Circadian Variability of Fibrinolytic Markers and Endothelial Function in Patients with Obstructive Sleep Apnea
Circadian Variability of Fibrinolytic Markers and Endothelial Function in Patients with Obstructive Sleep Apnea
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DOI：
10.5665/sleep.3414
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发表时间：
2014-02-01
期刊：
影响因子：
5.6
通讯作者：
Malow, Beth A.
中科院分区：
文献类型：
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作者：
Bagai, Kanika;Muldowney, James A. S., III;Malow, Beth A.
研究目标：阻塞性睡眠呼吸暂停（OSA）与心血管疾病密切相关，包括中风和急性冠脉综合征。纤溶酶原激活剂抑制剂-1 (PAI-1) 是组织型纤溶酶原激活剂 (t-PA) 的主要抑制剂，具有明显的昼夜节律，并且在 OSA 和心血管疾病中升高，可能是这两种疾病之间的重要联系。内皮功能障碍是心血管疾病的潜在病理生理机制之一，并且可能在 OSA 中发生改变。我们的主要目的是通过确定 24 小时内连续血液样本中 PAI-1 和 t-PA 的振幅（峰值水平）和中值（节律调整平均值）来比较 OSA 患者和正常对照中 PAI-1 和 t-PA 的昼夜节律变化。第二个目的是测量 OSA 患者与正常对照组相比的内皮功能标志物（肱动脉和桡动脉血流）。设置：横断面队列研究。患者或参与者：受试者年龄为 18 岁或以上，体重指数为 25-45 kg/m(2)，有或没有未经治疗的 OSA 证据。干预措施：在 24 小时内，每 2 小时收集一次 OSA 患者和匹配对照的血浆样本期间。测量 PAI-1 和 t-PA 抗原和活性。通过过夜多导睡眠图确认是否存在 OSA（呼吸暂停-呼吸不足指数为 5 或更高）。通过肱动脉血流介导的血管舒张和计算机化动脉脉搏波形分析来测量内皮功能。测量和结果：OSA 组中节律调整后的 PAI-1 抗原水平平均水平（21.8 ng/mL，95% 置信水平 [CI]，18 至 25.7）显着高于非 OSA 组（16 ng/mL，95% CI，12.2 至 25.7）。 19.8；P=0.03）。 OSA 组中节律调整后的 PAI-1 活性平均水平（23.9 IU/mL，95% CI，21.4 至 26.5）也显着高于非 OSA 组（17.2 IU/mL，95% CI，14.6 至 19.9；P < 0.001）。 PAI-1 活动幅度与 AHI 测量的 OSA 严重程度 (P = 0.02) 和睡眠期间最低氧水平 (P = 0.04) 之间存在很强的相关性。两组之间的内皮功能参数没有显着差异。 结论：与对照组相比，阻塞性睡眠呼吸暂停的存在会对昼夜纤溶平衡产生不利影响，其平均纤溶酶原激活剂抑制剂-1活性和抗原较高，而平均组织型纤溶酶原激活剂活性显着较低。这种扰动可能是阻塞性睡眠呼吸暂停患者心血管事件增加的重要机制。阻塞性睡眠呼吸暂停中的间歇性缺氧和生物钟基因活性的变化可能是造成这些结果的原因，值得进一步研究。纤溶平衡的有利变化可能是阻塞性睡眠呼吸暂停治疗中观察到的心血管事件减少的基础。
Study Objectives: Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls.Setting: Cross-sectional cohort study.Patients or Participants: Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA.Interventions: Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis.Measurements and Results: The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [ CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001). There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups.Conclusion: The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.