As mentioned above, the clinical presentation is contingent upon the degree of pulmonary obstruction, the presence of a VSD, and the relationship of the great arteries.

Patients with pulmonary obstruction

Patients often present with cyanosis in the newborn period, especially after the ductus closes. On physical examination TA with pulmonary oligemia would show central cyanosis, there would be normal pulses, and there may be a diminution of the right ventricular impulse. There may be a thrill present in the context of a restrictive VSD or severe PS. The presence of a holosystolic murmur in the left lower sternal border would suggest a VSD, while occasionally, the continuous murmur of the PDA may be auscultated. Additionally, a systolic ejection murmur may be heard at the left upper sternal border correlating with pulmonary stenosis. Clubbing may occur in older patients with unrepaired TA with chronic cyanosis.

Patients without pulmonary obstruction

Patients with a VSD and no pulmonary stenosis would have large pulmonary blood flow. These patients could be missed at birth as they are not cyanotic and may be discovered when pulmonary vascular resistance drops, and they exhibit pulmonary over circulation. This condition manifests with signs and symptoms of heart failure, with tachypnea or respiratory distress, poor feeding, and growth. In patients with pulmonary plethora, a physical examination would be significant for tachypnea, tachycardia, and hepatomegaly.[8]

In the era of enhanced antenatal ultrasound and fetal echocardiogram programs, the majority of these patients are diagnosed antenatally in the United States of America. The mean gestational age at diagnosis is approximately 22 weeks gestation, although the diagnosis is possible as early as 11 weeks.[9][10][11][12][13] A recent large multicenter study showed that the prevalence of prenatally diagnosed TA was between 0.2 to 0.9 per 10000, with an increasing proportion of cases diagnosed over time.[14]

Clinicians may pick up on patients not diagnosed antenatally at the time of critical congenital heart disease (CCHD) screening with hypoxemia or the presence of a heart murmur. Chest X-ray (CXR) may show decreased pulmonary vascular markings, which would signify pulmonary oligemia. The right heart border may also be prominent signifying right atrial dilation. The electrocardiogram (ECG) in this lesion is notable for a left superior axis (QRS axis -30 to -90), which a very characteristic finding. The right ventricular forces become diminished, and there may be evidence of left ventricular hypertrophy.[15] Echocardiography is diagnostic in TA. Two-dimensional echocardiography would show an absence of the TV and discordant sizes of the ventricular cavity with the left ventricle being larger than the right. Color flow Doppler would show absent flow across the tricuspid valve. Cardiac catheterization is not usually necessary for diagnostic purposes. However, when the atrial septum communication is restrictive and does not allow adequate blood flow from the right atrium to the left atrium, a balloon atrial septostomy by cardiac catheterization may be necessary. Genetic testing could be considered in this disease as there have been associations with trisomies, VACTERL, and 22q11.[16][17][10]

Initial management surrounds the stabilization of the patient. The initiation of prostaglandin soon after birth is imperative in cyanotic patients who have severe or critical pulmonary stenosis, or a very small VSD, with a ductal-dependent pulmonary blood supply. The patient who presents later on in infancy in heart failure with pulmonary over-circulation needs to be treated medically with diuretics.

Because there is only one functional ventricle (the left ventricle), all patients with TA undergo staged single ventricle palliation to provide adequate pulmonary and systemic blood flow and eventual separation of these circulatory systems. The choice of surgery for the first stage of palliation varies based on the anatomy of the great vessels, presence or absence of outflow tract obstruction and size of the VSD if present.

Patients with pulmonary obstruction

In patients with pulmonary obstruction, the first stage involves providing adequate pulmonary blood flow, via a systemic to pulmonary artery shunt, usually via a modified Blalock-Taussig (BT) shunt, also known as a Blalock-Taussig-Thomas (BTT) shunt. This provision is typically a connection utilizing a polytetrafluoroethylene tubular graft between the right subclavian and the right pulmonary artery.

Patients without pulmonary obstruction

In patients with unobstructed pulmonary blood flow (type Ic), the first stage may be the placement of a pulmonary artery (PA) band that may limit excessive blood flow to pulmonary vascular bed. In a small subset of patients, the VSD may be small enough to restrict the amount of pulmonary blood flow. These patients have a balanced circulation and, therefore, do not need pulmonary artery banding. Those patients go to the second stage of palliation, as described below.

Patients with D-TGA and subaortic obstruction

In patients with type II lesions who have a VSD that obstructs aortic blood flow, the first stage could be enlargement of the VSD or a Damus-Kaye-Stansel (anastomosis between the main pulmonary artery and ascending aorta) with a modified BT shunt.

Second and third stages

The second stage for type I and II lesions involves cavo-pulmonary anastomosis wherein the superior vena cava connects to the right pulmonary artery, the bidirectional Glenn or hemi-Fontan procedure. This change results in a passive flow of blood from the upper body into the pulmonary vessels. This surgery usually takes place at around six months.

The third stage is the Fontan procedure, first described in 1971 for TA.[18] The original Fontan involved end to end anastomosis of right atrial appendage to the proximal end of the right pulmonary artery. This procedure has undergone considerable modification since its inception. In the current era, it involves either an extra-cardiac or intra-atrial non-valved conduit between the inferior vena cava and the pulmonary arteries. This conduit may be fenestrated. The fenestration is performed as a means of providing a “pop-off” valve as the lungs adjust to the extra blood flow from the lower body.[19] The Fontan results in the total systemic venous return flowing passively into the pulmonary vessels and is usually performed at 2 to 3 years. Patients with progressive ventricular dysfunction may eventually require heart transplantation.[20]

The differentials for this disease include other lesions with cyanosis and decreased pulmonary blood flow, including isolated pulmonary atresia and tetralogy of Fallot.

• Atrial septal defect
• Pulmonic stenosis
• Pulmonary atresia
• Tricuspid stenosis
• Tetralogy of Fallot

The majority of patients who are unoperated die in the first year of life.[21] In the current era of earlier diagnosis and effective surgical treatment, most patients with TA live well into adulthood and have a good functional capacity. Operative mortality with the Fontan procedure is below 2%. A study by Sittiwangkul in 2004 is the most extensive study looking at outcomes of patients specifically with TA (between 1971 and 1999), reporting survival rates at 1, 5, and 20 years of 82%, 72%, and 61%, respectively.[22] The surgical outcomes have improved considerably over time with modifications of surgical techniques and innovation in the management of these patients. A more recent study by Mery et al. looking at outcomes of patients with the Fontan procedure done for various pathologies (including TA) showed transplant-free survival at 15 years was 92%, and freedom from a failure of the Fontan was 87%.[23]

There are numerous short and long term complications associated with each stage of palliation. The highest rate of interstage mortality is between the first and second stages of surgical palliation for single ventricles.  Patients who have undergone BT shunts are at risk for a variety of complications, including shunt obstruction. The mortality rate among patients who have undergone a modified BT shunt in the current era is still high. A recent study looking at outcomes in patients after BT shunt showed that in-hospital mortality after a modified BT shunt was 12%, with an additional 6% interval mortality. BT shunt thrombosis and or stenosis occurred in 20% of patients. Non-cardiac complications such as necrotizing enterocolitis and cerebral vascular accident are not insignificant occurrences after BT shunts.[24] Currently, most programs performing single ventricle palliation have home monitoring programs for shunted patients. These programs have been successful in improving outcomes for these patients.[25]

Complications encountered after PA band placement include migration of band. The band may be too lose requiring re-intervention. Additionally, research has described pulmonary artery stenosis or distortion of the pulmonary artery. A recent study showed that the use of bilateral PA bands, especially those with smaller diameter bands and longer band placement, requires a significant number of pulmonary arterial interventions.[26]

The Glenn surgery has excellent short and long term outcomes with operative mortality less than 1% and 5-year survival of 87%.[27] Long term complications are not common after this surgery, but thrombosis and thromboembolic events carry the highest mortality.[28]

There are myriad long-term complications associated following the Fontan. Such complications include arrhythmias, ventricular dysfunction, cyanosis, and protein-losing enteropathy.

Systolic and diastolic ventricular dysfunction is known to be a long term complication of single ventricle palliation. In the neonatal period after the BT shunt, the single effective ventricle is exposed to increased volume load, potentially leading to valvular regurgitation, which causes increased hemodynamic stress on the myocardium. The myocardium is also subject to chronic hypoxia in the context of intracardiac mixing. Following the Fontan, the ventricle goes from being volume overloaded to volume-depleted. This status can lead to acute systolic and diastolic dysfunction in the short term. However, shifting volume load and ventricular mass ratios may also have a long term impact on ventricular mechanics.[29] Systolic ventricular dysfunction is an independent risk factor for chronic Fontan failure.[23] Patients with failed Fontan circulation could end up requiring transplantation.[30][20]

Arrhythmia is not uncommon after the Fontan. They are mostly atrial tachycardias, which result due to suture lines placed in the right atrium. These suture lines may interfere with atrial conduction. The incidence of this complication has decreased with the extracardiac modification of this surgery.[31][23] Ventricular tachyarrhythmias have been described in these patients, but are much less common than atrial arrhythmias.

Thromboembolism can present in these patients. The overall prevalence of thromboembolism is around 11% and may occur in the Fontan conduit, right atrium, lungs (pulmonary embolism), or brain (stroke-systemic arterial emboli.) The risk of thromboembolism increases with the presence of an atriopulmonary connection or atrial arrhythmias.[32] There is an ongoing debate regarding the use of antiplatelet therapy versus anticoagulation to prevent this risk. Data has shown that the rate of thromboembolic and bleeding events associated with antiplatelet therapy is comparable to that associated with anticoagulation therapy.[33] The recent American Heart Association guidelines suggest that it is reasonable for all patients with Fontan circulation to receive antiplatelet therapy. Anticoagulation should only be for those with presumed risk factors, such as arrhythmias or previous thrombosis.[34] Newer direct oral anticoagulants are currently under research in pediatric cardiac populations. They are likely to be an attractive alternative to warfarin in the future.

Protein-losing enteropathy (PLE) is a well-described complication caused by lymphatic congestion, which can lead to spillage of lymph-rich material into the low-pressure intestinal tract. It occurs in 5% to 12% of patients after Fontan.[35] Longstanding PLE can affect the nutritional status of the patient. The mainstay of treatment for PLE is supportive. This treatment includes decreasing fluid overload with diuretic therapy, replacing albumin, replacing immunoglobulin and high protein, low-fat diet. Enteral corticosteroid use has demonstrated maintainance albumin levels and decrease symptoms.[34] Plastic bronchitis is another possible long term sequelae in patients with Fontan circulation. Thick secretions in the airway lumen characterize it. It occurs in around 4% of patients and is believed to be caused by spillage of proteinaceous lymph through lymphatic-bronchial communications.[36] There is variability in the lymphatic anatomy, which possibly explains why only some patients with similar degrees of venous hypertension develop PLE or plastic bronchitis, and others do not.

Patients with the Fontan procedure may have cyanosis for a variety of reasons. There may be some degree of right to left shunting across the fenestration in a Fontan. Systemic venous and pulmonary venous collaterals may develop, resulting in right-to-left shunting from the Fontan pathway to the atrium. Cyanosis may become exacerbated during exercise. Some patients may benefit from transcatheter fenestration closure or venovenous occlusion.[34]

 Other long-term complications experienced in TA include but are not limited to:

• Fontan associated liver disease (liver fibrosis and cirrhosis)
• Renal dysfunction
• Somatic growth problems
• Psychosocial and neurodevelopmental issues
• Decreased exercise tolerance

Patients with TA require regular and lifelong follow up with a cardiologist trained in congenital heart disease such as a pediatric cardiologist or adult congenital heart disease (ACHD) specialist. The frequency of follow up varies between stages of single ventricle palliation. Patients with the Fontan require at least yearly follow up.

History and physical examination are beneficial in predicting many of the complications described above. Mild jugular venous distension is common after cavo-pulmonary anastomosis, but marked jugular venous distension and or hepatomegaly should prompt further evaluation for Glenn or Fontan obstruction or systolic ventricular dysfunction of the heart. Edema and diarrhea may be present in the context of PLE. A history of palpitations should prompt further evaluation for arrhythmias. Respiratory distress may occur in the context of heart failure, and a history of thick airway secretions may suggest the presence of plastic bronchitis. We emphasize the need for a thorough history and physical examination on follow up visits in these patients.

In addition to clinical assessment on yearly follow up, ECG and transthoracic echocardiogram is necessary. A more extensive cardiovascular and extracardiac organ system surveillance should be performed every 3 to 4 years to monitor for the complications outlined above. The extensive cardiovascular system surveillance may include Holter 24-hour monitor, exercise stress test, pro-brain natriuretic peptide, cardiac magnetic resonance imaging, computed tomography angiography, and cardiac catheterization. Organ system surveillance includes monitoring organ function through blood tests and extra-cardiac imaging.[34][37]

Patients with surgically corrected TA can survive into childbearing age. There is growing experience with pregnancy in patients with the Fontan circulation. Nonetheless, these would be deemed high-risk pregnancies with increased risks for arrhythmias, heart failure, and thromboembolic complications. Counseling of these patients should take into account overall cardiovascular health and the status of noncardiac organ systems. These patients require joint management by an ACHD specialist and obstetrician specializing in high-risk pregnancies or maternal-fetal medicine specialist.[34][38]

• A high index of suspicion is necessary for TA in newborns with cyanosis and left axis deviation/left ventricular hypertrophy on ECG.
• Patients with TA have a single left ventricle (systemic ventricle), and hence, among the single ventricles have the best long term Fontan procedure outcomes.
• Among single ventricles, TA was the first type for which the Fontan palliation was performed in 1971.

An interprofessional team approach is imperative in the care of these patients. Patients with TA are usually cared for in a neonatal ICU (intensive care unit) preoperatively and postoperatively in a cardiac ICU. A collaborative approach between intensivists, cardiologists, and the surgeon is of paramount importance in ensuring good outcomes. Some of these patients have non-cardiac organ systems involved due to syndromes. Hence, consulting other pediatric sub-specialists becomes necessary. Nurses, respiratory therapists, perfusionists, nutritionists, and social workers are important parts of the comprehensive interprofessional medical team.[39] Critical care and neonatal nurses monitor patients, document status, and keep the rest of the team informed. [Level 5]

Upon discharge, these patients need to have a medical home and comprehensive care as their care is complex. A board-certified cardiology pharmacist should definitely have involvement in any anticoagulation vs. platelet-blocking debate, as well as performing medication reconciliation, verifying dosing of all drugs, and offering counsel to both patients, family, and team members. A good primary care provider is important to coordinate care and minimize the burden to the family.[40]) [Level 4]. Many studies are looking at neurodevelopmental outcomes in this cohort who are prone to delayed development, attention deficit hyperactivity disorder, and learning disorders.[41][42] [Level 3] Patients with TA are living longer and longer. With longer life expectancy, the ACHD specialist is crucial in caring for these patients and monitoring for long term complications. The 2018 Guidelines for the Management of adults with congenital heart disease emphasize the need for a smooth and effective transition of care from the pediatric cardiologist to ACHD specialists during late adolescence to early adulthood.[37] This collaborative interprofessional team paradigm will drive better outcomes. [Level 5]