PROJECT SUMMARY Poor sleep quality is a very common symptom in the WTC General responder cohort (WTCGRC). Comorbid conditions including obstructive sleep apnea (OSA) can contribute to poor sleep quality and daytime sleepiness and may affect cardiovascular health similar to the general population. The consequences of untreated OSA include disturbed sleep, excessive daytime sleepiness, and an increased risk for major adverse cardiovascular events (MACE). In OSA patients, plasma biomarkers associated with MACE such as highly sensitive C-reactive protein (hs-CRP) are elevated. We have previously shown in the WTC-CHEST study (NCT01466218) that presence or high risk of OSA is associated with elevated levels of hs-CRP. In the current proposal, we will evaluate whether CV risk in these WTC-CHEST OSA subjects is similar to the general population, and if hs-CRP is a predictor of MACE. Three distinct clinical phenotypes of OSA have been described: 1) a sleepy phenotype (2) a disturbed sleep phenotype and 3) a minimally symptomatic phenotype. WTCGRC with OSA has almost a 50% prevalence of the disturbed sleep phenotype in contrast to other populations with OSA, where the sleepy phenotype is predominant. The pathophysiology of OSA is complex and multifactorial and has been described using polysomnographically (PSG) determined endotypic traits: impaired upper airway anatomy, low arousal threshold, high ventilatory loop gain and altered neuro-muscular control of upper airway muscles. Our preliminary data shows that unlike in other populations, low arousal threshold endotype is the primary physiological endotype that leads to OSA. However, the relationship between endotypes and clinical phenotypes are unknown. In this proposal, we will determine whether the low arousal threshold physiological endotype is associated with the “Disturbed Sleep” clinical phenotype. We will also examine the association between a recently developed PSG index, the odds ratio product (ORP-9) that measures excessive overnight wakefulness and physiological endotypes and clinical phenotypes as a biomarker of disturbed sleep. There have been no studies determining the association of clinical phenotypes of OSA and plasma hs- CRP. Therefore, the third aim of this proposal will determine whether the “Disturbed Sleep” clinical phenotype of OSA in the WTCGRC is associated with increases in plasma hs-CRP. Finally, we will determine the relationship of hs-CRP with poor sleep quality in subjects without OSA but with other comorbidities in the WTCGRC. The studies proposed in this project will significantly advance our understanding of the consequences of poor sleep in the WTCGRC and will inform future screening recommendations for these participants.