically small, or collapsible, upper airway, 2) an unstable ventilatory control system, 3) a low respiratory arousal threshold from sleep, and 4) a poor upper airway muscle response during sleep. The broad term objective of this research is to better understand how these traits interact to produce OSA in individual patients, and then to use this information to design new treatments. Specifically, this grant aims to validate a novel technique for measuring and modeling the traits causing OSA (Aim 1), and then determine how effective non-continuous positive airway pressure therapies are at manipulating the traits (Aim 2). To achieve these objectives, the within-night and between-night repeatability of the measurements and model will be tested, along with the validity of the ventilatory stability and arousal threshold metrics. Note: the upper airway anatomy/collapsibility measurement has been previously validated and will not be repeated. Also, the upper airway (muscle) response measurement will not be validated because the methodology is straightforward. The ventilatory stability metric (loop gain), will be validated by administering hypoxic gas to individuals and comparing the hypoxic loop gain to the normoxic loop gain (hypoxia raises the loop gain). As there is not a gold standard for measuring loop gain, the new method is being validated by determining if it can detect a directional change in loop gain. The new arousal threshold measurement will be validated by comparing it to the arousal threshold determined from esophageal pressure monitoring.
In Aim 2, the effect of several interventions on each trait will be measured. The interventions that will be tested include upper airway surgery and oral appliances (to manipulate pharyngeal collapsibility), acetazolamide and supplemental oxygen (to manipulate the control of breathing), and eszopiclone (to manipulate the arousal threshold). Interventions to manipulate the upper airway muscle response will not be tested since currently there are not good candidate drugs for doing this. The studies proposed will not only improve our understanding of OSA pathophysiology, but could realistically lead to new therapeutic approaches.

Public Health Relevance

This grant describes a technique for measuring and modeling some of the important pathogenic traits causing sleep apnea. The effectiveness of non-CPAP treatments on each trait will also be tested. These studies could lead to a better understanding of sleep apnea pathogenesis and potentially new treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Twery, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Edwards, Bradley A; Andara, Christopher; Landry, Shane et al. (2016) Upper-Airway Collapsibility and Loop Gain Predict the Response to Oral Appliance Therapy in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 194:1413-1422
Taranto-Montemurro, Luigi; Edwards, Bradley A; Sands, Scott A et al. (2016) Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects. Am J Respir Crit Care Med 194:878-885
Genta, Pedro R; Edwards, Bradley A; Sands, Scott A et al. (2016) Tube Law of the Pharyngeal Airway in Sleeping Patients with Obstructive Sleep Apnea. Sleep 39:337-43
Sands, Scott A; Owens, Robert L; Malhotra, Atul (2016) New Approaches to Diagnosing Sleep-Disordered Breathing. Sleep Med Clin 11:143-52
Joosten, Simon A; Edwards, Bradley A; Wellman, Andrew et al. (2015) The Effect of Body Position on Physiological Factors that Contribute to Obstructive Sleep Apnea. Sleep 38:1469-78
Owens, Robert L; Edwards, Bradley A; Eckert, Danny J et al. (2015) An Integrative Model of Physiological Traits Can be Used to Predict Obstructive Sleep Apnea and Response to Non Positive Airway Pressure Therapy. Sleep 38:961-70
Sands, Scott A; Eckert, Danny J; Jordan, Amy S et al. (2014) Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med 190:930-7
Gederi, Elnaz; Nemati, Shamim; Edwards, Bradley A et al. (2014) Model-based estimation of loop gain using spontaneous breathing: a validation study. Respir Physiol Neurobiol 201:84-92
Genta, Pedro R; Owens, Robert L; Edwards, Bradley A et al. (2014) Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway. Respir Physiol Neurobiol 201:55-9
Wellman, Andrew; Genta, Pedro R; Owens, Robert L et al. (2014) Test of the Starling resistor model in the human upper airway during sleep. J Appl Physiol (1985) 117:1478-85

Showing the most recent 10 out of 19 publications