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BACKGROUND: Prenatal alcohol exposure (PAE) has been linked to congenital heart disease and fetal alcohol syndrome. The heart primarily relies on mitochondria to generate energy, so impaired mitochondrial function due to alcohol exposure can significantly affect cardiac development and function. Our study aimed to investigate the impact of PAE on myocardial and mitochondrial functions in offspring mice. METHODS: We administered 30% alcohol (3 g/kg) to pregnant C57BL/6 mice during the second trimester. We assessed cardiac function by transthoracic echocardiography, observed myocardial structure and fibrosis through staining tests and electron transmission microscopy, and detected cardiomyocyte apoptosis with dUTP nick end labeling assay and real-time quantitative PCR. Additionally, we measured the reactive oxygen species content, ATP level, and mitochondrial DNA copy number in myocardial mitochondria. Mitochondrial damage was evaluated by assessing the level of mitochondrial membrane potential and the opening degree of mitochondrial permeability transition pores. RESULTS: Our findings revealed that PAE caused cardiac systolic dysfunction, ventricular enlargement, thinned ventricular wall, cardiac fibrosis in the myocardium, scattered loss of cardiomyocytes, and disordered arrangement of myocardial myotomes in the offspring. Furthermore, we observed a significant increase in mitochondrial reactive oxygen species content, a decrease in mitochondrial membrane potential, ATP level, and mitochondrial DNA copy number, and sustained opening of mitochondrial permeability transition pores in the heart tissues of the offspring. CONCLUSIONS: These results indicated that PAE had adverse effects on the cardiac structure and function of the newborn mice and could trigger oxidative stress in their myocardia and contribute to mitochondrial dysfunction.
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Etanol , Ratones Endogámicos C57BL , Miocitos Cardíacos , Efectos Tardíos de la Exposición Prenatal , Especies Reactivas de Oxígeno , Animales , Femenino , Embarazo , Ratones , Efectos Tardíos de la Exposición Prenatal/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Etanol/efectos adversos , Etanol/toxicidad , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , Apoptosis/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Trastornos del Espectro Alcohólico Fetal/metabolismo , Trastornos del Espectro Alcohólico Fetal/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ecocardiografía , FibrosisRESUMEN
Cardiomyopathy (CM) is a heterogeneous group of myocardial diseases in children. This study aimed to identify demographic features, clinical presentation and prognosis of children with CM. Clinical characteristics and prognostic factors associated with mortality were evaluated by Cox proportional hazards regression analyses. Genetic testing was also conducted on a portion of patients. Among the 317 patients, 40.1%, 25.2%, 24.6% and 10.1% were diagnosed with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction cardiomyopathy (LVNC) and restrictive cardiomyopathy (RCM), respectively. The most common symptom observed was dyspnea (84.2%). Except for HCM, the majority of patients were classified as NYHA/Ross class III or IV. The five-year survival rates were 75.5%, 67.3%, 74.1% and 51.1% in DCM, HCM, LVNC and RCM, respectively. The ten-year survival rates were 60.1%, 56.1%, 57.2% and 41.3% in DCM, HCM, LVNC and RCM, respectively. Survival was inversely related to NYHA/Ross class III or IV in patients with DCM, HCM and RCM. Out of 42 patients, 32 were reported to carry gene mutations. CONCLUSIONS: This study demonstrates that CM, especially RCM, is related to a high incidence of death. NYHA/Ross class III or IV is a predictor of mortality in the patients and gene mutations may be a common cause. TRIAL REGISTRATION: MR-50-23-011798. WHAT IS KNOWN: ⢠Cardiomyopathy (CM) is a heterogeneous group of myocardial diseases and one of the leading causes of heart failure in children due to the lack of effective treatments. ⢠There remains scarce data on Asian pediatric populations though emerging studies have assessed the clinical characteristics and outcomes of CM. WHAT IS NEW: ⢠A retrospective study was conducted and the follow-up records were established to investigate the clinical characteristics, the profile of gene mutations and prognostic outcomes of children with CM in Western China. ⢠CM, especially RCM, is related to a high incidence of death. NYHA/Ross class III or IV is a predictor of mortality in the patients and gene mutations may be a common cause.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Cardiomiopatía Restrictiva , Niño , Humanos , Estudios Retrospectivos , Perfil Genético , Cardiomiopatías/genética , Cardiomiopatía Restrictiva/complicaciones , Cardiomiopatía Restrictiva/genética , Cardiomiopatía Dilatada/genéticaRESUMEN
BACKGROUND: Prenatal exposure to adverse factors can cause congenital heart defects. Ketamine, a widely used anesthetic drug, produces several adverse reactions such as tachycardia, hypertension, and laryngospasm, especially in pediatric patients. This study aimed to detect the effects of ketamine exposure during pregnancy on the cardiogenesis of mouse offspring and the potential mechanisms. METHODS: In this study, ketamine at an addictive dose (5 mg/kg) was administered to mice during early gestation to explore the epigenetic mechanism of its causing cardiac dysplasia. The cardiac morphology of the mouse offspring was observed through hematoxylin-eosin staining and transmission electron microscopy. The heart function of one-month-old neonates was detected by echocardiography. The expression of cardiomyogenesis-related genes was detected by western blot and RT-qPCR. The acetylation level of histone H3K9 at the Mlc2 promoter and its deacetylase level and activity were detected by CHIP-qPCR, RT-qPCR, and ELISA, respectively. RESULTS: Our data revealed that ketamine exposure during pregnancy could cause cardiac enlargement, myocardial sarcomere disorganization, and decreased cardiac contractile function in mouse offspring. Moreover, ketamine reduced the expression of Myh6, Myh7, Mlc2, Mef2c, and cTnI. The histone H3K9 acetylation level at the Mlc2 promoter was down-regulated by increasing the histone deacetylase activity and HDAC3 level upon ketamine administration. CONCLUSIONS: Our work indicates that H3K9 acetylation is a vital player in cardiac dysplasia in offspring caused by prenatal ketamine exposure and HDAC3 is a key regulatory factor.
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Cardiopatías Congénitas , Ketamina , Animales , Femenino , Ratones , Embarazo , Corazón , Cardiopatías Congénitas/metabolismo , Histonas/metabolismo , Ketamina/efectos adversos , MiocardioRESUMEN
BACKGROUND: To investigate the mechanisms of potential cardioprotective effects of epigallocatechin-3-gallate (EGCG) in pressure overload-induced cardiac dysfunction. METHODS: A chronic heart failure model was established using abdominal aortic constriction (AAC) surgery, rats were divided into sham, AAC, and AAC + EGCG groups. Echocardiography and tissue section staining were performed to evaluate cardiac function and pathology, respectively. Gene expression level were detected with quantitative real-time polymerase chain reactions. Label-free quantitative proteomics was used to investigate the whole proteomes of heart, and the differentially expressed proteins were analyzed using bioinformatics methods. Western blot was performed to validate the levels and the reliability of the differential proteins. RESULTS: Compared with the AAC group, systolic dysfunction was improved in AAC + EGCG group after EGCG treatment. EGCG inhibited myocardial fibrosis and cardiac hypertrophy after AAC, along with reducing atrial natriuretic protein, B-type natriuretic peptide, collagen types 1 and 3 alpha 1, and transforming growth factor ß-1. Quantitative proteomics identified a total of 162 differentially expressed proteins, among them, 18 were closely related to cardiovascular disorders. Bioinformatics analyses showed that EGCG played a therapeutic role mainly by changing energy metabolism processes, such as oxidative phosphorylation and lipid metabolism. Furthermore, NADH: ubiquinone oxidoreductase subunit S4, an important component of the mitochondrial respiratory chain, was increased after AAC and then reversed by EGCG, which was consistent with the proteomics results. CONCLUSIONS: EGCG may correct cardiac systolic dysfunction and prevent cardiac remodeling after heart failure via enhancing the energy metabolism, which provides us with new insights into cardioprotective effects of EGCG related to the energy metabolisms in pressure overload-induced cardiac dysfunction.
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Catequina , Insuficiencia Cardíaca , Animales , Cardiomegalia/patología , Catequina/análogos & derivados , Catequina/metabolismo , Catequina/farmacología , Catequina/uso terapéutico , Modelos Animales de Enfermedad , Metabolismo Energético , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Ratas , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: The purpose of this study was to explore a new algorithm model capable of leverage deep learning to screen and diagnose specific types of left-to-right shunt congenital heart disease (CHD) in children. METHODS: Using deep learning, screening models were constructed to identify 884 heart sound recordings from children with left-to-right shunt CHD. The most suitable model for each type was summarized and compared with expert auscultation. An exploratory analysis was conducted to assess whether there were correlations between heart sounds and left ventricular ejection fraction (LVEF), pulmonary artery pressure, and malformation size. RESULTS: The residual convolution recurrent neural network (RCRnet) classification model had higher accuracy than other models with respect to atrial septal defect (ASD), ventricular septum defect (VSD), patent ductus arteriosus (PDA) and combined CHD, and the best auscultation sites were determined to be the 4th, 5th, 2nd and 3rd auscultation areas, respectively. The diagnostic results of this model were better than those derived from expert auscultation, with sensitivity values of 0.932-1.000, specificity values of 0.944-0.997, precision values of 0.888-0.997 and accuracy values of 0.940-0.994. Absolute Pearson correlation coefficient values between heart sounds of the four types of CHD and LVEF, right ventricular systolic pressure (RVSP) and malformation size were all less than 0.3. CONCLUSIONS: The RCRnet model can preliminarily determine types of left-to-right shunt CHD and improve diagnostic efficiency, which may provide a new choice algorithmic CHD screening in children.
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Aprendizaje Profundo , Conducto Arterioso Permeable , Cardiopatías Congénitas , Defectos del Tabique Interatrial , Ruidos Cardíacos , Niño , Computadores , Cardiopatías Congénitas/diagnóstico por imagen , Defectos del Tabique Interatrial/diagnóstico por imagen , Humanos , Grabaciones de Sonido , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The aim of this study was to compare psoas compartment block (PCB) and supra-inguinal fascia iliaca compartment block (SFIB) in terms of pain management and the need for additional systemic analgesia in the perioperative phase of developmental dysplasia of the hip (DDH). MATERIALS AND METHODS: Sixty pediatric patients were randomized into the PCB group and the SFIB group. The Numeric Rating Scale (NRS) pain scores were used to assess postoperative pain during the initial 24 h after extubation. Sufentanil consumption, patient-controlled analgesia (PCA) demands, and complications were also recorded. RESULTS: The NRS pain scores were significantly lower in the PCB group than in the SFIB group at 0, 4, 8, 12, and 24 h after extubation (all P < 0.01). Postoperatively, 13.8% of patients in the PCB cohort received additional administration of sufentanil, in contrast to 63.3% of the SFIB cohort (P < 0.01). In the PCB group, 0 (0-0) mcg/kg sufentanil was administered, while in the SFIB group 0.1 (0-0.2) mcg/kg (P < 0.01). In addition, the PCB group had fewer PCA demands than the SFIB group within the initial 24 h (P < 0.01). It took less operating time to achieve SFIB as compared to PCB (P < 0.01). No adverse events related to two techniques were recorded. CONCLUSIONS: PCB provided a better perioperative pain management in pediatric patients with the DDH surgeries compared to SFIB. It also reduced the need for supplementary systemic analgesia.
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BACKGROUND: Our previous studies have demonstrated that Ca2+ desensitizing catechin could correct diastolic dysfunction in experimental animals with restrictive cardiomyopathy. In this study, it is aimed to assess the effects of green tea extract catechin on cardiac function and other clinical features in pediatric patients with cardiomyopathies. METHODS: Twelve pediatric cardiomyopathy patients with diastolic dysfunction were enrolled for the study. Echocardiography, ECG, and laboratory tests were performed before and after the catechin administration for 12 months. Comparison has been made in these patients before and after the treatment with catechin. Next Generation Sequencing was conducted to find out the potential causative gene variants in all patients. RESULTS: A significant decrease of isovolumetric relaxation time (115 ± 46 vs 100 ± 42 ms, P = 0.047 at 6 months; 115 ± 46 vs 94 ± 30 ms, P = 0.033 at 12 months), an increase of left ventricle end diastolic volume (40 ± 28 vs 53 ± 28 ml, P = 0.028 at 6 months; 40 ± 28 vs 48 ± 33 ml, P = 0.011 at 12 months) and stroke volume (25 ± 16 vs 32 ± 17 ml, P = 0.022 at 6 months; 25 ± 16 vs 30 ± 17 ml, P = 0.021 at 12 months) were observed with echocardiography in these patients 6-month after the treatment with catechin. Ejection fraction, left ventricular wall thickness, biatrial dimension remained unchanged. No significant side effects were observed in the patients tested. CONCLUSIONS: This study indicates that Ca2+ desensitizing green tea extract catechin, is helpful in correcting the impaired relaxation in pediatric cardiomyopathy patients with diastolic dysfunction.
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Camellia sinensis/química , Cardiomiopatías/tratamiento farmacológico , Catequina/farmacología , Extractos Vegetales/farmacología , Adolescente , Niño , Preescolar , Ecocardiografía , Electrocardiografía , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Identify genes probably associated with chronic heart failure and predict potential target genes for dilated cardiomyopathy using bioinformatics analyses. METHODS: Gene expression profiles (series number GSE3585 and GSE42955) of cardiomyopathy patients and healthy controls were downloaded from the Expression Omnibus Gene (GEO) database. Differential expression of genes (DEGS) between the two groups of total 14 cardiomyopathy patients and 10 healthy controls were subsequently identified by limma package of R. Database for Annotation, Visualization, and Integrated Discovery (DAVID Tool), which is an analysis of enriched biological processes. Search Tool for the Retrieval Interacting Genes (STRING) was used as well for the analysis of protein-protein interaction network (PPI). Prediction of the potential drugs was suggested based on the preliminarily identified genes using Connectivity Map (CMap). RESULTS: Eighty-nine DEGs were identified (57 up-regulated and 32 down-regulated). The most enrichment Gene Ontology (GO) terms (P < 0.05) contain genes involved in extracellular matrix (ECM) and biological adhesion signal pathways (P < 0.05, ES > 1.5) such as ECM-receptors, focal adhesion and transforming growth factor beta (TGF-ß), etc. Fifty-one differentially expressed genes were found to encode interacting proteins. Eleven key genes along with related transcription factors were identified including CTGF, POSTN, CORIN, FIGF, etc. CONCLUSION: Bioinformatics-based analyses reveal the targeted genes probably associated with cardiomyopathy, which provide clues for pharmacological therapies aiming at the targets.
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Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , Transcriptoma , Biología Computacional , Perfilación de la Expresión Génica , HumanosAsunto(s)
Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico por imagen , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Cardiomiopatía Hipertrófica/metabolismo , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/metabolismo , Humanos , Lactante , Mutación/genética , LinajeRESUMEN
Cardiac diastolic dysfunction (CDD) is the most common form of cardiovascular disorders, especially in elderly people. Cardiac troponin I (cTnI) plays a critical role in the regulation of cardiac function, especially diastolic function. Our previous studies showed that cTnI-low expression induced by histone acetylation modification might be one of the causes that result in diastolic dysfunction in ageing hearts. This study was designed to investigate whether epigallocatechin-3-gallate (EGCG) would modify histone acetylation events to regulate cTnI expression and then improve cardiac functions in ageing mice. Our study shows that EGCG improved cardiac diastolic function of aged mice after 8-week treatment. Low expression of cTnI in the ageing hearts was reversed through EGCG treatment. EGCG inhibited the expression of histone deacetylase 1 (HDAC1) and HDAC3, and the binding levels of HDAC1 in the proximal promoter of cTnI. Acetylated lysine 9 on histone H3 (AcH3K9) levels of cTnI's promoter were increased through EGCG treatment. Additionally, EGCG resulted in an ascent of the binding levels of transcription factors GATA4 and Mef2c with cTnI's promoter. Together, our data indicate that EGCG may improve cardiac diastolic function of ageing mice through up-regulating cTnI by histone acetylation modification. These findings provide new insights into histone acetylation mechanisms of EGCG treatment that may contribute to the prevention of CDD in ageing populations.
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Envejecimiento , Catequina/análogos & derivados , Corazón/efectos de los fármacos , Histonas/metabolismo , Troponina I/metabolismo , Acetilación/efectos de los fármacos , Animales , Antioxidantes/farmacología , Catequina/farmacología , Diástole , Factor de Transcripción GATA4/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/fisiopatología , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Troponina I/genéticaRESUMEN
Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. Studies have shown that the deficiency of cTnI or mutations in cTnI (particularly in the C-terminus of cTnI) results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium. The first clinical study revealing the association between restrictive cardiomyopathy (RCM) with cardiac troponin mutations was reported in 2003. In order to illustrate the mechanisms underlying the cTnI mutation caused cardiomyopathy, we have generated a cTnI gene knockout mouse model and transgenic mouse lines with the reported point mutations in cTnI C-terminus. In this paper, we summarize our studies using these animal models from our laboratory and the other in vitro studies using reconstituted filament and cultured cells. The potential mechanisms underlying diastolic dysfunction and heart failure caused by these cTnI C-terminal mutations are discussed as well. Furthermore, calcium desensitizing in correction of impaired relaxation in myocardial cells due to cTnI mutations is discussed. Finally, we describe a model of translational study, i.e., from bedside to bench and from bench to bedside. These studies may enrich our understanding of the mechanism underlying inherited cardiomyopathies and provide the clues to search for target-oriented medication aiming at the treatment of diastolic dysfunction and heart failure.