Congenital Vascular Syndromes

What every physician needs to know about congenital pulmonary vascular syndromes

Pulmonary vascular syndromes are most easily divided into pulmonary artery disease and pulmonary vein disease. Arterial diseases include supravalvular pulmonary stenosis, peripheral pulmonary artery stenosis, pulmonary artery sling and pulmonary artery agenesis/hypogenesis. These pulmonary artery diseases may also be related to congenital heart disease such as pulmonary valve stenosis, pulmonary valve atresia, subvalvular pulmonary stenosis or Tetralogy of Fallot.

Pulmonary vein disease can include pulmonary vein stenosis, total anomalous pulmonary venous return and partial anomalous pulmonary venous return. Diseases of the pulmonary veins may also be related to or confused with left sided cardiac disease, such as mitral valve stenosis.

A pulmonary artery sling is rare and develops when the left pulmonary artery derives from the right pulmonary artery and passes between the trachea and esophagus, causing compression of these structures. It typically presents in childhood but may present in adulthood. Hypoplasia, agenesis or stenosis of a pulmonary artery at the supravalvular level will obstruct blood flow partially, or totally, to the affected lung. Symptomatic adults present with clinical features similar to pulmonary hypertension or chronic pulmonary thromboembolic disease.

Both pulmonary arterial and pulmonary venous disease can ultimately result in increased right ventricular pressure strain and ultimately right ventricular failure if intervention is not pursued. The most important difference between pulmonary arterial disease and pulmonary venous disease is the presence of the pulmonary capillary bed that separates the vessels. Downstream pressures affect upstream pressures. When pulmonary venous disease is present, pulmonary capillary pressure is significantly elevated. This results in an increase in the hydrostatic forces in the pulmonary bed and leads to pulmonary edema and its associated consequences.

Classification of congenital pulmonary vascular syndromes

Separating pulmonary vascular diseases into arterial disease and venous diseases results in the following:

Pulmonary Artery Diseases:

1. Pulmonary valve stenosis or atresia

2. Pulmonary valve insufficiency

3. Supravalvular main pulmonary artery stenosis

4. Branch pulmonary artery stenosis

5. Pulmonary artery agenesis or hypogenesis

6. Pulmonary artery sling

Pulmonary Vein Disease:

1. Pulmonary Vein Stenosis

a. Isolated pulmonary vein stenosis

b. Multiple pulmonary vein stenosis

2. Total anomalous pulmonary venous return

a. Supracardiac

b. Intracardiac

c. Infracardiac

d. Mixed

3. Partial anomalous pulmonary venous return

Are you sure your patient has a congenital pulmonary vascular anomaly? What should you expect to find?

Patients with pulmonary artery slings typically present in childhood with symptoms related to compression of the trachea and/or esophagus. Children with tracheal compression develop varying degrees of stridor, cough, shortness of breath or wheezing. It can also be associated with coexisting central and acquired airway anomalies including complete tracheal rings, right upper lobe tracheal bronchus and tracheobronchomalacia. These abnormalities produce additional respiratory symptoms which can stimulate recurrent bronchitis, recurrent pneumonia, aspiration and tracheoesophageal fistula. In adulthood, patients present usually after an incidental finding on radiographic studies, requiring further evaluation by CT or MRI.

Patients with agenesis, hypogenesis or stenosis of the pulmonary artery may present with respiratory and cardiac symptoms related to decreased blood flow to the lungs and right ventricular hypertrophy as well as tricuspid regurgitation due to pulmonary hypertension and right heart failure. If this is isolated, it should be differentiated from other conditions associated with stenosis, which include congenital rubella, Williams syndrome, Noonan syndrome, Alagille syndrome, Ehlers-Danlos syndrome, LEOPARD syndrome and cutis laxa.

Pulmonary artery disease is usually obstructive (with the exception of pulmonary valve insufficiency). For obstructive disease, there is right heart pressure overload and ultimately right heart failure. Symptoms can include swelling, abdominal distention, nausea, vomiting and decreased appetite. Clinically, patients may show elevated jugular venous pulsations, a significant hepatojugular reflex, right ventricular heave, S3 or S4 gallop, a systolic ejection murmur that will either radiate to the back (for pulmonary valve or main pulmonary artery disease) or the axillae (for branch pulmonary artery disease), abdominal distention, dependent edema. Patients are usually not cyanotic as the blood that is able to traverse the lungs is usually fully saturated. Most forms of pulmonary artery disease present in young children, often with a murmur appreciated by their primary care provider.

Pulmonary vein disease is usually much more significant that pulmonary artery disease. TAPVR without obstruction will show mild cyanosis due to systemic venous blood return mixing with the pulmonary venous return and then shunting right to left through the atrial communication. TAPVR with obstruction as well pulmonary venous stenosis involving all pulmonary veins will present with symptoms and signs consistent with pulmonary edema, including cyanosis, tachypnea, orthopnea and cough. Many infants with obstructed TAPVR present in extremis.

Both pulmonary arterial and pulmonary venous obstruction can ultimately result in right heart failure. In right heart failure, the right ventricle is not capable of delivering the necessary cardiac output to the lungs and back to the systemic (left side) circulation. Initially, the right ventricle will dilate to result in an increase in the contractile force (Frank-Starling mechanism). However, ultimately further increases in RV dilation (i.e. stretch) do not result in an increased contractile force. A vicious cycle ensues with increased ventricular dilation, filling pressures but a decreased ability to expel the blood from the RV. Ultimately, these increased filling pressures are transmitted back to the systemic venous circulation resulting in edema, abdominal distention, hepatic congestion, nausea, vomiting, and decreased appetite.

While right heart failure is the ultimate outcome of severe pulmonary arterial disease without intervention, there are typically more subtle signs and symptoms of obstructive pulmonary artery disease. Often in children the first sign of pulmonary arterial disease is a murmur appreciated by a primary care provider. The murmur is typically harsher than that of a pulmonary flow murmur, however, it is often not as intense as an aortic or LV outflow murmur. Pulmonary valve disease may result in a decreased or absent P2 component of S2. Distal arterial obstruction may cause P2 to be accentuated, and in severe cases S2 may be single.

As discussed above, pulmonary venous anomalies often result in pulmonary edema, particularly when all pulmonary veins are involved. Infants with severe obstruction may present in extremis immediately following delivery. This is because during fetal life the pulmonary circulation is almost entirely bypassed via the foramen ovale at the atrial level and the ductus arteriosus at the arterial level. Respiratory distress including hypoxia, tachypnea, diaphoresis and increased work of breathing is often present. Due to the relatively small volume of airways, in comparison to adults and older children, rales are often not appreciated. Pulmonary venous disease detected in the newborn such as obstructed TAPVR or pulmonary vein stenosis often requires immediate intervention, and even with this outcomes remain poor.

Beware: there are other diseases that can mimic disease congenital pulmonary vascular anomalies

Because many pulmonary vascular malformations present with cyanosis (either mild or severe), other causes of cyanosis must also be considered in the differential diagnosis. This is most commonly congenital heart disease with right to left shunts. Some forms of congenital heart disease are associated with pulmonary vascular anomalies. For example, Tetralogy of Fallot may have subvalvular, valvular and supravalvular stenosis. In its most severe form, there is atresia of the pulmonary valve. This can result in ductal dependent pulmonary circulation in many cases. However, other cases may have multiple vessels from the aorta the supply blood flow to the pulmonary capillary bed. These vessels, called major (or multiple) aorto-pulmonary collateral arteries (MAPCAs) may need to be incorporated together in order for a complete repair to occur. Other forms of cyanotic heart disease that may mimic pulmonary arterial anomalies include tricuspid atresia, Ebstein’s anomaly, d-transposition of the great arteries and truncus arteriosus.

Pulmonary arterial congenital abnormalities decrease blood flow to the lung and increase right ventricular afterload. Patient’s develop right ventricular strain and similar conditions associated with pulmonary hypertension including acute and chronic pulmonary thromboembolic disease, idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with primary underlying conditions such as collagen vascular disease, valvular heart disease, left ventricular failure, pulmonary venoocclusive disease, vasculitis, mediastinal fibrosis and congenital heart disease.

Although most serious pulmonary arterial anomalies result from stenosis, dilation can also occur. Occasionally there is post-stenotic dilation of the pulmonary arteries. This likely occurs due to a high velocity jet that is directed against the vessel wall. Ultimately the wall will weaken and dilate. This can also occur because of a large volume load on the pulmonary arteries with severe pulmonary valve insufficiency. Perhaps the most severe cases occur with Tetralogy of Fallot with absent pulmonary valve. In these cases, the branch pulmonary arteries are quite dilated and usually require plication at the time of corrective surgery. With the dilation of the pulmonary arteries, the bronchi may also become compressed, leading to severe bronchomalacia. This group of patients not uncommonly requires positive pressure support for an extended period both before and after repair.

In addition, supravalvular pulmonary stenosis and branch pulmonary stenosis often present with a systolic heart murmur; other diseases with systolic murmurs should be in the differential diagnosis. This can include a large ASD, aortic stenosis, tricuspid regurgitation and mitral regurgitation.

Pulmonary venous disease is most commonly confused with obstructive left sided heart disease. Downstream pressures will result in the need for higher upstream pressures. Because the main symptoms of pulmonary venous disease are due to pulmonary edema from increased hydrostatic pressures in the pulmonary capillary bed, any disease that results in an increase in those hydrostatic forces will mimic obstructed pulmonary venous disease. This will include all diseases that increase the left atrial pressure. Left sided obstructive lesions are one such group. Mitral stenosis causes a direct increase in LA pressure. However, other left sided obstructions such as aortic stenosis and coarctation of the aorta can eventually result in increased left ventricular filling pressures due to the same Frank-Starling mechanism discussed above for right ventricular failure. However, when there is left heart failure the elevated pressures are transmitted back to the left atrium and pulmonary capillary bed. In addition, other causes of left heart failure, such as the cardiomyopathies will result in increased filing pressures and pulmonary capillary congestion.

TAPVR can be confused with other forms of cyanotic congenital heart disease, including transposition of the great vessels, Tetralogy of Fallot, tricuspid atresia, and truncus arteriosus. Obstructed pulmonary veins, both with and without total anomalous return, is most likely to be confused with obstructive left heart lesions. This especially includes mitral stenosis, and restrictive LV physiology which results in elevated left ventricular filling pressures, left atrial pressures and ultimately in pulmonary edema.

How and/or why did the patient develop a congenital pulmonary vascular syndrome?

Pulmonary vascular anomalies are often multifactorial in nature, although several arterial anomalies have genetic or environmental causes. Pulmonary artery anomalies can result from William’s Syndrome, Noonan Syndrome, Alagille Syndrome and Ehlers-Danlos Syndrome. Environmental causes include congenital rubella infection. Genetic syndromes associated with pulmonary venous abnormalities include heterotaxy syndromes, and rarely Turner Syndrome and Noonan Syndrome.

Which individuals are of greatest risk of developing a congenital pulmonary vascular syndrome?

Because most pulmonary vascular anomalies are multifactorial in nature, it is very difficult to predict which patients (or offspring) are at an increased risk. The exceptions to this are the genetic syndromes which result in pulmonary vascular anomalies. These include William’s, Noonan’s and Alagille Syndromes, which are inherited in an autosomal dominant fashion (although many cases are new mutations). Ehlers-Danlos syndrome may or may not have vascular anomalies. For the subtype with vascular anomalies, the inheritance pattern is also usually autosomal dominant.

What Laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

There are no laboratory tests which are useful in making the diagnosis of a congenital pulmonary vascular syndrome. However, once a vascular anomaly is identified, further testing may be useful to assess for other sequelae. Electrolytes, calcium and kidney function need assessment with William’s Syndrome and liver function should be assessed in Alagille Syndrome.

Other conditions which mimic pulmonary artery anomalies such as vasculitis, thromboembolic disease and collagen vascular diseases should be ruled out by laboratory testing.

Although laboratory testing cannot confirm a diagnosis of a pulmonary vascular anomaly, there are several important laboratory tests that may be useful in prognosis and guiding therapy. In particular, arterial and mixed venous blood gases will help elucidate the acuity of the child. Persistent acidosis is a sign of severe cardiopulmonary failure and may indicate the need for intubation, inotropic therapy and/or extracorporeal membrane oxygenation. Brain natriuretic peptide (BNP) or N-terminal BNP may be a useful marker to follow in assessing the direct stress the heart is experiencing.

What imaging studies will be helpful in making or excluding the diagnosis of a congenital pulmonary vascular syndrome?

Congenital pulmonary arterial disease

On chest radiograph, patients with pulmonary artery agenesis, hypogenesis and severe stenosis will display a smaller than normal ipsilateral lung and hilum with elevation of the diaphragm and shifting of the mediastinum to the affected side. The contralateral lung is hyperinflated and herniation may be noted across the mediastinum to the smaller hemithorax, and is most common in the right lung.

Interruption of the left pulmonary artery is commonly associated with right aortic (Tetralogy of Fallot) or cardiac anomalies, which are evident on standard chest radiograph. Vascular densities, rib notching and pleural thickening may also be observed due to the extensive collateral vessels which perfuse the lung, from the bronchial arteries, intercostal arteries, internal mammary, subclavian and/or coronary arteries.

Chest radiograph may simulate a mediastinal mass in asymptomatic adults with pulmonary artery slings, but this is usually confirmed with chest CT or MRI. With regards to pulmonary artery proximal interruption, the affected lung remains as radiographically dense as the normal lung, which differentiates this from other conditions, such as Swyer-James syndrome or other hypogenetic lung syndromes.

Most patients with pulmonary artery slings present in infancy because of associated tracheobronchial and cardiac abnormalities, which may include coughing, wheezing, recurrent bronchitis and pneumonias. In patients with isolated pulmonary vascular slings, very few patients present as asymptomatic adults. Chest radiographs typically demonstrate a possible mediastinal mass, while a barium esophagram or upper GI may show indentation of the esophagus, requiring further evaluation with chest CT or MRI.

Electrocardiography may demonstrate varying degrees of right ventricular hypertrophy or unusual electrical axes due to shifting of the mediastinum in patients with pulmonary artery anomalies. Patients with anomalous pulmonary venous return with elevated right-sided cardiac pressures may show right ventricular hypertrophy, usually characterized in V3 and V2 with P waves which are typically tall and peaked.

Transthoracic echocardiography is typically the most important study in the assessment of pulmonary vascular disease. It is particularly useful in arterial disease. The pulmonary valve, main pulmonary arteries and proximal branch pulmonary arteries can usually be easily assessed. RV pressures and gradients through the stenotic sites can also be estimated, although caution should be used in interpreting the gradients in the stenotic sites as they are often overestimated.

Transesophageal echocardiography is typically not useful for pulmonary arterial disease. The pulmonary valve and proximal main pulmonary artery can usually be visualized, however, the branch pulmonary arteries are typically very difficult to visualize.

Computed tomography scanning provides clear imaging of pulmonary arteries to detect vascular anomalies, including supravalvular stenosis. The advantages over pulmonary angiography include the ability to image lung parenchyma, the airways, and the heart to detect associated abnormalities. CT scans can also demonstrate the mediastinal segment of a pulmonary artery that may be absent or terminate within 1 cm of its origin. Anastomoses with collateral vessels may also be found. Typically, the bronchial branching pattern and pulmonary venous drainage remained normal in appearance.

High-resolution two-dimensional and three-dimensional magnetic resonance imaging with various modalities with or without contrast and angiographic techniques are all comprehensive and can accurately define anatomy for diagnosis and treatment planning.

See Figure 1, Figure 2 and Figure 3.

Figure 1.

Figure 2.

Figure 3.

Congenital pulmonary venous disease

On chest radiograph, patients with total anomalous pulmonary venous drainage have cardiomegaly due to increased pulmonary vascular resistance and increased cardiac blood flow. Pulmonary veins may also appear large in the lung fields and close to the hilum.

In patients with partial anomalous pulmonary venous return, who drain anomalous veins through a vertical vein into the left brachiocephalic vein, this vertical vein simulates a left sided superior vena cava. Venous structures which drain into the innominate vein, combined with a persistent left superior vena cava, create a large supracardiac shadow that, combined with a normal cardiac shadow, produces a “snowman” appearance.

When the anomalous veins drain into the inferior vena cava, a “scimitar” sign appears, typically traversing along the right cardiac border in the right lower lung field. Patients with scimitar syndrome typically do not have an associated atrial septal defect, but have associated pulmonary sequestration and an anomalous arterial supply to the lobe affected by the sequestration. If these anomalous veins become obstructed, evidence of pulmonary congestion may appear on a chest radiograph.

Transthoracic echocardiography is also the initial study of choice in pulmonary venous disease. The pulmonary veins can usually be easily visualized with this modality. Mean gradients can also be estimated. In addition, left heart obstructive disease can be essentially ruled out with the use of transthoracic echocardiography.

Transesophageal echocardiography can be useful in the evaluation of pulmonary venous anomalies. The pulmonary veins return to the most posterior portion of the heart. The esophagus is located directly posterior to the usual pulmonary venous return. This can allow for better delineation of the specifics of the pulmonary venous drainage.

Chest CT and MRI provide clear imaging of pulmonary vasculature to detect abnormalities. Newer techniques including 3D reconstruction and airway dynamics can also evaluate the extent of possible airway malacia. MRI is also very good at evaluating the pulmonary vasculature without contrast but is not as optimal as chest CT in evaluating lung parenchyma.

See Figure 4, Figure 5 and Figure 6.

Figure 4.

Figure 5.

Figure 6.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of congenital pulmonary vascular syndrome?

To truly evaluate the extent of cardiopulmonary function, pulmonary function tests can be performed to evaluate significant airway obstruction or restriction. Lung volumes via body plethysmography can also be used to accurately define airway restriction. Other ways to examine cardiopulmonary function include cardiopulmonary exercise testing or six minute walk tests.

What diagnostic procedures will be helpful in making or excluding congenital pulmonary vascular syndrome?

Noninvasive studies often allow diagnosis of pulmonary artery anomalies in children, but to accurately evaluate anatomy and hemodynamics, cardiac catheterization is usually required. Cardiac catheterization is often performed for pulmonary arterial diseases as well as pulmonary venous disease. Catheterization allows for direct pressure measurements, angiographic assessment of obstruction and cardiac function, including estimates of cardiac output and oxygen content. Therapeutic cardiac catheterization can also be considered, particularly for supravalvular pulmonary stenosis and/or branch pulmonary artery stenosis. Therapeutic cardiac catheterization may also be used in pulmonary venous disease, although it is in general more difficult to access the pulmonary veins than the pulmonary arteries. The pulmonary veins are typically accessed via an atrial level communication.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of congenital pulmonary vascular syndromes?

Genetic testing can be performed if there is concern the patient has a genetic syndrome. Potential genetic syndromes associated with pulmonary vascular syndromes, include the following:

William’s Syndrome – Assessment for ELN gene deletion on chromosome 7q11.23

Noonan Syndrome – Assessment for PTPN11 gene mutation on chromosome 12q224.13

Alagille Syndrome – Assessment for JAG1 gene mutation on chromosome 20p12, or NOTCH2 mutation on chromosome 1p12

Ehlers – Danlos Syndrome – Assessment for COL3A1 gene mutation on chromosome 2q32.2

Turner Syndrome – Assessment for single X chromosome

Occasionally lung biopsy may be helpful in assessing for pulmonary vascular disease that may develop due to pulmonary venous obstruction. However, this procedure is not without risk, and generally is not necessary when there are known pulmonary venous anomalies.

If you decide the patient has a congenital pulmonary vascular anomaly, how should they be managed?

Infants with pulmonary arterial slings undergo surgical resection early, which may be complicated by coexisting cardiac and tracheobronchial anomalies. Asymptomatic adults with slings noted on radiographs as incidental findings do not need surgical repair.

For adults with a supravalvular pulmonary stenosis, various surgical procedures with patch techniques are available. Balloon angioplasty may provide a short-term decrease in right ventricular hypertension and relieve symptoms of dyspnea and fatigue. Some centers perform stenting for pulmonary artery stenosis. Various vascular surgical reconstruction and conduit placement procedures are also performed in selected patients. Adults with central pulmonary artery hypoplasia and patients with supravalvular pulmonary stenosis in association with other cardiac anomalies may require careful assessment for management by an expert in congenital heart disease. Patients who do not respond to angioplasty may be considered for organ transplantation.

For the infant with a pulmonary arterial anomaly, the most important initial step is to ensure they are receiving adequate blood flow to the lungs. Inadequate pulmonary blood flow in the neonate will result in increasing cyanosis as blood will shunt right to left at the atrial level with a return to the pulmonary circulation. If inadequate pulmonary blood flow is present, prostaglandin E2 (Alprostadil) should be initiated to maintain patency of the ductus arterious. If pulmonary blood flow remains suboptimal even after the pulmonary vascular resistance has fallen, then surgery to ensure adequate blood flow is often undertaken. This may be a complete repair of the lesion, but may also be a systemic to pulmonary shunt, such as a modified Blalock-Taussig-Thomas shunt that connects a subclavian artery to a pulmonary artery.

Partial anomalous pulmonary venous return and non-obstructed total anomalous pulmonary venous return do not require emergent correction. Unobstructed TAPVR may be corrected in the neonatal period, but some centers will wait 1-2 months prior to repair. PAPVR repair often takes place even later in childhood. These patients should be followed by a pediatric cardiologist at regular intervals. PAPVR results in “ASD physiology” and thus a volume overload to the pulmonary vasculature. This volume overload must be corrected, but is not as urgent as a pressure overload in terms of causing permanent pulmonary vascular disease.

Obstructed TAPVR requires emergent surgical intervention. Once the diagnosis is established, immediate surgical correction is necessary to prevent or limit arterialization of the pulmonary veins. Occasionally, patients with obstructed TAPVR will be placed on ECMO so surgical planning can be completed.

What is the prognosis for patients managed in the recommended ways?

There are a number of aspects that determine a patient’s prognosis with a congenital pulmonary vascular syndrome. In general, patients with pulmonary valve stenosis or insufficiency and isolated supravalvular pulmonary stenosis should have an overall excellent outcome with normal activity tolerance and lifespan, in addition to limited to no medications. Branch pulmonary artery stenosis outcomes are variable. Isolated stenotic lesions can usually be managed surgically or with interventional cardiac catheterization. However, many patients, particularly those with syndromes, may require frequent interventions.

Adults with pulmonary artery anomalies may be asymptomatic if supravalvular stenosis is minimal, but present with the dyspnea and evidence of pulmonary hypertension, if the stenosis is severe or progressive. Adults with pulmonary artery hypogenesis or agenesis may be asymptomatic and do not require therapy. For symptomatic patients with pulmonary artery stenosis, balloon angioplasty may produce symptomatic benefit, which is typically transient, eventually requiring other interventions. Surgical patch techniques usually provide good outcomes, although reoperation may be necessary, especially for patients who have associated pulmonary valvular stenosis.

Pulmonary venous disease has a mixed prognosis. For disease that was initially non-obstructive, the expected outcome is excellent and may not require any additional medications or procedures beyond the initial operation. However, in cases of venous obstruction, recurrent obstruction and pulmonary hypertension are not infrequent. Pulmonary vasodilators such as phosphodiesterase 5 inhibitors, endothelin antagonists and prostacyclin derivatives may be of benefit, in addition to recurrent interventional cardiac catheterization and/or surgery. Children who require surgery for scimitar syndrome have a higher rate of postoperative pulmonary venous obstruction and abnormally diminished perfusion of the right lung.

Outcomes are also very dependent on the presence or absence of a genetic cause, and whether there are other associated abnormalities, such as aortic disease with William’s syndrome or liver disease with Alagille syndrome.

What other considerations exist for patients with congenital pulmonary vascular abnormalities?

Patients with congenital pulmonary vascular abnormalities remain at risk for endovascular infections. Patients with pulmonary artery abnormalities with extensive collateral vessel formation may develop hemoptysis if collateral vessels rupture. Patients with anomalous pulmonary venous return may develop dyspnea and hypoxemia if stools become thrombosed. During critical illness, patients may undergo placement of a central venous catheter, which may traverse the upper and pulmonary veins, thereby confusing interpretation of data and risking vascular thrombosis.

Patients with a genetic cause for her pulmonary vascular abnormalities, may require family and genetic counseling.

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This article originally appeared on Pulmonology Advisor