Echocardiographic evaluation of supracardiac anomalous pulmonary venous connection in children: comparison with multilayer spiral CT

Objective To explore the clinical value of transthoracic echocardiography (TTE) in the differentiation of Supracardiac Anomalous Pulmonary Venous Connection (SAPVC) in children. Materials and methods A total of 118 children with concurrent TTE and CT databases of cases diagnosed with SAPVCs were included. We analyzed the consistency between the two for the ability to diagnose the classification of SAPVC, drainage sites, ectopic pulmonary veins and the segments of superior vena cava (SVC). Results The consistency between TTE and CT in diagnosing the existence of SAPVC and the classification were 88.1% (95% CI: 80.9-93.4%) and 91.0% (95% CI: 84.1-95.6%), respectively. The error rate of partial type diagnosed by TTE was significantly higher than that of total and mixed type (20.5% vs. 2.8%, P = 0.003). The consistency between TTE and CT to determine drainage sites was 91.9% (95% CI: 85.2-96.2%). TTE had a significantly higher error rate in determining pulmonary vein drainage to the SVC than in those draining into the left innominate vein (17.5 vs. 2.5%, P = 0.007). The consistency of TTE and CT in judging the number of veins was 87.4% (95% CI: 79.7-92.9%). The error rate in determining the presence of 2 and 5 ectopic pulmonary veins was significantly higher than those of 1 and 4 veins (P < 0.05). Conclusion TTE for diagnosing partial SAPVC and identifying the drainage site of SVC has a high error rate of misdiagnosis and missed diagnosis. The extra attention should be given to these factors in clinical practice to improve the accuracy of TTE in diagnosing SAPVC.


Introduction
Anomalous pulmonary venous connection (APVC) is a type of congenital heart disease in which part or all of the pulmonary veins are directly or indirectly connected to the right atrium or systemic venous system, with an incidence of 5-6% [1]. SAPVC is the common type of APVC. Patients with SAPVC have complex drainage sites and diverse drainage branches. If they are not actively treated, the opportunity for surgery will be missed, and may cause serious consequences, which brings challenges to clinical diagnosis and surgical decision-making [2,3]. Multilayer for displaying normal and ectopic pulmonary veins. This study aimed to explore the consistency of TTE and CT in diagnosing SAPVC, and to analyze the causes of missed diagnosis and misdiagnosis of TTE.

Participants and setting
All procedures in this study involving human participants were performed in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics board of Xijing Hospital (approval No. KY20182066-C-1), and informed consent was obtained from all of patients. We selected 118 pediatric patients aged from 1 day to 18 years old from Sep. 1, 2016, to Sep. 31, 2021 [7], who were diagnosed with total, partial or mixed SAPVC by TTE or CT, as shown in Fig. 1. Among them, 13 cases were newborns, 61.5% of whom were male, aged from 2 to 28 days, with an average age of 18.8 ± 7.9 days. Fifty patients were infants, 64% of whom were male, aged from 1 to 10 months, with an average age of 4.0 ± 2.4 months. Twenty-five cases were young children, 44.0% of whom were male, aged from 1 to 3 years old, with an average age of 1.6 ± 0.9 years old. Sixteen cases were preschool children, 75.0% of whom were male, aged from 4 to 6 years old, with an average age of 5.1 ± 0.9 years old. Eight cases were school-age children, 62.5% of whom were male, aged from 8 to 13 years old, with an average age of 9.5 ± 1.9 years old. Six cases were adolescents, 66.7% of whom were male, aged from 13 to 18 years old, with an average age of 14.7 ± 1.8 years old. were selected as the echocardiography diagnostic instruments, with an S5-1 transducer (frequency 1-5 MHz) and an S8-3 transducer (frequency 3-8 MHz). All results were compared with the CT results. The TTE diagnosis of SAPVC was made by an experienced sonographer who has more than 8 years of experience in evaluating congenital heart disease in children. The following ultrasound features should be noted when applying different echocardiographic scan views to determine the classification of SAPVC: (1) The four pulmonary veins do not flow back into the left atrium, and there are abnormal blood vessels behind or outside the left atrium to help track the paths and drainage sites of the veins. (2) There is an abnormal vein adjacent to the descending aorta or ascending aorta that flows up into the LIV, SVC or AV. (3) The SVC could have a widened inner diameter and an increased flow velocity. (4) The size or ratio of the atria and ventricles are generally normal or abnormal. (5) The atrial septum might not be continuous and complete. (6) Tricuspid regurgitation is estimated to assess . SAPVC supracardiac anomalous pulmonary venous connec-tion;. TSAPVC total supracardiac anomalous pulmonary venous connection;. PSAPVC partial supracardiac anomalous pulmonary venous connection; the pulmonary artery pressure. (7) It is important to rule out other malformations.

TTE in the diagnosis of SAPVC
Standard views for complete visualization of the pulmonary veins and superior vena cava include the long axis of the parasternal left ventricle, the short axis of the high parasternal fundus, the four and five chambers of the apical heart and so on. In addition, nonstandard views, such as the long axis of the superior apical vena cava in the high position, at the apex of the heart, below the xiphoid process, or at the right supraclavicular fossa, are also important supplementary views to show the veins. Some nonstandard views are shown in Fig. 2.

MSCT diagnosis of SAPVC
Multilayer spiral CT (MSCT) is an examination method that provides additional information when SAPVC is diagnosed or suspected by TTE. The patients completed the image acquisition, such as axial, multiplanar reconstruction and VR reconstruction of the MSCT. According to the CT heart protocol, the measurement parameters, including 0.75 mm diameter, 1 mm layer thickness, and 0.8 mm layer interval, were set. The whole scan is administered by percutaneous injection into the peripheral veins in the foot or elbows. The dose of contrast agent was calculated according to 0.8-1 ml/ kg under 1 year old, 1-1.5 ml/kg over 1-5 years old, and 2-5 ml/kg for 5-18 years old. The injection speed was 0.8 ml/s for children under 1 year old, 1-2 ml/s for children 1-5 years old and 2-5 ml/s for children 5-18 years old. The scanning radiation dose of MSCT was in accordance with the automatic milliamp control technology, and the scanning range was from the thoracic entrance to the top of the liver. Subsequently, all data were transmitted to the workstation, and the image reading was completed by a radiologist with 8 years or more experience in cardiac assessment.

Determination of the different classifications of SAPVC and the drainage sites of the ectopic pulmonary veins
According to the pulmonary veins connected to the left atrium, SAPVC can be classified as a total SAPVC (TSAPVC), in which none of the four pulmonary veins connect with the left atrium; the partial SAPVC (PSAPVC), in which one, two or three pulmonary veins do not converge into the left atrium; and the mixed SAPVC (MSAPVC), in which two or more types of APVC are present simultaneously. The most common drainage sites for the veins include the left innominate vein (LIV) and the right superior vena cava (SVC), and a rarer site is the azygos vein (AV) (Fig. 3).

Determination of the numbers of ectopic pulmonary veins
TTE shows that a normal pulmonary venous system consists of 4 veins, 2 on each side, draining into the left atrium. In contrast, the anomalous pulmonary veins of SAPVC tend to converge posteriorly or laterally in the left atrium to form a common pulmonary venous trunk. When determining the number of veins, we first focus on judging the veins that enter the left atrium and then clarify the veins that do not flow back into the left atrium through multiple views. Subsequently, we follow up to find the drainage paths and sites of these veins. The methods of using TTE to determine the veins through multiple views are as follows: (1) If no pulmonary veins are found to open in the wall of the left atrium, the 4 veins are all ectopic pulmonary veins. We consider this to be total or mixed SAPVC. (2) If one pulmonary vein converging into the left atrium is visible in the left atrial

Statistical analysis
SPSS 22.0 statistical analysis software was used to analyze all data, and the normally distributed measurement data are expressed as the mean ± standard deviation. Categorical data are expressed as frequencies, and Fisher's exact probability method was used to compare the intergroup countable data. P < 0.05 was considered to indicate a statistically significant difference.

Patient clinical characteristics
The clinical characteristics of patients with SAPVC were obviously affected by the hemodynamics of APVC. Most patients were highly susceptible to colds or recurrent lung infections. The severity of the patient's symptoms were also closely related to the presence or absence of other cardiovascular malformations [8]. The most common cooccurring malformations were atrial septal defects or patent foramen ovale, followed by PDA and VSD. Isolated SAPVC accounted for 4.2% ( Table 1; Fig. 5).

The ability of TTE to judge the SAPVC classification
Among a total of 118 patients, 111 were diagnosed with SAPVC by CT, the 7 cases misdiagnosed by TTE were all partial types, and the misdiagnosis rate was 5.9% (95% CI: 2.4-11.8%, P < 0.05). The coincidence rate of TTE and CT in diagnosing the 67 TSAPVC cases was 97.0%. Typical echocardiography images are shown in Fig. 6. On TTE, wall, which can show any of the superior left, inferior left or superior right and inferior right branches, the patient is considered to have partial SAPVC with 3 ectopic pulmonary veins. (3) If two pulmonary veins can be found in the wall of the left atrium, they can show that two left or two right or one left and one right veins merge into the left atrium. We consider this to be the partial SAPVC of two ectopic pulmonary veins. (4) If three pulmonary veins can be found in the wall of the left atrium, two left and one right or two right and one left veins merge into the left atrium. We consider this to be the partial SAPVC of one ectopic pulmonary vein. (5) If four pulmonary veins can be found in the wall of the left atrium, we basically rule it out as not SAPVC.  Table 2.The concordance rate between TTE and CT in diagnosing the existence and classification of SAPVC was 88.1% (95% CI: 80.9% ~ 93.4%) and 91.0% (95% CI:  Fig. 6 The total SAPVC. The patient was a 2 months old boy, and easily catched colds in usual. A and B 2D and color Doppler image show that the multiple ectopic pulmonary veins converge into the common trunk (thin arrow), which was connected to the left innominate vein (thick arrows) via vertical vein, and eventually drained into superior vena cava. C and D 2D and color Doppler image fully show that the four pulmonary veins joined into the common pulmonary vein trunk (arrow) Fig. 5 The isolated partial SAPVC. The patient (male, 10 years old) had no abnormal clinical symptoms such as chest tightness and cyanosis in normal times, and no special medical history. No obvious abnormal cardiac structure was found in his multiple echocardiographic examinations. The isolated partial SAPVC was found occasionally by MSCT examination due to the pulmonary inflammation. The ectopic pulmonary vein was connected to the LIV via the VV and joined into the SVC.
(5.4%) with 2 branches, 3 cases (2.7%) with 3 branches, 67 cases (60.4%) with 4 branches, and 6 cases (5.4%) with 5 branches. On TTE, the misjudged or missed cases by TTE are shown in Table 4.The concordance rate of the TTE and CT diagnosis of the number of ectopic pulmonary veins was 87.4% (95% CI: 79.7%~92.9%). The error rate of TTE in in the partial type was significantly higher than that in the total and mixed types (20.5 vs. 2.8%, P = 0.003).

The ability of TTE in judging the drainage sites of pulmonary veins
Among 111 children confirmed by CT, there were 33 cases (29.7%) of drainage into the SVC, 77 cases (69.4%) of drainage into the LIV, and 1 case (4.5%) of drainage into the AV. In different drainage sites of veins, the TTE diagnosis was missed or consistent with that of CT in Table 3, and these children who are missed or misdiagnosed in this way are more likely to have a large atrial defect (Fig. 7). The concordance rate of TTE and CT diagnosis of drainage sites was 91.9% (95% CI: 85.2%~96.2%). The diagnostic error rate of drainage into the SVC by TTE was significantly higher than of drainage into the LIV (17.5 vs. 2.5%, P = 0.007).

The ability of TTE to judge the numbers of ectopic pulmonary veins
Among 111 cases confirmed by CT, abnormal pulmonary veins included 29 cases (26.1%) with 1 branch, 6 cases   A and B 2D and color Doppler showed that the continuity of the atrial septum was interrupted (arrow). C and D 2D and color Doppler showed that ectopic pulmonary veins flowed back into superior vena cava (arrow). E and F MSCT confirmed that it was PSAPVC combined with the huge atrial septal defect draining into the upper segment was 50.0% (2/4), the error rate of draining into the lower segment was 45.8% (11/24), and the error rate of draining into the middle segment was 0% (0/5).

Discussion
In total SAPVC, the 4 pulmonary veins do not converge into the left atrium, they form a common pulmonary venous trunk posterior or lateral to the left atrium. The common trunk usually ascends through the VV and connects with the LIV to join the SVC and then flows back into the right atrium (Fig. 3). Its typical echocardiography signs are that the venous arch formed by the VV and the LIV and the aorta next to it form a typical "double arch" sign ( Fig. 6). TTE can usually correctly diagnose TSAPVC [9].
In partial SAPVC, 1-3 pulmonary veins do not converge into the left atrium, and the branches or common trunks of the veins flow back into the right SVC, the right heart system or the body vein system through the LIV, or rarely, the AV (Fig. 3). In this study, we found that the identification of SAPVC and diagnosis of its staging had a high concordance rate with the MSCT diagnosis, while patients with missed diagnoses were mainly partial and isolated SAPVC. This was due to the complex anatomical variation of the branches or the common trunk branch of the veins in PSAPVC, which determining the number of veins was 10.3% for 1 branch, 66.7% for 2 branches, 0% for 3 branches, 14.9% for 4 branches, and 66.7% for 5 branches. The diagnostic error rate of TTE for 2 and 5 branches was significantly higher than that for 1 and 4 branches (P < 0.05).

The ability of TTE to judge the different segments of SVC
Among 33 cases of CT-confirmed ectopic pulmonary veins draining into the SVC, 4 cases (12.1%) drained into the upper segment, 5 cases (15.2%) drained into the middle segment, and 24 cases (72.7%) drained into the lower segment. On TTE, the misjudged or missed cases by TTE are shown in Table 5. Typical images of the veins flowing directly into SVC are shown in Fig. 8. The concordance rate of the TTE and CT diagnosis of the segments was 60.6% (95% CI: 42.1%~77.1%). In the different segments, the error rate of views showed that the four pulmonary veins had converged into the left atrium. There was a special situation in that sometimes, even though different ultrasound views showed that the four veins joined the left atrium, the examiners still could not completely rule out the possibility of no SAPVC. Because ectopic drainage of the 6th, 7th or even more branches of the variant veins might occur, attention should be given to looking for subtle indirect signs caused by multiple pulmonary veins. By analyzing the misdiagnosis and missed cases of different types of PSAPVCs, we found that the type of pulmonary veins flowing back into the SVC was easily misdiagnosed, especially for determining the different segments of the SVC. However, the accurate preoperative determination of different segments of the SVC plays a key role in the surgical plan [20,21]. This study found that the inferior segment was the most common and frequently missed or misdiagnosed site compared to the superior and middle segments. The keys to accurately determining the segments of the SVC by TTE included noticing the subtle indirect signs, such as the widened inner diameter or increased blood flow velocity of the SVC (Fig. 8). In addition, the flexible use of individual nonstandard echocardiography views, which significantly increase the display of different segments of the SVC, can also improve the detection of pulmonary veins.
TTE is of important clinical value in the diagnosis of SAPVC and can provide meaningful recommendations for surgeons. TTE can accurately detect the drainage paths, drainage sites and ectopic pulmonary veins of TSAPVCs. For PSAPVC, TTE should not only correctly determine the drainage sites but also carefully scan the numbers of pulmonary veins. To display different segments of the SVC, the use of nonstandard views, such as the long axis of the SVC, needs to be given serious attention, as should indirect signs, such as the inner diameter and the flow velocity of the SVC.

Conclusion
In conclusion, the methods that can effectively improve the detection rate of pulmonary veins of SAPVC and reduce the rate of missed diagnosis and misdiagnosis were as follows: (1) When the conventional standard views are poor, the various nonstandard views mentioned in the previous sections can be used to aid the diagnosis. (2) In some patients, the drainage sites of the pulmonary veins or the segments of the SVC cannot be clearly demonstrated even with nonstandard views, and special attention should be given to indirect signs, such as a widened inner diameter or an increased blood flow velocity of the SVC, to help determine the presence of SAPVC. (3) At the same time, the examiner must improve the diagnostic accuracy of the isolated SAPVC and could be missed due to the lack of typical echocardiography signs [10]. The isolated SAPVC was easily missed by TTE because its hemodynamics generally did not cause significant changes in the right heart system, the chambers were essentially normal in size, the inner diameter of the VV was usually very small, and it was less likely to be combined with pulmonary hypertension or other intracardiac malformations (Fig. 5) [11]. However, if nonstandard views were chosen with attention to subtle indirect signs (Fig. 4), the missed diagnosis rate could be significantly reduced.
The main drainage sites for SAPVC are the LIV, the VV, and the right SVC (Fig. 4). The correct preoperative determination of the drainage sites is important for the choice of surgical approach and to avoid secondary surgery [12,13]. Our study found that the error rate of TTE in determining the flow into the SVC was significantly higher than that of LIV, especially in patients with PSAPVC combined with a large atrial septal defect (Fig. 7), which is consistent with previous related studies [14]. The key to the correct determination of drainage sites by TTE is the skillful and flexible application of various nonstandard views of the SVC. These special views, such as the parasternal, high parasternal, apical and long axis views of the SVC in the right supraclavicular fossa, are particularly helpful in detecting the ectopic pulmonary veins in SAPVC.
Anatomical variations of the pulmonary vein branches or common trunks are common and complex in SAPVC [8][9][10][11][12][13][14][15]. They could present not only as a single or cotrunked variant of 4 pulmonary veins but also as a single or cotrunked variant of more than six or seven pulmonary veins. These factors make it difficult for surgeons to formulate surgical plans before surgery [16,17]. This study found that the ectopic pulmonary veins were mostly in the right superior, middle and inferior pulmonary veins, and that a common trunk branch of the two left veins was frequently observed. The error rate of TTE in identifying 2 and 5 veins was significantly higher than that for 1 and 4 veins. Ectopic drainage of one pulmonary vein mostly presented as one right superior pulmonary vein flowing back to the SVC or one left superior pulmonary vein flowing back to the LIV. The key to correctly determining the number of veins by TTE was to focus on the following two aspects. One was that the ectopic veins did not enter the left atrium but joined the LIV, SVC or AV, and the other was that the ectopic veins directly entered the left atrium. A method of avoiding misdiagnosing the numbers of pulmonary veins is shown in Fig. 4. Correctly searching for the distribution and drainage branch numbers of the veins could not only significantly improve the accuracy of TTE screening for SAPVC but also reduce the misdiagnosis rate or missed diagnosis rate [18,19]. A noteworthy situation was that the absence of SAPVC was not completely excluded even if different echocardiography enhance the understanding of the anatomy and hemodynamics of SAPVC. We should not mistake the normal superior intercostal vein, which is detected by the long axis of the LIV in the suprasternal fossa, as the VV. We should not ignore all veins draining into the left atrium, which is important to ensure an accurate interpretation of the numbers of pulmonary veins. (4) For patients with suspected SAPVC that cannot be confirmed by TTE, the application of MSCT can effectively improve the detection rate of pulmonary veins and reduce the rate of missed diagnosis or misdiagnosis.

Study limitations
There are some limitations of this study. First, the research object was only pediatric patients. In the future, there is a need to expand the study population and to pursue collaborative research in multiple centers. Second, this study only analyzed the diagnostic results of senior sonographers and did not consider the effect of clinical experience.