【摘要】：目的:阻塞性睡眠呼吸暫停(OSA)和高血壓(HTN)被認(rèn)為都會(huì)增加心血管事件及全因死亡的風(fēng)險(xiǎn)。在中年男性患者中,臨床上二者的重疊非常常見并且會(huì)進(jìn)一步增加心血管病時(shí)間的風(fēng)險(xiǎn)。隨著近年研究的不斷深入,OSA合并HTN患者靶器官損害的范圍不斷擴(kuò)大,新的可能的作用機(jī)制不斷被提出。本文以病例-對(duì)照研究方式探討:OSA合并高血壓患者睡眠結(jié)構(gòu)變化的特點(diǎn)及這種改變對(duì)血糖水平和血壓變異性的影響和OSA與血清肺表面活性物質(zhì)相關(guān)蛋白的關(guān)系。方法:本研究為病例-對(duì)照研究,按照納入和排除標(biāo)準(zhǔn)對(duì)所有研究對(duì)象完成人體測量學(xué)、問卷調(diào)查及整夜多導(dǎo)聯(lián)睡眠監(jiān)測,收集相關(guān)的臨床資料,完成采集血清標(biāo)本,評(píng)估病例與對(duì)照組間各觀察指標(biāo)的差異。第一部分:1.睡眠時(shí)相采用Rechtshaffen and Kales’標(biāo)準(zhǔn)分期(包括NREM期即N1-N4期,REM期),低氧指標(biāo)采集記錄AHI,LSaO2,MSaO2,ODI3,ODI4,采用標(biāo)準(zhǔn)方法測定空腹血糖和糖化血紅蛋白。AHI=15次/小時(shí)分組后,觀察睡眠時(shí)相的差異,分析不同低氧指標(biāo)對(duì)睡眠時(shí)相的影響;2.采用酶聯(lián)免疫吸附方法測定血清炎癥因子水平,評(píng)估各炎癥因子水平與睡眠時(shí)相和其他睡眠參數(shù)的關(guān)系。第二部分:1.采用標(biāo)準(zhǔn)方法測定空腹血糖和糖化血紅蛋白,觀察睡眠時(shí)相與二者的聯(lián)系;2.研究對(duì)象血壓水平、血壓變異性的評(píng)估采用動(dòng)態(tài)血壓監(jiān)測自動(dòng)記錄值,睡眠后覺醒次數(shù)(WASO)采用標(biāo)準(zhǔn)判定方法。觀察OSA和非OSA組間血壓水平和血壓變異性的差異,分析不同低氧指標(biāo)對(duì)各血壓變異性的影響;評(píng)估睡眠片段化(采用WASO評(píng)估)與血壓變異性指標(biāo)的聯(lián)系。第三部分:1.采用酶聯(lián)免疫吸附方法測定肺泡表面活性物質(zhì)相關(guān)蛋白(SPs,包括SP-A,SP-B,SP-C,SP-D)和Krebs von den Lungen-6(KL-6)。HI平均值分組后,觀察兩組間SP-A和SP-D的差異,分析不同人群中低氧指標(biāo)與SP-A和SP-D的聯(lián)系;AHI=15次/分分組后,分析低氧指標(biāo)與SP-B和SP-C的聯(lián)系,評(píng)價(jià)SP-B作為OSA診斷指標(biāo)的臨床價(jià)值。2.采用多頻脈沖震蕩肺功能測定技術(shù)采集患者肺功能和氣道阻力指標(biāo),分析肺泡表面活性物質(zhì)相關(guān)蛋白(SPs,包括SP-A,SP-B,SP-C,SP-D)與氣道阻力指標(biāo)間的聯(lián)系。結(jié)果:140名中年男性高血壓患者入選。OSA(AHI≥15次/小時(shí))的檢出率為45.8%平均年齡為44.6±7.65歲,平均BMI為27.77±3.05kg/m2。第一部分:1.相對(duì)于非osa患者,osa患者睡眠1期(n1)的時(shí)間百分比增加;氧減指數(shù)(odi)與rem期時(shí)間百分比呈負(fù)相關(guān);氧減指數(shù)(odi)與rem期時(shí)間百分比呈負(fù)向線性關(guān)系,在校正年齡和bmi后,二者的聯(lián)系仍然存在。2.與血清lbp水平較低組相比,血清lbp水平較高組的il-1β、il-6、tnf-α的水平也是升高的;n1時(shí)間百分比出現(xiàn)有統(tǒng)計(jì)學(xué)差異的延長(4.98±2.90vs7.623.55%,p=0.002),odi3和odi4明顯增加(17.43±8.34vs13.25±7.48次/小時(shí)±,p=0.05;8.04±4.34vs5.60±4.09次/小時(shí)),并且在校正bmi、年齡后lbp與二者之間仍存在正向線性關(guān)系。第二部分:1.在總體人群中,空腹血糖(fbg)與n1期時(shí)間百分比呈正相關(guān),而與n4期時(shí)間百分比呈負(fù)相關(guān)(rn1=0.221,p=0.009;rn4=0.205,p=0.015),在校正年齡、bmi、ahi后這種聯(lián)系仍然存在。在ahi5次/小時(shí)患者中,rem期時(shí)間百分比與空腹血糖呈較強(qiáng)正相關(guān)關(guān)系(r=0.522,p=0.003);而在重度osa(ahi30次/小時(shí))患者中rem期時(shí)間百分比卻與空腹血糖成反比(r=0.372,p=0.044),同時(shí)n1期與fbg呈正相關(guān)(r=0.524,p=0.001),n1期與糖化血紅蛋白(hba1c)的相關(guān)系數(shù)為r=0.372,但p值未達(dá)到統(tǒng)計(jì)學(xué)差異(p=0.052)。2.相對(duì)于非osa的患者,osa不僅夜間的舒張壓變異性更高,而且白天的舒張壓變異性也發(fā)生改變(9.57±2.11vs10.55±2.85mmhg,p=0.041);osa患者夜間覺醒次數(shù)的增加不僅升高夜間的血壓變異性,而且白天收縮壓變異性也會(huì)增加。第三部分:1.在非吸煙組中,hi和sp-a和sp-d存在較強(qiáng)的相關(guān)性(rsp-a=0.343,p=0.012,rsp-d=0.504,p0.001)。在校正年齡和bmi后,多元線性回歸分析的結(jié)果表明hi和sp-a和sp-d仍然存在聯(lián)系。與非osa患者相比,血清sp-b的濃度在osa組中是下降的(44.73±7.62vs41.39±6.01ng/ml,p=0.005),并與osa的嚴(yán)重程度成反比(rahi=0.221,p=0.009),而sp-c和kl-6與osa的關(guān)系沒有觀察到。血清sp-b水平對(duì)osa的診斷具有一定的診斷價(jià)值(敏感性:75.34%,95%ci:0.636-0.844,特異性:59.70%,95%ci:0.470-0.713);聯(lián)合sp-b和嗜睡量表(ess)可以很好的改善對(duì)osa診斷的敏感性(84.48%,95%ci:0.721-0.922)和特異性(94.44%,95%ci:0.836-0.985)。2.在非吸煙患者中,與非osa相比,osa組中表現(xiàn)為血清sp-a/b/d水平降低和肺周圍氣道阻力的升高;在非吸煙組患者中,血清sp-d水平與周圍氣道阻力(r5-20)呈反比,進(jìn)一步的分析發(fā)現(xiàn)在肥胖的非吸煙患者中sp-d水平和多個(gè)氣道阻力指標(biāo)間存在較強(qiáng)的聯(lián)系。結(jié)論:第一部分:osa合并htn的患者睡眠結(jié)構(gòu)發(fā)生了改變,表現(xiàn)為睡眠1期(n1)的延長和rem期的縮短;htn和osa+htn之間睡眠的片段化程度可能并沒有明顯的差異。血清lbp水平的升高會(huì)導(dǎo)致睡眠n1期的延長和睡眠片段化的加重,這種結(jié)果可能與夜間呼吸事件和覺醒次數(shù)的增加有關(guān)。第二部分:睡眠1期的延長可能升高空腹血糖的水平,osa的嚴(yán)重程度可能會(huì)改變睡眠時(shí)相與空腹血糖之間的關(guān)系。osa合htn患者血壓變異性的升高,不僅在夜間而且在白天也可以觀察到。夜間覺醒次數(shù)的增加會(huì)加劇HTN患者夜間血壓變異性的升高;在合并OSA患者中,這種影響可能會(huì)延長。第三部分:OSA可能會(huì)抑制SPs的合成,表現(xiàn)為血清SPs水平的下降;吸煙會(huì)干擾OSA與血清SPs之間的聯(lián)系;血清SP-B可能成為潛在的OSA的生物學(xué)標(biāo)記物,聯(lián)合ESS和血清SP-B的檢測結(jié)果可以為臨床診斷OSA提供幫助。OSA患者周圍氣道阻力(R5-R20)的升高可能與SPs的合成減少,特別是Sp-D的減少有關(guān);Sp-D的減少可能是肥胖患者中氣道阻力增加的潛在機(jī)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.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R544.1;R766

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