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) 是一种非常普遍的疾病，它会使心血管疾病的风险增加三倍。观察性研究表明持续气道正压通气 (CPAP) 治疗可以改善 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，表明尽管有效消除了间歇性缺氧 (IH)，OSA 患者的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 中的促炎环境，从而可能会导致 CPAP 治疗随机试验中观察到的残余心血管风险。因此，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 患者身上新鲜采集，我们发现补体膜攻击的沉积增加 EC 上的补体抑制剂 CD59 内化增加的结果 EC 表面，作为 OSA 内皮炎症的触发因素。我们证明这个过程是由 EC 胆固醇代谢和运输的改变响应 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以保护 EC 免受 MAC 诱导的炎症的影响，包括坚持使用 CPAP 的 OSA 患者。在同一项研究中，CPAP 对 MAC 沉积没有影响。与 CPAP 不同，他汀类药物不能消除 OSA 中的 IH 发作。然而，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来发挥内皮保护作用 OSA，提出了一种新的治疗策略，可以让 OSA 患者继续受益于 CPAP- 介导消除 IH 和碎片化睡眠，同时降低心血管风险。 OSA 中他汀类药物的使用患者比例一直很低：在跨越 20 年的研究中，只有 8-13% 的 OSA 患者服用他汀类药物过去十年，这表明这种潜在有益的疗法在 OSA 患者中并未得到充分利用。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 EC 从其他健康的 OSA 患者身上采集，以评估他汀类药物稳定的总体假设通过改善内皮胆固醇代谢和运输来改善内皮功能，无论依从性如何与 CPAP 治疗。为了解决这个总体假设，我们将确定 1) 他汀类药物是否会减少内皮细胞 OSA 中的炎症和促血栓性疾病，包括坚持 CPAP 的患者，这些患者可能会表达炎症标志物增加（目标 1），以及 2）他汀类药物是否可以减少内皮炎症并促进通过改善内皮胆固醇代谢和 OSA 运输来治疗血栓性疾病（目标 2）。这些研究将增进我们对内皮功能障碍和心血管疾病潜在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。由于目前有少数 OSA 患者用他汀类药物治疗，我们的研究将提供机制背景来证明实际临床试验的合理性确定他汀类药物治疗是否可以改善 OSA 的心血管结局。