Clinical Research On Guiding Role Of Catecholamine And EETs In Precise Treatment Of Children With OI

Research backgroundVasovagal syncope(VVS)and postural orthostatic tachycardia syndrome(POTS)are the most common types of children's orthostatic intolerance(OI).The children have recurrent syncope,dizziness,chest distress and other symptomswhich may be aggravated by changes of body position,emotional tension,standing for a long time,etc.,and relieved after supine position.These diseases are characterized by high incidence,easyly neglected,repeated attack,difficult diagnosis and good prognosis.Analysis of clinical data with large sample size helps to shorten the diagnosis and treatment cycle.Autonomic nerve dysfunction plays an important role in the pathogenesis of VVS and POTS,and it is of great clinical significance to evaluate autonomic nerve function in children with VVS and POTS.Catecholamine directly reflect autonomic nervous activity.The level of plasma adrenaline and norepinephrine(NE)increased before syncope occured to VVS patients,further increased rapidly when syncope occured.The occurrence of syncope and other symptoms in children with POTS may be related to the increase of plasma NE concentration during upright posture.It is speculated that high level of catecholamine may be an important factor for VVS and POTS.?-blocker can inhibit the excitability of sympathetic nerve,decrease catecholamine level.Theoretically,it is one of the effective drugs to treat such diseases,but there are inconsistencies in clinical practice.At present,there is a lack of effective biological indicators to evaluate the status of catecholamine in children and to guide the application of beta-blockers.Repeated or persistent symptoms of orthostatic intolerance seriously affect children's daily learning and life,bringing serious psychological and spiritual burden to the children and their families.The evaluation and intervention of the psychological state of children with VVS and POTS is an important part in the treatment of these diseases,.The 01 symptom score scale is mainly used to evaluate the clinical symptoms and therapeutic effect of 01 children,and there is no relevant study on whether there is a correlation with the severity of mood disorders in children.Epoxyeicosatrienoic acids(EETs)is an endothelial hyperpolarizing factor produced by arachidonic acid via cytochrome P450 pathway,which can act on the membrane of adjacent vascular smooth muscle cells to produce hyperglycation and vasorelaxation,resulting in vasodilation and hypotension.In terms of hemodynamics,the blood pressure of children with VVS and POTSmay be decreased due to excessive relaxation of peripheral blood vessels,it is suggested that vasodilative factors may be involved in the pathogenesis of VVS and POTS,but whether EETs is involved in the pathogenesis of VVS and POTS has not been investigated.Research objectives1.To analyze the clinical characteristics,and the variability of heart rates and blood pressure of children with VVS and pots and draw ROC curve,so as to find the clinical indicators guiding the early diagnosis and treatment.2.LC-MS/MS method was used to test the 24h urine catecholamine level in children,ROC curve was drawn to analyze the guiding value of NE level in the clinical application of ?-blocker for precise treatment of VVS and POTS;and to analyze the value of catecholamine and symptom score in predicting emotional disorders in children with VVS and POTS,guiding clinical treatment and early psychological intervention.3.Testing the level of 14,15-DHET which is metabolites of EETs by ELISA,and the correlations between the levels of arachidonic acid metabolites and urine catecholamines were analyzed to evaluate the role of EETs in the precise treatment of VVS and POTS in childrenResearch methods1.Analysing the clinical characteristics,blood pressure and heart rate variability of VVS and POTSThis study retrospectively analyzed the clinical data of children with with VVS and(or)POTS which were diagnosed in Qilu hospital of Shandong university,the patient's gender,age,weight,complained of symptoms,complained of symptoms,complaint time,inducement,basic systolic blood pressure,basic diastolic blood pressure,basic heart rate,the HUTT symptoms before positive attack,the time of positive attac.The data of blood pressure and heart rate during HUTT were recorded,including the systolic blood pressure,diastolic blood pressure and heart rate of children in supine position(1,5,10 min),upright position(1,5,10 min),tilted position(1,5,10,15,20,25,30,35 min),to evaluate the variability of heart rate and blood pressure during HUTT in children with VVS and(or)POTS and whether there is any difference between them and the negative and normal children.If the children were placed to the supine position when syncope or syncope symptoms occur during HUTT,then the data are included in the heart rate and blood pressure data of the time node before the placed to the supine position(no VVS positive reaction).According to the test results,the children's data were divided into VVS group,POTS group,POTS combined with VVS(VVS+POTS)group,negative group and healthy control group.The systolic blood pressure,diastolic blood pressure change and heart rate variability coefficient of each group were calculated and analyzed statistically.2.Assessing the role of catecholamine in guiding the precise treatment of children with VVS and POTSIn this study,38 children with unexplained recurrent syncope or premonitory syncope were selected,all of them were diagnosed as VVS by vertical tilt table test,and 20 healthy children were selected as control group.24 urine samples of 38 children with VVS were collected from the next day after diagnosis,and 24-hour urine NE level was measured by LC-MS/MS,they were given the basic treatment and oral metoprolol(0.5mg/kg.d,bid,for 3 month).The follow-up period was 3 months by telephone and outpatient.The follow-up contents included the frequency and degree of symptom attack,the compliance of treatment and drug tolerance,which were recorded in detail.The clinical data of 43 children with pots and VVS+POTS(19 cases with pots,24 cases with VVS+ POTS)were analyzed retrospectively.19 children with POTS were treated with basic therapy and oral metoprolol(the same as above),and the therapeutic effect was assessed the same as VVS.Individual interventions including basic treatment were used in the treatment of VVS+POTS.All patients were evaluated after 3 months.The frequency of syncope and its premonitory symptoms was taken as the main therapeutic index.The symptoms included syncope,dizziness,nausea,palpitation,headache,tremor of hands,chest distress and unclear vision.When the total score of symptoms decreased by more than 50%,the treatment was effective.ROC curve was used to analyze the predictive value of 24-hour urine NE for VVS and POTS.3.The role of catecholamine and OI scale in the assessment of emotional disorders in children with VVS and POTSIn this study,42 children with orthostatic intolerance were randomly selected from June 2017 to December 2018,aged 9-14 years old,who were diagnosed as VVS or POTS by HUTT.Children's anxiety and depression were assessed by SCARED and CDI,and children's OI symptom scale was used for symptom scoring.According to the scale score,the children were divided into anxiety and non-anxiety group,depression and non-depression group.The scores of the above scales were filled in by the children themselves after they were diagnosed and informed consent of their families was obtained.The data of SCARED was compared with the national norm group,and the data of CDI was compared with the CDI evaluation data of primary and secondary schools in urban and rural areas in Hefei conducted by Wang Jun and others in 2010.24 urine samples were collected from the next day after the diagnosis was confirmed.24-hours urine catecholamine level was tested by LC-MS/MS method,and the data of each group were statistically analyzed.The relationship between psychological scale scores and symptom scores of VVS and POTS was analyzed,and the ROC curve was used to evaluate the predictive value of symptom score scale for emotional disorders,ROC curve was used to evaluate the predictive value of symptom scale for emotional disorders.4.Preliminary study on the value of EETs in guiding the precise treatment of children with VVS and POTSIn this study,38 children who were hospitalized in the children's medical center of the hospital from June 2018 to June 2019 were randomly selected,all of whom were diagnosed as VVS orPOTS(VVS 26 cases,POTS 12 cases)by HUTT.The 24-hour urine 14,15-EETs(DHET)of the children were tested by ELISA,and the correlation analysis was anlyzed between the 24-hour urine 14,15-EETs and age,weight,24-hour urine volume,14,15-DHET concentration,basic systolic pressure,basic diastolic pressure,basic heart rate,24-hour urine Na+,K+,Cl-,Ca2+,24-hour urine catecholamine,lying renin,angiotensin,aldosterone.Results1.Analysis of clinical characteristics,blood pressure and heart rate variability of VVS and POTS(1)HUTT should be operated to determine whether the dianosises are VVS and POTS when 01 symptoms exist and organic lesions are eliminated.Systolic,diastolic and heart rate variability coefficients of VVS and POTS are significantly higher than those of healthy control group(P<0.05).(2)In VVS group,the CV of systolic blood pressure in upright tilt,supine and upright position was higher than that in POTS group(P<0.05),and the CV of heart rate in upright tilt,supine and upright position was lower than that in POTS group(P<0.01),the CV of heart rate in upright tilt,supine and upright position was lower than that in VVS+POTS group(P<0.01),and the CV of diastolic blood pressure in supine and upright position was lower than that in VVS+pots group(P<0.05).(3)The CV of systolic blood pressure in upright tilt of POTS group was lower than that in VVS+POTS group(P<0.05),the CV of systolic and diastolic blood pressure in upright tilt position were lower than those in VVS+POTS group(P<0.05),and the CV of heart rate in supine and upright position were significantly lower than those in VVS+POTS group(P<0.01).(4)Compared in VVS group,POTS group,VVS+POTS group and negative group,the heart rate variability coefficient of upright tilt position was significantly lower than that of supine and upright position(P<0.01),ROC curve analysis showed that when the heart rate variability coefficient of supine and upright position was?10.47%,it could be used as a reference index for HUTT examination.2.The results and clinical value of 24-hour urine NE testing in children with VVS and POTS(1)There was a significant individual difference in 24-hour urine NE level in children with VVS(dispersion coefficient is 44.63%),and it was significantly correlated with the basic systolic and diastolic pressures(r=0.604,P<0.001)and(r=0.400,P<0.05).(2)According to ROC curve analysis of therapeutic effect of metoprolol,the area under the curve is 0.926(95%confidence interval is 0.848-1).When 24-hour urine NE=34.84?g/24 h,the sensitivity and specificity of predicting value of metoprolol's therapeutic efficacy on VVS are 70%and 100%.(3)The 24-hour urine NE level of children with VVS+POTS was lower than that of children with POTS alone(P<0.01),the male children were more likely to have POTS alone,while the female children were more likely to have VVS in combination(P=0.01).The therapeutic efficacy of metoprolol in the treatment of POTS was 84.21%.3.The role of catecholamine and OI scale in the assessment of emotional disorders in children with WS and POTS(1)The score of SCARED in VVS group was higher than that in normal group(P<0.01),the score in VVS anxiety group was higher than that in non-anxiety group(P<0.01),the OI symptom score in anxiety group was higher than that in non-anxiety group(P<0.01).(2)Pearson analysis showed that there was a significant correlation between symptom score and SCARED score in VVS group(r=0.691,P<0.001).The area under ROC curve is 0.911(95%confidence interval is 0.804 to 1)according to the children's OI symptom score and whether they are combined with anxiety.When VVS children's symptom score=8.5,the sensitivity and specificity of OI symptom score in predicting VVS children suffering from anxiety disorder are 81.3%and 91.7%,respectively.(3)CDI score of VVS depression group was higher than that of Hefei normal group(P<0.01),OI symptom score of VVS depression group was higher than that of non depression group(P<0.001).(4)Pearson analysis showed that there was a correlation between OI symptom score and CDI score(r=0.46,P<0.05).The area under ROC curve was 0.688(95%confidence interval was 0.476 to 0.899)according to the children's OI symptom score and whether they suffered from depression.When the VVS children's OI symptom score was 7.5,the sensitivity and specificity of OI symptom score in predicting VVS children suffering from depression disorder are 87.5%and 55%,respectively.(5)The score of SCARED in POTS group was higher than that in the national norm group(P<0.05),the score of SCARED,somatization/panic,concise anxiety scale in POTS anxiety group was significantly higher than in non-anxiety group(P<0.01),and the scores of "dissociative anxiety,generalized anxiety,social phobia"were higher than that in non-anxiety group(P<0.05).All children with POTS had obvious school phobia.The level of 24h urine NE in children with anxiety disorder of POTS was lower than that in children without anxiety(P<0.05),and the rate of NE decreased was higher than that in children without anxiety(P<0.05).(6)Pearson correlation analysis showed that there was a significant correlation between OI symptom score and SCARED score(r=0.71,P<0.01)in POTS children.The area under ROC curve is 1(95%confidence interval is 1)according to children's symptom score and whether they suffered from anxiety disorder.When POTS children's symptom score=8,the sensitivity and specificity of OI symptom score in predicting POTS children suffering from anxiety disorder are 100%and 100%,respectively.Pearson correlation analysis showed that there was a correlation between OI symptom score and CDI score(r=0.625,P<0.05)in POTS children.4.A preliminary study on the value of EETs in guiding the precise treatment of children with VVS and POTS(1)The level of 14,15-DHET in 24-hour urine was correlated with 24-hour urine volume and 14,15-DHET concentration,and weakly correlated with the level of angiotension ? in supine position.(2)The 24-hour urine 14,15-DHET level of children with POTS was correlated with 24-hour urine volume and 14,15-DHET concentration,strongly correlated with 24-hour urine Na+(r=0.668,P=0.018),moderately correlated with 24h urine Ca2+(r=0.485,P=0.11),and moderately correlated with 24-hour urine Cl-(r=0.539,P=0.07);It was moderately correlated with 24-hour urine dopamine(r=0.512,P=0.089),weakly correlated with 24-hour urine NE(r=0.346,P=0.271).Conclusions1.The CV of heart rate and blood pressure can be used as a reference index to judge the autonomic nerve function of children with VVS and POTS.When CV of heart rate in supine and upright position is>10.47%,HUTT can be recommended.2.The 24-hour urine NE level can be used as a reference index to predict the therapeutic effect of metoprolol on VVS.3.The 24-hour urine NE level of children with POTS+VVS was lower than that of children with POTS alone.There are more males with POTS alone,and more females with POTS+VVS.?-blocker is more effective in treating patients with POTS alone,but it needs individualized treatment.4.The incidence rate of anxiety and depression in children with VVS and POTS was higher than that in children without anxiety.5.There was a positive correlation between the emotional disorder and the score of orthostatic intolerance.The children with high 01 score were more likely to have anxiety and depressive emotional disorder,and the symptoms were more serious.6.EETs may play a certain antagonistic effect on the pressor factors in children with POTS and VVS,and the effect on children with POTS may be more obvious.