Total anomalous pulmonary venous return (TAPVR) or connection (TAPVC)

TAPVR or TAPVC is a congenital cardiac anomaly in which the veins bringing blood back from the lungs (pulmonary veins) do not connect directly to the left atrium in the usual anatomical arrangement but instead, return pulmonary venous blood to the heart by way of an abnormal (anomalous) connection into the right atrium, either directly or indirectly.

TAPVC affects roughly 0.9 out of every 10,000 births and contributes to two percent of all live births with congenital heart disease.¹
 

Understanding the normal fetal heart and vascular development is critical for understanding the wide range of physiologic deviations and cardiac anomalies. The fundamental pulmonary buds are accompanied by the smooth muscle plexus, which is the foregut vascular plexus, during the early stages of development. The common pulmonary vein, which develops as an evagination from the heart, connects the pulmonary plexus to the heart. As a result, the pulmonary veins plexus and splanchnic plexus connections involute. The common pulmonary vein merges with the left atrium (LA), and right and left pulmonary veins connect directly to the LA. TAPVC is seen when there is failure of the conventional pulmonary vein connection, as well as the persistence of the embryonic connections between the systemic and pulmonary vasculature. Four subtypes of TAPVC are recognized, based on the anatomic location of the aberrant connection: supra-cardiac (type 1), cardiac (type 2), infra-cardiac (type 3), and mixed pattern (type 4). Type 1 is most common, and accounts for around 45 percent of all TAPVC. When some of the pulmonary veins connect normally, the pulmonary-systemic venous connections that remain are termed PAPVC.²
The consequence of TAPVC is that oxygenated blood returning form the lungs mixes with the de-oxygenated blood returning from the body; the entire systemic output then must pass through the foramen ovale into the left atrium and left ventricle, and will be desaturated to varying degrees depending on the ratio of pulmonary blood flow to systemic flow.  In cases of obstructed connections, the venous return in the pulmonary veins is impaired leading to increased venous pressure, congestion in the lungs, pulmonary edema and pulmonary hypertension. 

Typical prenatal ultrasonographic findings in Type 1 TAPVC include absence of pulmonary veins draining into the left atrium on the 4 chamber cardiac view,  an enlarged area behind the left atrium (post-LA space index of >1.27)  and identification of  a vertical vein to the left of the pulmonary artery connecting to the innominate vein or behind the heart draining to the azygous or superior vena cava (which is enlarged).   I In type 2 (cardiac) TAPVC the pulmonary veins connect to the coronary sinus or drain immediately to the of the right atrium. In type 3 (infra-cardiac) TAPVC the pulmonary veins connect to a confluence and a vertical vein that descends through the esophageal hiatus to drain to the hepatic, portal, or umbilical veins or ductus venosus. PAPVC occurs when only some of the pulmonary veins demonstrate an aberrant connection.  Though this physiology is similar to atrial septal defect and may be asymptomatic and difficult to diagnose in the prenatal period, the condition known as Scimitar Syndrome in which all or most of the right pulmonay veins drain to the inferior vena cava is often associated with right lung hypoplasia and should be suspected when there is rightward shift of the heart in the fetal thorax.  

TAPVC and PAPVC can arise alone but are frequently found in conjunction with other cardiac abnormalities, in approximately 28.3 %, even in the absence of cardiosplenic disorders such as heterotaxy. (5)  TAPVC and PAPVC are related to venous sinus atrial septal defect, however, this form of atrial septal defect is seldom identified prenatally. Atrial and ventricular septal defects, single ventricle, aortic coarctation, hypoplastic left heart syndrome, and other cardiac defects are also commonly seen in association with TAPVC or PAPVC. Extracardiac abnormalities are common with heterotaxy disorder but less so in TAPVC of the non-heterotaxy type. Scimitar syndrome is characterized by mesocardia/dextrocardia and concomitant right lung hypoplasia in addition to PAPVR. Single gene disorders such as Noonan’s Syndrome and Holt-Oram Syndrome have been occasionally reported in patients with TAPVR, as has sibling concordance (9). Cat-eye syndrome, caused by a partial duplication of chromosome 22q and characterized by pre-auricular tags, coloboma, and anal malformations is often associated with TAPVR (in up to 40% of these patients) and is considered by some to be the hallmark of this condition. (5)  Other chromosomal abnormalities are uncommon.¹

Any cardiac condition that causes chamber disproportion between the right and left sides of the heart should be considered when sorting the differential diagnoses. A discontinuous IVC with azygos continuance results in an enlarged azygos vein posterior towards the left atrium, which may be misidentified as a confluent vein. A persistent LSVC seen in the three-vessel-trachea view may look like a supra-cardiac TAPVC. Colour Doppler, can distinguish these two entities; in PLSVC blood flow will be noted toward the heart while in the vertical vein of TAPVR, flow will be in the opposite direction.¹

Sonographic detection of TAPVR and its variants remains difficult in the general screening population but is possible with fetal echocardiography and Doppler analysis. Numerous ultrasound features have been reported to be useful in prenatal diagnosis of this condition (Table 1). The most commonly described sonographic features associated with this diagnosis are ventricular disproportion, an enlarged space behind the left atrium, presence of a confluence behind the left atrium, and the presence of a vertical vein in either the three vessel view or the axial abdominal situs view. Under usual circumstances the space between the heart and spine on axial view should only contain the aorta, situated to the left of and anterior to, the spine. The presence of another vessel in this area, indicating a vertical vein or venous confluence, is consistent with the presence of TAPVR. Kawazu et al. described an increased “Post-LA space index” in affected fetuses, defined as the ratio of the left atrium-descending aorta distance to the diameter of the descending aorta.  A ratio of greater than 1.27 was found to be predictive of TAPVR. Colour and spectral (pulsed wave) Doppler can also aid in the diagnosis and can help to identify pulmonary venous obstruction (7). The normal pulmonary venous waveform exhibits a triphasic flow pattern with defined absence of forward flow at end of diastole. When obstruction is present this waveform becomes monophasic, with continuous, low-flow velocity. 

(Paladini et al (2018), in a meta-analysis of 15 studies of prenatally diagnosed cases reported ventricular disproportion in 59.2%, an increase in the region behind the left atrium in 58.1%, and a vertical vein in 59.3%. Colour/power Doppler was able to identify TAPVC in 84.9%. In around one-third of TAPVC instances, venous return was obstructed, Pulmonary venous obstruction should be suspected when the flow velocity in the vertical vein to systemic connection is >0.5 m/sec or when the typical pulmonary venous pulsatile flow is lost (7). 

Table 1: Sonographic signs associated with TAPVR/TAPVC

Once the clinical status has stabilized and the diagnosis definitively established using echocardiography, cross-sectional imaging and/or cardiac catheterization, individuals with TAPVC should have corrective surgery as soon as feasible. Oxygen therapy, inotropic assistance, and positive pressure or mechanical ventilation are examples of first-line supportive medical care. In the rare case of a restrictive foramen ovale, a balloon atrial septostomy may be required. Stents are occasionally implanted in the diagnostic and interventional catheterization laboratory in patients with symptomatic obstructed TAPVC to stabilize the neonate. As this is not considered a ductal-dependent cyanotic lesion, initiation of prostaglandins is generally not required if the diagnosis is clear, though not necessarily contraindicated if definitive diagnosis is likely to be delayed.²

The type of aberrant venous connection, the existence and extent of pulmonary venous obstruction, and the presence of other cardiac and extracardiac anomalies all influence prognosis. Because pulmonary venous obstruction is more common in type 3 (infra-cardiac) TAPVC, this type may have a poorer prognosis than other types. All types, however, can manifest obstruction and if undiagnosed prenatally, can present with severe cyanosis and pulmonary edema after birth, requiring immediate surgical intervention. Pulmonary venous obstruction was encountered in 34% of patients with prenatal diagnosis in Paladini’s systematic review ( 5) The prognosis for newborns who survive to surgical correction is generally favorable,¹ long-term survival has improved as medical care and surgical procedures have improved.²

1.   Abuhamad AZ, Chaoui R. A Practical Guide to Fetal Echocardiography: Normal and Abnormal Hearts. Lippincott Williams & Wilkins; 2012.
2.    Konduri A, Aggarwal S. Partial And Total Anomalous Pulmonary Venous Connection. In: StatPearls [Internet]. StatPearls Publishing; 2021.
3.    Shi X, Lu Y, Sun K. Research Progress in Pathogenesis of Total Anomalous Pulmonary Venous Connection. Precision Medicine. Published online 2020:173-178.
4.    Burroughs JT, Edwards JE. Total anomalous pulmonary venous connection. American heart journal. 1960;59(6):913-931.
5.    Paladini D, Pistorio A, Wu L, et al. Prenatal diagnosis of total and partial anomalous pulmonary venous connection: multicenter cohort study and meta‐analysis. Ultrasound in Obstetrics & Gynecology. 2018;52(1):24-34.
6.    Mai C, Isenburg J, Canfield M. National population-based estimates for major birth defects. National Birth Defects Prevention Network. 2019;1(1):1-3. doi:https://doi.org/10.1002/bdr2.1589
7.    Ganesan S, Brook MM, Silverman NH, Moon-Grady AJ. Prenatal Findings in Total Anomalous Pulmonary Venous Return. Journal of Ultrasound in Medicine. 2014;33(7):1193-1207. doi:10.7863/ultra.33.7.1193
8. Seale AN, Carvalho JS, Gardiner HM, Mellander M, Roughton M, Simpson J, Tometzki A, Uzun O, Webber SA, Daubeney PE; British Congenital Cardiac Association. Total anomalous pulmonary venous connection: impact of prenatal diagnosis. Ultrasound Obstet Gynecol 2012; 40: 310–318.
9. Kim HS, Jeong K, Cho HJ, Choi WY, Choi YE, Ma JS, Cho YK. Total anomalous pulmonary venous return in siblings. J Cardiovasc Ultrasound. 2014 Dec;22(4):213-9. doi: 10.4250/jcu.2014.22.4.213. Epub 2014 Dec 26. PMID: 25580197; PMCID: PMC4286644.
10. Li, T-G, Ma, B, Gao, Y-H, Zhang, R-H, Li, P-L, Da, Z-Q. Prenatal diagnosis of total anomalous pulmonary venous connection using 2D and HDlive flow combined with spatiotemporal image correlation. Echocardiography. 2022; 39: 1269– 1275. https://doi.org/10.1111/echo.15429
11.Kawazu Y, Inamura N, Shiono N, Kanagawa N, Narita J, Hamamichi Y, Kayatani F,  “Post-LA  space index” as a potential novel marker for the prenatal diagnosis of isolated total anomalous pulmonary venous return. UOG) 682-687 2014 Dec; 44(6)682-7 
12. Xin Wang, Ting‐Yang Yang, Ying‐Ying Zhang, Xiao‐Wei Liu, Ye Zhang, Lin Sun, Xiao‐Yan Gu, Zhuo Chen, Yong Guo, Chao Xue, Jian‐Cheng Han, Hao‐Gang Zhu, Yi‐Hua He, Diagnosis of fetal total anomalous pulmonary venous connection based on the post‐left atrium space ratio using artificial intelligence, Prenatal Diagnosis, 10.1002/pd.6220, 42, 10, (1323-1331), (2022)

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