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2.
PLoS One ; 15(10): e0240383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031469

RESUMO

The objective of this study was to assess the quality of life and psychological wellbeing of adults with congenital heart disease (CHD) in Chile, and to identify other associated factors. The study enrolled 68 patients aged between 18 and 72 (median 29), 35 being females. They completed a questionnaire, which included a quality of life assessment tool (the Medical Outcome Study 36-Item Short Form Health Survey), a number of psychological scales (the General Health Questionnaire, the Basic Psychological Needs Scales and the Beck Hopelessness Scale), a socioeconomic survey, and some clinical data. CHD patients reported worse scores in those scales assessing physical dimensions of quality of life (physical function (70.5), physical role functioning (64), vitality (65.3)), and general quality of life (58.6), than in emotional or social dimensions. Female gender was associated with lower scores in physical function (59.12 versus 82.66; p<0.01) and physical role functioning (53.68 versus 75; p<0.05); poverty was associated with worse results in physical function (61.92 versus 82.96; p<0.01), role physical (53.21 versus 79.63; p<0.01), vitality (60.89 versus 71.67; p<0.05), social role functioning (70.19 versus 82.87; p<0.05) and bodily pain (65.77 versus 81.2; p<0.05). Furthermore, we found that psychological scales had an association with quality of life, but clinical variables did not show significant correlations to any dimension. Poverty has an impact on the quality of life of CHD patients. This population only has a decrease in the quality of life physical dimensions, suggesting that quality of life depends on many different factors.


Assuntos
Cardiopatias Congênitas/psicologia , Pobreza , Qualidade de Vida , Adolescente , Adulto , Idoso , Chile , Emoções , Feminino , Nível de Saúde , Inquéritos Epidemiológicos , Cardiopatias Congênitas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto Jovem
3.
Am Heart J ; 229: 92-99, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32947058

RESUMO

The Anatomic and Physiological (AP) classification system proposed in the 2018 American College of Cardiology/American Heart Association adult congenital heart disease (ACHD) guidelines assigns 2 dimensions to each patient: anatomic class (AnatC) and physiological stage (PhyS). This approach has not been tested in practice; we assessed interrater reliability and identified sources of disagreement. METHODS: Consensus definitions for AP categories were developed with input from 4 experts. Research assistants (RAs) assigned AnatC/PhyS for patients in the Boston ACHD Biobank, a prospectively enrolled cohort of ambulatory ACHD patients ≥18 years old seen between 2012 and 2019. Two (of 4) expert reviewers then independently assigned AnatC/PhyS for 41 patients. Interrater reliability was assessed with linearly weighted kappa (κω) for agreement between (1) experts and (2) an RA and an expert. Experts examined disagreements and identified sources of variability and areas requiring clarification. RESULTS: Interexpert agreement for AnatC was excellent, with agreement on 38/41 (92.7%) cases and κω 0.88 [0.75, 1.01]. Agreement for PhyS was less robust, with consensus on 24/41 cases (59.5%), κω 0.57 [0.39, 0.75]. Expert-RA agreement was lower for AnatC (κω 0.77 [0.60, 0.95]), whereas PhyS was similar to interexpert agreement (κω 0.53 [0.34, 0.72]). There was ambiguity in the definitions of (1) arrhythmia status, (2) cyanotic CHD, and (3) valve disease. CONCLUSIONS: Although AnatC can be assessed reliably, that is not true for the PhyS part of the AP classification proposed in the 2018 American College of Cardiology/American Heart Association guidelines. Reliability of PhyS would be strengthened by more precise definitions readily interpretable in clinical practice.


Assuntos
Arritmias Cardíacas , Classificação/métodos , Consenso , Cardiopatias Congênitas , Doenças das Valvas Cardíacas , Adulto , American Heart Association , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Feminino , Coração/anatomia & histologia , Coração/fisiologia , Cardiopatias Congênitas/classificação , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Doenças das Valvas Cardíacas/diagnóstico , Doenças das Valvas Cardíacas/etiologia , Humanos , Masculino , Variações Dependentes do Observador , Estados Unidos
4.
PLoS One ; 15(9): e0239272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976507

RESUMO

OBJECTIVE: The aim of the current study was to investigate how cerebral and splanchnic oxygen saturation (rSO2-C and rSO2-A) in critically ill children transported in air ambulance was affected by flight with cabin pressurization corresponding to ≥ 5000 feet. A second aim was to investigate any differences between cyanotic and non-cyanotic children in relation to cerebral and splanchnic oxygen saturation during flight ≥ 5000 feet. The variability of the cerebral and splanchnic Near Infrared Spectroscopy (NIRS) sensors was evaluated. DESIGN: NIRS was used to measure rSO2-C and rSO2-A during transport of critically ill children in air ambulance. rSO2 data was collected and stored by the NIRS monitor and extracted and analyzed off-line after the transport. Prior to evaluation of the NIRS signals all zero and floor-effect values were removed. SETTING: The Pediatric Intensive Care Unit (PICU) at Astrid Lindgren Children's Hospital, Karolinska University Hospital in Stockholm, Sweden. PATIENTS: In total, 44 critically ill children scheduled for inter-hospital transport by a specialized pediatric transport team were included in the study between January 2014 and January 2019 (convenience sampling). INTERVENTION: No interventions were conducted. MEASUREMENTS: All study patients were monitored with a cerebral NIRS-sensor placed over the forehead and an abdominal NIRS-sensor placed in the infra-umbilical area for cerebral and splanchnic regional oxygen saturation monitoring, rSO2-C and rSO2-A, respectively. MAIN RESULTS: Complete rSO2-C and rSO2-A data was obtained in 39 patients. Median age was 12 days. Cyanotic congenital heart malformations were present in 9 patients (23%). In 22 patients (56%) rSO2-C decreased at altitude ≥ 5000 feet and in 24 patients (61%) rSO2-A decreased at altitude ≥ 5000 feet compared to baseline (p<0.0001). In 25 patients (64%) the rSO2-C/rSO2-A ratio was greater at altitude ≥ 5000 feet than at baseline. A ratio ≥ 1 was seen in 77% of patients at altitude ≥ 5000 feet compared to in 67% of patients at baseline. CONCLUSION: Both cerebral and splanchnic oxygen saturation decreased at altitude ≥ 5000 feet compared to baseline. In most patients, both cyanotic and non-cyanotic, cerebral oxygen saturation was preserved more than splanchnic oxygen saturation.


Assuntos
Encéfalo/metabolismo , Cardiopatias Congênitas/epidemiologia , Monitorização Fisiológica , Oxigênio/metabolismo , Resgate Aéreo , Altitude , Encéfalo/patologia , Pré-Escolar , Estado Terminal/epidemiologia , Feminino , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Masculino , Oximetria , Suécia/epidemiologia
5.
Sci Rep ; 10(1): 14909, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913193

RESUMO

Magnetic resonance (MR) imaging studies have demonstrated reduced global and regional brain volumes in infants with congenital heart disease (CHD). This study aimed to provide a more detailed evaluation of altered structural brain development in newborn infants with CHD compared to healthy controls using tensor-based morphometry (TBM). We compared brain development in 64 infants with CHD to 192 age- and sex-matched healthy controls. T2-weighted MR images obtained prior to surgery were analysed to compare voxel-wise differences in structure across the whole brain between groups. Cerebral oxygen delivery (CDO2) was measured in infants with CHD (n = 49) using phase contrast MR imaging and the relationship between CDO2 and voxel-wise brain structure was assessed using TBM. After correcting for global scaling differences, clusters of significant volume reduction in infants with CHD were demonstrated bilaterally within the basal ganglia, thalami, corpus callosum, occipital, temporal, parietal and frontal lobes, and right hippocampus (p < 0.025 after family-wise error correction). Clusters of significant volume expansion in infants with CHD were identified in cerebrospinal fluid spaces (p < 0.025). After correcting for global brain size, there was no significant association between voxel-wise brain structure and CDO2. This study localizes abnormal brain development in infants with CHD, identifying areas of particular vulnerability.


Assuntos
Encéfalo/patologia , Imagem de Tensor de Difusão/métodos , Cardiopatias Congênitas/patologia , Processamento de Imagem Assistida por Computador/métodos , Oxigênio/metabolismo , Adulto , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Idade Gestacional , Cardiopatias Congênitas/metabolismo , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos
7.
Medicine (Baltimore) ; 99(31): e21486, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756177

RESUMO

The diameter of femoral vessels was angiographically explored in pediatric patients with congenital heart disease (CHD) and compared with anthropometric and demographic indexes.A total of 153 pediatric patients younger than 3 years old were recruited. The sex, age, weight, and height of patients were recorded daily, and the body surface area (BSA) was calculated with the Mosteller formula.The values of mean left-right diameters were 3.13 (0.32) mm for the femoral artery (FA) and 5.14 (0.68) mm for the femoral vein (FV). The FA diameter (FA-Dm) and FV diameter (FV-Dm) were clearly related (R = 0.84, P < .001), and the FA-Dm/FV-Dm ratio ranged from 0.61 to 0.622. The diameters of femoral vessels were significantly correlated with age, height, weight and BSA (R = 0.63 to 0.73, P < .001). The FA-Dm and FV-Dm were most closely associated with the height of patients (FA-Dm: R = 0.73, P < .001; FV-Dm: R = 0.69, P < .001).The FV-Dm and FA-Dm were consistent with the weight, height, age and BSA in the surveyed pediatric patients. The FA-Dm and FV-Dm were closely associated with the height of pediatric patients. Furthermore, the FA-Dm/FV-Dm ratio was stable in these patients. Such estimations could help clinicians select the appropriate diameter of cannulation needles and catheters for interventional therapy pediatric patients with CHD.


Assuntos
Angiografia/estatística & dados numéricos , Artéria Femoral/diagnóstico por imagem , Veia Femoral/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Angiografia/métodos , Antropometria , Superfície Corporal , Feminino , Cardiopatias Congênitas/patologia , Humanos , Lactente , Masculino , Valores de Referência
8.
PLoS One ; 15(7): e0233582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735620

RESUMO

The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.


Assuntos
Processamento Alternativo , Atresia das Cóanas/patologia , Surdez/congênito , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/patologia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Ribonucleoproteína Nuclear Pequena U5/deficiência , Spliceossomos/fisiologia , Apoptose , Diferenciação Celular , Técnicas de Reprogramação Celular , Atresia das Cóanas/genética , Células Clonais , Surdez/genética , Surdez/patologia , Transição Epitelial-Mesenquimal , Éxons/genética , Face/embriologia , Facies , Feminino , Cabeça/embriologia , Cardiopatias Congênitas/genética , Humanos , Crista Neural/citologia , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Via de Sinalização Wnt
9.
BMC Cardiovasc Disord ; 20(1): 310, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600304

RESUMO

BACKGROUND: Correct detection of human cardiomyocyte death is essential for definitive diagnosis and appropriate management of cardiovascular diseases. Although current strategies have proven utility in clinical cardiology, they have some limitations. Our aim was to develop a new approach to monitor myocardial death using methylation patterns of circulating cell-free DNA (cf-DNA). METHODS: We first examined the methylation status of FAM101A in heart tissue and blood of individual donors using quantitative methylation-sensitive PCR (qMS-PCR). The concentrations and kinetics of cardiac cf-DNA in plasma from five congenital heart disease (CHD) children before and after they underwent cardiac surgery at serial time points were then investigated. RESULTS: We identified demethylated FAM101A specifically present in heart tissue. Importantly, our time course experiments demonstrated that the plasma cardiac cf-DNA level increased quickly during the early post-cardiac surgery phase, peaking at 4-6 h, decreased progressively (24 h) and returned to baseline (72 h). Moreover, cardiac cf-DNA concentrations pre- and post-operation were closely correlated with plasma troponin levels. CONCLUSIONS: We proposed a novel strategy for the correct detection of cardiomyocyte death, based on analysis of plasma cf-DNA carrying the cardiac-specific methylation signature. Our pilot study may lead to new tests for human cardiac pathologies.


Assuntos
Ácidos Nucleicos Livres/genética , Metilação de DNA , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Miócitos Cardíacos/patologia , Procedimentos Cirúrgicos Cardíacos , Morte Celular , Pré-Escolar , Epigenoma , Feminino , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas dos Microfilamentos/genética , Projetos Piloto , Fatores de Tempo , Resultado do Tratamento
10.
J Cardiovasc Magn Reson ; 22(1): 49, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600420

RESUMO

BACKGROUND: The right ventricle (RV) often fails when functioning as the systemic ventricle, but the cause is not understood. We tested the hypothesis that myofiber organization is abnormal in the failing systemic right ventricle. METHODS: We used diffusion-weighted cardiovascular magnetic resonance imaging to examine 3 failing hearts explanted from young patients with a systemic RV and one structurally normal heart with postnatally acquired RV hypertrophy for comparison. Diffusion compartment imaging was computed to separate the free diffusive component representing free water from an anisotropic component characterizing the orientation and diffusion characteristics of myofibers. The orientation of each anisotropic compartment was displayed in glyph format and used for qualitative description of myofibers and for construction of tractograms. The helix angle was calculated across the ventricular walls in 5 locations and displayed graphically. Scalar parameters (fractional anisotropy and mean diffusivity) were compared among specimens. RESULTS: The hypertrophied systemic RV has an inner layer, comprising about 2/3 of the wall, composed of hypertrophied trabeculae and an epicardial layer of circumferential myofibers. Myofibers within smaller trabeculae are aligned and organized with parallel fibers while larger, composite bundles show marked disarray, largely between component trabeculae. We observed a narrow range of helix angles in the outer, compact part of the wall consistent with aligned, approximately circumferential fibers. However, there was marked variation of helix angle in the inner, trabecular part of the wall consistent with marked variation in fiber orientation. The apical whorl was disrupted or incomplete and we observed myocardial whorls or vortices at other locations. Fractional anisotropy was lower in abnormal hearts while mean diffusivity was more variable, being higher in 2 but lower in 1 heart, compared to the structurally normal heart. CONCLUSIONS: Myofiber organization is abnormal in the failing systemic RV and might be an important substrate for heart failure and arrhythmia. It is unclear if myofiber disorganization is due to hemodynamic factors, developmental problems, or both.


Assuntos
Imagem de Difusão por Ressonância Magnética , Cardiopatias Congênitas/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Miocárdio/patologia , Miofibrilas/patologia , Disfunção Ventricular Direita/diagnóstico por imagem , Função Ventricular Direita , Adolescente , Pré-Escolar , Feminino , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/cirurgia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Humanos , Masculino , Valor Preditivo dos Testes , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/cirurgia , Adulto Jovem
11.
PLoS One ; 15(6): e0233007, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492036

RESUMO

BACKGROUND: In humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as "unexplained stillbirths"; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology. METHODS: Phenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples. RESULTS: There were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls. CONCLUSION: Embryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects.


Assuntos
Cardiopatias Congênitas/genética , Mutação de Sentido Incorreto , Receptor ErbB-2/genética , Natimorto/genética , Animais , Modelos Animais de Doenças , Feminino , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/genética , Bloqueio Cardíaco/metabolismo , Bloqueio Cardíaco/patologia , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Heterozigoto , Proteína Homeobox Nkx-2.5/genética , Homozigoto , Humanos , Camundongos , Camundongos Mutantes , Miocárdio/metabolismo , Miocárdio/patologia , Placenta/anormalidades , Placenta/patologia , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Biochem Biophys Res Commun ; 527(4): 847-853, 2020 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-32430170

RESUMO

Bone marrow mesenchymal stem cells (BMSCs) derived from cyanotic congenital heart disease (CCHD) exhibit deficient multi-lineage differentiation potential due to the abnormal accumulation of D-galactose. However, the underlying mechanisms have not yet been explored. Here, the multi-lineage differentiation potential of the BMSCs from CCHD and non-CCHD (NCHD) patients were assessed. BMSCs from CCHD patients exhibited inferior multi-lineage differentiation potential with reduced Notch1 protein and mRNA level. Bisulfite sequencing PCR results showed the methylation level of Notch1 promoter was raised, which inhibited the binding of NF-Ya. Exposure BMSCs from NCHD patients with D-galactose under hypoxia (4% O2) decreased the expression of Notch1. And activating Notch1 partially restored the deficient BMSCs of CCHD patients. In conclusion, the impaired multi-lineage differentiation potential of BMSCs from CCHD patients is owing to the decreased Notch1 level with a remarkable hypermethylation in its promoter region. Activated Notch1 signaling pathway could partially restore the deficient BMSCs in the CCHD patients, which may provide a new method on cell therapy in patients with CCHD.


Assuntos
Cardiopatias Congênitas/patologia , Células-Tronco Mesenquimais/patologia , Receptor Notch1/metabolismo , Transdução de Sinais , Células Cultivadas , Criança , Pré-Escolar , Metilação de DNA , Regulação para Baixo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Masculino , Células-Tronco Mesenquimais/metabolismo , Regiões Promotoras Genéticas , Receptor Notch1/genética
14.
BMC Med Genet ; 21(1): 95, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380971

RESUMO

BACKGROUND: Conotruncal heart defects (CTDs) are a group of congenital heart malformations that cause anomalies of cardiac outflow tracts. In the past few decades, many genes related to CTDs have been reported. Serum response factor (SRF) is a ubiquitous nuclear protein that acts as transcription factor, and SRF was found to be a critical factor in heart development and to be strongly expressed in the myocardium of the developing mouse and chicken hearts. The targeted inactivation of SRF during heart development leads to embryonic lethality and myocardial defects in mice. METHODS: To illustrate the relationship between SRF and human heart defects, we screened SRF mutations in 527 CTD patients, a cross sectional study. DNA was extracted from peripheral leukocyte cells for target sequencing. The mutations of SRF were detected and validated by Sanger sequencing. The affection of the mutations on wild-type protein was analyzed by in silico softwares. Western blot and real time PCR were used to analyze the changes of the expression of the mutant mRNA and protein. In addition, we carried out dual luciferase reporter assay to explore the transcriptional activity of the mutant SRF. RESULTS: Among the target sequencing results of 527 patients, two novel mutations (Mut1: c.821A > G p.G274D, the adenine(A) was mutated to guanine(G) at position 821 of the SRF gene coding sequences (CDS), lead to the Glycine(G) mutated to Asparticacid(D) at position 274 of the SRF protein amino acid sequences; Mut2: c.880G > T p.G294C, the guanine(G) was mutated to thymine (T) at position 880 of the SRF CDS, lead to the Glycine(G) mutated to Cysteine (C) at position 294 of the SRF protein amino acid sequences.) of SRF (NM_003131.4) were identified. Western blotting and real-time PCR showed that there were no obvious differences between the protein expression and mRNA transcription of mutants and wild-type SRF. A dual luciferase reporter assay showed that both SRF mutants (G274D and G294C) impaired SRF transcriptional activity at the SRF promoter and atrial natriuretic factor (ANF) promoter (p < 0.05), additionally, the mutants displayed reduced synergism with GATA4. CONCLUSION: These results suggest that SRF-p.G274D and SRF-p.G294C may have potential pathogenic effects.


Assuntos
Fator Natriurético Atrial/genética , Fator de Transcrição GATA4/genética , Cardiopatias Congênitas/genética , Fator de Resposta Sérica/genética , Sequência de Aminoácidos/genética , Animais , Estudos Transversais , Feminino , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Cardiopatias Congênitas/patologia , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Miocárdio/metabolismo , Miocárdio/patologia , Regiões Promotoras Genéticas/genética
15.
Dev Cell ; 53(3): 300-315.e4, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32369742

RESUMO

The cardiac neural crest arises in the hindbrain, then migrates to the heart and contributes to critical structures, including the outflow tract septum. Chick cardiac crest ablation results in failure of this septation, phenocopying the human heart defect persistent truncus arteriosus (PTA), which trunk neural crest fails to rescue. Here, we probe the molecular mechanisms underlying the cardiac crest's unique potential. Transcriptional profiling identified cardiac-crest-specific transcription factors, with single-cell RNA sequencing revealing surprising heterogeneity, including an ectomesenchymal subpopulation within the early migrating population. Loss-of-function analyses uncovered a transcriptional subcircuit, comprised of Tgif1, Ets1, and Sox8, critical for cardiac neural crest and heart development. Importantly, ectopic expression of this subcircuit was sufficient to imbue trunk crest with the ability to rescue PTA after cardiac crest ablation. Together, our results reveal a transcriptional program sufficient to confer cardiac potential onto trunk neural crest cells, thus implicating new genes in cardiovascular birth defects.


Assuntos
Reprogramação Celular , Cardiopatias Congênitas/patologia , Crista Neural/patologia , Animais , Embrião de Galinha , Cardiopatias Congênitas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Crista Neural/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo
16.
Mutat Res ; 852: 503163, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265037

RESUMO

Cardiac catheterization procedures are performed on about 20,000 children with congenital heart disease (CHD) annually in China. The procedure, which involves exposure to ionizing radiation, causes DNA damage and may lead to increased cancer risk. We have studied chromosomal aberrations (CA) in peripheral lymphocytes of CHD children. CA frequencies were assessed in an interventional group of 70 children who underwent cardiac catheterization and a control group of 51 children receiving open-heart surgery. Total CA and all chromosome-type aberrations were higher in the exposed children than in the control group. With respect to the type of septal defect, the translocation frequency was higher in patients with ventricular rather than atrial defects. Cardiac catheterization procedures increase CA frequencies and may also increase the risk of cancer.


Assuntos
Cateterismo Cardíaco/efeitos adversos , Aberrações Cromossômicas/efeitos da radiação , Cardiopatias Congênitas/cirurgia , Linfócitos/efeitos da radiação , Radiação Ionizante , Adolescente , Cateterismo Cardíaco/métodos , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , Cardiopatias Congênitas/patologia , Humanos , Linfócitos/imunologia , Masculino , Duração da Cirurgia , Cultura Primária de Células , Risco
17.
Adv Exp Med Biol ; 1236: 189-223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304074

RESUMO

Congenital heart defects (CHDs) are among the most common human birth defects. However, the etiology of a large proportion of CHDs remains undefined. Studies identifying the molecular and cellular mechanisms that underlie cardiac development have been critical to elucidating the origin of CHDs. Building upon this knowledge to understand the pathogenesis of CHDs requires examining how genetic or environmental stress changes normal cardiac development. Due to strong molecular conservation to humans and unique technical advantages, studies using zebrafish have elucidated both fundamental principles of cardiac development and have been used to create cardiac disease models. In this chapter we examine the unique toolset available to zebrafish researchers and how those tools are used to interrogate the genetic and environmental contributions to CHDs.


Assuntos
Meio Ambiente , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Peixe-Zebra/genética , Animais , Interação Gene-Ambiente , Coração/embriologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/patologia , Humanos , Peixe-Zebra/embriologia
18.
J Vis Exp ; (157)2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32225147

RESUMO

Congenital heart defects (CHD) are the most common type of birth defect in humans, affecting up to 1% of all live births. However, the underlying causes for CHD are still poorly understood. The developing mouse constitutes a valuable model for the study of CHD, because cardiac developmental programs between mice and humans are highly conserved. The protocol describes in detail how to produce mouse embryos of the desired gestational stage, methods to isolate and preserve the heart for downstream processing, quantitative methods to identify common types of CHD by histology (e.g., ventricular septal defects, atrial septal defects, patent ductus arteriosus), and quantitative histomorphometry methods to measure common muscular compaction phenotypes. These methods articulate all the steps involved in sample preparation, collection, and analysis, allowing scientists to correctly and reproducibly measure CHD.


Assuntos
Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/patologia , Histocitoquímica/métodos , Animais , Feminino , Coração/embriologia , Humanos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Inclusão em Parafina , Fenótipo
19.
J Vis Exp ; (157)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32310236

RESUMO

Improper formation or remodeling of the pharyngeal arch arteries (PAAs) 3, 4, and 6 contribute to some of the most severe forms of congenital heart disease. To study the formation of PAAs, we developed a protocol using whole-mount immunofluorescence coupled with benzyl alcohol/benzyl benzoate (BABB) tissue clearing, and confocal microscopy. This allows for the visualization of the pharyngeal arch endothelium at a fine cellular resolution as well as the 3D connectivity of the vasculature. Using software, we have established a protocol to quantify the number of endothelial cells (ECs) in PAAs, as well as the number of ECs within the vascular plexus surrounding the PAAs within pharyngeal arches 3, 4, and 6. When applied to the whole embryo, this methodology provides a comprehensive visualization and quantitative analysis of embryonic vasculature.


Assuntos
Artérias/diagnóstico por imagem , Região Branquial/irrigação sanguínea , Faringe/irrigação sanguínea , Animais , Embrião de Mamíferos , Endotélio Vascular/patologia , Cardiopatias Congênitas/patologia , Humanos , Imageamento Tridimensional , Imuno-Histoquímica , Microscopia Confocal
20.
J Surg Res ; 251: 38-46, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32113036

RESUMO

BACKGROUND: Surgical treatment of pulmonary atresia with intact ventricular septum (PA/IVS) in neonates is challenging because of the broad variations of right ventricular (RV) malformations. In this retrospective study, we summarized our 8-y experience in surgical management for neonatal PA/IVS patients. METHODS: Thirty-four neonates with PA/IVS between July 1, 2006 and June 30, 2014, were reviewed. Patients were categorized into three groups: mild, moderate, and severe RV hypoplasia according to RV morphology and development. Patients were on regular follow-up for at least 5 y. Overall survival, complications, reinterventions, risk factors for mortality, and health status were evaluated. RESULTS: 21 patients (61.8%) were treated with biventricular repair, eight patients (23.5%) with Fontan procedure, and one patient (2.9%) with bidirectional Glenn procedure. There were four postprocedural mortalities and one late death. The 5-y survival rates after final surgical repair for mild, moderate, and severe RV hypoplasia groups were 100%, 100%, and 88.9%, respectively. The reintervention rates were 0% (0/4), 21.4% (3/14), and 55.6% (5/9) for the subgroups, respectively. At the latest follow-up, most patients had a status characterized as New York Heart Association class I (88.9%, 24/27). CONCLUSIONS: Surgical management for PA/IVS in neonates should be individualized. Favorable early and long-term outcomes can be achieved in neonatal PA/IVS patients by individualized surgical strategies, regardless of the degree of RV hypoplasia. In spite of potential RV catch-up development, the degree of RV hypoplasia is a factor of paramount importance to assess PA/IVS in neonates.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/cirurgia , Atresia Pulmonar/cirurgia , Procedimentos Cirúrgicos Cardíacos/mortalidade , Feminino , Seguimentos , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/patologia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/patologia , Ventrículos do Coração/cirurgia , Humanos , Recém-Nascido , Masculino , Atresia Pulmonar/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
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