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OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
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Doença da Válvula Aórtica Bicúspide/diagnóstico , Biometria , Ecocardiografia , Coração Fetal/fisiopatologia , Ultrassonografia Pré-Natal , Adulto , Aorta/diagnóstico por imagem , Aorta/embriologia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/embriologia , Doença da Válvula Aórtica Bicúspide/embriologia , Circulação Sanguínea , Estudos de Casos e Controles , Feminino , Coração Fetal/diagnóstico por imagem , Coração Fetal/embriologia , Feto/irrigação sanguínea , Feto/diagnóstico por imagem , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Segundo Trimestre da Gravidez , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/embriologia , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/embriologiaRESUMO
OBJECTIVE: We described a case of fetal cardiac rhabdomyoma complicated by hydrops. And we discussed our approach during pregnancy. CASE REPORT: A 23-year-old woman primigravida was referred at 29 weeks of gestation (WG) to prenatal unit for a large hyperechogenic intracardiac mass associated with fetal hydrops. An intrauterine peritoneo-amniotic shunt was placed. Complete regression of ascites and pericardial effusions were observed after 34 WG with drain in good position. CONCLUSION: Cardiac rhabdomyoma is the most common prenatal cardiac tumor. These tumors are benign, asymptomatic and spontaneously regress after birth. However, in some cases, these tumors may cause severe obstructions on the fetal heart and need specific treatment.
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Drenagem/métodos , Doenças Fetais/terapia , Terapias Fetais/métodos , Neoplasias Cardíacas/embriologia , Hidropisia Fetal/terapia , Rabdomioma/embriologia , Ascite , Feminino , Doenças Fetais/diagnóstico , Coração Fetal/embriologia , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/terapia , Humanos , Hidropisia Fetal/diagnóstico , Gravidez , Rabdomioma/diagnóstico , Rabdomioma/terapia , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-ß1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.
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Infecções por Coxsackievirus , Enterovirus Humano B/patogenicidade , Coração Fetal , Cardiopatias Congênitas , Miócitos Cardíacos , Animais , Proliferação de Células , Correlação de Dados , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/virologia , Feminino , Coração Fetal/embriologia , Coração Fetal/patologia , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/virologia , Camundongos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Miócitos Cardíacos/virologia , Gravidez , Índice de Gravidade de Doença , Carga Viral/métodosRESUMO
OBJECTIVE: To analyze the incremental benefit of 3D/4D spatiotemporal image correlation (STIC) fetal echocardiography over 2D fetal echocardiography with respect to the accuracy of identification of anatomic details crucial for surgical decision-making and in predicting surgical approach in fetuses with double-outlet right ventricle (DORV). METHODS: This was a retrospective study of fetuses with DORV which had undergone both 2D echocardiography and 3D/4D STIC echocardiography and which underwent surgery postnatally in a tertiary pediatric cardiac center in Kerala between October 2015 and March 2019. All such cases with normal atrial arrangement, concordant atrioventricular connections and balanced ventricles were included. 2D and 3D/4D STIC fetal echocardiographic data were analyzed by two experienced observers blinded to the other dataset. Anatomic variables crucial for surgical decision-making, i.e. location and routability of the ventricular septal defect, relationship of the great arteries and presence of outflow obstruction, were compared between the two modalities with respect to agreement with postnatal echocardiography. The accuracy of prenatal prediction of the surgical pathway was compared between 2D and 3D/4D modalities with respect to the procedure undertaken. RESULTS: Included in the study were 22 fetuses with DORV which had undergone both 2D and 3D/4D imaging as well as postnatal surgery. Accuracy of prenatal interpretation of all four anatomic variables was significantly higher using 3D/4D STIC than using 2D fetal echocardiography (19/22 (86.4%) vs 8/22 (36.4%), P < 0.001). Surgical procedures included single-stage repair in 14 (63.5%) patients and a multistage approach in eight (36.4%). Prenatal prediction of the surgical pathway was significantly more accurate on 3D/4D STIC than on 2D echocardiography (20/22 (90.9%) vs 12/22 (54.5%), P = 0.021). Prenatal predictive accuracy of single-stage biventricular repair was significantly better for 3D/4D STIC than for 2D echocardiography (14/14 (100%) vs 8/14 (57.1%), P = 0.04). CONCLUSION: Addition of 3D/4D STIC to conventional 2D fetal echocardiography confers incremental benefit on the accuracy of identification of anatomic details crucial for surgical decision-making and the prediction of postnatal surgical approach in fetuses with DORV, thereby potentially aiding prenatal counseling. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Ecocardiografia Quadridimensional/estatística & dados numéricos , Ecocardiografia Tridimensional/estatística & dados numéricos , Coração Fetal/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Adulto , Procedimentos Cirúrgicos Cardíacos/métodos , Dupla Via de Saída do Ventrículo Direito/embriologia , Dupla Via de Saída do Ventrículo Direito/cirurgia , Feminino , Coração Fetal/embriologia , Coração Fetal/cirurgia , Humanos , Recém-Nascido , Valor Preditivo dos Testes , Gravidez , Estudos RetrospectivosRESUMO
OBJECTIVE: To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. METHODS: This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. RESULTS: In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. CONCLUSION: Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Coração Fetal/fisiopatologia , Feto/irrigação sanguínea , Pré-Eclâmpsia/fisiopatologia , Terceiro Trimestre da Gravidez/sangue , Adulto , Pressão Arterial , Estudos de Casos e Controles , Circulação Cerebrovascular , Feminino , Coração Fetal/diagnóstico por imagem , Coração Fetal/embriologia , Feto/embriologia , Feto/fisiopatologia , Idade Gestacional , Ventrículos do Coração/fisiopatologia , Humanos , Fator de Crescimento Placentário/sangue , Circulação Placentária , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Estudos Prospectivos , Fluxo Pulsátil , Análise de Regressão , Ultrassonografia Pré-Natal/métodos , Artéria Uterina/diagnóstico por imagem , Artéria Uterina/embriologia , Artéria Uterina/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Resistência VascularRESUMO
OBJECTIVES: To investigate the impact of abnormal perinatal loading conditions on cardiac geometry and function in term fetuses and neonates with transposition of the great arteries with intact interventricular septum (simple TGA), and to explore the predictive value of fetal cardiac parameters for an urgent balloon atrial septostomy (BAS) after birth. METHODS: This was a prospective longitudinal follow-up study of women delivering at term, including both uncomplicated pregnancies with normal outcome and pregnancies affected by fetal simple TGA. Conventional, spectral-tissue Doppler and speckle-tracking echocardiographic parameters were obtained within 1 week before delivery and within the first few hours after delivery. Neonates with simple TGA that required urgent BAS were assessed after the procedure and before corrective arterial switch surgery. Cardiac parameters were normalized by cardiac cycle length, ventricular end-diastolic length or end-diastolic dimension, as appropriate. Fetal and neonatal cardiac parameters were compared between simple-TGA cases and controls, and perinatal changes in the simple-TGA group were assessed. Receiver-operating-characteristics (ROC)-curve analysis was used to assess the predictive value of fetal cardiac parameters for urgent BAS after birth in the simple-TGA group. RESULTS: A total of 67 pregnant women delivering at term were included in the study (54 normal pregnancies and 13 with a diagnosis of fetal simple TGA). Compared with normal term fetuses, term fetuses with simple TGA exhibited more globular hypertrophied ventricles, increased biventricular systolic function and diastolic dysfunction (right ventricular (RV) sphericity index (SI), 0.58 vs 0.54; left ventricular (LV)-SI, 0.55 vs 0.49; combined cardiac output (CCO), 483 vs 406 mL/min/kg; LV torsion, 4.3 vs 3.0 deg/cm; RV isovolumetric relaxation time (IVRT'), 127 vs 102 ms; P < 0.01 for all). Compared with normal neonates, neonates with simple TGA demonstrated biventricular hypertrophy, a more spherical right ventricle and altered systolic and diastolic functional parameters (RV-SI, 0.61 vs 0.43; RV myocardial performance index, 0.47 vs 0.34; CCO, 697 vs 486 mL/min/kg; LV-IVRT', 100 vs 79 ms; RV-IVRT', 106 vs 71 ms; P < 0.001 for all). Paired comparison of neonatal and fetal cardiac indices in the simple-TGA group showed persistence of the fetal phenotype, increased biventricular systolic myocardial contractility and CCO, and diastolic dysfunction (RV systolic myocardial velocity (S'), 0.31 vs 0.24 cm/s; LV-S', 0.23 vs 0.18 cm/s; CCO, 697 vs 483 mL/min/kg; LV torsion, 1.1 vs 4.3 deg/cm; P < 0.001 for all). Several fetal cardiac parameters in term fetuses with simple TGA demonstrated high predictive value for an urgent BAS procedure after birth. Our proposed novel fetal cardiac index, LV rotation-to-shortening ratio, as a potential marker of subendocardial dysfunction, for a cut-off value of ≥ 0.23, had an area under the ROC curve (AUC) of 0.94, sensitivity of 100% and specificity of 83%. For RV/LV end-diastolic area ratio ≥ 1.33, pulmonary-valve-to-aortic-valve-dimension ratio ≤ 0.89, RV/LV cardiac output ratio ≥ 1.38 and foramen-ovale-dimension-to-total-interatrial-septal-length ratio ≤ 0.27, AUC was 0.93-0.98, sensitivity was 86% and specificity was 83-100% for all. CONCLUSIONS: Simple-TGA fetuses exhibited cardiac remodeling at term with more profound alterations in these cardiac parameters after birth, suggestive of adaptation to abnormal loading conditions and possible adaptive responses to hypoxemia. Perinatal adaptation in simple TGA might reflect persistence of the abnormal parallel arrangement of cardiovascular circulation and the presence of widely patent fetal shunts imposing volume load on the neonatal heart. The fetal cardiac parameters that showed high predictive value for urgent BAS after birth might reflect the impact of late-gestation pathophysiology and progressive hypoxemia on fetal cardiac geometry and function in simple TGA. If these findings are validated in larger prospective studies, detailed cardiac assessment of fetuses with simple TGA near term could facilitate improvements in perinatal management and refinement of the timing of postnatal intervention strategies to prevent adverse pregnancy outcomes. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Cateterismo Cardíaco/métodos , Ecocardiografia/métodos , Coração Fetal/diagnóstico por imagem , Transposição dos Grandes Vasos/cirurgia , Ultrassonografia Pré-Natal/métodos , Adulto , Septo Interatrial/embriologia , Septo Interatrial/fisiopatologia , Septo Interatrial/cirurgia , Débito Cardíaco , Feminino , Coração Fetal/embriologia , Coração Fetal/fisiopatologia , Seguimentos , Forame Oval/diagnóstico por imagem , Forame Oval/embriologia , Forame Oval/fisiopatologia , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Gravidez , Estudos Prospectivos , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/embriologiaRESUMO
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ release channels located on the ER membrane, which in mammals consist of 3 different subtypes (IP3R1, IP3R2, and IP3R3) encoded by 3 genes, Itpr1, Itpr2, and Itpr3, respectively. Studies utilizing genetic knockout mouse models have demonstrated that IP3Rs are essential for embryonic survival in a redundant manner. Deletion of both IP3R1 and IP3R2 has been shown to cause cardiovascular defects and embryonic lethality. However, it remains unknown which cell types account for the cardiovascular defects in IP3R1 and IP3R2 double knockout (DKO) mice. In this study, we generated conditional IP3R1 and IP3R2 knockout mouse models with both genes deleted in specific cardiovascular cell lineages. Our results revealed that deletion of IP3R1 and IP3R2 in cardiomyocytes by TnT-Cre, in endothelial / hematopoietic cells by Tie2-Cre and Flk1-Cre, or in early precursors of the cardiovascular lineages by Mesp1-Cre, resulted in no phenotypes. This demonstrated that deletion of both IP3R genes in cardiovascular cell lineages cannot account for the cardiovascular defects and embryonic lethality observed in DKO mice. We then revisited and performed more detailed phenotypic analysis in DKO embryos, and found that DKO embryos developed cardiovascular defects including reduced size of aortas, enlarged cardiac chambers, as well as growth retardation at embryonic day (E) 9.5, but in varied degrees of severity. Interestingly, we also observed allantoic-placental defects including reduced sizes of umbilical vessels and reduced depth of placental labyrinth in DKO embryos, which could occur independently from other phenotypes in DKO embryos even without obvious growth retardation. Furthermore, deletion of both IP3R1 and IP3R2 by the epiblast-specific Meox2-Cre, which targets all the fetal tissues and extraembryonic mesoderm but not extraembryonic trophoblast cells, also resulted in embryonic lethality and similar allantoic-placental defects. Taken together, our results demonstrated that IP3R1 and IP3R2 play an essential and redundant role in maintaining the integrity of fetal-maternal connection and embryonic viability.
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Retardo do Crescimento Fetal/genética , Coração Fetal/metabolismo , Cardiopatias Congênitas/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Placenta/metabolismo , Animais , Células Progenitoras Endoteliais/metabolismo , Feminino , Coração Fetal/embriologia , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Placenta/embriologia , GravidezRESUMO
OBJECTIVE: The aim of this study is to review our institution's experience with fetal cardiac rhabdomyoma, and to document the prenatal genetic testing for tuberous sclerosis complex (TSC) and clinical outcome of the affected pregnancies. STUDY DESIGN: During a four-year period, patients with fetal cardiac rhabdomyoma were detected by echocardiography in the second trimester of pregnancy. Molecular genetic analysis was conducted on fetuses to screen for variants of TSC1/TSC2 genes. We reviewed medical records of these affected pregnancies, including maternal demographics, sonographic findings, genotyping results and pregnancy outcomes. RESULTS: Eleven cases with fetal cardiac rhabdomyoma were studied during the study period. A pathogenic variant of TSC1/TSC2 genes was detected in all cases, including two with an inherited variant and nine with a de novo variant. Out of these eleven cases diagnosed prenatally, eight pregnancies were terminated and three continued till term. CONCLUSIONS: Cardiac rhabdomyoma is the prenatal sign of TSC. A molecular investigation of TSC1/TSC2 genes should be recommended for fetuses with a rhabdomyoma and the parents, and the prognostic counselling should include TSC and its consequences.
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Doenças Fetais/diagnóstico , Testes Genéticos/métodos , Neoplasias Cardíacas/diagnóstico , Diagnóstico Pré-Natal/métodos , Rabdomioma/diagnóstico , Adulto , Ecocardiografia/métodos , Feminino , Doenças Fetais/genética , Coração Fetal/diagnóstico por imagem , Coração Fetal/embriologia , Variação Genética/genética , Neoplasias Cardíacas/embriologia , Neoplasias Cardíacas/genética , Humanos , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Rabdomioma/embriologia , Rabdomioma/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
OBJECTIVE: To examine the association between fetal major heart defects and increased nuchal translucency thickness (NT), tricuspid regurgitation and abnormal flow in the ductus venosus in a large population of singleton pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation. METHODS: This was a retrospective study of prospectively collected data from singleton pregnancies attending for a routine ultrasound scan at 11-13 weeks' gestation, which included examination of fetal anatomy, measurement of NT and assessment of blood flow across the tricuspid valve and in the ductus venosus, according to a standardized protocol. The incidence of fetal NT ≥ 95th and ≥ 99th percentiles, tricuspid regurgitation and reversed a-wave in the ductus venosus in fetuses with and those without a major heart defect was determined and the performance of each marker and their combination in the detection of major heart defects was calculated. RESULTS: The study population of 93 209 pregnancies with no apparent chromosomal abnormality included 211 (0.23%) with a fetal major heart defect and 92 998 morphologically normal neonates. In 113 (53.6%) cases with a major heart defect, the diagnosis was made at the 11-13-week scan, in 82 (38.9%) at the 18-24-week scan, in 10 (4.7%) at the third-trimester scan and in six (2.8%) postnatally. At the 11-13-week scan, we diagnosed all cases of tricuspid or pulmonary atresia and polyvalvular dysplasia, > 90% of cases of hypoplastic left heart syndrome or atrioventricular septal defect, about 60% of complex heart defects and cases of left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), 30-40% of cases of tetralogy of Fallot and arch abnormalities, 25% of tricuspid valve abnormalities and about 15% of cases of transposition of the great arteries, but none of aortic or pulmonary stenosis or common arterial trunk. Fetal NT ≥ 95th or ≥ 99th percentile, tricuspid regurgitation or abnormal ductus venosus flow was observed in 77 (36.5%), 45 (21.3%), 61 (28.9%) and 58 (27.5%) fetuses with a major heart defect, respectively, and in 5678 (6.1%), 857 (0.9%), 1136 (1.2%) and 1644 (1.8%) of those without a heart defect. Any one of NT ≥ 95th percentile, tricuspid regurgitation or abnormal flow in the ductus venosus was found in 117 (55.5%; 95% CI, 48.5-62.3%) fetuses with a heart defect and in 8166 (8.8%; 95% CI, 8.6-9.0%) of those without a heart defect. Any one of NT ≥ 99th percentile or the other two markers was found in 99 (46.9%; 95% CI, 40.0-53.9%) fetuses with a heart defect and in 3517 (3.8%; 95% CI, 3.7-3.9%) of those without a heart defect. CONCLUSION: At 11-13 weeks' gestation, measurement of fetal NT and assessment of flow across the tricuspid valve and in the ductus venosus can lead to early diagnosis of major heart defect. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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Permeabilidade do Canal Arterial/diagnóstico por imagem , Coração Fetal/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Medição da Translucência Nucal/estatística & dados numéricos , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Adulto , Permeabilidade do Canal Arterial/embriologia , Permeabilidade do Canal Arterial/epidemiologia , Diagnóstico Precoce , Feminino , Coração Fetal/embriologia , Coração Fetal/fisiopatologia , Idade Gestacional , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/epidemiologia , Humanos , Incidência , Recém-Nascido , Medição da Translucência Nucal/métodos , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Fluxo Pulsátil , Estudos Retrospectivos , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/embriologia , Transposição dos Grandes Vasos/epidemiologia , Insuficiência da Valva Tricúspide/embriologia , Insuficiência da Valva Tricúspide/epidemiologiaRESUMO
OBJECTIVES: To explore the contribution of single-gene defects to the genetic cause of cardiac left-sided lesions (LSLs), and to evaluate the incremental diagnostic yield of whole-exome sequencing (WES) for single-gene defects in fetuses with LSLs without aneuploidy or a pathogenic copy-number variant (pCNV). METHODS: Between 10 April 2015 and 30 October 2018, we recruited 80 pregnant women diagnosed with a LSL who had termination of pregnancy and genetic testing. Eligible LSLs were aortic valve atresia or stenosis, coarctation of the aorta, mitral atresia or stenosis and hypoplastic left heart syndrome (HLHS). CNV sequencing (CNV-seq) and WES were performed sequentially on specimens from these fetuses and their parents. CNV-seq was used to identify aneuploidies and pCNVs, while WES was used to identify diagnostic genetic variants in cases without aneuploidy or pCNV. RESULTS: Of 80 pregnancies included in the study, 27 (33.8%) had a genetic diagnosis. CNV-seq analysis identified six (7.5%) fetuses with aneuploidy and eight (10.0%) with pCNVs. WES analysis of the remaining 66 cases revealed diagnostic genetic variants in 13 (19.7%) cases, indicating that the diagnostic yield of WES for the entire cohort was 16.3% (13/80). KMT2D was the most frequently mutated gene (7/66 (10.6%)) in fetuses with LSL without aneuploidy or pCNVs, followed by NOTCH1 (4/66 (6.1%)). HLHS was the most prevalent cardiac phenotype (4/7) in cases with a KMT2D mutation in this cohort. An additional six (9.1%) cases were found to have potentially deleterious variants in candidate genes. CONCLUSIONS: Single-gene defects contribute substantially to the genetic etiology of fetal LSLs. KMT2D mutations accounted for approximately 10% of LSLs in our fetal cohort. WES has the potential to provide genetic diagnoses in fetuses with LSLs without aneuploidy or pCNVs. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Contribución de los defectos unigénicos a las lesiones cardíacas congénitas del lado izquierdo en el ámbito prenatal OBJETIVOS: Estudiar la contribución de los defectos unigénicos a la causa genética de las lesiones cardíacas del lado izquierdo (LCLI) y evaluar el desempeño del diagnóstico incremental de la secuenciación hologenómica (SHG) para los defectos unigénicos en los fetos con LCLI sin aneuploidía o sin variación patógena en el número de copias (pCNV, por sus siglas en inglés). MÉTODOS: Entre el 10 de abril de 2015 y el 30 de octubre de 2018 se reclutaron 80 mujeres embarazadas diagnosticadas con LCLI, las cuales se sometieron a una interrupción del embarazo y a pruebas genéticas. Las LCLI elegibles eran la atresia o estenosis de la válvula aórtica, la coartación de la aorta, la atresia o estenosis mitral y el síndrome del hemicardio izquierdo hipoplásico (SHIH). La secuenciación CNV (CNV-seq) y la SHG se realizaron de forma secuencial en muestras de estos fetos y de sus padres. La CNV-seq se utilizó para identificar las aneuploidías y las pCNV, mientras que la SHG se utilizó para identificar las variantes genéticas de diagnóstico en los casos sin aneuploidías o pCNV. RESULTADOS: De 80 embarazos incluidos en el estudio, 27 (33,8%) tuvieron un diagnóstico genético. El análisis de la CNV-seq identificó seis (7,5%) fetos con aneuploidía y ocho (10,0%) con pCNV. El análisis de la SHG de los 66 casos restantes manifestó variantes genéticas de diagnóstico en 13 (19,7%) casos, lo que indica que el comportamiento del diagnóstico del SHG para toda la cohorte fue del 16,3% (13/80). El KMT2D fue el gen que mutó más frecuentemente (7/66 (10,6%)) en los fetos con LCLI sin aneuploidía o pCNV, seguido de NOTCH1 (4/66 (6,1%)). El SHIH fue el fenotipo cardíaco más prevalente (4/7) en los casos con mutación de KMT2D en esta cohorte. En seis casos (9,1%) adicionales se encontraron variantes potencialmente perjudiciales en los genes con riesgo. CONCLUSIONES: Los defectos unigénicos contribuyen sustancialmente a la etiología genética de las LCLI fetales. Las mutaciones de KMT2D representaron aproximadamente el 10% de las LCLI en esta cohorte fetal. La SHG tiene el potencial de proporcionar diagnósticos genéticos en fetos con LCLI sin aneuploidía o sin pCNV. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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Variações do Número de Cópias de DNA/genética , Sequenciamento do Exoma , Feto/anormalidades , Testes Genéticos/métodos , Cardiopatias Congênitas/genética , Aborto Eugênico , Aneuploidia , Proteínas de Ligação a DNA/genética , Feminino , Coração Fetal/anormalidades , Coração Fetal/embriologia , Feto/embriologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/embriologia , Humanos , Mutação , Proteínas de Neoplasias/genética , GravidezRESUMO
O incremento do arsenal diagnóstico do pré-natal, por meio de exames de ultrassom, com tecnologias de imagens cada vez mais perfeitas, proporciona o estudo detalhado da anatomia fetal. A mortalidade infantil está diretamente relacionada com as malformações congênitas fetais, especialmente com as alterações anatômicas do coração. Aproximadamente 90% das gestantes não apresentam nenhum fator de risco para malformações cardíacas congênitas (MCCs), portanto o rastreamento pré-natal deve ser realizado em todas as gestações, conforme sugestão da primeira Diretriz Brasileira de Cardiologia Fetal. A revisão bibliográfica da literatura sugere que o diagnóstico pré-natal das MCCs permite intervenções fetais durante o pré-natal e adequado planejamento do parto. Essas ações interferem na morbiletalidade perinatal e no prognóstico dos fetos portadores de cardiopatias, além de auxiliarem a equacionar as vagas nos hospitais de referência e estimarem os gastos na saúde pública e privada.(AU)
The improvement of the ultrasound scan used in the prenatal evaluations provides better images data for the study of the fetal heart. Congenital heart malformations are one of the most leading causes of infant death in the world. Ninety percent of pregnant women do not present any risk factors for Congenital Heart Malformations, so prenatal screening should be performed in all pregnancies, as suggested by the first Brazilian Guideline on Fetal Cardiology. The literature review propose that prenatal diagnosis of congenital heart malformations supports fetal care satisfactory delivery planning and interventions during prenatal. These kindness influences the prognosis of the cardiopathies, perinatal morbidity and mortality and help to reorganize hospital admission and public health care.(AU)
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Humanos , Feminino , Gravidez , Diagnóstico Pré-Natal/métodos , Coração Fetal/anormalidades , Coração Fetal/embriologia , Coração Fetal/fisiopatologia , Cardiopatias Congênitas/diagnóstico por imagem , Ecocardiografia , Mortalidade Infantil , Ultrassonografia Pré-Natal , Mortalidade PerinatalRESUMO
OBJECTIVES: Fetal endoscopic tracheal occlusion (FETO) is offered to fetuses with congenital diaphragmatic hernia (CDH) and severe lung hypoplasia to promote lung growth and may secondarily affect left heart growth. The effects of FETO on left heart hypoplasia (LHH) are not described post-CDH repair. METHODS: A retrospective analysis was performed for fetuses with left-sided CDH who underwent FETO and severity-matched controls from 2007 to 2016 at our institution. Echocardiographic, ultrasound, and MRI data were reviewed. Left heart dimensions were assessed prenatally and postnatally. Primary clinical outcome evaluated was death. RESULTS: Twelve FETO patients and 18 controls were identified. Fetal LHH was noted in both groups and worsened after FETO. Postnatal mitral valve dimensions were larger in the FETO group pre-CDH repair (P = .03). Post-CDH repair, mitral valve and left ventricular dimensions were not significantly different between groups (P = .79 and P = .63 respectively) while FETO aortic valve dimensions were smaller (P = .04). Extracorporeal membrane oxygenation use was lower in the FETO group. No associations were found between left heart dimensions and outcomes. CONCLUSION: Although increased lung growth was seen after FETO, fetal LHH persisted with relative normalization seen post-repair. Persistent LHH post-FETO could be secondary to a small contribution of pulmonary venous return to the fetal left heart and increased intrathoracic pressures post-FETO.
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Coração Fetal/embriologia , Fetoscopia/estatística & dados numéricos , Hérnias Diafragmáticas Congênitas/cirurgia , Ecocardiografia , Feminino , Coração Fetal/diagnóstico por imagem , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
TSP50, a testis-specific gene encoding a serine protease-like protein, was specifically expressed in the spermatocytes of testes but abnormally activated and expressed in many different kinds of cancers. Here, we aimed to analyze the expression of TSP50 in mouse embryo and its function in early embryonic development. Firstly, the distribution of TSP50 in oocytes and embryonic development was characterized by immunofluorescence, RT-PCR and western blotting, and the results showed that TSP50 was detected at all studied stages with a dynamic expression pattern. When overexpressed TSP50 in zygotes by microinjection, the zygotes development was highly accelerated. On the contrary, knocking down TSP50 expression by RNA interference greatly retarded the zygote development. Furthermore, TSP50 expression at embryonic day 6.5 (E6.5), day 8.5 (E8.5) and day 10.5 (E10.5) were increasingly enhanced, However, the expression of TSP50 decreased gradually in the development and differentiation of cardiac myocyte from E12.5 to postnatal (P0). Additionally, we found that TSP50 expression was decreased during cardiac myocyte differentiation of P19 cells. Overexpression of TSP50 could decrease the expression of GATA-4, and knockdown of TSP50 markedly increase the expression of GATA-4. Taken together, our data indicate that TSP50 may play an important role during the process of mouse embryonic development as well as myocardial cell differentiation.
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Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/enzimologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Coração Fetal/embriologia , Coração Fetal/enzimologia , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , GravidezRESUMO
Congenital double aortic arch (DAA) is an uncommon vascular anomaly; however, its prenatal detection is associated with congenital heart defects and chromosomal abnormalities, including 22q11 deletion. We present a case of DAA diagnosed prenatally. DAA can be diagnosed by prenatal ultrasound in the transverse three vessel-trachea view, which shows a trident image formed by a complete vascular ring and the ductus arteriosus. Postnatal magnetic resonance images in this view correlate well with prenatal ultrasound images and help in confirmation of diagnosis, evaluation of the risk of airway or esophageal compression, and planning of surgery.
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Aorta Torácica/diagnóstico por imagem , Síndromes do Arco Aórtico/diagnóstico por imagem , Coração Fetal/diagnóstico por imagem , Angiografia por Ressonância Magnética/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Aorta Torácica/anormalidades , Aorta Torácica/embriologia , Síndromes do Arco Aórtico/embriologia , Feminino , Coração Fetal/embriologia , Humanos , GravidezRESUMO
KEY POINTS: The contractile properties of human fetal cardiac muscle have not been previously studied. Small-scale approaches such as isolated myofibril and isolated contractile protein biomechanical assays allow study of activation and relaxation kinetics of human fetal cardiac muscle under well-controlled conditions. We have examined the contractile properties of human fetal cardiac myofibrils and myosin across gestational age 59-134 days. Human fetal cardiac myofibrils have low force and slow kinetics of activation and relaxation that increase during the time period studied, and kinetic changes may result from structural maturation and changes in protein isoform expression. Understanding the time course of human fetal cardiac muscle structure and contractile maturation can provide a framework to study development of contractile dysfunction with disease and evaluate the maturation state of cultured stem cell-derived cardiomyocytes. ABSTRACT: Little is known about the contractile properties of human fetal cardiac muscle during development. Understanding these contractile properties, and how they change throughout development, can provide valuable insight into human heart development, and provide a framework to study the early stages of cardiac diseases that develop in utero. We characterized the contractile properties of isolated human fetal cardiac myofibrils across 8-19 weeks of gestation. Mechanical measurements revealed that in early stages of gestation there is low specific force and slow rates of force development and relaxation, with increases in force and the rates of activation and relaxation as gestation progresses. The duration and slope of the initial, slow phase of relaxation, related to myosin detachment and thin filament deactivation rates, decreased with gestation age. F-actin sliding on human fetal cardiac myosin-coated surfaces slowed significantly from 108 to 130 days of gestation. Electron micrographs showed human fetal muscle myofibrils elongate and widen with age, but features such as the M-line and Z-band are apparent even as early as day 52. Protein isoform analysis revealed that ß-myosin is predominantly expressed even at the earliest time point studied, but there is a progressive increase in expression of cardiac troponin I (TnI), with a concurrent decrease in slow skeletal TnI. Together, our results suggest that cardiac myofibril force production and kinetics of activation and relaxation change significantly with gestation age and are influenced by the structural maturation of the sarcomere and changes in contractile filament protein isoforms.
Assuntos
Coração Fetal/fisiologia , Contração Miocárdica , Miofibrilas/fisiologia , Actinas/genética , Actinas/metabolismo , Adulto , Feminino , Coração Fetal/embriologia , Humanos , Masculino , Miofibrilas/metabolismo , Miofibrilas/ultraestrutura , Miosinas/genética , Miosinas/metabolismo , Troponina I/genética , Troponina I/metabolismoRESUMO
OBJECTIVE: The goal of our study was to evaluate the evolution of cardiac findings and assess the pregnancy outcome of fetuses with cardiac asymmetry at midgestation. METHODS: We reviewed all fetuses with cardiac asymmetry at echocardiograms performed at 18-22 weeks of gestation from 2006 to 2013. The data collected included the gestational age at diagnosis, serial echocardiographic findings, karyotype testing, and pregnancy outcome. Excluded were cases of classical hypoplastic left heart syndrome (HLHS) at initial echocardiogram (i.e., aortic (AO) and/or mitral atresia or dysplasia with normal intracardiac connections), heterotaxy syndrome, twin pregnancy, fetal growth restriction, and coarctation of the aorta. RESULTS: Our study included 278 fetuses with cardiac asymmetry (defined as Z-scores of left ventricle length or diameter of less than -2). A total of 202 (72%) fetuses had normal variations in cardiac growth by prenatal and neonatal echocardiography, 69 (25%) fetuses were confirmed to have HLHS variant by autopsy or neonatal echocardiography (with an overall survival of 4.3%), and seven (3%) fetuses were terminated before 24 weeks of gestation because of abnormal karyotypes. None of the cardiac measurements at the initial echocardiogram was significantly different between HLHS variant and normal cases. In the 69 fetuses ultimately diagnosed with HLHS variant, but not in the 202 normals, the Z-scores of all measured left heart structures decreased progressively between the first and the last prenatal echocardiograms (P < 0.01). CONCLUSIONS: The majority of the fetuses with cardiac asymmetry at 18-22 weeks have a good outcome. A minority of them progress to develop HLHS variant with advancing gestation.
Assuntos
Coração Fetal/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Feminino , Coração Fetal/anormalidades , Coração Fetal/embriologia , Seguimentos , Idade Gestacional , Ventrículos do Coração/anormalidades , Ventrículos do Coração/embriologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico por imagem , Recém-Nascido , Masculino , Gravidez , Resultado da Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Método Simples-Cego , Ultrassonografia Doppler em CoresRESUMO
Barker's concept of 'foetal programming' proposes that intrauterine growth restriction (IUGR) predicts complex metabolic diseases through relationships that may be further modified by the postnatal environment. Dietary restriction and deficit in methyl donors, folate, vitamin B12, and choline are used as experimental conditions of foetal programming as they lead to IUGR and decreased birth weight. Overfeeding and deficit in methyl donors increase central fat mass and lead to a dramatic increase of plasma free fatty acids (FFA) in offspring. Conversely, supplementing the mothers under protein restriction with folic acid reverses metabolic and epigenomic phenotypes of offspring. High-fat diet or methyl donor deficiency (MDD) during pregnancy and lactation produce liver steatosis and myocardium hypertrophy that result from increased import of FFA and impaired fatty acid ß-oxidation, respectively. The underlying molecular mechanisms show dysregulations related with similar decreased expression and activity of sirtuin 1 (SIRT1) and hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). High-fat diet and overfeeding impair AMPK-dependent phosphorylation of PGC-1α, while MDD decreases PGC-1α methylation through decreased expression of PRMT1 and cellular level of S-adenosyl methionine. The visceral manifestations of metabolic syndrome are under the influence of endoplasmic reticulum (ER) stress in overnourished animal models. These mechanisms should also deserve attention in the foetal programming effects of MDD since vitamin B12 influences ER stress through impaired SIRT1 deacetylation of HSF1. Taken together, similarities and synergies of high-fat diet and MDD suggest, therefore, considering their consecutive or contemporary influence in the mechanisms of complex metabolic diseases.
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Epigênese Genética , Ácidos Graxos/metabolismo , Desenvolvimento Fetal , Coração Fetal/metabolismo , Transtornos da Nutrição Fetal/metabolismo , Fígado/metabolismo , Animais , Feminino , Coração Fetal/embriologia , Coração Fetal/fisiologia , Genoma Humano , Humanos , Fígado/embriologia , Fígado/fisiologia , NutrigenômicaRESUMO
Introdução: A taquicardia sinusal inapropriada é rara na população em geral, tem maior prevalência em mulheres jovens e sua etiologia é desconhecida. Caracteriza-se por uma frequência cardíaca, persistentemente, elevada com uma resposta exagerada à atividade física. Objetivo: Relatar um caso raro de taquicardia sinusal inapropriada em fase precoce da gestação, enfatizando a importância da ecocardiografia fetal transvaginal. Relato de caso: Gestante encaminhada para realização de ecocardiografia transvaginal por taquicardia fetal persistente. Ao exame de nove semanas, o feto apresentava uma FC de 240 batimentos por minuto (bpm), com condução atrioventricular de um para um e sem sinais de hidropisia. Utilizados a digoxina e, posteriormente, o flecainide, ambos sem sucesso terapêutico. Iniciado sotatol com redução gradual e posterior normalização da FC fetal. O parto ocorreu a termo, concepto nasceu bem e evoluiu com taquicardia persistente. O eletrocardiograma realizado demonstrou onda P com morfologia de ritmo sinusal. As possíveis causas de taquicardia sinusal foram afastadas, confirmando assim o diagnóstico acima. Comentários: O autor reforça a importância da ecocardiografia fetal transvaginal para o diagnóstico e tratamento precoce de arritmias fetais, evitando complicações.
Introduction: The inappropriate sinus tachycardia is rare in the general population, more frequently affects young women, and its etiology is unknow. It is characterized by a persistently elevated cardiac frequency with na exaggerated response to physical activity. Objective: Report a rare case of inappropriate sinus tachycardia in the early phase of pregnancy and emphasize the importance of transvaginal fetal echocardiography. Case report: Pregnant referred due to persistente fetal tachycardia after obstretic ultrasonography. The transvaginal echocardiogram performed at 9 weeks' gestation showed a fetal heart rate of 240 beats min (bpm) with normal conduction from atria to ventricle (1:1)and no signal hydropsy. Digoxin therapy and Flecainide were used with no sucess. Sotatol use was chose when the fetal heart rate (HR) reduced to tolerable levels and then the number of heartbeats normalized at thirty six weeks gestation. The baby was born well at term and developed persistente tachycardia. The electrocardiogram performed showed P-ware morphology of sinus rhythm. Possible causes of sinus tachycardia were excluded, thus confirming the diagnosis above. Comments: The author describes the imortance of transvaginal fetal echocardiography for the diagnosis and early treatment of fetal arrhythmias avoiding complications.
Introducción: La taquicardia sinusal inapropiada es rara en la población en general, predomina mayormente en mujeres jóvenes y su etiología es desconocida. Se caracteriza por una frecuencia cardíaca, persistentemente, elevada con una respuesta exagerada a la actividad física. Objetivo: Relatar un caso raro de taquicardia sinusal inapropiada en fase precoz de la gestación, enfatizando la importancia de la ecocardiografía fetal transvaginal. Relato del caso: Gestante derivada para la realización del ecocardiograma transvaginal por taquicardia fetal persistente. En el examen de nueve semanas, el feto presentaba una FC de 240 latidos por minuto (lpm), con conducción aurículoventricular de uno para uno y sin señales de hidropesía. Se utilizó la digoxina y, posteriormente, el flecainide, ambos sin éxito terapéutico. Iniciado sotatol con reducción gradual y posterior normalización de FC fetal. El parto ocurrió a término, nació bien y evolucionó con taquicardia persistente. El electrocardiograma realizado demostró onda P con morfología de ritmo sinusal. Las posibles causas de taquicardia sinusal se eliminaron, confirmando así el diagnóstico señalado. Comentarios: El autor refuerza la importancia de la ecocardiografía fetal transvaginal para el diagnóstico y tratamiento precoz de arritmias fetales, evitando complicaciones
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Humanos , Feminino , Adulto , Coração Fetal/embriologia , Ecocardiografia/métodos , Ecocardiografia , Gestantes , Taquicardia Sinusal/complicações , Taquicardia Sinusal/diagnóstico , Arritmia Sinusal/terapiaRESUMO
Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (LVNC), a cardiomyopathy characterized by increased ratios of trabecular to compact myocardium. 14-3-3ε is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3ε is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3ε deletion did not appear to induce compensation by other 14-3-3 isoforms but led to ventricular noncompaction, with features similar to LVNC, resulting from a selective reduction in compact myocardium thickness. Abnormal compaction derived from a 50% decrease in cardiac proliferation as a result of a reduced number of cardiomyocytes in G(2)/M and the accumulation of cardiomyocytes in the G(0)/G(1) phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27(Kip1), possibly through both transcriptional and posttranslational mechanisms. Our work shows that 14-3-3ε regulates cardiogenesis and growth of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via both cyclin E1 and p27(Kip1). These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3ε as a new candidate gene in congenital human cardiomyopathies.
Assuntos
Proteínas 14-3-3/metabolismo , Cardiopatias Congênitas/embriologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas 14-3-3/deficiência , Proteínas 14-3-3/genética , Animais , Sequência de Bases , Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Ciclina E/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Primers do DNA/genética , Modelos Animais de Doenças , Feminino , Coração Fetal/anormalidades , Coração Fetal/embriologia , Coração Fetal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Ventrículos do Coração/anormalidades , Ventrículos do Coração/embriologia , Ventrículos do Coração/metabolismo , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Proteínas Oncogênicas/metabolismoRESUMO
Angiogenic growth factors are a class of molecules which exert a fundamental role in the process of blood vessel formation. Besides vasculogenic and angiogenic properties, these compounds mediate a complex series of patterning activities during organogenesis. Angiogenic factors cooperate in the growth and development of embryo tissues in a cross-talk between endothelial cells and tissue cells. It is well established that many tissue-derived factors are involved in blood vessel formation, but there is now emerging evidence that angiogenic factors and endothelial cells themselves represent a crucial source of instructive signals to non-vascular tissue cells during organ development. Thus, angiogenic factors and endothelial cell signalling are currently believed to provide fundamental cues for cell fate specification, embryo patterning, organ differentiation and postnatal tissue remodelling. This review article will summarize some of the recent advances in our understanding of the role of angiogenic factors and endothelial cells as effectors in organ formation.