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RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
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Polimorfismo de Nucleótido Simple , Transposición de los Grandes Vasos/genética , Animales , Células Cultivadas , Humanos , Ratones , Herencia Multifactorial , Miocitos Cardíacos/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Transposición de los Grandes Vasos/metabolismo , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , Pez CebraRESUMEN
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
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Variaciones en el Número de Copia de ADN/genética , Haploinsuficiencia/genética , Cardiopatías Congénitas/genética , Bases de Datos Genéticas , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Predisposición Genética a la Enfermedad/genética , Genómica/métodos , Humanos , Canales Iónicos/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1009679.].
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To explore the effect of a daily goal checklist on pediatric cardiac intensive care unit (PCICU) length of stay (LOS) after congenital heart surgery. This study is a prospective randomized single-center study. Group characteristics were as follows: STANDARD group: n = 30, 36.7% female, median age 0.9 years; control group: n = 33, 36.4% female, median age 1.1 years. Invasive ventilation time, STAT categories, mean vasoactive-inotropic score (VIS)24h, maximal (max.) VIS24h, mean VIS24-48h, max. VIS24-48h, VIS category, number of sedatives, analgesics, diuretics, number of deployed diagnostic modalities, morbidities, and mortality did not differ between both groups. Median PCICU LOS was 96.0 h (STANDARD group) versus 101.5 h (control group) (p = 0.63). In the overall cohort, univariate regression analysis identified age at surgery (b = -0.02), STAT category (b = 18.3), severity of CHD (b = 40.6), mean VIS24h (b = 3.5), max. VIS24h (b = 2.2), mean VIS24-48h (b = 6.5), and VIS category (b = 13.8) as significant parameters for prolonged PCICU LOS. In multivariate regression analysis, age at surgery (b = -0.2), severity of CHD (b = 44.0), and mean VIS24h (b = 6.7) were of significance. Within the STANDARD sub-group, univariate regression analysis determined STAT category (b = 32.3), severity of CHD (b = 70.0), mean VIS24h (b = 5.0), mean VIS24-48h (b = 5.9), number of defined goals (b = 2.6), number of achieved goals (b = 3.3), number of not achieved goals (b = 10.8), and number of unevaluated goals (b = 7.0) as significant parameters for prolonged PCICU LOS. Multivariate regression analysis identified the number of defined goals (b = 2.5) and the number of unevaluated goals (b = -3.0) to be significant parameters. Conclusion: The structured realization and recording of daily goals is of advantage in patients following pediatric cardiac surgery by reducing PCICU LOS. What is known: ⢠Communication errors are the most frequent reasons for adverse events in intensive care unit patients. ⢠Improved communication can be achieved by discussion and documentation of the patients' goals during daily rounds. What is new: ⢠In the overall cohort age at surgery, severity of congenital heart defect and mean vasoactive inotropic score within the first 24 hours had significant impact on pediatric cardiac intensive care unit (PCICU) length of stay (LOS). ⢠In the intervention group, the number of defined goals and the number of unevaluated goals were significant parameters for prolonged PCICU LOS.
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Procedimientos Quirúrgicos Cardíacos , Cardiopatías Congénitas , Humanos , Niño , Femenino , Lactante , Masculino , Estudios Prospectivos , Proyectos Piloto , Cardiopatías Congénitas/diagnóstico , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Costo de Enfermedad , Tiempo de InternaciónRESUMEN
Congenital coronary artery anomalies represent a rare cause for cardiac arrest in children and adults; however, most of these anomalies are asymptomatic and incidental findings. We report on a 14-year-old boy who was admitted to our hospital after cardiopulmonary resuscitation at home. Diagnostic workup including histopathology revealed parvovirus B19 in endomyocardial biopsy. Moreover, cardiac catheterisation as well as CT angiography identified an anomalous origin of the right coronary artery with an interarterial course. Since this anomalous coronary artery might have caused impaired myocardial perfusion causing cardiac arrest, surgical correction and implantation of a cardioverter defibrillator were performed. The further post-operative clinical course (7 months) has been uneventful.
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Reanimación Cardiopulmonar , Anomalías de los Vasos Coronarios , Paro Cardíaco , Masculino , Niño , Humanos , Adolescente , Anomalías de los Vasos Coronarios/diagnóstico , Muerte Súbita Cardíaca/etiologíaRESUMEN
Background and Objectives: Patients with congenital heart disease (CHD), especially as a concomitant syndromal disease of trisomy 21 (T21), are at risk for impaired neurodevelopment. This can also affect these patients' education. However, there continues to be a research gap in the educational development of CHD patients and T21 CHD patients. Materials and Methods: In total, data from 2873 patients from the German National Register for Congenital Heart Defects were analyzed. The data are based on two online education surveys conducted among patients registered in the National Register for Congenital Heart Defects (2017, 2020). Results: Of 2873 patients included (mean age: 14.1 ± 4.7 years, 50.5% female), 109 (3.8%) were identified with T21 (mean age: 12.9 ± 4.4 years, 49.5% female). T21 CHD participants had a high demand for early specific interventions (overall cohort 49.1%; T21 cohort 100%). T21 CHD children more frequently attended special schools and, compared to non-trisomy 21 (nT21) CHD patients, the probability of attending a grammar school was reduced. In total, 87.1% of nT21 CHD patients but 11% of T21 CHD patients were enrolled in a regular elementary school, and 12.8% of T21 CHD patients could transfer to a secondary school in contrast to 35.5% of nT21 CHD patients. Most of the T21 CHD patients were diagnosed with psychiatric disorders, e.g., learning, emotional, or behavioral disorders (T21 CHD patients: 82.6%; nT21 CHD patients: 31.4%; p < 0.001). Conclusions: CHD patients are at risk for impaired academic development, and the presence of T21 is an aggravating factor. Routine follow-up examinations should be established to identify developmental deficits and to provide targeted interventions.
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Síndrome de Down , Cardiopatías Congénitas , Humanos , Niño , Femenino , Adolescente , Masculino , Síndrome de Down/complicaciones , Síndrome de Down/diagnóstico , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/diagnóstico , Escolaridad , Instituciones Académicas , EmocionesAsunto(s)
Anticuerpos , Vacunas contra la COVID-19 , COVID-19 , Proteína Antagonista del Receptor de Interleucina 1 , Miocarditis , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Miocarditis/etiología , Miocarditis/inmunología , SARS-CoV-2 , VacunaciónRESUMEN
BACKGROUND: Diagnostic ultrasound has a crucial importance in clinical settings, especially in intensive care medicine where bedside ultrasound has become indispensable. Medical students as well as residents therefore have a strong interest in learning this useful skill. Since staff resources are limited, more and more universities are using student tutors in a peer-assisted learning concept (PAL) to teach medical students early in their training. To date, there is very sparse data about knowledge retention after peer-assisted teaching. The aim of this study was to evaluate whether PAL is a suitable method for teaching complex skills like abdominal ultrasound and to evaluate whether students do achieve adequate long-term knowledge retention after peer-assisted teaching. METHOD: A total of 40 volunteer 3rd to 5th year students were randomly assigned to a basic abdominal ultrasound course in small training groups of 5 persons each. Participants were evaluated using a pre-post-test design by a validated objective structured clinical examination (OSCE) before and immediately after the course. To measure the retention of knowledge, 15 former participants were randomly selected to repeat the OSCE assessment after one year. RESULTS: All groups showed a significant improvement in practical skills and knowledge gain after the training with mean values of 13.1 for pre-test compared to 83.5 (maximum 100 points) for post-test (pâ<â0.001). The overall score achieved after one year was 78.7 and did not significantly differ from the post-test result. CONCLUSION: PAL is effective for teaching abdominal ultrasound. Students were able to accomplish a satisfactory level of ultrasound skills. We further demonstrated that PAL can assure long-term knowledge retention.
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Competencia Clínica , Educación de Pregrado en Medicina , Ultrasonografía , Abdomen/diagnóstico por imagen , Curriculum , Educación de Pregrado en Medicina/métodos , Evaluación Educacional , Humanos , Grupo ParitarioRESUMEN
BACKGROUND: The aim of this study was to characterize the influence of cardiopulmonary bypass (CPB) on myocardial remodeling in newborns and children. METHODS: Biopsies from the right atrium were taken before and after CPB from 4 newborns (5-11 days old) and 7 children (8 months-16 years old). Immunostainings on 10 µm heart tissue frozen sections were performed to detect c-kit+ cells, leukocytes (CD45+ cells), Ki67+ cycling cells. The percentage of 8-hydroxy-guanosine (8-dOHG)+cardiomyocytes and non-cardiomyocytes [(8-dOHG)+-index] were determined to quantify oxidative stress. RESULTS: Δ c-kit+CD45- cells (resident cardiac stem cells) were increased in newborns (2.2 ± 1.9/mm2) and decreased in children - 1.5 ± 0.7/mm2, p < 0.01. The (8-dOHG)+-index was reduced by 43% in newborns and by 20% in children. CPB did not influence cardiac cell turnover; high cell proliferation was seen in newborns before and after CPB. Cardiopulmonary bypass significantly decreased the leucocyte infiltration in newborns to 40 ± 8%, p < 0.05, but not in children. Infiltration with eosinophils (eosinophils/CD45%) was completely abolished in the myocardium of newborns p < 0.05 and reduced to 22 ± 8% in children after CPB, n.s. CONCLUSIONS: Immediate response and remodeling of the myocardium to CPB differs between newborns, older infants and children. Especially an increased number of c-kit expressing CD45 cells after CPB were seen in neonates in comparison to children. The clinical value of such observation needs to be further assessed in larger cohorts of patients.
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Puente Cardiopulmonar , Inflamación/patología , Antígenos Comunes de Leucocito/metabolismo , Miocardio/patología , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Recuento de Células , Humanos , Recién Nacido , Miocitos Cardíacos/patologíaRESUMEN
BACKGROUND: MicroRNAs (miRNAs) are small RNAs regulating gene expression post-transcriptionally. While acquired changes of miRNA and mRNA profiles in cancer have been extensively studied, little is known about expression changes of circulating miRNAs and messenger RNAs (mRNA) in monogenic constitutional anomalies affecting several organ systems, like Marfan syndrome (MFS). We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy. METHODS: MiRNA and mRNA expression profiles were determined in blood samples from MFS patients (n = 7) and from healthy volunteer controls (n = 7) by microarray analysis. Enrichment analyses of altered mRNA expression were identified using bioinformatic tools. RESULTS: A total of 28 miRNAs and 32 mRNAs were found to be significantly altered in MFS patients compared to controls (> 2.0-fold change, adjusted P < 0.05). The expression of 11 miRNA and 6 mRNA candidates was validated by RT-qPCR in an independent cohort of 26 MFS patients and 26 matched HV controls. Significant inverse correlations were evident between 8 miRNAs and 5 mRNAs involved in vascular pathology, inflammation and telomerase regulation. Significant positive correlations were present for 7 miRNAs with age, for 2 miRNAs with the MFS aortic root status (Z-score) and for 7 miRNAs with left ventricular end-diastolic diameter in MFS patients. In addition, miR-331-3p was significantly up-regulated in MFS patients without mitral valve prolapse (MVP) as compared with patients with MVP. CONCLUSIONS: Our data show deregulated gene and miRNA expression profiles in the peripheral blood of MFS patients, demonstrating several candidates for prognostic biomarkers for cardiovascular manifestations in MFS as well as targets for novel therapeutic approaches. A deregulation of miRNA expression seems to play an important role in MFS, highlighting the plethora of effects on post-transcriptional regulation of miRNAs and mRNAs initiated by constitutional mutations in single genes. Trial registration Nr: EA2/131/10 . Registered 28 December, 2010.
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Perfilación de la Expresión Génica , Síndrome de Marfan/sangre , Síndrome de Marfan/genética , MicroARNs/genética , ARN Mensajero/genética , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Humanos , Masculino , MicroARNs/metabolismo , Sistemas de Lectura Abierta/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: Somatic development is impaired in children with congenital heart defects (CHDs), and head circumference seems to be a strong predictor of neurodevelopmental prognosis. The aim of this study was to generate up-to-date reference values for the somatic development (head circumference, body weight, and length/height) of children with CHDs. STUDY DESIGN: Our study population consisted of all patients included in the PAN study (Prävalenz angeborener Herzfehler bei Neugeborenen in Deutschland), which was conducted prospectively over a 3-year study period by the Competence Network for Congenital Heart Defects. All children with mild, moderate, and severe CHDs born in 2006-2009 in Germany were enrolled. For computing of z-scores, only children with the following characteristics were included: appropriate for gestational age, nonsyndromic disease, term or post-term delivery, and no cardiac surgery. RESULTS: There were 2818 patients included. New z-scores for the described somatic measures of children with mild, moderate, and severe CHDs were computed. Comparisons with the KiGGS study (Gesundheit von Kindern und Jugendlichen in Deutschland) and the Berlin Longitudinal Study revealed significantly lower measurements for all measures-most notably in children with severe CHDs and/or cardiac surgery. In our cohort, no catch-up growth was seen after cardiac surgery. CONCLUSION: Children with severe CHDs demonstrated the most abnormal pattern in growth, including head circumference before and after cardiac surgery, which is indicative of accompanying brain pathology unrelated to operative injury.
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Estatura/fisiología , Peso Corporal/fisiología , Desarrollo Infantil/fisiología , Cabeza/crecimiento & desarrollo , Cardiopatías Congénitas/fisiopatología , Cefalometría , Preescolar , Femenino , Cardiopatías Congénitas/cirugía , Humanos , Lactante , Recién Nacido , Modelos Lineales , Estudios Longitudinales , Masculino , Estudios Prospectivos , Valores de ReferenciaRESUMEN
BACKGROUND: Marfan's syndrome (MFS) is an autosomal dominant inheritance disorder with a 1/5,000 live-birth prevalence. It is characterized by a wide range of clinical manifestations with more than 3,000 mutations identified in the FBN1 gene. In this study, we aimed to determine if specific patterns of circulating micro-RNAs (miRNAs) are associated with MFS-associated with cardiovascular diseases. METHODS: Microarray-based miRNA profiling was performed on blood samples of 12 MFS patients, and 12 healthy volunteers (HVs) controls and the differences in miRNA abundance between the two groups were validated using independent cohorts of 22 MFS and of 22 HV controls by real-time quantitative polymerase chain reaction (RT-qPCR). Enrichment analyses of altered miRNA abundance were predicted using bioinformatics tools. RESULTS: Altered miRNA abundance levels were determined between MFS (n = 34) and HVs (n = 34). In a screening phase, we analyzed 12 patients with MFS and 12 HVs by miRNA microarray. We found 198 miRNAs that were significantly altered in MFS patients as compared with HVs, including 16 miRNAs with a more than 1.5-fold change. Out of these 16 miRNAs, 10 showed a decreased abundance and 6 showed an increased abundance. In the validation phase, we analyzed independent cohorts of 22 MFS and of 22 HV controls by RT-qPCR. We confirmed the direction of abundance changes and the significance of different abundances between MFS patients and HVs for four miRNAs, namely, miR-362-5p, miR-339-3p, miR-340-5p, and miR-210-3p. Only the miR-150-5p showed a significant correlation with mitral valve prolapse (p = 0.010). The predicted targets for the validated miRNAs were associated with signal transduction, tissue remodeling, and cellular interaction pathways. CONCLUSION: The altered abundance level of different miRNAs in whole blood of MFS patients lays the ground to the development of novel diagnostic approaches with altered miRNAs levels associated with MFS with manifestations associated with cardiovascular diseases.
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MicroARN Circulante/genética , Síndrome de Marfan/genética , Transcriptoma , Adolescente , Adulto , Estudios de Casos y Controles , Niño , MicroARN Circulante/sangre , Biología Computacional , Femenino , Perfilación de la Expresión Génica/métodos , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Síndrome de Marfan/sangre , Síndrome de Marfan/diagnóstico , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Background: Infections and autoimmune disorders are more frequent in Down syndrome, suggesting abnormality of adaptive immunity. Although the role of B cells and antibodies is well characterized, knowledge regarding T cells is limited. Methods: Lymphocyte subpopulations of 40 children and adolescents with Down syndrome and 51 controls were quantified, and phenotype and functionality of antigen-specific effector T cells were analyzed with flow cytometry after polyclonal and pathogen-specific stimulation (with varicella-zoster virus [VZV] and cytomegalovirus [CMV]). Results were correlated with immunoglobulin (Ig) G responses. Results: Apart from general alterations in the percentage of lymphocytes, regulatory T cells, and T-helper 1 and 17 cells, all major T-cell subpopulations showed higher expression of the inhibitory receptor PD-1. Polyclonally stimulated effector CD4+ T-cell frequencies were significantly higher in subjects with Down syndrome, whereas their inhibitory receptor expression (programmed cell death 1 [PD-1] and cytotoxic T-lymphocyte antigen 4 [CTLA-4]) was similar to that of controls and cytokine expression profiles were only marginally altered. Pathogen-specific immunity showed age-appropriate levels of endemic infection, with correlation of CMV-specific cellular and humoral immunity in all subjects. Among VZV IgG-positive individuals, a higher percentage of VZV-specific T-cell-positive subjects was seen in those with Down syndrome. Conclusions: Despite alterations in lymphocyte subpopulations, individuals with Down syndrome can mount effector T-cell responses with similar phenotype and functionality as controls but may require higher effector T-cell frequencies to ensure pathogen control.
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Síndrome de Down/inmunología , Inmunidad Celular/inmunología , Adolescente , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Niño , Citomegalovirus/inmunología , Femenino , Herpesvirus Humano 3/inmunología , Humanos , Masculino , FenotipoRESUMEN
BACKGROUND: It is under debate whether the cumulative effects of intensive endurance exercise induce chronic cardiac damage, mainly involving the right heart. The aim of this study was to examine the cardiac structure and function in long-term elite master endurance athletes with special focus on the right ventricle by contrast-enhanced cardiovascular magnetic resonance. METHODS AND RESULTS: Thirty-three healthy white competitive elite male master endurance athletes (age range, 30-60 years) with a training history of 29±8 years, and 33 white control subjects pair-matched for age, height, and weight underwent cardiopulmonary exercise testing, echocardiography including tissue-Doppler imaging and speckle tracking, and cardiovascular magnetic resonance. Indexed left ventricular mass and right ventricular mass (left ventricular mass/body surface area, 96±13 and 62±10 g/m(2); P<0.001; right ventricular mass/body surface area, 36±7 and 24±5 g/m(2); P<0.001) and indexed left ventricular end-diastolic volume and right ventricular end-diastolic volume (left ventricular end-diastolic volume/body surface area, 104±13 and 69±18 mL/m(2); P<0.001; right ventricular end-diastolic volume/body surface area, 110±22 and 66±16 mL/m(2); P<0.001) were significantly increased in athletes in comparison with control subjects. Right ventricular ejection fraction did not differ between athletes and control subjects (52±8 and 54±6%; P=0.26). Pathological late enhancement was detected in 1 athlete. No correlations were found for left ventricular and right ventricular volumes and ejection fraction with N-terminal pro-brain natriuretic peptide, and high-sensitive troponin was negative in all subjects. CONCLUSIONS: Based on our results, chronic right ventricular damage in elite endurance master athletes with lifelong high training volumes seems to be unlikely. Thus, the hypothesis of an exercise-induced arrhythmogenic right ventricular cardiomyopathy has to be questioned.
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Atletas , Medios de Contraste , Imagen por Resonancia Cinemagnética/métodos , Resistencia Física/fisiología , Función Ventricular Izquierda/fisiología , Función Ventricular Derecha/fisiología , Adulto , Estudios Transversales , Ecocardiografía/métodos , Prueba de Esfuerzo/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters.
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Factor de Transcripción COUP II/genética , Cardiopatías Congénitas/genética , Animales , Sitios de Unión , Factor de Transcripción COUP II/metabolismo , Línea Celular , Exoma , Femenino , Humanos , Masculino , Ratones , Mutación Missense , Linaje , Estudios Prospectivos , Transcripción GenéticaRESUMEN
BACKGROUND: MicroRNAs (miRNAs) are a class of regulatory RNAs that regulate gene expression post-transcriptionally. Little, however, is known on the expression profile of circulating miRNAs in Tetralogy of Fallot (TOF) patients late after surgical repair. In this study, we aimed to identify the specific patterns of circulating miRNAs in blood of patients with repaired, non-syndromic TOF and to assess whether these specific miRNAs may be useful to differentiate patients with and without heart failure. METHODS: SurePrint™ 8 × 60 K Human v16 miRNA arrays were used to determine miRNA expression profiles in 15 healthy controls and 37 patients after TOF repair of whom 3 had symptomatic right heart failure. The expression levels of selected miRNAs have been validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Enrichment analyses of altered miRNA expression were predicted using bioinformatic tools. RESULTS: Compared with healthy controls, a total of 49, 58 and 77 miRNAs were found to be significantly altered in TOF patients (TOF-all), TOF patients with (TOF-HF) and without symptomatic right heart failure (TOF-noHF) (>2.0-fold change, adjusted P < 0.05), respectively. Three miRNAs namely miR-181d-5p, miR-206 and miR-625-5p were validated by RT-qPCR in all TOF groups. The area under the receiver operating characteristic curve (AUC) for miR-181d-5p, miR-206 and miR-625-5p were 0.987, 0.993 and 0.769 in TOF-all and 0.990, 0.994 and 0.749 in TOF-noHF, respectively. Moreover, expression levels of miR-625-5p, miR-1233-3p and miR-421 were lower in TOF-HF compared to TOF-noHF (P = 0.012). CONCLUSIONS: Altered expression levels of circulating miRNAs were found in TOF patients late after surgical repair and are different to those seen in the right ventricular myocardium of infants with TOF. Expression levels of miR-421, miR-1233-3p and miR-625-5p are lower in TOF patients with symptomatic right heart failure and thus may indicate disease progression in these patients.
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MicroARN Circulante/genética , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/genética , Tetralogía de Fallot/sangre , Tetralogía de Fallot/genética , Adulto , MicroARN Circulante/metabolismo , Femenino , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/complicaciones , Humanos , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Tetralogía de Fallot/complicacionesRESUMEN
BACKGROUND: Children with congenital heart defects (CHDs) are at high risk for myocardial failure after operative procedures with cardiopulmonary bypass (CPB). Recent studies suggest that microRNAs (miRNA) are involved in the development of CHDs and myocardial failure. Therefore, the aim of this study was to determine alterations in the miRNA profile in heart tissue after cardiac surgery using CPB. METHODS: In total, 14 tissue samples from right atrium were collected from patients before and after connection of the CPB. SurePrint™ 8 × 60K Human v21 miRNA array and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) were employed to determine the miRNA expression profile from three patients before and after connection of the CPB. Enrichment analyses of altered miRNA expression were predicted using bioinformatic tools. RESULTS: According to miRNA array, a total of 90 miRNAs were significantly altered including 29 miRNAs with increased and 61 miRNAs with decreased expression after de-connection of CPB (n = 3) compared to before CPB (n = 3). Seven miRNAs had been validated using RT-qPCR in an independent cohort of 11 patients. Enrichment analyses applying the KEGG database displayed the highest correlation for signaling pathways, cellular community, cardiovascular disease and circulatory system. CONCLUSION: Our result identified the overall changes of the miRNome in right atrium tissue of patients with CHDs after CPB. The differentially altered miRNAs lay a good foundation for further understanding of the molecular function of changed miRNAs in regulating CHDs and after CPB in particular.
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Puente Cardiopulmonar , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Cardiopatías Congénitas/metabolismo , MicroARNs/metabolismo , Niño , Preescolar , Análisis por Conglomerados , Estudios de Cohortes , Biología Computacional , Femenino , Atrios Cardíacos/metabolismo , Humanos , Lactante , Masculino , Miocardio/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de Tiempo , Distribución TisularRESUMEN
Evidence-based medicine has contributed substantially to the quality of medical care in pediatric and adult cardiology. However, our impression from the bedside is that a substantial number of Cochrane reviews generate inconclusive data that are of limited clinical benefit. We performed a systematic synopsis of Cochrane reviews published between 2001 and 2015 in the field of pediatric cardiology. Main outcome parameters were the number and percentage of conclusive, partly conclusive, and inconclusive reviews as well as their recommendations and their development over three a priori defined intervals. In total, 69 reviews were analyzed. Most of them examined preterm and term neonates (36.2%), whereas 33.3% included also non-pediatric patients. Leading topics were pharmacological issues (71.0%) followed by interventional (10.1%) and operative procedures (2.9%). The majority of reviews were inconclusive (42.9%), while 36.2% were conclusive and 21.7% partly conclusive. Although the number of published reviews increased during the three a priori defined time intervals, reviews with "no specific recommendations" remained stable while "recommendations in favor of an intervention" clearly increased. Main reasons for missing recommendations were insufficient data (n = 41) as well as an insufficient number of trials (n = 22) or poor study quality (n = 19). There is still need for high-quality research, which will likely yield a greater number of Cochrane reviews with conclusive results.
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Cardiología , Metaanálisis como Asunto , Literatura de Revisión como Asunto , Cardiología/normas , Niño , Bases de Datos Factuales/normas , Medicina Basada en la Evidencia , Humanos , Edición/normasRESUMEN
BACKGROUND: Neurological dysfunction may occur after corrective cardiac surgery using cardio-pulmonary bypass (CPB) with or without circulatory arrest. Different neurophysiological monitoring systems have been employed to detect neurological complications and possible brain injury in infants and children during and after cardiac surgery. The value of Elecetroencephalogram (EEG) in infants and children at risk for neurological sequelae has not been systematically studied. METHODS: Sequential performance of two EEGs before and after cardiac surgery at a tertiary University Hospital to screen for possible brain injury after cardiac surgery in neonates and children undergoing CPB surgery. In addition, a complete neurological examination and assessment by a physiotherapist was performed. RESULTS: Over a 4-year period, in 313 patients (age: 54.2 ± 55.7 months; normal initial EEG) after cardiac surgery CPB (duration of surgery: 146.0 ± 58.9 min; aortic cross clamp time: 34.1 ± 19.1 min), a 19-channel EEG recording was performed 2.4 ± 1.8 days prior to and 11.6 ± 5.3 days after cardiac surgery. An abnormal EEG was detected in only 8 of 313 patients (2.5%; focal slowing: 1, generalised slowing: 5, epiletiform discharges: 2) after cardiac surgery, while the EEG was normal in the remaining 305 patients (97.5%). In 1 patient, an intra-cerebral pathology was seen on MRI (ischemic); in 5 patients, follow-up EEGs were performed, which revealed normalized findings. None of the 8 patients demonstrated new focal neurological deficits on physical examination, but 33 (9.7%) children demonstrated minor abnormalities (e.g., subtle motor asymmetry, increase in muscle tone, etc.), which were unrelated to abnormal EEG findings. CONCLUSIONS: According to the used protocol, pathological EEG findings were very infrequent in our study cohort. The routine and indiscriminative recording of EEGs in children before and after corrective or palliative cardiac surgery for congenital heart disease using CPB is not recommended. Further intra-operative neuromonitoring methods with immediate intervention should be evaluated.
Asunto(s)
Daño Encefálico Crónico/diagnóstico , Isquemia Encefálica/diagnóstico , Electroencefalografía , Cardiopatías Congénitas/cirugía , Complicaciones Intraoperatorias/diagnóstico , Monitoreo Intraoperatorio , Complicaciones Posoperatorias/diagnóstico , Puente Cardiopulmonar , Niño , Preescolar , Femenino , Paro Cardíaco Inducido , Humanos , Imagen por Resonancia Magnética , Masculino , Examen Neurológico , Tempo Operativo , Factores de RiesgoRESUMEN
BACKGROUND: Approximately 6000 children are born with CHD in Germany each year. It is increasingly rare that these children die from their chronic illness. In the present study, data recorded in the National Register for Congenital Heart Defects with respect to the prevalence of specific lesions and sex distribution are compared with that recorded in a published German prevalence study (Prevalence Study) and with the meta-analysis by van der Linde et al. METHODS: A descriptive data analysis was performed using a minimal data set. The demographic data included sex and birth year; the medical data comprised the cardiovascular diagnosis according to the short list of the International Paediatric and Congenital Cardiac Code. RESULTS: As the data analysis shows, the National Register is a clinical register including primarily clinical cases/cases relevant to healthcare. The prevalence values and sex ratios recorded in the register are closer to the values given in the literature than those determined by the Prevalence Study. Severe CHD was slightly over-represented in the National Register compared with the van der Linde et al meta-analysis. The deviations with respect to prevalence values are within an acceptable range. CONCLUSION: With its 48,000 patients, the National Register plays a unique and important role for research in the field of CHD. Samples from the National Register can be used as a gold standard for future studies, as the patient population registered in it can be considered representative of CHD in Germany and Europe.