Tetralogy of Fallot

Description

Tetralogy of Fallot was originally described as a combination of four abnormalities: ventricular septal defect (VSD), right ventricular outflow tract obstruction, overriding aorta and right ventricular hypertrophy. There is typically an anterior malalignement of the conal septum. The right ventricular hypertrophy is a consequence of the overriding aorta exposing the RV to systemic pressures, the large VSD equalizing pressure +/- RVOT obstruction. The VSD is a perimembranous defect. In some cases, TOF can be associated with complete atresia of the pulmonary valve (TOF-Pulmonary Atresia) or with coronary anomalies. The rare form of TOF with absent pulmonary valve is associated with an absent / rudimentary pulmonary annulus which is stenotic. Because of the free pulmonary insufficiency, there is progressive dilation (aneurysmal) of the pulmonary arteries, which may lead to severe obstruction of the airways. Some are associated with an absent ductus. 

More of Fetal TOF with absent pulmonary valve syndrome.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, occurring in approximately 1 in 3500 live births and accounting for 7–10% of all congenital heart disease cases. First described by Niels Stenson in 1671 and later thoroughly characterized by Etienne-Louis Arthur Fallot in 1888, TOF involves a specific association of cardiac malformations.

Defining Features and Morphology:

Historically, TOF was defined by four constant features: pulmonary stenosis, a ventricular septal defect (VSD), dextroposition (overriding) of the aorta, and right ventricular (RV) hypertrophy. However, from a physiological and anatomical perspective, the underlying issue is primarily a malalignment of the ventricular septum with the infundibular septum, specifically an antero-cephalad deviation of the infundibular septum. This deviation leads to the other characteristic features:

• Ventricular Septal Defect (VSD): There is a large, subaortic, and typically perimembranous VSD. This VSD is generally non-restrictive, meaning it's large enough to equalize systolic pressures between both ventricles. In some cases, the VSD can be "doubly committed" (to both aortic and pulmonary valves) due to an absent or deficient infundibular septum.

• Overriding Aorta: The aorta overrides the ventricular septum, meaning it is positioned over both the right and left ventricles. The degree of override is variable.

• Right Ventricular Outflow Tract (RVOT) Obstruction: This is a key component, varying greatly in severity and extent. The obstruction can occur at multiple levels:

  • Infundibular (subpulmonary) stenosis: This is the dominant lesion in most patients, caused by the malalignment of the outlet septum and hypertrophy of muscle bundles like the parietal and septal bands. The infundibulum can be hypoplastic or elongated.

  • Pulmonary valvar stenosis: The pulmonary valve annulus can be narrowed, and the valve itself can be thickened with adherent leaflets, producing varying degrees of obstruction. The valve may have one, two, or three cusps. Extreme forms may have pulmonary atresia. In these cases, there is often an absent ductus arteriosus and MAPCAs.

  • Pulmonary artery stenosis: Narrowing can also occur in the main pulmonary artery or at the origins of its branches (right and left pulmonary arteries). The main pulmonary artery is often small or hypoplastic compared to the aorta.

• Right Ventricular Hypertrophy (RVH): This develops secondary to the RVOT obstruction and the VSD, as the right ventricle works harder to pump blood against the obstruction. However, in neonates, RVH is a normal finding and thus not a distinguishing feature for diagnosis at birth. RVH can also be secondary to RV being exposed to the overriding aorta, exposing the RV to systemic afterload. A persistent positive T-wave in lead V1 beyond the first week of life should raise suspicion for right ventricular hypertrophy, and tetralogy of Fallot should be excluded.

Pathophysiology and Clinical Presentation:

The clinical presentation of TOF is highly variable, largely dependent on the severity of the RVOT obstruction and the VSD size/hemodynamic effects.

• Cyanosis: The hallmark symptom, resulting from a right-to-left shunt across the VSD, where deoxygenated blood from the right ventricle flows into the systemic circulation. Cyanosis can be constant or intermittent, appearing with exertion or crying.

• "Pink Tet": In cases with mild RVOT obstruction, a left-to-right shunt may predominate, and patients may not exhibit cyanosis at rest. These infants might present with symptoms of pulmonary "overcirculation" or congestive heart failure due to the ventricular septal defect (as well as sometimes contributor of a PDA). However, the RVOT obstruction can worsen over time, leading to eventual cyanosis.

• Hypoxic Spells ("Tet Spells"): These are acute, severe episodes of increased cyanosis, hyperpnea (rapid breathing), and irritability. See the section on TET spells below. 

• Heart Murmur: A loud systolic ejection murmur is typically heard at the mid and upper left sternal border, originating from the RVOT stenosis. The intensity and duration of the murmur can vary with the severity of obstruction. A loud, single second heart sound (S2) or a soft pulmonary component of S2 is characteristic.

Diagnosis:

• Clinical Suspicion: TOF should be suspected in a cyanotic infant with a stenotic murmur, a normal heart size on chest X-ray, clear lung fields, and signs of right ventricular overload.

• Echocardiography: Echocardiography is the primary diagnostic tool. Key features on echocardiogram include:

  • Visualization of a large VSD with the aorta overriding it in parasternal or subcostal long-axis views. Typically overriding less than 50%, otherwise we often will use the nomenclature of double outlet right ventricle with a TOF phenotype. 

  • Documentation of pulmonary valve specificities/diameter/gradient in parasternal or subcostal short-axis views.

  • Assessment of the RVOT, pulmonary valve, and main pulmonary artery in parasternal or subcostal short-axis views to localize obstruction sites and estimate pulmonary artery size.

  • Color flow Doppler helps visualize turbulent flow across the RVOT obstruction and bidirectional shunting across the VSD.

  • The presence of a right aortic arch (in about 25% of cases) can be suspected with counterclockwise transducer rotation in a suprasternal notch long-axis view.

• Other Investigations:

  • Electrocardiography (ECG): Usually shows right axis deviation and RVH, but without a strain pattern since RV pressure is not suprasystemic.

    1. In cyanotic TOF, right axis deviation (RAD) typically ranges from +120 to +150 degrees. In the acyanotic form of TOF, the QRS axis can be normal.

    2. In older children, peaked P waves may indicate right atrial enlargement. RAH is also occasionally present in TOF

    3. After corrective surgery for TOF, a long QRS duration, such as 190 milliseconds (ms), and a complete right bundle branch block (RBBB) can be seen.

  • Chest X-ray: Often reveals a normal heart size with decreased pulmonary vascular markings and a classic "boot-shaped" heart due to a hypoplastic main pulmonary artery segment and RV hypertrophy.

  • Cardiac Catheterization: While echocardiography is often sufficient for diagnosis, cardiac catheterization may be performed to assess specific anatomy like branch pulmonary stenosis or anomalous coronary arteries. This is specifically important when there is suspicion of MAPCAs, which can easily be missed by echocardiography. The precise MAPCAs configuration sometimes benefit from cardiac MRI/CT chest angiography. 

Associated Conditions:

TOF is one of the congenital heart diseases most frequently associated with extracardiac anomalies and genetic syndromes.

• Chromosome 22q11 deletion (DiGeorge syndrome): This microdeletion is found in about 15–35% of TOF patients. It is more prevalent in TOF with pulmonary atresia.

• Other Syndromes: Trisomies (21, 18, 13, 9), Velocardiofacial syndrome, Holt-Oram, Alagille, Cat eye syndrome, and various single gene mutations (e.g., TBX1, NKX2.5, GATA4).

• Cardiac Anomalies:

  • Right aortic arch: Present in about 25% of patients.

  • Atrial septal defect (ASD) or patent foramen ovale (PFO).

  • Complete atrioventricular septal defect (AVSD): Occurs in about 2% to 5% of patients, especially those with Down syndrome.

  • Anomalous coronary arteries: Important to identify pre-surgically, especially an anterior interventricular artery arising from the right coronary artery, which may cross the RVOT.

  • Patent Ductus Arteriosus (PDA): Can be present.

Embryological Considerations:

The exact embryological mechanisms are not fully understood. It is thought to involve disturbances in the development of the cardiac outflow tract, possibly related to abnormal rotation and separation of the bulbus cordis and truncus arteriosus, or inadequate development of the right ventricular conus. Recent evidence points to the role of the secondary (anterior) heart field, whose ablation in chick embryos has produced TOF-like features.

Management and Treatment:

• Medical Management: Limited for TOF. Propranolol may be used for hypercyanotic spells (see TET spells below). Prostaglandin E1 infusion is used in cases where pulmonary blood flow is ductus-dependent, such as in TOF with pulmonary atresia. However, some of these infants may not have a ductus, in which case PGE is not useful.

• "Pink TOF": in those with limited RVOT obstruction, these patients may be repaired later in life (3 to 6 months), but ongoing surveillance should occur as they may develop signs of congestive heart failure and require support in the community for ongoing growth, as well as consideration for earlier repair. 

• Surgical Repair: Primary repair is the preferred approach, typically performed electively between 3 to 6 months of age, or earlier if symptomatic. The goal is complete repair:

  • Closure of the VSD. Usually through the right atrium to minimize RV dysfunction.

  • Relief of RVOT obstruction: Involves right ventricular muscle bundle resection (infundibulotomy) and/or pulmonary valvotomy.

  • Pulmonary artery augmentation: May involve transannular patching to enlarge the pulmonary valve annulus and main/branch pulmonary arteries. Valve-sparing repair is attempted when possible.

• Palliative Procedures: For small or high-risk symptomatic neonates/infants, palliative strategies such as RVOT stenting, PDA stenting, or a Blalock-Taussig-Thomas (BTT) shunt may be used to improve pulmonary blood flow until complete repair can be safely performed. If the concern is excessive pulmonary blood flow due to the size of the VSD and prematurity - banding/diuresis could be considered. 

Prognosis and Long-Term Outlook:

The outcome for TOF is generally good with low surgical mortality and good long-term survival. However, reinterventions are common, primarily for issues related to the right ventricular outflow tract.

• Pulmonary Regurgitation (PR): A common long-term consequence, particularly after transannular patch repair, which can lead to RV dilatation and dysfunction, potentially requiring pulmonary valve replacement later in life.

• Residual RVOT Obstruction or Residual VSD: May necessitate reoperation or catheter intervention.

• Arrhythmias: Ventricular arrhythmias and sudden death are recognized long-term complications, often related to residual RVOT obstruction, significant PR, or RV dilatation.

• Aortic Dilatation: Long-term dilatation of the ascending aorta can occur.

Ductus arteriosus in TOF

In the context of Tetralogy of Fallot (TOF), an absent ductus arteriosus is typically observed in specific variants:

• Tetralogy of Fallot with Absent Pulmonary Valve Syndrome.

  • This condition is characterized by a hypoplastic pulmonary valve annulus and rudimentary leaflets leading to pulmonary stenosis and regurgitation, often with aneurysmal enlargement of the main and/or branch pulmonary arteries.

  • While the ductus arteriosus is typically absent in infants with this syndrome, a ligamentum arteriosum may be found, indicating that the ductus was present during fetal development.

  • The presence of a patent ductus arteriosus is variable in fetuses with this syndrome, although it is not infrequently observed. It has been suggested that pulmonary regurgitation in the fetus might contribute to the closure of the ductus.

• Tetralogy of Fallot with Pulmonary Atresia (TOF/PA) when Major Aortopulmonary Collateral Arteries (MAPCAs) are present.

  • In these cases, the arterial duct hardly ever coexists with MAPCAs, as the lungs are primarily supplied by these collateral arteries.

  • An extreme form of TOF with pulmonary atresia, sometimes referred to as Type IV truncus arteriosus or pseudotruncus, is characterized by the absence of any vestige of pulmonary arteries or their branches, with blood supply to the lungs derived entirely from MAPCAs. In such instances, the ductus arteriosus would consequently be absent.

Conversely, in many forms of TOF with pulmonary atresia, the circulation is dependent on the patency of the ductus arteriosus for pulmonary blood flow. In these situations, the ductus is present, although it may be narrow or poorly developed, or its closure may be delayed for days or weeks.

Qp/Qs < 1

• If the pulmonary stenosis is severe, total RV resistance increases and it leads to a right-to-left shunt across the VSD. 

  • Qp/Qs can be estimated by measuring aortic saturation (e.g., via pulse oximetry). 

  • If the cardiac output is normal, assuming a normal systemic A-V difference (oxygen consumption in the systemic compartment) of 30%,

  • Aortic Saturation - 30% = Mixed venous saturation will be Aortic Saturation - 30%

  • The Mixed venous saturation will be the same as the Pulmonary Artery saturation because there is no left to right enrichment in oxygen (the RA oxygen saturation will be the same as the RV oxygen saturation, which will be the same as the PA oxygen saturation). 

  • Pulmonary vein saturation is 100% if no V/Q mismatch 

  • As such, if aortic saturation is 85%: then Qp/Qs = (Aortic Sat - Mixed Venous Sat) / (Pulm Vein Sat - Pulmonary Artery Sat) = (85-55)/(100-55) = 30/45 = 2/3 (0.67). 

• Morphological Consequences: Reduced pulmonary blood flow means the pulmonary arteries receive insufficient blood and may grow poorly. This can influence the decision for surgical intervention, especially when saturation is too low to promote adequate pulmonary artery development.

Echocardiographic Assessment of Tetralogy of Fallot (TOF) and Variants (theoretical concepts):

1. Types of TOF

Typical TOF

• Defined by anterior malalignment of the conal septum, leading to:

  • Right ventricular outflow tract obstruction (RVOTO).

  • Large, unrestrictive ventricular septal defect (VSD).

  • Overriding aorta.

  • Right ventricular hypertrophy (RVH) (develops postnatally).

TOF with Pulmonary Atresia (TOF/PA)

• Spectrum of hypoplasia or atresia of the central pulmonary arteries.

• Aortopulmonary collaterals (APCs) are common:

  • Abnormal, tortuous vessels that connect the systemic and pulmonary circulations.

  • Can arise directly from the aorta or from primary/secondary branches above or below the diaphragm.

TOF with Absent Pulmonary Valve

• Unguarded right ventricular outflow causes:

  • Free pulmonary regurgitation (PR), leading to RV dilation.

  • Aneurysmal dilation of the main, right, and left pulmonary arteries (PAs).

  • Absent PDA in most cases.

• VSD characteristics:

  • Large, unrestrictive, subaortic, involving the membranous septum.

• Additional Features:

  • Anterior malalignment of the conal septum with infundibular hypoplasia, causing subpulmonary obstruction.

  • Variable degrees of right-sided obstruction, including pulmonary annular hypoplasia and valvular dysplasia.

  • Main and branch PA hypoplasia or discrete stenoses.

  • Right aortic arch (25%).

  • Coronary anomalies (5%): A large branch of the **right coronary artery (RCA) may supply the LAD territory and cross over the RVOT.

2. Pathophysiology of TOF and Variants

• Cyanosis due to right-to-left shunting at the VSD.

• If a PFO or ASD is present, an additional right-to-left shunt at the atrial level may occur if RV and RA pressures exceed LA pressure.

• Severity of cyanosis depends on the degree of RVOTO.

  • "Pink TOF": Minimal RVOTO → left-to-right VSD shunt → possible congestive symptoms.

  • TOF/PA: Pulmonary flow is entirely dependent on systemic-to-pulmonary connections (e.g., PDA, bronchial arteries, APCs).

  • TOF with absent pulmonary valve: Severe pulmonary regurgitation results in RV volume overload.

3. Echocardiographic Goals

Preoperative Assessment

1. Right Ventricular Outflow Tract (RVOT) Obstruction

   • Image the infundibulum and pulmonary valve using:

     • Subxiphoid views.

     • Parasternal short-axis (PSSA) and long-axis (PSLA) views.

   • Define the level(s) of obstruction using color and spectral Doppler:

     • Pulsed-wave Doppler (PW) across RVOT and pulmonary valve.

     • Continuous-wave Doppler (CW) to measure gradients.

2. Pulmonary Atresia

   • Measure distance between RVOT and main pulmonary artery (MPA).

3. Pulmonary Arteries

   • Assess pulmonary annulus, MPA, and branch PAs for size, confluence, and presence of stenosis.

   • Use low and high parasternal and infraclavicular windows to visualize branch PAs as distally as possible.

4. VSD Assessment

   • Determine location, size, and relationship to the tricuspid and aortic valves.

   • Rule out additional VSDs.

   • Note: Equal LV and RV pressures result in low-velocity transseptal flow, so decrease the Nyquist limit to improve flow visualization.

5. Coronary Arteries

   • Identify origin and course, particularly in relation to the RVOT.

   • Rule out a coronary artery crossing the RVOT.

6. Aortic Arch Anatomy

   • Determine sidedness and branching pattern.

   • Note: ~25% of TOF patients have a right aortic arch.

7. Ductus Arteriosus and Systemic-Pulmonary Collaterals

   • Assess for a PDA (left or right-sided).

   • Evaluate descending aorta and subclavian arteries with color Doppler for aortopulmonary collaterals (APCs).

   • Risk of APCs increases if the branch PAs and PDA are small.

8. Associated Anomalies

   • ASD vs. PFO.

   • Mitral stenosis or subaortic stenosis (rare but should be ruled out).

   • Left superior vena cava (LSVC).

   • Partial anomalous pulmonary venous connection (PAPVC).

9. Aortic Dimensions

   • Measure aortic annulus, root, sinotubular junction (STJ), and ascending aorta at the level of the right pulmonary artery (RPA).

Postoperative Assessment

1. RVOT and MPA Obstruction

   • Assess for residual obstruction using 2D, color, and spectral Doppler.

   • Measure peak and mean gradients.

2. Aneurysm Formation

   • Rule out aneurysms of the RVOT or MPA (look for large echo-free spaces anterior/lateral to the RVOT and MPA).

3. RV-to-PA Conduit Evaluation

   • Assess for stenosis and measure peak and mean gradients from multiple views.

4. Pulmonary Regurgitation (PR)

   • Evaluate PR severity using:

     • Color Doppler jet width.

     • CW Doppler across the pulmonary valve (slope of retrograde flow).

     • Flow reversal in the branch PAs.

5. Branch PA Stenosis

   • Use low and high parasternal and infraclavicular views to assess distal PAs.

   • Measure diameters of normal and stenotic segments.

6. Residual Shunts

   • VSDs: Determine size, location, direction of flow, and peak transseptal gradient.

   • ASDs: Evaluate residual atrial-level shunts and direction of flow.

7. Tricuspid Valve and RV Function

   • Assess tricuspid regurgitation (TR) severity.

   • Estimate RV pressure using:

     • TR jet velocity.

     • Trans-VSD gradient.

     • Septal configuration (systolic septal flattening suggests RV volume load, but may be misleading if RBBB or septal dyskinesia is present).

8. RV Size and Function

   • Assess RV volume overload (diastolic septal flattening, qualitative RV size, and 3D RV volume).

   • Evaluate RV function using:

     • 2D imaging from multiple views.

     • 3D echo (if feasible).

     • TAPSE (tricuspid annular plane systolic excursion).

9. Systemic-Pulmonary Collaterals

   • Evaluate for aortopulmonary collaterals and runoff in the descending aorta using spectral Doppler.

10. Aortic Dimensions and LV Function

• Reassess aortic annulus, root, and ascending aorta.

• Evaluate LV size and function.

TET spell

Main principle is to use non-pharmacological intervention to revert the TET spell crisis:

1. Calm the infant to decrease oxygen demands and relieve anxiety (attempt to calm the crying irritable infant by non pharmacologic methods)

   1. Calm, quiet room or gentle music, soothing measures, avoid any painful or distressful interventions, limit the personnel to key members in the room, decrease amount of ambient light to provide a calmer environment.

2. Place patient knee chest position – this position will increase peripheral resistance in the lower extremities and increases SVR; and this will decrease right to left shunt through VSD and improve pulmonary blood follow

3. Provide 100% oxygen (pulmonary vasodilator) by blow-by or hood. Avoid containment measures or elements that may agitate the child. 

4. Contact cardiology team to be aware of situation

If these non-pharmacological elements fail - will need pharmacological opiates to reduce distress:

5. Subcutaneous morphine 0.05 mg/kg or 0.1 mg/kg. 

6. May also attempt intranasal fentanyl 3-5 mcg/kg. 

7. If IV already in place – use IV route. Avoid putting IV at beginning of TET spell as this may worsen the situation in terms of agitation of the child.

If this fails (refractory Tet spell):

8. Make sure cardiovascular surgery team aware of situation

9. Obtain IV or intra-osseus and administer: Bolus 10-20 mL/kg of Normal Saline and then pass to next steps of the algorithm:

10. IV beta blocker (esmolol), which leads to relaxation of RVOT with improved pulmonary blood flow. Unless baby is hypotensive. If baby hypotensive go to Phenylephrine first. 

    1. Emolol 100-500 mcg/kg/dose loading over 1 min and then 100-300 mcg/kg/min infusion.

11. Phenylephrine 5 mcg/kg/dose over 1 minute and then 0.1 to 0.4 mcg/kg/min infusion (peripheral vasoconstriction)

12. Bicarbonate if very acidotic. (1-2 mmol/kg/dose)

13. Keep operating room on standby

There is a nice algorithm available also on the web here from Perth Children's Hospital.

Another algorithm available here.

Apical views indicating the Tetralofy of Fallot, the large perimembranous central ventricular septal defect with aortic override. The mild deviation of the conal septum with no significant obstruction and the pulmonary valve and main pulmonary artery of normal size without obstruction.

Subcostal views showing the aorta override and the mild deviation of the conal septum

Small patent arterial duct (PDA) measuring 0.21 cm, shunting briefly right to left in early systole and left to right most of the cardiac cycle.

PLAX with sweep in 2D and in Colour indicating the overriding Aorta and the malalignement ventricular septal defect

Apical view with sweep in 2D and 2D colour showing the overriding aorta, malalignement VSD and some mild aortic insufficiency. 

Unifocalization: The goal is to connect all lung segments to the native pulmonary arteries. If a MAPCA supplies a lung segment that is not supplied by the native pulmonary arteries (a "non-communicating" MAPCA), this collateral is surgically harvested and reconnected (unifocalized) onto the native pulmonary artery. This ensures complete pulmonary vascularization and allows the lungs to receive blood at lower, more appropriate pulmonary artery pressures.

Embolization: If a MAPCA supplies a lung segment that is already adequately supplied by a native pulmonary artery (a "communicating" MAPCA), that MAPCA can be embolized (blocked) because it is redundant and adds unnecessary systemic flow to that segment. 

MAPCAs by colour flow

Apical views by 2D and 2D-Colour showing the VSD and the overriding aorta with flow from LV and RV going to the Aorta

Subcostal view for visualization of the VSD, Pulmonary valvular atresia (virtual) and some MAPCAs observed by Colour

Catheterism indicating the MAPCAs

Case 4 - Echocardiography in TOF with pulmonary stenosis and a small PDA

Short axis outlining the RCA and the pulmonary valve. The thymus is well vizualized on top (although this is not sufficient to rule out Di George syndrome)

Right sided aortic arch in this particular scan by evaluation of the branching pattern of the first aortic vessel. 

Pathological example from the Maude Abbott Medical Museum