Analysis Of Risk Factors For Death And Gene Screening In Pediatric Primary Dilated Cardiomyopathy

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Clinical profiles and Risk factors for cardiac death in pediatric primary dilated cardiomyopathy patientsBackground:Dilated cardiomyopathy(DCM)is a heterogeneous cardiomyopathy,characterized by ventricular enlargement and reduced myocardial systolic function,with insidious onset,no specific manifestations,and usually manifested as progressive heart failure(HF),malignant arrhythmia,thromboembolism,and sudden cardiac death.DCM accounts for the highest proportion of childhood cardiomyopathy,accounting for 51%-59%of pediatric cardiomyopathy.The annual incidence of DCM in children is 0.18-0.73 per 100,000.DCM is the main cause of HF in children.Although some progress has been made in the management of heart failure in patients with DCM,the prognosis is poor and the mortality rate is still high.Epidemiological studies abroad have found that the 1-year survival rate after diagnosis of DCM is about 69%-72%,and the 5-year survival rate after diagnosis is 54%-63%.Nearly 40%of children with DCM received heart transplantation or died within 2 years after diagnosis,most of whom died of progressive HF and its complications.Previous studies have suggested that there is a complex relationship between age,gender and primary DCM,and the conclusions are not the same.The predictive value of echocardiographic parameters and serological indicators for prognosis cannot be ignored.The predictive effect of various factors on cardiac death is still controversial.This study retrospectively explored the clinical data of primary DCM in children,in order to further clarify the clinical characteristics of DCM and risk factors for death prognosis,so as to provide reference for future clinical evaluation.Aim:This retrospective study was sought to determine and identify the clinical characteristics and risk factors for predicting cardiac death in childhood primary dilated cardiomyopathy patients in our center in recent 10 years.Methods:A total of 138 pediatric patients aged 0-15 diagnosed with primary dilated cardiomyopathy(DCM)from January 2011 to December 2020 in Shandong provincial hospital were included in this study.We noted the genders,clinical symptoms,and collected laboratory values,electrocardiograms,and echocardiograms.The prognostic data after follow-up were collected and statistically analyzed.Results:1.From January 2011 to December 2020,138 children aged 0-15 met the inclusion criteria,including 62(44.9%)males and 92(55.1%)females.The median age of onset was 10 months.79(57.2%)patients developed DCM before the age of 1 year.8(5.8%)patients had positive family histories of DCM.111(82.8%)patients presented with respiratory symptoms,such as cough or dyspnea.2.Among these 138 patients,79(57.2%)suffered from severe systolic dysfunction[left ventricular ejection fraction(LVEF)<30%].121(87.7%)children reached cardiac function class ?/? at the time of onset.3.The median follow-up time was 12 months.46 patients occurred cardiac death,and the overall cardiac death rate was 33%.Most deaths(40/46)occurred within the first six months after the diagnosis of DCM.4.Survival free from cardiac death was 86.2%at 1 year and 71.7%at 5-year after presentation in this group.Kaplan-Meier analysis also showed that the cardiac mortality of DCM in children was higher in men(41.9%)than in women(26.3%);According to the age of onset,there is a complex relationship between cardiac death and age.There was no statistical difference in the survival rate between the early cohort(n=56,2011-2015)and the late cohort(n=82,2016-2020)with cardiac death as the end point until January 2021.5.Cox univariate regression analysis showed that multiple factors are related to the prognosis of childhood primary DCM death.Multivariate Cox regression analysis identified several independent cardiac death factors,including an age of 12 months to 5 years[hazard ratio(HR)2.928;95%confidence interval(CI)1.192-7.190;P=0.019]or 10 years to 15 years old[hazard ratio(HR)3.854;95%confidence interval(CI)1.291-11.511;P=0.016]at diagnosis,elevated serum alanine aminotransferase(ALT)levels(HR 2.763;95%CI 1.328-5.746;P=0.007),and the need for the invasive mechanical ventilator(HR 3.311;95%CI 1.356-8.085;P=0.009).Conclusion:1.The onset children with primary DCM is young and the mortality is high.2.One year after the diagnosis of DCM is a high-risk period of cardiac death.3.The specific age of onset,elevated serum alanine aminotransferase and the need for an invasive mechanical ventilator are independent predictors of cardiac death in children with primary DCM.Part ? Genetic screening of primary pediatric dilated cardiomyopathyBackgroundDilated cardiomyopathy(DCM)is a common myocardial disease,which is mainly characterized by left ventricular enlargement and decreased myocardial systolic function.It can lead to heart failure and sudden cardiac death in children.With the development of metabolic disease detection and gene detection,the clinical diagnosis level of the cause of DCM has been greatly improved,and some clear causes of cardiomyopathy have the hope of reversion and obvious improvement after treatment,thus improving the survival rate of DCM children.About 15-25%of sporadic patients and 20-40%of familial patients with DCM are associated with genetic mutations.It is of great significance to clarify the etiology and pathogenesis of DCM from the perspective of molecular genetics.Current study holds that more than 60 genes are related to the onset of DCM and are mainly autosomal dominant genetics,which are involved in the structure or function of cytosotstructure,bridge,nucleotysis,muscle syringes and mitochondrial or calcium binding.Identifying pathogenic genetic mutations can help asymptomatic family members assess their risk of cardiomyopathy.At present,foreign studies have found that the most common mutation in adult patients with DCM is the TTN gene truncation mutation,but a low proportion in pediatric DCM patients.The carrying ratio of TTN truncation mutation in Chinese DCM patients,especially in children,is unknown and still needs further research.Aim:Through genetic detection of some children with primary dilated cardiomyopathy in our center,we can identify the existence of pathogenic gene mutations,the characteristics of DCM patients with positive mutation and the correlation between genotype and phenotype,providing the clues for the study of pathogenesis in DCM.Methods:There were 46 children who were diagnosed with primary DCM at the age of 0-13 who were admitted from 2014 to 2020,also a part of patients in the first study.We collected clinical data including the age at onset,clinical symptoms,cardiac function evaluation,laboratory data,ECG and echocardiography data;The prognostic data after follow-up were collected and statistically analyzed.Genomic DNA was extracted from peripheral blood samples for gene testing,and the pathogenicity of all variants was evaluated according to ACMG guidelines.Then Sanger sequencing was performed on patients and their relatives to determine the source of variation.According to the results of genetic analysis,the patients were divided into 2 groups for statistical analysis to further understand the correlation between genotype and phenotypeResults:1.From 2014 to 2020,46 children aged 0-13 with primary DCM met the inclusion criteria,including 20 males and 26 females.The median age of onset was 6.5 months,and children under 1 year old accounted for the most(67.4%).2.The median follow-up time was 12.5 months.A total of 10 patients(7 males,3 females)died of heart failure or sudden cardiac death.The median survival time was 7 months.3.According to ACMG guidelines,16 pathogenic or likely pathogenic mutations of 10 genes related to DCM were found in the blood of 16 children with DCM,respectively.16 gene mutations included 5 missense mutations,5 nonsense mutations,4 frameshift mutations and 2 splice sites,of which 2 identical RBM20 gene mutation sites existed in a pair of monozygotic twins,and 10 mutation sites were novel.10 mutation sites belong to sarcomere genes.Nine mutation-positive children developed DCM before the age of 1 year.4.We identified 6 pathogenic mutations(5 novel)in the titin(TTN)gene,resulting truncating TTN mutations in 6(13%)out of 46 patients.Correlations between TTN mutations and clinical outcomes were assessed,of which 3 children(1 male,2 females)died,and the LVEFs of 3 children(1 male,2 females)recovered to more than 55%.5.In the genotype-positive group,6 children(4 males,2 females)died of cardiac death,including TTN truncating mutation(c.50065C>T?c.98421₉8422insGG?c.374542A>T),NKX2-5 gene mutation(c.242delA),TNNT2 gene mutation(c.422G>A),and TNNI3 gene mutation(c.544G>A).Among them,TTN gene,TNNT2 gene and TNNI3 gene are all sarcomere genes.6.Except for arrhythmia,the gene-positive group was significantly more than the genenegative group,there are no statistical differences in gender distribution,age of onset,LVEF,LVEDD Z-value and serum NT-proBNP level,and outcome of children(death and recovery)between the gene-positive group and gene-negative group.Conclusion:1.DCM is a genetically heterogeneous disease.The genetic cause was found in 34.8%of children with primary DCM through next-generation sequencing technology.2.Sarcomere mutations are the most common genetic cause of childhood dilated cardiomyopathy.In this study,10 novel gene mutations were discovered(including 5 novel truncating TTN variants),which expanded the genetic mutation spectrum of DCM and provided new clues for studying the pathogenesis of DCM.3.Through the analysis of the clinical and genotype characteristics of TTN gene truncation mutations and the RBM20 gene mutation,this study provides more evidence for further research on the role of inheritance in DCM.