The goal of this proposal is to develop a novel study design to safely and ethically conduct a long-term randomized controlled trial among patients at high risk for both sleep apnea and cardiovascular events in order to determine whether effective positive airway pressure (PAP) therapy reduces cardiovascular risk. Patients with transient ischemic attack (TIA) have a high prevalence of sleep apnea (60-80%), and they are at high risk within 1 year for cardiovascular events (myocardial infarction, congestive heart failure, completed stroke, and cardiovascular death) despite current preventive strategies. Therefore, the treatment of sleep apnea may represent a novel therapeutic target to reduce cardiovascular outcomes in this high risk population. The proposed study is a randomized controlled trial among patients with TIA comparing strategies for the diagnosis and treatment of sleep apnea with usual care over 12 months at 2 sites (Yale University School of Medicine and Indiana University School of Medicine). Patients with TIA will be randomly assigned to either usual care or a diagnosis and treatment approach that includes ambulatory polysomnography and initiation of autotitrating CPAP for sleep apnea in a 1:2 (control: intervention) randomization scheme. Intervention patients with sleep apnea will then receive either a standard CPAP treatment intervention or an enhanced protocol designed to increase long-term CPAP adherence. The Primary Aims will consist of determining whether such an intervention results in clinically significant reductions in several domains of markers of cardiovascular risk, the optimal adherence levels to achieve these improvements, and whether an enhanced intervention protocol results in improved long-term CPAP adherence rates. The primary and secondary outcomes will include: (a) the impact of CPAP on pathophysiologic markers in various domains of cardiovascular risk including: inflammation (CRP, Il-6), heightened sympathetic activity/parasympathetic withdrawal (plasma catecholamines and heart rate variability (HRV)), insulin resistance (HOMA-IR, HbA1C), endothelial injury (flow mediated vasodilation), and atherosclerosis (carotid intima-media thickness); (b) long term (12 month) CPAP adherence; and (c) cardiovascular event rate (pilot data). This proposed project will provide the data needed to plan a future effectiveness strategy trial of CPAP among patients with TIA to reduce cardiovascular events, and will be conducted by a transdisciplinary research team that has a previously formed collaboration, thus leveraging our significant existing infrastructure. (End of Abstract)