David W. Brown Boston Children’s Hospital; Harvard Medical School, Boston, MA, USA Pulmonary venous anomalies include many anatomic variations, with a wide range of clinical presentations and outcomes. The anomalies may be grouped into four categories: The presentation ranges from normal, in those with variations on the normal number of pulmonary veins, to life‐threatening disease in the neonate with obstructed total anomalous pulmonary venous connection. Fortunately, the vast majority of pulmonary venous anomalies may now be readily and rapidly diagnosed by echocardiography. The incidence of pulmonary venous anomalies varies widely according to the anomaly observed. An abnormal number of pulmonary veins is commonly encountered; a single right or single left pulmonary vein is present in nearly 25% of the population in anatomic studies [1], and a third pulmonary vein is present on either side in 1.6–2% [1]. Cor triatriatum, an example of stenotic pulmonary venous connection due to incomplete incorporation of the common pulmonary vein into the left atrium, occurs in three in 100,000 of the worldwide population [2]. Partial anomalous pulmonary venous connection (PAPVC) has been described in autopsy series in 400–700 in 100,000 specimens [1], with isolated PAPVC in 160 of 100,000. Total anomalous pulmonary venous connection (TAPVC) has been described in nine in 100,000 of the population [3,4]. Most cases of pulmonary venous anomalies are sporadic. However, there are known syndromic associations for PAPVC, most notably the Turner and Noonan syndromes [5,6]. TAPVC similarly has syndromic associations including cat‐eye, Holt–Oram, and the asplenia syndromes. Numerous case reports of nonsyndromic familial cases suggest a heritable genetic cause, with heterogenous genetic loci reported; one gene for familial TAPVC in a large Utah kindred was mapped to chromosome 4p13‐q12 [7]. More recently, whole exome sequencing techniques in six sporadic cases of TAPVC in a Chinese population identified two previously unidentified associated candidate mutations, one in activin A receptor type II‐like 1 (ACVRL1) and a second in sarcoglycan delta (SGCD) [8]. The classification of pulmonary venous anomalies is based on an understanding of the embryologic development of the pulmonary veins, and the relationships between the pulmonary veins, systemic veins, and atria. The lungs and tracheobronchial tree are derived from the foregut, and the pulmonary vascular bed is formed by a portion of the splanchnic plexus. Thus, early in gestation, the primitive lung drains via the splanchnic venous plexus into the systemic circulation via the umbilicovitelline and cardinal venous systems. At 32–33 days of gestation, the pulmonary veins subsequently establish a communication with the common pulmonary vein, which becomes incorporated into the posterior aspect of the developing left atrium. The precise origin and site of development of the common pulmonary vein has been controversial, with some believing this derives from an evagination in the sinoatrial region of the heart that grows out toward the lungs [9], others that the common vein arises from the pulmonary venous plexus confluence and grows toward the heart [1]. More recent work that includes analysis of embryologic cell expression markers suggests that the common pulmonary vein derives from the midpharyngeal endothelial strand, a structure in the dorsal mesocardium that from early stages connects the endocardium of the primitive heart tube to the splanchnic venous plexus. This structure subsequently lumenizes to form the common pulmonary vein, but appears to be connected to the endothelium of the heart from the beginning [10–12]. The common pulmonary vein becomes incorporated into the posterior aspect of the left atrium, between the left and right horns of the sinus venosus, superior to the coronary sinus, and leftward of septum primum; ultimately two right and two left pulmonary veins connect directly to the left atrium. Once the communication of the common pulmonary vein with the left atrium has become established, the primitive connections of the pulmonary venous system to the systemic venous system are no longer necessary, and typically regress [13]. Nearly all of the pulmonary venous anomalies considered in this chapter may be seen as a result of abnormal development of the common pulmonary vein and varying patterns of persistence of embryologic pulmonary‐to‐systemic venous connections. An abnormal number of pulmonary veins results from irregular incorporation of the common pulmonary vein into the left atrium. With normal incorporation of the common pulmonary vein, two right and two left pulmonary veins connect directly and separately to the left atrium. When incomplete incorporation of either the right or left side occurs, a single pulmonary vein may drain that lung; a single left pulmonary vein is more frequently observed than a single right [1]. More rarely with even less complete incorporation, a common pulmonary vein accepts veins from both sides and then drains into the left atrium; this is seen most often in those with asplenia forms of heterotaxy [1]. When more than typical incorporation occurs, a third pulmonary vein on either the right or left side is observed [1]. This results when the common pulmonary vein incorporates normally into the left atrium, resulting in normally positioned pulmonary venous connections, but due to interatrial anatomy the pulmonary venous inflow is directed into the morphologic right atrium. Most commonly this is due to anatomically leftward malposition or malattachment of the septum primum, which can result in partial or total anomalous pulmonary venous drainage, depending upon the degree of malposition and number of veins affected (Figure 10.1). This is commonly encountered in those with polysplenia syndrome due to an absence of the septum secundum and the resulting anatomic leftward malposition of the septum primum [14]. Another frequently encountered example is common atrium as also observed in the heterotaxy syndromes, where virtual absence of the atrial septum results in ipsilateral drainage of the pulmonary veins into respective sides of the common atrium. Sinus venosus defect is a type of anomalous pulmonary venous drainage with normal connections that occurs due to “unroofing” or absence of the sinus venosus tissue between the right pulmonary veins and the superior vena cava or right atrium [15,16]. This topic is covered in detail in Chapter 12. It is important to note that despite the absence of the sinus venosus septum, the pulmonary veins in the variants of sinus venosus defect remain normally connected to the left atrium. Stenotic connections may be seen in individual pulmonary veins with normal connections to the heart, in anomalously connecting veins, or as stenosis of the common pulmonary vein, which manifests as cor triatriatum sinister. Stenosis of the individual pulmonary veins is a rare disorder that may result from abnormal incorporation of the common pulmonary vein into the left atrium [17]; trauma or manipulation provoking inflammation may be antecedent events. Pulmonary vein stenosis can be found in otherwise structurally normal hearts, or in association with congenital heart defects, commonly atrial or ventricular septal defects [18], or less often with complex heart disease such as the heterotaxy syndromes [19]. The stenosis can be extraparenchymal, with obstruction at the pulmonary vein/left atrial junction, intraparenchymal with diffuse involvement of the smaller pulmonary veins in the lung, or both. Upstream progression of the disease from the left atrial junction toward the hilum of the lung frequently occurs, and can progress to atresia [20]. Recent investigations have implicated intimal proliferation of abnormal myofibroblasts in the pathology of this disease [21,22]. Finally, stenosis of anomalously connecting pulmonary veins is commonly encountered, particularly in those with TAPVC below the diaphragm. Figure 10.1 Malposition of the septum primum. (a) Mild leftward malposition with normal pulmonary venous connections results in anomalous drainage of the right upper and lower pulmonary veins to the right atrium. (b) With more severe malposition of the septum primum, drainage of all four pulmonary veins is directed anomalously into the right atrium. Note the absence of a well‐developed septum secundum; this is common in patients with the polysplenia forms of heterotaxy syndrome. LA, left atrium; LPV, left pulmonary veins; RA, right atrium; RPV, right pulmonary veins. This results from incomplete incorporation of the common pulmonary vein into the posterior aspect of the left atrium. Cor triatriatum has many variations, the classic form consisting ofa membranous partition that divides the left atrium into a chamber that receives the pulmonary veins posteriorly, anda chamber that communicates with the mitral valve anteriorly and inferiorly (Figure 10.2a). A communicating orifice of varying size is typically present, the atrial septum is usually intact, and the left atrial appendage is on the distal side of the cor triatriatum membrane as a feature of the anatomic left atrium [23]. Variations include the presence of an atrial septal defect, which communicates between the right atrium and either the pulmonary venous chamber or the distal true left atrial chamber; decompressing anomalous venous connections; “subtotal” cor triatriatum, which can involve the veins from only one side of the lung; and atresia of the dividing membrane, termed “complete” cor triatriatum (Figure 10.2). Figure 10.2 Cor triatriatum variants. (a) Classic cor triatriatum. Right and left pulmonary veins (RPV, LPV) drain to the pulmonary venous confluence (PVC), with a discrete membrane between the PVC and true left atrium (LA); the only egress for blood is through the opening in the membrane. (b) Cor triatriatum with defect between the PVC and the right atrium (RA), which allows for decompression of pulmonary venous blood. (c) Cor triatriatum with decompressing vertical vein (VV) to the left innominate vein (LIV), which allows for decompression of the PVC. (d) Pulmonary venous return decompresses via a communication between the PVC and the RA, and then crosses to the true LA via a patent foramen ovale. (e) Decompressing vertical vein that descends below the diaphragm to connect to the systemic venous circulation via the hepatic or portal veins. (f) “Partial” or subtotal cor triatriatum with normally draining left pulmonary veins; the right pulmonary veins communicate with the true LA via a stenotic orifice. (g) Subtotal cor triatriatum of the right pulmonary veins along with partial anomalous venous return of the left pulmonary veins via the LIV. (h) Subtotal cor triatriatum of the right pulmonary veins to the RA with normal drainage of the left pulmonary veins to the LA. IVC, inferior vena cava; LV, left ventricle; RV, right ventricle; SVC, superior vena cava. This is a rare and typically lethal disorder, with functionally no communication present between the pulmonary venous confluence and the heart or the systemic veins. A blind‐ending pouch is present at the confluence of the pulmonary veins with no outlet for flow [24]. This occurs with one or more (but not all) pulmonary venous connections to the systemic venous circulation, with a wide anatomic spectrum of variations possible (Figure 10.3). As mentioned previously, PAPVC must be considered distinct from cases of partial anomalous pulmonary venous drainage. Left‐sided pulmonary veins typically form anomalous connections to left cardinal vein derivatives (such as the left innominate vein and coronary sinus), and right‐sided veins typically connect to derivatives of the right cardinal system (superior and inferior vena cavae), although crossed drainage across the midline is possible as the splanchnic venous plexus is a midline structure. With reclassification of many cases previously considered PAPVC to the superior vena cava and right atrium as sinus venosus defects or malposition of the septum primum, the most common form of PAPVC is left pulmonary veins to the left innominate vein, followed by right pulmonary venous connections to the inferior vena cava. With left‐sided pulmonary venous connection to the left innominate vein, one or more left pulmonary veins connect to the innominate vein by a persistent embryologic vein, named a vertical vein due to its orientation (Figure 10.3a); an atrial septal defect is commonly present. Other less common sites of left‐sided connection include to a persistent left superior vena cava, coronary sinus (Figure 10.3b), or to right‐sided venous structures such as the superior vena cava, the azygos vein, and the inferior vena cava [25]. Anomalous right pulmonary venous connection of all or some of the right pulmonary veins to the inferior vena cava is frequently encountered as part of a malformation termed scimitar syndrome (Figure 10.3c). This term was coined to describe the crescent‐shaped (Turkish scimitar sword‐like) shadow seen on roentgenograms in the right lower lung field, projected by the right pulmonary vein as it courses to join the inferior vena cava at or just below the diaphragm [26]. This syndrome is frequently associated with other anomalies of right lung development, including hypoplasia of the right lung and right pulmonary artery, secondary dextrocardia, bronchial abnormalities, anomalous arterial connection to the right lung from the aorta, and pulmonary sequestration [26,27]. This occurs with all pulmonary venous connections to the systemic venous circulation. Embryologically, TAPVC results from failure to establish a normal connection between the pulmonary venous plexus and the common pulmonary vein before the connections with the splanchnic venous system have regressed. The most commonly used anatomic classification of TAPVC is based on the site of connection(s) between the pulmonary and systemic veins [28]: Figure 10.3 Variants of partial anomalous pulmonary venous connection (PAPVC). (a) Anomalous connection of the two left pulmonary veins (LPV) to the left innominate vein (LIV) to the superior vena cava (SVC); the right pulmonary veins (RPV) connect normally to the left atrium. (b) Anomalous connection of the left pulmonary veins to the coronary sinus (CS). (c) Anomalous connection of the right pulmonary veins to the inferior vena cava (IVC) to the right atrium junction; in association with right lung hypoplasia this is termed “scimitar syndrome.” See text for more details. With all types, an interatrial communication to allow blood to enter the systemic circulation is necessary to sustain life, so that a patent foramen ovale or atrial septal defect is considered part of the malformation. Supracardiac TAPVC (Figure 10.4a) is the most common type (47% in the largest published series [29]), and among this group the most common site of connection is to the leftward aspect of the innominate vein (36% of all cases of TAPVC [29]). A pulmonary venous confluence is typically present posterior to the left atrium that drains via a left‐sided ascending vertical vein to the innominate vein. This vertical vein usually passes anterior to the left pulmonary artery and mainstem bronchus, although occasionally this will pass between these structures, which usually results in clinically significant obstruction to pulmonary venous flow. Supracardiac TAPVC with right‐sided connections to the right superior vena cava or azygos vein occur, but are less common; a similar but right‐sided vertical vein is observed, which typically courses anterior to the hilum of the right lung. Cardiac TAPVC (Figure 10.4b) occurs in 16% of cases [29,30], and involves an anomalous connection between the pulmonary venous confluence and the coronary sinus, with a venous vessel connecting typically in the region of the left atrioventricular groove. The coronary veins drain normally into the proximal end of the coronary sinus, and the typically severely dilated coronary sinus drains normally into the right atrium; the coronary sinus septum is usually intact. Infradiaphragmatic TAPVC (Figure 10.4c) occurs in 13–23% [29,30] with an anomalous connection typically to the umbilicovitelline system below the diaphragm. A descending vertical vein typically originates from the confluence of the pulmonary veins to course below the diaphragm (just anterior to the esophagus in the esophageal hiatus) to form connections with the portal venous system (most common), ductus venosus, hepatic vein, or inferior vena cava. Obstruction is frequently present with infradiaphragmatic forms of TAPVC for a number of reasons, most commonly due to intrinsic narrowing of the connecting vessel, the interposition of the hepatic sinusoids between the pulmonary venous drainage and the heart for those that drain via the portal vein, and constriction of the ductus venosus. Mixed TAPVC (Figure 10.4d) is the least common type (7–10% [29,30]) with often complex variations of the above forms of venous connections represented. The pathophysiology of the various forms of pulmonary venous anomalies depends entirely upon the nature of the anomaly, the degree of mixing of systemic and pulmonary venous blood, and the presence or absence of obstruction to pulmonary venous flow. Anomalies that result in pulmonary venous obstruction cause pulmonary venous hypertension in the affected lobe or lobes. With an increase in the number of lobes affected and worsening obstruction, the pulmonary venous hypertension is transmitted back through the vascular bed of the lung, to result in pulmonary capillary and pulmonary artery hypertension. A cascade of effects on the pulmonary vasculature results, from acute changes such as pulmonary edema and reflex pulmonary vasoconstriction, to chronic alterations in pulmonary vascular resistance, vessel reactivity, and vascular remodeling. The effects of this dramatic increase in afterload on the right side of the heart include initially compensatory right ventricular hypertrophy, subsequent chamber enlargement, contractile dysfunction, and eventual right heart failure. Figure 10.4 Variants of total anomalous pulmonary venous connection (TAPVC). (a) Supracardiac: both right (RPV) and left (LPV) pulmonary veins join a common pulmonary venous confluence behind the heart, which drains via a vertical vein to the undersurface of the left innominate vein, and thence to the right atrium. (b) Cardiac: the pulmonary venous confluence connects to the coronary sinus (CS), and thence to the right atrium via the CS ostium. (c) Infradiaphragmatic: the pulmonary venous confluence drains inferiorly via a vertical vein to the portal vein (PV) or hepatic veins (HV) and thence to the right atrium. (d) Mixed connections: the LPV drain to the left innominate vein (LIV), and RPV to the CS in this example. IVC, inferior vena cava; SMV, superior mesenteric vein; SV, splenic vein. The pathophysiology of most of the various forms of PAPVC is similar to that of an atrial septal defect, with increased pulmonary blood flow due to recirculation of oxygenated blood through the lungs. This is dependent upon the extent of the pulmonary vascular bed drained by the anomalously connecting vein(s), as well as the status of the atrial septum. The excess flow through the right heart and lungs leads to dilation of the right atrium, right ventricle, and pulmonary vascular bed. With PAPVC of a single pulmonary vein and an intact atrial septum, typically the anomalous blood flow is 20–25% of total pulmonary blood flow [31], which is rarely clinically apparent. With PAPVC of an entire lung with an intact atrial septum, due to the greater compliance of the right atrium and right ventricle relative to the left side of the heart, the anomalously draining blood usually represents 66% rather than 50% of pulmonary venous drainage. When encountered with forms of scimitar syndrome (see Figure 10.3c), the net shunt tends to be lower (24–32% of pulmonary blood flow) due to abnormalities of the right lung parenchyma and pulmonary vasculature [32]. The subsequent development of pulmonary vascular disease with most forms of PAPVC is rare, but has been reported, especially in association with scimitar syndrome [33]. If a small atrial septal defect is present with PAPVC, the pathophysiology is similar to that discussed earlier. If a large atrial septal defect is present, the degree of left‐to‐right shunt is often significantly increased, with pulmonary recirculation not only of blood from the anomalously draining lung but also half or more of the normally connecting lung’s blood via the atrial septal defect. Partial anomalous pulmonary venous drainage shares similar pathophysiology to PAPVC, with the degree of left‐to‐right shunt dependent upon the number of pulmonary veins redirected to the right atrium by the malpositioned septum. The pathophysiology seen with TAPVC depends greatly upon the presence or absence of pulmonary venous obstruction, as well as the adequacy of the interatrial defect to allow flow to the systemic circulation. In the absence of pulmonary venous obstruction, there is complete mixing of systemic and pulmonary venous blood in the right atrium; as the resistance to pulmonary blood flow is significantly lower than that of the systemic circulation, there is significant pulmonary overcirculation (often 3–5 times normal) and the systemic saturation may be 90% or higher (resulting often in clinically inapparent cyanosis). Right ventricular dilation and hypertrophy frequently occur, along with varying degrees of pulmonary hypertension. The size of the interatrial communication with TAPVC plays a critical role. With worsening restriction to flow across the atrial septum, there is not only a dramatic increase in pulmonary overcirculation (and worsening pulmonary hypertension) but diminished systemic output. Similarly, with extrinsic or intrinsic obstruction to pulmonary venous flow, the cascade of pulmonary vascular changes discussed may occur. Infants with obstructed TAPVC typically present in the first weeks of life, with a rapid and fulminant progression of dyspnea to cardiorespiratory failure [34]. Any detailed assessment of the pulmonary venous connections and drainage must by necessity include an assessment of the systemic venous anatomy, right and left atria, and atrial septum. These structures are imaged from multiple acoustic windows, including the subxiphoid, apical, left parasternal, high right parasternal, and suprasternal notch. Two‐ and three‐dimensional imaging along with careful color and spectral Doppler techniques are used to render complete imaging of these structures. As the majority of pulmonary venous anomalies are diagnosed in infants and children, transthoracic echocardiography is the preferred modality and can yield a diagnosis in the vast majority of cases. However, transesophageal echocardiography (TEE) may be a helpful adjunct diagnostic modality in the older patient with poor transthoracic acoustic windows. Cardiac magnetic resonance imaging or cardiac computed tomography (CT) are excellent alternative imaging modalities for delineation of both systemic and pulmonary venous anatomy in those in whom a complete diagnosis cannot be obtained with echocardiographic techniques [35,36]. The subxiphoid window is ideal for the evaluation of pulmonary veins in infants and young children. The parasternal, subclavicular, and suprasternal windows are more useful in older patients; the right parasternal and subxiphoid windows can often provide better imaging of the connection of the right upper pulmonary vein than the left parasternal view. In both long‐ and short‐axis subxiphoid views the right upper pulmonary vein can be imaged entering the left atrium superiorly and just posterior to the right superior vena cava. The suprasternal notch view is particularly helpful in infants, where the so‐called “crab view” can frequently demonstrate the drainage of all four pulmonary veins (Figure 10.5). TEE can be helpful in patients with suboptimal transthoracic acoustic windows. The typical acoustic views for establishing this diagnosis are the subxiphoid, apical, and high parasternal short‐axis views, all of which can demonstrate the site of connection of the pulmonary veins to the posterior aspect of the anatomic left atrium, as well as establish the plane of septum primum and demonstrate any attachments to the wall of the left atrium (Figure 10.6). In older patients, a low parasternal short‐axis window (Figure 10.7, Video 10.1) is frequently the most helpful, as the views from the subxiphoid and suprasternal notch are typically not adequate to demonstrate the position of the septum primum. In addition to 2D imaging, color Doppler is critical in demonstrating the anomalous drainage toward the anatomic right atrium. Due to the absence of septum secundum encountered in patients with polyspenia syndrome, establishing the landmarks of the anatomic left atrium is important to distinguish this entity from “ipsilateral” pulmonary veins, in which true anomalous connection of the right pulmonary veins occurs to the anatomic right of the right horn of the sinus venosus. Pulsed‐ and continuous‐wave spectral Doppler may be helpful in demonstrating any restriction to flow of the anomalously draining pulmonary veins due to restricting attachments of septum primum, although this is rarely encountered clinically. Figure 10.5 Normal pulmonary venous connection. Suprasternal notch view of the pulmonary veins and left atrium with 2D imaging (a) and color Doppler flow mapping (b) showing the “crab” view. Two left and two right pulmonary veins drain normally into the left atrium – the “legs” of the crab; the right superior vena cava and left atrial appendage are the “claws.” Figure 10.6 Anomalous pulmonary venous drainage. (a) Partial: subxiphoid long‐axis image in this patient with mild leftward malposition of the septum primum (SP) demonstrates flow from the normally connecting right pulmonary veins (RPV) into the right atrium (RA). (b) Total: apical 2D image in this patient with severe leftward malposition of the septum primum shows the lack of septum secundum superiorly, normal pulmonary venous connections to the posterior aspect of the left atrium, and leftward malposition of SP resulting in total anomalous pulmonary venous drainage. LA, left atrium; PV, pulmonary veins; RV, right ventricle. Figure 10.7 Total anomalous pulmonary venous drainage. Parasternal short‐axis image with 2D imaging (a) and color Doppler flow mapping (b)
CHAPTER 10
Pulmonary Venous Anomalies
Definition
Incidence
Etiology
Morphology and classification
Developmental considerations
Anatomy
Abnormal numbers of pulmonary veins
Normal pulmonary venous connections with anomalous drainage
Sinus venosus defect
Stenotic connections
Cor triatriatum sinister
Atresia of the common pulmonary vein
Partial anomalous pulmonary venous connection
Total anomalous pulmonary venous connection
Pathophysiology
Imaging
Imaging of abnormal number of pulmonary veins
Imaging of normal pulmonary vein connections with anomalous drainage
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