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)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Twery, Michael
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Brigham and Women's Hospital
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Genta, Pedro R; Sands, Scott A; Butler, James P et al. (2017) Airflow Shape Is Associated With the Pharyngeal Structure Causing OSA. Chest 152:537-546
Taranto-Montemurro, Luigi; Sands, Scott A; Azarbarzin, Ali et al. (2017) Effect of 4-Aminopyridine on Genioglossus Muscle Activity during Sleep in Healthy Adults. Ann Am Thorac Soc 14:1177-1183
Sands, Scott A; Mebrate, Yoseph; Edwards, Bradley A et al. (2017) Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure. Am J Respir Crit Care Med 195:237-246
Taranto-Montemurro, Luigi; Sands, Scott A; Edwards, Bradley A et al. (2017) Reply: Is the Muscle the Only Potential Target of Desipramine in Obstructive Sleep Apnea Syndrome? Am J Respir Crit Care Med 195:1678-1679
Horner, Richard L; Grace, Kevin P; Wellman, Andrew (2017) A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology 22:861-873
Taranto-Montemurro, Luigi; Sands, Scott A; Edwards, Bradley A et al. (2017) Effects of Tiagabine on Slow Wave Sleep and Arousal Threshold in Patients With Obstructive Sleep Apnea. Sleep 40:
Landry, Shane A; Joosten, Simon A; Sands, Scott A et al. (2017) Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement. Respirology 22:1219-1224
Marques, Melania; Genta, Pedro R; Sands, Scott A et al. (2017) Effect of Sleeping Position on Upper Airway Patency in Obstructive Sleep Apnea Is Determined by the Pharyngeal Structure Causing Collapse. Sleep 40:
Azarbarzin, Ali; Sands, Scott A; Taranto-Montemurro, Luigi et al. (2017) Estimation of Pharyngeal Collapsibility During Sleep by Peak Inspiratory Airflow. Sleep 40:
Joosten, Simon A; Landry, Shane A; Sands, Scott A et al. (2017) Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnoea. Respirology 22:1662-1669

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