Obstructive Sleep Apnea (OSA), a prevalent respiratory disorder of sleep, is associated with severe cardiovascular consequences including hypertension, stroke, and heart failure. The mechanism of vascular disease in OSA is largely unknown. This knowledge gap has affected the ability to conduct large controlled studies due to inability to determine primary outcomes. The treatment for OSA is not well tolerated. The limited understanding of the mechanism of OSA related vascular disease has hindered the emergence of therapies that target specifically OSA related cardiovascular risk or disease. Endothelial dysfunction in patients and animal models of OSA precedes the manifestation of hypertension. Patients with OSA have impaired endothelial mediated vascular response to vasodilators and hypoxia. Understanding the mechanism of endothelial dysfunction in OSA is critical to understanding the mechanism of vascular disease in OSA. The microcirculation accounts for most of the vascular resistance in hypertension and is involved early in the pathogenesis of hypertension and other vascular diseases. Evaluation of the microcirculation in OSA patients is critical to understanding the pathogenesis of vascular disease in OSA. To date, evaluation of endothelial function in OSA relied mostly on animal models of intermittent hypoxia and yielded sometimes conflicting results regarding the mechanism of endothelial dysfunction in OSA. To date, there has not been a direct evaluation of the endothelial function of the microcirculation in OSA patients. We developed a novel method to directly examine the function of the microcirculation in patients with OSA. This method enables the isolation of endothelial cells for real time quantification of genetic markers of vascular disease. Our preliminary data already identified several likely pathways in the mechanism of endothelial dysfunction of the microcirculation in these patients. The methods proposed in this application will enable testing of all of these relevant pathways entirely in OSA patients. This will address several of the methodological concerns regarding the use of intermittent hypoxia animal models. Therefore, the methods proposed will advance the field of study of vascular disease in general, and OSA in particular. The team of investigators assembled for this proposal includes established scientists in oxidant biology and endothelial function. The findings of the proposed research are very likely to immediately and positively the understanding of the mechanism of vascular disease in OSA.
This study will evaluate the mechanism of endothelial dysfunction in patients with OSA. The findings will advance the understanding of vascular disease in sleep apnea, a major cause of morbidity and mortality in this population. The result will be immediately applicable to planning needed randomized controlled trials evaluating the effects of treatment of sleep apnea on cardiovascular disease.
|Varadharaj, Saradhadevi; Porter, Kyle; Pleister, Adam et al. (2015) Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction. Respir Physiol Neurobiol 207:40-7|