RESUMEN
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.
Asunto(s)
Codón sin Sentido , Lateralidad Funcional/genética , Homocigoto , Infertilidad Masculina/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Animales , Dineínas Axonemales/genética , Dineínas Axonemales/metabolismo , Axonema/metabolismo , Proteínas de Ciclo Celular , Niño , Preescolar , Cilios/ultraestructura , Femenino , Regulación de la Expresión Génica , Ligamiento Genético , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Linaje , Polimorfismo de Nucleótido Simple , Cola del Espermatozoide , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families. METHODS: Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of PLD1 knockout mice. RESULTS: Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve. CONCLUSIONS: The findings support a role for PLD1 in normal heart valvulogenesis.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Prolapso de la Válvula Mitral/genética , Mixoma/genética , Fosfolipasa D/genética , Animales , Embrión de Pollo , Ecocardiografía , Exoma/genética , Regulación de la Expresión Génica , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Cardiopatías Congénitas/fisiopatología , Humanos , Ratones , Ratones Noqueados , Prolapso de la Válvula Mitral/fisiopatología , Mixoma/fisiopatología , Eliminación de SecuenciaRESUMEN
BACKGROUND: Laterality in the vertebrate embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid across the embryonic node. Defects in these processes cause heterotaxy, the abnormal formation and arrangement of visceral organs that can range from complete inversion of symmetry to the selective misarrangement of organs. However, our understanding of the genetic causality for laterality defects in human beings remains relatively limited. METHODS: We performed whole exome sequencing in a consanguineous family with heterotaxia. To interrogate the pathogenic potential of the discovered variant, we used an in vivo system in which the potential of the candidate gene to induce L-R asymmetry was tested by transient suppression and CRISPR/Cas9-induced deletions. We also used in vitro assays to test a possible link between our exome-derived candidate and Notch signaling. RESULTS: We identified a homozygous 2 bp deletion in MMP21, encoding matrix metalloproteinase-21, as the sole coding mutation that segregated with the phenotype. Transient suppression or CRISPR/Cas9-mediated deletion of mmp21 in zebrafish embryos induced cardiac looping defects, with concomitant disruption of laterality markers in the lateral plate mesoderm and disrupted notch signalling in vitro and in vivo. CONCLUSIONS: Our data implicate loss of MMP21 as a cause of heterotaxy in humans with concomitant defects in Notch signaling. In support of this finding, a homozygous missense mutation in MMP21 was identified previously in mice with N-Ethyl-N-Nitrosourea (ENU)-induced heterotaxy. Taken together, these observations suggest a role of matrix metalloproteinases in the establishment of asymmetric organ development, likely through the regulation of morphogenetic signals.
Asunto(s)
Síndrome de Heterotaxia/genética , Metaloproteinasas de la Matriz Secretadas/genética , Animales , Secuencia de Bases , Niño , Consanguinidad , Análisis Mutacional de ADN , Exoma , Femenino , Síndrome de Heterotaxia/enzimología , Homocigoto , Humanos , Masculino , Linaje , Receptores Notch/metabolismo , Eliminación de Secuencia , Transducción de Señal , Adulto Joven , Pez CebraRESUMEN
BACKGROUND: Truncus arteriosus (TA) accounts for ~1% of congenital heart defects. The aetiology of isolated TA is largely unknown but when occurring as part of a syndrome, it is mostly associated with chromosome 22q11 deletion. Vice versa, the most common congenital heart defects associated with chromosome 22q11 deletion are conotruncal malformations. In this study we investigated the cause of multiple conotruncal malformations accompanied by athymia in a consanguineous family. METHODS AND RESULTS: Whole exome analysis revealed a homozygous deleterious mutation in the NKX2-6 gene. CONCLUSIONS: NKX2-6 encodes a homeobox-containing protein which is expressed in mouse embryo at E8.0-E9.5 at the caudal pharyngeal arches and the outflow tract. A single missense mutation was previously implicated in the aetiology of familial isolated TA; however, null mice are entirely normal. The clear phenotype associated with a homozygous deleterious mutation in the present report, falls well within the spectrum of the cardiac defects seen in DiGeorge syndrome, is in agreement with NKX2-6 downstream location in the TBX1 signalling pathway and confirms NKX2-6 role in human cardiogenesis.
Asunto(s)
Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Proteínas de Homeodominio/genética , Mutación/genética , Timo/anomalías , Adolescente , Animales , Secuencia de Bases , Niño , Familia , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Datos de Secuencia Molecular , LinajeRESUMEN
Truncus arteriosus accounts for approximately 1% of congenital heart defects and the cause of isolated non-syndromic truncus arteriosus is largely unknown. In order to identify the underlying molecular defect in a consanguineous family with recurrent tuncus arteriosus, homozygosity mapping followed by whole exome sequencing was performed. This resulted in the identification of a homozygous mutation, Arg1299Cys, in the PLXND1 gene. The mutation affected a highly conserved residue, segregated with the disease in the family and was absent from available SNP databases and ethnic matched controls. in silico comparative modeling revealed that the mutation resides in the N-terminal segment of the human plexin-D1 intracellular region which interacts with the catalytic GTPase-activating protein homology region. The mutation likely destabilizes the intracellular region, perturbing its anchoring and catalytic activity. The phenotype in human PLXND1 mutation is closely related to that of knockout mice for PLXND1, its co-receptor neuropilin-1 or its ligand SEMA3C. It is therefore suggested that SEMA3C signaling, propagated through the heterodimer receptor plexin-D1/neuropilin, is important for truncus arteriosus septation. Confirmation of this observation will require the identification of PLXND1 mutations in additional patients. Exome analysis is valuable for molecular investigation of single patients with congenital heart defects in whom chromosomal copy number variants have been excluded.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Estudios de Asociación Genética , Cardiopatías Congénitas/genética , Tronco Arterial/fisiopatología , Animales , Moléculas de Adhesión Celular Neuronal/metabolismo , Preescolar , Mapeo Cromosómico , Exoma , Femenino , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Masculino , Glicoproteínas de Membrana , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mutación , Linaje , Semaforinas/metabolismo , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
BACKGROUND: Significant advancements in understanding the molecular pathophysiology of laterality determination were recently made. However, there are large gaps in our knowledge of the initial processes that lead to laterality defects, such as heterotaxy syndrome (HS, also known as situs ambiguous) and situs inversus totalis (SIT). The former refers to abnormal distribution of visceral organs, and the latter refers to a complete laterality inversion of both abdominal and thoracic viscera. METHODS: In order to identify a mutated gene in SIT and HS patients, the authors performed homozygosity mapping in a consanguineous family with laterality disorders identified in two siblings. RESULTS: A homozygous deleterious mutation in the CCDC11 gene was identified in the patients. The mutation resulted in an abnormally smaller protein in the patient's skin fibroblasts. The parents and five healthy siblings were heterozygous for the mutation, which was not present in 112 anonymous controls. CONCLUSIONS: Few genes have been associated with both SIT and HS, usually accompanied by other abnormalities. The authors suggest that CCDC11 is associated with autosomal recessive laterality defects of diverse phenotype resulting in SIT in one individual family member who is otherwise healthy, and in complex laterality anomalies (HS) in another member. This report underscores the importance of CCDC11 in laterality determination.
Asunto(s)
Genes Recesivos , Síndrome de Heterotaxia/genética , Mutación , Situs Inversus/genética , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Western Blotting , Mapeo Cromosómico , Consanguinidad , Fibroblastos , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , ARN/genética , ARN/aislamiento & purificación , Análisis de Secuencia de ADNRESUMEN
Intracardiac echogenic foci (ECFs), probably representing microcalcifications of the papillary muscles, are a common finding in fetal ultrasonic screening examinations. Their significance is unclear, and their value as markers for chromosomal anomalies is debatable. It also is unknown whether ECFs predict abnormal cardiac performance. This prospective study analyzed and compared the systolic and diastolic properties of the heart in 28 fetuses with ECFs and 70 fetuses without ECFs using both conventional and novel myocardial deformation methods. The findings suggest that left-sided ECFs do not predict depressed left- or right-side systolic or diastolic properties in the fetus. A longitudinal study that would follow ECF fetuses into their childhood is warranted to confirm the findings of this study.
Asunto(s)
Corazón Fetal/diagnóstico por imagen , Hemodinámica , Ultrasonografía Prenatal , Femenino , Corazón Fetal/patología , Edad Gestacional , Humanos , Embarazo , Estudios ProspectivosRESUMEN
PURPOSE OF REVIEW: To describe the results of two recent prospective studies that may indicate how to monitor, diagnose, and treat fetuses with neonatal lupus manifesting with heart involvement and to summarize additional research reports regarding the pathophysiology and outcomes of this rare condition. RECENT FINDINGS: The PR Interval and Dexamethasone Evaluation study found 10 cases of neonatal lupus (10%) with three first-degree atrioventricular blocks (AVBs) and three complete heart blocks. The study included 98 pregnancies in 95 women with anti-SSA/Ro antibodies who completed weekly fetal Doppler echocardiogram-based evaluation. The authors concluded that they were unable to detect first-degree AVB before progression to complete heart block. A similar observational prospective study was performed in 70 fetuses of 56 mothers using tissue velocity fetal kinetocardiogram for measurement of PR prolongation. In this study, six fetuses (8.5%) showed first-degree AVB, and fast normalization of heart function was achieved through maternal treatment with fluorinated steroids. The authors concluded that fetal kinetocardiogram can detect first-degree AVB in the fetus exposed to maternal anti-SSA/Ro or anti-SSB/La antibodies or both and that fluorinated steroids given on detection were associated with normalized atrioventricular conduction in fetuses with first-degree AVB. SUMMARY: Echo Doppler seems a less reliable method for early detection of fetus first-degree AVB, and it is suggested that fetal kinetocardiogram or fetal electrocardiography are preferred. Although atrioventricular block reverses spontaneously in some fetuses, parents and treating physicians should consider immediate treatment with fluorinated steroids once a first-degree AVB is detected due to the high risk of rapid progression to complete blockage.
Asunto(s)
Anticuerpos Antinucleares/sangre , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/tratamiento farmacológico , Bloqueo Cardíaco/prevención & control , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Complicaciones del Embarazo/inmunología , Corticoesteroides/uso terapéutico , Bloqueo Atrioventricular/congénito , Ecocardiografía Doppler , Femenino , Bloqueo Cardíaco/congénito , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/tratamiento farmacológico , Humanos , Recién Nacido , Cinetocardiografía , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal , Ultrasonografía PrenatalRESUMEN
Conventional techniques for the assessment of cardiac function on the basis of M-mode or 2-dimensional modalities are technically difficult, load dependent, and provide information on global ventricular function only. Newer techniques, which analyze myocardial performance, such as tissue velocity, strain, and especially the less load dependent strain rate, may provide more appropriate information. Myocardial systolic and diastolic motion and performance were calculated using tissue velocity, strain, and strain rate imaging on a large cohort of normal fetuses. The assessment of myocardial performance was feasible in all 98 normal fetuses. Normal systolic and diastolic values for tissue velocity, strain, and strain rate were established. All data were highly reproducible. Tissue velocity was age dependent, whereas strain and strain rate were stable throughout gestation. All parameters were heart rate independent. In conclusion, fetal myocardial velocity, strain, and strain rate measurements are easy to obtain and reproducible, and therefore, may serve as reference data. Increases in tissue velocity throughout gestation probably reflect the growth of the fetal heart, whereas intrinsic myocardial properties as measured by strain rate do not change. In comparison with recently published myocardial performance values in children, these strain rate data suggest that fetal myocontractile properties that are already established during the second half of pregnancy remain constant throughout gestation and after birth.
Asunto(s)
Corazón Fetal/fisiología , Contracción Miocárdica , Velocidad del Flujo Sanguíneo , Femenino , Edad Gestacional , Frecuencia Cardíaca , Humanos , Variaciones Dependientes del Observador , Embarazo , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los Resultados , Volumen Sistólico , Función VentricularRESUMEN
BACKGROUND: Surgical repair of tetralogy of Fallot may leave the patient with pulmonary regurgitation, causing eventual right ventricle dilatation and dysfunction. Predicting clinical deterioration may help to determine the best timing for intervention. OBJECTIVES: To assess whether the clinical and humoral status of patients in the second decade after repair of ToF is worse than that of patients in the first decade after repair. METHODS: Twenty-one patients with repaired ToF underwent clinical assessment, electrocardiogram, echocardiogram and measurement of plasma B-type natriuretic peptide and N-terminal pro-BNP as well as the 6 minute walk distance test. Patients were divided into two groups: group A - less than 10 years after repair (n=10, age < 12 years old), and group B - more than 10 years after repair (n=11, age > 12 years old). The age at repair was similar in both groups. RESULTS: In all but one patient the distance in the 6 min walk test was less than the minimum for age. RV end-diastolic volume and the 6 min walk test correlated with age. NT-proBNP levels were significantly higher in the ToF group compared to 26 healthy controls (P < 0.0001) and were inversely correlated with RV ejection fraction. Comparison of the two groups showed no difference in RV end-diastolic volume indexed for body surface area, pulmonary regurgitation severity, right or left ventricular myocardial performance index, RV ejection fraction, QRS duration, or 6 min walk indexed to minimum for age. CONCLUSIONS: In this group of patients with similar age at operation and pulmonary regurgitation severity, most clinical, echocardiographic and humoral parameters were not worse in the second decade after repair of ToF. These data suggest that very early pulmonary valve replacement may not be of benefit.
Asunto(s)
Complicaciones Posoperatorias/diagnóstico , Tetralogía de Fallot/cirugía , Adolescente , Adulto , Análisis de Varianza , Niño , Preescolar , Ecocardiografía , Electrocardiografía , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Péptido Natriurético Encefálico/sangre , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/fisiopatología , Insuficiencia de la Válvula Pulmonar/sangre , Insuficiencia de la Válvula Pulmonar/diagnóstico , Insuficiencia de la Válvula Pulmonar/fisiopatología , Estadísticas no Paramétricas , Tetralogía de Fallot/sangre , Tetralogía de Fallot/fisiopatología , Resultado del TratamientoRESUMEN
Anomalous pulmonary artery arising from the aorta is a rare congenital anomaly. The midterm results of repair of this malformation by Gore-Tex graft interposition were examined in 5 patients: 3 with anomalous right pulmonary artery and 2 with anomalous left pulmonary artery from the ascending aorta. Echocardiography was adequate in 4 cases for diagnosis, planning the operation, and follow-up. Angiography was needed for diagnosis in one case where the echocardiographic findings were unclear. The mean follow-up period was 4 years. One patient with tracheoesophageal fistula and cardiac malformation died 2 months after the operation due to multi-organ failure. Three patients needed re-operation because of graft narrowing, and one was without problems 5.2 years postoperatively. In anomalous pulmonary artery from the ascending aorta, repair should be performed as early as possible to prevent pulmonary hypertensive changes. When the anomalous pulmonary artery cannot be anastomosed directly to the main pulmonary artery, an interposition graft can be placed safely without cardiopulmonary bypass. With appropriate follow-up, this can be a satisfactory solution, although it carries the risk of re-operation due to graft narrowing.
Asunto(s)
Implantación de Prótesis Vascular/métodos , Prótesis Vascular , Politetrafluoroetileno , Arteria Pulmonar/anomalías , Arteria Pulmonar/cirugía , Aorta/cirugía , Implantación de Prótesis Vascular/efectos adversos , Femenino , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/cirugía , Humanos , Lactante , Recién Nacido , Masculino , Reoperación , Resultado del TratamientoRESUMEN
The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.
Asunto(s)
Secuencia de Bases , Proteínas Portadoras/genética , Síndrome de Heterotaxia/genética , Hidrocefalia/veterinaria , Levocardia/genética , Eliminación de Secuencia , Proteínas Portadoras/metabolismo , Cilios , Consanguinidad , Exoma , Femenino , Síndrome de Heterotaxia/metabolismo , Síndrome de Heterotaxia/patología , Homocigoto , Humanos , Hidrocefalia/genética , Hidrocefalia/metabolismo , Hidrocefalia/patología , Lactante , Levocardia/metabolismo , Levocardia/patología , Datos de Secuencia Molecular , Fenotipo , Análisis de Secuencia de ADNRESUMEN
Mechanical events and electromechanical coupling are analyzed simultaneously in the atria and ventricles using tissue velocity imaging. Normal values for these parameters are provided.
Asunto(s)
Ecocardiografía Doppler , Atrios Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Función Ventricular , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Modelos Lineales , Masculino , Persona de Mediana EdadRESUMEN
Congenital cardiac defects such as peripheral pulmonary stenosis are well described in Alagille syndrome (AGS), which is transmitted in an autosomal dominant inheritance. Haploinsufficiency of the Jagged1 (JAG1) gene has been shown to cause AGS. Abdominal coarctation is an uncommon vascular congenital anomaly which has been described only three times in AGS. Recently, expression of the Jagged1 gene has been found in the developing heart and in multiple associated vascular structures, including the descending aorta. Mutation analysis of the Jagged1 gene in this fourth reported patient with coarctation of the abdominal aorta in AGS and right subclavian stenosis identified a mutation deletion (1485 Del CT). This agrees with the Jagged1 expression studies and suggests that coarctation of aorta may be a component of AGS.
Asunto(s)
Síndrome de Alagille/genética , Aorta Abdominal/anomalías , Coartación Aórtica/genética , Mutación , Proteínas/genética , Síndrome de Alagille/patología , Aorta Abdominal/patología , Coartación Aórtica/patología , Secuencia de Bases , Proteínas de Unión al Calcio , ADN , Humanos , Péptidos y Proteínas de Señalización Intercelular , Proteína Jagged-1 , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana , Proteínas Serrate-JaggedRESUMEN
OBJECTIVES: The purpose of this study was to determine the reliability and accuracy of automated border detection using acoustic quantification in children. BACKGROUND: Acoustic quantification has shown promise in adult patients as a method for on-line estimation of left ventricular size and function. However, in children, the smaller ventricular size might magnify the importance of measurement error. METHODS: We compared the cross-sectional area and fractional area change of the left ventricle as measured on line by acoustic quantification with the area and fractional area change derived by hand-digitizing the endocardial border of the left ventricle off line, both with and without the papillary muscles included in the left ventricular cavity. RESULTS: The areas and area change fractions from the two methods were highly correlated, both with inclusion and exclusion of the papillary muscles for off-line analysis. However, the regression slope was closer to unity when the papillary muscles were excluded from the left ventricular cavity during off-line digitization of the endocardial border. Analysis of agreement between the two methods showed good agreement for area measurements and fair agreement for function measurements. The magnitude of the difference between the two methods for area measurement was directly proportional to the size of the ventricle. That is, the larger the ventricle the larger the difference between the area measurements by the two methods. DISCUSSION: Automatic border detection using acoustic quantification appears to be an acceptable method for estimating the cross-sectional area and fractional area change of the left ventricle in children.
RESUMEN
Singleton pregnancy in patients with single ventricle after the Fontan operation has been reported with significant offspring and maternal complications. We report a twin pregnancy and premature delivery, in a patient following the Fontan operation.
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Anomalías Múltiples , Procedimiento de Fontan , Cardiopatías Congénitas/cirugía , Embarazo Gemelar , Cesárea , Femenino , Cardiopatías Congénitas/fisiopatología , Humanos , Recién Nacido , Nacimiento Vivo , Embarazo , Nacimiento Prematuro , Adulto JovenRESUMEN
A contralateral persistent superior vena cava (PSVC) can occur in a normal child or in association with congenital heart defects (CHDs). Its prevalence has been demonstrated in relatively small cohorts. We aim to assess the frequency of a PSVC in a large cohort of children with and without CHDs. To estimate its significance, we have searched for a PSVC in all children referred for echocardiography in our institution during a 16.5-year period. A group of 17,219 children comprised 8,140 children with a structural heart anomaly and 9,079 children with a structurally normal heart. Association between a PSVC and specific classes of CHD were looked for. A total of 288 children (1.7%) had a PSVC; 0.56% (51 of 9,079) in the normal heart group and 2.9% (237 of 8,140) in the congenital heart anomalies group. Odds ratio for having heart anomaly in the presence of PSVC was 5.2 (95% confidence interval 3.7 to 7.0). A PSVC was above all associated with atrioventricular septal defects, conotruncal malformations, and left-sided defects. The odds ratio of having PSVC in the aforementioned malformations compared with the normal heart group was 23.8, 13.6, and 11.0, respectively. In conclusion, although present in normal subjects, PSVC was more often associated with congenital heart and other anomalies, especially with atrioventricular septal defects, conotruncal malformations, and left-sided defects.
Asunto(s)
Anomalías Múltiples , Ecocardiografía , Cardiopatías Congénitas/epidemiología , Malformaciones Vasculares/epidemiología , Vena Cava Superior/anomalías , Niño , Femenino , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/fisiopatología , Humanos , Israel/epidemiología , Masculino , Oportunidad Relativa , Prevalencia , Estudios Retrospectivos , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/fisiopatología , Vena Cava Superior/diagnóstico por imagen , Vena Cava Superior/fisiopatologíaRESUMEN
BACKGROUND: Functional assessment of the fetal heart has always been a challenge. Automatic functional imaging (AFI), a novel non-Doppler methodology based on 2-dimensional acoustic markers tracking, measures myocardial deformation regardless of angle of interrogation. Thus, we studied the validity of AFI in segmental and global assessment of myocardial function in the fetus. METHODS: AFI-based myocardial deformation parameters including segmental tissue velocity, strain, and strain rate as well as biventricular global strain and strain rate were measured from raw scan-line data obtained from 28 normal fetuses (20-38, median 28 weeks of gestation). Interobserver and intraobserver variability was analyzed. AFI data were compared with analogous Doppler-derived tissue velocity imaging parameters measured in the same 28 fetuses. RESULTS: AFI was feasible in 94% of the fetuses studied with high reproducibility. AFI-based tissue velocity (3.9 +/- 1 cm/s) was comparable with tissue velocity imaging-based velocity (4 +/- 1.6 cm/s) in the right ventricle and in the left ventricle (AFI velocity 3.3 +/- 0.6 vs tissue velocity imaging 3.1 +/- 0.9 cm/s). Strain rate obtained by these two methods was also similar. Biventricular global strain and strain rate measured 16 +/- 4% and 1.6 +/- .5 seconds(-1), respectively. Tissue velocity increased whereas segmental strain rate decreased throughout gestation. Strain remained unchanged. Global strain rate significantly decreased with gestational age (r = -0.7). CONCLUSION: AFI, a novel non-Doppler methodology, allows fast and accurate quantification of segmental and global myocardial function in the fetus. AFI-based tissue velocity increases with gestational age whereas segmental and the new parameter global strain rate decrease throughout gestation.
Asunto(s)
Ecocardiografía Doppler en Color/métodos , Corazón Fetal/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Volumen Sistólico/fisiología , Automatización , Estudios de Cohortes , Femenino , Corazón Fetal/fisiología , Edad Gestacional , Humanos , Contracción Miocárdica/fisiología , Variaciones Dependientes del Observador , Embarazo , Valores de Referencia , Sensibilidad y Especificidad , Ultrasonografía Prenatal , Función Ventricular Izquierda/fisiología , Función Ventricular Derecha/fisiologíaRESUMEN
BACKGROUND: Anthracyclines are widely used in the treatment of pediatric cancer but their use is associated with cardiotoxicity. The cardiotoxic effect may become clinically apparent many years after therapy, and no reliable method exists for early detection of cardiac damage while the patient is receiving the drug. The natriuretic peptides have been established as markers for anthracycline-induced cardiotoxicity in adults and markers for cardiac dysfunction in children. We examined whether N-terminal proB-type natriuretic peptide (NT-proBNP) may be used as a marker for anthracycline-induced cardiotoxicity in children. METHODS: Twenty-three consecutive pediatric patients with newly diagnosed cancer were enrolled in this study. All patients received anthracycline-containing chemotherapy. Fifty-four age-matched children served as controls. Serial measurements of plasma NT-proBNP levels were taken before and after each anthracycline-containing course. Echocardiograms were performed before initiation of treatment and at the end of the study. RESULTS: Plasma levels of NT-proBNP were within normal limits before treatment and increased significantly only after the first anthracycline dose (from 150+/-112 to 327+/-321 pg/mL, mean+/-SD, P=0.02) and not after subsequent doses. This increase was attributed mainly to a subgroup of patients who received more than 25 mg/m of doxorubicin. In 14 patients (61%), the highest NT-proBNP level occurred after the first anthracycline dose. All patients had normal echocardiograms and none developed heart failure. CONCLUSIONS: NT-proBNP increases significantly after the first anthracycline course in a subset of pediatric cancer patients. This increase is not associated with clinical or echocardiographic evidence of cardiac dysfunction. Anthracyclines may be more cardiotoxic in the first course than in subsequent courses. Longer follow-up of these patients is necessary to determine whether NT-proBNP can be used as an early marker for anthracycline-induced cardiotoxicity.
Asunto(s)
Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/efectos adversos , Corazón/efectos de los fármacos , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Ecocardiografía , Femenino , Humanos , Lactante , MasculinoRESUMEN
Myocardial bridging (MB) is a rare coronary anomaly in children that is typically associated with hypertrophic cardiomyopathy or left ventricular hypertrophy. Several reports, mainly in adults, have suggested an association between MB and sudden death or ischemia without other cardiac abnormalities. In this report, we describe an 11-year-old girl with syncope and manifestations of cardiac ischemia associated with MB of the middle segment of the left anterior descending artery. The coronary anomaly was not associated with left ventricular hypertrophy. Surgical unroofing of the affected coronary artery segment resulted in complete recovery. MB should be included in the differential diagnosis of children presenting with syncope and signs of ischemia even in the absence of ventricular hypertrophy.