急进高原军事应激对心血管系统的影响及其药物防护研究

发布时间：2018-09-06 13:08

【摘要】：背景:高原低氧环境对人体的损伤已被广泛认知,运动应激所致损伤的研究也有很多。但急进低氧环境下运动应激对人体的影响,特别是对心脏功能和结构造成影响的相关研究较少,低氧运动状态下的人体心脏功能改变与损伤具体机制目前尚不清楚。阶梯进驻高原和吸氧是目前预防与治疗急性高原反应时广泛采用的手段,却不方便于大批人员急进高原时应用。寻找便捷有效的适用于急进高原军事应激的高原疾病防治药物十分必要。第一部分健康男性青年低压氧舱模拟急进高原低氧运动对心血管系统影响目的:观察急性低氧环境下运动对心脏功能影响及运动能力变化的特点和规律。方法:招募18-35岁健康男性青年志愿者,先于平原采集基线临床试验资料,其后进入低压氧舱采集临床试验资料(n=67)。低压氧舱在0.5h内由大气压101kPa降压至61.6kPa (相当于4km高度)后,志愿者在舱内进行平板运动试验(TET)。观察比较志愿者在低压氧舱与平原常氧时TET运动能力的变化,运动前、后的血氧饱和度(Sp02)变化,运动不同时相的心率(HR)、血压(SBP/DBP)及心率血压乘积(RPP)的变化,入舱前后血气各项指标结果的变化。结果1.志愿者平原常氧TET皆为阴性,进入低压氧舱后12名志愿者TET阳性(n=67),表现为ST段压低,持续时间大于2min,主要集中在Ⅱ、Ⅲ、aVF导联,其中1人在运动2阶段时出现偶发室早。2.志愿者低压氧舱内TET运动MET值较平原常氧时显著下降(n=67,P0.01)。3.志愿者低压氧舱与平原常氧比较,Sp02运动前(98.36±1.42vs. 83.70±4.53)与运动后(95.12±8.16vs. 75.81±4.80)均显著下降(n=67,P0.01)。低氧与运动对Sp02下降的影响具有交互作用(n=67,P0.01)。4.志愿者在进行TET时,低压氧舱和平原常氧组内比较,HR、SBP及RPP运动时逐渐上升,休息后逐渐下降;DBP在运动后逐渐下降,休息后逐渐上升(n=67,P0.01)。进舱前后组间TET同时相比SBP/DBP均有显著差异(n=67, P0.01),HR及RPP仅在运动时相差异显著(n=67, P0.05)。低氧与运动对于HR和RPP的影响有显著交互作用(n=67,P0.05),对SBP和DBP的交互作用不显著(n=67,P0.05)。5.志愿者在低压氧舱TET后,动脉血气各项结果与平原基线比较,PH显著升高,其余项目除剩余碱外均显著降低(n=67,P0.05)。第二部分曲美他嗪对健康青年男性地转急进高原军事应激的防护作用研究目的:前瞻性队列研究观察曲美他嗪对急进高原低氧军事应激的保护作用。方法:按低压氧舱入组标准招募急进高原实地志愿者,随机分为安慰剂对照组(n=38)和盐酸曲美他嗪组(n=40),急进高原前7天开始服药(20mg, 3/日)。由北京乘火车经西宁中转,次日到达格尔木市区(海拔2.8km),第3日清晨乘汽车急进试验地(海拔4km～4.5km)。按照第一部分低压氧舱试验流程进行试验,格尔木市区出发前及TET前后各填写一份高原症状评分量表。结果1.对照组(n=38) TET阳性9人,曲美他嗪组(n=40)阳性5人,主要表现为Ⅱ、Ⅲ、aVF导联ST段压低,持续时间大于2min,对照组出现1人偶发房早,1人偶发室早。2.曲美他嗪组(n=40) TET运动MET值显著高于对照组(n=38,P0.05)3.血氧饱和度:两组志愿者组内比较,TET运动后Sp02均显著低于运动前(P0.01):两组间比较运动前Sp02无明显差异,运动后曲美他嗪组Sp02略低于对照组,但差异不显著。曲美他嗪与运动对Sp02影响的交互作用不显著(P0.05)。4.两组志愿者TET组内HR、SBP和RPP均随运动显著增加,休息时显著下降(P0.01); DBP均随运动显著下降,休息时显著上升(P0.01)。组间比较曲美他嗪组HR较对照组有所下降但差异不显著(P0.05),曲美他嗪与运动对两组HR的交互作用不显著(P0.05)。TET各相同时相SBP、DBP和RPP组间比较及曲美他嗪与运动对三者的交互作用均不显著(P0.05)。5.曲美他嗪组(n=40)与对照组(n=38)动脉血气结果无显著差异(P0.05)。6.从2.8km急进4km～4.5km高度其后进行TET运动,AMS发生率逐步增高,头痛、气喘和心悸等症状逐步加重,其中TET运动后较出发前差异显著(n=38,P0.0125)。疲劳/虚弱、胃肠道反应、腹胀、活动能力减退和呼吸困难略有加重但差异不显著(P0.05)。曲美他嗪对AMS及急性高原反应症状具有一定的降低作用,但差异不够显著(P0.05)。第三部分大鼠低压氧舱模拟急性低氧运动造成心肌应激损伤与曲美他嗪防护研究目的:在细胞与分子水平探讨急性低氧运动心肌损伤机制与曲美他嗪的防护作用。方法:使用动物低压氧舱模拟低氧(61.6kPa, 4km)、被动转轮(18m/min, 4h)强制大鼠跑步作为应激源,建立急性低氧运动应激动物模型,曲美他嗪作为干预药物。64只清洁级雄性SD大鼠,按照是否低氧处理,是否进行跑步,是否服用曲美他嗪,分为8组:①对照组(NC);②药物对照组(TC);③跑步组(NCR);④跑步药物组(TCR);⑤低氧组(NH);⑥低氧药物组(TH);⑦低氧跑步组(NHR);⑧低氧跑步药物组(THR)。试验结束即刻抽血冻存,使用ELISA法检测各组大鼠血清高敏C反应蛋白(hs-CRP)、超氧化物歧化酶(SOD)、缺血修饰白蛋白(IMA)、心型脂肪酸结合蛋白(H-FABP),剪取大鼠心肌制备石蜡切片,HE染色观察心肌细胞病理改变,TUNEL染色观察心肌细胞凋亡情况。结果1.血清标志物①hs-CRP:跑步组、低氧组均较对照组显著升高(P0.05);跑步药物组较跑步组显著下降(P0.05);低氧跑步组较对照组、跑步组和低氧组都显著升高(P0.01);低氧跑步药物组较低氧跑步组显著下降(P0.05)。②SOD:跑步组、低氧组均较对照组显著降低(P0.05);跑步药物组较跑步组显著升高(P0.05);低氧药物组较低氧组显著升高(P0.05);低氧跑步组较对照组、跑步组和低氧组都显著降低(P0.01);低氧跑步药物组相比低氧跑步组显著升高(P0.05)。③IMA:跑步组、低氧组均较对照组显著升高(P0.05);跑步药物组较跑步组显著下降(P0.05);低氧药物组较低氧组显著下降(P0.05);低氧跑步组较对照组、跑步组和低氧组都显著升高(P0.01);低氧跑步药物组较低氧跑步组显著下降(P 0.05)。④H-FABP:低氧组均较对照组显著升高(P0.05);低氧药物组较低氧组显著下降(P0.05);低氧跑步组较对照组、跑步组和低氧组都显著升高(P0.05);低氧跑步药物组较低氧跑步组显著下降(P0.05)2. HE染色:对照组、药物对照组和跑步组心肌细胞形态均匀,细胞核结构清晰,细胞横纹和闰盘清晰,心肌纤维均匀整齐。跑步组心肌细胞形态尚可,部分细胞淡染。低氧组心肌纤维排列稍紊乱,中间散在少量结缔组织,部分心肌细胞肌浆凝聚,出现空泡。低氧药物组心肌纤维略有紊乱,形态较低氧组略好。低氧跑步组心肌纤维排列紊乱呈波浪状,肌浆凝聚,形成红染、粗细不一的横带,部分细胞核固缩甚至碎裂溶解。低氧跑步药物组心肌纤维形态较低氧运动组略好,但不及低氧药物组。8组中低氧跑步组心肌形态改变情况最重,曲美他嗪对心肌细胞的损伤性变化有减轻作用。3.TUNEL染色计算凋亡指数凋亡指数低氧组显著高于对照组,显著低于低氧药物组(P0.05);低氧跑步组显著高于其他各组(P0.01),低氧跑步药物组较之显著降低(P0.01);跑步药物组略高于对照组,略低于运动组,但差异不显著(P0.05)。结论1.低氧时机体运动耐量明显降低,运动和低氧对于心率、血压和RPP的影响具有交互作用,运动可加重低氧对心率、血压、RPP的不利影响。急性低氧运动时AMS发生率显著增加,造成心肌缺血样变化,主要表现为心电图Ⅱ、Ⅲ、aVF导联ST段压低。2.曲美他嗪对急进高原低氧运动人员的心血管系统具有保护作用,可以显著提高运动耐量,减轻心肌缺血性改变,不影响运动时的心率、血压和RPP。3.急性低氧时运动加重了大鼠心肌的氧化应激反应,造成心肌细胞损伤和凋亡。曲美他嗪可在一定程度上保护急性低氧运动造成的心肌应激损伤。
[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.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R82

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