高血压合并阻塞性睡眠呼吸暂停患者睡眠结构改变的临床特点及发病机制的相关研究
发布时间：2018-09-03 11:10
【摘要】：目的:阻塞性睡眠呼吸暂停(OSA)和高血压(HTN)被认为都会增加心血管事件及全因死亡的风险。在中年男性患者中,临床上二者的重叠非常常见并且会进一步增加心血管病时间的风险。随着近年研究的不断深入,OSA合并HTN患者靶器官损害的范围不断扩大,新的可能的作用机制不断被提出。本文以病例-对照研究方式探讨:OSA合并高血压患者睡眠结构变化的特点及这种改变对血糖水平和血压变异性的影响和OSA与血清肺表面活性物质相关蛋白的关系。方法:本研究为病例-对照研究,按照纳入和排除标准对所有研究对象完成人体测量学、问卷调查及整夜多导联睡眠监测,收集相关的临床资料,完成采集血清标本,评估病例与对照组间各观察指标的差异。第一部分:1.睡眠时相采用Rechtshaffen and Kales’标准分期(包括NREM期即N1-N4期,REM期),低氧指标采集记录AHI,LSaO2,MSaO2,ODI3,ODI4,采用标准方法测定空腹血糖和糖化血红蛋白。AHI=15次/小时分组后,观察睡眠时相的差异,分析不同低氧指标对睡眠时相的影响;2.采用酶联免疫吸附方法测定血清炎症因子水平,评估各炎症因子水平与睡眠时相和其他睡眠参数的关系。第二部分:1.采用标准方法测定空腹血糖和糖化血红蛋白,观察睡眠时相与二者的联系;2.研究对象血压水平、血压变异性的评估采用动态血压监测自动记录值,睡眠后觉醒次数(WASO)采用标准判定方法。观察OSA和非OSA组间血压水平和血压变异性的差异,分析不同低氧指标对各血压变异性的影响;评估睡眠片段化(采用WASO评估)与血压变异性指标的联系。第三部分:1.采用酶联免疫吸附方法测定肺泡表面活性物质相关蛋白(SPs,包括SP-A,SP-B,SP-C,SP-D)和Krebs von den Lungen-6(KL-6)。HI平均值分组后,观察两组间SP-A和SP-D的差异,分析不同人群中低氧指标与SP-A和SP-D的联系;AHI=15次/分分组后,分析低氧指标与SP-B和SP-C的联系,评价SP-B作为OSA诊断指标的临床价值。2.采用多频脉冲震荡肺功能测定技术采集患者肺功能和气道阻力指标,分析肺泡表面活性物质相关蛋白(SPs,包括SP-A,SP-B,SP-C,SP-D)与气道阻力指标间的联系。结果:140名中年男性高血压患者入选。OSA(AHI≥15次/小时)的检出率为45.8%平均年龄为44.6±7.65岁,平均BMI为27.77±3.05kg/m2。第一部分:1.相对于非osa患者,osa患者睡眠1期(n1)的时间百分比增加;氧减指数(odi)与rem期时间百分比呈负相关;氧减指数(odi)与rem期时间百分比呈负向线性关系,在校正年龄和bmi后,二者的联系仍然存在。2.与血清lbp水平较低组相比,血清lbp水平较高组的il-1β、il-6、tnf-α的水平也是升高的;n1时间百分比出现有统计学差异的延长(4.98±2.90vs7.623.55%,p=0.002),odi3和odi4明显增加(17.43±8.34vs13.25±7.48次/小时±,p=0.05;8.04±4.34vs5.60±4.09次/小时),并且在校正bmi、年龄后lbp与二者之间仍存在正向线性关系。第二部分:1.在总体人群中,空腹血糖(fbg)与n1期时间百分比呈正相关,而与n4期时间百分比呈负相关(rn1=0.221,p=0.009;rn4=0.205,p=0.015),在校正年龄、bmi、ahi后这种联系仍然存在。在ahi5次/小时患者中,rem期时间百分比与空腹血糖呈较强正相关关系(r=0.522,p=0.003);而在重度osa(ahi30次/小时)患者中rem期时间百分比却与空腹血糖成反比(r=0.372,p=0.044),同时n1期与fbg呈正相关(r=0.524,p=0.001),n1期与糖化血红蛋白(hba1c)的相关系数为r=0.372,但p值未达到统计学差异(p=0.052)。2.相对于非osa的患者,osa不仅夜间的舒张压变异性更高,而且白天的舒张压变异性也发生改变(9.57±2.11vs10.55±2.85mmhg,p=0.041);osa患者夜间觉醒次数的增加不仅升高夜间的血压变异性,而且白天收缩压变异性也会增加。第三部分:1.在非吸烟组中,hi和sp-a和sp-d存在较强的相关性(rsp-a=0.343,p=0.012,rsp-d=0.504,p0.001)。在校正年龄和bmi后,多元线性回归分析的结果表明hi和sp-a和sp-d仍然存在联系。与非osa患者相比,血清sp-b的浓度在osa组中是下降的(44.73±7.62vs41.39±6.01ng/ml,p=0.005),并与osa的严重程度成反比(rahi=0.221,p=0.009),而sp-c和kl-6与osa的关系没有观察到。血清sp-b水平对osa的诊断具有一定的诊断价值(敏感性:75.34%,95%ci:0.636-0.844,特异性:59.70%,95%ci:0.470-0.713);联合sp-b和嗜睡量表(ess)可以很好的改善对osa诊断的敏感性(84.48%,95%ci:0.721-0.922)和特异性(94.44%,95%ci:0.836-0.985)。2.在非吸烟患者中,与非osa相比,osa组中表现为血清sp-a/b/d水平降低和肺周围气道阻力的升高;在非吸烟组患者中,血清sp-d水平与周围气道阻力(r5-20)呈反比,进一步的分析发现在肥胖的非吸烟患者中sp-d水平和多个气道阻力指标间存在较强的联系。结论:第一部分:osa合并htn的患者睡眠结构发生了改变,表现为睡眠1期(n1)的延长和rem期的缩短;htn和osa+htn之间睡眠的片段化程度可能并没有明显的差异。血清lbp水平的升高会导致睡眠n1期的延长和睡眠片段化的加重,这种结果可能与夜间呼吸事件和觉醒次数的增加有关。第二部分:睡眠1期的延长可能升高空腹血糖的水平,osa的严重程度可能会改变睡眠时相与空腹血糖之间的关系。osa合htn患者血压变异性的升高,不仅在夜间而且在白天也可以观察到。夜间觉醒次数的增加会加剧HTN患者夜间血压变异性的升高;在合并OSA患者中,这种影响可能会延长。第三部分:OSA可能会抑制SPs的合成,表现为血清SPs水平的下降;吸烟会干扰OSA与血清SPs之间的联系;血清SP-B可能成为潜在的OSA的生物学标记物,联合ESS和血清SP-B的检测结果可以为临床诊断OSA提供帮助。OSA患者周围气道阻力(R5-R20)的升高可能与SPs的合成减少,特别是Sp-D的减少有关;Sp-D的减少可能是肥胖患者中气道阻力增加的潜在机制。
[Abstract]:OBJECTIVE: Obstructive sleep apnea (OSA) and hypertension (HTN) are thought to increase the risk of cardiovascular events and all-cause mortality. Clinical overlap between OSA and HTN is common in middle-aged men and further increases the risk of cardiovascular disease duration. In this study, the characteristics of sleep structure changes in patients with OSA complicated with hypertension and their effects on blood glucose levels and blood pressure variability and the relationship between OSA and serum pulmonary surfactant-associated protein were investigated by case-control study. In the control study, anthropometry, questionnaires and night-long polysomnography were performed on all subjects according to inclusion and exclusion criteria, and relevant clinical data were collected. Serum samples were collected to assess the differences between the two groups. Part 1: Rechtshaffen and Kales'standard scores were used during sleep. AHI, LSaO2, MSaO2, ODI3, ODI4 were collected and recorded. Fasting blood glucose and glycosylated hemoglobin were measured by standard method. AHI = 15 times / hour grouping. Sleep phase differences were observed and the effects of different hypoxic indexes on sleep phase were analyzed. 2. Serum inflammation was measured by enzyme-linked immunosorbent assay (ELISA). Factor levels were assessed to assess the relationship between inflammatory factors and sleep phases and other sleep parameters. Part II: 1. Fasting blood glucose and glycosylated hemoglobin were measured by standard methods to observe the relationship between sleep phases and the two; 2. Blood pressure level of subjects, blood pressure variability was assessed by ambulatory blood pressure monitoring automatic recording value, sleep after sleep. Wake-up times (WASO) were measured by standard method. The differences of blood pressure levels and blood pressure variability between OSA and non-OSA groups were observed, and the effects of different hypoxic indexes on blood pressure variability were analyzed. The relationship between sleep fragmentation (WASO) and blood pressure variability was evaluated. Part 3: 1. Alveolar surface activity was measured by enzyme-linked immunosorbent assay (ELISA). Sexual substance-related proteins (SPs, including SP-A, SP-B, SP-C, SP-D) and Krebs von den Lungen-6 (KL-6). After HI average grouping, the differences of SP-A and SP-D between the two groups were observed, and the relationship between hypoxia index and SP-A and SP-D in different populations was analyzed; after AHI = 15 times/sub-grouping, the relationship between hypoxia index and SP-B and SP-C was analyzed, and SP-B as a diagnostic index of OSA was evaluated. Clinical value. 2. Pulmonary function and airway resistance were measured by multi-frequency pulsed concussion pulmonary function test, and the relationship between SPs (including SP-A, SP-B, SP-C, SP-D) and airway resistance was analyzed. The average age was 44.6 (+ 7.65 years) and BMI was 27.77 (+ 3.05 kg/m2). Part 1: Compared with non-OSA patients, the percentage of sleep duration (n1) in OSA patients increased; OD was negatively correlated with the percentage of REM duration; OD was negatively correlated with the percentage of REM duration; and OD was negatively correlated with the percentage of REM duration, and the association was found after adjusting for age and bmi. The levels of IL-1 beta, IL-6 and TNF-a in the group with higher serum LBP levels were also higher than those in the group with lower serum LBP levels; the percentage of N1 time was prolonged statistically (4.98 [2.90] vs 7.623.55%, P = 0.002); ODI 3 and ODI 4 were significantly increased (17.43 [8.34] vs 13.25 [7.48 times an hour], P = 0.05; 8.04 [4.34] vs 5.60 [4.09 times a hour], P = 0.05; 8.04 [4.34] vs 5.60 [4.09 The second part: 1. In general population, fasting blood glucose (fbg) was positively correlated with the percentage of N1 phase, but negatively correlated with the percentage of N4 phase (rn1 = 0.221, P = 0.009; RN4 = 0.205, P = 0.015). The association still existed after adjusted age, bmi, ahi. The percentage of REM duration was positively correlated with fasting blood glucose (r = 0.522, P = 0.003) in patients with AHI 5 times/hour, but inversely correlated with fasting blood glucose (r = 0.372, P = 0.044) in patients with severe OSA (ahi 30 times/hour), and positively correlated with FBG (r = 0.524, P = 0.001) in patients with N1 and glycosylated hemoglobin (hba1c). The coefficient was r = 0.372, but p value did not reach statistical difference (p = 0.052). 2. compared with non-OSA patients, OSA not only had higher night blood pressure variability, but also had a change in daytime diastolic blood pressure variability (9.57 + 2.11 vs 10.55 + 2.85 mmhg, P = 0.041); the increase of nocturnal awakening times in OSA patients not only increased night blood pressure variability, but also increased daytime blood pressure variability. Systolic blood pressure variability will also increase. Part 3: 1. In non-smoking group, there is a strong correlation between hi and SP-A and SP-D (rsp-a = 0.343, P = 0.012, rsp-d = 0.504, p0.001). After adjusting for age and bmi, the results of multiple linear regression analysis show that hi and SP-A and SP-D are still associated. Compared with non-OSA patients, the concentration of serum SP-B is still in OSA group. Serum levels of SP-C and KL-6 were not observed in OSA patients (sensitivity: 75.34%, 95% ci: 0.636-0.844, specificity: 59.70%, 95% ci: 0.470-0.713). Sleep Scale (ess) can improve the sensitivity (84.48%, 95% ci: 0.721-0.922) and specificity (94.44%, 95% ci: 0.836-0.985). 2. In non-smoking patients, compared with non-osa, the level of serum sp-a/b/d decreased and the increase of peripheral airway resistance; in non-smoking patients, the level of serum SP-D and peripheral airway resistance increased. Resistance (r5-20) was inversely correlated. further analysis revealed a strong association between SP-D levels and multiple airway resistance indices in obese non-smokers. conclusion: part one: the sleep structure of patients with OSA and HTN changed, including prolongation of sleep phase 1 (n1) and shortening of REM period; fragmentation of sleep between HTN and OSA + htn. Increased serum LBP levels may lead to prolonged sleep N1 and aggravated sleep fragmentation, which may be related to increased nocturnal respiratory events and wakefulness. Part 2: prolonged sleep stage 1 may increase fasting blood glucose levels, and the severity of OSA may change sleep phases and wakefulness Increased blood pressure variability in patients with OSA and HTN was observed not only at night but also during the day. Increased frequency of nocturnal arousal exacerbated the increase in nocturnal blood pressure variability in patients with HTN; this effect may be prolonged in patients with OSA. Part III: OSA may inhibit the synthesis of SPs, as shown in blood. Serum SP-B may be a potential biomarker of OSA, and combined with ESS and serum SP-B test results may be helpful for clinical diagnosis of OSA. The decrease of Sp-D may be a potential mechanism of increased airway resistance in obese patients.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R544.1;R766
本文编号：2219811
[Abstract]:OBJECTIVE: Obstructive sleep apnea (OSA) and hypertension (HTN) are thought to increase the risk of cardiovascular events and all-cause mortality. Clinical overlap between OSA and HTN is common in middle-aged men and further increases the risk of cardiovascular disease duration. In this study, the characteristics of sleep structure changes in patients with OSA complicated with hypertension and their effects on blood glucose levels and blood pressure variability and the relationship between OSA and serum pulmonary surfactant-associated protein were investigated by case-control study. In the control study, anthropometry, questionnaires and night-long polysomnography were performed on all subjects according to inclusion and exclusion criteria, and relevant clinical data were collected. Serum samples were collected to assess the differences between the two groups. Part 1: Rechtshaffen and Kales'standard scores were used during sleep. AHI, LSaO2, MSaO2, ODI3, ODI4 were collected and recorded. Fasting blood glucose and glycosylated hemoglobin were measured by standard method. AHI = 15 times / hour grouping. Sleep phase differences were observed and the effects of different hypoxic indexes on sleep phase were analyzed. 2. Serum inflammation was measured by enzyme-linked immunosorbent assay (ELISA). Factor levels were assessed to assess the relationship between inflammatory factors and sleep phases and other sleep parameters. Part II: 1. Fasting blood glucose and glycosylated hemoglobin were measured by standard methods to observe the relationship between sleep phases and the two; 2. Blood pressure level of subjects, blood pressure variability was assessed by ambulatory blood pressure monitoring automatic recording value, sleep after sleep. Wake-up times (WASO) were measured by standard method. The differences of blood pressure levels and blood pressure variability between OSA and non-OSA groups were observed, and the effects of different hypoxic indexes on blood pressure variability were analyzed. The relationship between sleep fragmentation (WASO) and blood pressure variability was evaluated. Part 3: 1. Alveolar surface activity was measured by enzyme-linked immunosorbent assay (ELISA). Sexual substance-related proteins (SPs, including SP-A, SP-B, SP-C, SP-D) and Krebs von den Lungen-6 (KL-6). After HI average grouping, the differences of SP-A and SP-D between the two groups were observed, and the relationship between hypoxia index and SP-A and SP-D in different populations was analyzed; after AHI = 15 times/sub-grouping, the relationship between hypoxia index and SP-B and SP-C was analyzed, and SP-B as a diagnostic index of OSA was evaluated. Clinical value. 2. Pulmonary function and airway resistance were measured by multi-frequency pulsed concussion pulmonary function test, and the relationship between SPs (including SP-A, SP-B, SP-C, SP-D) and airway resistance was analyzed. The average age was 44.6 (+ 7.65 years) and BMI was 27.77 (+ 3.05 kg/m2). Part 1: Compared with non-OSA patients, the percentage of sleep duration (n1) in OSA patients increased; OD was negatively correlated with the percentage of REM duration; OD was negatively correlated with the percentage of REM duration; and OD was negatively correlated with the percentage of REM duration, and the association was found after adjusting for age and bmi. The levels of IL-1 beta, IL-6 and TNF-a in the group with higher serum LBP levels were also higher than those in the group with lower serum LBP levels; the percentage of N1 time was prolonged statistically (4.98 [2.90] vs 7.623.55%, P = 0.002); ODI 3 and ODI 4 were significantly increased (17.43 [8.34] vs 13.25 [7.48 times an hour], P = 0.05; 8.04 [4.34] vs 5.60 [4.09 times a hour], P = 0.05; 8.04 [4.34] vs 5.60 [4.09 The second part: 1. In general population, fasting blood glucose (fbg) was positively correlated with the percentage of N1 phase, but negatively correlated with the percentage of N4 phase (rn1 = 0.221, P = 0.009; RN4 = 0.205, P = 0.015). The association still existed after adjusted age, bmi, ahi. The percentage of REM duration was positively correlated with fasting blood glucose (r = 0.522, P = 0.003) in patients with AHI 5 times/hour, but inversely correlated with fasting blood glucose (r = 0.372, P = 0.044) in patients with severe OSA (ahi 30 times/hour), and positively correlated with FBG (r = 0.524, P = 0.001) in patients with N1 and glycosylated hemoglobin (hba1c). The coefficient was r = 0.372, but p value did not reach statistical difference (p = 0.052). 2. compared with non-OSA patients, OSA not only had higher night blood pressure variability, but also had a change in daytime diastolic blood pressure variability (9.57 + 2.11 vs 10.55 + 2.85 mmhg, P = 0.041); the increase of nocturnal awakening times in OSA patients not only increased night blood pressure variability, but also increased daytime blood pressure variability. Systolic blood pressure variability will also increase. Part 3: 1. In non-smoking group, there is a strong correlation between hi and SP-A and SP-D (rsp-a = 0.343, P = 0.012, rsp-d = 0.504, p0.001). After adjusting for age and bmi, the results of multiple linear regression analysis show that hi and SP-A and SP-D are still associated. Compared with non-OSA patients, the concentration of serum SP-B is still in OSA group. Serum levels of SP-C and KL-6 were not observed in OSA patients (sensitivity: 75.34%, 95% ci: 0.636-0.844, specificity: 59.70%, 95% ci: 0.470-0.713). Sleep Scale (ess) can improve the sensitivity (84.48%, 95% ci: 0.721-0.922) and specificity (94.44%, 95% ci: 0.836-0.985). 2. In non-smoking patients, compared with non-osa, the level of serum sp-a/b/d decreased and the increase of peripheral airway resistance; in non-smoking patients, the level of serum SP-D and peripheral airway resistance increased. Resistance (r5-20) was inversely correlated. further analysis revealed a strong association between SP-D levels and multiple airway resistance indices in obese non-smokers. conclusion: part one: the sleep structure of patients with OSA and HTN changed, including prolongation of sleep phase 1 (n1) and shortening of REM period; fragmentation of sleep between HTN and OSA + htn. Increased serum LBP levels may lead to prolonged sleep N1 and aggravated sleep fragmentation, which may be related to increased nocturnal respiratory events and wakefulness. Part 2: prolonged sleep stage 1 may increase fasting blood glucose levels, and the severity of OSA may change sleep phases and wakefulness Increased blood pressure variability in patients with OSA and HTN was observed not only at night but also during the day. Increased frequency of nocturnal arousal exacerbated the increase in nocturnal blood pressure variability in patients with HTN; this effect may be prolonged in patients with OSA. Part III: OSA may inhibit the synthesis of SPs, as shown in blood. Serum SP-B may be a potential biomarker of OSA, and combined with ESS and serum SP-B test results may be helpful for clinical diagnosis of OSA. The decrease of Sp-D may be a potential mechanism of increased airway resistance in obese patients.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R544.1;R766
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