Obstructive sleep apnea (OSA) has been linked to hypertension, heart failure and other cardiac and vascular diseases. Endothelial dysfunction is an important contributor to cardiac and vascular pathophysiology and predicts the development of future cardiovascular disease. Hypoxemia, blood pressure surges, oxidative stress and metabolic and inflammatory dysregulation in OSA may contribute to impairment of endothelial function. However, whether endothelial dysfunction is indeed present in OSA is controversial, and the mechanisms of any such dysfunction are unclear. This proposal tests the overall hypotheses that there are distinct abnormalities in endothelial mediated dilation of conductance and/or resistance arterial blood vessels in OSA patients, that the endothelial dysfunction may be explained by neural, vasoactive, inflammatory and/or progenitor cell mechanisms, and that effective therapy with continuous positive airway pressure (CPAP) attenuates these abnormalities, with consequent improvement in endothelial dysfunction.
Specific Aims are: 1) To test the hypothesis that patients with OSA have an impairment in tonic endothelial function, as well as impaired endothelial responses to provocative stimuli such as flow-mediated dilation and acetylcholine. 2) To test the hypothesis that neural, vasoactive, inflammatory and/or progenitor cell mechanisms contribute to impaired endothelial function in patients with OSA, and that these mechanisms and consequent endothelial dysfunction are more manifest after overnight untreated OSA. 3) To test the hypothesis that long-term effective therapy of OSA using CPAP improves endothelial function by attenuation of abnormalities in neural, vasoactive, inflammatory and endothelial progenitor cell mechanisms described in Specific Aims # 1 and #2. These studies apply novel developments in vascular biology to the understanding of cardiovascular disease in a multi-system disorder with a high and rising prevalence. The integrity of the hypotheses will be tested with careful exclusion of potential confounding variables such as obesity, hypertension and left ventricular dysfunction. Exciting preliminary data support the feasibility and promise of the hypotheses to be tested. Identification of the mechanisms mediating vascular disease in OSA will enhance our understanding of disease pathophysiology, and may provide opportunities for new therapeutic strategies. ? ?
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