Division of Pulmonary, Allergy, and Critical Care Medicine.
Department of Pediatrics, and.
Ann Am Thorac Soc. 2023 Jul;20(7):1029-1037. doi: 10.1513/AnnalsATS.202209-761OC.
Increased cardiovascular risk in obstructive sleep apnea (OSA) persists after continuous positive airway pressure (CPAP) and alternative therapies are needed. Impaired endothelial protection against complement is a cholesterol-dependent process that initiates endothelial inflammation in OSA, which increases cardiovascular risk. To investigate directly whether lowering cholesterol improves endothelial protection against complement and its proinflammatory effects in OSA. Newly diagnosed patients with OSA ( = 87) and OSA-free controls ( = 32) participated. Endothelial cells and blood were collected at baseline, after 4 weeks of CPAP therapy, and again after 4 weeks of 10 mg atorvastatin versus placebo using a randomized, double-blind, parallel-group design. Primary outcome was the proportion of a complement inhibitor, CD59, on the endothelial cell plasma membrane in OSA patients after 4 weeks of statins versus placebo. Secondary outcomes were complement deposition on endothelial cells and circulating levels of its downstream proinflammatory factor, angiopoietin-2, after statins versus placebo. Baseline expression of CD59 was lower, whereas complement deposition on endothelial cells and levels of angiopoietin-2 were greater, in patients with OSA compared with controls. CPAP did not affect expression of CD59 or complement deposition on endothelial cells in patients with OSA, regardless of adherence. Compared with placebo, statins increased expression of endothelial complement protector CD59 and lowered complement deposition in patients with OSA. Good CPAP adherence was associated with increased angiopoietin-2 levels, which was reversed by statins. Statins restore endothelial protection against complement and reduce its downstream proinflammatory effects, suggesting a potential approach to reduce residual cardiovascular risk after CPAP in patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT03122639).
阻塞性睡眠呼吸暂停（OSA）患者的心血管风险在持续气道正压通气（CPAP）治疗后仍然增加，需要替代治疗。补体对内皮的保护作用受损是一个胆固醇依赖性过程，它会引发 OSA 中的内皮炎症，从而增加心血管风险。本研究旨在直接研究降低胆固醇是否能改善 OSA 患者内皮对补体的保护作用及其促炎作用。新诊断的 OSA 患者（n=87）和 OSA 无患者（n=32）参与了这项研究。采用随机、双盲、平行分组设计，在基线时、CPAP 治疗 4 周后和阿托伐他汀 10mg 治疗 4 周后，分别采集内皮细胞和血液。主要终点是 OSA 患者在他汀治疗 4 周后内皮细胞血浆膜上补体抑制剂 CD59 的比例与安慰剂相比。次要终点是他汀治疗与安慰剂相比，内皮细胞上补体沉积和其下游促炎因子血管生成素-2 的循环水平。与对照组相比，OSA 患者的 CD59 表达水平较低，而内皮细胞上的补体沉积和血管生成素-2 水平较高。无论 CPAP 依从性如何，CPAP 治疗均不能影响 OSA 患者 CD59 的表达或内皮细胞上补体的沉积。与安慰剂相比，他汀类药物增加了 OSA 患者内皮补体保护蛋白 CD59 的表达，并降低了补体在 OSA 患者中的沉积。良好的 CPAP 依从性与血管生成素-2 水平升高有关，而他汀类药物可逆转这一作用。他汀类药物可恢复内皮对补体的保护作用，并降低其下游的促炎作用，提示他汀类药物可能是降低 OSA 患者 CPAP 后残余心血管风险的一种方法。该临床试验已在 www.clinicaltrials.gov 注册（NCT03122639）。
