Giuliana Grossi

Sleep studies provide a wealth of physiological information that can advance many aspects of clinical practice. In an interview at SLEEP 2023, Reena Mehra, MD, MS, director and professor of medicine at the Sleep Disorders Center, Cleveland Clinic, highlighted the potential offered by endophenotypes yielded from sleep studies in predicting clinical outcomes, including conditions like atrial fibrillation (AF).

"It can be helpful in terms of screening, in terms of prediction of outcomes which helps you then risk stratify populations, and also for treatment responsiveness," she said. "So, these biomarkers from the sleep studies can be useful to us in a variety of ways."

Much of sleep apnea treatment is focused on managing patient symptoms. In recent years, the field of endophenotyping has garnered significant attention, signaling a growing recognition of the need to move beyond simplistic measures.

"Integrating (clinical symptom management) with the objective data that you get from a sleep study is important," she explained.

Mehra and her team from the Cleveland Clinic received a Discovery Accelerator Award which will allow them to collaborate with IBM to further examine how different facets of sleep apnea pathophysiology contribute to AF.  CPAP therapy is the first-line treatment, but the optimal option depends on the individual.

Advancements had led to additional treatment avenues like hypoglossal nerve stimulation and oral appliances and Mehra shared her motivation to find a way to determine which specific treatment strategy is best for each patient.

"I think there's opportunity to look at it more, or even doing cluster analyses where you can see if there are groupings of symptoms, and polysomnographic findings, endophenotypes, from the sleep studies–that when you take them together-do a better job of figuring out who's going to derive benefit from maybe a specific therapy."

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In recent years, the field of endophenotyping has garnered significant attention in sleep health, signaling a growing recognition of the need to move beyond simplistic measures.

Reena Mehra, MD: Biomarkers and Endophenotypes for Personalized Patient Care

The efficacy and safety of once-nightly sodium oxybate, also known as ON-SXB or FT218, for treating adults with narcolepsy was demonstrated in the pivotal phase 3 REST-ON trial. The trial evaluated an investigational extended-release formulation of the therapy and successfully met its coprimary endpoints. 

In addition to the groundbreaking phase 3 data, the interim findings from the ongoing RESTORE trial were presented by John Harsh, PhD, Clinical Research Director, Comprehensive Care for Sleep Disorders, Colorado Sleep Institute, at 

The open-label, switch study evaluated patient preferences regarding both once-nightly and twice-nightly doses of sodium oxybate as well as further examining the safety and efficacy profiles.

Out of 78 patients who completed preference questionnaires, 73 (93.6%) expressed a preference for the once-nightly dosing regimen of sodium oxybate indicating the convenience and simplicity of taking the medication once a night was highly favored by the majority.

"With twice-nightly, patients were missing their second dose at least once in a while, and the consequences were notable," Harsh said in an interview with 

Results from RESTORE were derived from an analysis of 180 patients, including REST-ON trial patients (n = 15, 8.3%), oxybate-naive individuals (n = 35, 19.4%), and switch patients (n = 130, 72.2%). Most of the patients were white (83.3%) and female (67.8%), with a mean age of 35 years ranging from 16 - 84.

"All these participants in the open-label extension had a couple of months for titration, 24 months or more for stable dosing, and then one week follow up," he explained. "We were able to collect data on adverse events, adverse drug reactions, get some idea of patient preference and patient experiences and especially in relation to the second night dosing for the twice nightly (sodium oxybate)."

Stern T, Roy A, Shapiro C, et al. 0579 Long-Term Safety of Once-Nightly Oxybate for Narcolepsy: RESTORE Study Interim Analysis of Data. 

Roy A, Harsh J, Ajayi A, Stern T, Dubow J, Gudeman J. 0581 Patient Preferences and Nocturnal Experiences With Oxybate Therapy for Narcolepsy: RESTORE Study Interim Analysis. 

Patients participating in the open-label extension trial had a few months for titration, more than 24 months for stable dosing, and a one-week follow up.

John Harsh, PhD: Interim Results Show Once-Nightly ON-SXB Dose is Preferred by Patients

Endophenotypes derived from sleep studies hold immense potential for predicting clinical outcomes, including conditions like atrial fibrillation, Reena Mehra, MD, MS, director, professor of medicine, at the Sleep Disorders Center, Cleveland Clinic, explained in an interview at 

“In sleep studies, we collect a wealth of information on physiology and we use a very cursory amount of that information clinically,” she said.

Among the studies presented by investigators from the Cleveland Clinic, data from a review of 170,000 sleep studies from the institution’s registries were featured at the conference. The study assessed the relationship between sleep apnea and atrial fibrillation (AF) and identified the significant role of hypoxia.

“The idea is that the sleep studies house a wealth of data and information in terms of physiologic signals from the brain, the heart, the lungs, the breathing, and even muscle,” Mehra said. “How can we use these data to harness the power it has to do a better job of predicting clinical outcomes and looking at treatment responsiveness?”

 received a Discovery Accelerator Award and is currently working with IBM to further examine how different facets of sleep apnea pathophysiology contribute to AF and other clinical outcomes.

“(The award) will allow us to collaborate with them and do some signal processing analyses, apply machine learning algorithms in a more refined way, to really get at the degree of hypoxia, heart rate arousal response, other EEG arousals and fragmentation of sleep, and potentially-associated sympathetic activation,” Mehra said.

“How can we use these data to harness the power it has to do a better job of predicting clinical outcomes and looking at treatment responsiveness?” Dr. Reena Mehra asks.

Reena Mehra, MD: Exploring Endophenotypes for Predicting Clinical Sleep Outcomes

, Reena Mehra, MD, MS, director, professor of medicine, at the Sleep Disorders Center, Cleveland Clinic, discussed the accumulation of data that led to multiple presentations at 

 has a high magnitude of established associations with AF, and the development of new AF. There's also evidence indicating the apneas and hypopneas, are linked with discrete episodes of cardiac arrhythmias. 

"In total, (these) data really support a causal relationship based upon the data that has accrued over the last several decades," Mehra said.

However, it is crucial to recognize that obstructive sleep apnea is often underdiagnosed, despite its high prevalence. 

"It is highly prevalent, with nearly 1 billion people worldwide afflicted with sleep apnea, but it's estimated that about 85% of individuals with sleep apnea have not been diagnosed," she explained. "So, this is a problem because atrial fibrillation, in particular, is an epidemic–it will increase by fivefold by the year 2050 compared to where it is now."

The possibility that sleep apnea could be one of the unrecognized factors exacerbating the growing rates of AF emphasizes the necessity of awareness, screening, diagnosing, and treating sleep apnea, according to Mehra.

The latest investigation, led by Catherine Heinzinger, DO, evaluated the Cleveland Clinic's registries of approximately 170,000 sleep studies, to assess the relationship between sleep apnea and AF. The results showed an emphasis on the role of hypoxia, rather than any subtypes of sleep apnea.

"The percentage of time spent below a threshold of 90% oxygen saturation, (Heinzinger) found, was the strongest factor that was predictive of the development of atrial fibrillation, beyond the traditional metric that we use called the Apnea-Hypopnea Index (AHI)," she explained.

The possibility that sleep apnea could be one of the unrecognized factors exacerbating the growing rates of AF emphasizes the necessity of awareness, screening, diagnosing, and treating sleep apnea.

Giuliana Grossi

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