The Relationship Between Mitochondrial Fission,Fusion Imbalance And Myocardial Dysfunction In Sepsis

Objective(1)To investigate the corrrelation between metabolic energy dysfunction and organs dysfunction in septic shock patients(2)To investigate the charatertiscs of myocardial mitochondrial fission and fusion,and related molecular mechanisms in sepsis rat(3)To investigate the effect of the regulation of mitochondrial fission and fusion imbalance on myocardial energy metabolism and functionMethods(1)The septic shock patients were prospectively observed,who with mechanical ventilation from October 2016 to January 2017.All the patients received transcutaneous oxygen challenge test(10 min-OCT inspired 1.0 Fi02 for 10-min),simultaneous arterial and central venous blood gas were obtained to calculate Ratio,patients were divided into three groups based on level of 10 min-OCT and Ratio:Group A(10 min-OCT>66mmHg and Ratio<1.23);Group B(10 min-OCT<66mmHg)Group C(10 min-OCT>66mmHg and Ratio>1.23).All the patients’ general information,TO,T24,T48 haemodynamics(MAP Lac ScvO2)and organs dysfunction data(KIDGO score SOFA score)were collected.(2)SD rats were divided into four groups randomly(8 in each group):Group SAM;Group CLP2h;Group CLP10h;GroupCLP18h.RT-PCR technology were applied to assess the level of Drp1、Mfn2、Opa1 mRNA,protein level of Drpl were assessed by Western Blot technology.Myocardial mitochondrial fission and fusion were assessed by transmission electron microscope.(3)SD rats were divided into four groups randomly(8 in each group):Group SAM;Group SAM+Mdi;Group CLP;Group CLP+Mdi.Cardiac function of rats in each group were assessed by echocardiography 18h after operations.Myocardial mitochondrial fission and fusion were assessed by transmission electron microscope,and the level of complex IV and ATP in myocardium were measured.Result(1)49 patients were included in the study,The utilization rate of inotropes in Group B and Group C were significantly higher in Group A(P<0.05),but no significant difference between Group B and Group C(P>0.05).There was no significant difference in the incidence of AKI among three groups at TO(P=0.114),but Group C had a significantly higher incidence of AKI than Group A at both T24 and T48(P=0.038).Group C had a significantly higher aggravating AKI rate than both Group A and Group B(P=0.015).Group C had a significantly higher SOFA score than Group A(P<0.05).Group C had a significantly higher Mortality than Group A(P=0.001).The ratio predicted in 24hours after resuscitation the area of which the SOFA score under the ROC curves was 0.766.(2)There were no difference in myocardial mitochondrial morphology between Group SAM and Group CLP2h,The Group CLP10h and Group CLP18h had myocardial mitochondrial morphology imbalance compared with Group SAM.Group SAM had a significantly lower Drpl mRNA and protein level than CLP10h and Group CLP18h(P<0.05);Group SAM had a significantly lower Mfn2 and OPA1 mRNA level in Group CLP2h,Group CLP 1 Oh and Group CLP 18h(P<0.05).(3)The Group CLP had significantly myocardial mitochondrial morphology difference compared with Group SAM,and Group CLP+Mdi had significantly better myocardial mitochondrial morphology than Group CLP.Group CLP had significantly higher complex IV and ATP level than Group SAM(P<0.05),and CLP+Mdi Group had significantly higher complex Ⅳ and ATP level than Group CLP(P<0.05)Group CLP had significantly lower LVEF、SV than Group SAM,but Group CLP+Mdi had a significantly higher LVEF、SV than Group CLP.ConclusionPart one:(1)Apply of 10 min-OCT and Ratio is helpful to determine oxygen utilization abnormability in septic shock patients.(2)If anaerobic metabolism still persists exit after circulation recovery,the septic shock patients will have a worse organs dysfunction and prognosis(3)Organs dysfunction in organs with abundant mitochondria like heart and kidney are likely to be in progress when septic shock patients combine tissue oxygen utilization abnormal.(4)Ratio showned a good value for prediction of the progression of organ dysfunction in septic shock patients.Part two:(1)The CLP sepsis rats myocardium had a excessive fission mitochondria,which is related to the sepsis-induced myocardial dysfunction.(2)Drp1 protein expression was associated with excessively mitochondrial fission in septic myocardial.Part three:(1)Excessive fission mitochondria is associated with oxidation respiratory abnormal,and excessive fission mitochondria palys an important role in the sepsis-induced myocardial dysfunction.(2)Reduction of excessive fission mitochondria might be a new therapeutic target for sepsis-induced myocardial dysfunction.(3)Mdivi-1 intraperitoneal could correct excessively mitochondrial fission and improve the cardiac function in septic shock.