【作者】 赵青；

【导师】 柳志红；

【作者基本信息】 北京协和医学院 ， 内科学， 2011， 博士

【摘要】 目的：阻塞性睡眠呼吸暂停(Obstructive sleep apnea,OSA)在人群中普遍存在,而且与心血管疾病关系密切。国外流行病学资料显示OSA发生冠心病的风险明显增加,然而国内相关的研究数据较少,本研究旨在通过横断面研究,采用多功能睡眠记录仪(Polysomnography, PSG)结合冠状动脉造影(Coronary angiography,CAG),了解国人OSA患者中冠心病(Coronary artery disease,CAD)的发生率,并探讨两者之间关系和临床特点。方法：连续入选2009年01月—2010年6月以胸痛待查入住阜外医院心内科五区行冠状动脉造影(CAG)的患者,详细询问病史,排除心力衰竭、慢性阻塞性肺病等疾病后,完成问卷调查,获取身高、体重、吸烟史、饮酒史、高血压病史、糖尿病史等临床资料；进行整夜的PSG,排除中枢性呼吸睡眠暂停；并于次日清晨空腹抽取静脉血,检测常规生化指标,包括血糖、血脂等。根据PSG的结果和美国睡眠医学会确定成年人睡眠呼吸暂停的诊断标准,将所有患者分为四组：(1)无OSA组：睡眠呼吸暂停低通气指数(AHI)<5；(2)轻度OSA组：5<AHI<15；(3)中度OSA组：15<AHI<30；(4)重度OSA组：30<AHI。结果：257例患者入选,无OSA组56例,轻度OSA组79例,中度OSA组61例,重度OSA组61例。四组患者的年龄、性别、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖、高血压的发生率等无显著性差异。四组之间方差分析显示,AHI、ODI、平均血氧饱和度、最低血氧饱和度与血氧饱和度低于90%的时间(TST)均具有显著性差异(P<0.001)。相关分析显示AHI与ODI相关性最高(r=0.978),其次是最低血氧饱和度(r=-0.561),TST(r=0.392),最后是平均血氧饱和度(r=-0.355)。无OSA组、轻度OSA组、中度OSA组和重度OSA组中,经CAG确诊CAD的患者分别为44.6%:60.0%:70.5%:72.1%(P<0.01)；Logistic回归分析,最低血氧饱和度与CAD的发生显著相关(P=0.024)结论：OSA与冠心病的发生和发展关系密切。本研究发现在PSG的参数中,ODI与AHI相关性最高,校正混杂因素后相关系数为0.974。在评价血氧的各指标中,最低血氧饱和度与AHI相关性最高。CAD的发生率在国人OSA患者中明显增加,随着OSA的严重程度呈递增趋势；多元回归分析,OSA是冠心病的独立危险因素。目的：阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)普遍存在,OSA患者是罹患心血管疾病高危人群,且该人群也具有代谢性综合征的高危因素,但其机制并不十分清楚。OSA与代谢紊乱之间的独立关系可能是一条导致心血管疾病的途径。胰岛素抵抗(insulin resistance, IR)是心血管疾病和代谢性综合征的重要的共同环节之一。本文通过夜间多功能睡眠记录仪(Polysomnography, PSG),结合稳态模型胰岛素抵抗指数(HOMA-IR)及相关糖代谢指标的检测,探讨国人中OSA及与胰岛素抵抗的相关性。方法：连续入选2009年10月—2010年6月因打鼾在本中心行PSG检查的患者。排除糖尿病、心力哀竭以及多种内分泌性疾病等。PSG检查当晚获取患者的详细临床资料和病史,包括身高、体重、吸烟史、饮酒史、高血压病史、糖尿病史等；受试者在清晨6：00采取空腹的静脉血液标本。在本院临床检验中心检测各种血液生化指标,包括胰岛素、血糖、血脂、高敏C反应蛋白等。以HOMA2-IR指数来衡量胰岛素抵抗。HOMA2法是将空腹血糖和空腹胰岛素输入软件HOMA Calculator V2.2.2,计算HOMA2-IR。结果：入选符合入排标准的患者218例,其中男性176例,女性42例,平均(57.1±10.1)岁。其中无OSA组对照人群50名,轻度OSA组64名,中度OSA组61名,重度OSA组43名。四组间性别、吸烟史、饮酒史等均无显著性差异。无OSA组、中度OSA和重度OSA组之间年龄无显著性差异,而轻度OSA组的年龄较低；体重指数(Body mass index, BMI)指数在四组间存在显著差异(P<0.001)。四组之间方差分析显示,呼吸暂停低通气指数(Apnea hypopnea index, AHI)、减氧饱和度指数(Oxygen desaturation index, ODI)、平均血氧饱和度、最低血氧饱和度与血氧饱和度低于90%的时间(TST)均具有显著性差异(P<0.001)。四组间空腹胰岛素、HOMA指数存在显著差异。与无OSA组、轻度OSA组、中度OSA组三组相比,重度OSA组的空腹胰岛素显著增加；与无OSA组、中度OSA组两组相比,重度OSA组的与HOMA2指数显著增加。Pearson相关分析提示HOMA指数与TST的相关性最高(r=0.305,P<0.001),其次是BMI指数(r= 0.247,P<0.001)、AHI/ODI (r=0.20, P<0.01)、平均血氧饱和度(r=-0.151,P<0.05)；空腹胰岛素水平与TST的相关性最高(r=0.331,P<0.001),其次是BMI指数(r=0.227,P=0.001)、AHI/ODI (r=0.19,P>0.01).平均血氧饱和度(r=-0.170,P<0.05)。校正年龄、性别、BMI指数等指标后,偏相关分析提示：HOMA指数仍与TST的相关性最高(r=0.302,P<0.001),其次是AHI(r=0.142,P<0.05)；空腹胰岛素水平也是与TST的相关性最高(r=0.328,P<0.001),其次是平均血氧饱和度(r=-0.150, P<0.05)、ODI (r= 0.136, P<0.05)以PSG的各指标(AHI、ODI、平均血氧饱和度、最低血氧饱和度和TST)、BMI、高密度脂蛋白胆固醇和糖化血红蛋白为自变量,以HOMA胰岛素抵抗指数为因变量,进行逐步回归分析；最后,TST、平均血氧饱和度、BMI三个参数进入回归方程,提示OSA造成的低氧血症和肥胖对胰岛素抵抗均有显著性影响(P<0.001)结论：与无OSA组相比,重度OSA组的空腹胰岛素水平、HOMA2胰岛素抵抗指数显著增加；Pearson相关分析提示HOMA指数与TST的相关性最高,校正年龄、性别、BMI指数等指标后,两者之间的相关性依然显著存在。多元回归分析提示胰岛素抵抗与OSA造成的低氧血症的指标和肥胖独立相关,随着血氧程度的降低,特别是随着血氧饱和度低于90%的时间的增加、平均血氧饱和度的降低,胰岛素抵抗显著增加,提示OSA是胰岛素抵抗的重要影响因素。目的：阻塞性睡眠呼吸暂停(Obstructive sleep apnea, OSA)在成人中普遍存在,是冠心病(Coronary heart disease, CAD)发生发展的独立危险因素。大量国内外资料显示代谢综合征是心血管疾病的独立危险因素。而且越来越多的临床证据表明OSA与代谢综合征密切相关。由于混杂因素众多(包括肥胖等),OSA与代谢综合征之间的机制十分复杂。持续气道正压通气(Continuous positive airway pressure, CPAP)是阻塞性睡眠呼吸暂停的有效的治疗方法。然而,对于已经接受最优化药物治疗的冠心病合并阻塞性睡眠呼吸暂停患者,CPAP是否能改善代谢紊乱和生活质量尚不清楚。本研究旨在通过前瞻性随机对照研究应用CPAP对OSA进行干预治疗,探讨OSA是否通过引起代谢紊乱而促进冠心病的发生发展。方法：本研究入选2009年3月到2010年9月期间就诊于本中心确诊中重度OSA合并冠心病的患者,而且这些冠心病患者已经应用最优化的药物治疗冠心病和高血压等。排除中枢性呼吸暂停、心力衰竭、严重的呼吸系统疾病等。56名符合入排标准的患者签署知情同意,6名患者在导入期被排除,其余50名患者按照1:1的比例随机分为两组：CPAP组和对照组。CPAP组患者接受6个月的CPAP治疗+常规治疗；对照组患者仅接受常规治疗。两组患者在随机前收集基线人口学特征和病史,检测空腹的血液生化学指标,计算稳态模型胰岛素抵抗指数(HOMA2-IR),评价患者的Epworth嗜睡评分(Epworth sleepiness score, ESS)和生活质量评价量表等。两组患者均于随机后1、3和6个月后进行诊室随访,重新评估血液生化指标、人口学特征以及生活质量等。结果：两组间比较,基线收集所有的数据均无显著性差异,只有糖化血红蛋白存在显著性差异(P=0.024)。经过6个月的随访,与对照组相比,CPAP治疗显著降低空腹胰岛素水平(P=0.026)。于此相对应,CPAP组的HOMA2-IR指数较对照组亦显著降低(P＝0.021)。而其他血液生化学指标,在两组间比较均无显著性差异。1个月、3个月和6个月随访时,CPAP组患者的舒张压较对照组均显著降低(P=0.004)。与此相反,在随访期间,两组间收缩压和心率的变化均没有达到显著性差异。1个月治疗后,与对照组相比,CPAP组日间嗜睡症状明显改善(CPAP组△-5.24±2.35 vs对照组△-0.48±2.26,P<0.001),而且这种差异一直持续到6个月。6个月随访后,与CPAP组相比,对照组的抑郁评分显著增加(P=0.002)。焦虑评分在治疗前后的两组之间无显著变化。经过6个月的治疗,两组间SF-36生活质量量表的八个维度评分均未达到显著性差异。结论：本研究通过前瞻性随机对照研究证实,在中重度OSA合并最优化药物治疗的冠心病患者中,CPAP治疗可以改善胰岛素抵抗,降低系统血压,特别是舒张压,并改善ESS评分,提示OSA有可能通过引起一系列代谢性紊乱,特别是胰岛素抵抗,来促进冠心病的发生发展,为冠心病的二级预防提供了新的治疗靶点,所以积极的治疗OSA对冠心病患者大有裨益。更多还原

【Abstract】 Objective:A number of recent studies suggest that obstructive sleep apnea (OSA) may have a tight relationship with cardiovascular diseases. The epidemiological studies overboard have suggested that patients with OSA have an increased risk for coronary artery disease (CAD). However, the data in China is rare. The objective of the current study is to determine the incidence of CAD in patients with OSA, and to evaluate the clinical relationship between CAD and OSA, using coronary angiography (CAG) and polysomnography (PSG).Methods:Consecutive patients who underwent CAG from January 2009 to June 2010 in our department were enrolled into the current study. The patients who have heart failure, chronic pulmonary diseases were excluded. After overnight PSG, patients with central sleep apnea were excluded. The clinical characteristics were collected including height, weight, smoke habit, alcohol consumption, and medical history, et al. In the next morning, fasting blood samples was drawn from an antecubital vein for determination of insulin, blood glucose, lipid profiles, et al. All patients were divided into four groups according to the severity of OSA. (1) no OSA group:apnea hypopnea index (AHI)<5; (2) mild OSA group:5≤AHI<15; (3) moderate OSA group:15≤AHI<30; (3) severe OSA group:30≤AHI。Results:257 patients were included and divided into four groups according to the severity of OSA. There were 56 patients in no OSA group,79 patients in mild OSA group,61 patients in moderate OSA group, and 61 patients in severe OSA group. In the analysis of variance, AHI, Oxygen desaturation index (ODI), average oxygen saturation, minimal oxygen saturation, and oxygen saturation below 90%(TST) were all significantly different between the four groups (P<0.001). In Pearson correlation, ODI was the most significantly correlated with AHI (r=0.978). The other factors correlated with AHI included minimal oxygen saturation (r=-0.561), TST (r=0.392), average oxygen saturation (r=-0.355).The incidence of CAD were 44.6%:60.0%:70.5%:72.1% (P<0.01) in no OSA group, mild OSA group, moderate OSA group, and severe OSA group, respectively. In logistic regression analysis, minimal oxygen saturation was significantly correlated with CAD (P=0.024).Conclusions:OSA is tightly related with the development of CAD. Among all the PSG variables, ODI was the most significantly correlated with AHI even after adjustment for confounders. Among all the variables for oxygen saturation, minimal oxygen saturation was the most significantly correlated with AHI. The incidence of CAD was significantly higher in OSA patients than no OSA patients, and had an increased trend with the severity of OSA. OSA is the independent risk factors. Objective:Obstructive sleep apnea (OSA) has high prevalence and wide spectrum in adults. OSA patients are in high risk of cardiovascular diseases, and also have high risk factors for metabolic syndrome. However, the mechanism of OSA is not very clear. The independent relationship between OSA and metabolic disorders might be one pathway contributing to cardiovascular diseases. Insulin resistance is an important linkage between cardiovascular diseases and metabolic syndrome. The aim of the current study is to determine the relationship between OSA and insulin resistance by polysomnography (PSG) and homeostatic model assessment of insulin resistance (HOMA-IR).Methods:Consecutive snoring patients were enrolled from the Sleep Center of Fuwai Hospital from October 2009 to June 2010. All patients underwent overnight PSG using an Embletta recording device in the current study. The patients who have diabetes, heart failure, and other endocrine diseases were excluded. The clinical characteristics were collected including height, weight, smoke habit, alcohol consumption, and medical history. In the morning at 6:00, fasting blood samples were drawn from an antecubital vein for determination of insulin, blood glucose, lipid profiles, high sensitivity C-reactive protein, et al at the local clinical testing center. Insulin resistance was evaluated by HOMA2-IR. HOMA2-IR was calculated by software HOMA Calculator V2.2.2 where fasting blood glucose and fasting insulin levels were enrolled.Results:218 patients after matched with the Inclusion and Exclusion criteria were enrolled.176 patients were males while 42 were females. The average age is (57.1±10.1) years. All patients were divided into four groups according to the severity of OSA. There were 50 patients in no OSA group,64 patients in mild OSA group,61 patients in moderate OSA group, and 43 patients in severe OSA group. There were no significant differences in sex, smoker, and alcohol consumption between the four groups. The age of mild OSA group is significantly lower than the other three groups. Body mass index (BMI) is also significantly different between the four groups. In the analysis of variance, apnea hypopnea index (AHI), Oxygen desaturation index (ODI), average oxygen saturation, minimal oxygen saturation, and oxygen saturation below 90%(TST) were all significantly different between the four groups. Fasting insulin levels and HOMA-IR indexes were also significantly different between the four groups. Fasting insulin levels were significantly higher in severe OSA group than the other three groups. HOMA-IR indexes were significantly higher in severe OSA group than no OSA group, and moderate OSA group.In Pearson correlation, TST was the most significantly correlated with HOMA index (r= 0.305, P<0.001). The other factors correlated with HOMA index included BMI index (r= 0.247, P<0.001)、AHI/ODI(r= 0.20, P<0.01)、average oxygen saturation (r=-0.151, P<0.05). Meanwhile, TST was also the most significantly correlated with fasting insulin levels (r= 0.331,P<0.001). The other factors correlated with fasting insulin levels included BMI index (r= 0.227,P=0.001)、AHI/ODI(r= 0.19, P<0.01)、average oxygen saturation (r=-0.170, P<0.05). In partial correlation adjusted for age, sex, and BMI index, TST was still the most significantly correlated with HOMA index (r=0.302, P<0.001), and the other factor significantly correlated HOMA index was AHI(r= 0.142, P<0.05); moreover, TST was still the most significantly correlated with fasting insulin levels (r= 0.328, P<0.001), and the other two factors significantly correlated fasting insulin levels were average oxygen saturation (r=-0.150, P<0.05) and ODI (r=0.136, P<0.05).In multiple logistic regression analysis, TST, average oxygen saturation, and BMI were significantly correlated with HOMA-IR (P<0.001).Conclusions:Fasting insulin levels and HOMA-IR index were significantly higher in severe OSA group than no OSA groups. In Pearson correlation, TST was the most significantly correlated with both HOMA index and fasting insulin levels, even after adjustment for age, sex, and BMI. In multiple logistic regression analysis, insulin resistance was independently correlated with the variables of hypoxemia and obesity. Insulin resistance increased with the severity of hypoxemia. OSA is independently related with insulin resistance. Background:Obstructive sleep apnea (OSA) is prevalent in adult and is an independent risk factor for the development of coronary artery disease (CAD). Lots of data suggest that metabolic syndrome is also an independent risk factor for CAD. More and more clinical studies reveal that OSA is tightly related with metabolic syndrome. However, due to many confounding factors, the mechanism between OSA and metabolic syndrome is very complicated. Continuous positive airway pressure (CPAP) is an effective therapy for OSA. However, for patients who already have OSA and CAD with optimal medications, whether CPAP can improve metabolic disorders and quality of life is not clear. This is a prospective randomized controlled study to evaluate the effects of CPAP on metabolic disorders in Chinese cohorts with CAD under optimal medications.Methods:Patients with CAD and moderate to severe OSA were enrolled from the Sleep Center of Fuwai Hospital from May 2009 to September 2010. These CAD patients were optimal treated for CAD and hypertension. The patients who have heart failure, chronic pulmonary diseases, and central sleep apnea were excluded.56 patients were enrolled; however,6 patients were excluded in sham-CPAP phase. Thus 50 patients were randomized into two groups:CPAP group and control group. Patients in CPAP group accept CPAP treatment and standard care; control group only accept standard care. Before randomization, the clinical characteristics were collected and blood biochemical profiles were measured, as well as assessment of Epworth sleepiness score (ESS) and quality of life. The patients of the two patients were followed up at 1 month,3 months and 6 months after randomization. Clinical characteristics, blood biochemical profiles and quality of life were re-assessed and compared with the data of baseline.Results:At baseline, all the data were matched between the two groups except HbAlc. After 6 months, compared with control group, CPAP treatment significantly reduced the levels of fasting insulin (P=0.026). At the same time, HOMA2 indexes in CPAP group were also significantly reduced by CPAP treatment (P=0.021). However, the other blood biochemical measurements remained unchanged between the CPAP group and control group. Compared with control group, CPAP treatment markedly reduced the morning diastolic BP (P=0.023) at 1 month,3 months, and 6 months follow-up. In contrast, there were no significant changes in systolic BP and heart rate. After 1 month CPAP treatment, ESS scores were significantly improved in CPAP group compared with control group (Δ-5.2±3.1 vsΔ-0.5±3.2, respectively, P<0.001).And this significant deference remained until the sixth month. The depression score was significantly increased in control group compared with CPAP group after 6 months (P=0.002). On the other hand, the anxiety score had no deference between the two groups. The quality of life also had no significant changes in CPAP group compared with control group.Conclusions:In the current study, CPAP treatment for 6 month was associated with significant improvement in insulin resistance, reduction in diastolic BP and improvement in ESS score of patients with both moderate-to-severe OS A and CAD on optimal medication. This study suggested that OSA might cause a series of metabolic disorders, especially insulin resistance, which could further promote the development of CAD. This provides a new target for the second prevention of CAD. So CPAP treatment for OSA has great benefits for CAD patients.更多还原