The Microcirculation in OSA

OSA 的微循环

• 批准号: 8233917
• 负责人: Rami N Khayat
• 金额: $ 19.06万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233917
• 关键词: 7,8-dihydrobiopterin; Accounting; Address; Affect; Affinity; Aftercare; Algorithms; Animal Model; Biology; Biopsy; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Conflict (Psychology); Controlled Study; Coronary; Data; Doppler Ultrasound; Endothelial Cells; Enzymes; Evaluation; Functional disorder; Genetic Markers; Genetic Transcription; Heart; Heart failure; High Pressure Liquid Chromatography; Human; Hypertension; Hypoxia; Immunohistochemistry; Knowledge; Measurement; Measures; Mediating; Methods; Microcirculation; Morbidity - disease rate; NADP; Natural regeneration; Nitric Oxide; Obstructive Sleep Apnea; Oxidants; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Plasma; Polymerase Chain Reaction; Population; Production; Proteins; Randomized Controlled Trials; Research; Research Personnel; Respiration Disorders; Role; Scientist; Sleep; Sleep Apnea Syndromes; Source; Staining method; Stains; Stroke; Subcutaneous Tissue; Superoxide Dismutase; Superoxides; Techniques; Testing; Time; Up-Regulation; Vascular Diseases; Vascular resistance; Vasodilator Agents; Xanthines; brachial artery; cardiovascular risk factor; care delivery; dihydroethidium; field study; high risk; human NOS3 protein; mortality; novel; primary outcome; protein expression; public health relevance; research study; response; subcutaneous; superoxide dismutase 1; tetrahydrobiopterin; treatment effect; uptake

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.

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的血管病变机制在很大程度上是未知的。由于无法确定主要结果，这种知识差距影响了开展大型对照研究的能力。阻塞性睡眠呼吸暂停的治疗耐受性不佳。对OSA相关血管疾病机制的有限了解阻碍了专门针对OSA相关心血管危险或疾病的治疗方法的出现。OSA患者和动物模型的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是了解OSA中血管疾病发生机制的关键。微循环占高血压血管阻力的大部分，在高血压和其他血管疾病的发病过程中起着早期作用。评估OSA患者的微循环对了解OSA患者血管疾病的发病机制至关重要。迄今为止，对OSA中内皮功能的评估主要依赖于间歇性缺氧的动物模型，并且关于OSA中内皮功能障碍的机制有时会产生相互矛盾的结果。迄今为止，还没有对OSA患者微循环内皮功能的直接评价。我们开发了一种直接检测OSA患者微循环功能的新方法。这种方法能够分离内皮细胞，实时定量血管疾病的遗传标记。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的几种可能途径。本应用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。这将解决关于使用间歇性缺氧动物模型的几个方法学问题。因此，所提出的方法将推动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。本研究的发现极有可能立即对OSA中血管病变的机制有积极的认识。

项目成果

Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction.

• DOI: 10.1016/j.resp.2014.12.012
• 发表时间: 2015-02-01
• 期刊: RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
• 影响因子: 2.3
• 作者: Varadharaj, Saradhadevi;Porter, Kyle;Pleister, Adam;Wannemacher, Jacob;Sow, Angela;Jarjoura, David;Zweier, Jay L.;Khayat, Rami N.
• 通讯作者: Khayat, Rami N.