A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

OBJECTIVE: To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. METHODS: Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). RESULTS: The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. CONCLUSION Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM.
Humans ; Cardiomyopathy, Dilated/genetics* ; Male ; Adult ; Female ; Carrier Proteins/chemistry* ; Middle Aged ; Mutation ; Exome Sequencing ; Mutation, Missense ; Retrospective Studies ; Myosin Binding Protein C

Bayesian network Meta-analysis was conducted to assess the efficacy and safety of different Chinese medicine injections for dilated cardiomyopathy(DCM). CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, Cochrane Library, ProQuest, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov were searched for the randomized controlled trial(RCT) from the inception to January 2024. The quality of the included RCT was evaluated using the Cochrane's risk of bias assessment tool, and the quality of evidence for outcomes was assessed by GRADE. Stata 16.0 and RevMan 5.4 softwares were used for Meta-analysis. A total of 57 RCTs involving 4 812 subjects, 6 Chinese medicine injections and 6 outcome indicators were included. Bayesian network Meta-analysis indicated that:(1) In terms of increasing clinical total effectiveness rate, except Shenqi Fuzheng Injection + conventional western medicine, other 5 Chinese medicine injections combined with conventional western medicine outperformed conventional western medicine alone, and Xinmailong Injection + conventional western medicine had the best effect.(2) In terms of improving left ventricular ejection fraction, all of the 6 Chinese medicine injections combined with conventional western medicine were superior to conventional western medicine alone, and Shengmai Injection + conventional western medicine had the highest likelihood of being the best intervention.(3) On account of reducing left ventricular end-diastolic dimension, Shenfu Injection + conventional western medicine, Shenmai Injection + conventional western medicine, Huangqi Injection + conventional western medicine, and Xinmailong Injection + conventional western medicine outperformed conventional western medicine alone except Shengmai Injection + conventional western medicine, and Huangqi Injection + conventional western medicine had the highest probability of being the best treatment.(4) In terms of decreasing BNP, Huangqi Injection + conventional western medicine, Shenfu Injection + conventional western medicine, and Shenmai Injection + conventional western medicine were better than conventional western medicine alone, and Huangqi Injection + conventional western medicine had the highest likelihood of being the best treatment.(5) Considering the improvement in 6-min walk test, Shenmai Injection + conventional western medicine were superior to conventional western medicine alone.(6) In the case of improving cardiac output, Shenmai Injection + conventional western medicine, Shengmai Injection + conventional western medicine, Xinmailong Injection + conventional western medicine, and Shenqi Fuzheng Injection + conventional western medicine outperformed conventional western medicine alone except Shenfu Injection + conventional western medicine, thereinto, Shenmai Injection + conventional western medicine might be the optimal choice for increasing cardiac output level.(7) For safety, no statistically significant difference in adverse events was recorded between the experimental group and the control group(P=0.24). Bayesian network Meta-analysis showed that the addition of Chinese medicine injections to conventional western medicine exerted a more positive effect for DCM, and had advantages in alleviating clinical symptoms and improving cardiac function. However, due to the overall low quality of the included articles, the low inclusion of certain Chinese medicine injections, and the lack of direct comparison between different Chinese medicine injections, the results need to be further confirmed.
Humans ; Bayes Theorem ; Cardiomyopathy, Dilated/physiopathology* ; Drugs, Chinese Herbal/administration & dosage* ; Injections ; Randomized Controlled Trials as Topic ; Treatment Outcome

OBJECTIVE: To explore the clinical phenotype and genetic features of a child with dilated cardiomyopathy (DCM). METHODS: Clinical data of the child who had presented at the Zhengzhou Children's Hospital on April 28, 2020 was collected. Trio-whole exome sequencing (trio-WES) was carried out for the child and her parents, and candidate variants were validated by Sanger sequencing. "FHL2" was taken as the key word to retrieve related literature from January 1, 1997 to October 31, 2021 in the PubMed database and was also searched in the ClinVar database as a supplement to analyze the correlation between genetic variants and clinical features. RESULTS: The patient was a 5-month-old female infant presented with left ventricular enlargement and reduced systolic function. A heterozygous missense variant c.391C>T (p.Arg131Cys) in FHL2 gene was identified through trio-WES. The same variant was not detected in either of her parents. A total of 10 patients with FHL2 gene variants have been reported in the literature, 6 of them had presented with DCM, 2 with hypertrophic cardiomyopathy (HCM), and 2 with sudden unexplained death (SUD). Phenotypic analysis revealed that patients with variants in the LIM 3 domain presented hypertrophic cardiomyopathy and those with variants of the LIM 0~2 and LIM 4 domains had mainly presented DCM. The c.391C>T (p.Arg131Cys) has been identified in a child with DCM, though it has not been validated among the patient's family members. Based on the guidelines of the American College of Medical Genetics and Genomics, the c.391C>T(p.Arg131Cys) variant was re-classified as likely pathogenic (PS2+PM2_Supporting+PP3+PP5). CONCLUSION The heterozygous missense variant of c.391C>T (p.Arg131Cys) in the FHL2 gene probably predisposed to the DCM in this child, which has highlighted the importance of WES in the clinical diagnosis and genetic counseling.
Female ; Humans ; Cardiomyopathy, Dilated/genetics* ; Cardiomyopathy, Hypertrophic ; Genetic Counseling ; Genomics ; Heterozygote ; Muscle Proteins/genetics* ; Transcription Factors ; LIM-Homeodomain Proteins/genetics*

The mutations of TTN gene that encodes titin are the most common mutation type among the genetic causes of dilated cardiomyopathy (DCM). This article reviews the worldwide studies on potential molecular pathogenesis (transcription, post-translational modification, etc.), clinical phenotypes, and gene therapies of pediatric DCM caused by TTN mutations, with the hope of providing a reference for the precision treatment of pediatric DCM caused by TTN mutations.
Humans ; Cardiomyopathy, Dilated/therapy* ; Connectin/genetics* ; Genetic Therapy ; Mutation ; Phenotype

OBJECTIVES: To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM). METHODS: A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data. RESULTS: Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05). CONCLUSIONS There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.
Male ; Female ; Humans ; Child ; Stroke Volume ; Retrospective Studies ; Ventricular Function, Left ; Phenotype ; Cardiomyopathy, Dilated/diagnosis* ; Mutation ; ATPases Associated with Diverse Cellular Activities/genetics* ; Membrane Proteins/genetics* ; Mitochondrial Proteins/genetics*

Humans ; Muscular Dystrophy, Duchenne/diagnosis* ; Cardiomyopathy, Dilated/diagnosis* ; Echocardiography ; Patients

Humans ; Propionic Acidemia/complications* ; Cardiomyopathy, Dilated/etiology*

Bayesian network Meta-analysis was performed to evaluate the efficacy and safety of different Chinese patent medicines in the treatment of dilated cardiomyopathy. The PubMed, EMbase, Cochrane Library, CNKI, Wanfang, and VIP were searched for the randomized controlled trial(RCT) from the inception to May 2023. The quality of the included RCT was evaluated by the Cochrane risk of bias assessment tool, and the data were analyzed by RStudio 3.6.3 calling the "gemtc" package. A total of 96 RCTs involving 8 452 patients, 11 Chinese patent medicines, and 8 outcome indicators were included. Network Meta-analysis is described as follows.(1)In terms of improving clinical total effective rate, except Yixinshu Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Xinshuai Mixture + conventional western medicine, the other Chinese patent medicines combined with conventional western medicine were superior to conventional western medicine alone, and Shenqi Yiqi Dropping Pills + conventional western medicine had the best effect.(2)In terms of improving left ventricular ejection fraction(LVEF), except Yixinshu Capsules + conventional western medicine and Shensong Yangxin Capsules + conventional western medicine, other Chinese patent medicines combined with conventional western medicine outperformed conventional western medicine alone, and Shexiang Baoxin Pills + conventional western medicine had the best effect.(3)In terms of reducing left ventricular end-diastolic dimension(LVEDD), Getong Tongluo Capsules + conventional western medicine, Xinshuai Mixture + conventional western medicine, Huangqi Mixture + conventional western medicine, Tongxinluo Capsules + conventional western medicine, Wenxin Granules + conventional western medicine, and Qili Qiangxin Capsules + conventional western medicine were better than conventional western medicine alone, and Wenxin Granules + conventional western medicine had the best effect.(4)There was no significant difference in reducing left ventricular end-systolic diameter(LVESD) between Chinese patent medicines combined with conventional western medicine and conventional western medicine alone.(5)In terms of improving 6-minute walking trail(6MWT), Yangxinshi Tablets + conventional western medicine, Yixinshu Capsules + conventional western medicine, Shenqi Yiqi Dropping Pills + conventional western medicine, Wenxin Granules + conventional western medicine, and Qili Qiangxin Capsules + conventional western medicine were superior to conventional western medicine alone, and Shenqi Yiqi Dropping Pills + conventional western medicine had the best effect.(6)In reducing brain natriuretic peptide(BNP), Xinshuai Mixture + conventional western medicine ourperformed conventional western medicine alone.(7)In reducing hypersensitive C-reactive protein(hs-CRP), Shenqi Yiqi Dropping Pills + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine outperformed conventional western medicine alone, and Qili Qiangxin Capsules + conventional western medicine had the best effect.(8)In terms of safety, adverse reactions were reported in both groups. In conclusion, Chinese patent medicine combined with conventional western medicine were more effective in the treatment of dilated cardiomyopathy. The combinations relieve clinical symptoms and improve cardiac function indexes, and thus can be used according to the patients' conditions in clinical practice. However, limited by the quality and sample size of the included studies, the conclusion remains to be verified by multi-center, large-sample, and high-quality RCT in the future.
Humans ; Bayes Theorem ; Cardiomyopathy, Dilated/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Natriuretic Peptide, Brain ; Network Meta-Analysis ; Nonprescription Drugs/therapeutic use* ; Stroke Volume ; Ventricular Function, Left

Dystrophinopathies, including Duchenne muscular dystrophy, Becker muscular dystrophy and dilated cardiomyopathy, are X-linked recessive genetic disorders due to variants of the dystrophin gene, which can seriously affect quality of life and health. Genetic diagnosis plays a crucial role in their diagnosis, treatment, and prevention. How to rationally select and standardize the use of various genetic techniques is a skill that clinicians must acquire. By compiling expertise of experts from the relevant areas and guidelines published home and abroad, this consensus has provided a guidance from the perspective of genetic diagnosis for the selection of genetic techniques, testing strategies, and detection process for dystrophinopathies.
Humans ; Quality of Life ; Consensus ; Dystrophin/genetics* ; Muscular Dystrophy, Duchenne/therapy* ; Cardiomyopathy, Dilated/genetics* ; Electrocardiography