Pharmacological Approach to Cardiovascular Risk in OSA

? DESCRIPTION (provided by applicant): Obstructive Sleep Apnea (OSA) is associated with severe cardiovascular consequences including hypertension, stroke, and heart failure. The mechanism of cardiovascular disease (CVD) in OSA remains unknown. OSA results in sub-clinical vascular endothelial dysfunction (VED) that later develops into hypertension and end stage CVD. It is estimated that up to 50% of all OSA patients do not tolerate the standard device therapy, leaving them exposed to the progression of cardiovascular risk status. VED, the earliest reversible vascular abnormality in OSA, can potentially be targeted to modify the CVD risk status of OSA patients. However, the limited understanding of the mechanism of OSA related endothelial dysfunction has hindered the development of therapies that can specifically target CVD in OSA. Due to technical considerations, mechanistic studies of endothelial function in OSA rely heavily on animal models of intermittent hypoxia and have yielded conflicting results at times. We developed several novel methods to directly examine the function of the endothelial microcirculation in patients with OSA. These methods enable the isolation of non-diseased vascular endothelial tissue from OSA patients and the performance of quantification of genetic markers and examination of critical pathways of vascular disease directly in OSA patients. Our preliminary data identified targetable pathways of endothelial dysfunction in OSA patients. The methods proposed in this application will enable ex-vivo and in-vivo testing of several relevant pathways completely in OSA patients. The design of the research supplants animal models avoiding important related pitfalls and allowing immediate applicability of the findings to patients. Testing for non-device high-potential pharmacological interventions in OSA will have immediate impact on the clinical practice of caring for patients with OSA, especially those who are intolerant of device therapy. Additionally, the work proposed will provide an immediate foundation for subsequent critically needed clinical trials in this area. The findings of the proposed research will immediately impact the understanding and treatment of vascular disease. The central hypothesis of this proposal is that endothelial dysfunction in OSA is due to a reversible dysfunction in nitric oxide synthase and that this dysfunction can be targeted in the early stages of the OSA to slow the progression of vascular disease in OSA patients.