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.

Clinical Presentation and Therapy of Total Anomalous Pulmonary Venous Return.

Total anomalous pulmonary venous return (TAPVR) is rare (accounting for about 1% of all CHD) and can occur as a single lesion or in combination with other types of CHD (such as heterotaxy or HLHS). TAPVR is defined as an abnormal connection where all pulmonary veins do not drain into the left atrium but into the right atrium either directly or through a vein that is connected to the right atrium. TAPVR can be divided into four anatomic groups (Fig. 32.1): (1) supracardiac (about 55%), (2) cardiac (about 30%), (3) infracardiac (about 13%), and (4) mixed (very rare). In addition, it can be divided into two physiological types: nonobstructed and obstructed. Embryologically, all pulmonary veins usually connect to a pulmonary venous confluence that connects to the left atrium. If this connection does not occur, the pulmonary venous confluence connects to a systemic vein instead.

Retinoic Acid: A Key Regulator of Lung Development.

Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development.

Congenital diaphragmatic hernia-associated pulmonary hypertension.

Congenital diaphragmatic hernia (CDH) is a neonatal pathology in which intrathoracic herniation of abdominal viscera via diaphragmatic defect results in aberrant pulmonary and cardiovascular development. Despite decades of study and many advances in the diagnosis and treatment of CDH, morbidity and mortality remain high, largely due to pulmonary hypertension (PH), along with pulmonary hypoplasia and cardiac dysfunction. In patients with CDH, hypoplastic pulmonary vasculature and alterations in multiple molecular pathways lead to pathophysiologic pulmonary vasculopathy and, for severe CDH, sustained, elevated pulmonary arterial pressures. This review addresses the multiple anatomic and physiologic changes that underlie CDH-associated PH (CDH-PH), along with the multimodal treatment strategies that exist currently and future therapies currently under investigation.

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.

The morphogenesis and associated anomalous pulmonary venous drainage in sinus venosus defect.

BACKGROUND: Sinus venosus defect (SVD) is an unusual type of interatrial communication (IAC) and is virtually always associated with partial anomalous pulmonary venous drainage (PAPVD) of the right pulmonary veins (RPV) to the superior vena cava (SVC) or right atrium (RA). However, its definite morphogenesis is still elusive, and diagnostic fallibility continues. METHODS: We conducted a retrospective review of the echocardiograms, cardiac catheterization data, computed tomographic findings, and surgical notes of 44 children with surgery-confirmed isolated SVD from 1977 to 2016. We investigated the location of the IAC and its boundaries within the atrial septum and its anatomic relationship with the adjacent structures, including the anomalously draining RPV. We also tried to explore any possible associated abnormalities which might be implicated in the morphogenesis of SVD. RESULTS: Two distinct types of IAC were defined. Forty patients had an IAC that was located posterosuperior to the intact fossa ovalis (superior type), and all were associated with PAPVD of the right upper and often the right middle pulmonary veins to the SVC. The remaining 4 patients had an IAC that was located posterior to the intact fossa ovalis (inferior type), and all were associated with PAPVD of all the RPV to the RA. Another consistently associated abnormality was a defect between the anomalously draining RPV posteriorly and the SVC or RA anteriorly. All these 44 patients underwent successful surgical baffling the associated PAPVD via the IAC into the left atrium. CONCLUSION: A defect between the RPV posteriorly and the SVC or RA anteriorly will result in SVD, and an unusual type of IAC, and PAPVD of the RPV to the SVC or RA. The IAC is not a true atrial septal defect in the atrial septum proper, but it actually represents the left atrial orifice of the unroofed RPV.

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.

Imaging of anomalous pulmonary venous connections by multidetector CT angiography using third-generation dual source CT scanner.

Abnormal embryological development of the pulmonary veins can manifest as either partial or total anomalous drainage into the systemic venous circulation. Echocardiography does not provide adequate information in all cases as the optimal visualization of anomalous structures is limited by the availability of acoustic window; also it is highly operator dependent. However, multidetector CT angiography, with its multiplanar reformatting and volume rendering techniques, offers precise information about the three-dimensional anatomy and spatial relationships of the cardiovascular structures. With advent of dual source CT scanners and use of advanced dose reduction techniques, this information can be obtained in a short time with minimal radiation dose. In this pictorial essay, we present the multidetector CT imaging findings of the spectrum of total and partial anomalous pulmonary venous connections, using a third-generation dual source CT scanner.

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.

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.

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.

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.

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 diagnoses of an uncommon isolated obstructed supracardiac total anomalous pulmonary venous connection: Case report and review of the literature (CARE compliant).

INTRODUCTION: Total anomalous pulmonary venous connection is an uncommon congenital heart disease. Four types are described based on the site of pulmonary venous drainage: supracardiac, cardiac, infradiaphragmathic, and mixed connection. In most cases of supracardiac type, the common venous confluence drains through an ascending left vertical vein into the brachiocephalic vein, right superior vena cava, and then into the right atrium. Anomalous connection of the pulmonary venous confluence directly to the right SVC, especially the obstructed form is an unusual and severe supracardiac variant. The prenatal diagnosis is challenging. PATIENT CONCERNS: We present a case report of a fetus diagnosed with TAPVC at 23 gestational weeks. DIAGNOSIS INTERVENTIONS: The 4-chamber view showed a small left atrium, with a "smooth" posterior wall and the absence of pulmonary vein connection. This is the first case of prenatally diagnosed isolated, obstructed supracardiac type with drainage directly into the right superior vena cava. CONCLUSION: The obstetrician and fetal cardiologist should be cautious at the direct and indirect echocardiographic signs of this condition. A prenatal diagnose of isolated, obstructed form is important for adequate planning of delivery and postnatal surgery in a tertiary center.

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.