Vascular endothelial dysfunction in sleep apnea

摘要 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两倍。 观察性研究表明持续气道正压(CPAP)治疗可改善 阻塞性睡眠呼吸暂停综合征患者的心血管结局。然而，最近的3项随机临床试验未能证实这些发现， 这表明，尽管间歇性低氧(IH)已被有效消除，但OSA患者的心血管风险依然存在。我们的 初步数据显示，CPAP可能意外地加剧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残留的心血管风险。因此， 迫切需要针对阻塞性睡眠呼吸暂停综合征相关心血管风险的替代疗法。使用内皮细胞(ECs) 从阻塞性睡眠呼吸暂停综合征患者新鲜获取的资料中，我们发现补体膜攻击沉积增加。 在内皮细胞上的复合体(MAC)，这是补体抑制剂CD59内化增加的结果 EC表面，作为阻塞性睡眠呼吸暂停综合征内皮炎症的触发因素。我们证明了这个过程是由 高血压时EC胆固醇代谢和转运的改变，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可以保护内皮细胞免受MAC诱导的炎症， 包括坚持CPAP的阻塞性睡眠呼吸暂停综合征患者。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阻塞性睡眠呼吸暂停综合征的IH发作。然而，通过降低系统性和细胞性 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发挥内皮保护作用 OSA，提出了一种新的治疗策略，可能允许OSA患者继续受益于CPAP- 中介消除高血压和零碎的睡眠，同时降低他们的心血管风险。他汀类药物在阻塞性睡眠呼吸暂停综合征中的应用 患者人数一直很低：在跨越两年的研究中，只有8%-13%的OSA患者服用了他汀类药物 过去十年，这一潜在有益的治疗方法在阻塞性睡眠呼吸暂停综合征患者中得到了极大的利用。我们 将使用严格的随机、双盲、平行分组、安慰剂对照研究设计和ECS 从其他健康的阻塞性睡眠呼吸暂停患者身上采集，以评估他汀类药物稳定的总体假设 改善内皮细胞胆固醇代谢和转运的内皮功能与黏附性无关 接受CPAP治疗。为了解决这一总体假设，我们将确定1)他汀类药物是否会减少内皮细胞 阻塞性睡眠呼吸暂停患者的炎症和血栓前状态，包括坚持CPAP的患者可能表达的 增加炎症标志物(目标1)，以及2)他汀类药物是否减少内皮炎症和促进 通过改善血管内皮细胞胆固醇代谢和阻塞性睡眠呼吸暂停低密度脂蛋白的转运导致血栓形成(目标2)。这些 研究将促进我们对内皮功能障碍和心血管疾病的机制的理解 尽管进行了有效的CPAP治疗，但阻塞性睡眠呼吸暂停的风险似乎仍持续存在。因为少数阻塞性睡眠呼吸暂停综合症患者目前 使用他汀类药物治疗，我们的研究将提供机制背景，证明实际的临床试验是合理的 确定他汀类药物是否能改善阻塞性睡眠呼吸暂停综合征患者的心血管结局。

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.