【摘要】：背景:高原低氧環(huán)境對人體的損傷已被廣泛認(rèn)知,運(yùn)動(dòng)應(yīng)激所致?lián)p傷的研究也有很多。但急進(jìn)低氧環(huán)境下運(yùn)動(dòng)應(yīng)激對人體的影響,特別是對心臟功能和結(jié)構(gòu)造成影響的相關(guān)研究較少,低氧運(yùn)動(dòng)狀態(tài)下的人體心臟功能改變與損傷具體機(jī)制目前尚不清楚。階梯進(jìn)駐高原和吸氧是目前預(yù)防與治療急性高原反應(yīng)時(shí)廣泛采用的手段,卻不方便于大批人員急進(jìn)高原時(shí)應(yīng)用。尋找便捷有效的適用于急進(jìn)高原軍事應(yīng)激的高原疾病防治藥物十分必要。第一部分健康男性青年低壓氧艙模擬急進(jìn)高原低氧運(yùn)動(dòng)對心血管系統(tǒng)影響目的:觀察急性低氧環(huán)境下運(yùn)動(dòng)對心臟功能影響及運(yùn)動(dòng)能力變化的特點(diǎn)和規(guī)律。方法:招募18-35歲健康男性青年志愿者,先于平原采集基線臨床試驗(yàn)資料,其后進(jìn)入低壓氧艙采集臨床試驗(yàn)資料(n=67)。低壓氧艙在0.5h內(nèi)由大氣壓101kPa降壓至61.6kPa (相當(dāng)于4km高度)后,志愿者在艙內(nèi)進(jìn)行平板運(yùn)動(dòng)試驗(yàn)(TET)。觀察比較志愿者在低壓氧艙與平原常氧時(shí)TET運(yùn)動(dòng)能力的變化,運(yùn)動(dòng)前、后的血氧飽和度(Sp02)變化,運(yùn)動(dòng)不同時(shí)相的心率(HR)、血壓(SBP/DBP)及心率血壓乘積(RPP)的變化,入艙前后血?dú)飧黜?xiàng)指標(biāo)結(jié)果的變化。結(jié)果1.志愿者平原常氧TET皆為陰性,進(jìn)入低壓氧艙后12名志愿者TET陽性(n=67),表現(xiàn)為ST段壓低,持續(xù)時(shí)間大于2min,主要集中在Ⅱ、Ⅲ、aVF導(dǎo)聯(lián),其中1人在運(yùn)動(dòng)2階段時(shí)出現(xiàn)偶發(fā)室早。2.志愿者低壓氧艙內(nèi)TET運(yùn)動(dòng)MET值較平原常氧時(shí)顯著下降(n=67,P0.01)。3.志愿者低壓氧艙與平原常氧比較,Sp02運(yùn)動(dòng)前(98.36±1.42vs. 83.70±4.53)與運(yùn)動(dòng)后(95.12±8.16vs. 75.81±4.80)均顯著下降(n=67,P0.01)。低氧與運(yùn)動(dòng)對Sp02下降的影響具有交互作用(n=67,P0.01)。4.志愿者在進(jìn)行TET時(shí),低壓氧艙和平原常氧組內(nèi)比較,HR、SBP及RPP運(yùn)動(dòng)時(shí)逐漸上升,休息后逐漸下降;DBP在運(yùn)動(dòng)后逐漸下降,休息后逐漸上升(n=67,P0.01)。進(jìn)艙前后組間TET同時(shí)相比SBP/DBP均有顯著差異(n=67, P0.01),HR及RPP僅在運(yùn)動(dòng)時(shí)相差異顯著(n=67, P0.05)。低氧與運(yùn)動(dòng)對于HR和RPP的影響有顯著交互作用(n=67,P0.05),對SBP和DBP的交互作用不顯著(n=67,P0.05)。5.志愿者在低壓氧艙TET后,動(dòng)脈血?dú)飧黜?xiàng)結(jié)果與平原基線比較,PH顯著升高,其余項(xiàng)目除剩余堿外均顯著降低(n=67,P0.05)。第二部分曲美他嗪對健康青年男性地轉(zhuǎn)急進(jìn)高原軍事應(yīng)激的防護(hù)作用研究目的:前瞻性隊(duì)列研究觀察曲美他嗪對急進(jìn)高原低氧軍事應(yīng)激的保護(hù)作用。方法:按低壓氧艙入組標(biāo)準(zhǔn)招募急進(jìn)高原實(shí)地志愿者,隨機(jī)分為安慰劑對照組(n=38)和鹽酸曲美他嗪組(n=40),急進(jìn)高原前7天開始服藥(20mg, 3/日)。由北京乘火車經(jīng)西寧中轉(zhuǎn),次日到達(dá)格爾木市區(qū)(海拔2.8km),第3日清晨乘汽車急進(jìn)試驗(yàn)地(海拔4km～4.5km)。按照第一部分低壓氧艙試驗(yàn)流程進(jìn)行試驗(yàn),格爾木市區(qū)出發(fā)前及TET前后各填寫一份高原癥狀評分量表。結(jié)果1.對照組(n=38) TET陽性9人,曲美他嗪組(n=40)陽性5人,主要表現(xiàn)為Ⅱ、Ⅲ、aVF導(dǎo)聯(lián)ST段壓低,持續(xù)時(shí)間大于2min,對照組出現(xiàn)1人偶發(fā)房早,1人偶發(fā)室早。2.曲美他嗪組(n=40) TET運(yùn)動(dòng)MET值顯著高于對照組(n=38,P0.05)3.血氧飽和度:兩組志愿者組內(nèi)比較,TET運(yùn)動(dòng)后Sp02均顯著低于運(yùn)動(dòng)前(P0.01):兩組間比較運(yùn)動(dòng)前Sp02無明顯差異,運(yùn)動(dòng)后曲美他嗪組Sp02略低于對照組,但差異不顯著。曲美他嗪與運(yùn)動(dòng)對Sp02影響的交互作用不顯著(P0.05)。4.兩組志愿者TET組內(nèi)HR、SBP和RPP均隨運(yùn)動(dòng)顯著增加,休息時(shí)顯著下降(P0.01); DBP均隨運(yùn)動(dòng)顯著下降,休息時(shí)顯著上升(P0.01)。組間比較曲美他嗪組HR較對照組有所下降但差異不顯著(P0.05),曲美他嗪與運(yùn)動(dòng)對兩組HR的交互作用不顯著(P0.05)。TET各相同時(shí)相SBP、DBP和RPP組間比較及曲美他嗪與運(yùn)動(dòng)對三者的交互作用均不顯著(P0.05)。5.曲美他嗪組(n=40)與對照組(n=38)動(dòng)脈血?dú)饨Y(jié)果無顯著差異(P0.05)。6.從2.8km急進(jìn)4km～4.5km高度其后進(jìn)行TET運(yùn)動(dòng),AMS發(fā)生率逐步增高,頭痛、氣喘和心悸等癥狀逐步加重,其中TET運(yùn)動(dòng)后較出發(fā)前差異顯著(n=38,P0.0125)。疲勞/虛弱、胃腸道反應(yīng)、腹脹、活動(dòng)能力減退和呼吸困難略有加重但差異不顯著(P0.05)。曲美他嗪對AMS及急性高原反應(yīng)癥狀具有一定的降低作用,但差異不夠顯著(P0.05)。第三部分大鼠低壓氧艙模擬急性低氧運(yùn)動(dòng)造成心肌應(yīng)激損傷與曲美他嗪防護(hù)研究目的:在細(xì)胞與分子水平探討急性低氧運(yùn)動(dòng)心肌損傷機(jī)制與曲美他嗪的防護(hù)作用。方法:使用動(dòng)物低壓氧艙模擬低氧(61.6kPa, 4km)、被動(dòng)轉(zhuǎn)輪(18m/min, 4h)強(qiáng)制大鼠跑步作為應(yīng)激源,建立急性低氧運(yùn)動(dòng)應(yīng)激動(dòng)物模型,曲美他嗪作為干預(yù)藥物。64只清潔級雄性SD大鼠,按照是否低氧處理,是否進(jìn)行跑步,是否服用曲美他嗪,分為8組:①對照組(NC);②藥物對照組(TC);③跑步組(NCR);④跑步藥物組(TCR);⑤低氧組(NH);⑥低氧藥物組(TH);⑦低氧跑步組(NHR);⑧低氧跑步藥物組(THR)。試驗(yàn)結(jié)束即刻抽血凍存,使用ELISA法檢測各組大鼠血清高敏C反應(yīng)蛋白(hs-CRP)、超氧化物歧化酶(SOD)、缺血修飾白蛋白(IMA)、心型脂肪酸結(jié)合蛋白(H-FABP),剪取大鼠心肌制備石蠟切片,HE染色觀察心肌細(xì)胞病理改變,TUNEL染色觀察心肌細(xì)胞凋亡情況。結(jié)果1.血清標(biāo)志物①hs-CRP:跑步組、低氧組均較對照組顯著升高(P0.05);跑步藥物組較跑步組顯著下降(P0.05);低氧跑步組較對照組、跑步組和低氧組都顯著升高(P0.01);低氧跑步藥物組較低氧跑步組顯著下降(P0.05)。②SOD:跑步組、低氧組均較對照組顯著降低(P0.05);跑步藥物組較跑步組顯著升高(P0.05);低氧藥物組較低氧組顯著升高(P0.05);低氧跑步組較對照組、跑步組和低氧組都顯著降低(P0.01);低氧跑步藥物組相比低氧跑步組顯著升高(P0.05)。③IMA:跑步組、低氧組均較對照組顯著升高(P0.05);跑步藥物組較跑步組顯著下降(P0.05);低氧藥物組較低氧組顯著下降(P0.05);低氧跑步組較對照組、跑步組和低氧組都顯著升高(P0.01);低氧跑步藥物組較低氧跑步組顯著下降(P 0.05)。④H-FABP:低氧組均較對照組顯著升高(P0.05);低氧藥物組較低氧組顯著下降(P0.05);低氧跑步組較對照組、跑步組和低氧組都顯著升高(P0.05);低氧跑步藥物組較低氧跑步組顯著下降(P0.05)2. HE染色:對照組、藥物對照組和跑步組心肌細(xì)胞形態(tài)均勻,細(xì)胞核結(jié)構(gòu)清晰,細(xì)胞橫紋和閏盤清晰,心肌纖維均勻整齊。跑步組心肌細(xì)胞形態(tài)尚可,部分細(xì)胞淡染。低氧組心肌纖維排列稍紊亂,中間散在少量結(jié)締組織,部分心肌細(xì)胞肌漿凝聚,出現(xiàn)空泡。低氧藥物組心肌纖維略有紊亂,形態(tài)較低氧組略好。低氧跑步組心肌纖維排列紊亂呈波浪狀,肌漿凝聚,形成紅染、粗細(xì)不一的橫帶,部分細(xì)胞核固縮甚至碎裂溶解。低氧跑步藥物組心肌纖維形態(tài)較低氧運(yùn)動(dòng)組略好,但不及低氧藥物組。8組中低氧跑步組心肌形態(tài)改變情況最重,曲美他嗪對心肌細(xì)胞的損傷性變化有減輕作用。3.TUNEL染色計(jì)算凋亡指數(shù)凋亡指數(shù)低氧組顯著高于對照組,顯著低于低氧藥物組(P0.05);低氧跑步組顯著高于其他各組(P0.01),低氧跑步藥物組較之顯著降低(P0.01);跑步藥物組略高于對照組,略低于運(yùn)動(dòng)組,但差異不顯著(P0.05)。結(jié)論1.低氧時(shí)機(jī)體運(yùn)動(dòng)耐量明顯降低,運(yùn)動(dòng)和低氧對于心率、血壓和RPP的影響具有交互作用,運(yùn)動(dòng)可加重低氧對心率、血壓、RPP的不利影響。急性低氧運(yùn)動(dòng)時(shí)AMS發(fā)生率顯著增加,造成心肌缺血樣變化,主要表現(xiàn)為心電圖Ⅱ、Ⅲ、aVF導(dǎo)聯(lián)ST段壓低。2.曲美他嗪對急進(jìn)高原低氧運(yùn)動(dòng)人員的心血管系統(tǒng)具有保護(hù)作用,可以顯著提高運(yùn)動(dòng)耐量,減輕心肌缺血性改變,不影響運(yùn)動(dòng)時(shí)的心率、血壓和RPP。3.急性低氧時(shí)運(yùn)動(dòng)加重了大鼠心肌的氧化應(yīng)激反應(yīng),造成心肌細(xì)胞損傷和凋亡。曲美他嗪可在一定程度上保護(hù)急性低氧運(yùn)動(dòng)造成的心肌應(yīng)激損傷。
[Abstract]:BACKGROUND: The injury of high altitude hypoxic environment to human body has been widely recognized, and there are many studies on the injury caused by exercise stress.But the effect of acute hypoxic environment on human body, especially on the function and structure of heart, is seldom studied. It is not clear at present. Stairway and oxygen inhalation are widely used in the prevention and treatment of acute altitude reaction, but it is not convenient for large numbers of people to use when they enter the plateau. Objective: To observe the effects of acute hypoxic exercise on cardiac function and the changes of exercise ability in acute hypoxic environment. Methods: Healthy male volunteers aged 18-35 were recruited to collect baseline clinical trial data before plain, and then entered hypoxic chamber to collect clinical trial data (n = 6). 7. Volunteers were subjected to a treadmill exercise test (TET) in a hypobaric oxygen chamber from 101 kPa to 61.6 kPa (equivalent to 4 km altitude) within 0.5 hours. The changes of TET exercise ability, blood oxygen saturation (Sp02), heart rate (HR) and blood pressure (SBP/D) in different phases of exercise were observed and compared between hypobaric oxygen chamber and plain normoxia. BP, heart rate and blood pressure product (RPP), blood gas changes before and after entering the cabin. Results 1. Volunteer plain normal oxygen TET were negative. After entering the hypobaric chamber, 12 volunteers were TET positive (n = 67), showing ST-segment depression, lasting longer than 2 minutes, mainly concentrated in lead II, III, aVF, one of them occurred occasionally during exercise 2 stages. The TET exercise MET value in the hypobaric oxygen chamber of the volunteers was significantly lower than that in the plain normal oxygen chamber (n=67, P 0.01). 3. Compared with the plain normal oxygen chamber, the TET exercise MET value in the hypobaric oxygen chamber of the volunteers decreased significantly (n=67, P 0.01) before and after exercise (98.36 In TET, HR, SBP and RPP increased gradually during exercise and decreased gradually after rest. DBP decreased gradually after exercise and increased gradually after rest (n = 67, P 0.01). TET before and after entering the cabin was significantly different from that of SBP / DBP (n = 67, P 0.01). HR and RPP were only in the exercise phase. Hypoxia and exercise had significant interaction on HR and RPP (n = 67, P 0.05), but no significant interaction on SBP and DBP (n = 67, P 0.05). 5. After TET in hypobaric chamber, the arterial blood gas of the volunteers was significantly higher than that of the plain baseline, and the PH of the other items was significantly lower (n = 67, P 0.05). Objective: To observe the protective effect of trimetazidine on acute altitude hypoxic military stress in healthy young men by prospective cohort study. Methods: Field volunteers were recruited according to the criteria of hypobaric chamber entry and randomly divided into placebo control group (n = 38) and salt control group (n = 38). Trimetazidine acid group (n=40) was administered 7 days before entering the plateau (20mg, 3/day). The train was transferred from Beijing to Xining, and the next day arrived at Golmud city (2.8km above sea level). On the morning of the 3rd day, the vehicle was rushed into the test site (4km-4.5km above sea level). According to the first part of the low-pressure oxygen chamber test process, the test was carried out in Golmud city before departure and before and after TET. Results 1. TET positive 9 persons in control group (n=38) and 5 persons in trimetazidine group (n=40), mainly manifested as ST segment depression in lead II, III, aVF, lasting longer than 2 minutes. One person in control group had incidental atrial premature, one person had incidental ventricular premature. 2. TET motor MET value in trimetazidine group (n=40) was significantly higher than that in control group (n=38, P 0.05) 3. Oxygen saturation: Sp02 after TET was significantly lower than that before exercise (P 0.01). Sp02 of trimetazidine group was slightly lower than that of control group, but the difference was not significant. The interaction between trimetazidine and exercise on Sp02 was not significant (P 0.05). Compared with the control group, the HR of trimetazidine group decreased, but the difference was not significant (P 0.05). The interaction between trimetazidine and exercise on HR of the two groups was not significant (P 0.05). There was no significant difference in arterial blood gas between the trimetazidine group (n=40) and the control group (n=38) (P 0.05). Fatigue/weakness, gastrointestinal reactions, abdominal distention, decreased activity and dyspnea were slightly aggravated, but the difference was not significant (P 0.05). Trimetazidine could reduce AMS and symptoms of acute altitude reaction, but the difference was not significant (P 0.05). The third part was hypobaric chamber simulated acute hypoxia in rats. Objective: To explore the mechanism of myocardial injury induced by exercise and the protective effect of trimetazidine at cellular and molecular levels. Methods: Rats were exposed to simulated hypoxia (61.6 kPa, 4 km) in an animal hypobaric chamber and forced to run on a passive wheel (18 m/min, 4 h) as a stress source to establish acute hypoxic transport. Sixty-four clean-grade male SD rats were divided into 8 groups according to hypoxic treatment, running and taking trimetazidine: control group (NC), drug control group (TC), running group (NCR), running drug group (TCR), running drug group (NH), hypoxic drug group (TH). Group NHR; _Hypoxic running drug group (THR). Blood samples were frozen at the end of the experiment. Serum high-sensitivity C-reactive protein (hs-CRP), superoxide dismutase (SOD), ischemic modified albumin (IMA), heart-type fatty acid binding protein (H-FABP) were detected by ELISA. Myocardial paraffin sections were prepared and observed by HE staining. Results 1. Serum markers (hs-CRP) were significantly higher in the running group and the hypoxic group than in the control group (P 0.05); the running drug group was significantly lower than the running group (P 0.05); the hypoxic running group was significantly higher than the control group, the running group and the hypoxic running group were significantly higher (P 0.01); SOD: Running group, hypoxic group were significantly lower than the control group (P 0.05); Running drug group was significantly higher than the running group (P 0.05); Hypoxic drug group was significantly higher than the hypoxic group (P 0.05); Hypoxic running group was significantly lower than the control group, running group and hypoxic running drug group were significantly higher than the hypoxic running group (P 0.01); Hypoxic running drug group was significantly higher than the hypoxic running group (P 0.05). (05). 3) IMA: Compared with the control group, the hypoxia group was significantly higher (P 0.05); the running drug group was significantly lower (P 0.05); the hypoxia drug group was significantly lower (P 0.05); the hypoxia drug group was significantly lower (P 0.05); the hypoxia running group was significantly higher than the control group, the running group and the hypoxia group were significantly higher (P 0.01); the hypoxia running drug group was significantly lower than the hypoxia running group (P 0.05). P: Hypoxic group was significantly higher than the control group (P 0.05); hypoxic drug group was significantly lower than the hypoxic group (P 0.05); hypoxic running group was significantly higher than the control group, running group and hypoxic group (P 0.05); hypoxic running drug group was significantly lower than the hypoxic running group (P 0.05) 2. HE staining: control group, drug control group and running group myocardial cell morphology was uniform. In the running group, the myocardial cells were still in shape, and some of the cells were lightly stained. In the hypoxic group, the myocardial fibers were slightly disordered, scattered in a small number of connective tissues, and some of the myocardial cells were coagulated and vacuoles appeared. The myocardial fibers in the hypoxic running group were arranged in a wavy pattern, and the myocardial plasma coagulated, forming red-stained, transverse bands of different sizes. Some of the nuclei were coagulated or even fragmented and dissolved. The myocardial fibers in the hypoxic running group were slightly better than those in the hypoxic running group, but the changes of myocardial morphology were the most serious in the hypoxic running group, trimetazide group. TUNEL staining showed that the apoptosis index of hypoxic group was significantly higher than that of control group (P 0.05), hypoxic running group was significantly higher than other groups (P 0.01), hypoxic running drug group was significantly lower than that of control group (P 0.01); running drug group was slightly higher than that of control group, slightly lower than that of hypoxic running drug group. Exercise can aggravate the adverse effects of hypoxia on heart rate, blood pressure and RPP. The incidence of AMS increases significantly during acute hypoxic exercise, which results in myocardial ischemia-like changes. ECG II, III, aVF lead ST segment depression. 2. Trimetazidine has protective effect on cardiovascular system of acute altitude hypoxic exercise personnel, can significantly improve exercise tolerance, reduce myocardial ischemic changes, do not affect exercise heart rate, blood pressure and RPP. 3. Exercise during acute hypoxia aggravates oxidative stress response of rat myocardium, causing heart failure. Trimetazidine can protect myocardium from stress injury induced by acute hypoxic exercise to a certain extent.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R82

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