Abstract Chronic obstructive pulmonary disease (COPD, which includes chronic bronchitis and emphysema) and obstructive sleep apnea (OSA) are both common diseases with major cardiovascular sequelae. The concomitant presence of COPD and OSA is referred to as overlap syndrome (OVS), which has a very poor prognosis with his risk of cardiovascular mortality. Our data demonstrate an association between OSA treatment and improved mortality in individuals with OVS, but to date data are not definitive and underlying mechanisms are undefined. In theory, in individuals with baseline (sustained) hypoxemia, further intermittent hypoxemia due to OSA may promote pulmonary vasoconstriction and elevated pulmonary vascular resistance. Thus, the right ventricle (RV) may be particularly affected by OVS. Of note, we have robust preliminary data showing the impact of OVS on the RV and reversibility with intervention. To investigate these concepts further, we propose two specific aims. First, we will perform a cross-sectional study to compare specific markers of cardiovascular risk among those with OSA vs. COPD vs. OVS. This aim will test the hypothesis that OVS has worsen endothelial function as compared with individuals afflicted with either disease alone. We will quantify other markers of cardiovascular risk such as cardiac MRI and plasma biomarkers including novel microRNAs. We have recent prominent publications suggesting a major role of miR-210 in the pathogenesis of OSA induced vascular risk. We will also employ novel imaging methods to assess potential biomarkers for mechanistic insights and to identify robust surrogate outcome measures for subsequent studies. Second, we will perform a mechanistic clinical study to compare the improvement in RV mass among individuals who receive bi-level positive airway pressure (PAP) as compared to individuals who receive oxygen (O2), which is the current standard of care. This aim will test the hypothesis that bi-level PAP therapy improves markers of cardiovascular risk as compared with O2 therapy. In addition to cardiac MRI we will assess other biomarker of cardiovascular risk as in Aim 1. Such findings will lay the groundwork for a multicenter randomized controlled trial, which we believe will be required to change the current standard of care. Our proposal will also inform basic research on the interactions of sustained plus intermittent hypoxemia. Given the high vascular risk among these individuals, the very high population prevalence of disease and the lack of current data, further mechanistic research is imperative.