Vascular endothelial dysfunction in sleep apnea

睡眠呼吸暂停中的血管内皮功能障碍

• 批准号: 10589074
• 负责人: Sanja Jelic
• 金额: $ 71.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10589074
• 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; Epithelium; 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; Random Allocation; Randomized; Research Design; Residual state; Risk Factors; Running; Sampling; Sleep Apnea Syndromes; Sleep Fragmentations; Specific qualifier value; VWF gene; Weibel-Palade Bodies; atorvastatin; cardiovascular disorder risk; cardiovascular risk factor; cholesterol trafficking; cohort; endoplasmic reticulum stress; endothelial dysfunction; epithelial injury; experience; glycoprotein 340; improved; 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; randomized, clinical trials; receptor for advanced glycation endproducts; response; vascular endothelial dysfunction; vascular injury; vesicle-associated membrane protein; von Willebrand Factor

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.

摘要 阻塞性睡眠呼吸暂停（OSA）是一种非常普遍的疾病，使心血管疾病的风险增加两倍。 观察性研究表明，持续气道正压通气（CPAP）治疗可改善 OSA的心血管结局。然而，最近的3项随机临床试验未能证实这些发现， 表明尽管有效地消除了间歇性缺氧（IH），但OSA患者的心血管风险仍然存在。我们 初步数据表明，CPAP可能意外地加重OSA的促炎环境， 可能导致CPAP治疗随机试验中观察到的残余心血管风险。因此，在本发明中， 迫切需要针对OSA相关心血管风险的替代疗法。使用内皮细胞（EC） 从OSA患者新鲜采集，我们发现补体膜攻击的沉积增加， 复合物（MAC）对EC的影响，这是补体抑制剂CD 59从EC中内化增加的结果。 EC表面，作为OSA中内皮炎症的触发因素。我们发现这个过程是由 改变EC胆固醇代谢和运输响应IH，并被他汀类药物阻断。我们发现 与安慰剂相比，随机分配的他汀类药物治疗可保护EC免受MAC诱导的炎症， 包括坚持CPAP的OSA患者。在同一研究中，CPAP对MAC沉积没有影响。 与CPAP不同，他汀类药物不能消除OSA中的IH发作。然而，通过降低系统和细胞 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来发挥内皮保护作用， OSA，这表明一种新的治疗策略，可以让OSA患者继续受益于CPAP- 介导消除IH和零碎睡眠，同时降低心血管风险。他汀类药物在OSA中的使用 患者的比例一直很低：在跨越20世纪的研究中，只有8-13%的OSA患者服用他汀类药物。 在过去十年中，表明这种潜在的有益治疗在OSA患者中被大大利用不足。我们 将采用严格的随机、双盲、平行组、安慰剂对照研究设计和EC 从其他健康的OSA患者中收集，以评估他汀类药物稳定 通过改善内皮细胞胆固醇代谢和运输来改善内皮细胞功能， 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内皮细胞 OSA中的炎症和血栓前状态，包括在坚持CPAP的患者中， 增加的炎症标志物（目的1），和2）他汀类药物是否减少内皮炎症和促炎症反应， 通过改善内皮胆固醇代谢和OSA的运输来治疗血栓性疾病（目的2）。这些 这些研究将促进我们对内皮功能障碍和心血管疾病机制的理解， 尽管进行了有效的CPAP治疗，OSA的风险似乎仍然存在。由于目前少数OSA患者 他汀类药物治疗，我们的研究将提供机制背景，以证明一个实际的临床试验， 确定他汀类药物治疗是否改善OSA患者的心血管结局。