预先应用甲状腺激素对心肌缺血—再灌注损伤保护作用的实验和临床研究
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摘要
实施体外循环(cardiopulmonary bypass,CPB)心脏直视手术的患者在经历了手术中的全心缺血-再灌注损伤之后,T_3血清水平可显著降低。这种情况在小儿患者中尤为常见。研究发现,在实施CPB心脏直视手术的全部小儿,手术后均出现了T_3和T_4血清水平降低,即Ⅱ型正常甲状腺病态综合征(euthyroid sick syndrome,ESS),并可对小儿的预后造成不利影响。
目前针对手术后ESS的主要治疗措施是:在手术后发现患者的甲状腺激素血清水平降低后,通过补充性应用外源性甲状腺激素使其血清水平恢复到正常范围。但是,手术后补充性应用外源性甲状腺激素不能保证对ESS获得一致的满意治疗效果,并有可能对患者CPB心脏直视手术后已发生紊乱的内环境造成进一步的干扰,不利于患者的康复。另外,通过手术后补充性应用外源性甲状腺激素使其血清水平恢复到正常范围亦有可能消除ESS对机体的有益作用。
已有研究证实,甲状腺激素具有明确的心肌保护作用。有鉴于手术后补充性应用外源性甲状腺激素的种种不良影响,我们设想如果在小儿CPB心脏直视手术前预先应用外源性甲状腺素,不仅可通过促使心肌组织肌球蛋白重链(myosin heavy chain,MHC)α和热休克蛋白70(heat shock protein 70,HSP70)表达增强来发挥抗缺血-再灌注损伤的心肌保护作用,而且可避免手术后补充性应用外源性甲状腺素所致的不良影响。但是,目前尚无在小儿CPB心脏手术前应用外源性甲状腺激素进行手术中心肌缺血-再灌注损伤保护和手术后ESS预防的研究报道。
为此,我们设计了本研究,其内容包括动物实验和临床试验两部分。目的在于明确预先应用外源性甲状腺激素是否对心肌缺血-再灌注损伤具有保护作用,并探讨其心肌保护的相关机制。旨在为今后临床工作中应用这一简单的心肌保护干预措施提供有价值的理论依据。其中动物实验包括三方面的内容。
第一部分动物实验
一、预先应用不同剂量左旋甲状腺素钠对心肌缺血-再灌注损伤的保护作用
采用未成年健康雌性Wistar大鼠(鼠龄35天)48只,称重后随机平均分为六组(每组8只):空白对照组(BC组)、对照组(C组)、10μg组、20μg组、40μg组和80μg组。BC组和C组大鼠在实验前采用普通饲料喂养7天;10μg组、20μg组、40μg组和80μg组大鼠在实验前除了采用普通饲料喂养7天之外,每天还通过灌胃方式分别应用左旋甲状腺素钠(levothyroxine-sodium,L)10μg/100g体重、20μg/100g体重、40μg/100g和80μg/100g体重进行预处理。第8天对大鼠再次称重,并抽取外周静脉血检测甲状腺激素血清水平。大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组的心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min和再灌注10 min时的冠脉流量;再灌注15 min时收集冠脉流出液测定肌酸激酶心肌型同工酶(myocardial-bound creatine kinase,CK-MB)活性;实验结束时留取心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和甲状腺激素受体(thyroid hormone receptor,TR)mRNA表达。
结果显示,与BC组和C组比较,20μg组、40μg组和80μg组实验当天的大鼠的体重均显著减轻。并且40μg组和80μg组实验当天大鼠的体重均显著低于10μg组。与BC组和C组比较,20μg组、40μg组和80μg组实验当天的甲状腺激素血清水平均显著升高。10μg组、20μg组、40μg组和80μg组的甲状腺激素血清水平随左旋甲状腺素钠的用量增加而升高,其中80μg组的甲状腺激素血清水平显著高于10μg组、20μg组和40μg组。
与BC组和C组比较,10μg组、20μg组、40μg组和80μg组心率和dp/dt_(max)的基础值均显著升高。80μg组收缩压和-dp/dt_(max)基础值均显著高于10μg组和20μg组。
与BC组比较,40μg组和80μg组再灌注期的心率恢复率均显著降低,10μg组、20μg组、40μg组和80μg组再灌注期的收缩压和±dp/dt_(max)恢复率均显著降低;与C组比较,10μg组、20μg组、40μg组和80μg组再灌注期的心率和dp/dt_(max)恢复率均显著升高,10μg组在再灌注20 min和30 min时以及20μg组在再灌注30 min时的收缩压恢复率均显著升高,10μg组、20μg组和40μg组整个再灌注期和80μg组再灌注30min时的-dp/dt_(max)恢复率均显著升高。四个实验组之间比较,80μg组再灌注30 min时的收缩压恢复率低于10μg组;40μg组和80μg组再灌注30 min时的±dp/dt_(max)恢复率显著低于10μg组和20μg组。
与BC组和C组比较,10μg组、20μg组、40μg组和80μg组平衡期和再灌注期的冠脉流量均显著增加。
与BC组比较,10μg组、20μg组、40μg组和80μg组再灌注期冠脉流出液中的CK-MB活性均显著升高;与C组比较,10μg组、20μg组和40μg组再灌注期冠脉流出液中的CK-MB活性均显著降低。在四个实验组,再灌注期冠脉流出液中的CK-MB活性随左旋甲状腺素钠用量增加而升高,其中80μg组显著高于10μg组、20μg组和40μg组。
四个实验组的心室肌组织HSP70表达均显著强于BC组和C组。10μg组和20μg组的心室肌组织HSP70表达均显著强于40μg组和80μg组。
与BC组和C组比较,四个实验组的心室肌组织MHCαmRNA表达均显著升高,并且20μg组、40μg组和80μg组的心室肌组织TRα1 mRNA表达均显著升高。但是,心室肌组织MHCαmRNA和TRα1 mRNA表达在四个实验组之间比较均无显著差异。
二、芬太尼和舒芬太尼对预先应用左旋甲状腺素钠心肌保护作用的影响
采用未成年的健康雌性Wistar大鼠(鼠龄35天)56只,随机分为七组(每组8只):空白对照组(BC组)、对照组(C组)、左旋甲状腺素钠10μg组(10μg组)、芬太尼组(F组)、舒芬太尼组(S组)、芬太尼加左旋甲状腺素钠组(F+L组)和舒芬太尼加左旋甲状腺素钠组(S+L组)。BC组、C组、F组和S组大鼠在实验前采用普通饲料喂养7天;10μg组、F+L组和S+L组大鼠除了在实验前采用普通饲料喂养7天之外,每天还通过灌胃方式应用左旋甲状腺素钠10μg/100g体重进行预处理。第8天大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程。其中F组和F+L组采用含芬太尼30μg/L的KH液灌注,S组和S+L组采用含舒芬太尼3μg/L的KH液灌注,其余各组采用KH液灌注。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min和再灌注10 min时的冠脉流量;再灌注15 min时收集冠脉流出液测定CK-MB活性;实验结束时留取大鼠心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和TR mRNA表达。
结果显示,七组心率和收缩压的基础值均无显著差异;10μg组、F+L组和S+L组±dp/dt_(max)的基础值均显著高于BC组、C组、F组和S组。
与BC组比较,F组和S组再灌注期全部的血流动力学指标均显著降低;与C组比较,10μg组、F+L组和S+L组再灌注期全部的血流动力学指标均显著升高;与F组和S组比较,10μg组、F+L组和S+L组再灌注期全部的血流动力学指标均显著升高。但是,再灌注期全部的血流动力学指标在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组平衡期和再灌注期的冠脉流量均显著高于C组、F组和S组。但是,平衡期和再灌注期的冠脉流量在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组再灌注期冠脉流出液中的CK-MB活性均显著高于BC组,但均显著低于C组、F组和S组。再灌注期冠脉流出液中的CK-MB活性在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组的心室肌组织HSP70表达均显著强于BC组、C组、F组和S组。但是,心室肌组织HSP70表达在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组的心室肌组织MHCαmRNA表达均显著高于C组、F组和S组。但是,心室肌组织MHCαmRNA表达在10μg组、F+L组和S+L组之间比较均无显著差异。另外,心室肌组织TRα1 mRNA表达在所有各组之间比较均无显著差异。
三、线粒体ATP敏感性钾离子通道与预先应用左旋甲状腺素钠心肌保护作用的关系
采用未成年的雌性健康Wistar大鼠(鼠龄35天)32只,随机分为四组(每组8只):空白对照组(BC组)、对照组(C组)、左旋甲状腺素钠10μg组(10μg组)和格列本脲加左旋甲状腺素钠组(G+L组)。BC组和C组大鼠在实验前采用普通饲料喂养7天;10μg组和G+L组大鼠除了采用普通饲料喂养7天之外,每天还通过灌胃方式应用左旋甲状腺素钠10μg/100g体重进行预处理。第8天大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程,其中G+L组采用含有格列本脲30μmol/L的KH液灌注,其余各组采用KH液灌注。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min时和再灌注10 min时的冠脉流量;再灌注15 min时的收集冠脉流出液测定CK-MB活性;实验结束时留取大鼠心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和TR mRNA表达。
结果显示,四组心率和收缩压的基础值均无显著差异;10μg组和G+L组±dp/dt_(max)的基础值均显著高于BC组和C组。
与C组比较,10μg组和G+L组再灌注期全部的血流动力学指标均显著升高;但是,再灌注期全部的血流动力学指标在10μg组和G+L组之间比较均无显著差异。
10μg组和G+L组平衡期和再灌注期的冠脉流量均显著高于C组,并且10μg组和G+L组平衡期的冠脉流量均显著高于BC组。但是,平衡期和再灌注期的冠脉流量在10μg组和G+L组之间比较均无显著差异。
10μg组和G+L组再灌注期冠脉流出液中的CK-MB活性均显著高于BC组,但是均显著低于C组。再灌注期冠脉流出液中的CK-MB活性在10μg组和G+L组之间比较无显著差异。
10μg组和G+L组的心室肌组织HSP70表达均显著强于BC组和C组。但是,心室肌组织HSP70表达在10μg组和G+L组之间比较无显著差异。
10μg组和G+L组的心室肌组织MHCαmRNA表达均显著高于BC组和C组。但是,心室肌组织MHCαmRNA表达量在10μg组和G+L组之间比较无显著差异。另外,心室肌组织TRα1 mRNA表达在四组之间比较均无显著差异。
通过上述三个动物实验的结果,我们得出以下结论:
1.预先应用小剂量左旋甲状腺素钠可对心肌缺血-再灌注损伤产生明确的保护作用,但是应用较大剂量的左旋甲状腺素钠可减弱其心肌保护作用,而且可导致高甲状腺素血症。
2.在本实验所采用的四个左旋甲状腺素钠剂量中,以10μg/100g体重的心肌保护作用最佳,而且不导致高甲状腺素血症的发生。
3.预先应用左旋甲状腺素钠的心肌保护作用可能是与心肌组织HSP70和MHCαmRNA表达增强有关。
4.芬太尼和舒芬太尼对预先应用左旋甲状腺素钠的心肌保护作用无影响。
5.线粒体ATP敏感性钾离子通道可能与预先应用左旋甲状腺素钠的心肌保护作用机制无关。
第二部分临床试验部分:小儿体外循环心脏直视手术前应用小剂量甲状腺素片的心肌保护作用
本临床试验共包括40例年龄3～12岁、拟在CPB下实施择期简单先天性心脏病(房间隔缺损、室间隔缺损、卵圆孔未闭和动脉导管未闭)矫正手术的小儿,将小儿随机平均分为两组(每组20例):对照组和试验组。试验组小儿在手术前每天按0.4mg/kg体重口服甲状腺素片,共4天;对照组小儿手术前不服用此药。所有小儿的围手术期处理严格按照医院操作常规进行。检测小儿入院时、麻醉前以及手术后第1天、第2天、第4天的甲状腺激素血清水平变化,并在小儿入院时、手术后即刻以及手术后第1天和第2天观察并记录小儿的血流动力学指标,记录小儿保留气管插管时间、ICU停留时间以及在ICU中正生性肌力药物的使用情况。
在手术结束前,每组随机选取6例小儿留取右心房肌肉标本,采用western-blotting技术检测心房肌组织HSP70表达,采用实时定量PCR技术检测心房肌组织TR和MHC mRNA表达。在手术后24h时取血,采用AXSYM全自动免疫分析仪定量测定CK-MB血清活性,定性检测肌钙蛋白Ⅰ(troponinⅠ,TnⅠ)的阳性率。
结果显示,与入院时的基础值比较,对照组手术后第1天、第2天和第4天的T_3和FT_3血清水平以及手术后第1天的TSH、T_4和FT_4血清水平均显著降低。与入院时的基础值比较,试验组手术后第1天、第2天和第4天的T_3和FT_3血清水平以及手术后第1天的TSH血清水平均显著降低。
与对照组比较,试验组手术后第1天和第2天的T_3、FT_3和T_4血清水平以及手术后第1天的FT_4血清水平均显著升高。
与对照组比较,试验组的正性肌力药物使用率、CK-MB血清活性、TnⅠ血清阳性率和心房肌组织MHCβmRNA表达均显著降低,心房肌组织HSP70和MHCαmRNA表达均显著增强。
根据本临床试验的结果,我们得出以下结论:
1.在CPB下实施简单先天性心脏病矫正手术的小儿,手术后可发生Ⅱ型ESS。
2.虽然小儿CPB心脏直视手术前短期补充性应用小剂量甲状腺素片可减小手术后甲状腺激素血清水平降低的严重程度,并预防Ⅱ型ESS的发生,但是小儿手术后仍可发生Ⅰ型ESS。
3.小儿CPB心脏直视手术前短期补充小剂量甲状腺素片具有明确心肌保护作用,并且手术前短期补充应用小剂量甲状腺素片的心肌保护作用可能与甲状腺激素调控心肌组织HSP70和MHCαmRNA表达增强有关。
After the patients undergoing open heart surgery with cardiopulmonary bypass(CPB) experience global ischemia/reperfusion(I/R) injury during surgery,serum level of T_3 decreases significantly.This problem is especially common in pediatric patients.It has been demonstrated that all pediatric patients undergoing open heart surgery with CPB present the significant decreased serum levels of T_3 and T_4 after surgery,which is named as typeⅡEuthyroid sick syndrome(ESS) and may cause undesirable impact on the children's prognosis.
The available main therapeutic measure aimed at the postoperative ESS is that when decreased serum levels of thyroid hormones are detected during postoperative period, supplemental administration of exogenous thyroid hormones restores the serum levels of thyroid hormones to normal limits.However,postoperative supplemental administration of exogenous thyroid hormones can not ensure to achieve consistent and adequate therapeutic effect for ESS.Also,it may further interfere with the disturbed inner environment after open heart surgery with CPB,which is adverse to recuperate the patients' health.When serum levels of thyroid hormones are restored to normal limits by the postoperative supplemental administration of exogenous thyroid hormones,moreover,the beneficial effects of ESS may also be abolished.
It has been demonstrated that thyroid hormones can produce the definite cardioprotecton.In view of possible disadvantages of the postoperative supplemental administration of exogenous thyroid hormones,we consider that in pediatric patients undergoing the open heart surgery with CPB,preemptive administration of exogenous thyroid hormones before surgery may not only protect the myocardium against I/R injury during surgery by increasing the expression of myosin heavy chainα(MHCα) and heat shock protein 70(HSP70) in myocardial tissues,but also can avoid the adverse effects by the postoperative supplemental administration of exogenous thyroid hormones.However, there has been no published data on protection of myocardial I/R injury during surgery and prevention of postoperative ESS by administrating exogenous thyroid hormones before open heart surgery with CPB in pediatric patients.
Therefore,we designed this study including an animal experiment and a clinical trial. Our purposes were to determine whether preemptive administration of exogenous thyroid hormones could protect the myocardium against I/R injury and to explore the inherent mechanisms of the cardioprotecton by preemptive administration of thyroid hormones.By this study,we hoped to provide some useful rationales for further use of this simple cardioprotective measure in clinical practice.The animal experiment of this study was divided into three subunits.
Animal Experiment
Part 1.Protective effects of preemptive administration of different-dose levothyroxine-sodium against myocardial ischemia-reperfusion injury
After weighing,48 healthy female immature(aged 35 days) Wistar rats were randomly allocated into the six groups(8 rats in each group):blank control group(group BC),control group(group BC),10μg group(group 10μg),20μg group(group 20μg),40μg group(group 40μg) and 80μg group(group 80μg).The rats in groups BC and C were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups 10μg,20μg,40μg and 80μg were also pre-treated with levothyroxine-sodium 10μg/100g weight,20μg/100g weight,40μg/100g weight 80μg/100g weight,respectively,through a gastric tube every day.On the eighth day, all rats were again weighed and then underwent peripheral venous puncture to take blood sample for detection of serum levels of thyroid hormones.The hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion,whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hemodynamic variables including heart rate,systolic blood pressure(SBP),and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during balance period and at 10 min during reperfusion period,respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of cardiac enzyme-myocardial-bound creatine kinase(CK-MB).At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting, and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed that compared with groups BC and C,rats' weight on the experiment day was significantly lower in groups 20μg,40μg and 80μg.Also,rats' weight on the experiment day was significantly lower in groups 40μg and 80μg than in group 10μg.The serum levels of thyroid hormones were significantly higher in groups 20μg, 40μg and 80μg than in groups BC and C.The serum levels of thyroid hormones in groups 10μg,20μg,40μg and 80μg increased with the dosage of the levothyroxine-sodium,and the serum levels of thyroid hormones were significantly higher in group 80μg than in groups 10μg,20μg and 40μg.
As compared with groups BC and C,baselines of both heart rate and dp/dt_(max) were significantly higher in groups 10μg,20μg,40μg and 80μg.Baselines of SBP and -dp/dt_(max) were significantly higher in group 80μg than in groups 10μg and 20μg.
As compared with group BC,recovery rates of heart rate during reperfusion period significantly decreased in groups 40μg and 80μg,and recovery rates of both SBP and±dp/dt_(max) significantly decreased in groups 10μg,20μg,40μg and 80μg.As compared with group C,recovery rates of both heart rate and dp/dt_(max) during reperfusion period significantly increased in groups 10μg,20μg,40μg and 80μg,recovery rate of SBP during reperfusion period significantly increased at 20 min and 30 min in group 10μg and at 30 min in group 20μg,recovery rate of -dp/dt_(max) during reperfusion period significantly increased at all observed time points in groups 10μg,20μg and 40μg,and at 30 min in group 80μg.Comparisons among all four experiment groups,recovery rate of SBP at 30 min during reperfusion period was significantly lower in group 80μg than in group 10μg, and recovery rate of±dp/dt_(max) at 30 min during reperfusion period was significantly lower in groups 40μg and 80μg than in groups 10μg and 20μg.
As compared with groups BC and C,coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg,20μg,40μg and 80μg.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly higher in groups 10μg,20μg,40μg and 80μg than in group BC,but was significantly lower in groups 10μg,20μg and 40μg than in group C.Comparisons among all four experiment groups,the activity level of CK-MB in the coronary perfusion fluid during reperfusion period increased with the dosage of levothyroxine-sodium,and was significantly higher in group 80μg than in groups 10μg,20μg and 40μg.
The ventricular myocardial expression of HSP70 was stronger in four experiment groups than in groups BC and C,and significantly increased in groups 10μg and 20μg compared with groups 40μg and 80μg.
As compared with groups BC and C,the ventricular myocardial expression of MHCαmRNA significantly increased in four experimental groups,and the ventricular myocardial expression of TRα1 mRNA significantly increased in groups 20μg,40μg and 80μg. However,there were no significant differences in the ventricular myocardial expression of MHCαmRNA and TRα1 mRNA among four experiment groups.
Part 2.The influences of fentanyl and sufentanil on cardioprotection of preemptive levothyroxine-sodium administration
Fifty-six healthy,female immature(aged 35 days) Wistar rats were randomly allocated into the seven groups(8 rats in each group):blank control group(group BC), control group(group C),levothyroxine-sodium 10μg group(group 10μg),fentanyl group (group F),sufentanil group(group S),combined fentanyl and levothyroxine-sodium(group F+L) and combined sufentanil and levothyroxine-sodium(group S+L).The rats in groups BC,C,F and S were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups F+L,S+L and 10μg were also pre-treated with levothyroxine sodium 10μg/100g weight,through a gastric tube every day.On the eighth day,the hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion, whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hearts were perfused with KH fluid containing fentanyl 30μg/L in the F and F+L groups,with KH fluid containing sufentanil 3μg/L in the S and S+L groups,and with KH fluid in other groups, respectively.The hemodynamic variables including heart rate,systolic blood pressure (SBP),and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during balance period and at 10 min during reperfusion period, respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of CK-MB.At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting,and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed no significant differences in baselines of both heart rate and SBP among seven groups.Baselines of±dp/dt_(max) were significantly higher in groups 10μg,F+L and S+L than in groups BC,C,F and S.
As compared with group BC,all hemodynamic variables during reperfusion period significantly decreased in groups F and S.As compared with group C,all hemodynamic variables during reperfusion period significantly increased in groups 10μg,F+L and S+L. All hemodynamic variables during reperfusion period were significantly higher in groups 10μg,F+L and S+L than in groups F and S.However,there were no significant differences in all hemodynamic variables during reperfusion period among groups 10μg,F+L and S+L.
The coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,there were no significant differences in the coronary perfusion flows in balance period and reperfusion period among groups 10μg,F+L and S+L.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly higher in groups 10μg,F+L and S+L than in group BC,but lower in groups 10μg,F+L and S+L than in groups C,F and S.The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was not significant different among groups 10μg,F+L and S+L.
The ventricular myocardial expression of HSP70 significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,there were no obvious differences in the ventricular myocardial expression of HSP70 among groups 10μg,F+L and S+L.
The ventricular myocardial expression of MHCαmRNA significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,the ventricular myocardial expression of MHCαmRNA was not significant different among groups 10μg, F+L and S+L.Also,there were no significant differences in the ventricular myocardial expression of TRα1 mRNA among all seven groups.
Part 3.The relationship between mitochondrial K_(ATP) and cardioprotection of preemptive levothyroxine-sodium administration
Thirty-two healthy,female immature(aged 35 days) Wistar rats were randomly allocated into the four groups(8 rats in each group):blank control group(group BC), control group(group C),levothyroxine-sodium 10μg group(group 10μg) and combined glibenclimide and levothyroxine-sodium group(group G+L).The rats in groups BC and C were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups 10μg and G+L were also pre-treated with levothyroxine-sodium 10μg/100g weight,through a gastric tube every day.On the eighth day,the hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion,whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hearts were perfused with KH fluid containing glibenclimide 30μmol/L in group G+L,and with KH fluid in other groups, respectively.The hemodynamic variables including heart rate,systolic blood pressure,and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during the balance period and at 10 min during reperfusion period,respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of CK-MB.At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting,and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed no significant differences in baselines of both heart rate and SBP among four groups.However,baselines of±dp/dt_(max) significantly increased in groups 10μg and G+L compared with groups BC and C.
As compared with group C,all hemodynamic variables during reperfusion period significantly increased in groups 10μg and G+L.However,all hemodynamic variables during reperfusion period were not significant different between groups 10μg and G+L.
The coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg and G+L compared with group C.Also,the coronary perfusion flow in balance period significantly increased in groups 10μg and G+L compared with group BC.However,there were no significant differences in the coronary perfusion flows in balance period and reperfusion period between groups 10μg and G+L.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly lower in groups 10μg and G+L than in group C,but significantly higher in groups 10μg and G+L than in group BC.There were no significant differences in the activity level of CK-MB in the coronary perfusion fluid during reperfusion period between groups 10μg and G+L.
The ventricular myocardial expression of HSP70 significantly increased in groups 10μg and G+L than in groups BC and C.However,there was no significant difference in the ventricular myocardial expression of HSP70 between groups 10μg and G+L.
The ventricular myocardial expression of MHCαmRNA significantly increased in groups 10μg and G+L compared with groups BC and C.However,there was no significant difference in the ventricular myocardial expression of MHCαmRNA between groups 10μg and G+L.Also,the ventricular myocardial expression of TRα1 mRNA was not significant different among all four groups.
Based on the results from all three animal experiments,the following conclusions could be drawn.
1.Preemptive administration of small-dose levothyroxine-sodium can protect myocardium against I/R injury,whereas preemptive administration of larger dose levothyroxine-sodium can only produce an attenuated cardioprotection effect and might result in occurrence of hyperthyroidism.
2.Of four dosages of levothyroxine-sodium used in this experiment,a dosage of 10μg/100g weight achieves the best cardioprotection effect without occurrence of hyperthyroidism.
3.The cardioprotective effect of preemptive levothyroxine-sodium administration is probably contributed to the increased myocardial expression of HSP70 and MHCαmRNA.
4.Both fentanyl and sufentanil do not influence the cardioprotective effect of preemptive levothyroxine-sodium administration.
5.Mitochondrial ATP sensitive potassium channel is not probably involved in the mechanism of the cardioprotection by preemptive levothyroxine-sodium administration.
Clinical trial
The cardioprotective effect of small-dose thyroid hormone tablet administration before open heart surgery with cardiopulmonary bypass in children
Forty children aged 3-12 year,scheduled for elective simple congenital heart diseases (atrial septal defect,ventricular septal defect,patent foramen ovale and patent ductus arteriosus) surgery with cardiopulmonary bypass(CPB) were included in this clinical trial. They were randomly allocated equally into two groups:control group(n=20) and trial group(n=20).The children in the trial group took thyroid hormone tablet 0.4 mg/kg weight every day for four days before surgery,while the children in the control group were not given this tablet.In perioperative period,all children were treated according to the standing guidelines of the hospital.The serum levels of thyroid hormones were detected at following observed points:administration day,before anesthesia,and 1st,2nd and 4th day after surgery.The hemodynamic parameters were recorded at following observed points: administration day,immediately after surgery,and 1st and 2nd day after surgery.Also, duration of intubation and ICU stay,and the application of inotropic drugs in the ICU were noted.
During surgery,right atria samples were taken from six children randomly chosen in each group to detect the myocardial expression of HSP70 by Western-blotting and the myocardial expression of TR mRNA and MHC mRNA by RT-PCR.At 24 hour after surgery,the blood samples were also taken to quantitatively assess serum activity of CK-MB and to qualitatively assay the positive ratio of TnI by AXSYM automatic immunoassay systems.
The results showed that compared with the baselines on the administration day,in control group,the serum levels of both T_3 and FT_3 on the 1st,2nd and 4th day after surgery, and the serum levels of TSH,T_4 and FT_4 on the 1st day after surgery significantly decreased.As compared with the baselines on the administration day,in trial group,the serum levels of T_3 and FT_3 on the 1st,2nd and 4th day after surgery,and the level serum TSH on the 1st day after surgery significantly decreased.
The serum levels of T_3,FT_3 and T_4 on the 1st and 2nd day after surgery,the serum level of FT_4 on the 1st day after surgery were significantly higher in the trial group than in control group.
The application rate of inotropic drugs in ICU,the serum activity of CK-MB,the positive ratio of TnI and the atrial myocardial expression of MHCβmRNA significantly decreased,and the atrial myocardial expression of HSP70 and MHCαmRNA significantly increased in the trial group compared with control group.
Based on the results of this clinical trial,the following conclusions could be drawn.
1.In children undergoing simple open heart surgery with CPB,TypeⅡESS may occur after surgery.
2.A short-term administration of small-dose thyroid hormone tablet before surgery in children undergoing open heart surgery with CPB can reduce the severity of decreased serum levels of thyroid hormones after surgery and prevent occurrence of postoperative typeⅡESS.However,typeⅠESS may still occur after surgery in the children.
3.A short-term administration of small-dose thyroid hormone tablet before surgery in children undergoing open heart surgery with CPB can produce definite cardioprotecton. Also,the cardioprotective effects by administration of small-dose thyroid hormone tablet before surgery may be contributed to the increased myocardial expression of HSP70 and MHCαmRNA.
目前针对手术后ESS的主要治疗措施是:在手术后发现患者的甲状腺激素血清水平降低后,通过补充性应用外源性甲状腺激素使其血清水平恢复到正常范围。但是,手术后补充性应用外源性甲状腺激素不能保证对ESS获得一致的满意治疗效果,并有可能对患者CPB心脏直视手术后已发生紊乱的内环境造成进一步的干扰,不利于患者的康复。另外,通过手术后补充性应用外源性甲状腺激素使其血清水平恢复到正常范围亦有可能消除ESS对机体的有益作用。
已有研究证实,甲状腺激素具有明确的心肌保护作用。有鉴于手术后补充性应用外源性甲状腺激素的种种不良影响,我们设想如果在小儿CPB心脏直视手术前预先应用外源性甲状腺素,不仅可通过促使心肌组织肌球蛋白重链(myosin heavy chain,MHC)α和热休克蛋白70(heat shock protein 70,HSP70)表达增强来发挥抗缺血-再灌注损伤的心肌保护作用,而且可避免手术后补充性应用外源性甲状腺素所致的不良影响。但是,目前尚无在小儿CPB心脏手术前应用外源性甲状腺激素进行手术中心肌缺血-再灌注损伤保护和手术后ESS预防的研究报道。
为此,我们设计了本研究,其内容包括动物实验和临床试验两部分。目的在于明确预先应用外源性甲状腺激素是否对心肌缺血-再灌注损伤具有保护作用,并探讨其心肌保护的相关机制。旨在为今后临床工作中应用这一简单的心肌保护干预措施提供有价值的理论依据。其中动物实验包括三方面的内容。
第一部分动物实验
一、预先应用不同剂量左旋甲状腺素钠对心肌缺血-再灌注损伤的保护作用
采用未成年健康雌性Wistar大鼠(鼠龄35天)48只,称重后随机平均分为六组(每组8只):空白对照组(BC组)、对照组(C组)、10μg组、20μg组、40μg组和80μg组。BC组和C组大鼠在实验前采用普通饲料喂养7天;10μg组、20μg组、40μg组和80μg组大鼠在实验前除了采用普通饲料喂养7天之外,每天还通过灌胃方式分别应用左旋甲状腺素钠(levothyroxine-sodium,L)10μg/100g体重、20μg/100g体重、40μg/100g和80μg/100g体重进行预处理。第8天对大鼠再次称重,并抽取外周静脉血检测甲状腺激素血清水平。大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组的心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min和再灌注10 min时的冠脉流量;再灌注15 min时收集冠脉流出液测定肌酸激酶心肌型同工酶(myocardial-bound creatine kinase,CK-MB)活性;实验结束时留取心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和甲状腺激素受体(thyroid hormone receptor,TR)mRNA表达。
结果显示,与BC组和C组比较,20μg组、40μg组和80μg组实验当天的大鼠的体重均显著减轻。并且40μg组和80μg组实验当天大鼠的体重均显著低于10μg组。与BC组和C组比较,20μg组、40μg组和80μg组实验当天的甲状腺激素血清水平均显著升高。10μg组、20μg组、40μg组和80μg组的甲状腺激素血清水平随左旋甲状腺素钠的用量增加而升高,其中80μg组的甲状腺激素血清水平显著高于10μg组、20μg组和40μg组。
与BC组和C组比较,10μg组、20μg组、40μg组和80μg组心率和dp/dt_(max)的基础值均显著升高。80μg组收缩压和-dp/dt_(max)基础值均显著高于10μg组和20μg组。
与BC组比较,40μg组和80μg组再灌注期的心率恢复率均显著降低,10μg组、20μg组、40μg组和80μg组再灌注期的收缩压和±dp/dt_(max)恢复率均显著降低;与C组比较,10μg组、20μg组、40μg组和80μg组再灌注期的心率和dp/dt_(max)恢复率均显著升高,10μg组在再灌注20 min和30 min时以及20μg组在再灌注30 min时的收缩压恢复率均显著升高,10μg组、20μg组和40μg组整个再灌注期和80μg组再灌注30min时的-dp/dt_(max)恢复率均显著升高。四个实验组之间比较,80μg组再灌注30 min时的收缩压恢复率低于10μg组;40μg组和80μg组再灌注30 min时的±dp/dt_(max)恢复率显著低于10μg组和20μg组。
与BC组和C组比较,10μg组、20μg组、40μg组和80μg组平衡期和再灌注期的冠脉流量均显著增加。
与BC组比较,10μg组、20μg组、40μg组和80μg组再灌注期冠脉流出液中的CK-MB活性均显著升高;与C组比较,10μg组、20μg组和40μg组再灌注期冠脉流出液中的CK-MB活性均显著降低。在四个实验组,再灌注期冠脉流出液中的CK-MB活性随左旋甲状腺素钠用量增加而升高,其中80μg组显著高于10μg组、20μg组和40μg组。
四个实验组的心室肌组织HSP70表达均显著强于BC组和C组。10μg组和20μg组的心室肌组织HSP70表达均显著强于40μg组和80μg组。
与BC组和C组比较,四个实验组的心室肌组织MHCαmRNA表达均显著升高,并且20μg组、40μg组和80μg组的心室肌组织TRα1 mRNA表达均显著升高。但是,心室肌组织MHCαmRNA和TRα1 mRNA表达在四个实验组之间比较均无显著差异。
二、芬太尼和舒芬太尼对预先应用左旋甲状腺素钠心肌保护作用的影响
采用未成年的健康雌性Wistar大鼠(鼠龄35天)56只,随机分为七组(每组8只):空白对照组(BC组)、对照组(C组)、左旋甲状腺素钠10μg组(10μg组)、芬太尼组(F组)、舒芬太尼组(S组)、芬太尼加左旋甲状腺素钠组(F+L组)和舒芬太尼加左旋甲状腺素钠组(S+L组)。BC组、C组、F组和S组大鼠在实验前采用普通饲料喂养7天;10μg组、F+L组和S+L组大鼠除了在实验前采用普通饲料喂养7天之外,每天还通过灌胃方式应用左旋甲状腺素钠10μg/100g体重进行预处理。第8天大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程。其中F组和F+L组采用含芬太尼30μg/L的KH液灌注,S组和S+L组采用含舒芬太尼3μg/L的KH液灌注,其余各组采用KH液灌注。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min和再灌注10 min时的冠脉流量;再灌注15 min时收集冠脉流出液测定CK-MB活性;实验结束时留取大鼠心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和TR mRNA表达。
结果显示,七组心率和收缩压的基础值均无显著差异;10μg组、F+L组和S+L组±dp/dt_(max)的基础值均显著高于BC组、C组、F组和S组。
与BC组比较,F组和S组再灌注期全部的血流动力学指标均显著降低;与C组比较,10μg组、F+L组和S+L组再灌注期全部的血流动力学指标均显著升高;与F组和S组比较,10μg组、F+L组和S+L组再灌注期全部的血流动力学指标均显著升高。但是,再灌注期全部的血流动力学指标在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组平衡期和再灌注期的冠脉流量均显著高于C组、F组和S组。但是,平衡期和再灌注期的冠脉流量在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组再灌注期冠脉流出液中的CK-MB活性均显著高于BC组,但均显著低于C组、F组和S组。再灌注期冠脉流出液中的CK-MB活性在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组的心室肌组织HSP70表达均显著强于BC组、C组、F组和S组。但是,心室肌组织HSP70表达在10μg组、F+L组和S+L组之间比较均无显著差异。
10μg组、F+L组和S+L组的心室肌组织MHCαmRNA表达均显著高于C组、F组和S组。但是,心室肌组织MHCαmRNA表达在10μg组、F+L组和S+L组之间比较均无显著差异。另外,心室肌组织TRα1 mRNA表达在所有各组之间比较均无显著差异。
三、线粒体ATP敏感性钾离子通道与预先应用左旋甲状腺素钠心肌保护作用的关系
采用未成年的雌性健康Wistar大鼠(鼠龄35天)32只,随机分为四组(每组8只):空白对照组(BC组)、对照组(C组)、左旋甲状腺素钠10μg组(10μg组)和格列本脲加左旋甲状腺素钠组(G+L组)。BC组和C组大鼠在实验前采用普通饲料喂养7天;10μg组和G+L组大鼠除了采用普通饲料喂养7天之外,每天还通过灌胃方式应用左旋甲状腺素钠10μg/100g体重进行预处理。第8天大鼠麻醉后将其心脏取出,采用Langendorff装置建立离体心脏缺血-再灌注模型,BC组心脏持续灌注80 min而不实施停灌注,其他各组心脏均顺序经历平衡30 min、常温停灌注20 min和再灌注30 min的处理过程,其中G+L组采用含有格列本脲30μmol/L的KH液灌注,其余各组采用KH液灌注。实验中连续监测心率、收缩压、±dp/dt_(max)等血流动力学指标;测定平衡10 min时和再灌注10 min时的冠脉流量;再灌注15 min时的收集冠脉流出液测定CK-MB活性;实验结束时留取大鼠心室肌标本,采用Western-blotting技术检测HSP70表达,采用实时定量PCR技术检测MHC和TR mRNA表达。
结果显示,四组心率和收缩压的基础值均无显著差异;10μg组和G+L组±dp/dt_(max)的基础值均显著高于BC组和C组。
与C组比较,10μg组和G+L组再灌注期全部的血流动力学指标均显著升高;但是,再灌注期全部的血流动力学指标在10μg组和G+L组之间比较均无显著差异。
10μg组和G+L组平衡期和再灌注期的冠脉流量均显著高于C组,并且10μg组和G+L组平衡期的冠脉流量均显著高于BC组。但是,平衡期和再灌注期的冠脉流量在10μg组和G+L组之间比较均无显著差异。
10μg组和G+L组再灌注期冠脉流出液中的CK-MB活性均显著高于BC组,但是均显著低于C组。再灌注期冠脉流出液中的CK-MB活性在10μg组和G+L组之间比较无显著差异。
10μg组和G+L组的心室肌组织HSP70表达均显著强于BC组和C组。但是,心室肌组织HSP70表达在10μg组和G+L组之间比较无显著差异。
10μg组和G+L组的心室肌组织MHCαmRNA表达均显著高于BC组和C组。但是,心室肌组织MHCαmRNA表达量在10μg组和G+L组之间比较无显著差异。另外,心室肌组织TRα1 mRNA表达在四组之间比较均无显著差异。
通过上述三个动物实验的结果,我们得出以下结论:
1.预先应用小剂量左旋甲状腺素钠可对心肌缺血-再灌注损伤产生明确的保护作用,但是应用较大剂量的左旋甲状腺素钠可减弱其心肌保护作用,而且可导致高甲状腺素血症。
2.在本实验所采用的四个左旋甲状腺素钠剂量中,以10μg/100g体重的心肌保护作用最佳,而且不导致高甲状腺素血症的发生。
3.预先应用左旋甲状腺素钠的心肌保护作用可能是与心肌组织HSP70和MHCαmRNA表达增强有关。
4.芬太尼和舒芬太尼对预先应用左旋甲状腺素钠的心肌保护作用无影响。
5.线粒体ATP敏感性钾离子通道可能与预先应用左旋甲状腺素钠的心肌保护作用机制无关。
第二部分临床试验部分:小儿体外循环心脏直视手术前应用小剂量甲状腺素片的心肌保护作用
本临床试验共包括40例年龄3～12岁、拟在CPB下实施择期简单先天性心脏病(房间隔缺损、室间隔缺损、卵圆孔未闭和动脉导管未闭)矫正手术的小儿,将小儿随机平均分为两组(每组20例):对照组和试验组。试验组小儿在手术前每天按0.4mg/kg体重口服甲状腺素片,共4天;对照组小儿手术前不服用此药。所有小儿的围手术期处理严格按照医院操作常规进行。检测小儿入院时、麻醉前以及手术后第1天、第2天、第4天的甲状腺激素血清水平变化,并在小儿入院时、手术后即刻以及手术后第1天和第2天观察并记录小儿的血流动力学指标,记录小儿保留气管插管时间、ICU停留时间以及在ICU中正生性肌力药物的使用情况。
在手术结束前,每组随机选取6例小儿留取右心房肌肉标本,采用western-blotting技术检测心房肌组织HSP70表达,采用实时定量PCR技术检测心房肌组织TR和MHC mRNA表达。在手术后24h时取血,采用AXSYM全自动免疫分析仪定量测定CK-MB血清活性,定性检测肌钙蛋白Ⅰ(troponinⅠ,TnⅠ)的阳性率。
结果显示,与入院时的基础值比较,对照组手术后第1天、第2天和第4天的T_3和FT_3血清水平以及手术后第1天的TSH、T_4和FT_4血清水平均显著降低。与入院时的基础值比较,试验组手术后第1天、第2天和第4天的T_3和FT_3血清水平以及手术后第1天的TSH血清水平均显著降低。
与对照组比较,试验组手术后第1天和第2天的T_3、FT_3和T_4血清水平以及手术后第1天的FT_4血清水平均显著升高。
与对照组比较,试验组的正性肌力药物使用率、CK-MB血清活性、TnⅠ血清阳性率和心房肌组织MHCβmRNA表达均显著降低,心房肌组织HSP70和MHCαmRNA表达均显著增强。
根据本临床试验的结果,我们得出以下结论:
1.在CPB下实施简单先天性心脏病矫正手术的小儿,手术后可发生Ⅱ型ESS。
2.虽然小儿CPB心脏直视手术前短期补充性应用小剂量甲状腺素片可减小手术后甲状腺激素血清水平降低的严重程度,并预防Ⅱ型ESS的发生,但是小儿手术后仍可发生Ⅰ型ESS。
3.小儿CPB心脏直视手术前短期补充小剂量甲状腺素片具有明确心肌保护作用,并且手术前短期补充应用小剂量甲状腺素片的心肌保护作用可能与甲状腺激素调控心肌组织HSP70和MHCαmRNA表达增强有关。
After the patients undergoing open heart surgery with cardiopulmonary bypass(CPB) experience global ischemia/reperfusion(I/R) injury during surgery,serum level of T_3 decreases significantly.This problem is especially common in pediatric patients.It has been demonstrated that all pediatric patients undergoing open heart surgery with CPB present the significant decreased serum levels of T_3 and T_4 after surgery,which is named as typeⅡEuthyroid sick syndrome(ESS) and may cause undesirable impact on the children's prognosis.
The available main therapeutic measure aimed at the postoperative ESS is that when decreased serum levels of thyroid hormones are detected during postoperative period, supplemental administration of exogenous thyroid hormones restores the serum levels of thyroid hormones to normal limits.However,postoperative supplemental administration of exogenous thyroid hormones can not ensure to achieve consistent and adequate therapeutic effect for ESS.Also,it may further interfere with the disturbed inner environment after open heart surgery with CPB,which is adverse to recuperate the patients' health.When serum levels of thyroid hormones are restored to normal limits by the postoperative supplemental administration of exogenous thyroid hormones,moreover,the beneficial effects of ESS may also be abolished.
It has been demonstrated that thyroid hormones can produce the definite cardioprotecton.In view of possible disadvantages of the postoperative supplemental administration of exogenous thyroid hormones,we consider that in pediatric patients undergoing the open heart surgery with CPB,preemptive administration of exogenous thyroid hormones before surgery may not only protect the myocardium against I/R injury during surgery by increasing the expression of myosin heavy chainα(MHCα) and heat shock protein 70(HSP70) in myocardial tissues,but also can avoid the adverse effects by the postoperative supplemental administration of exogenous thyroid hormones.However, there has been no published data on protection of myocardial I/R injury during surgery and prevention of postoperative ESS by administrating exogenous thyroid hormones before open heart surgery with CPB in pediatric patients.
Therefore,we designed this study including an animal experiment and a clinical trial. Our purposes were to determine whether preemptive administration of exogenous thyroid hormones could protect the myocardium against I/R injury and to explore the inherent mechanisms of the cardioprotecton by preemptive administration of thyroid hormones.By this study,we hoped to provide some useful rationales for further use of this simple cardioprotective measure in clinical practice.The animal experiment of this study was divided into three subunits.
Animal Experiment
Part 1.Protective effects of preemptive administration of different-dose levothyroxine-sodium against myocardial ischemia-reperfusion injury
After weighing,48 healthy female immature(aged 35 days) Wistar rats were randomly allocated into the six groups(8 rats in each group):blank control group(group BC),control group(group BC),10μg group(group 10μg),20μg group(group 20μg),40μg group(group 40μg) and 80μg group(group 80μg).The rats in groups BC and C were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups 10μg,20μg,40μg and 80μg were also pre-treated with levothyroxine-sodium 10μg/100g weight,20μg/100g weight,40μg/100g weight 80μg/100g weight,respectively,through a gastric tube every day.On the eighth day, all rats were again weighed and then underwent peripheral venous puncture to take blood sample for detection of serum levels of thyroid hormones.The hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion,whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hemodynamic variables including heart rate,systolic blood pressure(SBP),and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during balance period and at 10 min during reperfusion period,respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of cardiac enzyme-myocardial-bound creatine kinase(CK-MB).At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting, and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed that compared with groups BC and C,rats' weight on the experiment day was significantly lower in groups 20μg,40μg and 80μg.Also,rats' weight on the experiment day was significantly lower in groups 40μg and 80μg than in group 10μg.The serum levels of thyroid hormones were significantly higher in groups 20μg, 40μg and 80μg than in groups BC and C.The serum levels of thyroid hormones in groups 10μg,20μg,40μg and 80μg increased with the dosage of the levothyroxine-sodium,and the serum levels of thyroid hormones were significantly higher in group 80μg than in groups 10μg,20μg and 40μg.
As compared with groups BC and C,baselines of both heart rate and dp/dt_(max) were significantly higher in groups 10μg,20μg,40μg and 80μg.Baselines of SBP and -dp/dt_(max) were significantly higher in group 80μg than in groups 10μg and 20μg.
As compared with group BC,recovery rates of heart rate during reperfusion period significantly decreased in groups 40μg and 80μg,and recovery rates of both SBP and±dp/dt_(max) significantly decreased in groups 10μg,20μg,40μg and 80μg.As compared with group C,recovery rates of both heart rate and dp/dt_(max) during reperfusion period significantly increased in groups 10μg,20μg,40μg and 80μg,recovery rate of SBP during reperfusion period significantly increased at 20 min and 30 min in group 10μg and at 30 min in group 20μg,recovery rate of -dp/dt_(max) during reperfusion period significantly increased at all observed time points in groups 10μg,20μg and 40μg,and at 30 min in group 80μg.Comparisons among all four experiment groups,recovery rate of SBP at 30 min during reperfusion period was significantly lower in group 80μg than in group 10μg, and recovery rate of±dp/dt_(max) at 30 min during reperfusion period was significantly lower in groups 40μg and 80μg than in groups 10μg and 20μg.
As compared with groups BC and C,coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg,20μg,40μg and 80μg.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly higher in groups 10μg,20μg,40μg and 80μg than in group BC,but was significantly lower in groups 10μg,20μg and 40μg than in group C.Comparisons among all four experiment groups,the activity level of CK-MB in the coronary perfusion fluid during reperfusion period increased with the dosage of levothyroxine-sodium,and was significantly higher in group 80μg than in groups 10μg,20μg and 40μg.
The ventricular myocardial expression of HSP70 was stronger in four experiment groups than in groups BC and C,and significantly increased in groups 10μg and 20μg compared with groups 40μg and 80μg.
As compared with groups BC and C,the ventricular myocardial expression of MHCαmRNA significantly increased in four experimental groups,and the ventricular myocardial expression of TRα1 mRNA significantly increased in groups 20μg,40μg and 80μg. However,there were no significant differences in the ventricular myocardial expression of MHCαmRNA and TRα1 mRNA among four experiment groups.
Part 2.The influences of fentanyl and sufentanil on cardioprotection of preemptive levothyroxine-sodium administration
Fifty-six healthy,female immature(aged 35 days) Wistar rats were randomly allocated into the seven groups(8 rats in each group):blank control group(group BC), control group(group C),levothyroxine-sodium 10μg group(group 10μg),fentanyl group (group F),sufentanil group(group S),combined fentanyl and levothyroxine-sodium(group F+L) and combined sufentanil and levothyroxine-sodium(group S+L).The rats in groups BC,C,F and S were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups F+L,S+L and 10μg were also pre-treated with levothyroxine sodium 10μg/100g weight,through a gastric tube every day.On the eighth day,the hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion, whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hearts were perfused with KH fluid containing fentanyl 30μg/L in the F and F+L groups,with KH fluid containing sufentanil 3μg/L in the S and S+L groups,and with KH fluid in other groups, respectively.The hemodynamic variables including heart rate,systolic blood pressure (SBP),and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during balance period and at 10 min during reperfusion period, respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of CK-MB.At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting,and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed no significant differences in baselines of both heart rate and SBP among seven groups.Baselines of±dp/dt_(max) were significantly higher in groups 10μg,F+L and S+L than in groups BC,C,F and S.
As compared with group BC,all hemodynamic variables during reperfusion period significantly decreased in groups F and S.As compared with group C,all hemodynamic variables during reperfusion period significantly increased in groups 10μg,F+L and S+L. All hemodynamic variables during reperfusion period were significantly higher in groups 10μg,F+L and S+L than in groups F and S.However,there were no significant differences in all hemodynamic variables during reperfusion period among groups 10μg,F+L and S+L.
The coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,there were no significant differences in the coronary perfusion flows in balance period and reperfusion period among groups 10μg,F+L and S+L.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly higher in groups 10μg,F+L and S+L than in group BC,but lower in groups 10μg,F+L and S+L than in groups C,F and S.The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was not significant different among groups 10μg,F+L and S+L.
The ventricular myocardial expression of HSP70 significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,there were no obvious differences in the ventricular myocardial expression of HSP70 among groups 10μg,F+L and S+L.
The ventricular myocardial expression of MHCαmRNA significantly increased in groups 10μg,F+L and S+L compared with groups C,F and S.However,the ventricular myocardial expression of MHCαmRNA was not significant different among groups 10μg, F+L and S+L.Also,there were no significant differences in the ventricular myocardial expression of TRα1 mRNA among all seven groups.
Part 3.The relationship between mitochondrial K_(ATP) and cardioprotection of preemptive levothyroxine-sodium administration
Thirty-two healthy,female immature(aged 35 days) Wistar rats were randomly allocated into the four groups(8 rats in each group):blank control group(group BC), control group(group C),levothyroxine-sodium 10μg group(group 10μg) and combined glibenclimide and levothyroxine-sodium group(group G+L).The rats in groups BC and C were fed with normal food for 7 days before experiment.Except for feeding with normal food for 7 days before experiment,the rats in groups 10μg and G+L were also pre-treated with levothyroxine-sodium 10μg/100g weight,through a gastric tube every day.On the eighth day,the hearts were harvested from the anesthetized rats,and appended to a Langendorff apparatus for isolated heart perfusion model.The hearts in group BC were perfused with KH fluid for 80 min without zero-perfusion,whereas the hearts in other groups experienced in order a 30-min balance period,a 20-min normothermic zero-perfusion and a 30-min reperfusion period.The hearts were perfused with KH fluid containing glibenclimide 30μmol/L in group G+L,and with KH fluid in other groups, respectively.The hemodynamic variables including heart rate,systolic blood pressure,and±dp/dt_(max) were continuously monitored.The coronary perfusion flow was recorded at 10 min during the balance period and at 10 min during reperfusion period,respectively.At 15 min during reperfusion period,the coronary perfusion fluid was collected for detection of CK-MB.At the end of perfusion,the ventricular muscle samples were taken to detect expression of HSP70 by Western-blotting,and expression of both MHC mRNA and thyroid hormone receptor(TR) mRNA by quantitative RT-PCR.
The results showed no significant differences in baselines of both heart rate and SBP among four groups.However,baselines of±dp/dt_(max) significantly increased in groups 10μg and G+L compared with groups BC and C.
As compared with group C,all hemodynamic variables during reperfusion period significantly increased in groups 10μg and G+L.However,all hemodynamic variables during reperfusion period were not significant different between groups 10μg and G+L.
The coronary perfusion flows in balance period and reperfusion period significantly increased in groups 10μg and G+L compared with group C.Also,the coronary perfusion flow in balance period significantly increased in groups 10μg and G+L compared with group BC.However,there were no significant differences in the coronary perfusion flows in balance period and reperfusion period between groups 10μg and G+L.
The activity level of CK-MB in the coronary perfusion fluid during reperfusion period was significantly lower in groups 10μg and G+L than in group C,but significantly higher in groups 10μg and G+L than in group BC.There were no significant differences in the activity level of CK-MB in the coronary perfusion fluid during reperfusion period between groups 10μg and G+L.
The ventricular myocardial expression of HSP70 significantly increased in groups 10μg and G+L than in groups BC and C.However,there was no significant difference in the ventricular myocardial expression of HSP70 between groups 10μg and G+L.
The ventricular myocardial expression of MHCαmRNA significantly increased in groups 10μg and G+L compared with groups BC and C.However,there was no significant difference in the ventricular myocardial expression of MHCαmRNA between groups 10μg and G+L.Also,the ventricular myocardial expression of TRα1 mRNA was not significant different among all four groups.
Based on the results from all three animal experiments,the following conclusions could be drawn.
1.Preemptive administration of small-dose levothyroxine-sodium can protect myocardium against I/R injury,whereas preemptive administration of larger dose levothyroxine-sodium can only produce an attenuated cardioprotection effect and might result in occurrence of hyperthyroidism.
2.Of four dosages of levothyroxine-sodium used in this experiment,a dosage of 10μg/100g weight achieves the best cardioprotection effect without occurrence of hyperthyroidism.
3.The cardioprotective effect of preemptive levothyroxine-sodium administration is probably contributed to the increased myocardial expression of HSP70 and MHCαmRNA.
4.Both fentanyl and sufentanil do not influence the cardioprotective effect of preemptive levothyroxine-sodium administration.
5.Mitochondrial ATP sensitive potassium channel is not probably involved in the mechanism of the cardioprotection by preemptive levothyroxine-sodium administration.
Clinical trial
The cardioprotective effect of small-dose thyroid hormone tablet administration before open heart surgery with cardiopulmonary bypass in children
Forty children aged 3-12 year,scheduled for elective simple congenital heart diseases (atrial septal defect,ventricular septal defect,patent foramen ovale and patent ductus arteriosus) surgery with cardiopulmonary bypass(CPB) were included in this clinical trial. They were randomly allocated equally into two groups:control group(n=20) and trial group(n=20).The children in the trial group took thyroid hormone tablet 0.4 mg/kg weight every day for four days before surgery,while the children in the control group were not given this tablet.In perioperative period,all children were treated according to the standing guidelines of the hospital.The serum levels of thyroid hormones were detected at following observed points:administration day,before anesthesia,and 1st,2nd and 4th day after surgery.The hemodynamic parameters were recorded at following observed points: administration day,immediately after surgery,and 1st and 2nd day after surgery.Also, duration of intubation and ICU stay,and the application of inotropic drugs in the ICU were noted.
During surgery,right atria samples were taken from six children randomly chosen in each group to detect the myocardial expression of HSP70 by Western-blotting and the myocardial expression of TR mRNA and MHC mRNA by RT-PCR.At 24 hour after surgery,the blood samples were also taken to quantitatively assess serum activity of CK-MB and to qualitatively assay the positive ratio of TnI by AXSYM automatic immunoassay systems.
The results showed that compared with the baselines on the administration day,in control group,the serum levels of both T_3 and FT_3 on the 1st,2nd and 4th day after surgery, and the serum levels of TSH,T_4 and FT_4 on the 1st day after surgery significantly decreased.As compared with the baselines on the administration day,in trial group,the serum levels of T_3 and FT_3 on the 1st,2nd and 4th day after surgery,and the level serum TSH on the 1st day after surgery significantly decreased.
The serum levels of T_3,FT_3 and T_4 on the 1st and 2nd day after surgery,the serum level of FT_4 on the 1st day after surgery were significantly higher in the trial group than in control group.
The application rate of inotropic drugs in ICU,the serum activity of CK-MB,the positive ratio of TnI and the atrial myocardial expression of MHCβmRNA significantly decreased,and the atrial myocardial expression of HSP70 and MHCαmRNA significantly increased in the trial group compared with control group.
Based on the results of this clinical trial,the following conclusions could be drawn.
1.In children undergoing simple open heart surgery with CPB,TypeⅡESS may occur after surgery.
2.A short-term administration of small-dose thyroid hormone tablet before surgery in children undergoing open heart surgery with CPB can reduce the severity of decreased serum levels of thyroid hormones after surgery and prevent occurrence of postoperative typeⅡESS.However,typeⅠESS may still occur after surgery in the children.
3.A short-term administration of small-dose thyroid hormone tablet before surgery in children undergoing open heart surgery with CPB can produce definite cardioprotecton. Also,the cardioprotective effects by administration of small-dose thyroid hormone tablet before surgery may be contributed to the increased myocardial expression of HSP70 and MHCαmRNA.
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