RESUMEN
The cardiac extracellular matrix (cECM) is fundamental for organ morphogenesis and maturation, during which time it undergoes remodeling, yet little is known about whether mechanical forces generated by the heartbeat regulate this remodeling process. Using zebrafish as a model and focusing on stages when cardiac valves and trabeculae form, we found that altering cardiac contraction impairs cECM remodeling. Longitudinal volumetric quantifications in wild-type animals revealed region-specific dynamics: cECM volume decreases in the atrium but not in the ventricle or atrioventricular canal. Reducing cardiac contraction resulted in opposite effects on the ventricular and atrial ECM, whereas increasing the heart rate affected the ventricular ECM but had no effect on the atrial ECM, together indicating that mechanical forces regulate the cECM in a chamber-specific manner. Among the ECM remodelers highly expressed during cardiac morphogenesis, we found one that was upregulated in non-contractile hearts, namely tissue inhibitor of matrix metalloproteinase 2 (timp2). Loss- and gain-of-function analyses of timp2 revealed its crucial role in cECM remodeling. Altogether, our results indicate that mechanical forces control cECM remodeling in part through timp2 downregulation.
Asunto(s)
Matriz Extracelular , Corazón , Inhibidor Tisular de Metaloproteinasa-2 , Pez Cebra , Animales , Pez Cebra/embriología , Pez Cebra/metabolismo , Matriz Extracelular/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/genética , Corazón/embriología , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Morfogénesis , Atrios Cardíacos/embriología , Atrios Cardíacos/metabolismo , Fenómenos Biomecánicos , Regulación del Desarrollo de la Expresión Génica , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/embriologíaRESUMEN
OBJECTIVE: Prediction of fetal growth restriction (FGR) and small of gestational age (SGA) infants by using various ultrasound cardiac parameters in a logistic regression model. METHODS: In this retrospective study we obtained standardized ultrasound images of 357 fetuses between the 20th and 39th week of gestation, 99 of these fetuses were between the 3rd and 10th growth percentile, 61 smaller than 3rd percentile and 197- appropriate for gestational age over the 10th percentile (control group). Several cardiac parameters were studied. The cardiothoracic ratio and sphericity of the ventricles was calculated. A binary logistic regression model was developed for prediction of growth restriction using the cardiac and biometric parameters. RESULTS: There were noticeable differences between the control and study group in the sphericity of the right ventricle (p = 0.000), left and right longitudinal ventricle length (pright = 0.000, pleft = 0.000), left ventricle transverse length (p = 0.000), heart diameter (p = 0.002), heart circumference (p = 0.000), heart area (p = 0.000), and thoracic diameter limited by the ribs (p = 0.002). There was no difference of the cardiothoracic ratio between groups. The logistic regression model achieved a prediction rate of 79.4 % with a sensitivity of 74.5 % and specificity of 83.2 %. CONCLUSION: The heart of growth restricted infants is characterized by a more globular right ventricle, shorter ventricle length and smaller thorax diameter. These parameters could improve prediction of FGR and SGA.
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Retardo del Crecimiento Fetal , Recién Nacido Pequeño para la Edad Gestacional , Ultrasonografía Prenatal , Humanos , Retardo del Crecimiento Fetal/diagnóstico por imagen , Femenino , Estudios Retrospectivos , Embarazo , Recién Nacido , Corazón Fetal/diagnóstico por imagen , Adulto , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Edad Gestacional , Modelos Logísticos , Valor Predictivo de las PruebasRESUMEN
During heart development, the embryonic ventricle becomes enveloped by the epicardium, which adheres to the outer apical surface of the heart. This is concomitant with onset of ventricular trabeculation, where a subset of cardiomyocytes lose apicobasal polarity and delaminate basally from the ventricular wall. Llgl1 regulates the formation of apical cell junctions and apicobasal polarity, and we investigated its role in ventricular wall maturation. We found that llgl1 mutant zebrafish embryos exhibit aberrant apical extrusion of ventricular cardiomyocytes. While investigating apical cardiomyocyte extrusion, we identified a basal-to-apical shift in laminin deposition from the internal to the external ventricular wall. We find that epicardial cells express several laminin subunits as they adhere to the ventricle, and that the epicardium is required for laminin deposition on the ventricular surface. In llgl1 mutants, timely establishment of the epicardial layer is disrupted due to delayed emergence of epicardial cells, resulting in delayed apical deposition of laminin on the ventricular surface. Together, our analyses reveal an unexpected role for Llgl1 in correct timing of epicardial development, supporting integrity of the ventricular myocardial wall.
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Proteínas de Ciclo Celular , Ventrículos Cardíacos , Proteínas de Pez Cebra , Pez Cebra , Animales , Polaridad Celular , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/embriología , Laminina/metabolismo , Laminina/genética , Mutación/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Pericardio/metabolismo , Pericardio/embriología , Pericardio/citología , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Ciclo Celular/metabolismoRESUMEN
The formed hearts of vertebrates are widely different in anatomy and performance, yet their embryonic hearts are surprisingly similar. Developmental and molecular biology are making great advances in reconciling these differences by revealing an evolutionarily conserved building plan to the vertebrate heart. This suggests that perspectives from evolution may improve our understanding of the formation of the human heart. Here, we exemplify this approach by discussing atrial and ventricular septation and the associated processes of remodeling of the atrioventricular junction and formation of the atrioventricular insulating plane.
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Evolución Biológica , Humanos , Animales , Ventrículos Cardíacos/embriología , Atrios Cardíacos/embriología , Corazón/embriología , Corazón/crecimiento & desarrolloRESUMEN
OBJECTIVES: The aim of the study was to compare left ventricle stroke volume in healthy, eutrophic fetuses in the 2nd and 3rd trimesters evaluated using the velocity time integral and aortic annulus area with left ventricular stroke volume measured using Simpson's single-plane rule and to determine the discrepancy equation. METHODS: The study included 354 fetuses. In each fetus, during the same examination, simultaneous assessment of stroke volume was performed by pulsed-wave Doppler using the product of the velocity time integral and aortic annulus area and by the fetalHQ® software using Simpson's single-plane rule. The Mann-Whitney U test was used to compare the "product-derived" stroke volume and stroke volume using fetalHQ® software values in the 2nd and 3rd trimesters separately. The agreement between the two methods were verified using Bland-Altman analysis. A linear regression model was used to obtain the discrepancy equation. RESULTS: In the 2nd trimester, the mean percentage difference between both the techniques showed that the stroke volume values determined using pulsed-wave Doppler were, on average, 88% higher than the stroke volume values determined using fetalHQ®. The upper limit of agreement between the compared techniques was approximately 146% and the lower limit of agreement was equal to 29.6%. In the 3rd trimester, the results indicated that the stroke volume values determined using pulsed-wave Doppler were, on average, 76% higher than the stroke volume values determined using fetalHQ®. The upper limit of agreement between the compared techniques was approximately 129% and the lower limit of agreement was 23%. Based on the results of the linear regression models, discrepancy formulas of the stroke volume values were obtained. The equations to calculate the predicted mean and standard deviations were used to compute the reference intervals for the mean, 5th and 95th centiles. CONCLUSION: The calculation of left ventricular stroke volume using pulsed Doppler has higher result in relation to stroke volume determined using Simpson's rule significantly. The aortic annulus area showed a higher correlation regarding stroke volume than the velocity time integral in both the 2nd and 3rd trimesters. Stroke volume increased with the increase in aortic annulus area, whereas the velocity time integral remained relatively constant. The retrospective analysis of the collected material enabled the determination of the discrepancy equation.
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Ventrículos Cardíacos , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Volumen Sistólico , Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Ultrasonografía Prenatal/métodos , Volumen Sistólico/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Reproducibilidad de los Resultados , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/embriología , Adulto , Interpretación de Imagen Asistida por Computador/métodosRESUMEN
The heart, which is the first organ to develop, is highly dependent on its form to function1,2. However, how diverse cardiac cell types spatially coordinate to create the complex morphological structures that are crucial for heart function remains unclear. Here we integrated single-cell RNA-sequencing with high-resolution multiplexed error-robust fluorescence in situ hybridization to resolve the identity of the cardiac cell types that develop the human heart. This approach also provided a spatial mapping of individual cells that enables illumination of their organization into cellular communities that form distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, which support their specialization according to the cellular ecosystem and anatomical region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities using in vivo conditional genetic mouse models and in vitro human pluripotent stem cell systems revealed multicellular signalling pathways that orchestrate the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. These detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodelling the human heart offer new insights into structural heart diseases and the engineering of complex multicellular tissues for human heart repair.
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Tipificación del Cuerpo , Corazón , Miocardio , Animales , Humanos , Ratones , Corazón/anatomía & histología , Corazón/embriología , Cardiopatías/metabolismo , Cardiopatías/patología , Ventrículos Cardíacos/anatomía & histología , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/embriología , Hibridación Fluorescente in Situ , Modelos Animales , Miocardio/citología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Análisis de Expresión Génica de una Sola CélulaRESUMEN
OBJECTIVE: Image quality of fetal echocardiography (FE) has improved in the recent era, but few recent studies have reported the accuracy of FE, specifically in single ventricle (SV) congenital heart disease (CHD). This study aimed to assess the ability of FE to correctly predict SV-CHD postnatal anatomy and physiology in a contemporary cohort. METHODS: The contemporary clinical reports of patients with SV-CHD, in which FE was performed between July 2017 and July 2021, were compared with postnatal echocardiograms from a formal quality assurance program. SV fetuses were grouped by anatomical subtype. Diagnostic errors were designated as major if the error would have caused significant alteration in parental counseling or postnatal management. The remaining errors were classified as minor. Physiological discrepancies, including prostaglandin-E (PGE) dependency, atrioventricular valve regurgitation (AVVR), pulmonary venous obstruction and restrictive atrial septum (RAS), were assessed by chart review of the postnatal course. RESULTS: A total of 119 subjects were analyzed. SV subtypes in the cohort included hypoplastic left heart syndrome (HLHS) (n = 68), tricuspid atresia (n = 16), double-inlet left ventricle (n = 12), unbalanced atrioventricular canal (UAVC) (n = 11), heterotaxy (n = 9) and other (n = 3). The rate of major anatomical and physiological errors was low (n = 6 (5.0%)). A higher proportion of minor errors was noted in HLHS and tricuspid atresia, but the differences were not statistically significant. Physiological discrepancies were uncommon, with three major discrepancies, including underestimation of the degree of venous obstruction in one non-HLHS fetus with total anomalous pulmonary venous return, overestimation of RAS in one HLHS fetus and incorrect prediction of PGE dependency in one case false-negative for pulmonary blood flow. No discrepancy in degree of AVVR or RAS affected postnatal care. Minor physiological discrepancies included two false-positive predictions of PGE dependency with one false-positive for ductal-dependent systemic flow and one false-positive for pulmonary blood flow. CONCLUSIONS: In this contemporary review of FE at our center, there was high accuracy in describing anatomical and physiological findings in SV-CHD. Major physiological discrepancies were uncommon but included important cases of false-negative prediction of PGE dependency and underestimation of obstruction of total anomalous pulmonary venous return. These data can inform more accurate counseling of families with SV-CHD fetuses and guide diagnostic improvement efforts. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Ecocardiografía , Cardiopatías Congénitas , Ventrículos Cardíacos , Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/embriología , Ultrasonografía Prenatal/métodos , Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/anomalías , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/fisiopatología , Corazón Fetal/embriología , Corazón Fetal/anomalías , Errores Diagnósticos/estadística & datos numéricos , Estudios Retrospectivos , Estudios de Cohortes , Adulto , Recién NacidoRESUMEN
That the highly trabeculated ventricular walls of the developing embryos transform to the arrangement during the fetal stages, when the mural architecture is dominated by the thickness of the compact myocardium, has been explained by the coalescence of trabeculations, often erroneously described as 'compaction'. Recent data, however, support differential rates of growth of the trabecular and compact layers as the major driver of change. Here, these processes were assessed quantitatively and visualized in standardized views. We used a larger dataset than has previously been available of mouse hearts, covering the period from embryonic day 10.5 to postnatal day 3, supported by images from human hearts. The volume of the trabecular layer increased throughout development, in contrast to what would be expected had there been 'compaction'. During the transition from embryonic to fetal life, the rapid growth of the compact layer diminished the proportion of trabeculations. Similarly, great expansion of the central cavity reduced the proportion of the total cavity made up of intertrabecular recesses. Illustrations of the hearts with the median value of left ventricular trabeculation confirm a pronounced growth of the compact wall, with prominence of the central cavity. This corresponds, in morphological terms, to a reduction in the extent of the trabecular layer. Similar observations were made in the human hearts. We conclude that it is a period of comparatively slow growth of the trabecular layer, rather than so-called compaction, that is the major determinant of the changing morphology of the ventricular walls of both mouse and human hearts.
Asunto(s)
Ventrículos Cardíacos , Animales , Humanos , Ratones , Ventrículos Cardíacos/anatomía & histología , Ventrículos Cardíacos/embriología , Edad GestacionalRESUMEN
Introducción: Pese al incremento en conocimientos de la morfogénesis cardiaca humana, se conoce poco sobre los detalles cuantitativos en ello. Objetivo: Describir cuantitativamente el desarrollo del miocardio ventricular compacto y no compacto y su correlación con la longitud cráneo rabadilla. Métodos: Estudio descriptivo, transversal en 18 embriones humanos de los estadios 17 al 23 de Carnegie, pertenecientes a la Embrioteca de la Universidad de Ciencias Médicas de Villa Clara. Se midió la longitud del embrión, el grosor del miocardio compacto, trabecular y total en la pared lateral de ambos ventrículos y del vértice cardiaco. Resultados: El grosor de la pared lateral del miocardio compacto aumenta en ambos ventrículos desde los estadios 17 al 23 de Carnegie, de 0,06 mm hasta 0,17 mm en el derecho y de 0,09 mm hasta 0,23 mm en el izquierdo. El grosor de la pared lateral trabeculada disminuye con el avance de los estadios, de 0,43 mm a 0,34 mm en el derecho y de 0,45 mm a 0,37 mm en el izquierdo. El grosor de la pared lateral total aumenta de 0,48 mm a 0,51 mm en el ventrículo derecho y de 0,52 mm a 0,62 mm en el izquierdo. El grosor de la pared del vértice compacto aumenta de 0,19 mm a 0,25 mm. Conclusiones: La compactación de la pared ventricular aumenta con el desarrollo; la longitud cráneo raquis se relaciona con el grosor del miocardio ventricular(AU)
Introduction: Despite the increase in knowledge of human morphogenesis, especially cardiogenesis and the processes by which the morphology of the ventricular myocardium is defined, little is known about the quantitative details in it. Objectives: To quantitatively describe the development of compact and non-compact ventricular myocardium and its correlation with cranio-rump length. Methods: descriptive, cross-sectional study in 18 human embryos from Carnegie stages 17 to 23, belonging to the Embryoteca of the Villa Clara University of Medical Sciences. The length of the embryo, the thickness of the compact, trabecular and total myocardium were measured in the lateral wall of both ventricles and the cardiac apex. Results: The thickness of the lateral wall of the compact myocardium increases in both ventricles from Carnegie stages 17 to 23, from 0.06 mm to 0.17 mm in the right and from 0.09 to 0.23 mm in the left ventricles. The thickness of the trabeculated lateral wall decreases with the advancement of the stages, from 0.43 mm to 0.34 mm in the right and from 0.45 mm to 0.37 mm in the left. The total lateral wall thickness increases from 0.48 mm to 0.51 mm in the right ventricle and from 0.52 mm to 0.62 mm in the left. The wall thickness of the compact vertex increases from 0.19 mm to 0.25 mm. Conclusions: Ventricular wall compaction increases with development; the cranio-spinal length is related to the thickness of the ventricular myocardium(AU)
Asunto(s)
Humanos , Estructuras Embrionarias/embriología , Ventrículos Cardíacos/embriología , Morfogénesis/fisiología , Epidemiología Descriptiva , Estudios TransversalesRESUMEN
There is no effective treatment for the total recovery of myocardial injury caused by an anticancer drug, doxorubicin (Dox). In this study, using a Dox-induced cardiac injury model, we compared the cardioprotective effects of ventricular cells harvested from 11.5-day old embryonic mice (E11.5) with those from E14.5 embryos. Our results indicate that tail-vein-infused E11.5 ventricular cells are more efficient at homing into the injured adult myocardium, and are more angiogenic, than E14.5 ventricular cells. In addition, E11.5 cells were shown to mitigate the cardiomyopathic effects of Dox. In vitro, E11.5 ventricular cells were more migratory than E14.5 cells, and RT-qPCR analysis revealed that they express significantly higher levels of cytokine receptors Fgfr1, Fgfr2, Pdgfra, Pdgfrb and Kit. Remarkably, mRNA levels for Fgf1, Fgf2, Pdgfa and Pdgfb were also found to be elevated in the Dox-injured adult heart, as were the FGF1 and PDGFB protein levels. Addition of exogenous FGF1 or PDGFB was able to enhance E11.5 ventricular cell migration in vitro, and, whereas their neutralizing antibodies decreased cell migration. These results indicate that therapies raising the levels of FGF1 and PDGFB receptors in donor cells and or corresponding ligands in an injured heart could improve the efficacy of cell-based interventions for myocardial repair.
Asunto(s)
Trasplante de Células , Doxorrubicina/efectos adversos , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Miocardio/patología , Proteínas Proto-Oncogénicas c-sis/metabolismo , Envejecimiento/genética , Animales , Movimiento Celular , Electrocardiografía , Embrión de Mamíferos/patología , Regulación de la Expresión Génica , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/trasplante , Ratones Endogámicos C57BL , Neovascularización Fisiológica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismoRESUMEN
OBJECTIVES: The primary aim of this study was to evaluate the feasibility of automated measurement of fetal atrioventricular (AV) plane displacement (AVPD) over several cardiac cycles using myocardial velocity traces obtained by color tissue Doppler imaging (cTDI). The secondary objectives were to establish reference ranges for AVPD during the second half of normal pregnancy, to assess fetal AVPD in prolonged pregnancy in relation to adverse perinatal outcome and to evaluate AVPD in fetuses with a suspicion of intrauterine growth restriction (IUGR). METHODS: The population used to develop the reference ranges consisted of women with an uncomplicated singleton pregnancy at 18-42 weeks of gestation (n = 201). The prolonged-pregnancy group comprised women with an uncomplicated singleton pregnancy at ≥ 41 + 0 weeks of gestation (n = 107). The third study cohort comprised women with a singleton pregnancy and suspicion of IUGR, defined as an estimated fetal weight < 2.5th centile or an estimated fetal weight < 10th centile and umbilical artery pulsatility index > 97.5th centile (n = 35). Cineloops of the four-chamber view of the fetal heart were recorded using cTDI. Regions of interest were placed at the AV plane in the left and right ventricular walls and the interventricular septum, and myocardial velocity traces were integrated and analyzed using an automated algorithm developed in-house to obtain mitral (MAPSE), tricuspid (TAPSE) and septal (SAPSE) annular plane systolic excursion. Gestational-age specific reference ranges were constructed and normalized for cardiac size. The correlation between AVPD measurements obtained using cTDI and those obtained by anatomic M-mode were evaluated, and agreement between these two methods was assessed using Bland-Altman analysis. The mean Z-scores of fetal AVPD in the cohort of prolonged pregnancies were compared between cases with normal and those with adverse outcome using Mann-Whitney U-test. The mean Z-scores of fetal AVPD in IUGR fetuses were compared with those in the normal reference population using Mann-Whitney U-test. Inter- and intraobserver variability for acquisition of cTDI recordings and offline analysis was assessed by calculating coefficients of variation (CV) using the root mean square method. RESULTS: Fetal MAPSE, SAPSE and TAPSE increased with gestational age but did not change significantly when normalized for cardiac size. The fitted mean was highest for TAPSE throughout the second half of gestation, followed by SAPSE and MAPSE. There was a significant correlation between MAPSE (r = 0.64; P < 0.001), SAPSE (r = 0.72; P < 0.001) and TAPSE (r = 0.84; P < 0.001) measurements obtained by M-mode and those obtained by cTDI. The geometric means of ratios between AVPD measured by cTDI and by M-mode were 1.38 (95% limits of agreement (LoA), 0.84-2.25) for MAPSE, 1.00 (95% LoA, 0.72-1.40) for SAPSE and 1.20 (95% LoA, 0.92-1.57) for TAPSE. In the prolonged-pregnancy group, the mean ± SD Z-scores for MAPSE (0.14 ± 0.97), SAPSE (0.09 ± 1.02) and TAPSE (0.15 ± 0.90) did not show any significant difference compared to the reference ranges. Twenty-one of the 107 (19.6%) prolonged pregnancies had adverse perinatal outcome. The AVPD Z-scores were not significantly different between pregnancies with normal and those with adverse outcome in the prolonged-pregnancy cohort. The mean ± SD Z-scores for SAPSE (-0.62 ± 1.07; P = 0.006) and TAPSE (-0.60 ± 0.89; P = 0.002) were significantly lower in the IUGR group compared to those in the normal reference population, but the differences were not significant when the values were corrected for cardiac size. The interobserver CVs for the automated measurement of MAPSE, SAPSE and TAPSE were 28.1%, 17.7% and 15.3%, respectively, and the respective intraobserver CVs were 33.5%, 15.0% and 17.9%. CONCLUSIONS: This study showed that fetal AVPD can be measured automatically by integrating cTDI velocities over several cardiac cycles. Automated analysis of AVPD could potentially help gather larger datasets to facilitate use of machine-learning models to study fetal cardiac function. The gestational-age associated increase in AVPD is most likely a result of increasing cardiac size, as the AVPD normalized for cardiac size did not change significantly between 18 and 42 weeks. A decrease was seen in TAPSE and SAPSE in IUGR fetuses, but not after correction for cardiac size. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Nodo Atrioventricular/diagnóstico por imagen , Ecocardiografía Doppler en Color/estadística & datos numéricos , Corazón Fetal/diagnóstico por imagen , Sístole/fisiología , Ultrasonografía Prenatal/estadística & datos numéricos , Nodo Atrioventricular/embriología , Velocidad del Flujo Sanguíneo , Estudios de Factibilidad , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/fisiopatología , Corazón Fetal/embriología , Peso Fetal , Edad Gestacional , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Humanos , Embarazo , Flujo Pulsátil , Valores de Referencia , Volumen Sistólico , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/embriología , Tabique Interventricular/diagnóstico por imagen , Tabique Interventricular/embriologíaRESUMEN
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.
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Técnicas de Cultivo de Célula/métodos , Insuficiencia Cardíaca/terapia , Infarto del Miocardio/terapia , Miocitos Cardíacos/trasplante , Células Madre Pluripotentes/fisiología , Animales , Diferenciación Celular , Línea Celular , Proliferación Celular , Modelos Animales de Enfermedad , Embrión de Mamíferos , Desarrollo Embrionario/fisiología , Atrios Cardíacos/citología , Atrios Cardíacos/embriología , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/patología , Humanos , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Miocitos Cardíacos/fisiología , RatasRESUMEN
The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.
Asunto(s)
Linaje de la Célula/genética , Corazón/embriología , Línea Primitiva/embriología , Animales , Linaje de la Célula/fisiología , Femenino , Gástrula , Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/genética , Corazón/fisiología , Atrios Cardíacos/embriología , Ventrículos Cardíacos/embriología , Masculino , Mesodermo , Ratones , Ratones Endogámicos C57BL , Morfogénesis , Línea Primitiva/fisiología , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodosRESUMEN
Echogenic intracardiac focus (EIF) constitutes a finding in the ultrasound study that indicates an area which is echogenically bright in the fetal heart and is as bright as the bone that moves synchronically to the atrioventricular valves. Microcalcifications of the papillary muscles or chordae tendinae are being represented by this echogenicity and are mostly present in the left ventricle (90% of cases). EIF appears usually at the ultrasound that is realized in the mid-trimester in a percentage that reaches 3.5% in euploid fetuses and 15% to 30% in fetuses with trisomy 21. In the current paper, the rare and curious case of a 21-year-old primigravida woman is described, who presented for ultrasound scan at the 12th week of gestation. The scan revealed the presence of EIF, which is very rare, as it is well-known that it usually appears in the second trimester of pregnancy. Counseling and debriefing for dismissing parents' anxiety is necessary as well as further examinations, because EIF has low sensitivity. This specific case report could constitute a beginning in the research of whether investigating EIF in the first trimester of pregnancy is possible and which are the benefits of its detection for the mother, the fetus and the whole family, in clinical practice.
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Síndrome de Down/diagnóstico , Corazón Fetal/diagnóstico por imagen , Ventrículos Cardíacos/embriología , MicroARNs/genética , Primer Trimestre del Embarazo , Ultrasonografía Prenatal/métodos , Femenino , Edad Gestacional , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Embarazo , Adulto JovenRESUMEN
BACKGROUND: This study evaluated whether an increased left ventricular (LV) pump function accompanying reduction of lung liquid volume in fetal lambs was related to increased LV preload, augmented LV contractility, or both. METHODS: Eleven anesthetized preterm fetal lambs (gestation 128 ± 2 days) were instrumented with (1) an LV micromanometer-conductance catheter to obtain LV end-diastolic volume (EDV) and end-diastolic pressure (EDP), the maximal rate of rise of LV pressure (dP/dtmax), LV output, LV stroke work, and LV end-systolic elastance (Ees), a relatively load-independent measure of contractility; (2) an endotracheal tube to measure mean tracheal pressure and to reduce lung liquid volume. LV transmural pressure was calculated as LV EDP minus tracheal pressure. RESULTS: Reducing lung liquid volume by 16 ± 4 ml kg-1 (1) augmented LV output (by 16%, P = 0.001) and stroke work (29%, P < 0.001), (2) increased LV EDV (12%, P < 0.001), (3) increased LV transmural pressure (2.2 mmHg, P < 0.001), (4) did not change LV dP/dtmax normalized for EDV (P > 0.7), and (5) decreased LV Ees (20%, P < 0.01). CONCLUSION: These findings suggest a rise in LV pump function evident after reduction of lung liquid volume in fetal lambs was related to increased LV preload secondary to lessening of external LV constraint, without any associated rise in LV contractility. IMPACT: This study has shown that reducing the volume of liquid filling the fetal lungs lessens the degree of external constraint on the heart. This lesser constraint permits a rise in left ventricular dimensions and thus greater cardiac filling that leads to increased left ventricular pumping performance. This study has defined a mechanism whereby a reduction in lung liquid volume results in enhanced pumping performance of the fetal heart. These findings suggest that a reduction in lung liquid volume which occurs during the birth transition contributes to increases in left ventricular dimensions and pumping performance known to occur with birth.
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Líquidos Corporales , Ventrículos Cardíacos/embriología , Pulmón/embriología , Ovinos/embriología , Animales , Ventrículos Cardíacos/fisiopatología , Contracción Miocárdica , Función Ventricular IzquierdaRESUMEN
OBJECTIVES: To assess differences in cardiac morphology and function in fetuses of mothers with gestational diabetes mellitus (GDM) compared to controls, and to assess whether, in women with GDM, fetal cardiac changes are accentuated with advancing gestational age. METHODS: We studied 112 women with GDM and 224 women with uncomplicated pregnancy at 24-40 weeks' gestation. In all fetuses, a standard four-chamber oblique view was obtained and offline speckle-tracking analysis was performed to measure right and left endocardial global longitudinal strain (GLS) and tricuspid and mitral annular plane systolic excursion. Global sphericity index was also calculated. Echocardiographic parameters were compared between GDM fetuses and controls at two gestational time periods of 24 + 0 to 32 + 0 weeks and 32 + 1 to 40 + 1 weeks. RESULTS: At 24 + 0 to 32 + 0 weeks, we phenotyped 43 fetuses from mothers with GDM and 71 from uncomplicated pregnancies, and, at 32 + 1 to 40 + 1 weeks, we phenotyped 69 fetuses from mothers with GDM and 153 from women with uncomplicated pregnancy. In fetuses of mothers with GDM, compared to controls, right ventricular functional indices were consistently lower both at 24 + 0 to 32 + 0 weeks and at 32 + 1 to 40 + 1 weeks. Right ventricular GLS was reduced in the GDM group at 24 + 0 to 32 + 0 weeks (adjusted mean difference, 0.7%; 95% CI, 0.3-1.1%) and at 32 + 1 to 40 + 1 weeks (adjusted mean difference, 0.9%; 95% CI, 0.6-1.1%). Fetal left ventricular global longitudinal function was similar in GDM pregnancies compared with controls, with the exception of the contractility of the left ventricular basal segment, which was reduced. Global sphericity index was reduced in GDM pregnancies only at 32 + 1 to 40 + 1 weeks (adjusted mean difference, -0.4; 95% CI, -0.7 to 0.1). CONCLUSIONS: The offspring of women with GDM are at high risk for development of cardiovascular disease in childhood and early adulthood. Our study demonstrates that GDM is associated with a reduction mainly in fetal right ventricular function, compared to controls, and this response is not exaggerated with increasing gestational age. Further studies are needed to determine whether fetuses with the observed alterations in cardiac function are those at highest risk for subsequent development of cardiovascular disease. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Diabetes Gestacional/fisiopatología , Corazón Fetal/embriología , Ventrículos Cardíacos/embriología , Segundo Trimestre del Embarazo/fisiología , Tercer Trimestre del Embarazo/fisiología , Adulto , Estudios de Casos y Controles , Estudios Transversales , Diabetes Gestacional/diagnóstico por imagen , Ecocardiografía , Femenino , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/fisiopatología , Edad Gestacional , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Embarazo , Ultrasonografía Prenatal , Función VentricularRESUMEN
OBJECTIVE: To construct nomograms for fetal cardiac, ventricular and atrial relative size and geometry parameters from 18 to 41 weeks' gestation using a low-risk population of singleton pregnancies. METHODS: This was a prospective cohort study of 602 low-risk singleton pregnancies undergoing comprehensive fetal echocardiography, from 18 to 41 weeks of gestation, to assess fetal cardiac, atrial and ventricular relative size and sphericity, ventricular dominance, wall asymmetry and relative wall thickness. Intra- and interobserver measurement reproducibility was evaluated using intraclass correlation coefficients (ICC). In order to construct reference ranges across pregnancy, parametric regressions were tested to model each measurement against gestational age and estimated fetal weight. The measurements evaluated were: cardiothoracic ratio; atrial-to-heart area ratios; ventricular-to-heart area ratios; cardiac, ventricular and atrial sphericity indices; right-to-left basal and midventricular ratios; septal-to-free wall thickness ratios; and relative wall thickness. RESULTS: Fetal cardiac, ventricular and atrial morphometry for assessing relative size and geometry could be successfully performed in > 95% of the population, with moderate-to-excellent interobserver reproducibility (ICC, 0.623-0.907) and good-to-excellent intraobserver reproducibility (ICC, 0.787-0.938). Cardiothoracic ratio and ventricular right-to-left ratio showed a modest increase throughout gestation. Atrial-to-heart and ventricular-to-heart area ratios, atrial sphericity indices and septal-to-free wall thickness ratios were constant with gestational age. Left and right ventricular basal sphericity indices showed a tendency to decrease at the end of gestation, while left and right midventricular sphericity indices tended to decrease in the second trimester. The cardiac sphericity index and left and right relative wall thickness showed a modest decrease with gestational age. Nomograms across gestation were constructed for all echocardiographic parameters described. CONCLUSIONS: The assessment of cardiac, ventricular and atrial relative size and geometry is feasible and reproducible in the fetus. We provide standardized reference ranges for these parameters throughout gestation, enabling the accurate assessment of cardiac remodeling patterns during fetal life. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Ecocardiografía/estadística & datos numéricos , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/embriología , Nomogramas , Ultrasonografía Prenatal/estadística & datos numéricos , Adulto , Estudios de Factibilidad , Femenino , Edad Gestacional , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/embriología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Humanos , Tamaño de los Órganos , Embarazo , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
Ca2+ signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca2+ transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca2+ efflux in cardiomyocytes. It is involved in cardiogenesis, while the mechanism is unclear. Here, using the forward genetic screening in zebrafish, we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene (mutantLDD353/ncx1hL154P) that led to smaller hearts with reduced heart rate and weak contraction. Mechanistically, the number of ventricular but not atrial cardiomyocytes was reduced in ncx1hL154P zebrafish. These defects were mimicked by knockdown or knockout of ncx1h. Moreover, ncx1hL154P had cytosolic and mitochondrial Ca2+ overloading and Ca2+ transient suppression in cardiomyocytes. Furthermore, ncx1hL154P and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions, while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes. These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish, and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción GATA/genética , Regulación del Desarrollo de la Expresión Génica , Miocitos Cardíacos/metabolismo , Intercambiador de Sodio-Calcio/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Calcio/metabolismo , Embrión no Mamífero/citología , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Factores de Transcripción GATA/metabolismo , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/metabolismo , Hibridación in Situ , Microscopía Confocal , Mutación , Miocitos Cardíacos/citología , Organogénesis/genética , Intercambiador de Sodio-Calcio/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
OBJECTIVES: Fetal cardiac function can be evaluated using a variety of parameters. Among these, cardiac cycle time-related parameters, such as filling time fraction (FTF) and ejection time fraction (ETF), are promising but rarely studied. We aimed to report the feasibility and reproducibility of fetal FTF and ETF measurements using pulsed-wave Doppler, to provide reference ranges for fetal FTF and ETF, after evaluating their relationship with heart rate (HR), gestational age (GA) and estimated fetal weight (EFW), and to evaluate their potential clinical utility in selected fetal conditions. METHODS: This study included a low-risk prospective cohort of singleton pregnancies and a high-risk population of fetuses with severe twin-twin transfusion syndrome (TTTS), aortic stenosis (AoS) or aortic coarctation (CoA), from 18 to 41 weeks' gestation. Left ventricular (LV) and right ventricular inflow and outflow pulsed-wave Doppler signals were analyzed, using valve clicks as landmarks. FTF was calculated as: (filling time/cycle time) × 100. ETF was calculated as: (ejection time/cycle time) × 100. Intraclass correlation coefficients (ICC) were used to evaluate the intra- and interobserver reproducibility of FTF and ETF measurements in low-risk fetuses. The relationships of FTF and ETF with HR, GA and EFW were evaluated using multivariate regression analysis. Reference ranges for FTF and ETF were then constructed using the low-risk population. Z-scores of FTF and ETF in the high-risk fetuses were calculated and analyzed. RESULTS: In total, 602 low-risk singleton pregnancies and 54 high-risk fetuses (nine pairs of monochorionic twins with severe TTTS, 16 fetuses with AoS and 20 fetuses with CoA) were included. Adequate Doppler traces for FTF and ETF could be obtained in 95% of low-risk cases. Intraobserver reproducibility was good to excellent (ICC, 0.831-0.905) and interobserver reproducibility was good (ICC, 0.801-0.837) for measurements of all timing parameters analyzed. Multivariate analysis of FTF and ETF in relation to HR, GA and EFW in low-risk fetuses identified HR as the only variable predictive of FTF, while ETF was dependent on both HR and GA. FTF increased with decreasing HR in low-risk fetuses, while ETF showed the opposite behavior, decreasing with decreasing HR. Most recipient twins with severe TTTS showed reduced FTF and preserved ETF. AoS was associated with decreased FTF and increased ETF in the LV, with seemingly different patterns associated with univentricular vs biventricular postnatal outcome. The majority of fetuses with CoA had FTF and ETF within the normal range in both ventricles. CONCLUSIONS: Measurement of FTF and ETF using pulsed-wave Doppler is feasible and reproducible in the fetus. The presented reference ranges account for associations of FTF with HR and of ETF with HR and GA. These time fractions are potentially useful for clinical monitoring of cardiac function in severe TTTS, AoS and other fetal conditions overloading the heart. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Corazón Fetal/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/embriología , Ultrasonografía Doppler de Pulso/estadística & datos numéricos , Ultrasonografía Prenatal/estadística & datos numéricos , Coartación Aórtica/diagnóstico por imagen , Coartación Aórtica/embriología , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/embriología , Estudios de Factibilidad , Femenino , Corazón Fetal/embriología , Corazón Fetal/fisiopatología , Peso Fetal , Transfusión Feto-Fetal/diagnóstico por imagen , Transfusión Feto-Fetal/embriología , Edad Gestacional , Frecuencia Cardíaca , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/embriología , Humanos , Embarazo , Embarazo Gemelar , Estudios Prospectivos , Valores de Referencia , Análisis de Regresión , Reproducibilidad de los Resultados , Volumen Sistólico , Gemelos , Ultrasonografía Doppler de Pulso/métodos , Ultrasonografía Prenatal/métodosRESUMEN
During heart formation, the heart grows and undergoes dramatic morphogenesis to achieve efficient embryonic function. Both in fish and amniotes, much of the growth occurring after initial heart tube formation arises from second heart field (SHF)-derived progenitor cell addition to the arterial pole, allowing chamber formation. In zebrafish, this process has been extensively studied during embryonic life, but it is unclear how larval cardiac growth occurs beyond 3 days post-fertilisation (dpf). By quantifying zebrafish myocardial growth using live imaging of GFP-labelled myocardium we show that the heart grows extensively between 3 and 5 dpf. Using methods to assess cell division, cellular development timing assay and Kaede photoconversion, we demonstrate that proliferation, CM addition, and hypertrophy contribute to ventricle growth. Mechanistically, we show that reduction in Mef2c activity (mef2ca+/-;mef2cb-/-), downstream or in parallel with Nkx2.5 and upstream of Ltbp3, prevents some CM addition and differentiation, resulting in a significantly smaller ventricle by 3 dpf. After 3 dpf, however, CM addition in mef2ca+/-;mef2cb-/- mutants recovers to a normal pace, and the heart size gap between mutants and their siblings diminishes into adulthood. Thus, as in mice, there is an early time window when SHF contribution to the myocardium is particularly sensitive to loss of Mef2c activity.