RESUMEN
OBJECTIVE: We present rapid diagnosis of trisomy 18 of maternal origin by quantitative fluorescent polymerase chain reaction (QF-PCR) analysis following tissue culture failure for conventional cytogenetic analysis in a fetus with holoprosencephaly (HPE), ventricular septal defect (VSD), arthrogryposis of bilateral wrists and aplasia of the thumbs. CASE REPORT: A 22-year-old, primigravid woman was referred for first-trimester ultrasound screening at 13 weeks of gestation, and the fetus was found to have HPE and VSD. The pregnancy was subsequently terminated at 14 weeks of gestation, and a malformed fetus was delivered with cebocephaly, arthrogryposis of bilateral wrists and aplasia of the thumbs. The umbilical cord and placental tissues were collected for genetic analysis. However, tissue culture failure for conventional cytogenetic analysis occurred because of contamination. QF-PCR analysis using the polymorphic DNA markers of D18S1369 (18q12.2) and D18S1361 (18q22.3) confirmed trisomy 18 of maternal origin. CONCLUSION: QF-PCR analysis is useful for rapid confirmation of trisomy 18 and the parental origin when tissue culture failure for conventional cytogenetic analysis occurs in pregnancy suspicious of fetal trisomy 18.
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Artrogriposis/diagnóstico , Defectos del Tabique Interventricular/diagnóstico , Holoprosencefalia/diagnóstico , Reacción en Cadena de la Polimerasa/métodos , Síndrome de la Trisomía 18/diagnóstico , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/embriología , Anomalías Múltiples/genética , Aborto Eugénico , Adulto , Artrogriposis/embriología , Artrogriposis/genética , Análisis Citogenético , Femenino , Pruebas Genéticas , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Holoprosencefalia/embriología , Holoprosencefalia/genética , Humanos , Embarazo , Pulgar/anomalías , Síndrome de la Trisomía 18/embriología , Síndrome de la Trisomía 18/genética , Muñeca/anomalíasRESUMEN
Congenital ventricular outpouchings (CVOs) are rare congenital heart defects with limited data regarding prognosis and outcomes. We aimed to describe the characteristics, outcomes and factors associated with morbidity and mortality of prenatally diagnosed CVOs using our institutional experience and a review of published cases. A total of 86 cases of prenatally diagnosed CVOs were identified, including 3 from our institution and 83 cases identified from a review of the literature. Fetal and postnatal outcomes were analyzed for each case. Pericardial effusions (44%) and ventricular dysfunction (17%) were the most common associated findings. Excluding cases that resulted in pregnancy termination, mortality was 17%, with the majority (11/13) occurring in the prenatal period. Factors associated with mortality included an outpouching located on the left ventricle, a diagnosis of hydrops fetalis, the presence of a pericardial effusion, and an earlier gestational age at diagnosis. Of those that survived to delivery, 57% remained asymptomatic without the need for intervention, and the outpouching regressed or resolved in an additional 15%. Prenatally diagnosed congenital ventricular outpouchings are a dynamic form of congenital heart disease with a high fetal mortality rate. The outcomes associated with the outpouchings appear to be the most variable in the prenatal period and the first year after birth. Serial prenatal and postnatal evaluations should be performed to evaluate for a change in the characteristics of the outpouching.
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Defectos del Tabique Interventricular/diagnóstico por imagen , Mortalidad Perinatal , Ecocardiografía Doppler en Color , Femenino , Edad Gestacional , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/mortalidad , Humanos , Imagenología Tridimensional , Recién Nacido , Embarazo , Estudios Retrospectivos , Ultrasonografía PrenatalRESUMEN
Fetuses with large ventricular septal defects (VSDs) must be closely monitored during the perinatal period. Intrauterine assessment of size of septal defects with bidimensional echocardiography are unreliable. The objective of the present study is to document the contribution of flow pattern analysis in the fetal aortic isthmus for prenatal identification of large non-restrictive VSDs requiring immediate postnatal attention. We conducted a cross-sectional retrospective study of Doppler recordings from patients referred to our Fetal Cardiology Unit and diagnosed with one or multiple VSDs from January 2006 to November 2015. Three groups were defined: (1) large non-restrictive VSDs (n = 11) with postnatal cardiac failure (2) small restrictive VSDs (n = 28) asymptomatic, and (3) absence of cardiac abnormality (n = 66). The Isthmic end-Systolic Index (ISI) was computed to quantify aortic isthmus flow and compared between the three groups. Fetuses with restrictive VSD and control group showed similar ISI: stable at 0.20 ± 0.01 up to 27 weeks of gestation and dropping later due to the fall of end-systolic velocities in the aortic isthmus. By 35 weeks, a brief end-systolic retrograde flow was present, associated with a further fall of ISI down to -0.26 ± 0.05. In contrast, ISI of fetuses with large non-restrictive VSDs were unchanged throughout gestation (0.18 ± 0.06), becoming significantly higher during the last weeks of gestation compared to the two other groups (p < 0.001). In fetuses with VSDs, the ISI measurement from the aortic isthmus Doppler flow during the second half of gestation is a reliable predictor of a large non-restrictive defect with risk of major postnatal clinical impact.
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Aorta Torácica/diagnóstico por imagen , Defectos del Tabique Interventricular/diagnóstico , Ultrasonografía Prenatal/métodos , Aorta Torácica/patología , Velocidad del Flujo Sanguíneo , Estudios Transversales , Ecocardiografía , Femenino , Defectos del Tabique Interventricular/embriología , Humanos , Embarazo , Estudios Retrospectivos , Ultrasonografía DopplerRESUMEN
Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue crucial in cardiac development and a potentially useful surrogate for evaluating the development of heart tissue. To understand epigenetic mechanisms that may play a role in the development of VSD, genome-wide DNA methylation assay on placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 unaffected controls was performed using the Illumina HumanMethylation450 BeadChip assay. We identified a total of 80 highly accurate potential CpGs in 80 genes for detection of VSD; area under the receiver operating characteristic curve (AUC ROC) 1.0 with significant 95% CI (FDR) p-values < 0.05 for each individual locus. The biological processes and functions for many of these differentially methylated genes are previously known to be associated with heart development or disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). In addition, we identified 8 microRNAs that have the potential to be biomarkers for the detection of VSD including: miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting VSD.
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Epigénesis Genética , Defectos del Tabique Interventricular/genética , Placenta/metabolismo , Estudios de Casos y Controles , Islas de CpG , Metilación de ADN/genética , Femenino , Corazón Fetal/anomalías , Corazón Fetal/embriología , Corazón Fetal/metabolismo , Marcadores Genéticos , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/etiología , Humanos , Recién Nacido , Masculino , MicroARNs/genética , EmbarazoRESUMEN
The limitations of traditional two-dimensional (2D) echocardiography in accurate diagnosis of ventricular septal defect (VSD) prompt the necessity of spatio-temporal image correlation (STIC) technology. Our study attemped to reconstruct the volume data of VSD using STIC rendering mode, and dynamically display the specific location and surrounding structure of VSD, in order to assist conventional 2D echocardiography. A total of 20 fetuses diagnosed as VSD using 2D echocardiography were enrolled in our study. Multiplane imaging mode was applied to obtain 2D four-chamber view, five-chamber view, and main artery short-axis view. STIC rendering mode was performed to collect volume data and visualize the shape, specific location and surrounding structure of VSD. A more detailed VSD classification for 20 VSD cases was identified. Based on the specific location and surrounding structure under STIC images, they were further subdivided into different types. STIC rendering mode intuitively showed the specific shape and surrounding structure of VSD. STIC technology can be used for definite classification and diagnosis of VSD, combining with 2D echocardiography to make a better therapeutic intervention in clinical practice. Clin. Anat. 32:408-420, 2019. © 2019 Wiley Periodicals, Inc.
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Defectos del Tabique Interventricular/patología , Ultrasonografía Prenatal/métodos , Adulto , Ecocardiografía , Femenino , Edad Gestacional , Defectos del Tabique Interventricular/diagnóstico por imagen , Defectos del Tabique Interventricular/embriología , Humanos , Embarazo , Adulto JovenRESUMEN
The aim of this study was to analyse the anatomy of the ventricular septal defect (VSD) in heart specimens with interruption of the aortic arch (IAA) in order to explore the hypothesis of different embryologic mechanisms for the different anatomic types of IAA. We examined 42 human heart specimens, 25 with IAA as the main disease with concordant atrioventricular and ventriculo-arterial connections and two distinct great arteries, and 17 hearts with IAA associated with other malformations [six common arterial trunk (CAT), five double-outlet right ventricle (DORV), three transposition of the great arteries (TGA), three atrioventricular septal defect (AVSD)]. The interruption was classified according to Celoria and Patton. We focused on the anatomy of the VSD viewed from the right ventricular side. There were 15 IAA type A, 27 type B, no type C. The VSD in IAA type B was always an outlet VSD, located between the two limbs of the septal band, with posterior malalignment of the outlet septum in hearts with concordant ventriculo-arterial connections, without any fibrous tricuspid-aortic continuity. In addition, the aortic arch was always completely absent. Conversely, the VSD in IAA type A could be of any type (outlet in six, muscular in four, central perimembranous in two, inlet in three) and the aortic arch was either atretic or absent. In addition, IAA type B, when found in the setting of another anomaly, was always associated with neural crest-related anomalies (CAT and DORV), whereas IAA type A was found in association with anomalies not related to the neural crest (TGA and AVSD). These results reinforce the hypothesis that different pathogenic mechanisms are responsible for the two types of IAA, and the inclusion of IAA type B in the group of neural crest defects. Conversely, IAA type A could be due to overlapping mechanisms: flow-related defect (coarctation-like) and neural crest contribution.
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Aorta Torácica/anomalías , Defectos del Tabique Interventricular/embriología , HumanosRESUMEN
Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.
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Aberraciones Cromosómicas , Defectos del Tabique Interventricular/diagnóstico , Amniocentesis , Preescolar , Ecocardiografía , Femenino , Edad Gestacional , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Humanos , Lactante , Recién Nacido , Masculino , Análisis por Micromatrices , Embarazo , Resultado del Embarazo , Remisión Espontánea , Ultrasonografía PrenatalRESUMEN
Deletions of chromosome 1p36 are associated with a high incidence of congenital heart defects (CHDs). The arginine-glutamic acid dipeptide repeats gene (RERE) is located in a critical region for CHD on chromosome 1p36 and encodes a cardiac-expressed nuclear receptor co-regulator. Mutations affecting RERE cause atrial and ventricular septal defects (VSDs) in humans, and RERE-deficient mice also develop VSDs. During cardiac development, mesenchymal cells destined to form part of the atrioventricular (AV) septum are generated when endocardial cells in the AV canal undergo epithelial-to-mesenchymal transition (EMT) and migrate into the space between the endocardium and the myocardium. These newly generated mesenchymal cells then proliferate to fill the developing AV endocardial cushions. Here, we demonstrate that RERE-deficient mouse embryos have reduced numbers of mesenchymal cells in their AV endocardial cushions owing to decreased levels of EMT and mesenchymal cell proliferation. In the endocardium, RERE colocalizes with GATA4, a transcription factor required for normal levels of EMT and mesenchymal cell proliferation. Using a combination of in vivo and in vitro studies, we show that Rere and Gata4 interact genetically in the development of CHDs, RERE positively regulates transcription from the Gata4 promoter and GATA4 levels are reduced in the AV canals of RERE-deficient embryos. Tissue-specific ablation of Rere in the endocardium leads to hypocellularity of the AV endocardial cushions, defective EMT and VSDs, but does not result in decreased GATA4 expression. We conclude that RERE functions in the AV canal to positively regulate the expression of GATA4, and that deficiency of RERE leads to the development of VSDs through its effects on EMT and mesenchymal cell proliferation. However, the cell-autonomous role of RERE in promoting EMT in the endocardium must be mediated by its effects on the expression of proteins other than GATA4.This article has an associated First Person interview with the first author of the paper.
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Proteínas Portadoras/metabolismo , Factor de Transcripción GATA4/genética , Regulación del Desarrollo de la Expresión Génica , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas Represoras/deficiencia , Alelos , Animales , Proliferación Celular , Embrión de Mamíferos/metabolismo , Cojinetes Endocárdicos/embriología , Cojinetes Endocárdicos/metabolismo , Cojinetes Endocárdicos/patología , Endocardio/embriología , Endocardio/metabolismo , Endocardio/patología , Transición Epitelial-Mesenquimal/genética , Factor de Transcripción GATA4/metabolismo , Mesodermo/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células 3T3 NIH , Proteínas del Tejido Nervioso/genética , Proteínas Represoras/genéticaRESUMEN
Hypoplastic left heart syndrome (HLHS) encapsulates a spectrum of complex congenital cardiovascular malformations involving varying degrees of underdevelopment of the left-sided heart structures. However, despite improved survival rates since the introduction of staged surgical reconstruction, treatment options for HLHS remain palliative rather than curative. A major limiting factor in the development of definitive curative therapy for HLHS is an incomplete understanding of its pathogenesis. Currently, the aetiology HLHS is best conceptualised by the 'flow theory' of cardiogenesis, which states that normal cardiac development is reliant on the interrelationship of normal flow patterns of blood through the developing heart, and appropriate growth of the cardiac valves and myocardium. Thus, congenital cardiac malformations, such as HLHS, are thought to arise when these two processes are incorrectly coupled in utero. The rationale for the hypothesis proposed herein rests upon the flow theory of cardiogenesis. Morphological studies of HLHS indicate that, although underdeveloped, all left-sided cardiac structures are present and anatomically correct. Further, of the various structural abnormalities that can occur within the spectrum of HLHS, the presence of a ventricular septal defect (VSD) is rare. The rarity of a VSD within the morphological spectrum of HLHS suggests the syndrome may not develop in the presence of a functionally significant VSD. Presumably, the presence of a functional VSD establishes a communication between the two ventricles during cardiac development, and preserves the normal pressure-flow-dependent growth of the left ventricular (LV) myocardium, despite inflow/outflow valve defects. It is proposed that surgical creation of a VSD in utero will 'rescue' the LV of hearts with left-sided valvular deformities that render them susceptible to the development of HLHS later in gestation. In evaluating this hypothesis, potential techniques for surgical creation of a VSD in utero are offered. These techniques are based on already established catheter-based in utero interventions, and conventional postnatal percutaneous procedures for VSD creation. Further discussion is also offered on techniques to avoid, and manage, potential complications (i.e. conduction system damage) of the proposed technique(s). Finally, if VSD creation in utero is indeed practically feasible, and successfully establishes the hypothesised hemodynamic and myocardial growth normalisation within the abnormally developing LV, the clinical implications are profound. This procedure may hold a potential cure for almost every sub-type of HLHS.
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Terapias Fetales/métodos , Feto/cirugía , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Circulación Coronaria/fisiología , Femenino , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/fisiopatología , Defectos del Tabique Interventricular/cirugía , Hemorreología/fisiología , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/embriología , Síndrome del Corazón Izquierdo Hipoplásico/fisiopatología , Modelos Cardiovasculares , EmbarazoRESUMEN
OBJECTIVE: This study was undertaken to clarify the natural course of ventricular septal defect, and to find an index that would help in prenatal counseling. METHODS: Between January 2010 and December 2014, 18 188 fetuses underwent echocardiographic examinations. Of these, 228 isolated ventricular septal defect cases were retrospectively reviewed. RESULTS: In this retrospective study, the incidence of isolated ventricular septal defect was 1.25% (228/18 188). There were 146 patients who underwent echocardiography after delivery in order to confirm the natural course of patients with isolated ventricular septal defect. Of the 146 cases, 64 cases (43.84%) had the ventricular septal defect naturally closed in the fetal period. Of the 82 patients with ventricular septal defect at birth, 25 patients showed natural closure during follow-up. However, four patients (2.74%) required surgical treatment for ventricular septal defect. In case of perimembranous defects, natural closure is more frequent in the fetal period than in the postnatal period. CONCLUSION: Our results indicate that 60.96% (89/146) of isolated ventricular septal defects diagnosed during the fetal life are closed naturally. Perimembranous type defect, small defect (<2 mm) and maternal age less than 35 years are the good prognostic factors for the natural closure during fetal life. © 2017 John Wiley & Sons, Ltd.
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Defectos del Tabique Interventricular/diagnóstico , Defectos del Tabique Interventricular/embriología , Adulto , Femenino , Defectos del Tabique Interventricular/cirugía , Humanos , Edad Materna , Embarazo , Complicaciones del Embarazo/diagnóstico , Pronóstico , Remisión Espontánea , Estudios Retrospectivos , Ultrasonografía PrenatalRESUMEN
Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/ß-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development.
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Corazón/embriología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Animales , Cadherinas/metabolismo , Adhesión Celular , Comunicación Celular , Membrana Celular/metabolismo , Proliferación Celular , Células Cultivadas , Pérdida del Embrión/patología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/patología , Ratones Noqueados , Miocitos Cardíacos/ultraestructura , Especificidad de Órganos , Transporte de Proteínas , beta Catenina/metabolismo , Proteína de Unión al GTP cdc42/genéticaRESUMEN
OBJECTIVE: To study the effects of ethanol vapour exposure on development of atrial and ventricular septa of chick embryo. METHODS: The experimental study was conducted at the College of Physicians and Surgeons, Islamabad, from 2006 to 2007. The experimental and control groups were further divided into three subgroups based on the day of sacrifice. The experimental group was exposed to ethanol vapours produced in a specially-designed vapour chamber and then compared with age-matched controls. RESULTS: There were 90 eggs in each of the two groups. The development of inter-ventricular septum completed at day 7 of development in chick embryo. Ethanol vapour exposure produced a small discontinuity at day 10 of development in a chick embryo which may be labelled as ventricular septal defect since ventricular development is completed by day 7. Interatrial septum formed till day 7 with small perforations which persisted till hatching. CONCLUSIONS: Ethanol vapour exposure may lead to ventricular septal defect.
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Anomalías Inducidas por Medicamentos/embriología , Tabique Interatrial/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Defectos del Tabique Interatrial/embriología , Defectos del Tabique Interventricular/embriología , Tabique Interventricular/efectos de los fármacos , Anomalías Inducidas por Medicamentos/patología , Animales , Tabique Interatrial/embriología , Tabique Interatrial/patología , Embrión de Pollo , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interventricular/patología , Tabique Interventricular/embriología , Tabique Interventricular/patologíaRESUMEN
OBJECTIVE: The study objective was to analyze the anatomy of the ventricular septal defect found in various phenotypes of outflow tract defects. METHODS: We reviewed 277 heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis (isolated outlet ventricular septal defect, 19); tetralogy of Fallot (71); tetralogy of Fallot with pulmonary atresia (51); common arterial trunk (54); double outlet right ventricle (65) with subaortic, doubly committed, or subpulmonary ventricular septal defect; and interrupted aortic arch type B (17). Special attention was paid to the rims of the ventricular septal defect viewed from the right ventricular side and the relationships between the tricuspid and aortic valves. RESULTS: The ventricular septal defect was always located in the outlet of the right ventricle, between the 2 limbs of the septal band. There was a fibrous continuity between the tricuspid and aortic valves in 74% of specimens with isolated outlet ventricular septal defect, 66% of specimens with tetralogy of Fallot, 39% of specimens with tetralogy of Fallot with pulmonary atresia, 4.6% of specimens with double outlet right ventricle, 1.8% of specimens with common arterial trunk, and zero of specimens with interrupted aortic arch type B (P < .005). When present, this continuity always involved the anterior tricuspid leaflet. CONCLUSIONS: The ventricular septal defect in outflow tract defects is always an outlet ventricular septal defect, cradled between the 2 limbs of the septal band. However, there are some differences regarding the posteroinferior and superior rims of the ventricular septal defect. These differences suggest an anatomic continuum from the isolated outlet ventricular septal defect to the interrupted aortic arch type B rather than distinct physiologic phenotypes, related to various degrees of abnormal rotation of the outflow tract during heart development: minimal in isolated outlet ventricular septal defect; incomplete in tetralogy of Fallot, tetralogy of Fallot with pulmonary atresia, and double outlet right ventricle; absent in common arterial trunk; and excessive in interrupted aortic arch type B.
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Anomalías Múltiples , Aorta Torácica/anomalías , Ventrículo Derecho con Doble Salida/embriología , Defectos del Tabique Interventricular/embriología , Tetralogía de Fallot/embriología , Transposición de los Grandes Vasos/embriología , Ventrículo Derecho con Doble Salida/clasificación , Defectos del Tabique Interventricular/clasificación , Humanos , Morfogénesis , Fenotipo , Terminología como Asunto , Tetralogía de Fallot/clasificación , Transposición de los Grandes Vasos/clasificaciónRESUMEN
AIMS: The organization and maturation of ventricular cardiomyocytes from the embryonic to the adult form is crucial for normal cardiac function. We have shown that a polarity protein, Scrib, may be involved in regulating the early stages of this process. Our goal was to establish whether Scrib plays a cell autonomous role in the ventricular myocardium, and whether this involves well-known polarity pathways. METHODS AND RESULTS: Deletion of Scrib in cardiac precursors utilizing Scrib(flox) mice together with the Nkx2.5-Cre driver resulted in disruption of the cytoarchitecture of the forming trabeculae and ventricular septal defects. Although the majority of mice lacking Scrib in the myocardium survived to adulthood, they developed marked cardiac fibrosis. Scrib did not physically interact with the planar cell polarity (PCP) protein, Vangl2, in early cardiomyocytes as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signalling. However, Scrib interacted with Rac1 physically in embryonic cardiomyocytes and genetically to result in ventricular abnormalities, suggesting that this interaction is crucial for the development of the early myocardium. CONCLUSIONS: The Scrib-Rac1 interaction plays a crucial role in the organization of developing cardiomyocytes and formation of the ventricular myocardium. Thus, we have identified a novel signalling pathway in the early, functioning, heart muscle. These data also show that the foetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.
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Defectos del Tabique Interventricular/metabolismo , Ventrículos Cardíacos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miocardio/metabolismo , Neuropéptidos/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Animales , Línea Celular , Polaridad Celular , Células Madre Embrionarias/metabolismo , Fibrosis , Genotipo , Edad Gestacional , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Ventrículos Cardíacos/embriología , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Morfogénesis , Complejos Multiproteicos , Miocardio/patología , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , Ratas , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismoRESUMEN
RATIONALE: Our previous study has shown that yes-associated protein (YAP) plays a crucial role in the phenotypic modulation of vascular smooth muscle cells (SMCs) in response to arterial injury. However, the role of YAP in vascular SMC development is unknown. OBJECTIVE: The goal of this study was to investigate the functional role of YAP in cardiovascular development in mice and determine the mechanisms underlying YAP's actions. METHODS AND RESULTS: YAP was deleted in cardiomyocytes and vascular SMCs by crossing YAP flox mice with SM22α-Cre transgenic mice. Cardiac/SMC-specific deletion of YAP directed by SM22α-Cre resulted in perinatal lethality in mice because of profound cardiac defects including hypoplastic myocardium, membranous ventricular septal defect, and double outlet right ventricle. The cardiac/SMC-specific YAP knockout mice also displayed severe vascular abnormalities including hypoplastic arterial wall, short/absent brachiocephalic artery, and retroesophageal right subclavian artery. Deletion of YAP in mouse vascular SMCs induced expression of a subset of cell cycle arrest genes including G-protein-coupled receptor 132 (Gpr132). Silencing Gpr132 promoted SMC proliferation, whereas overexpression of Gpr132 attenuated SMC growth by arresting cell cycle in G0/G1 phase, suggesting that ablation of YAP-induced impairment of SMC proliferation was mediated, at least in part, by induction of Gpr132 expression. Mechanistically, YAP recruited the epigenetic repressor histone deacetylase-4 to suppress Gpr132 gene expression via a muscle CAT element in the Gpr132 gene. CONCLUSIONS: YAP plays a critical role in cardiac/SMC proliferation during cardiovascular development by epigenetically regulating expression of a set of cell cycle suppressors.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Anomalías Cardiovasculares/genética , Corazón Fetal/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Miocitos Cardíacos/citología , Miocitos del Músculo Liso/citología , Fosfoproteínas/fisiología , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Aneurisma/genética , Animales , Tronco Braquiocefálico/anomalías , Anomalías Cardiovasculares/embriología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , División Celular , Células Cultivadas , Ventrículo Derecho con Doble Salida/embriología , Ventrículo Derecho con Doble Salida/genética , Regulación del Desarrollo de la Expresión Génica/genética , Genes Letales , Genes cdc , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Músculo Liso Vascular/patología , Miocitos Cardíacos/patología , Miocitos del Músculo Liso/patología , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Ratas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/biosíntesis , Receptores Acoplados a Proteínas G/genética , Arteria Subclavia/anomalías , Proteínas Señalizadoras YAPRESUMEN
OBJECTIVES: To evaluate, in a cohort of 248 fetuses seen at a tertiary referral center, the frequency of isolated ventricular septal defects (VSD) among all congenital heart defects (CHD), the association with chromosomal and postnatal anomalies and the rate of spontaneous closure. METHODS: This was a 6-year study on 10,800 women referred for fetal echocardiography, with 995 confirmed cases of CHD. The prevalence and characteristics of VSDs were analyzed, including follow-up until 1 year of age. Multivariate binary logistic regression analysis was performed to test the independent contribution of the ratio of the diameter of the VSD to that of the aorta (VSD/aorta ratio) (< 0.5 or ≥ 0.5) and location of VSD (perimembranous or muscular) in the prediction of spontaneous closure before the age of 1 year. RESULTS: Two hundred and forty-eight VSDs (24.9% of all CHDs) were diagnosed, of which 216 (87.1%) were muscular and 32 (12.9%) perimembranous. Median gestational age at diagnosis was 30.4 (range, 17-41) weeks and mean size 2.6 ± 0.77 mm. Clinically relevant chromosomal anomalies were found in one (3.1%) perimembranous VSD compared with none in 216 muscular defects (P = 0.12). Postnatal malformations were diagnosed in eight of the 211 cases (3.8%) evaluated at 12 months postpartum. Spontaneous closure occurred prenatally in 13 fetuses (5.2%) and postnatally in 151 of the 198 infants (76.3%) who had an open VSD at birth. Closure was predicted by the VSD/aorta ratio (odds ratio (OR) 0.445 (95% CI, 0.216-0.914); P < 0.03) and location (OR 0.385 (95% CI, 0.160-0.926); P < 0.03). CONCLUSIONS: In our fetal cardiology unit, isolated muscular VSD is today the most prevalent CHD. In contrast to the findings of postnatal studies, muscular VSDs were more common than perimembranous VSDs. Perimembranous VSDs were associated with a higher risk of chromosomal anomalies than were muscular VSDs, which had a similar risk to those of normal pregnancies. Spontaneous closure of the VSD was frequent and occurred in most cases postnatally.
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Aberraciones Cromosómicas/embriología , Ecocardiografía Doppler en Color , Asesoramiento Genético , Defectos del Tabique Interventricular/diagnóstico por imagen , Cariotipificación , Ecocardiografía Doppler en Color/métodos , Femenino , Estudios de Seguimiento , Edad Gestacional , Defectos del Tabique Interventricular/embriología , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Resultado del Embarazo , Prevalencia , Remisión Espontánea , Ultrasonografía PrenatalRESUMEN
This study concerns the morphological differentiation between double outlet right ventricle (DORV) and aortic dextroposition (AD) defects, namely tetralogy of Fallot and Eisenmenger anomaly. Indeed, despite the similar condition in terms of sequential ventriculo-arterial connections, DORV and AD are two distinct morphological entities. It is proposed that the borderline between these two groups of malformations is represented by the specific insertion of the infundibular septum into the left anterior cranial division of the septomarginal trabeculation (or septal band) occurring in ADs and lacking in DORV. Furthermore, the spiraliform versus straight parallel arrangement of the great arteries in the two groups of anomalies is emphasized as an additional and distinctive morphological feature. Emphasis is also given to the association of straight parallel great arteries conotruncal malformations, DORV and transposition of the great arteries, with the asplenia type of heterotaxy laterality defects. Within this context, the absence of subaortic ventricular septal defect and concomitantly of spiraliform great arteries in the asplenia group of heterotaxy anomalies, as detected by this study, further substantiates our belief of not mixing collectively the ADs with the DORV in clinico-pathological diagnosis.