| Dilated Cardiomyopathy(DCM)is the most common Cardiomyopathy in children under 18 years of age and the most common cause of heart failure(HF)and heart transplantation,with a 1-year mortality rate of 20% and a 4-year mortality rate of 56%.But so far,there is still a lack of effective treatment and early risk prediction models for pediatric dilated cardiomyopathy.Researches have shown that age,family history of sudden death,history of syncope,systolic blood pressure,serum sodium,brain natriuretic peptide precursor,malignant arrhythmia,ventricular dilation,ventricular ejection fraction,myocardial fibrosis,genetic mutations associated with poor prognosis of dilated cardiomyopathy.In particular,gene mutation can help to study the mechanism of DCM and prevent sudden death in children with dilated cardiomyopathy.Therefore,the prognosis of dilated cardiomyopathy can be improved by studying the clinical characteristics and gene mutations of children with dilated cardiomyopathy,looking for early risk factors,developing risk prediction models and early intervention methods.Part Ⅰ Clinical study of dilated cardiomyopathy in children Objectives To find the early risk factors of dilated cardiomyopathy and construct the risk prediction model in order to realize the early intervention by summarizing the clinical data of dilated cardiomyopathy with the cardiac function level III/IV in children.Methods Cases of children diagnosed with DCM and heart failure who were hospitalized at the First Affiliated Hospital of Guangxi Medical University from March 2003 to September 2021 were collected.The general data,symptoms and signs,laboratory test results,electrocardiograph,chest x-ray,echocardiography,cardiac MRI,and therapeutic drugs of the included cases were collected;and the results of left ventricular end-diastolic dimension and left ventricular ejection fraction were collected during follow-up.The primary follow-up outcome was death.The follow-up endpoint was the time of the last follow-up or the time of death;according to the degree of heart failure of the children at the time of initial diagnosis,the ROSS/NYHA cardiac function assessment level I or II was divided into cardiac function level I/II group,ROSS/NYHA cardiac function assessment level III or IV was divided into cardiac function level III/IV group,and the clinical data and prognosis of the two groups of patients were retrospectively analyzed,and the early risk factors were explored.Results(1)A total of 121 children with DCM were collected,accounting for37.9 per 100,000 of all hospitalized cases aged less than 18 years in the hospital during the same period.Among the participants,69(57%)were males and 52(43%)were females.The average age at the onset of cardiac function level I,cardiac function grade II,cardiac function grade III,and cardiac function iv was6.9±4.8 years old,8.0±4.5 years old,10.2± 5.6 years,12.1± 4.4 years old,respectively,and the difference in the average age increase between the cardiac function grading groups was statistically significant(P=0.017).The average follow-up time of children with cardiac function grade I,cardiac function grade II,cardiac function grade III,and cardiac function grade IV was 80.0± 20.0months,39.0±46.1 months,29.2± 43.8 months,12.8 ± 28.2 months,respectively,and the difference in the reduction in follow-up time between the cardiac function grading groups was statistically significant(P=0.011).At the same time,the rate of admission to the ICU and the increase in mortality rate between the various cardiac function grading groups were statistically significant(P=0.002,P<0.001).(2)There were 82 patients in grade III/IV group with a mean age of 10.8±5.4years,and 39 patients in grade I/II group with a mean age of 7.9±4.4 years.The difference in the mean age of onset was statistically significant between the two groups(P=0.004).There were statistically significant differences in ICU admission rate,mean follow-up time and mortality rate between class III/IV cardiac function group and class I/II cardiac function group(P<0.05).In addition,the proportion of males in grade III/IV group and grade I/II group was 63.4%and 43.5%,respectively,and the difference of male proportion reduction between the two groups was statistically significant(P=0.04).There was no significant difference in race,duration of symptoms or history of multiple hospital admissions between the two groups.(3)The symptoms and signs of 121 children with DCM were analyzed.Compared with the cardiac function I/II group,the rate of ascites in the cardiac function III/IV group was significantly lower(P=0.042).The mean systolic blood pressure at admission(97.2±14.4mm Hg)in the class III/IV group was significantly lower than that in the class I/II group(104.1±14.4mm Hg)(P=0.012).(4)In laboratory examination of 121 children with cardiac function grade III/IV group,compared with cardiac function grade I/II group,serum sodium decreased,urea nitrogen,creatinine,uric acid,brain natriuretic peptide precursor levels increased,and red blood cell distribution width increased,the differences were statistically significant(P<0.05).(5)In terms of instrument examination,the ECG results of 121 children showed no statistically significant difference between the abnormal ECG manifestations of grade III/IV group and grade I/II group.The mean cardiothoracic ratio(0.684±0.055)in grade III/IV was significantly higher than that in grade I/II(0.631±0.060),and the difference was statistically significant(P< 0.001).Comparing with cardiac I/II grade group,the difference of the left ventricular end-diastolic volume,left ventricular end-diastolic diameter,left ventricular end-systolic diameter,the left atrium and right ventricle diameter,left ventricular ejection fraction,aortic regurgitation,and tricuspid regurgitation in cardiac function grade III/IV group had statistical significance(P<0.05).(6)Among the 17 children who underwent cardiac magnetic resonance examination,9(52.9%)were found to have myocardial fibrosis,including 6patients in grade III/IV group with 5 patients died,and 3 patients in grade I/II group,all of whom survived.Compared with cardiac ultrasound examination at the same time,there were no statistically significant differences in left ventricular end-diastolic diameter and left atrial inner diameter in cardiac MRI group,and there were statistically significant differences in left ventricular enddiastolic posterior wall thickness,left ventricular septum thickness and left ventricular ejection fraction(P<0.05).(7)In terms of drug therapy,there were statistically significant differences in the increased use rates of β blockers,furosemide,spironolone and digoxin in class III/IV cardiac function group compared with class I/II cardiac function group(P<0.05).There were statistically significant differences in left ventricular enddiastolic diameter between the conventional treatment group,the conventional +hormone group,and the conventional + hormone + immunoglobulin group at 1and 3 months after treatment(P < 0.05).There were statistically significant differences in left ventricular ejection fraction between the conventional treatment group,the conventional + hormone group,and the conventional +hormone + immunoglobulin group 6 months after treatment(P < 0.05).The difference in survival rate among the three groups was statistically significant,and the survival rate of conventional + hormone group and conventional +hormone + immunoglobulin group was significantly higher than that of conventional group(P<0.05).(8)In the follow-up of cardiac ultrasound at 1 month,3 months,6 months,1year,2 years and 3 years after treatment,compared with the LVEF at the onset,the increase of LVEF at the 6th month was statistically significant in the whole group,the cardiac function III/IV group and the cardiac function I/II group(P <0.05).At 1 month and 3 months after treatment,compared with the cardiac function I/II group,the difference of increased LVEDD and decreased LVEF in the cardiac function III/IV group was statistically significant(P<0.05).(9)Compared with the cardiac function level I/II group,Kaplan-Meier survival analysis showed that the overall survival rate of the cardiac function level III/IV group in the 1st,2nd,and 5th years was significantly lower than that in the cardiac function level I/II group.Cox regression analysis suggested that cardiac function level III/IV remained a risk factor for DCM death after adjusting for sex,age,heart rate,ventricular function,laboratory examination and drug use(Risk ratio [HR] 2.663,95% confidence period [CI] 1.408-5.038,P<0.005).(10)In terms of risk factor analysis,age,systolic blood pressure,serum sodium and left ventricular end-diastolic diameter Z value were independent risk factors for DCM children with grade III/IV heart function(P<0.05)in multi-factor binary logistic regression analysis.Age,systolic blood pressure,serum sodium and z value of left ventricular end diastolic diameter were used to construct ROC curve and multivariate logistic regression model.Among them,age ≥12.4years was 2 points,systolic blood pressure ≤ 91 mm Hg was 1 point,serum sodium ≤ 135.50 mmol/L was 2 points,and left ventricular end-diastolic diameter Z value ≥ 7.23 was 1 point.After ROC curve analysis was performed again,cut-off score was 2.The sensitivity and specificity for predicting dilated cardiomyopathy with grade III/IV cardiac function were 85% and 80%(area under curve [AUC]O.898,95% confidence period [CI] 0.838-0.959).Age,systolic blood pressure,serum sodium,and left ventricular end-diastolic diameter Z-value in the nomograph risk models were used to predict dilated cardiomyopathy with cardiac function grade III/IV with 73.2% sensitivity and79.5% specificity(area under the curve [AUC]O.832,95% confidence period[CI] 0.754-0.910).Conclusions(1)DCM cases accounted for 37.9/100,000 of all hospitalized cases under 18 years of age in our hospital during the same period.(2)Children in the cardiac function III/IV group were older and more likely to be male,have lower systolic blood pressure measurements,be admitted to the intensive care unit.(3)In children with DCM,the improvement of LVEDD and LVEF in the cardiac function III/IV group after treatment was worse than that in the cardiac function I/II group,and the risk of death was higher.(4)Conventional treatment combined with hormone and immunoglobulin can improve the prognosis of DCM.(5)During follow-up,LVEF improvement was most significant at 6 months after treatment.(6)Age,systolic blood pressure,serum sodium and left ventricular end-diastolic diameter Z value are independent risk factors for DCM children with cardiac function grade III/IV,which can lay a foundation for the construction of risk prediction model for DCM patients with cardiac function grade III/IV.Part Ⅱ Study on pathogenic genes of dilated cardiomyopathy in children Objectives Through the detection of known DCM pathogenic genes in children with DCM,the relationship between gene mutation and clinical characteristics of DCM was studied in order to achieve early intervention and accurate diagnosis and treatment.Methods The genetic test results and clinical information of children diagnosed with dilated cardiomyopathy in the First Affiliated Hospital of Guangxi Medical University from June 2015 to July 2021 were collected.According to the pathogenicity of genes,the pathogenic and likely pathogenic were divided into one group,and the uncertain significance was divided into one group.The clinical indicators of the two groups were compared,and the genetic test results were summarized.Results(1)A total of 27 DCM cases were included,including 16 males and 11 females,with an average age of 8.5±4.4(0.3 ～ 13.7)years.Among them,10 patients were complicated with cardiac function grade I/II,and 3 patients died,with a mortality rate of 30%.Of the 17 patients with cardiac function grade III/IV,12 died,and 9 died within 1 year of diagnosis,with a mortality rate of70.5%.The mean follow-up time was 19.3±17.9 months.There were 5 cases with pathogenic significance,8 cases with likely pathogenic significance,and 14 cases with uncertain significance.13 cases(48.1%)were pathogenic and likely pathogenic with an average age of 8.9±4.9 years,and 14 cases(51.9%)were uncertain significance with an average age of 8.0±4.2 years.The two groups in age,sex,cardiac function III/IV proportion,heart rate and systolic blood pressure on admission,serum sodium,blood uric acid,red blood cell distribution width and poor R wave progression,abnormal Q wave,supraventricular tachycardia,ventricular tachycardia,left ventricular end-diastolic diameter,left ventricular end-systolic diameter,left ventricular ejection fraction,medication(ACEI/ARNI,beta blockers,furosemide,spironolactone and digoxin),follow-up time and mortality were no significant differences(P>0.05).(2)Among the 27 children,22 gene mutations were found,with a total of 62 mutation sites.In the 62 mutation sites,the top three were TTN 21(33.8%),TPM1,SCN5 A 4(6.4%),SYNE1,PKP2,DMD,DSP,FLNC 3(4.8%).Among the 62 gene mutation sites,there were 5(8.1%)with clear pathogenicity,8(12.9%)with suspected pathogenicity,and 49(79%)with uncertain significance.In terms of variant types,there were 53 missense mutations,3 frameshift mutations,4 nonsense mutations,and 2 splice mutations.(3)Among the 27 children,9 children(33.3%)were found to have 1 gene mutation,18 children(66.7%)were found to have two or more gene mutations,in which 13 children(48.2%)were found to have 2 gene mutations,4 children were found to have 3 gene mutations and 1 child(3.7%)was found to have 4gene mutations.(4)Among the 5 cases with definite genetic pathogenicity,2 of them survived and had cardiac function grade I/II at the time of onset;3 of them died,and had cardiac function grade III at the time of onset.Conclusions(1)In the detection of pathogenic genes,the proportion of cases found to be pathogenic or likely pathogenic was 48.1%.(2)Among the pathogenic genes detected in children with DCM,TTN gene detection locus rate was the highest,and missense mutation was the main mutation type,and 66.7% cases had 2 or more gene mutations.Part Ⅲ Bioinformatics analysis of genes related to FKTN mutant dilated cardiomyopathy Objectives Through bioinformatics analysis of genes related to FKTN(Fukutin)mutation dilated cardiomyopathy in 1 case,the pathogenesis of FKTN related DCM was discussed and treatment strategies were sought.Methods The clinical data in one case of FKTN gene mutation leading to dilated cardiomyopathy was collected,and the GSE138280 gene expression profile related to FKTN was downloaded from the Gene Expression Omnibus database to find the differentially expressed genes,and the pathogenic mechanism and therapeutic targets were found through the analysis of gene ontology,enrichment pathways,and protein interaction networks.Results In the biogenesis analysis of FKTN gene,Compared with the healthy control group,5636 differentially expressed genes were identified in the FKTN mutant group,of which 2630 were upregulated and 3006 were downregulated.Among the upregulated genes,GO analysis found that they were mainly concentrated in inflammatory response and extracellular matrix collagen fiber proliferation;KEGG pathway analysis found that they were mainly enriched in cytokine-cytokine receptor interaction,interleukin 17 signaling pathway,and tumor necrosis factor signaling Pathway,chemokine signaling pathway,P53 signaling pathway and extracellular matrix receptor interaction;protein interaction network analysis found that the key node genes were Fn1,CD44,Kif18 a,CXC,Saa3.Among the down-regulated genes,GO analysis found that they were mainly concentrated in calcium transport,myocardial contraction,endoplasmic reticulum,muscle segments,microtubules,and Protein glycosylation;KEGG pathway analysis found that they were mainly enriched in myocardial contraction,dilated cardiomyopathy,calcium signaling pathway;protein interaction network analysis found that the key node genes were Asb15 and Efcab2.Conclusions The pathogenesis of mice with FKTN mutation-related DCM may be related to intracardiac calcium homeostasis,cardiomyocyte inflammation,microtubule abnormalities,and extracellular matrix hyperplasia. |
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