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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102321-05
Application #
8848104
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Twery, Michael
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
$425,019
Indirect Cost
$178,769
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Messineo, Ludovico; Taranto-Montemurro, Luigi; Azarbarzin, Ali et al. (2018) Breath-holding as a means to estimate the loop gain contribution to obstructive sleep apnoea. J Physiol 596:4043-4056
Taranto-Montemurro, Luigi; Sands, Scott A; Grace, Kevin P et al. (2018) Neural memory of the genioglossus muscle during sleep is stage-dependent in healthy subjects and obstructive sleep apnoea patients. J Physiol 596:5163-5173
Azarbarzin, Ali; Sands, Scott A; Marques, Melania et al. (2018) Palatal prolapse as a signature of expiratory flow limitation and inspiratory palatal collapse in patients with obstructive sleep apnoea. Eur Respir J 51:
Sands, Scott A; Terrill, Philip I; Edwards, Bradley A et al. (2018) Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea. Sleep 41:
Sands, Scott A; Edwards, Bradley A; Terrill, Philip I et al. (2018) Phenotyping Pharyngeal Pathophysiology using Polysomnography in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 197:1187-1197
Sands, Scott A; Edwards, Bradley A; Terrill, Philip I et al. (2018) Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J 52:
Marques, Melania; Genta, Pedro R; Azarbarzin, Ali et al. (2018) Retropalatal and retroglossal airway compliance in patients with obstructive sleep apnea. Respir Physiol Neurobiol 258:98-103
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
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) Reply: Is the Muscle the Only Potential Target of Desipramine in Obstructive Sleep Apnea Syndrome? Am J Respir Crit Care Med 195:1678-1679

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