Vascular endothelial dysfunction in sleep apnea

睡眠呼吸暂停中的血管内皮功能障碍

基本信息

批准号：
10367416
负责人：
Sanja Jelic
金额：
$ 71.48万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367416
关键词：
Address Adherence Adult Affect Alternative Therapies American Angiogenic Factor Angiopoietin-2 Blood Vessels Cardiovascular system Cell Adhesion Cell Adhesion Molecules Cell surface Cholesterol Cholesterol Homeostasis Clinical Trials Complement Complement Inactivators Complement Membrane Attack Complex Continuous Positive Airway Pressure Cytoplasmic Granules Data Deposition Double-Blind Method E-Selectin Endoplasmic Reticulum Endothelial Cells Endothelium Epithelial Esterification Harvest Hypoxia Impairment Inflammation Inflammatory Intercellular adhesion molecule 1 Lipids Lung Mechanical ventilation Mediating Membrane Proteins Minority Molecular NF-kappa B Newly Diagnosed Nuclear Translocation Observational Study Obstructive Sleep Apnea Outcome Patients Placebos Plasma Process Proteins Pulmonary Surfactant-Associated Protein D Randomized Randomized Clinical Trials Research Design Residual state Risk Factors Running Sampling Sleep Sleep Apnea Syndromes Specific qualifier value VWF gene Weibel-Palade Bodies atorvastatin base cardiovascular disorder risk cardiovascular risk factor cholesterol trafficking cohort endoplasmic reticulum stress endothelial dysfunction epithelial injury experience glycoprotein 340 improved improved functioning in vitro Model inflammatory marker inflammatory milieu late endosome lung volume mortality novel therapeutic intervention oxysterol binding protein placebo controlled study pressure protein B randomized placebo controlled trial randomized trial receptor for advanced glycation endproducts response thrombotic vascular endothelial dysfunction vascular injury vesicle-associated membrane protein von Willebrand Factor

项目摘要

Abstract Obstructive sleep apnea (OSA), a highly prevalent condition, triples the risk for cardiovascular disease. Observational studies suggested that continuous positive airway pressure (CPAP) therapy improves cardiovascular outcomes in OSA. However, 3 recent randomized clinical trials failed to confirm those findings, indicating that cardiovascular risk persists in OSA despite effective elimination of intermittent hypoxia (IH). Our preliminary data suggest that CPAP may unexpectedly exacerbate the pro-inflammatory milieu in OSA, which may contribute to the residual cardiovascular risk observed in randomized trials of CPAP therapy. Thus, alternative therapies for OSA-related cardiovascular risk are urgently needed. Using endothelial cells (ECs) freshly harvested from OSA patients, we identified increased deposition of the complement membrane attack complex (MAC) on ECs, a consequence of increased internalization of the complement inhibitor CD59 from the EC surface, as a trigger of endothelial inflammation in OSA. We showed that this process is mediated by alterations in EC cholesterol metabolism and trafficking in response to IH and is blocked by statins. We found that randomly allocated statin therapy protects ECs from MAC-induced inflammation compared to placebo, including in OSA patients adherent with CPAP. In the same study, CPAP had no impact on MAC deposition. Unlike CPAP, statins do not eliminate IH episodes in OSA. However, by lowering systemic and cellular cholesterol levels, statins may exert endothelial protection by inhibiting complement-mediated vascular injury in OSA, suggesting a novel therapeutic strategy that may allow OSA patients to continue to benefit from CPAP- mediated elimination of IH and fragmented sleep while reducing their cardiovascular risk. Statin use among OSA patients has been consistently low: only 8-13% of OSA patients are prescribed statins in studies spanning the last decade, indicating that this potentially beneficial therapy has been vastly underutilized in OSA patients. We will use rigorous randomized, double blind, parallel group, placebo controlled study design and ECs harvested from otherwise healthy OSA patients to assess the overall hypothesis that statins stabilize endothelial function by improving endothelial cholesterol metabolism and trafficking regardless of the adherence with CPAP therapy. To address this overall hypothesis, we will determine 1) whether statins reduce endothelial inflammation and pro-thrombotic conditions in OSA, including in patients adherent to CPAP who may express increased inflammatory markers (Aim 1), and 2) whether statins reduce endothelial inflammation and pro- thrombotic conditions by improving endothelial cholesterol metabolism and trafficking in OSA (Aim 2). These studies will advance our understanding of the mechanisms underlying endothelial dysfunction and cardiovascular risk in OSA that seem to persist despite effective CPAP therapy. Since a minority of OSA patients are currently treated with statins, our study will provide the mechanistic background to justify a practical clinical trial to determine if statin therapy improves cardiovascular outcomes in OSA.

抽象的阻塞性睡眠呼吸暂停（OSA）是一种高度普遍的状况，是心血管疾病的风险。观察性研究表明，连续阳性气道压力（CPAP）治疗有所改善 OSA的心血管结局。但是，最近有3项随机临床试验未能确认这些发现，表明尽管有效消除间歇性缺氧（IH），但OSA中心血管风险仍然存在。我们的初步数据表明，CPAP可能会意外地加剧OSA的促炎环境，这可能有助于在CPAP治疗的随机试验中观察到的残留心血管风险。因此，迫切需要针对OSA相关的心血管风险的替代疗法。使用内皮细胞（EC）从OSA患者那里收获的新鲜收获，我们确定了补体膜攻击的沉积增加 EC上的复合物（MAC），这是补体抑制剂CD59内在化增加的结果 EC表面，作为OSA内皮炎症的触发。我们表明此过程是由 EC胆固醇代谢和贩运对IH的改变，并被他汀类药物阻塞。我们发现与安慰剂相比包括在OSA患者使用CPAP的患者。在同一项研究中，CPAP对MAC沉积没有影响。与CPAP不同，他汀类药物不会消除OSA中的IH情节。但是，通过降低全身和细胞胆固醇水平，他汀类药物可能通过抑制补体介导的血管损伤而施加内皮保护 OSA提出了一种新型的治疗策略，可能使OSA患者继续受益于CPAP- 介导的消除IH和零散的睡眠，同时降低其心血管风险。 OSA中的他汀类药物的使用患者一直持续很低：在跨越研究的研究中，只有8-13％的OSA患者是他的汀类药物。过去的十年，这表明在OSA患者中，这种潜在的有益疗法的充分利用不足。我们将使用严格的随机，双盲，平行组，安慰剂对照研究设计和ECS 从其他健康的OSA患者中收获，以评估他汀类药物稳定的总体假设内皮功能通过改善内皮胆固醇代谢和贩运，无论依从性如何进行CPAP治疗。为了解决这一总体假设，我们将确定1）他汀类药物是否减少了内皮 OSA中的炎症和促性疾病，包括遵守CPAP的患者可能表达的CPAP 增加炎症标志物（AIM 1），以及2）他汀类药物是否减少内皮炎症和促进通过改善OSA中内皮胆固醇代谢和贩运的血栓形成条件（AIM 2）。这些研究将提高我们对内皮功能障碍和心血管内部机制的理解尽管有效的CPAP疗法，OSA的风险似乎仍然存在。由于目前有少数OSA患者通过他汀类药物治疗，我们的研究将提供机械背景，以证明一项实际临床试验合理确定他汀类药物治疗是否改善了OSA中的心血管结局。