The Microcirculation in OSA

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠呼吸障碍，与严重的心血管后果相关，包括高血压、中风和心力衰竭。阻塞性睡眠呼吸暂停综合征中血管疾病的机制在很大程度上是未知的。由于无法确定主要结局，这种知识差距影响了进行大型对照研究的能力。OSA的治疗耐受性不好。对OSA相关血管疾病机制的有限理解阻碍了特异性靶向OSA相关心血管风险或疾病的治疗的出现。在OSA患者和动物模型中，内皮功能障碍先于高血压的表现。OSA患者对血管扩张剂和缺氧的内皮介导的血管反应受损。了解OSA中内皮功能障碍的机制对于了解OSA血管疾病的机制至关重要。微循环是高血压血管阻力的主要来源，是高血压及其他血管疾病发病的早期环节。对OSA患者微循环的评价对于了解OSA血管疾病的发病机制至关重要。迄今为止，OSA内皮功能的评价主要依赖于间歇性缺氧的动物模型，有时产生相互矛盾的结果，在OSA内皮功能障碍的机制。到目前为止，还没有一个直接的评价OSA患者的微循环内皮功能。 我们开发了一种新的方法来直接检查阻塞性睡眠呼吸暂停患者的微循环功能。该方法能够分离内皮细胞，以真实的实时定量血管疾病的遗传标志物。我们的初步数据已经确定了这些患者微循环内皮功能障碍机制中的几种可能途径。本申请中提出的方法将能够在OSA患者中完全测试所有这些相关途径。这将解决几个方法上的问题，使用间歇性缺氧动物模型。因此，提出的方法将推进血管疾病的研究领域，特别是OSA。为这项提议而组建的研究小组包括氧化生物学和内皮功能方面的知名科学家。本研究的结果将有助于对阻塞性睡眠呼吸暂停综合征血管病变机制的认识。 公共卫生相关性：本研究将评价OSA患者内皮功能障碍的机制。这些发现将促进对睡眠呼吸暂停中血管疾病的理解，这是该人群发病率和死亡率的主要原因。该结果将立即适用于规划所需的随机对照试验，以评估睡眠呼吸暂停治疗对心血管疾病的影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.