Continuous Positive Airway Pressure, Arousability and Links to Mechanisms in Obstructive Sleep Apnea (CALM-OSA). - New approaches to understanding the mechanisms of treatments for obstructive sleep apnea (OSA) are desperately needed. OSA affects fifty-four million Americans, leading to significant morbidity and mortality, including hypertension, heart failure, stroke, and neurocognitive impairment. Continuous positive airway pressure (CPAP) is the primary treatment for OSA. However, poor adherence (only 50% use CPAP at one year) and inconsistent impact on neurocognitive and cardiovascular outcomes among users limit CPAP's effectiveness. Traditional measures of OSA severity (apnea-hypopnea index), symptoms, and the psychosocial factors affecting CPAP adherence account for only a fraction of the heterogeneity in response to CPAP. Understanding the mechanisms and biomarkers that predict CPAP success is vital to the health of millions. We hypothesize that arousal threshold (ArTH) in persons with OSA is a key determinant of CPAP adherence and the neurocognitive and cardiovascular responses to CPAP therapy. ArTH reflects a person’s propensity to awaken from a respiratory stimulus. People with low ArTH wake up easily, experience less hypoxia, and are less sleepy than those with high ArTH. Our robust preliminary data indicate that a low ArTH predicts poor CPAP adherence and that individuals with high ArTH show greater improvements in executive and frontal lobe function with CPAP. Knowing whether and how ArTH impacts response to CPAP can identify ArTH as a modifiable biomarker of CPAP success. For example, targeting CPAP to those with a high ArTH or raising ArTH with hypnotic medications or behavioral therapies to improve adherence and neurocognition can create a precision medicine approach to OSA therapy. For this to become a reality, the OSA field must bridge this gap by prospectively validating ArTH’s role in outcomes while accounting for essential confounders of adherence and modifying the ArTH to understand the mechanisms of how ArTH can influence CPAP response. Our overall objective is to bridge this gap by testing whether ArTH is a mechanistic determinant of CPAP success using a prospective, mechanistic clinical trial. We will randomize individuals newly diagnosed with OSA (n=250) to CPAP with a placebo or CPAP with eszopiclone (a medication that raises ArTH). We will measure CPAP adherence and changes in executive function and endothelial function over 12 weeks. Our specific aims include: 1) determining how ArTH affects adherence to CPAP therapy; 2) evaluating the mechanism of ArTH in the neurocognitive response to CPAP; and 3) exploring the link between ArTH and cardiovascular response to CPAP. We hypothesize that a high ArTH will be associated with improved CPAP adherence and neurocognitive and cardiovascular responses to CPAP, with sleep duration and depth, biomarkers of neuro-axonal damage, and oxidative stress mediating these effects. Ultimately, our results can lead to personalized OSA approaches that challenge the “CPAP-for- all” status quo and could improve outcomes for millions suffering from OSA.
