TAPVR: Molecular Pathways and Animal Models.

The venous pole of the heart where the pulmonary veins will develop encompasses the sinus venosus and the atrium. In the fourth week of development, the sinus venosus consists of a left and a right part receiving blood from the common cardinal vein, the omphalomesenteric and umbilical veins. Asymmetrical expansion of the common atrium corresponds with a rightward shift of the connection of the sinus to the atrium. The right-sided part of the sinus venosus including its tributing cardinal veins enlarges to form the right superior and inferior vena cava that will incorporate into the right atrium. The left-sided part in human development largely obliterates and remodels to form the coronary sinus in adults. In approximately the same time window (4th-fifth weeks), a splanchnic vascular plexus surrounds the developing lung buds (putative lungs) with a twofold connection. Of note, during early developmental stages, the primary route of drainage from the pulmonary plexus is toward the systemic veins and not to the heart. After lumenization of the so-called mid-pharyngeal endothelial strand (MPES), the first anlage of the pulmonary vein, the common pulmonary vein can be observed in the dorsal mesocardium, and the primary route of drainage will gradually change toward a cardiac drainage. The splanchnic pulmonary venous connections with the systemic cardinal veins will gradually disappear during normal development. In case of absence or atresia of the MPES, the pulmonary-to-systemic connections will persist, clinically resulting in total anomalous pulmonary venous return (TAPVR). This chapter describes the developmental processes and molecular pathways underlying anomalous pulmonary venous connections.

Does Fetal Pulmonary Venous Flow Impedance Increase in Pregnancies With Placental Insufficiency-Related Oligohydramnios in the Third Trimester?

OBJECTIVES: In placental insufficiency, alteration of left heart compliance occurs, with consequent increased placental vascular impedance. Pulmonary vein flow patterns could reflect altered left atrial pressure. Although the fetal pulmonary venous pulsatility index (PVPI) has been reported as an early marker to evaluate fetal cardiac dysfunction, no studies have been focused on its correlation with oligohydramnios. The aim of this study was to determine whether fetal pulmonary venous flow impedance was greater in women with placental insufficiency-related oligohydramnios than in women with adequate amounts of amniotic fluid during the third trimester. METHODS: The fetal PVPI and the umbilical arterial systolic-to-diastolic (S/D) ratio were measured by Doppler echocardiography in 130 pregnant women between 28 and 39 gestational weeks. Pregnant women were divided into 2 groups according to the amount of amniotic fluid. The PVPI and umbilical arterial S/D ratio were compared between 19 pregnancies with oligohydramnios and 111 with adequate amniotic fluid. RESULTS: The mean gestational age and estimated fetal weight were not significantly different between the groups. The maternal age was higher in the oligohydramnios group than in the control group (mean ± SD, 36.89 ± 5.88 versus 34.06 ± 4.79 years; P = .023). The mean PVPI was significantly higher in the oligohydramnios group than in the control group (1.13 ± 0.22 versus 0.89 ± 0.31; P < .001). There was no significant difference in umbilical arterial S/D ratio between the groups (P = .142). CONCLUSIONS: The PVPI could be used as an early diagnostic marker of fetal deterioration in placental insufficiency-related oligohydramnios.

Fetal case of right atrial isomerism with infracardiac total anomalous pulmonary venous connection and agenesis of the ductus venosus.

After birth, the ductus venosus becomes an important route connecting the pulmonary and systemic venous systems for survival in infracardiac total anomalous pulmonary venous connection. We encountered a fetal case of right atrial isomerism with infracardiac total anomalous pulmonary venous connection and agenesis of ductus venosus. Prenatal echocardiography suggested that the fetus had severe pulmonary venous obstruction; however, no obstructive lesions were detected at the level of the vertical vein that drained into the portal veins. Therefore, we concluded that emergency surgical pulmonary venous obstruction release was the only way for the fetus to survive. However, the saturation level was maintained above 70% due to the abundant communications via the hepatic sinusoid over 1 week after birth. In conclusion, hepatic sinusoids can be a sufficient route for pulmonary venous return and may not cause severe pulmonary venous obstruction in infracardiac total anomalous pulmonary venous connection with agenesis of ductus venosus.

Transcription Factors Regulating Embryonic Development of Pulmonary Vasculature.

Lung morphogenesis is a highly orchestrated process beginning with the appearance of lung buds on approximately embryonic day 9.5 in the mouse. Endodermally derived epithelial cells of the primitive lung buds undergo branching morphogenesis to generate the tree-like network of epithelial-lined tubules. The pulmonary vasculature develops in close proximity to epithelial progenitor cells in a process that is regulated by interactions between the developing epithelium and underlying mesenchyme. Studies in transgenic and knockout mouse models demonstrate that normal lung morphogenesis requires coordinated interactions between cells lining the tubules, which end in peripheral saccules, juxtaposed to an extensive network of capillaries. Multiple growth factors, microRNAs, transcription factors, and their associated signaling cascades regulate cellular proliferation, migration, survival, and differentiation during formation of the peripheral lung. Dysregulation of signaling events caused by gene mutations, teratogens, or premature birth causes severe congenital and acquired lung diseases in which normal alveolar architecture and the pulmonary capillary network are disrupted. Herein, we review scientific progress regarding signaling and transcriptional mechanisms regulating the development of pulmonary vasculature during lung morphogenesis.

Comprehensive Cross-sectional Imaging of the Pulmonary Veins.

The pulmonary veins carry oxygenated blood from the lungs to the heart, but their importance to the radiologist extends far beyond this seemingly straightforward function. The anatomy of the pulmonary veins is variable among patients, with several noteworthy variant and anomalous patterns, including supernumerary pulmonary veins, a common ostium, anomalous pulmonary venous return, and levoatriocardinal veins. Differences in pulmonary vein anatomy and the presence of variant or anomalous anatomy can be of critical importance, especially for preoperative planning of pulmonary and cardiac surgery. The enhancement or lack of enhancement of the pulmonary veins can be a clue to clinically important disease, and the relationship of masses to the pulmonary veins can herald cardiac invasion. The pulmonary veins are also an integral part of thoracic interventions, including lung transplantation, pneumonectomy, and radiofrequency ablation for atrial fibrillation. This fact creates a requirement for radiologists to have knowledge of the pre- and postoperative imaging appearances of the pulmonary veins. Many of these procedures are associated with important potential complications involving the pulmonary veins, for which diagnostic imaging plays a critical role. A thorough knowledge of the pulmonary veins and a proper radiologic approach to their evaluation is critical for the busy radiologist who must incorporate the pulmonary veins into a routine "search pattern" at computed tomography (CT) and magnetic resonance imaging. This article is a comprehensive CT-based imaging review of the pulmonary veins, including their embryology, anatomy (typical and anomalous), surgical implications, pulmonary vein thrombosis, pulmonary vein stenosis, pulmonary vein pseudostenosis, and the relationship of tumors to the pulmonary veins. Online supplemental material is available for this article. ©RSNA, 2017.

Z-scores for fetal left atrial size and left atrium-descending aorta distance in fetuses with isolated total anomalous pulmonary venous connection.

OBJECTIVES: To construct Z-score reference ranges for fetal left atrial (LA) size and left atrium-descending aorta distance (LDD or 'post-LA distance') at 20 to 40 weeks' gestation and to compare these parameters between fetuses with isolated total anomalous pulmonary venous connection (TAPVC) and normal fetuses. METHODS: Three hundred thirty-three normal singleton fetuses from 20 to 40 weeks' gestation were enrolled in a prospective cross-sectional study. Six cardiovascular dimensions were obtained by two-dimensional echocardiography. Z-score reference ranges of these measurements were determined against gestational age (GA) and fetal biometric variables, using regression analysis of the mean and standard deviation. Also, we reviewed fetal echocardiograms from ten fetuses with postnatal diagnosis of isolated TAPVC and made the measurements on archived images. Subsequently, all parameters were compared between the normal and TAPVC groups. RESULTS: A simple linear regression model was the best description of the mean and standard deviation of most variables in normal cases, with the exception of the mean LDD based on GA, which was best fitted by a quadratic regression. Fetuses with TAPVC had significantly lower LA size Z-scores [80% (8/10) of which were under -2] and increased LDD Z-scores [100% (10/10) of which were greater than 2]. Using an LDD Z-score of >2.22 was both highly sensitive (100%) and specific (98.5%) for distinguishing between TAPVC and normal hearts. CONCLUSION: Normal data and Z-scores of fetal LA size and LDD were provided against GA and fetal biometry. This could be useful for quantitative assessment of fetal TAPVC. Increased post-LA distance and decreased LA size may be markers for the prenatal diagnosis of TAPVC. © 2017 John Wiley & Sons, Ltd.

Comparing levocardia and dextrocardia in fetuses with heterotaxy syndrome: prenatal features, clinical significance and outcomes.

BACKGROUND: To investigate the differences in cardiovascular disease, extracardiac anomalies and outcomes between fetuses with levocardia and dextrocardia. METHODS: Clinical demographics, prenatal features, postnatal characteristics and the outcomes of fetuses with levocardia or dextrocardia were recorded and analyzed. RESULTS: Sixty-five fetuses with dextrocardia and thirty-eight fetuses with levocardia were enrolled. Right ventricle outlet obstruction, atrioventricular septal defect and intestinal malrotation were common in both groups. Univentricular physiology, transposition of the great arteries and esophageal atresia were more frequent in fetuses with levocardia, whereas abnormal pulmonary venous connection, double outlet of right ventricle, left ventricle outlet obstruction and brain abnormalities were more frequent in the dextrocardia group. The accuracy of evaluating cardiac malformations was high, but the sensitivity in assessing extracardiac abnormalities was low. CONCLUSIONS: Although the disorders have certain overlapping features, there are several differences between fetuses with levocardia and dextrocardia. These findings might improve patient counseling and perinatal management.

Prenatal diagnosis of total anomalous pulmonary venous connection by 2D and 3D fetal echocardiography.

OBJECTIVE: Prenatal diagnosis of total anomalous pulmonary venous connection (TAPVC) by fetal echocardiography (FE) remains a challenge. We sought to ascertain the diagnostic accuracy of 2D and 3D spatiotemporal image correlation (STIC) FE and the potential incremental value of 3D STIC FE for prenatal diagnosis and assessment of TAPVC. METHODS: This study was conducted retrospectively in a single tertiary referral center. The study population consisted of 74 TAPVC from 17 063 fetuses by FE from August 2010 to April 2016. The 3D volume acquisition was also performed by STIC. RESULTS: A total of 17 063 fetal echocardiograms in our institution were queried and 74 (0.4%) were identified with TAPVC. In the TAPVC group, 11 had postnatal echocardiographic study, 25 had autopsies, 36 declined autopsy and 2 lost for follow-up. The sensitivity of FE for diagnosis of TAPVC was 97.14%, specificity 99.98%, respectively. In our cohort, 31 fetuses were evaluated by both 2D and 3D STIC and were confirmed by postnatal echocardiography or autopsies. TAPVC was diagnosed in all 31 patients (100%) by both 2D FE and 3D STIC. Furthermore, the classification of subtypes of TAPVC and accurate diagnosis of the drainage pathway was correct in 26 (83.9%) and 24 (77.4%) cases by 2D FE, respectively; but in 31 (100%) and 31 (100%) cases by 3D STIC. CONCLUSION: 2D and 3D STIC FE provide accurate diagnosis of TAPVC with excellent sensitivity and specificity. 3D STIC FE has incremental value in further evaluation of classification of TAPVC types and drainage pathways.

Role of four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation in detecting fetal pulmonary veins.

BACKGROUND: Prenatal diagnosis of fetal total anomalous pulmonary vein connection (TAPVC) remains challenging for most screening sonographers. The purpose of this study was to evaluate the use of four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation (4D-HDFI) in identifying pulmonary veins in normal and TAPVC fetuses. MATERIAL & METHODS: We retrospectively reviewed and performed 4D-HDFI in 204 normal and 12 fetuses with confirmed diagnosis of TAPVC. Cardiac volumes were available for postanalysis to obtain 4D-rendered images of the pulmonary veins. For the normal fetuses, two other traditional modalities including color Doppler and HDFI were used to detect the number of pulmonary veins and comparisons were made between each of these traditional methods and 4D-HDFI. RESULTS: For conventional echocardiography, HDFI modality was superior to color Doppler in detecting more pulmonary veins in normal fetuses throughout the gestational period. 4D-HDFI was the best method during the second trimester of pregnancy in identifying normal fetal pulmonary veins. 4D-HDFI images vividly depicted the figure, course, and drainage of pulmonary veins in both normal and TAPVC fetuses. CONCLUSION: HDFI and the advanced 4D-HDFI technique could facilitate identification of the anatomical features of pulmonary veins in both normal and TAPVC fetuses; 4D-HDFI therefore provides additional and more precise information than conventional echocardiography techniques.

Prenatal Echocardiographic Assessment of Foramen Ovale Appearance in Fetuses with D-Transposition of the Great Arteries and Impact on Neonatal Outcome.

INTRODUCTION: Neonates with D-transposition of the great arteries (dTGA) may die at birth because of the inadequate intracardiac mixing due to a misdiagnosed restrictive foramen ovale. We reviewed our experience in echocardiographic assessment and perinatal management of fetuses with dTGA searching for new features that may predict the need for urgent balloon atrial septostomy (BAS) immediately after birth. PATIENTS AND METHODS: We included fetuses diagnosed with dTGA between January 2000 and December 2014. We assessed pre- and postnatal appearance of the foramen ovale, ductus arteriosus and pulmonary veins. Both the diagnostic findings at the time of last prenatal echocardiogram and those findings deriving from a retrospective reevaluation of stored videos were considered. BAS was defined as urgent if performed in neonates with restrictive foramen ovale and severe hypoxemia. RESULTS: We reviewed 40 fetuses with dTGA. 20/40 fetuses received urgent BAS at birth. Not only the restrictive but also the hypermobile and the redundant appearance of the foramen ovale was significantly associated with urgent BAS (p < 0.0001, p = 0.002 and p = 0.0001, respectively). CONCLUSIONS: Prenatal evaluation of the foramen ovale appearance in fetuses with dTGA is still challenging. Based on our experience, also the redundant foramen ovale appearance may need urgent BAS at birth.

Levoatriocardinal Vein and Mimics: Spectrum of Imaging Findings.

OBJECTIVE: This article focuses on the embryology, hemodynamics, and CT and MRI features of levoatriocardinal vein. Levoatriocardinal vein, a form of pulmonary systemic connection, is most commonly seen in left heart obstructive lesions, providing an alternative egress for pulmonary venous blood. CONCLUSION: Levoatriocardinal vein can be differentiated from other more common anomalies, such as anomalous pulmonary venous return, persistent left superior vena cava, and dilated left superior intercostal vein, by its distinctive imaging features.

Embryology and anatomy of intrapulmonary shunts.

Pulmonary vascular shunting poses a major clinical risk. In this brief overview, we discuss the morphological aspects of shunting vessels in the lung, their development, and the regulation of their patency.

[HISTOGENESIS AND PECULIARITIES OF STRUCTURAL ORGANIZATION OF THE CARDIAC MUSCLE TISSUE IN THE WALLS OF HUMAN CAVAL AND PULMONARY VEINS].

To study the structural organization and histogenesis of the cardiac muscle tissue in the walls of human caval and pulmonary veins, the heart was examined in 3 human embryos (at weeks 6-7 of development) and 20 fetuses (at weeks 9-10, 16, 19, 22 and 24 of development), as well as segments of caval and pulmonary veins of adult men and women (n = 50) located at various distances from the heart. The methods of light and electron microscopy were used in this work. To obtain the isolated cells from the walls of caval and pulmonary veins, the method of tissue alkaline dissociation was used. An immunohistochemical study with the monoclonal antibodies against cardiac troponin T was performed. It was found that the cardiomyocytes in humans were located in the middle and outer tunics of caval and pulmonary veins, where they formed thick layers. In the pulmonary veins of the adult humans, cardiac muscle fibers did not reach the intrapulmonary areas, in the inferior vena cava their layer did not extend beyond the pericardium, in the superior vena cava, its length was 2.5-3.0 cm. The formation of the pulmonary vein orifices occured by sequential inclusion of the wall of the common pulmonary vein, and later--of the right and left pulmonary veins into the wall of the left atrium. During the formation of the orifices of the caval veins, the gradual inclusion of the wall of the venous sinus in the wall of the right atrium was observed, resulting in caval veins opening directly into the cavity of the right atrium. The veins studied were referred to the veins of the muscular type with the strong development of muscular elements containing the myocardial component.

Lineage tree for the venous pole of the heart: clonal analysis clarifies controversial genealogy based on genetic tracing.

RATIONALE: Genetic tracing experiments and cell lineage analyses are complementary approaches that give information about the progenitor cells of a tissue. Approaches based on gene expression have led to conflicting views about the origin of the venous pole of the heart. Whereas the heart forms from 2 sources of progenitor cells, the first and second heart fields, genetic tracing has suggested a distinct origin for caval vein myocardium, from a proposed third heart field. OBJECTIVE: To determine the cell lineage history of the myocardium at the venous pole of the heart. METHODS AND RESULTS: We used retrospective clonal analyses to investigate lineage segregation for myocardium at the venous pole of the mouse heart, independent of gene expression. CONCLUSIONS: Our lineage analysis unequivocally shows that caval vein and atrial myocardium share a common origin and demonstrates a clonal relationship between the pulmonary vein and progenitors of the left venous pole. Clonal characteristics give insight into the development of the veins. Unexpectedly, we found a lineage relationship between the venous pole and part of the arterial pole, which is derived exclusively from the second heart field. Integration of results from genetic tracing into the lineage tree adds a further temporal dimension to this reconstruction of the history of venous myocardium and the arterial pole.

Evaluation of normal fetal pulmonary veins using B-flow imaging with spatiotemporal image correlation and by traditional color Doppler echocardiography.

OBJECTIVE: The purpose of our report is to evaluate the use of color Doppler echocardiography (CDE) with four chamber view (4CV), scanning around left atrium, and four-dimensional echocardiography with B-flow imaging and spatiotemporal image correlation (4D BF-STIC) in detecting fetal pulmonary veins at 17 to 40 weeks' gestation. METHODS: This was a prospective study. Color Doppler echocardiography with 4CV, scanning around left atrium, and 4D BF-STIC were used to detect the pulmonary veins in 460 normal fetuses at 17 to 40 weeks of gestation. Routine prenatal screening was used to confirm that the fetuses were in good health with no cardiac or extra cardiac anomalies. All patients underwent follow up at one year. Twenty-two patients were excluded from the study. The number of pulmonary veins visualized using each method was recorded and then compared in six subgroups according to gestational age. RESULTS: Four-dimensional echocardiography with B-flow imaging and spatiotemporal image correlation was the best method to detect the greatest number of pulmonary veins between 17 and 31 weeks of gestation. Scanning around left atrium detected more pulmonary veins than the traditional 4CV method throughout the gestational period. CONCLUSIONS: The scanning around left atrium method proved to be the most suited for detecting pulmonary veins in clinical practice. 4D BF-STIC was superior in detecting the greatest number of pulmonary veins before 32 gestational weeks, but had limited clinical usage because it was very time-consuming and experience-dependent. The 4D method should be considered as a complement to traditional two-dimensional sonography, because it facilitates understanding of the anatomy and the spatial relationships of the cardiac structures.

Three-dimensional and molecular analysis of the venous pole of the developing human heart.

BACKGROUND: Various congenital malformations and many abnormal rhythms originate from the venous pole of the heart. Because of rapid changes during morphogenesis, lack of molecular and lineage data, and difficulties in presenting complex morphogenetic changes in the developing heart in a clear fashion, the development of this region in human has been difficult to grasp. METHODS AND RESULTS: To gain insight into the development of the different types of myocardium forming the venous pole of the human heart, we performed an immunohistochemical and 3-dimensional analysis of serial sections of human embryos ranging from 22 through 40 days of development. Three-dimensional models were prepared in a novel interactive portable format providing crucial spatial information and facilitating interpretation. As in the mouse, the systemic venous myocardium expresses the transcription factor TBX18, whereas the pulmonary venous myocardium expresses NKX2-5. In contrast to the mouse, a systemic venous sinus is identified upstream from the atrial chambers, albeit initially with nonmyocardial walls. From the outset, as in the mouse, the pulmonary vein empties to a chamber with atrial, rather than systemic venous, characteristics. Compared with the mouse, the vestibular spine is a more prominent structure. CONCLUSIONS: The similarities in gene expression in the distinctive types of myocardium surrounding the systemic and pulmonary venous tributaries in man and mouse permit extrapolation of the conclusions drawn from transgenic and lineage studies in the mouse to the human, showing that the systemic and pulmonary venous myocardial sleeves are derived from distinct developmental lineages.

Evaluation of normal fetal pulmonary veins from the early second trimester by enhanced-flow (e-flow) echocardiography.

OBJECTIVES: To explore the feasibility of using enhanced-flow (e-flow) imaging technology to identify fetal pulmonary veins and establish gestational age-specific reference values at 12-40 weeks' gestation. METHODS: The pulmonary venous internal diameter, peak systolic and diastolic flow velocities and visualization rate were analyzed in 332 normal fetuses at 12-40 weeks of gestation. Two-dimensional gray-scale (2D) ultrasound, color Doppler and e-flow imaging were used to detect the pulmonary veins in the four-chamber view by taking the lung as the penetration window. RESULTS: The pulmonary veins could be visualized as early as 12 weeks' gestational age by e-flow imaging. The right and left pulmonary venous internal diameters and peak systolic and diastolic flow velocities increased with increasing gestational age. Between 12 and 40 gestational weeks, the internal diameter and both the systolic and diastolic flow velocities of the fetal right pulmonary vein were significantly larger than were those of the left vein (P < 0.05). Of 118 fetuses at 12-22 gestational weeks, the visualization rate of the four pulmonary veins (left superior and inferior, right superior and inferior) was 5.9% (7/118) by 2D ultrasound, 41.5% (49/118) by color Doppler and 61.9% (73/118) by e-flow imaging. The visualization rate by e-flow imaging was significantly higher than that using the other two techniques (P < 0.001). CONCLUSION: e-flow imaging is apparently a feasible and promising technology with which to identify the fetal pulmonary veins in the early stages of the second trimester.