Tetralogy of Fallot: Pathogenesis, Pathophysiology, Clinical Features, Types, Diagnosis, Management and Prevention

Tetralogy of Fallot (TOF): A Comprehensive Overview

~Introduction

Tetralogy of Fallot (TOF) is one of the most common and well-known congenital cyanotic heart diseases, accounting for approximately 10% of all congenital heart defects. First described by the French physician Étienne-Louis Arthur Fallot in 1888, TOF is characterized by a combination of four anatomical cardiac abnormalities that result from a single embryological defect — malalignment of the infundibular septum.

These four classic defects are:

1. Ventricular Septal Defect (VSD)

2. Pulmonary Stenosis (Right Ventricular Outflow Tract Obstruction)

3. Overriding of the Aorta

4. Right Ventricular Hypertrophy

The combination of these abnormalities leads to a right-to-left shunt of blood, causing systemic desaturation and cyanosis. Over the years, advances in surgical techniques and postoperative care have transformed TOF from a fatal childhood condition into a treatable and largely correctable disease with excellent long-term outcomes.

~Embryology and Pathogenesis

Normal Cardiac Development

During normal embryological development, the truncus arteriosus divides into the pulmonary artery and aorta through the formation of the aorticopulmonary septum. The interventricular septum grows upward to meet this septum, ensuring proper alignment of the great vessels with the ventricles.

Pathogenesis of Tetralogy of Fallot

In TOF, there is anterior and cephalad (upward) displacement of the infundibular or conal septum, leading to:

• Misalignment of the ventricular septum.

• Narrowing of the right ventricular outflow tract.

• An aorta that overrides both ventricles.

• Secondary right ventricular hypertrophy due to increased pressure load.

This single developmental defect explains the four key features of TOF, collectively resulting in a right-to-left shunt and systemic cyanosis.

~Anatomical Components

1. Ventricular Septal Defect (VSD)

A large, usually nonrestrictive, malalignment VSD is present in almost all cases of TOF. The defect lies in the membranous portion of the septum and allows free communication between the left and right ventricles.

2. Pulmonary Stenosis

This can occur at multiple levels:

• Infundibular (subvalvular) stenosis: caused by abnormal septal alignment.

• Valvular stenosis: thickened or fused pulmonary valve leaflets.

• Supravalvular stenosis: narrowing above the valve in the main pulmonary artery.

The degree of pulmonary obstruction determines the severity of cyanosis and symptoms.

3. Overriding Aorta

The aortic root is displaced to the right, lying directly above the VSD, and receives blood from both ventricles. The extent of overriding can range from 5% to 95%.

4. Right Ventricular Hypertrophy

As the right ventricle pumps against the resistance caused by pulmonary stenosis, its muscular wall thickens, producing concentric hypertrophy.

~Pathophysiology

The hemodynamic consequences of TOF depend mainly on the severity of pulmonary outflow obstruction.

• Mild obstruction: Left-to-right shunt through the VSD; minimal cyanosis (“pink Tetralogy”).

• Severe obstruction: Right-to-left shunt; deoxygenated blood enters systemic circulation, leading to cyanosis.

This right-to-left shunting causes:

• Hypoxemia

• Cyanosis

• Polycythemia (compensatory increase in red cell mass)

• Clubbing of fingers and toes

The reduced pulmonary blood flow also leads to decreased oxygenation of blood returning to the left heart and chronic tissue hypoxia.

~Clinical Features

Age of Presentation

Cyanosis may be apparent soon after birth but is often noticeable within the first few months of life. Some infants with mild obstruction may remain relatively asymptomatic until later childhood.

Symptoms

• Cyanosis: The hallmark of TOF, due to mixing of oxygenated and deoxygenated blood.

• Dyspnea on exertion: Worsens with crying or feeding.

• “Tet spells” (Hypercyanotic spells): Sudden episodes of deepening cyanosis, hypoxia, and possible syncope or seizures due to increased right-to-left shunting.

• Clubbing: Thickening of the fingertips in chronic cyanosis.

• Squatting behavior: Children instinctively squat during exertion to increase systemic vascular resistance, which reduces right-to-left shunting and improves oxygenation.

• Growth retardation: Poor weight gain and delayed development due to chronic hypoxia.

~Physical Examination

• Cyanosis and clubbing of fingers and toes.

• Parasternal heave: Due to right ventricular hypertrophy.

• Systolic murmur: Harsh ejection murmur heard best at the left upper sternal border, caused by turbulent flow through the stenotic pulmonary outflow tract.

• Single second heart sound (S2): Pulmonary component (P2) is diminished due to pulmonary stenosis.

• In severe cases, central cyanosis and exercise intolerance are striking.

~Types of Tetralogy of Fallot

1. Classical TOF

The standard combination of the four anomalies described above.

2. TOF with Pulmonary Atresia

Complete obstruction of the right ventricular outflow tract; blood reaches the lungs through collateral vessels (major aortopulmonary collaterals).

3. TOF with Pulmonary Valve Hypoplasia

Severe underdevelopment of the pulmonary valve and arteries.

4. TOF with Absent Pulmonary Valve

Rare variant; pulmonary regurgitation causes massive dilation of the pulmonary arteries, compressing the bronchi.

5. Pseudotruncus Arteriosus

Extreme form where pulmonary arteries are absent, and the lungs are supplied by collateral arteries from the aorta.

~Complications

1. Hypoxic (Tet) Spells: Life-threatening episodes of profound cyanosis and hypoxia.

2. Brain abscess: Due to right-to-left shunt allowing bacteria to bypass pulmonary filtration.

3. Cerebral thrombosis or stroke: Caused by polycythemia and hyperviscosity.

4. Infective endocarditis: Infection of the abnormal endocardium.

5. Heart failure: Usually after long-standing untreated disease.

6. Sudden death: During severe hypoxic spells or arrhythmia.

~Diagnostic Evaluation

1. Chest X-Ray

• Boot-shaped heart (Coeur-en-sabot): Due to right ventricular hypertrophy and concavity of the pulmonary artery segment.

• Oligemic lung fields: Reduced pulmonary vascular markings due to decreased pulmonary blood flow.

• Right-sided aortic arch in 25% of cases.

2. Electrocardiogram (ECG)

• Right axis deviation.

• Right ventricular hypertrophy.

• Occasionally right atrial enlargement.

3. Echocardiography

• Confirms diagnosis and delineates anatomy.

• Shows VSD, degree of aortic override, right ventricular hypertrophy, and severity of pulmonary stenosis.

• Doppler echocardiography helps quantify gradients across the pulmonary outflow tract.

4. Cardiac Catheterization and Angiography

• Used when surgical planning requires precise anatomical detail.

• Measures pressure gradients and oxygen saturation at various cardiac levels.

~Hypercyanotic (Tet) Spells: Mechanism and Management

Mechanism

A sudden decrease in systemic vascular resistance or an increase in right ventricular outflow obstruction leads to increased right-to-left shunting, reducing pulmonary blood flow and oxygenation.

Precipitating factors: crying, feeding, defecation, or awakening from sleep.

Clinical Features

• Deep cyanosis

• Tachypnea

• Irritability or loss of consciousness

• Possible convulsions

Emergency Management

1. Positioning: Knee-chest position to increase systemic vascular resistance.

2. Oxygen: Administer 100% oxygen.

3. Morphine (0.1 mg/kg IV or IM): Calms the child and reduces hyperpnea.

4. Beta-blockers (Propranolol): Reduces infundibular spasm.

5. Intravenous fluids: To expand intravascular volume.

6. Sodium bicarbonate: If metabolic acidosis is present.

7. Phenylephrine: May be used to raise systemic vascular resistance.

8. Emergency surgery: If spells are recurrent or unresponsive.

~Management of Tetralogy of Fallot

1. Medical Management

Temporary stabilization before surgical correction includes:

• Preventing dehydration and hyperviscosity.

• Managing anemia.

• Avoiding hypoxic spells with beta-blockers.

• Treating iron deficiency.

2. Palliative Surgery

Used in infants too small or unstable for total correction.

Blalock–Taussig (BT) Shunt (Classic and Modified)

• A subclavian artery is connected to the pulmonary artery to increase pulmonary blood flow.

• The modified BT shunt uses a Gore-Tex graft instead of direct anastomosis.

Waterston–Cooley or Potts Shunts

• Now rarely used; create connections between the aorta and pulmonary artery branches.

Palliative procedures improve oxygenation and allow the child to grow before definitive repair.

3. Corrective (Definitive) Surgery

Performed ideally between 6 months and 2 years of age, depending on patient condition.

Procedure Components

1. Closure of VSD: Using a patch to prevent right-to-left shunt.

2. Relief of pulmonary stenosis: Resection of obstructing muscle or patch enlargement of the right ventricular outflow tract.

3. Reconstruction of pulmonary valve/artery if needed.

Approaches

• Transventricular (through the right ventricle)

• Transatrial–transpulmonary (preferred) — preserves right ventricular function.

Postoperative Outcome:
Survival rate exceeds 95% in specialized centers. Long-term prognosis is excellent, though lifelong follow-up is necessary.

~Postoperative Complications

1. Residual VSD

2. Pulmonary regurgitation (common after transannular patch repair)

3. Right ventricular dilation and dysfunction

4. Arrhythmias (especially ventricular tachycardia)

5. Residual right ventricular outflow obstruction

6. Endocarditis

Lifelong cardiology follow-up with periodic echocardiography and sometimes cardiac MRI is recommended.

~Prognosis

Without surgical correction, the prognosis is poor:

• 25% die in the first year of life.

• 50% die by age five.

• Only 10–15% survive beyond age 20.

With surgical correction:

• Excellent survival: Over 90% survive beyond 20 years post-surgery.

• Normal growth and activity: Most children lead near-normal lives.

• Good quality of life: Though some may require reoperations or valve replacements later in life.

~Associated Conditions

• Right aortic arch (in 25% of cases)

• Patent ductus arteriosus

• Atrial septal defect

• Coronary artery anomalies (important for surgical planning)

• 22q11 deletion syndrome (DiGeorge syndrome)

• Down syndrome (rarely)

~Recent Advances

1. Early Neonatal Repair: With improved surgical techniques, complete correction in early infancy has become the standard in many centers.

2. Transcatheter Interventions: Evolving techniques allow percutaneous valve replacements in repaired TOF patients.

3. 3D Echocardiography and MRI: Provide detailed anatomical and functional assessment pre- and post-surgery.

4. Genetic Testing: Helps identify associated chromosomal abnormalities like 22q11 deletion.

5. Improved Postoperative Care: Advances in ICU management, cardiopulmonary bypass, and anesthesia have reduced mortality.

~Prevention and Counseling

While TOF cannot always be prevented, several measures can reduce risk:

• Prenatal care: Adequate maternal nutrition and folate supplementation.

• Avoid teratogens: Especially alcohol, isotretinoin, and infections during pregnancy.

• Rubella immunization before conception.

• Fetal echocardiography in high-risk pregnancies for early detection.

• Genetic counseling for families with history of congenital heart disease.

~Conclusion

Tetralogy of Fallot is a classic example of how advances in medical science can transform outcomes for congenital heart diseases. Once considered a fatal malformation, it is now a correctable defect with excellent survival and quality of life. Early diagnosis, proper management of hypoxic spells, and timely surgical intervention are critical for favorable outcomes.

With continued improvements in surgical techniques, postoperative care, and genetic understanding, the long-term outlook for patients with TOF is increasingly optimistic. Lifelong follow-up, however, remains essential to monitor for residual lesions and maintain cardiac health throughout adulthood.